Clinical Review

CASE Chronic pelvic pain from endometriosis

A 40-year-old woman (G0) has a 20-year history of chronic pelvic pain. Stage III endometriosis is diagnosed on laparoscopic excision of endometriotic tissue. Postoperative pain symptoms include dysmenorrhea and deep dyspareunia, and the patient is feeling anxious. Physical examination reveals a retroverted uterus, right adnexal fullness and tenderness, and tenderness on palpation of the right levator ani and right obturator internus; rectovaginal examination findings are unremarkable. The patient, though now engaged in a pelvic floor physical therapy program, has yet to achieve the pain control she desires. After reviewing the treatment strategies for endometriosis with the patient, she elects definitive surgical management with minimally invasive hysterectomy and salpingo-oophorectomy. What pre-, intra-, and postoperative pain management plan do you devise for this patient?

Chronic pelvic pain presents a unique clinical challenge, as pain typically is multifactorial, and several peripheral pain generators may be involved. Although surgery can be performed to manage anatomically based disease processes, it does not address pain from musculoskeletal or neuropathic sources. A complete medical history and a physical examination are of utmost importance in developing a comprehensive multimodal management plan that may include surgery as treatment for the pain.

The standard of care for surgery is a minimally invasive approach (vaginal, laparoscopic, or robot-assisted laparoscopic), as it causes the least amount of trauma. Benefits of minimally invasive surgery include shorter hospitalization and faster recovery, likely owing to improved perioperative pain control, decreased blood loss, and fewer infections. Although this approach minimizes surgical trauma and thereby helps decrease the surgical stress response, the patient experience can be optimized with use of enhanced recovery pathways (ERPs), a multimodal approach to perioperative care.

ERPs were initially proposed as a means of reducing the degree of surgical injury and the subsequent physiologic stress response.¹ This multimodal approach begins in the outpatient setting, includes preoperative and intraoperative modalities, and continues postoperatively. In patients with chronic pain, ERPs are even more important. Assigning “prehabilitation” and setting expectations for surgery goals are the first step in improving the patient experience. Intraoperative use of opioid-sparing anesthetics or regional anesthesia can improve recovery. After surgery, patients with chronic pain and/or opioid dependence receive medications on a schedule, along with short-interval follow-up. Ultimately, reducing acute postoperative pain may lower the risk of developing chronic pain.

In this article on patients with chronic pelvic pain, we highlight elements of ERPs within the framework of enhanced recovery after surgery. Many of the interventions proposed here also can be used to improve the surgical experience of patients without chronic pain.

Preadmission education, expectations, and optimization

Preoperative counseling for elective procedures generally occurs in the outpatient setting. Although discussion traditionally has covered the type of procedure and its associated risks, benefits, and alternatives, new guidelines suggest a more mindful and comprehensive approach is warranted. Individualized patient-centered education programs have a positive impact on the perioperative course, effecting reductions in preoperative anxiety, opioid requirements, and hospital length of stay.² From a pain management perspective, the clinician can take some time during preoperative counseling to inform the patient about the pain to be expected from surgery, the ways the pain will be managed intraoperatively and postoperatively, and the multimodal strategies that will be used throughout the patient’s stay² and that may allow for early discharge. Although preadmission counseling still should address expectations for the surgery, it also presents an opportunity both to assess the patient’s ability to cope with the physical and psychological stress of surgery and to offer the patient appropriate need-based interventions, such as prehabilitation and cognitive-behavioral therapy (CBT).

Prehabilitation is the process of increasing functional capacity before surgery in order to mitigate the stress of the surgery. Prehabilitation may involve aerobic exercise, strength training, or functional task training. The gynecologic surgery literature lacks prehabilitation data, but data in the colorectal literature support use of a prehabilitation program for patients having a scheduled colectomy, with improved postoperative recovery.³ Although the colectomy cohort predominantly included older men, the principle that guides program implementation is the same: improve recovery after the stress of abdominal surgery. Indeed, a patient who opts for an elective surgery may have to wait several weeks before undergoing the procedure, and during this period behavioral interventions can take effect. With postoperative complications occurring more often in patients with reduced functional capacity, the data support using prehabilitation to decrease the incidence of postoperative complications, particularly among the most vulnerable patients.⁴ However, a definitive recommendation on use of pelvic floor exercises as an adjunct to prehabilitation cannot be made.⁴ Successful prehabilitation takes at least 4 weeks and should be part of a multimodal program that addresses other behavioral risk factors that may negatively affect recovery.⁵ For example, current tobacco users have compromised pulmonary status and wound healing immediately after surgery, and use more opioids.⁶ Conversely, smoking cessation for as little as 4 weeks before surgery is associated with fewer complications.⁷ In addition, given that alcohol abuse may compromise the surgical stress response and increase the risk of opioid misuse, addressing alcohol abuse preoperatively may improve postoperative recovery.⁸

Treating mood disorders that coexist with chronic pain disorders is an important part of outpatient multimodal management—psychological intervention is a useful adjunct to prehabilitation in reducing perioperative anxiety and improving postoperative functional capacity.⁹ For patients who have chronic pain and are undergoing surgery, it is important to address any anxiety, depression, or poor coping skills (eg, pain catastrophizing) to try to reduce the postoperative pain experience and decrease the risk of chronic postsurgical pain (CPSP).^10,11

Before surgery, patients with chronic pain syndromes should be evaluated for emotional distress and pain coping ability. When possible, they should be referred to a pain psychologist, who can initiate CBT and other interventions. In addition, pain coping skills can be developed or reinforced to address preoperative anxiety and pain catastrophizing. These interventions, which may include use of visual imagery, breathing exercises, and other relaxation techniques, are applicable to the management of postoperative anxiety as well.

Read about preoperative multimodal analgesia and intra- and postoperative management.

Preoperative multimodal analgesia

Multimodal analgesia has several benefits. Simultaneous effects can be generated on multiple pain-related neurotransmitters, and a synergistic effect (eg, of acetaminophen and a nonsteroidal anti-inflammatory drug [NSAID]) can improve pain management. In addition, small doses of multiple medications can be given, instead of a large dose of a single medication. Of course, this strategy must be modified in elderly and patients with impaired renal function, who are at high risk for polypharmacy.

Preoperative administration of 3 medications—a selective cyclooxygenase 2 (COX-2) inhibitor, acetaminophen, and a gabapentinoid—is increasingly accepted as part of multimodal analgesia. The selective COX-2 inhibitor targets inflammatory prostaglandins and has anti-inflammatory and analgesic effects; acetaminophen, an effective analgesic with an unclear mechanism of action, can reduce postoperative opioid consumption¹² and works synergistically with NSAIDs¹³; and the gabapentinoid gabapentin has an analgesic effect likely contributing to decreased movement-related pain and subsequent improved functional recovery (data are mixed on whether continuing gabapentin after surgery prevents CPSP).¹⁴⁻¹⁶

Although serotonin and norepinephrine reuptake inhibitors (SNRIs) are commonly used in outpatient management of chronic pelvic pain, data suggest that their role in perioperative pain management is evolving. As SNRIs may reduce central nervous system (CNS) sensitization,¹⁷ their analgesic effect is thought to result from increased descending inhibitory tone in the CNS, which makes this class of medication ideal for patients with chronic neuropathic pain.¹⁵

Limited data also suggest a role for SNRIs in decreasing immediate postoperative pain and CPSP in high-risk patients. Studies of duloxetine use in the immediate perioperative period have found reduced postoperative acute pain and opioid use.^18,19 In addition, a short course of low-dose (37.5 mg) venlafaxine both before and after surgery has demonstrated a reduction in postoperative opioid use and a reduction in movement-related pain 6 months after surgery.²⁰

Intraoperative management

The surgical and anesthesia teams share the goal of optimizing both pain control and postoperative recovery. Surgical team members, who want longer-acting anesthetics for infiltration of incision sites, discuss with the anesthesiologist the appropriateness of using peripheral nerve blocks or neuraxial anesthesia, given the patient’s history and planned procedure. Anesthesia team members can improve anesthesia and minimize intraoperative opioid use through several methods, including total intravenous anesthesia,²¹ dexamethasone,²² ketorolac,²³ and intravenous ketamine. Ketamine, in particular, has a wide range of surgical applications and has been found to reduce postoperative pain, postoperative pain medication use, and the risk of CPSP.²

Incision sites should be infiltrated before and after surgery. Lidocaine traditionally is used for its rapid onset of action in reducing surgical site pain, but its short half-life may limit its applicability to postoperative pain. Recently, bupivacaine (half-life, 3.5 hours) and liposomal bupivacaine (24–34 hours) have gained more attention. Both of these medications appear to be as effective as lidocaine in reducing surgical site pain.²⁴

Transversus abdominis plane (TAP) blocks have been used as an adjunct in pain management during abdominopelvic surgery. Although initial data on postoperative pain and opioid use reductions with TAP blocks were inconclusive,²⁵ more recent data showed a role for TAP blocks in a multimodal approach for reducing opioid use during laparoscopic and open surgery.^26,27 Given the small number of studies on using liposomal bupivacaine for peripheral nerve blocks (eg, TAP blocks) in postoperative pain management, current data are inconclusive.²⁸

Postoperative management

The ERP approach calls for continuing multimodal analgesia after surgery—in most cases, scheduling early use of oral acetaminophen and ibuprofen, and providing short-acting, low-dose opioid analgesia as needed. All patients should be given a bowel regimen. Similar to undergoing prehabilitation for surgery, patients should prepare themselves for recovery. They should be encouraged to engage in early ambulation and oral intake and, when clinically appropriate, be given same-day discharge for minimally invasive surgical procedures.

Patients with chronic pain before surgery are at increased risk for suboptimal postoperative pain management, and those who are dependent on opioids require additional perioperative measures for adequate postoperative pain control. In these complicated cases, it is appropriate to enlist a pain specialist, potentially before surgery, to help plan perioperative and postoperative pain management.² Postoperative pain management for opioid-dependent patients should include pharmacologic and nonpharmacologic interventions, such as use of nonopioid medications (eg, gabapentin) and continuation of CBT. Patients with chronic pain should be closely followed up for assessment of postoperative pain control and recovery.

CASE Resolved

Surgical management is one aspect of the longer term multimodal pain management strategy for this patient. After preoperative pelvic floor physical therapy, she is receptive to starting a trial of an SNRI for her pain and mood symptoms. Both interventions allow for optimization of her preoperative physical and psychological status. Expectations are set that she will be discharged the day of surgery and that the surgery is but one component of her multimodal treatment plan. In addition, before surgery, she takes oral acetaminophen, gabapentin, and celecoxib—previously having had no contraindications to these medications. During surgery, bupivacaine is used for infiltration of all incision sites, and the anesthesia team administers ketamine and a TAP block. After surgery, the patient is prepared for same-day discharge and given the NSAIDs and acetaminophen she is scheduled to take over the next 72 hours. She is also given a limited prescription for oxycodone for breakthrough pain. An office visit 1 to 2 weeks after surgery is scheduled.

ERP strategies for surgical management of endometriosis have not only improved this patient’s postoperative recovery but also reduced her surgical stress response and subsequent transition to chronic postoperative pain. Many of the strategies used in this case are applicable to patients without chronic pain.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

CASE Chronic pelvic pain from endometriosis

A 40-year-old woman (G0) has a 20-year history of chronic pelvic pain. Stage III endometriosis is diagnosed on laparoscopic excision of endometriotic tissue. Postoperative pain symptoms include dysmenorrhea and deep dyspareunia, and the patient is feeling anxious. Physical examination reveals a retroverted uterus, right adnexal fullness and tenderness, and tenderness on palpation of the right levator ani and right obturator internus; rectovaginal examination findings are unremarkable. The patient, though now engaged in a pelvic floor physical therapy program, has yet to achieve the pain control she desires. After reviewing the treatment strategies for endometriosis with the patient, she elects definitive surgical management with minimally invasive hysterectomy and salpingo-oophorectomy. What pre-, intra-, and postoperative pain management plan do you devise for this patient?

Chronic pelvic pain presents a unique clinical challenge, as pain typically is multifactorial, and several peripheral pain generators may be involved. Although surgery can be performed to manage anatomically based disease processes, it does not address pain from musculoskeletal or neuropathic sources. A complete medical history and a physical examination are of utmost importance in developing a comprehensive multimodal management plan that may include surgery as treatment for the pain.

The standard of care for surgery is a minimally invasive approach (vaginal, laparoscopic, or robot-assisted laparoscopic), as it causes the least amount of trauma. Benefits of minimally invasive surgery include shorter hospitalization and faster recovery, likely owing to improved perioperative pain control, decreased blood loss, and fewer infections. Although this approach minimizes surgical trauma and thereby helps decrease the surgical stress response, the patient experience can be optimized with use of enhanced recovery pathways (ERPs), a multimodal approach to perioperative care.

ERPs were initially proposed as a means of reducing the degree of surgical injury and the subsequent physiologic stress response.¹ This multimodal approach begins in the outpatient setting, includes preoperative and intraoperative modalities, and continues postoperatively. In patients with chronic pain, ERPs are even more important. Assigning “prehabilitation” and setting expectations for surgery goals are the first step in improving the patient experience. Intraoperative use of opioid-sparing anesthetics or regional anesthesia can improve recovery. After surgery, patients with chronic pain and/or opioid dependence receive medications on a schedule, along with short-interval follow-up. Ultimately, reducing acute postoperative pain may lower the risk of developing chronic pain.

In this article on patients with chronic pelvic pain, we highlight elements of ERPs within the framework of enhanced recovery after surgery. Many of the interventions proposed here also can be used to improve the surgical experience of patients without chronic pain.

Preadmission education, expectations, and optimization

Preoperative counseling for elective procedures generally occurs in the outpatient setting. Although discussion traditionally has covered the type of procedure and its associated risks, benefits, and alternatives, new guidelines suggest a more mindful and comprehensive approach is warranted. Individualized patient-centered education programs have a positive impact on the perioperative course, effecting reductions in preoperative anxiety, opioid requirements, and hospital length of stay.² From a pain management perspective, the clinician can take some time during preoperative counseling to inform the patient about the pain to be expected from surgery, the ways the pain will be managed intraoperatively and postoperatively, and the multimodal strategies that will be used throughout the patient’s stay² and that may allow for early discharge. Although preadmission counseling still should address expectations for the surgery, it also presents an opportunity both to assess the patient’s ability to cope with the physical and psychological stress of surgery and to offer the patient appropriate need-based interventions, such as prehabilitation and cognitive-behavioral therapy (CBT).

Prehabilitation is the process of increasing functional capacity before surgery in order to mitigate the stress of the surgery. Prehabilitation may involve aerobic exercise, strength training, or functional task training. The gynecologic surgery literature lacks prehabilitation data, but data in the colorectal literature support use of a prehabilitation program for patients having a scheduled colectomy, with improved postoperative recovery.³ Although the colectomy cohort predominantly included older men, the principle that guides program implementation is the same: improve recovery after the stress of abdominal surgery. Indeed, a patient who opts for an elective surgery may have to wait several weeks before undergoing the procedure, and during this period behavioral interventions can take effect. With postoperative complications occurring more often in patients with reduced functional capacity, the data support using prehabilitation to decrease the incidence of postoperative complications, particularly among the most vulnerable patients.⁴ However, a definitive recommendation on use of pelvic floor exercises as an adjunct to prehabilitation cannot be made.⁴ Successful prehabilitation takes at least 4 weeks and should be part of a multimodal program that addresses other behavioral risk factors that may negatively affect recovery.⁵ For example, current tobacco users have compromised pulmonary status and wound healing immediately after surgery, and use more opioids.⁶ Conversely, smoking cessation for as little as 4 weeks before surgery is associated with fewer complications.⁷ In addition, given that alcohol abuse may compromise the surgical stress response and increase the risk of opioid misuse, addressing alcohol abuse preoperatively may improve postoperative recovery.⁸

Treating mood disorders that coexist with chronic pain disorders is an important part of outpatient multimodal management—psychological intervention is a useful adjunct to prehabilitation in reducing perioperative anxiety and improving postoperative functional capacity.⁹ For patients who have chronic pain and are undergoing surgery, it is important to address any anxiety, depression, or poor coping skills (eg, pain catastrophizing) to try to reduce the postoperative pain experience and decrease the risk of chronic postsurgical pain (CPSP).^10,11

Before surgery, patients with chronic pain syndromes should be evaluated for emotional distress and pain coping ability. When possible, they should be referred to a pain psychologist, who can initiate CBT and other interventions. In addition, pain coping skills can be developed or reinforced to address preoperative anxiety and pain catastrophizing. These interventions, which may include use of visual imagery, breathing exercises, and other relaxation techniques, are applicable to the management of postoperative anxiety as well.

Read about preoperative multimodal analgesia and intra- and postoperative management.

Preoperative multimodal analgesia

Multimodal analgesia has several benefits. Simultaneous effects can be generated on multiple pain-related neurotransmitters, and a synergistic effect (eg, of acetaminophen and a nonsteroidal anti-inflammatory drug [NSAID]) can improve pain management. In addition, small doses of multiple medications can be given, instead of a large dose of a single medication. Of course, this strategy must be modified in elderly and patients with impaired renal function, who are at high risk for polypharmacy.

Preoperative administration of 3 medications—a selective cyclooxygenase 2 (COX-2) inhibitor, acetaminophen, and a gabapentinoid—is increasingly accepted as part of multimodal analgesia. The selective COX-2 inhibitor targets inflammatory prostaglandins and has anti-inflammatory and analgesic effects; acetaminophen, an effective analgesic with an unclear mechanism of action, can reduce postoperative opioid consumption¹² and works synergistically with NSAIDs¹³; and the gabapentinoid gabapentin has an analgesic effect likely contributing to decreased movement-related pain and subsequent improved functional recovery (data are mixed on whether continuing gabapentin after surgery prevents CPSP).¹⁴⁻¹⁶

Although serotonin and norepinephrine reuptake inhibitors (SNRIs) are commonly used in outpatient management of chronic pelvic pain, data suggest that their role in perioperative pain management is evolving. As SNRIs may reduce central nervous system (CNS) sensitization,¹⁷ their analgesic effect is thought to result from increased descending inhibitory tone in the CNS, which makes this class of medication ideal for patients with chronic neuropathic pain.¹⁵

Limited data also suggest a role for SNRIs in decreasing immediate postoperative pain and CPSP in high-risk patients. Studies of duloxetine use in the immediate perioperative period have found reduced postoperative acute pain and opioid use.^18,19 In addition, a short course of low-dose (37.5 mg) venlafaxine both before and after surgery has demonstrated a reduction in postoperative opioid use and a reduction in movement-related pain 6 months after surgery.²⁰

Intraoperative management

The surgical and anesthesia teams share the goal of optimizing both pain control and postoperative recovery. Surgical team members, who want longer-acting anesthetics for infiltration of incision sites, discuss with the anesthesiologist the appropriateness of using peripheral nerve blocks or neuraxial anesthesia, given the patient’s history and planned procedure. Anesthesia team members can improve anesthesia and minimize intraoperative opioid use through several methods, including total intravenous anesthesia,²¹ dexamethasone,²² ketorolac,²³ and intravenous ketamine. Ketamine, in particular, has a wide range of surgical applications and has been found to reduce postoperative pain, postoperative pain medication use, and the risk of CPSP.²

Incision sites should be infiltrated before and after surgery. Lidocaine traditionally is used for its rapid onset of action in reducing surgical site pain, but its short half-life may limit its applicability to postoperative pain. Recently, bupivacaine (half-life, 3.5 hours) and liposomal bupivacaine (24–34 hours) have gained more attention. Both of these medications appear to be as effective as lidocaine in reducing surgical site pain.²⁴

Transversus abdominis plane (TAP) blocks have been used as an adjunct in pain management during abdominopelvic surgery. Although initial data on postoperative pain and opioid use reductions with TAP blocks were inconclusive,²⁵ more recent data showed a role for TAP blocks in a multimodal approach for reducing opioid use during laparoscopic and open surgery.^26,27 Given the small number of studies on using liposomal bupivacaine for peripheral nerve blocks (eg, TAP blocks) in postoperative pain management, current data are inconclusive.²⁸

Postoperative management

The ERP approach calls for continuing multimodal analgesia after surgery—in most cases, scheduling early use of oral acetaminophen and ibuprofen, and providing short-acting, low-dose opioid analgesia as needed. All patients should be given a bowel regimen. Similar to undergoing prehabilitation for surgery, patients should prepare themselves for recovery. They should be encouraged to engage in early ambulation and oral intake and, when clinically appropriate, be given same-day discharge for minimally invasive surgical procedures.

Patients with chronic pain before surgery are at increased risk for suboptimal postoperative pain management, and those who are dependent on opioids require additional perioperative measures for adequate postoperative pain control. In these complicated cases, it is appropriate to enlist a pain specialist, potentially before surgery, to help plan perioperative and postoperative pain management.² Postoperative pain management for opioid-dependent patients should include pharmacologic and nonpharmacologic interventions, such as use of nonopioid medications (eg, gabapentin) and continuation of CBT. Patients with chronic pain should be closely followed up for assessment of postoperative pain control and recovery.

CASE Resolved

Surgical management is one aspect of the longer term multimodal pain management strategy for this patient. After preoperative pelvic floor physical therapy, she is receptive to starting a trial of an SNRI for her pain and mood symptoms. Both interventions allow for optimization of her preoperative physical and psychological status. Expectations are set that she will be discharged the day of surgery and that the surgery is but one component of her multimodal treatment plan. In addition, before surgery, she takes oral acetaminophen, gabapentin, and celecoxib—previously having had no contraindications to these medications. During surgery, bupivacaine is used for infiltration of all incision sites, and the anesthesia team administers ketamine and a TAP block. After surgery, the patient is prepared for same-day discharge and given the NSAIDs and acetaminophen she is scheduled to take over the next 72 hours. She is also given a limited prescription for oxycodone for breakthrough pain. An office visit 1 to 2 weeks after surgery is scheduled.

ERP strategies for surgical management of endometriosis have not only improved this patient’s postoperative recovery but also reduced her surgical stress response and subsequent transition to chronic postoperative pain. Many of the strategies used in this case are applicable to patients without chronic pain.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

CASE Chronic pelvic pain from endometriosis

A 40-year-old woman (G0) has a 20-year history of chronic pelvic pain. Stage III endometriosis is diagnosed on laparoscopic excision of endometriotic tissue. Postoperative pain symptoms include dysmenorrhea and deep dyspareunia, and the patient is feeling anxious. Physical examination reveals a retroverted uterus, right adnexal fullness and tenderness, and tenderness on palpation of the right levator ani and right obturator internus; rectovaginal examination findings are unremarkable. The patient, though now engaged in a pelvic floor physical therapy program, has yet to achieve the pain control she desires. After reviewing the treatment strategies for endometriosis with the patient, she elects definitive surgical management with minimally invasive hysterectomy and salpingo-oophorectomy. What pre-, intra-, and postoperative pain management plan do you devise for this patient?

Chronic pelvic pain presents a unique clinical challenge, as pain typically is multifactorial, and several peripheral pain generators may be involved. Although surgery can be performed to manage anatomically based disease processes, it does not address pain from musculoskeletal or neuropathic sources. A complete medical history and a physical examination are of utmost importance in developing a comprehensive multimodal management plan that may include surgery as treatment for the pain.

The standard of care for surgery is a minimally invasive approach (vaginal, laparoscopic, or robot-assisted laparoscopic), as it causes the least amount of trauma. Benefits of minimally invasive surgery include shorter hospitalization and faster recovery, likely owing to improved perioperative pain control, decreased blood loss, and fewer infections. Although this approach minimizes surgical trauma and thereby helps decrease the surgical stress response, the patient experience can be optimized with use of enhanced recovery pathways (ERPs), a multimodal approach to perioperative care.

ERPs were initially proposed as a means of reducing the degree of surgical injury and the subsequent physiologic stress response.¹ This multimodal approach begins in the outpatient setting, includes preoperative and intraoperative modalities, and continues postoperatively. In patients with chronic pain, ERPs are even more important. Assigning “prehabilitation” and setting expectations for surgery goals are the first step in improving the patient experience. Intraoperative use of opioid-sparing anesthetics or regional anesthesia can improve recovery. After surgery, patients with chronic pain and/or opioid dependence receive medications on a schedule, along with short-interval follow-up. Ultimately, reducing acute postoperative pain may lower the risk of developing chronic pain.

In this article on patients with chronic pelvic pain, we highlight elements of ERPs within the framework of enhanced recovery after surgery. Many of the interventions proposed here also can be used to improve the surgical experience of patients without chronic pain.

Preadmission education, expectations, and optimization

Preoperative counseling for elective procedures generally occurs in the outpatient setting. Although discussion traditionally has covered the type of procedure and its associated risks, benefits, and alternatives, new guidelines suggest a more mindful and comprehensive approach is warranted. Individualized patient-centered education programs have a positive impact on the perioperative course, effecting reductions in preoperative anxiety, opioid requirements, and hospital length of stay.² From a pain management perspective, the clinician can take some time during preoperative counseling to inform the patient about the pain to be expected from surgery, the ways the pain will be managed intraoperatively and postoperatively, and the multimodal strategies that will be used throughout the patient’s stay² and that may allow for early discharge. Although preadmission counseling still should address expectations for the surgery, it also presents an opportunity both to assess the patient’s ability to cope with the physical and psychological stress of surgery and to offer the patient appropriate need-based interventions, such as prehabilitation and cognitive-behavioral therapy (CBT).

Prehabilitation is the process of increasing functional capacity before surgery in order to mitigate the stress of the surgery. Prehabilitation may involve aerobic exercise, strength training, or functional task training. The gynecologic surgery literature lacks prehabilitation data, but data in the colorectal literature support use of a prehabilitation program for patients having a scheduled colectomy, with improved postoperative recovery.³ Although the colectomy cohort predominantly included older men, the principle that guides program implementation is the same: improve recovery after the stress of abdominal surgery. Indeed, a patient who opts for an elective surgery may have to wait several weeks before undergoing the procedure, and during this period behavioral interventions can take effect. With postoperative complications occurring more often in patients with reduced functional capacity, the data support using prehabilitation to decrease the incidence of postoperative complications, particularly among the most vulnerable patients.⁴ However, a definitive recommendation on use of pelvic floor exercises as an adjunct to prehabilitation cannot be made.⁴ Successful prehabilitation takes at least 4 weeks and should be part of a multimodal program that addresses other behavioral risk factors that may negatively affect recovery.⁵ For example, current tobacco users have compromised pulmonary status and wound healing immediately after surgery, and use more opioids.⁶ Conversely, smoking cessation for as little as 4 weeks before surgery is associated with fewer complications.⁷ In addition, given that alcohol abuse may compromise the surgical stress response and increase the risk of opioid misuse, addressing alcohol abuse preoperatively may improve postoperative recovery.⁸

Treating mood disorders that coexist with chronic pain disorders is an important part of outpatient multimodal management—psychological intervention is a useful adjunct to prehabilitation in reducing perioperative anxiety and improving postoperative functional capacity.⁹ For patients who have chronic pain and are undergoing surgery, it is important to address any anxiety, depression, or poor coping skills (eg, pain catastrophizing) to try to reduce the postoperative pain experience and decrease the risk of chronic postsurgical pain (CPSP).^10,11

Before surgery, patients with chronic pain syndromes should be evaluated for emotional distress and pain coping ability. When possible, they should be referred to a pain psychologist, who can initiate CBT and other interventions. In addition, pain coping skills can be developed or reinforced to address preoperative anxiety and pain catastrophizing. These interventions, which may include use of visual imagery, breathing exercises, and other relaxation techniques, are applicable to the management of postoperative anxiety as well.

Read about preoperative multimodal analgesia and intra- and postoperative management.

Preoperative multimodal analgesia

Multimodal analgesia has several benefits. Simultaneous effects can be generated on multiple pain-related neurotransmitters, and a synergistic effect (eg, of acetaminophen and a nonsteroidal anti-inflammatory drug [NSAID]) can improve pain management. In addition, small doses of multiple medications can be given, instead of a large dose of a single medication. Of course, this strategy must be modified in elderly and patients with impaired renal function, who are at high risk for polypharmacy.

Preoperative administration of 3 medications—a selective cyclooxygenase 2 (COX-2) inhibitor, acetaminophen, and a gabapentinoid—is increasingly accepted as part of multimodal analgesia. The selective COX-2 inhibitor targets inflammatory prostaglandins and has anti-inflammatory and analgesic effects; acetaminophen, an effective analgesic with an unclear mechanism of action, can reduce postoperative opioid consumption¹² and works synergistically with NSAIDs¹³; and the gabapentinoid gabapentin has an analgesic effect likely contributing to decreased movement-related pain and subsequent improved functional recovery (data are mixed on whether continuing gabapentin after surgery prevents CPSP).¹⁴⁻¹⁶

Although serotonin and norepinephrine reuptake inhibitors (SNRIs) are commonly used in outpatient management of chronic pelvic pain, data suggest that their role in perioperative pain management is evolving. As SNRIs may reduce central nervous system (CNS) sensitization,¹⁷ their analgesic effect is thought to result from increased descending inhibitory tone in the CNS, which makes this class of medication ideal for patients with chronic neuropathic pain.¹⁵

Limited data also suggest a role for SNRIs in decreasing immediate postoperative pain and CPSP in high-risk patients. Studies of duloxetine use in the immediate perioperative period have found reduced postoperative acute pain and opioid use.^18,19 In addition, a short course of low-dose (37.5 mg) venlafaxine both before and after surgery has demonstrated a reduction in postoperative opioid use and a reduction in movement-related pain 6 months after surgery.²⁰

Intraoperative management

The surgical and anesthesia teams share the goal of optimizing both pain control and postoperative recovery. Surgical team members, who want longer-acting anesthetics for infiltration of incision sites, discuss with the anesthesiologist the appropriateness of using peripheral nerve blocks or neuraxial anesthesia, given the patient’s history and planned procedure. Anesthesia team members can improve anesthesia and minimize intraoperative opioid use through several methods, including total intravenous anesthesia,²¹ dexamethasone,²² ketorolac,²³ and intravenous ketamine. Ketamine, in particular, has a wide range of surgical applications and has been found to reduce postoperative pain, postoperative pain medication use, and the risk of CPSP.²

Incision sites should be infiltrated before and after surgery. Lidocaine traditionally is used for its rapid onset of action in reducing surgical site pain, but its short half-life may limit its applicability to postoperative pain. Recently, bupivacaine (half-life, 3.5 hours) and liposomal bupivacaine (24–34 hours) have gained more attention. Both of these medications appear to be as effective as lidocaine in reducing surgical site pain.²⁴

Transversus abdominis plane (TAP) blocks have been used as an adjunct in pain management during abdominopelvic surgery. Although initial data on postoperative pain and opioid use reductions with TAP blocks were inconclusive,²⁵ more recent data showed a role for TAP blocks in a multimodal approach for reducing opioid use during laparoscopic and open surgery.^26,27 Given the small number of studies on using liposomal bupivacaine for peripheral nerve blocks (eg, TAP blocks) in postoperative pain management, current data are inconclusive.²⁸

Postoperative management

The ERP approach calls for continuing multimodal analgesia after surgery—in most cases, scheduling early use of oral acetaminophen and ibuprofen, and providing short-acting, low-dose opioid analgesia as needed. All patients should be given a bowel regimen. Similar to undergoing prehabilitation for surgery, patients should prepare themselves for recovery. They should be encouraged to engage in early ambulation and oral intake and, when clinically appropriate, be given same-day discharge for minimally invasive surgical procedures.

Patients with chronic pain before surgery are at increased risk for suboptimal postoperative pain management, and those who are dependent on opioids require additional perioperative measures for adequate postoperative pain control. In these complicated cases, it is appropriate to enlist a pain specialist, potentially before surgery, to help plan perioperative and postoperative pain management.² Postoperative pain management for opioid-dependent patients should include pharmacologic and nonpharmacologic interventions, such as use of nonopioid medications (eg, gabapentin) and continuation of CBT. Patients with chronic pain should be closely followed up for assessment of postoperative pain control and recovery.

CASE Resolved

Surgical management is one aspect of the longer term multimodal pain management strategy for this patient. After preoperative pelvic floor physical therapy, she is receptive to starting a trial of an SNRI for her pain and mood symptoms. Both interventions allow for optimization of her preoperative physical and psychological status. Expectations are set that she will be discharged the day of surgery and that the surgery is but one component of her multimodal treatment plan. In addition, before surgery, she takes oral acetaminophen, gabapentin, and celecoxib—previously having had no contraindications to these medications. During surgery, bupivacaine is used for infiltration of all incision sites, and the anesthesia team administers ketamine and a TAP block. After surgery, the patient is prepared for same-day discharge and given the NSAIDs and acetaminophen she is scheduled to take over the next 72 hours. She is also given a limited prescription for oxycodone for breakthrough pain. An office visit 1 to 2 weeks after surgery is scheduled.

ERP strategies for surgical management of endometriosis have not only improved this patient’s postoperative recovery but also reduced her surgical stress response and subsequent transition to chronic postoperative pain. Many of the strategies used in this case are applicable to patients without chronic pain.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Endometriosis is one of the more daunting diagnoses that gynecologists treat. In this roundtable discussion, moderated by OBG Management Board Member Arnold P. Advincula, MD, 2 leading surgeons discuss endometriosis diagnosis as well as medical and surgical management.

First-time evaluation

Arnold P. Advincula, MD: When a patient presents to your practice for the first time and you suspect endometriosis, what considerations tailor your evaluation, and what does that evaluation involve?

Hye-Chun Hur, MD, MPH: The diagnosis is contingent on a patient’s presenting profile. How symptomatic is she? How old is she? What are her reproductive goals? The gold standard for diagnosis is a histologic diagnosis, which is surgical. Depending on the age profile, however, and how close she is to menopause, the patient may be managed medically. Even women in the young reproductive age group may be managed medically if symptoms are responsive to medical treatment.

Douglas N. Brown, MD: I agree. When a patient presents without a laparoscopy, or a tissue diagnosis, but the symptoms are consistent with likely endometriosis (depending on where she is in her reproductive cycle and what her goals are), I think treating with a first-line therapy—hormonal treatments such as progestin-only oral contraceptive pills—is acceptable. I usually conduct a treatment trial period of 3 to 6 months to see if she obtains any symptom relief.

If that first-line treatment fails, generally you can move to a second-line treatment.

I have a discussion in which I either offer a second-line treatment, such as medroxyprogesterone (Depo-Provera) or leuprolide acetate (Lupron Depot), or get a tissue diagnosis, if possible, by performing laparoscopy. If first-line or even second-line therapy fails, you need to consider doing a diagnostic laparoscopy to confirm or deny the diagnosis.

Dr. Advincula: Are there any points in the evaluation of a patient who visits your practice for the first time where you would immediately offer a surgical approach, as opposed to starting with medical management?

Dr. Hur: A large percentage of my patients undergo surgical evaluation, as surgical diagnosis is the gold standard. If you look at the literature, even among surgeons, the accuracy of visual diagnosis is not great.^1,2 I target individuals who are either not responsive to medical treatment or who have never tried medical treatment but are trying to conceive, so they are not medical candidates, or individuals who genuinely want a diagnosis for surgical management—sometimes even before first-line medical treatment.

Dr. Brown: Your examination sometimes also dictates your approach. A patient may never have had a laparoscopy or hormone therapy, but if you find uterosacral ligament nodularity, extreme pain on examination, and suspicious findings on ultrasound or otherwise, a diagnostic laparoscopy may be warranted to confirm the diagnosis.

Endometrioma management

Dr. Advincula: Let’s jump ahead. You have decided to proceed with laparoscopy and you encounter an endometrioma. What is your management strategy, particularly in a fertility-desiring patient?

Dr. Hur: Even if a woman has not undergone first-line medical treatment, if she is trying to conceive or presents with infertility, it’s a different balancing act for approaching the patient. When a woman presents, either with an ultrasound finding or an intraoperative finding of an endometrioma, I am a strong advocate of treating symptomatic disease, which means complete cyst excision. Good clinical data suggest that reproductive outcomes are improved for spontaneous pregnancy rates when you excise an endometrioma.^3-6

Dr. Advincula: What are the risks of excision of an endometrioma cyst that patients need to know about?

Dr. Brown: Current standard of care is cystectomy, stripping the cyst wall away from the ovarian cortex. There is some concern that the stripping process, depending on how long the endometrioma has been present within the ovary, can cause some destruction to the underlying oocytes and perhaps impact that ovary’s ability to produce viable eggs.

Some studies, from France in particular, have investigated different energy sources, such as plasma energy, that make it possible to remove part of the cyst and then use the plasma energy to vaporize the rest of the cyst wall that may be lying on the cortex. Researchers looked at anti-Müllerian hormone levels, and there does seem to be a difference in terms of how you remove the cyst.^7-9 This energy source is not available to everyone; it’s similar to laser but does not have as much penetration. Standard of care is still ovarian stripping.

The conversation with the patient—if she is already infertile and this cyst is a problem—would be that it likely needs to be removed. There is a chance that she may need assisted reproduction; she might not be able to get pregnant on her own due either to the presence of the endometrioma or to the surgical process of removing it and stripping.

Dr. Advincula: How soon after surgery can a patient start to pursue trying to get pregnant?

Dr. Hur: I think there is no time restraint outside of recovery. As long as the patient has a routine postoperative course, she can try to conceive, spontaneously or with assisted reproduction. Some data suggest, however, that ovarian reserve is diminished immediately after surgery.^10–12 If you look at the spontaneous clinical pregnancy outcomes, they are comparable 3 to 6 months postsurgery.^4,12–14

Dr. Brown: I agree. Time is of the essence with a lot of patients, many of whom present after age 35.

Dr. Hur: It’s also important to highlight that there are 2 presentations with endometrioma: the symptomatic patient and the asymptomatic patient. In the asymptomatic patient, her age, reproductive goals, and the bilaterality (whether it is present on both sides or on one side) of the endometrioma are important in deciding on a patient-centered surgical plan. For someone with a smaller cyst, unilateral presentation, and maybe older age at presentation, it may or may not impact assisted reproductive outcomes.

If the patient is not symptomatic and she is older with bilateral endometriomas less than 4 cm, some data suggest that patient might be better served in a conservative fashion.^6,15–17 Then, once she is done with assisted reproduction, we might be more aggressive surgically by treating the finding that would not resolve spontaneously without surgical management. It is important to highlight that endometriomas do not resolve on their own; they require surgical management.

Read about managing endometriosis for the patient not seeking fertility

Endometriosis management for the patient not seeking fertility

Dr. Advincula: Let’s now consider a patient on whom you have performed laparoscopy not only to diagnose and confirm the evidence of endometriosis but also to treat endometriosis, an endometrioma, and potentially deeply infiltrative disease. But this person is not trying to get pregnant. Postoperatively, what is your approach?

Dr. Brown: Suppressive therapy for this patient could be first-line or second-line therapy, such as a Lupron Depot or Depo-Provera. We keep the patient on suppressive therapy (whatever treatments work for her), until she’s ready to get pregnant; then we take her off. Hopefully she gets pregnant. After she delivers, we reinitiate suppressive therapy. I will follow these women throughout their reproductive cycle, and I think having a team of physicians who are all on the same page can help this patient manage her disease through her reproductive years.

Dr. Hur: If a patient presented warranting surgical management once, and she is not menopausal, the likelihood that disease will recur is quite high. Understanding the nature and the pathology of the disease, hormonal suppression would be warranted. Suppression is not just for between pregnancies, it’s until the patient reaches natural menopause. It’s also in the hopes of suppressing the disease so she does not need recurrent surgeries.

We typically do not operate unless patients have recurrence of symptoms that no longer respond to medical therapy. Our hope is to buy them more time closer to the age of natural menopause so that medical repercussions do not result in hysterectomy and ovary removal, which have other nongynecologic manifestations, including negative impact on bone and cardiac health.

The role of the LNG-IUD

Dr. Advincula: Something that often comes up is the role of a levonorgestrel-releasing intrauterine device (LNG-IUD) as one therapy option, either preoperatively or postoperatively. What is your perspective?

Dr. Hur: I reserve the LNG-IUD as a second-line therapy for patients, predominantly because it allows direct delivery of the medication to the womb (rather than systemic exposure of the medication). For patients who experience adverse effects due to systemic exposure to first-line treatments, it might be a great option. However, I do not believe that it consistently suppresses the ovaries, which we understand feeds the pathology of the hormonal stimulation, and so typically I will reserve it as a second-line treatment.

Dr. Brown: I utilize the LNG-IUD in a similar fashion. I may have patients who have had a diagnostic laparoscopy somewhere else and were referred to me because they now have known stage 3 or 4 endometriosis without endometriomas. Those patients, if they are going to need suppressive therapy after surgery and are not ready to get pregnant, do very well with the LNG-IUD, and I will place it during surgery under anesthesia. If a patient has endometriomas seen at the time of surgery, we could still place an LNG-IUD at the time of surgery. We may need to add on an additional medication, however, like another oral progesterone. I do have patients that use both an IUD and either combined oral contraceptive pills and/or oral progestins. Those patients usually have complicated cases with very deep infiltrative disease.

Read about managing endometriosis involving the bowel

Managing endometriosis involving the bowel

Dr. Advincula: Patients often are quite concerned when the words “endometriosis” and “bowel” come together. How do you manage disease that involves the bowel?

Illustration: Kimberly Martens for OBG Management

Dr. Hur: A lot of patients with endometriosis have what I call neighboring disease—it’s not limited just to the pelvis, but it involves the neighboring organs including the bowel and bladder. Patients can present with symptoms related to those adjacent organs. However, not all disease involving the bowel or bladder manifests with symptoms, and patients with symptoms may not have visible disease.

Typically, when a patient presents with symptoms of bowel involvement, where the bowel lumen is narrowed to more than 50% and/or she has functional manifestations (signs of obstruction that result in abnormal bowel function), we have serious conversations about a bowel resection. If she has full-thickness disease without significant bowel dysfunction—other than blood in her stool—sometimes we talk about more conservative treatment because of the long-term manifestations that a bowel resection could have.

Dr. Brown: I agree completely. It is important to have a good relationship with our colorectal surgeons. If I suspect that the patient has narrowing of the lumen of the large bowel or she actually has symptoms such as bloody diarrhea during menstruation—which is suggestive of deep, infiltrative and penetrative disease—I will often order a colonoscopy ahead of time to get confirmed biopsies. Then the patient discussion occurs with our colorectal surgeon, who operates with me jointly if we decide to proceed with a bowel resection. It’s important to have subspecialty colleagues involved in this care, because a low anterior resection is a very big surgery and there can be down-the-stream complications.

The importance of multidisciplinary care

Dr. Advincula: What are your perspectives on a multidisciplinary or interdisciplinary approach to the patient with endometriosis?

Dr. Brown: As I previously mentioned, it is important to develop a good relationship with colorectal surgery/urology. In addition, behavioral therapists may be involved in the care of patients with endometriosis, for a number of reasons. The disease process is fluid. It will change during the patient’s reproductive years, and you need to manage it accordingly based on her symptoms. Sometimes the diagnosis is not made for 5 to 10 years, and that can lead to other issues: depression, fibromyalgia, or irritable bowel syndrome.

The patient may have multiple issues plus endometriosis. I think having specialists such as gastroenterologists and behavioral therapists on board, as well as colorectal and urological surgeons who can perform these complex surgeries, is very beneficial to the patient. That way, she benefits from the team’s focus and is cared for from start to finish.

Dr. Hur: I like to call the abdomen a studio. It does not have separate compartments for each organ system. It’s one big room, and often the neighboring organs are involved, including the bowel and bladder. I think Dr. Brown’s observation—the multidisciplinary approach to a patient’s comprehensive care—is critical. Like any surgery, preoperative planning and preoperative assessment are essential, and these steps should include the patient. The discussion should cover not only the surgical outcomes that the surgeons expect, but also what the patient expects to be improved. For example, for patients with extensive disease and bowel involvement, a bowel resection is not always the right approach because it can have potential long-term sequelae. Balancing the risks associated with surgery with the long-term benefits is an important part of the discussion.

Dr. Advincula: Those are both excellent perspectives. Endometriosis is a very complicated disease state, does require a multidisciplinary approach to management, and there are implications and strategies that involve both the medical approach to management and the surgical approach.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Endometriosis is one of the more daunting diagnoses that gynecologists treat. In this roundtable discussion, moderated by OBG Management Board Member Arnold P. Advincula, MD, 2 leading surgeons discuss endometriosis diagnosis as well as medical and surgical management.

First-time evaluation

Arnold P. Advincula, MD: When a patient presents to your practice for the first time and you suspect endometriosis, what considerations tailor your evaluation, and what does that evaluation involve?

Hye-Chun Hur, MD, MPH: The diagnosis is contingent on a patient’s presenting profile. How symptomatic is she? How old is she? What are her reproductive goals? The gold standard for diagnosis is a histologic diagnosis, which is surgical. Depending on the age profile, however, and how close she is to menopause, the patient may be managed medically. Even women in the young reproductive age group may be managed medically if symptoms are responsive to medical treatment.

Douglas N. Brown, MD: I agree. When a patient presents without a laparoscopy, or a tissue diagnosis, but the symptoms are consistent with likely endometriosis (depending on where she is in her reproductive cycle and what her goals are), I think treating with a first-line therapy—hormonal treatments such as progestin-only oral contraceptive pills—is acceptable. I usually conduct a treatment trial period of 3 to 6 months to see if she obtains any symptom relief.

If that first-line treatment fails, generally you can move to a second-line treatment.

I have a discussion in which I either offer a second-line treatment, such as medroxyprogesterone (Depo-Provera) or leuprolide acetate (Lupron Depot), or get a tissue diagnosis, if possible, by performing laparoscopy. If first-line or even second-line therapy fails, you need to consider doing a diagnostic laparoscopy to confirm or deny the diagnosis.

Dr. Advincula: Are there any points in the evaluation of a patient who visits your practice for the first time where you would immediately offer a surgical approach, as opposed to starting with medical management?

Dr. Hur: A large percentage of my patients undergo surgical evaluation, as surgical diagnosis is the gold standard. If you look at the literature, even among surgeons, the accuracy of visual diagnosis is not great.^1,2 I target individuals who are either not responsive to medical treatment or who have never tried medical treatment but are trying to conceive, so they are not medical candidates, or individuals who genuinely want a diagnosis for surgical management—sometimes even before first-line medical treatment.

Dr. Brown: Your examination sometimes also dictates your approach. A patient may never have had a laparoscopy or hormone therapy, but if you find uterosacral ligament nodularity, extreme pain on examination, and suspicious findings on ultrasound or otherwise, a diagnostic laparoscopy may be warranted to confirm the diagnosis.

Endometrioma management

Dr. Advincula: Let’s jump ahead. You have decided to proceed with laparoscopy and you encounter an endometrioma. What is your management strategy, particularly in a fertility-desiring patient?

Dr. Hur: Even if a woman has not undergone first-line medical treatment, if she is trying to conceive or presents with infertility, it’s a different balancing act for approaching the patient. When a woman presents, either with an ultrasound finding or an intraoperative finding of an endometrioma, I am a strong advocate of treating symptomatic disease, which means complete cyst excision. Good clinical data suggest that reproductive outcomes are improved for spontaneous pregnancy rates when you excise an endometrioma.^3-6

Dr. Advincula: What are the risks of excision of an endometrioma cyst that patients need to know about?

Dr. Brown: Current standard of care is cystectomy, stripping the cyst wall away from the ovarian cortex. There is some concern that the stripping process, depending on how long the endometrioma has been present within the ovary, can cause some destruction to the underlying oocytes and perhaps impact that ovary’s ability to produce viable eggs.

Some studies, from France in particular, have investigated different energy sources, such as plasma energy, that make it possible to remove part of the cyst and then use the plasma energy to vaporize the rest of the cyst wall that may be lying on the cortex. Researchers looked at anti-Müllerian hormone levels, and there does seem to be a difference in terms of how you remove the cyst.^7-9 This energy source is not available to everyone; it’s similar to laser but does not have as much penetration. Standard of care is still ovarian stripping.

The conversation with the patient—if she is already infertile and this cyst is a problem—would be that it likely needs to be removed. There is a chance that she may need assisted reproduction; she might not be able to get pregnant on her own due either to the presence of the endometrioma or to the surgical process of removing it and stripping.

Dr. Advincula: How soon after surgery can a patient start to pursue trying to get pregnant?

Dr. Hur: I think there is no time restraint outside of recovery. As long as the patient has a routine postoperative course, she can try to conceive, spontaneously or with assisted reproduction. Some data suggest, however, that ovarian reserve is diminished immediately after surgery.^10–12 If you look at the spontaneous clinical pregnancy outcomes, they are comparable 3 to 6 months postsurgery.^4,12–14

Dr. Brown: I agree. Time is of the essence with a lot of patients, many of whom present after age 35.

Dr. Hur: It’s also important to highlight that there are 2 presentations with endometrioma: the symptomatic patient and the asymptomatic patient. In the asymptomatic patient, her age, reproductive goals, and the bilaterality (whether it is present on both sides or on one side) of the endometrioma are important in deciding on a patient-centered surgical plan. For someone with a smaller cyst, unilateral presentation, and maybe older age at presentation, it may or may not impact assisted reproductive outcomes.

If the patient is not symptomatic and she is older with bilateral endometriomas less than 4 cm, some data suggest that patient might be better served in a conservative fashion.^6,15–17 Then, once she is done with assisted reproduction, we might be more aggressive surgically by treating the finding that would not resolve spontaneously without surgical management. It is important to highlight that endometriomas do not resolve on their own; they require surgical management.

Read about managing endometriosis for the patient not seeking fertility

Endometriosis management for the patient not seeking fertility

Dr. Advincula: Let’s now consider a patient on whom you have performed laparoscopy not only to diagnose and confirm the evidence of endometriosis but also to treat endometriosis, an endometrioma, and potentially deeply infiltrative disease. But this person is not trying to get pregnant. Postoperatively, what is your approach?

Dr. Brown: Suppressive therapy for this patient could be first-line or second-line therapy, such as a Lupron Depot or Depo-Provera. We keep the patient on suppressive therapy (whatever treatments work for her), until she’s ready to get pregnant; then we take her off. Hopefully she gets pregnant. After she delivers, we reinitiate suppressive therapy. I will follow these women throughout their reproductive cycle, and I think having a team of physicians who are all on the same page can help this patient manage her disease through her reproductive years.

Dr. Hur: If a patient presented warranting surgical management once, and she is not menopausal, the likelihood that disease will recur is quite high. Understanding the nature and the pathology of the disease, hormonal suppression would be warranted. Suppression is not just for between pregnancies, it’s until the patient reaches natural menopause. It’s also in the hopes of suppressing the disease so she does not need recurrent surgeries.

We typically do not operate unless patients have recurrence of symptoms that no longer respond to medical therapy. Our hope is to buy them more time closer to the age of natural menopause so that medical repercussions do not result in hysterectomy and ovary removal, which have other nongynecologic manifestations, including negative impact on bone and cardiac health.

The role of the LNG-IUD

Dr. Advincula: Something that often comes up is the role of a levonorgestrel-releasing intrauterine device (LNG-IUD) as one therapy option, either preoperatively or postoperatively. What is your perspective?

Dr. Hur: I reserve the LNG-IUD as a second-line therapy for patients, predominantly because it allows direct delivery of the medication to the womb (rather than systemic exposure of the medication). For patients who experience adverse effects due to systemic exposure to first-line treatments, it might be a great option. However, I do not believe that it consistently suppresses the ovaries, which we understand feeds the pathology of the hormonal stimulation, and so typically I will reserve it as a second-line treatment.

Dr. Brown: I utilize the LNG-IUD in a similar fashion. I may have patients who have had a diagnostic laparoscopy somewhere else and were referred to me because they now have known stage 3 or 4 endometriosis without endometriomas. Those patients, if they are going to need suppressive therapy after surgery and are not ready to get pregnant, do very well with the LNG-IUD, and I will place it during surgery under anesthesia. If a patient has endometriomas seen at the time of surgery, we could still place an LNG-IUD at the time of surgery. We may need to add on an additional medication, however, like another oral progesterone. I do have patients that use both an IUD and either combined oral contraceptive pills and/or oral progestins. Those patients usually have complicated cases with very deep infiltrative disease.

Read about managing endometriosis involving the bowel

Managing endometriosis involving the bowel

Dr. Advincula: Patients often are quite concerned when the words “endometriosis” and “bowel” come together. How do you manage disease that involves the bowel?

Illustration: Kimberly Martens for OBG Management

Dr. Hur: A lot of patients with endometriosis have what I call neighboring disease—it’s not limited just to the pelvis, but it involves the neighboring organs including the bowel and bladder. Patients can present with symptoms related to those adjacent organs. However, not all disease involving the bowel or bladder manifests with symptoms, and patients with symptoms may not have visible disease.

Typically, when a patient presents with symptoms of bowel involvement, where the bowel lumen is narrowed to more than 50% and/or she has functional manifestations (signs of obstruction that result in abnormal bowel function), we have serious conversations about a bowel resection. If she has full-thickness disease without significant bowel dysfunction—other than blood in her stool—sometimes we talk about more conservative treatment because of the long-term manifestations that a bowel resection could have.

Dr. Brown: I agree completely. It is important to have a good relationship with our colorectal surgeons. If I suspect that the patient has narrowing of the lumen of the large bowel or she actually has symptoms such as bloody diarrhea during menstruation—which is suggestive of deep, infiltrative and penetrative disease—I will often order a colonoscopy ahead of time to get confirmed biopsies. Then the patient discussion occurs with our colorectal surgeon, who operates with me jointly if we decide to proceed with a bowel resection. It’s important to have subspecialty colleagues involved in this care, because a low anterior resection is a very big surgery and there can be down-the-stream complications.

The importance of multidisciplinary care

Dr. Advincula: What are your perspectives on a multidisciplinary or interdisciplinary approach to the patient with endometriosis?

Dr. Brown: As I previously mentioned, it is important to develop a good relationship with colorectal surgery/urology. In addition, behavioral therapists may be involved in the care of patients with endometriosis, for a number of reasons. The disease process is fluid. It will change during the patient’s reproductive years, and you need to manage it accordingly based on her symptoms. Sometimes the diagnosis is not made for 5 to 10 years, and that can lead to other issues: depression, fibromyalgia, or irritable bowel syndrome.

The patient may have multiple issues plus endometriosis. I think having specialists such as gastroenterologists and behavioral therapists on board, as well as colorectal and urological surgeons who can perform these complex surgeries, is very beneficial to the patient. That way, she benefits from the team’s focus and is cared for from start to finish.

Dr. Hur: I like to call the abdomen a studio. It does not have separate compartments for each organ system. It’s one big room, and often the neighboring organs are involved, including the bowel and bladder. I think Dr. Brown’s observation—the multidisciplinary approach to a patient’s comprehensive care—is critical. Like any surgery, preoperative planning and preoperative assessment are essential, and these steps should include the patient. The discussion should cover not only the surgical outcomes that the surgeons expect, but also what the patient expects to be improved. For example, for patients with extensive disease and bowel involvement, a bowel resection is not always the right approach because it can have potential long-term sequelae. Balancing the risks associated with surgery with the long-term benefits is an important part of the discussion.

Dr. Advincula: Those are both excellent perspectives. Endometriosis is a very complicated disease state, does require a multidisciplinary approach to management, and there are implications and strategies that involve both the medical approach to management and the surgical approach.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Endometriosis is one of the more daunting diagnoses that gynecologists treat. In this roundtable discussion, moderated by OBG Management Board Member Arnold P. Advincula, MD, 2 leading surgeons discuss endometriosis diagnosis as well as medical and surgical management.

First-time evaluation

Arnold P. Advincula, MD: When a patient presents to your practice for the first time and you suspect endometriosis, what considerations tailor your evaluation, and what does that evaluation involve?

Hye-Chun Hur, MD, MPH: The diagnosis is contingent on a patient’s presenting profile. How symptomatic is she? How old is she? What are her reproductive goals? The gold standard for diagnosis is a histologic diagnosis, which is surgical. Depending on the age profile, however, and how close she is to menopause, the patient may be managed medically. Even women in the young reproductive age group may be managed medically if symptoms are responsive to medical treatment.

Douglas N. Brown, MD: I agree. When a patient presents without a laparoscopy, or a tissue diagnosis, but the symptoms are consistent with likely endometriosis (depending on where she is in her reproductive cycle and what her goals are), I think treating with a first-line therapy—hormonal treatments such as progestin-only oral contraceptive pills—is acceptable. I usually conduct a treatment trial period of 3 to 6 months to see if she obtains any symptom relief.

If that first-line treatment fails, generally you can move to a second-line treatment.

I have a discussion in which I either offer a second-line treatment, such as medroxyprogesterone (Depo-Provera) or leuprolide acetate (Lupron Depot), or get a tissue diagnosis, if possible, by performing laparoscopy. If first-line or even second-line therapy fails, you need to consider doing a diagnostic laparoscopy to confirm or deny the diagnosis.

Dr. Advincula: Are there any points in the evaluation of a patient who visits your practice for the first time where you would immediately offer a surgical approach, as opposed to starting with medical management?

Dr. Hur: A large percentage of my patients undergo surgical evaluation, as surgical diagnosis is the gold standard. If you look at the literature, even among surgeons, the accuracy of visual diagnosis is not great.^1,2 I target individuals who are either not responsive to medical treatment or who have never tried medical treatment but are trying to conceive, so they are not medical candidates, or individuals who genuinely want a diagnosis for surgical management—sometimes even before first-line medical treatment.

Dr. Brown: Your examination sometimes also dictates your approach. A patient may never have had a laparoscopy or hormone therapy, but if you find uterosacral ligament nodularity, extreme pain on examination, and suspicious findings on ultrasound or otherwise, a diagnostic laparoscopy may be warranted to confirm the diagnosis.

Endometrioma management

Dr. Advincula: Let’s jump ahead. You have decided to proceed with laparoscopy and you encounter an endometrioma. What is your management strategy, particularly in a fertility-desiring patient?

Dr. Hur: Even if a woman has not undergone first-line medical treatment, if she is trying to conceive or presents with infertility, it’s a different balancing act for approaching the patient. When a woman presents, either with an ultrasound finding or an intraoperative finding of an endometrioma, I am a strong advocate of treating symptomatic disease, which means complete cyst excision. Good clinical data suggest that reproductive outcomes are improved for spontaneous pregnancy rates when you excise an endometrioma.^3-6

Dr. Advincula: What are the risks of excision of an endometrioma cyst that patients need to know about?

Dr. Brown: Current standard of care is cystectomy, stripping the cyst wall away from the ovarian cortex. There is some concern that the stripping process, depending on how long the endometrioma has been present within the ovary, can cause some destruction to the underlying oocytes and perhaps impact that ovary’s ability to produce viable eggs.

Some studies, from France in particular, have investigated different energy sources, such as plasma energy, that make it possible to remove part of the cyst and then use the plasma energy to vaporize the rest of the cyst wall that may be lying on the cortex. Researchers looked at anti-Müllerian hormone levels, and there does seem to be a difference in terms of how you remove the cyst.^7-9 This energy source is not available to everyone; it’s similar to laser but does not have as much penetration. Standard of care is still ovarian stripping.

The conversation with the patient—if she is already infertile and this cyst is a problem—would be that it likely needs to be removed. There is a chance that she may need assisted reproduction; she might not be able to get pregnant on her own due either to the presence of the endometrioma or to the surgical process of removing it and stripping.

Dr. Advincula: How soon after surgery can a patient start to pursue trying to get pregnant?

Dr. Hur: I think there is no time restraint outside of recovery. As long as the patient has a routine postoperative course, she can try to conceive, spontaneously or with assisted reproduction. Some data suggest, however, that ovarian reserve is diminished immediately after surgery.^10–12 If you look at the spontaneous clinical pregnancy outcomes, they are comparable 3 to 6 months postsurgery.^4,12–14

Dr. Brown: I agree. Time is of the essence with a lot of patients, many of whom present after age 35.

Dr. Hur: It’s also important to highlight that there are 2 presentations with endometrioma: the symptomatic patient and the asymptomatic patient. In the asymptomatic patient, her age, reproductive goals, and the bilaterality (whether it is present on both sides or on one side) of the endometrioma are important in deciding on a patient-centered surgical plan. For someone with a smaller cyst, unilateral presentation, and maybe older age at presentation, it may or may not impact assisted reproductive outcomes.

If the patient is not symptomatic and she is older with bilateral endometriomas less than 4 cm, some data suggest that patient might be better served in a conservative fashion.^6,15–17 Then, once she is done with assisted reproduction, we might be more aggressive surgically by treating the finding that would not resolve spontaneously without surgical management. It is important to highlight that endometriomas do not resolve on their own; they require surgical management.

Read about managing endometriosis for the patient not seeking fertility

Endometriosis management for the patient not seeking fertility

Dr. Advincula: Let’s now consider a patient on whom you have performed laparoscopy not only to diagnose and confirm the evidence of endometriosis but also to treat endometriosis, an endometrioma, and potentially deeply infiltrative disease. But this person is not trying to get pregnant. Postoperatively, what is your approach?

Dr. Brown: Suppressive therapy for this patient could be first-line or second-line therapy, such as a Lupron Depot or Depo-Provera. We keep the patient on suppressive therapy (whatever treatments work for her), until she’s ready to get pregnant; then we take her off. Hopefully she gets pregnant. After she delivers, we reinitiate suppressive therapy. I will follow these women throughout their reproductive cycle, and I think having a team of physicians who are all on the same page can help this patient manage her disease through her reproductive years.

Dr. Hur: If a patient presented warranting surgical management once, and she is not menopausal, the likelihood that disease will recur is quite high. Understanding the nature and the pathology of the disease, hormonal suppression would be warranted. Suppression is not just for between pregnancies, it’s until the patient reaches natural menopause. It’s also in the hopes of suppressing the disease so she does not need recurrent surgeries.

We typically do not operate unless patients have recurrence of symptoms that no longer respond to medical therapy. Our hope is to buy them more time closer to the age of natural menopause so that medical repercussions do not result in hysterectomy and ovary removal, which have other nongynecologic manifestations, including negative impact on bone and cardiac health.

The role of the LNG-IUD

Dr. Advincula: Something that often comes up is the role of a levonorgestrel-releasing intrauterine device (LNG-IUD) as one therapy option, either preoperatively or postoperatively. What is your perspective?

Dr. Hur: I reserve the LNG-IUD as a second-line therapy for patients, predominantly because it allows direct delivery of the medication to the womb (rather than systemic exposure of the medication). For patients who experience adverse effects due to systemic exposure to first-line treatments, it might be a great option. However, I do not believe that it consistently suppresses the ovaries, which we understand feeds the pathology of the hormonal stimulation, and so typically I will reserve it as a second-line treatment.

Dr. Brown: I utilize the LNG-IUD in a similar fashion. I may have patients who have had a diagnostic laparoscopy somewhere else and were referred to me because they now have known stage 3 or 4 endometriosis without endometriomas. Those patients, if they are going to need suppressive therapy after surgery and are not ready to get pregnant, do very well with the LNG-IUD, and I will place it during surgery under anesthesia. If a patient has endometriomas seen at the time of surgery, we could still place an LNG-IUD at the time of surgery. We may need to add on an additional medication, however, like another oral progesterone. I do have patients that use both an IUD and either combined oral contraceptive pills and/or oral progestins. Those patients usually have complicated cases with very deep infiltrative disease.

Read about managing endometriosis involving the bowel

Managing endometriosis involving the bowel

Dr. Advincula: Patients often are quite concerned when the words “endometriosis” and “bowel” come together. How do you manage disease that involves the bowel?

Illustration: Kimberly Martens for OBG Management

Dr. Hur: A lot of patients with endometriosis have what I call neighboring disease—it’s not limited just to the pelvis, but it involves the neighboring organs including the bowel and bladder. Patients can present with symptoms related to those adjacent organs. However, not all disease involving the bowel or bladder manifests with symptoms, and patients with symptoms may not have visible disease.

Typically, when a patient presents with symptoms of bowel involvement, where the bowel lumen is narrowed to more than 50% and/or she has functional manifestations (signs of obstruction that result in abnormal bowel function), we have serious conversations about a bowel resection. If she has full-thickness disease without significant bowel dysfunction—other than blood in her stool—sometimes we talk about more conservative treatment because of the long-term manifestations that a bowel resection could have.

Dr. Brown: I agree completely. It is important to have a good relationship with our colorectal surgeons. If I suspect that the patient has narrowing of the lumen of the large bowel or she actually has symptoms such as bloody diarrhea during menstruation—which is suggestive of deep, infiltrative and penetrative disease—I will often order a colonoscopy ahead of time to get confirmed biopsies. Then the patient discussion occurs with our colorectal surgeon, who operates with me jointly if we decide to proceed with a bowel resection. It’s important to have subspecialty colleagues involved in this care, because a low anterior resection is a very big surgery and there can be down-the-stream complications.

The importance of multidisciplinary care

Dr. Advincula: What are your perspectives on a multidisciplinary or interdisciplinary approach to the patient with endometriosis?

Dr. Brown: As I previously mentioned, it is important to develop a good relationship with colorectal surgery/urology. In addition, behavioral therapists may be involved in the care of patients with endometriosis, for a number of reasons. The disease process is fluid. It will change during the patient’s reproductive years, and you need to manage it accordingly based on her symptoms. Sometimes the diagnosis is not made for 5 to 10 years, and that can lead to other issues: depression, fibromyalgia, or irritable bowel syndrome.

The patient may have multiple issues plus endometriosis. I think having specialists such as gastroenterologists and behavioral therapists on board, as well as colorectal and urological surgeons who can perform these complex surgeries, is very beneficial to the patient. That way, she benefits from the team’s focus and is cared for from start to finish.

Dr. Hur: I like to call the abdomen a studio. It does not have separate compartments for each organ system. It’s one big room, and often the neighboring organs are involved, including the bowel and bladder. I think Dr. Brown’s observation—the multidisciplinary approach to a patient’s comprehensive care—is critical. Like any surgery, preoperative planning and preoperative assessment are essential, and these steps should include the patient. The discussion should cover not only the surgical outcomes that the surgeons expect, but also what the patient expects to be improved. For example, for patients with extensive disease and bowel involvement, a bowel resection is not always the right approach because it can have potential long-term sequelae. Balancing the risks associated with surgery with the long-term benefits is an important part of the discussion.

Dr. Advincula: Those are both excellent perspectives. Endometriosis is a very complicated disease state, does require a multidisciplinary approach to management, and there are implications and strategies that involve both the medical approach to management and the surgical approach.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

In this Update, I report on the latest US Preventive Services Task Force (USPSTF) cervical cancer screening recommendations. In addition, I describe the results of 2 studies, a large prospective multicenter study of the accuracy of sentinel lymph node (SLN) biopsy in endometrial cancer, and a proof-of-concept review of use of checkpoint blockade to increase immune response and of its possible role in endometrial cancer.

hrHPV testing used alone as primary screening for cervical cancer: USPSTF recommendations

US Preventive Services Task Force. Draft recommendation statement: cervical cancer: screening. https://www.uspreventiveservicestaskforce.org/Page/Document/draft-recommendation-statement/cervical-cancer-screening2. Published October 2017. Accessed February 5, 2018.

‌

Despite our rapid advances in understanding the molecular underpinnings of cancer, gynecologic malignancies are still a major cause of morbidity and mortality among women. Cervical cancer stands as an example of how a cancer screening test can be implemented to reduce mortality. In this section, I report on the USPSTF cervical cancer screening recommendations, which were updated in October 2017.

Even with the widespread implementation of screening programs for cervical cancer in the United States, 13,240 women will be diagnosed with the disease in 2018, and 4,170 will die from cervical cancer.¹ Most often, cervical cancer occurs in women who have not been adequately screened. It is now recognized that the human papillomavirus (HPV) is the cause of cervical cancer.²

While cervical cytology has long been used as a screening test for cervical cancer, testing for high-risk HPV subtypes (hrHPV testing) also has been used as a screening modality. Traditionally, hrHPV testing is used in combination with cervical cytology, so called cotesting. There is convincing evidence that cervical cytology, as well as strategies that use hrHPV testing, can detect high-grade cervical precancers and cancers and thereby reduce mortality. However, cervical cancer screening is also associated with frequent follow-ups, invasive procedures performed to assess abnormal results, psychological distress, and adverse pregnancy outcomes of treatment for precancerous lesions.

The USPSTF based its new cervical cancer screening recommendations on clinical trial data and decision modeling of various screening strategies, and weighed the benefits and harms of each strategy.

Recommendations from the USPSTF

hrHPV screening for cervical cancer.  TheUSPSTF recommends screening with cervical cytology every 3 years for women 21 to 29 years of age. For women 30 to 65 years of age, screening with cytology every 3 years, or hrHPV testing alone used every 5 years, is recommended.

Data from large randomized trials suggest cytologic screening is slightly less sensitive than hrHPV testing in detecting high-grade (grade 2 or 3) cervical intraepithelial neoplasia (CIN). However, hrHPV testing results in more follow-up tests and colposcopies. In a decision model, the USPSTF found that cotesting increased the number of follow-up tests but did not increase detection of grade 3 CIN or invasive cancer. This is the first clinical guideline to recommend hrHPV testing used alone for screening. The American College of Obstetricians and Gynecologists (ACOG) continues to recommend cotesting (cytology in combination with hrHPV) as a primary screening modality in this population.³

Exceptions. According to the USPSTF, 3 populations should not be screened: women over 65 years of age with adequate prior screening who are not otherwise at high risk for cervical cancer; women under  21 years of age; and women who have had a hysterectomy and do not have a history of grade 2 or 3 CIN or cancer.

Summary. The USPSTF recommendations are intended for the general population and are not applicable to women with a history of high-grade CIN or cervical cancer, women with in utero exposure to diethylstilbestrol, and women who are immunocompromised. The remaining USPSTF recommendations are largely in line with guidelines published by ACOG and other groups.^3,4

Read about SLN biopsy to stage endometrial cancer

SLN biopsy for staging endometrial cancer

Rossi EC, Kowalski LD, Scalici J, et al. A comparison of sentinel lymph node biopsy to lymphadenectomy for endometrial cancer staging (FIRES trial): a multicentre, prospective, cohort study. Lancet Oncol. 2017;18(3):384-392.

‌

Surgery is the cornerstone of treatment for most gynecologic cancers. The widespread use of minimally invasive surgical techniques and the introduction of less radical procedures for gynecologic cancers have helped reduce surgical morbidity.

For endometrial cancer, the role of lymphadenectomy is controversial. Data from prospective trials of this procedure suggest an association with increased morbidity and long-term sequelae, such as lymphedema, and no association with improved survival.^5,6

SLN biopsy is an important advance and a potential alternative nodal evaluation method that may be associated with decreased morbidity. In this more limited assessment technique, the first nodal drainage basins of a tumor are identified and removed for pathologic evaluation.

Accuracy of SLN biopsy in endometrial cancer was the subject of Rossi and colleagues' recent large prospective multicenter study, the Fluorescence Imaging for Robotic Endometrial Sentinel lymph node biopsy (FIRES) trial.

Details of the study

Rossi and colleagues conducted the FIRES trial to estimate the sensitivity of SLN biopsy in detecting nodal metastases in women with stage I endometrial cancer. Patients (N = 385) from 10 US sites were enrolled in the study. SLN evaluation was performed after cervical injection of indocyanine green followed by robotic-assisted hysterectomy. After identification of the SLN, participants underwent pelvic lymphadenectomy. Performance of para-aortic lymphadenectomy was optional.

Mapping of the SLN was feasible in 86% of patients, including bilateral mapping in 52%. Twelve percent of the participants had nodal metastases. SLN biopsy had a sensitivity of 97% in women who had identification of the SLNs. Similarly, the negative predictive value was high, 99.6%. The procedure was associated with acceptable short-term toxicity with adverse events in 9% of study participants. Common complications included neurologic complications, respiratory distress, nausea and vomiting, and, in 3 patients, bowel injury.

Accurate detection of nodal metastases. Results of the study suggest SLN biopsy is accurate in detecting nodal metastases in women with endometrial cancer. Although long-term toxicity was not examined, other work suggests the lymphedema rates associated with SLN biopsy may be lower than those of lymphadenectomy. While the study described impressive performance characteristics, there remain technical challenges. Even among skilled surgeons trained for the protocol, there was no nodal mapping in nearly half of the women with endometrial cancer. Women without node mapping require full lymphadenectomy thus negating the possible benefits of the procedure.

Read about immunotherapy for gynecologic cancers

Immunotherapy for gynecologic cancers

Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409-413.

‌

In oncology, precision medicine is rapidly becoming a standard treatment approach. Therapies are being used to target specific genetic alterations in tumors. In cancer immunotherapy, the immune system is being used to facilitate clearance of cancer cells.

The most common mechanism of action of clinically used immunotherapeutic agents is blockade of programmed cell death protein 1 (PD-1), a lymphocyte receptor that prevents the immune system from targeting the body's own cells.⁷ Cancers that have mutations in the DNA mismatch repair (MMR) proteins display microsatellite instability (MSI) and produce high levels of abnormal proteins.⁸ These abnormal proteins serve as tumor antigens that can be targeted by the body's normal immune system. 

In May 2017, the US Food and Drug Administration (FDA) granted accelerated approval of the PD-1 blocking antibody pembrolizumab for the treatment of unresectable or metastatic MSI-high (MSI-H) or MMR-deficient solid tumors.9 The approval was based on data from 149 patients treated in 5 studies that demonstrated a response rate of 39.6%, including responses that lasted at least 6 months in 78% of participants. This was the first ever cancer drug that received FDA approval based on a tumor's biomarker profile without regard to the site of origin. I describe the results of a study by Le and colleagues that examines the possible role of immunotherapy in a variety of solid tumors in this section.

Details of the study

This study examined the clinical efficacy of PD-1 blockade in 86 patients with advanced, MMR-deficient tumors from 12 different sites. Endometrial cancer was the second most frequent primary tumor site in 17% of patients. Within the cohort, the overall objective response rate was 53%, which included 21% of patients with complete radiographic response (no imaging evidence of cancer). Disease control, either complete or partial response or stable disease, was achieved in 77% of patients. After a median follow-up of 12.5 months, neither the median progression-free survival (PFS) nor median overall survival had been reached. The authors estimated that 2-year overall survival was 64%, substantially higher than expected for patients with advanced solid tumors.

Le and colleagues also performed several in vivo laboratory experiments to explore the mechanisms by which patients responded. In addition, they used sequencing to determine the prevalence of MMR deficiency in 12,019 cancer samples that included 32 distinct tumor types (FIGURE). Endometrial cancer had the highest frequency of MMR deficiency (17%). Four percent of cervical cancers and less than 2% of ovarian cancers were MMR-deficient.

The promise of immunotherapy for endometrial cancer. This study's data and other emerging data have important implications for women with gynecologic cancer, particularly endometrial cancer. First, given the frequency of MMR mutations among women with endometrial cancer, MMR testing should be strongly considered for these patients. Many institutions have protocols for reflex testing with immunohistochemistry for women with endometrial cancer. For women with positive test results, germline sequencing can be performed to determine if they have an inherited MMR deficiency, Lynch syndrome. Presence of an MMR deficiency is an important factor in cancer screening and potential treatment.

Second, the impressive results of PD-1 blockade in patients with MMR-deficient tumors suggest that this treatment strategy may be important for women with recurrent or metastatic endometrial cancer. The ideal timing of immunotherapy for women with endometrial cancer is an area of active ongoing study.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

In this Update, I report on the latest US Preventive Services Task Force (USPSTF) cervical cancer screening recommendations. In addition, I describe the results of 2 studies, a large prospective multicenter study of the accuracy of sentinel lymph node (SLN) biopsy in endometrial cancer, and a proof-of-concept review of use of checkpoint blockade to increase immune response and of its possible role in endometrial cancer.

hrHPV testing used alone as primary screening for cervical cancer: USPSTF recommendations

US Preventive Services Task Force. Draft recommendation statement: cervical cancer: screening. https://www.uspreventiveservicestaskforce.org/Page/Document/draft-recommendation-statement/cervical-cancer-screening2. Published October 2017. Accessed February 5, 2018.

‌

Despite our rapid advances in understanding the molecular underpinnings of cancer, gynecologic malignancies are still a major cause of morbidity and mortality among women. Cervical cancer stands as an example of how a cancer screening test can be implemented to reduce mortality. In this section, I report on the USPSTF cervical cancer screening recommendations, which were updated in October 2017.

Even with the widespread implementation of screening programs for cervical cancer in the United States, 13,240 women will be diagnosed with the disease in 2018, and 4,170 will die from cervical cancer.¹ Most often, cervical cancer occurs in women who have not been adequately screened. It is now recognized that the human papillomavirus (HPV) is the cause of cervical cancer.²

While cervical cytology has long been used as a screening test for cervical cancer, testing for high-risk HPV subtypes (hrHPV testing) also has been used as a screening modality. Traditionally, hrHPV testing is used in combination with cervical cytology, so called cotesting. There is convincing evidence that cervical cytology, as well as strategies that use hrHPV testing, can detect high-grade cervical precancers and cancers and thereby reduce mortality. However, cervical cancer screening is also associated with frequent follow-ups, invasive procedures performed to assess abnormal results, psychological distress, and adverse pregnancy outcomes of treatment for precancerous lesions.

The USPSTF based its new cervical cancer screening recommendations on clinical trial data and decision modeling of various screening strategies, and weighed the benefits and harms of each strategy.

Recommendations from the USPSTF

hrHPV screening for cervical cancer.  TheUSPSTF recommends screening with cervical cytology every 3 years for women 21 to 29 years of age. For women 30 to 65 years of age, screening with cytology every 3 years, or hrHPV testing alone used every 5 years, is recommended.

Data from large randomized trials suggest cytologic screening is slightly less sensitive than hrHPV testing in detecting high-grade (grade 2 or 3) cervical intraepithelial neoplasia (CIN). However, hrHPV testing results in more follow-up tests and colposcopies. In a decision model, the USPSTF found that cotesting increased the number of follow-up tests but did not increase detection of grade 3 CIN or invasive cancer. This is the first clinical guideline to recommend hrHPV testing used alone for screening. The American College of Obstetricians and Gynecologists (ACOG) continues to recommend cotesting (cytology in combination with hrHPV) as a primary screening modality in this population.³

Exceptions. According to the USPSTF, 3 populations should not be screened: women over 65 years of age with adequate prior screening who are not otherwise at high risk for cervical cancer; women under  21 years of age; and women who have had a hysterectomy and do not have a history of grade 2 or 3 CIN or cancer.

Summary. The USPSTF recommendations are intended for the general population and are not applicable to women with a history of high-grade CIN or cervical cancer, women with in utero exposure to diethylstilbestrol, and women who are immunocompromised. The remaining USPSTF recommendations are largely in line with guidelines published by ACOG and other groups.^3,4

Read about SLN biopsy to stage endometrial cancer

SLN biopsy for staging endometrial cancer

Rossi EC, Kowalski LD, Scalici J, et al. A comparison of sentinel lymph node biopsy to lymphadenectomy for endometrial cancer staging (FIRES trial): a multicentre, prospective, cohort study. Lancet Oncol. 2017;18(3):384-392.

‌

Surgery is the cornerstone of treatment for most gynecologic cancers. The widespread use of minimally invasive surgical techniques and the introduction of less radical procedures for gynecologic cancers have helped reduce surgical morbidity.

For endometrial cancer, the role of lymphadenectomy is controversial. Data from prospective trials of this procedure suggest an association with increased morbidity and long-term sequelae, such as lymphedema, and no association with improved survival.^5,6

SLN biopsy is an important advance and a potential alternative nodal evaluation method that may be associated with decreased morbidity. In this more limited assessment technique, the first nodal drainage basins of a tumor are identified and removed for pathologic evaluation.

Accuracy of SLN biopsy in endometrial cancer was the subject of Rossi and colleagues' recent large prospective multicenter study, the Fluorescence Imaging for Robotic Endometrial Sentinel lymph node biopsy (FIRES) trial.

Details of the study

Rossi and colleagues conducted the FIRES trial to estimate the sensitivity of SLN biopsy in detecting nodal metastases in women with stage I endometrial cancer. Patients (N = 385) from 10 US sites were enrolled in the study. SLN evaluation was performed after cervical injection of indocyanine green followed by robotic-assisted hysterectomy. After identification of the SLN, participants underwent pelvic lymphadenectomy. Performance of para-aortic lymphadenectomy was optional.

Mapping of the SLN was feasible in 86% of patients, including bilateral mapping in 52%. Twelve percent of the participants had nodal metastases. SLN biopsy had a sensitivity of 97% in women who had identification of the SLNs. Similarly, the negative predictive value was high, 99.6%. The procedure was associated with acceptable short-term toxicity with adverse events in 9% of study participants. Common complications included neurologic complications, respiratory distress, nausea and vomiting, and, in 3 patients, bowel injury.

Accurate detection of nodal metastases. Results of the study suggest SLN biopsy is accurate in detecting nodal metastases in women with endometrial cancer. Although long-term toxicity was not examined, other work suggests the lymphedema rates associated with SLN biopsy may be lower than those of lymphadenectomy. While the study described impressive performance characteristics, there remain technical challenges. Even among skilled surgeons trained for the protocol, there was no nodal mapping in nearly half of the women with endometrial cancer. Women without node mapping require full lymphadenectomy thus negating the possible benefits of the procedure.

Read about immunotherapy for gynecologic cancers

Immunotherapy for gynecologic cancers

Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409-413.

‌

In oncology, precision medicine is rapidly becoming a standard treatment approach. Therapies are being used to target specific genetic alterations in tumors. In cancer immunotherapy, the immune system is being used to facilitate clearance of cancer cells.

The most common mechanism of action of clinically used immunotherapeutic agents is blockade of programmed cell death protein 1 (PD-1), a lymphocyte receptor that prevents the immune system from targeting the body's own cells.⁷ Cancers that have mutations in the DNA mismatch repair (MMR) proteins display microsatellite instability (MSI) and produce high levels of abnormal proteins.⁸ These abnormal proteins serve as tumor antigens that can be targeted by the body's normal immune system. 

In May 2017, the US Food and Drug Administration (FDA) granted accelerated approval of the PD-1 blocking antibody pembrolizumab for the treatment of unresectable or metastatic MSI-high (MSI-H) or MMR-deficient solid tumors.9 The approval was based on data from 149 patients treated in 5 studies that demonstrated a response rate of 39.6%, including responses that lasted at least 6 months in 78% of participants. This was the first ever cancer drug that received FDA approval based on a tumor's biomarker profile without regard to the site of origin. I describe the results of a study by Le and colleagues that examines the possible role of immunotherapy in a variety of solid tumors in this section.

Details of the study

This study examined the clinical efficacy of PD-1 blockade in 86 patients with advanced, MMR-deficient tumors from 12 different sites. Endometrial cancer was the second most frequent primary tumor site in 17% of patients. Within the cohort, the overall objective response rate was 53%, which included 21% of patients with complete radiographic response (no imaging evidence of cancer). Disease control, either complete or partial response or stable disease, was achieved in 77% of patients. After a median follow-up of 12.5 months, neither the median progression-free survival (PFS) nor median overall survival had been reached. The authors estimated that 2-year overall survival was 64%, substantially higher than expected for patients with advanced solid tumors.

Le and colleagues also performed several in vivo laboratory experiments to explore the mechanisms by which patients responded. In addition, they used sequencing to determine the prevalence of MMR deficiency in 12,019 cancer samples that included 32 distinct tumor types (FIGURE). Endometrial cancer had the highest frequency of MMR deficiency (17%). Four percent of cervical cancers and less than 2% of ovarian cancers were MMR-deficient.

The promise of immunotherapy for endometrial cancer. This study's data and other emerging data have important implications for women with gynecologic cancer, particularly endometrial cancer. First, given the frequency of MMR mutations among women with endometrial cancer, MMR testing should be strongly considered for these patients. Many institutions have protocols for reflex testing with immunohistochemistry for women with endometrial cancer. For women with positive test results, germline sequencing can be performed to determine if they have an inherited MMR deficiency, Lynch syndrome. Presence of an MMR deficiency is an important factor in cancer screening and potential treatment.

Second, the impressive results of PD-1 blockade in patients with MMR-deficient tumors suggest that this treatment strategy may be important for women with recurrent or metastatic endometrial cancer. The ideal timing of immunotherapy for women with endometrial cancer is an area of active ongoing study.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

In this Update, I report on the latest US Preventive Services Task Force (USPSTF) cervical cancer screening recommendations. In addition, I describe the results of 2 studies, a large prospective multicenter study of the accuracy of sentinel lymph node (SLN) biopsy in endometrial cancer, and a proof-of-concept review of use of checkpoint blockade to increase immune response and of its possible role in endometrial cancer.

hrHPV testing used alone as primary screening for cervical cancer: USPSTF recommendations

US Preventive Services Task Force. Draft recommendation statement: cervical cancer: screening. https://www.uspreventiveservicestaskforce.org/Page/Document/draft-recommendation-statement/cervical-cancer-screening2. Published October 2017. Accessed February 5, 2018.

‌

Despite our rapid advances in understanding the molecular underpinnings of cancer, gynecologic malignancies are still a major cause of morbidity and mortality among women. Cervical cancer stands as an example of how a cancer screening test can be implemented to reduce mortality. In this section, I report on the USPSTF cervical cancer screening recommendations, which were updated in October 2017.

Even with the widespread implementation of screening programs for cervical cancer in the United States, 13,240 women will be diagnosed with the disease in 2018, and 4,170 will die from cervical cancer.¹ Most often, cervical cancer occurs in women who have not been adequately screened. It is now recognized that the human papillomavirus (HPV) is the cause of cervical cancer.²

While cervical cytology has long been used as a screening test for cervical cancer, testing for high-risk HPV subtypes (hrHPV testing) also has been used as a screening modality. Traditionally, hrHPV testing is used in combination with cervical cytology, so called cotesting. There is convincing evidence that cervical cytology, as well as strategies that use hrHPV testing, can detect high-grade cervical precancers and cancers and thereby reduce mortality. However, cervical cancer screening is also associated with frequent follow-ups, invasive procedures performed to assess abnormal results, psychological distress, and adverse pregnancy outcomes of treatment for precancerous lesions.

The USPSTF based its new cervical cancer screening recommendations on clinical trial data and decision modeling of various screening strategies, and weighed the benefits and harms of each strategy.

Recommendations from the USPSTF

hrHPV screening for cervical cancer.  TheUSPSTF recommends screening with cervical cytology every 3 years for women 21 to 29 years of age. For women 30 to 65 years of age, screening with cytology every 3 years, or hrHPV testing alone used every 5 years, is recommended.

Data from large randomized trials suggest cytologic screening is slightly less sensitive than hrHPV testing in detecting high-grade (grade 2 or 3) cervical intraepithelial neoplasia (CIN). However, hrHPV testing results in more follow-up tests and colposcopies. In a decision model, the USPSTF found that cotesting increased the number of follow-up tests but did not increase detection of grade 3 CIN or invasive cancer. This is the first clinical guideline to recommend hrHPV testing used alone for screening. The American College of Obstetricians and Gynecologists (ACOG) continues to recommend cotesting (cytology in combination with hrHPV) as a primary screening modality in this population.³

Exceptions. According to the USPSTF, 3 populations should not be screened: women over 65 years of age with adequate prior screening who are not otherwise at high risk for cervical cancer; women under  21 years of age; and women who have had a hysterectomy and do not have a history of grade 2 or 3 CIN or cancer.

Summary. The USPSTF recommendations are intended for the general population and are not applicable to women with a history of high-grade CIN or cervical cancer, women with in utero exposure to diethylstilbestrol, and women who are immunocompromised. The remaining USPSTF recommendations are largely in line with guidelines published by ACOG and other groups.^3,4

Read about SLN biopsy to stage endometrial cancer

SLN biopsy for staging endometrial cancer

Rossi EC, Kowalski LD, Scalici J, et al. A comparison of sentinel lymph node biopsy to lymphadenectomy for endometrial cancer staging (FIRES trial): a multicentre, prospective, cohort study. Lancet Oncol. 2017;18(3):384-392.

‌

Surgery is the cornerstone of treatment for most gynecologic cancers. The widespread use of minimally invasive surgical techniques and the introduction of less radical procedures for gynecologic cancers have helped reduce surgical morbidity.

For endometrial cancer, the role of lymphadenectomy is controversial. Data from prospective trials of this procedure suggest an association with increased morbidity and long-term sequelae, such as lymphedema, and no association with improved survival.^5,6

SLN biopsy is an important advance and a potential alternative nodal evaluation method that may be associated with decreased morbidity. In this more limited assessment technique, the first nodal drainage basins of a tumor are identified and removed for pathologic evaluation.

Accuracy of SLN biopsy in endometrial cancer was the subject of Rossi and colleagues' recent large prospective multicenter study, the Fluorescence Imaging for Robotic Endometrial Sentinel lymph node biopsy (FIRES) trial.

Details of the study

Rossi and colleagues conducted the FIRES trial to estimate the sensitivity of SLN biopsy in detecting nodal metastases in women with stage I endometrial cancer. Patients (N = 385) from 10 US sites were enrolled in the study. SLN evaluation was performed after cervical injection of indocyanine green followed by robotic-assisted hysterectomy. After identification of the SLN, participants underwent pelvic lymphadenectomy. Performance of para-aortic lymphadenectomy was optional.

Mapping of the SLN was feasible in 86% of patients, including bilateral mapping in 52%. Twelve percent of the participants had nodal metastases. SLN biopsy had a sensitivity of 97% in women who had identification of the SLNs. Similarly, the negative predictive value was high, 99.6%. The procedure was associated with acceptable short-term toxicity with adverse events in 9% of study participants. Common complications included neurologic complications, respiratory distress, nausea and vomiting, and, in 3 patients, bowel injury.

Accurate detection of nodal metastases. Results of the study suggest SLN biopsy is accurate in detecting nodal metastases in women with endometrial cancer. Although long-term toxicity was not examined, other work suggests the lymphedema rates associated with SLN biopsy may be lower than those of lymphadenectomy. While the study described impressive performance characteristics, there remain technical challenges. Even among skilled surgeons trained for the protocol, there was no nodal mapping in nearly half of the women with endometrial cancer. Women without node mapping require full lymphadenectomy thus negating the possible benefits of the procedure.

Read about immunotherapy for gynecologic cancers

Immunotherapy for gynecologic cancers

Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409-413.

‌

In oncology, precision medicine is rapidly becoming a standard treatment approach. Therapies are being used to target specific genetic alterations in tumors. In cancer immunotherapy, the immune system is being used to facilitate clearance of cancer cells.

The most common mechanism of action of clinically used immunotherapeutic agents is blockade of programmed cell death protein 1 (PD-1), a lymphocyte receptor that prevents the immune system from targeting the body's own cells.⁷ Cancers that have mutations in the DNA mismatch repair (MMR) proteins display microsatellite instability (MSI) and produce high levels of abnormal proteins.⁸ These abnormal proteins serve as tumor antigens that can be targeted by the body's normal immune system. 

In May 2017, the US Food and Drug Administration (FDA) granted accelerated approval of the PD-1 blocking antibody pembrolizumab for the treatment of unresectable or metastatic MSI-high (MSI-H) or MMR-deficient solid tumors.9 The approval was based on data from 149 patients treated in 5 studies that demonstrated a response rate of 39.6%, including responses that lasted at least 6 months in 78% of participants. This was the first ever cancer drug that received FDA approval based on a tumor's biomarker profile without regard to the site of origin. I describe the results of a study by Le and colleagues that examines the possible role of immunotherapy in a variety of solid tumors in this section.

Details of the study

This study examined the clinical efficacy of PD-1 blockade in 86 patients with advanced, MMR-deficient tumors from 12 different sites. Endometrial cancer was the second most frequent primary tumor site in 17% of patients. Within the cohort, the overall objective response rate was 53%, which included 21% of patients with complete radiographic response (no imaging evidence of cancer). Disease control, either complete or partial response or stable disease, was achieved in 77% of patients. After a median follow-up of 12.5 months, neither the median progression-free survival (PFS) nor median overall survival had been reached. The authors estimated that 2-year overall survival was 64%, substantially higher than expected for patients with advanced solid tumors.

Le and colleagues also performed several in vivo laboratory experiments to explore the mechanisms by which patients responded. In addition, they used sequencing to determine the prevalence of MMR deficiency in 12,019 cancer samples that included 32 distinct tumor types (FIGURE). Endometrial cancer had the highest frequency of MMR deficiency (17%). Four percent of cervical cancers and less than 2% of ovarian cancers were MMR-deficient.

The promise of immunotherapy for endometrial cancer. This study's data and other emerging data have important implications for women with gynecologic cancer, particularly endometrial cancer. First, given the frequency of MMR mutations among women with endometrial cancer, MMR testing should be strongly considered for these patients. Many institutions have protocols for reflex testing with immunohistochemistry for women with endometrial cancer. For women with positive test results, germline sequencing can be performed to determine if they have an inherited MMR deficiency, Lynch syndrome. Presence of an MMR deficiency is an important factor in cancer screening and potential treatment.

Second, the impressive results of PD-1 blockade in patients with MMR-deficient tumors suggest that this treatment strategy may be important for women with recurrent or metastatic endometrial cancer. The ideal timing of immunotherapy for women with endometrial cancer is an area of active ongoing study.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Despite universal agreement that antibiotic overprescribing is a problem, the practice continues to vex us. Antibiotic use—whether appropriate or not—has been linked to rising rates of antimicrobial resistance, disruption of the gut microbiome leading to Clostridium difficile infections (CDI), allergic reactions, and increased health care costs (see Table 1).^1-6 And yet, clinicians continue to overprescribe this class of medication.

A 2016 report from the CDC estimates that at least 30% of antibiotics prescribed in US outpatient settings are unnecessary.⁷ Another report cites a slightly higher figure across a variety of health care settings.⁸ Pair these findings with the fact that there are currently few new drugs in development to target resistant bacteria, and you have the potential for a postantibiotic era in which common infections could become lethal.⁷

In 2003, the CDC launched its “Get Smart: Know When Antibiotics Work” program (now known as “Be Antibiotics Aware”), focused on decreasing inappropriate antibiotic use in the outpatient setting.⁹ In 2015, the White House released the National Action Plan for Combating Antibiotic-Resistant Bacteria, with a goal of decreasing inappropriate outpatient antibiotic use by 50% and inappropriate inpatient use by 20% by 2020.¹⁰ And, on an international level, the World Health Organization (WHO) in 2015 developed a five-year strategic framework for implementing its Global Action Plan on Antimicrobial Resistance.¹¹

Family practitioners are on the front lines of this battle. Here’s what we can do now.

WHEN AND WHERE ARE ANTIBIOTICS MOST OFTEN INAPPROPRIATELY PRESCRIBED?

The diagnosis leading to the most frequent inappropriate prescribing of antibiotics is acute respiratory tract infection (ARTI), which includes bronchitis, otitis media, pharyngitis, sinusitis, tonsillitis, the common cold, and pneumonia. Up to 40% of antibiotic prescriptions for these conditions are unnecessary.^8,12 Bronchitis is the most common ARTI diagnosis associated with inappropriate antibiotic prescriptions, while sinusitis, suppurative otitis media, and pharyngitis are the diagnoses associated with the lion’s share of all (appropriate and inappropriate) antibiotic prescriptions within the ARTI category.^8,9,12,13 Refer to national clinical guidelines, which delineate when antibiotic treatment is appropriate for these conditions.^14-16

With respect to setting, there are conflicting findings as to whether antibiotic prescribing differs in office-based versus emergency department (ED) settings.

• One study found a higher rate of antibiotic prescribing during ED visits than office visits (21% vs 9%), even though, between 2007 and 2009, more antibiotic prescriptions were written for adults in primary care offices than in either outpatient hospital clinics or EDs.¹⁷
• In a cross-sectional study using data from 2005 to 2010 National Ambulatory Medical Care Surveys (NAMCS) and National Hospital Ambulatory Medical Care Surveys (NHAMCS), more than half of patients with uncomplicated acute rhinosinu­sitis received a prescription for antibiotics, but there was no overall difference in antibiotic prescriptions between primary care and ED presentation.¹⁸
• A retrospective analysis found that between 2006 and 2010, outpatient hospital practices (56%) and community-practice offices (60%) prescribed more antibiotics for ARTIs than EDs did (51%).¹²

STICK TO NARROW-SPECTRUM AGENTS WHEN POSSIBLE

Using broad-spectrum antibiotics, such as quinolones or imipenem, firstline, contributes more to the problem of antibiotic resistance than does prescribing narrow-spectrum antibiotics such as amoxicillin, cephalexin, or trimethoprim-sulfamethoxazole.⁷ Yet between 2007 and 2009, broad-spectrum agents were prescribed for 61% of outpatient adult visits in which patients received an antibiotic prescription.¹⁷ Quinolones (25%), macrolides (20%), and aminopenicillins (12%) were most commonly prescribed, and antibiotic prescriptions were most often written for respiratory conditions, such as bronchitis, for which we now know antibiotics are rarely indicated.¹⁷

Between 2006 and 2008, pediatric patients who received antibiotic prescriptions were given broad-spectrum agents 50% of the time, of which macrolides were the class most commonly prescribed.¹³

More recently, researchers examined the frequency with which clinicians prescribe narrow-spectrum, firstline antibiotics for otitis media, sinusitis, and pharyngitis using 2010 to 2011 NAMCS/NHAMCS data. They found that providers used firstline agents recommended by professional guidelines 52% of the time, although it was estimated that they would have been appropriate in 80% of cases; pediatric patients were more likely to receive appropriate firstline antibiotics than adult patients.¹⁹ Macrolides, especially azithromycin, were the most common non-firstline antibiotics prescribed.^19,20 The bottom line is that when antibiotics are indicated for upper respiratory infections (otitis media, sinusitis, and pharyngitis), clinicians should prescribe a narrow-spectrum antibiotic first.

ANTIBIOTIC OVERPRESCIBING AFFECTS THE GUT AND BEYOND

The human intestinal microbiome is composed of a diverse array of bacteria, viruses, and parasites.²¹ The main functions of the gut microbiome include interacting with the immune system and participating in biochemical reactions in the gut, such as absorption of fat-soluble vitamins and the production of vitamin K.

As we know, antibiotics decrease the diversity of gut bacteria, which, in turn, can cause less efficient nutrient extraction, as well as vulnerability to enteric infections.²¹ It is well known, for example, that the bacterial gut microbiome can either inhibit or promote diarrheal illnesses such as those caused by CDI. CDI is now the most common health care-related infection, accounting for about a half-million health care facility infections per year.²² It extends hospital stays an average of almost 10 days and is estimated to cost the health care system $6.3 billion annually.²³

Antibiotics can also eliminate antibiotic-susceptible organisms, allowing resistant organisms to proliferate.⁴ They also promote the transmission of genes for antibiotic resistance between gut bacteria.⁴

Beyond the gut

Less well known is that gut bacteria can promote or inhibit extraintestinal infections.

Gut bacteria and HIV. In early HIV infections, for example, gut populations of Lactobacillus and Bifidobacteria are reduced, and the gut barrier becomes compromised.²⁴ Increasing translocation of bacterial products is associated with HIV disease progression. Preservation of Lactobacillus populations in the gut is associated with markers predictive of better HIV outcomes, including a higher CD4 count, a lower viral load, and less evidence of gut microbial translocation.²⁴ This underscores the importance of maintaining healthy gut flora in patients with HIV, using such steps as avoiding unnecessary antibiotics.

Gut bacteria and stress, depression. Antibiotics directly induce the expression of key genes that affect the stress response.²⁵ While causative studies are lacking, there is a growing body of evidence suggesting that the gut microbiome is involved in two-way communication with the brain and can affect, and be affected by, stress and depression.^21,26-30 Diseases and conditions that seem to have a putative connection to a disordered microbiome (dysbiosis) include depression, anxiety, Crohn disease, type 2 diabetes, and obesity. (For a discussion of the relationship between the gut microbiome and diabetes, see Endocrine Consult: The Gut Microbiome in Type 2 Diabetes.)

Gut bacteria and childhood obesity. Repeated use of broader-spectrum antibiotics in children younger than 24 months of age increases the risk for childhood obesity.^1,6 One theory for the association is that the effects of broad-spectrum antibiotics on the intestinal flora of young children may alter long-term energy homeostasis, resulting in a higher risk for obesity.¹

Gut bacteria and asthma. Studies demonstrate differences in the gut microbiomes of asthmatic and nonasthmatic patients. These differences affect the activities of helper T-cell subsets (Th1 and Th2), which in turn affect the development of immune tolerance.³¹

Although additional studies are needed to confirm these findings, the evidence collected thus far should make us all pause before prescribing drugs that can alter our microbiome in complex and only partially understood ways.

WHAT CAN WE DO RIGHT NOW?

The issues created by the inappropriate prescribing of antibiotics have been known for decades, and multiple attempts have been made to find solutions and implement change. Although some small successes have occurred, little overall progress has been made in reducing antibiotic prescribing in the general population. A historical review of why clinicians prescribe antibiotics inappropriately and the interventions that have successfully reduced this prescribing may prove valuable as we continue to look for new, effective answers.

Why do we overprescribe antibiotics? A 2015 systematic literature review found that patient demand, pharmaceutical company marketing activities, limited up-to-date information sources, and fear of losing patients are major reasons providers cite for prescribing antibiotics.³²

In a separate study that explored antibiotic prescribing habits for acute bronchitis, clinicians cited “patient demand” as the major reason for prescribing antibiotics. Respondents also reported that “other physicians were responsible for inappropriate antibiotic prescribing.”³³

Strategies that work

Some early intervention programs directed at reducing antibiotic prescribing demonstrated success (see Table 2).^34-36

One example comes from a 1996-1998 study of four primary care practices.³⁴ Researchers evaluated the impact of a multidimensional intervention effort targeted at clinicians and patients and aimed at lowering the use of antimicrobial agents for acute uncomplicated bronchitis in adults. It incorporated multiple elements, including office-based and household patient educational materials and a clinician intervention involving education, practice profiling, and academic detailing. Clinicians in this program reduced their rates of antibiotic prescribing for uncomplicated bronchitis from 74% to 48%.³⁴

Employing EMRs. A more recent study focused on use of electronic medical rec­ords (EMRs) and communications to modify clinician antibiotic prescribing.³⁵ By sending clinicians monthly emails comparing their prescribing patterns to those of peers and “typical top performers,” inappropriate antibiotic prescriptions for ARTIs went from 19.9% to 3.7%.³⁵

In another effort, the same researchers modified providers’ EMRs to detect when potentially inappropriate antibiotics were prescribed. The system then prompted the clinician to provide an “antibiotic justification note,” which remained visible in the patient’s chart. This approach, which encouraged providers to follow prescribing guidelines by capitalizing on their concerns about their reputations, produced a 77% reduction in antibiotic prescribing.³⁵

Focusing on the public. Studies have also examined the effectiveness of educating the public about when antibiotics are not likely to be helpful and of the harms of unnecessary antibiotics.

Studies conducted in Tennessee and Wisconsin that combined prescriber and community education about unnecessary antibiotics for children found that the intervention reduced antibiotic prescribing in both locations by about 19%, compared with about a 9% reduction in the control groups.^36,37

DOES PRESCRIBING ANTIBIOTICS AFFECT PATIENT SATISFACTION?

The results are mixed as to whether prescribing antibiotics affects patient satisfaction. Two studies in the early 2000s found that both patients and parents reported higher satisfaction with clinicians who explained why antibiotics were not indicated versus those who simply prescribed them—and that such explanations do not need to take a lot of time (see Table 3 for patient care tips).^37,38

A more recent study found that higher antibiotic prescribing practices in Britain were associated with modestly higher patient satisfaction ratings.³⁹ The authors of this study noted, however, that reduced antibiotic prescribing may be a proxy for other practice patterns that affected satisfaction ratings.

REDUCING ANTIBIOTIC PRESCRIBING REDUCES RESISTANCE

There is also strong evidence that when clinicians decrease antibiotic prescribing, antimicrobial resistance follows suit. One of the earlier landmark studies to demonstrate this was a Finnish study published in 1997.⁴⁰ The authors found that a reduction of macrolide antibiotic consumption in Finland led to a reduction in streptococci macrolide resistance from 16.5% to 8.6%.⁴⁰

Multiple studies have since demonstrated similar results for both respiratory and urinary tract infections.^41,42 A 2017 meta-analysis of 32 studies found that antibiotic stewardship programs reduced the incidence of infections and colonization with multidrug-resistant Gram-negative bacteria (by 51%), extended-spectrum beta-lactamase–producing Gram-negative bacteria (48%), and methicillin-resistant Staphylococcus aureus (37%). There was also a reduction in the incidence of CDI (32%).⁴³

Despite universal agreement that antibiotic overprescribing is a problem, the practice continues to vex us. Antibiotic use—whether appropriate or not—has been linked to rising rates of antimicrobial resistance, disruption of the gut microbiome leading to Clostridium difficile infections (CDI), allergic reactions, and increased health care costs (see Table 1).^1-6 And yet, clinicians continue to overprescribe this class of medication.

A 2016 report from the CDC estimates that at least 30% of antibiotics prescribed in US outpatient settings are unnecessary.⁷ Another report cites a slightly higher figure across a variety of health care settings.⁸ Pair these findings with the fact that there are currently few new drugs in development to target resistant bacteria, and you have the potential for a postantibiotic era in which common infections could become lethal.⁷

In 2003, the CDC launched its “Get Smart: Know When Antibiotics Work” program (now known as “Be Antibiotics Aware”), focused on decreasing inappropriate antibiotic use in the outpatient setting.⁹ In 2015, the White House released the National Action Plan for Combating Antibiotic-Resistant Bacteria, with a goal of decreasing inappropriate outpatient antibiotic use by 50% and inappropriate inpatient use by 20% by 2020.¹⁰ And, on an international level, the World Health Organization (WHO) in 2015 developed a five-year strategic framework for implementing its Global Action Plan on Antimicrobial Resistance.¹¹

Family practitioners are on the front lines of this battle. Here’s what we can do now.

WHEN AND WHERE ARE ANTIBIOTICS MOST OFTEN INAPPROPRIATELY PRESCRIBED?

The diagnosis leading to the most frequent inappropriate prescribing of antibiotics is acute respiratory tract infection (ARTI), which includes bronchitis, otitis media, pharyngitis, sinusitis, tonsillitis, the common cold, and pneumonia. Up to 40% of antibiotic prescriptions for these conditions are unnecessary.^8,12 Bronchitis is the most common ARTI diagnosis associated with inappropriate antibiotic prescriptions, while sinusitis, suppurative otitis media, and pharyngitis are the diagnoses associated with the lion’s share of all (appropriate and inappropriate) antibiotic prescriptions within the ARTI category.^8,9,12,13 Refer to national clinical guidelines, which delineate when antibiotic treatment is appropriate for these conditions.^14-16

With respect to setting, there are conflicting findings as to whether antibiotic prescribing differs in office-based versus emergency department (ED) settings.

• One study found a higher rate of antibiotic prescribing during ED visits than office visits (21% vs 9%), even though, between 2007 and 2009, more antibiotic prescriptions were written for adults in primary care offices than in either outpatient hospital clinics or EDs.¹⁷
• In a cross-sectional study using data from 2005 to 2010 National Ambulatory Medical Care Surveys (NAMCS) and National Hospital Ambulatory Medical Care Surveys (NHAMCS), more than half of patients with uncomplicated acute rhinosinu­sitis received a prescription for antibiotics, but there was no overall difference in antibiotic prescriptions between primary care and ED presentation.¹⁸
• A retrospective analysis found that between 2006 and 2010, outpatient hospital practices (56%) and community-practice offices (60%) prescribed more antibiotics for ARTIs than EDs did (51%).¹²

STICK TO NARROW-SPECTRUM AGENTS WHEN POSSIBLE

Using broad-spectrum antibiotics, such as quinolones or imipenem, firstline, contributes more to the problem of antibiotic resistance than does prescribing narrow-spectrum antibiotics such as amoxicillin, cephalexin, or trimethoprim-sulfamethoxazole.⁷ Yet between 2007 and 2009, broad-spectrum agents were prescribed for 61% of outpatient adult visits in which patients received an antibiotic prescription.¹⁷ Quinolones (25%), macrolides (20%), and aminopenicillins (12%) were most commonly prescribed, and antibiotic prescriptions were most often written for respiratory conditions, such as bronchitis, for which we now know antibiotics are rarely indicated.¹⁷

Between 2006 and 2008, pediatric patients who received antibiotic prescriptions were given broad-spectrum agents 50% of the time, of which macrolides were the class most commonly prescribed.¹³

More recently, researchers examined the frequency with which clinicians prescribe narrow-spectrum, firstline antibiotics for otitis media, sinusitis, and pharyngitis using 2010 to 2011 NAMCS/NHAMCS data. They found that providers used firstline agents recommended by professional guidelines 52% of the time, although it was estimated that they would have been appropriate in 80% of cases; pediatric patients were more likely to receive appropriate firstline antibiotics than adult patients.¹⁹ Macrolides, especially azithromycin, were the most common non-firstline antibiotics prescribed.^19,20 The bottom line is that when antibiotics are indicated for upper respiratory infections (otitis media, sinusitis, and pharyngitis), clinicians should prescribe a narrow-spectrum antibiotic first.

ANTIBIOTIC OVERPRESCIBING AFFECTS THE GUT AND BEYOND

The human intestinal microbiome is composed of a diverse array of bacteria, viruses, and parasites.²¹ The main functions of the gut microbiome include interacting with the immune system and participating in biochemical reactions in the gut, such as absorption of fat-soluble vitamins and the production of vitamin K.

As we know, antibiotics decrease the diversity of gut bacteria, which, in turn, can cause less efficient nutrient extraction, as well as vulnerability to enteric infections.²¹ It is well known, for example, that the bacterial gut microbiome can either inhibit or promote diarrheal illnesses such as those caused by CDI. CDI is now the most common health care-related infection, accounting for about a half-million health care facility infections per year.²² It extends hospital stays an average of almost 10 days and is estimated to cost the health care system $6.3 billion annually.²³

Antibiotics can also eliminate antibiotic-susceptible organisms, allowing resistant organisms to proliferate.⁴ They also promote the transmission of genes for antibiotic resistance between gut bacteria.⁴

Beyond the gut

Less well known is that gut bacteria can promote or inhibit extraintestinal infections.

Gut bacteria and HIV. In early HIV infections, for example, gut populations of Lactobacillus and Bifidobacteria are reduced, and the gut barrier becomes compromised.²⁴ Increasing translocation of bacterial products is associated with HIV disease progression. Preservation of Lactobacillus populations in the gut is associated with markers predictive of better HIV outcomes, including a higher CD4 count, a lower viral load, and less evidence of gut microbial translocation.²⁴ This underscores the importance of maintaining healthy gut flora in patients with HIV, using such steps as avoiding unnecessary antibiotics.

Gut bacteria and stress, depression. Antibiotics directly induce the expression of key genes that affect the stress response.²⁵ While causative studies are lacking, there is a growing body of evidence suggesting that the gut microbiome is involved in two-way communication with the brain and can affect, and be affected by, stress and depression.^21,26-30 Diseases and conditions that seem to have a putative connection to a disordered microbiome (dysbiosis) include depression, anxiety, Crohn disease, type 2 diabetes, and obesity. (For a discussion of the relationship between the gut microbiome and diabetes, see Endocrine Consult: The Gut Microbiome in Type 2 Diabetes.)

Gut bacteria and childhood obesity. Repeated use of broader-spectrum antibiotics in children younger than 24 months of age increases the risk for childhood obesity.^1,6 One theory for the association is that the effects of broad-spectrum antibiotics on the intestinal flora of young children may alter long-term energy homeostasis, resulting in a higher risk for obesity.¹

Gut bacteria and asthma. Studies demonstrate differences in the gut microbiomes of asthmatic and nonasthmatic patients. These differences affect the activities of helper T-cell subsets (Th1 and Th2), which in turn affect the development of immune tolerance.³¹

Although additional studies are needed to confirm these findings, the evidence collected thus far should make us all pause before prescribing drugs that can alter our microbiome in complex and only partially understood ways.

WHAT CAN WE DO RIGHT NOW?

The issues created by the inappropriate prescribing of antibiotics have been known for decades, and multiple attempts have been made to find solutions and implement change. Although some small successes have occurred, little overall progress has been made in reducing antibiotic prescribing in the general population. A historical review of why clinicians prescribe antibiotics inappropriately and the interventions that have successfully reduced this prescribing may prove valuable as we continue to look for new, effective answers.

Why do we overprescribe antibiotics? A 2015 systematic literature review found that patient demand, pharmaceutical company marketing activities, limited up-to-date information sources, and fear of losing patients are major reasons providers cite for prescribing antibiotics.³²

In a separate study that explored antibiotic prescribing habits for acute bronchitis, clinicians cited “patient demand” as the major reason for prescribing antibiotics. Respondents also reported that “other physicians were responsible for inappropriate antibiotic prescribing.”³³

Strategies that work

Some early intervention programs directed at reducing antibiotic prescribing demonstrated success (see Table 2).^34-36

One example comes from a 1996-1998 study of four primary care practices.³⁴ Researchers evaluated the impact of a multidimensional intervention effort targeted at clinicians and patients and aimed at lowering the use of antimicrobial agents for acute uncomplicated bronchitis in adults. It incorporated multiple elements, including office-based and household patient educational materials and a clinician intervention involving education, practice profiling, and academic detailing. Clinicians in this program reduced their rates of antibiotic prescribing for uncomplicated bronchitis from 74% to 48%.³⁴

Employing EMRs. A more recent study focused on use of electronic medical rec­ords (EMRs) and communications to modify clinician antibiotic prescribing.³⁵ By sending clinicians monthly emails comparing their prescribing patterns to those of peers and “typical top performers,” inappropriate antibiotic prescriptions for ARTIs went from 19.9% to 3.7%.³⁵

In another effort, the same researchers modified providers’ EMRs to detect when potentially inappropriate antibiotics were prescribed. The system then prompted the clinician to provide an “antibiotic justification note,” which remained visible in the patient’s chart. This approach, which encouraged providers to follow prescribing guidelines by capitalizing on their concerns about their reputations, produced a 77% reduction in antibiotic prescribing.³⁵

Focusing on the public. Studies have also examined the effectiveness of educating the public about when antibiotics are not likely to be helpful and of the harms of unnecessary antibiotics.

Studies conducted in Tennessee and Wisconsin that combined prescriber and community education about unnecessary antibiotics for children found that the intervention reduced antibiotic prescribing in both locations by about 19%, compared with about a 9% reduction in the control groups.^36,37

DOES PRESCRIBING ANTIBIOTICS AFFECT PATIENT SATISFACTION?

The results are mixed as to whether prescribing antibiotics affects patient satisfaction. Two studies in the early 2000s found that both patients and parents reported higher satisfaction with clinicians who explained why antibiotics were not indicated versus those who simply prescribed them—and that such explanations do not need to take a lot of time (see Table 3 for patient care tips).^37,38

A more recent study found that higher antibiotic prescribing practices in Britain were associated with modestly higher patient satisfaction ratings.³⁹ The authors of this study noted, however, that reduced antibiotic prescribing may be a proxy for other practice patterns that affected satisfaction ratings.

REDUCING ANTIBIOTIC PRESCRIBING REDUCES RESISTANCE

There is also strong evidence that when clinicians decrease antibiotic prescribing, antimicrobial resistance follows suit. One of the earlier landmark studies to demonstrate this was a Finnish study published in 1997.⁴⁰ The authors found that a reduction of macrolide antibiotic consumption in Finland led to a reduction in streptococci macrolide resistance from 16.5% to 8.6%.⁴⁰

Multiple studies have since demonstrated similar results for both respiratory and urinary tract infections.^41,42 A 2017 meta-analysis of 32 studies found that antibiotic stewardship programs reduced the incidence of infections and colonization with multidrug-resistant Gram-negative bacteria (by 51%), extended-spectrum beta-lactamase–producing Gram-negative bacteria (48%), and methicillin-resistant Staphylococcus aureus (37%). There was also a reduction in the incidence of CDI (32%).⁴³

Despite universal agreement that antibiotic overprescribing is a problem, the practice continues to vex us. Antibiotic use—whether appropriate or not—has been linked to rising rates of antimicrobial resistance, disruption of the gut microbiome leading to Clostridium difficile infections (CDI), allergic reactions, and increased health care costs (see Table 1).^1-6 And yet, clinicians continue to overprescribe this class of medication.

A 2016 report from the CDC estimates that at least 30% of antibiotics prescribed in US outpatient settings are unnecessary.⁷ Another report cites a slightly higher figure across a variety of health care settings.⁸ Pair these findings with the fact that there are currently few new drugs in development to target resistant bacteria, and you have the potential for a postantibiotic era in which common infections could become lethal.⁷

In 2003, the CDC launched its “Get Smart: Know When Antibiotics Work” program (now known as “Be Antibiotics Aware”), focused on decreasing inappropriate antibiotic use in the outpatient setting.⁹ In 2015, the White House released the National Action Plan for Combating Antibiotic-Resistant Bacteria, with a goal of decreasing inappropriate outpatient antibiotic use by 50% and inappropriate inpatient use by 20% by 2020.¹⁰ And, on an international level, the World Health Organization (WHO) in 2015 developed a five-year strategic framework for implementing its Global Action Plan on Antimicrobial Resistance.¹¹

Family practitioners are on the front lines of this battle. Here’s what we can do now.

WHEN AND WHERE ARE ANTIBIOTICS MOST OFTEN INAPPROPRIATELY PRESCRIBED?

The diagnosis leading to the most frequent inappropriate prescribing of antibiotics is acute respiratory tract infection (ARTI), which includes bronchitis, otitis media, pharyngitis, sinusitis, tonsillitis, the common cold, and pneumonia. Up to 40% of antibiotic prescriptions for these conditions are unnecessary.^8,12 Bronchitis is the most common ARTI diagnosis associated with inappropriate antibiotic prescriptions, while sinusitis, suppurative otitis media, and pharyngitis are the diagnoses associated with the lion’s share of all (appropriate and inappropriate) antibiotic prescriptions within the ARTI category.^8,9,12,13 Refer to national clinical guidelines, which delineate when antibiotic treatment is appropriate for these conditions.^14-16

With respect to setting, there are conflicting findings as to whether antibiotic prescribing differs in office-based versus emergency department (ED) settings.

• One study found a higher rate of antibiotic prescribing during ED visits than office visits (21% vs 9%), even though, between 2007 and 2009, more antibiotic prescriptions were written for adults in primary care offices than in either outpatient hospital clinics or EDs.¹⁷
• In a cross-sectional study using data from 2005 to 2010 National Ambulatory Medical Care Surveys (NAMCS) and National Hospital Ambulatory Medical Care Surveys (NHAMCS), more than half of patients with uncomplicated acute rhinosinu­sitis received a prescription for antibiotics, but there was no overall difference in antibiotic prescriptions between primary care and ED presentation.¹⁸
• A retrospective analysis found that between 2006 and 2010, outpatient hospital practices (56%) and community-practice offices (60%) prescribed more antibiotics for ARTIs than EDs did (51%).¹²

STICK TO NARROW-SPECTRUM AGENTS WHEN POSSIBLE

Using broad-spectrum antibiotics, such as quinolones or imipenem, firstline, contributes more to the problem of antibiotic resistance than does prescribing narrow-spectrum antibiotics such as amoxicillin, cephalexin, or trimethoprim-sulfamethoxazole.⁷ Yet between 2007 and 2009, broad-spectrum agents were prescribed for 61% of outpatient adult visits in which patients received an antibiotic prescription.¹⁷ Quinolones (25%), macrolides (20%), and aminopenicillins (12%) were most commonly prescribed, and antibiotic prescriptions were most often written for respiratory conditions, such as bronchitis, for which we now know antibiotics are rarely indicated.¹⁷

Between 2006 and 2008, pediatric patients who received antibiotic prescriptions were given broad-spectrum agents 50% of the time, of which macrolides were the class most commonly prescribed.¹³

More recently, researchers examined the frequency with which clinicians prescribe narrow-spectrum, firstline antibiotics for otitis media, sinusitis, and pharyngitis using 2010 to 2011 NAMCS/NHAMCS data. They found that providers used firstline agents recommended by professional guidelines 52% of the time, although it was estimated that they would have been appropriate in 80% of cases; pediatric patients were more likely to receive appropriate firstline antibiotics than adult patients.¹⁹ Macrolides, especially azithromycin, were the most common non-firstline antibiotics prescribed.^19,20 The bottom line is that when antibiotics are indicated for upper respiratory infections (otitis media, sinusitis, and pharyngitis), clinicians should prescribe a narrow-spectrum antibiotic first.

ANTIBIOTIC OVERPRESCIBING AFFECTS THE GUT AND BEYOND

The human intestinal microbiome is composed of a diverse array of bacteria, viruses, and parasites.²¹ The main functions of the gut microbiome include interacting with the immune system and participating in biochemical reactions in the gut, such as absorption of fat-soluble vitamins and the production of vitamin K.

As we know, antibiotics decrease the diversity of gut bacteria, which, in turn, can cause less efficient nutrient extraction, as well as vulnerability to enteric infections.²¹ It is well known, for example, that the bacterial gut microbiome can either inhibit or promote diarrheal illnesses such as those caused by CDI. CDI is now the most common health care-related infection, accounting for about a half-million health care facility infections per year.²² It extends hospital stays an average of almost 10 days and is estimated to cost the health care system $6.3 billion annually.²³

Antibiotics can also eliminate antibiotic-susceptible organisms, allowing resistant organisms to proliferate.⁴ They also promote the transmission of genes for antibiotic resistance between gut bacteria.⁴

Beyond the gut

Less well known is that gut bacteria can promote or inhibit extraintestinal infections.

Gut bacteria and HIV. In early HIV infections, for example, gut populations of Lactobacillus and Bifidobacteria are reduced, and the gut barrier becomes compromised.²⁴ Increasing translocation of bacterial products is associated with HIV disease progression. Preservation of Lactobacillus populations in the gut is associated with markers predictive of better HIV outcomes, including a higher CD4 count, a lower viral load, and less evidence of gut microbial translocation.²⁴ This underscores the importance of maintaining healthy gut flora in patients with HIV, using such steps as avoiding unnecessary antibiotics.

Gut bacteria and stress, depression. Antibiotics directly induce the expression of key genes that affect the stress response.²⁵ While causative studies are lacking, there is a growing body of evidence suggesting that the gut microbiome is involved in two-way communication with the brain and can affect, and be affected by, stress and depression.^21,26-30 Diseases and conditions that seem to have a putative connection to a disordered microbiome (dysbiosis) include depression, anxiety, Crohn disease, type 2 diabetes, and obesity. (For a discussion of the relationship between the gut microbiome and diabetes, see Endocrine Consult: The Gut Microbiome in Type 2 Diabetes.)

Gut bacteria and childhood obesity. Repeated use of broader-spectrum antibiotics in children younger than 24 months of age increases the risk for childhood obesity.^1,6 One theory for the association is that the effects of broad-spectrum antibiotics on the intestinal flora of young children may alter long-term energy homeostasis, resulting in a higher risk for obesity.¹

Gut bacteria and asthma. Studies demonstrate differences in the gut microbiomes of asthmatic and nonasthmatic patients. These differences affect the activities of helper T-cell subsets (Th1 and Th2), which in turn affect the development of immune tolerance.³¹

Although additional studies are needed to confirm these findings, the evidence collected thus far should make us all pause before prescribing drugs that can alter our microbiome in complex and only partially understood ways.

WHAT CAN WE DO RIGHT NOW?

The issues created by the inappropriate prescribing of antibiotics have been known for decades, and multiple attempts have been made to find solutions and implement change. Although some small successes have occurred, little overall progress has been made in reducing antibiotic prescribing in the general population. A historical review of why clinicians prescribe antibiotics inappropriately and the interventions that have successfully reduced this prescribing may prove valuable as we continue to look for new, effective answers.

Why do we overprescribe antibiotics? A 2015 systematic literature review found that patient demand, pharmaceutical company marketing activities, limited up-to-date information sources, and fear of losing patients are major reasons providers cite for prescribing antibiotics.³²

In a separate study that explored antibiotic prescribing habits for acute bronchitis, clinicians cited “patient demand” as the major reason for prescribing antibiotics. Respondents also reported that “other physicians were responsible for inappropriate antibiotic prescribing.”³³

Strategies that work

Some early intervention programs directed at reducing antibiotic prescribing demonstrated success (see Table 2).^34-36

One example comes from a 1996-1998 study of four primary care practices.³⁴ Researchers evaluated the impact of a multidimensional intervention effort targeted at clinicians and patients and aimed at lowering the use of antimicrobial agents for acute uncomplicated bronchitis in adults. It incorporated multiple elements, including office-based and household patient educational materials and a clinician intervention involving education, practice profiling, and academic detailing. Clinicians in this program reduced their rates of antibiotic prescribing for uncomplicated bronchitis from 74% to 48%.³⁴

Employing EMRs. A more recent study focused on use of electronic medical rec­ords (EMRs) and communications to modify clinician antibiotic prescribing.³⁵ By sending clinicians monthly emails comparing their prescribing patterns to those of peers and “typical top performers,” inappropriate antibiotic prescriptions for ARTIs went from 19.9% to 3.7%.³⁵

In another effort, the same researchers modified providers’ EMRs to detect when potentially inappropriate antibiotics were prescribed. The system then prompted the clinician to provide an “antibiotic justification note,” which remained visible in the patient’s chart. This approach, which encouraged providers to follow prescribing guidelines by capitalizing on their concerns about their reputations, produced a 77% reduction in antibiotic prescribing.³⁵

Focusing on the public. Studies have also examined the effectiveness of educating the public about when antibiotics are not likely to be helpful and of the harms of unnecessary antibiotics.

Studies conducted in Tennessee and Wisconsin that combined prescriber and community education about unnecessary antibiotics for children found that the intervention reduced antibiotic prescribing in both locations by about 19%, compared with about a 9% reduction in the control groups.^36,37

DOES PRESCRIBING ANTIBIOTICS AFFECT PATIENT SATISFACTION?

The results are mixed as to whether prescribing antibiotics affects patient satisfaction. Two studies in the early 2000s found that both patients and parents reported higher satisfaction with clinicians who explained why antibiotics were not indicated versus those who simply prescribed them—and that such explanations do not need to take a lot of time (see Table 3 for patient care tips).^37,38

A more recent study found that higher antibiotic prescribing practices in Britain were associated with modestly higher patient satisfaction ratings.³⁹ The authors of this study noted, however, that reduced antibiotic prescribing may be a proxy for other practice patterns that affected satisfaction ratings.

REDUCING ANTIBIOTIC PRESCRIBING REDUCES RESISTANCE

There is also strong evidence that when clinicians decrease antibiotic prescribing, antimicrobial resistance follows suit. One of the earlier landmark studies to demonstrate this was a Finnish study published in 1997.⁴⁰ The authors found that a reduction of macrolide antibiotic consumption in Finland led to a reduction in streptococci macrolide resistance from 16.5% to 8.6%.⁴⁰

Multiple studies have since demonstrated similar results for both respiratory and urinary tract infections.^41,42 A 2017 meta-analysis of 32 studies found that antibiotic stewardship programs reduced the incidence of infections and colonization with multidrug-resistant Gram-negative bacteria (by 51%), extended-spectrum beta-lactamase–producing Gram-negative bacteria (48%), and methicillin-resistant Staphylococcus aureus (37%). There was also a reduction in the incidence of CDI (32%).⁴³

From the University of North Dakota School of Medicine & Health Sciences, Fargo, ND.

Abstract

• Objective: To review the management of community-acquired pneumonia (CAP) in adults.
• Methods: Review of the literature.
• Results: Approximately 4 to 5 million cases of CAP are diagnosed in the United States annually, accounting for significant morbidity and mortality. While numerous studies have previously shown pneumococcus to be the most common causative pathogen, the 2015 EPIC study found that in nearly two-thirds of patients with CAP who required hospitalization, no pathogen was detected. Symptoms and signs of respiratory tract infection are useful in helping to diagnose pneumonia; however, they are less sensitive than chest imaging studies. Laboratory tests used in diagnosing pneumonia include sputum Gram stain and culture, blood culture, urinary antigen, polymerase chain reaction, and biologic markers. In empiric treatment of CAP, both the typical and atypical pathogens should be targeted. Influenza vaccine and pneumococcal polysaccharide and conjugate vaccines should be administered as recommended by the CDC to reduce risk of CAP.
• Conclusion: CAP is a common illness with high rates of morbidity and mortality. Treatment is for the most part empirical; diagnostic testing can be used to identify the causative organism and guide pathogen-specific therapy.

Key words: community-acquired pneumonia; adults; management; vaccines.

Despite advances in medical science, pneumonia remains a major cause of morbidity and mortality. In 2014, 50,620 patients in the United States died from the disease [1]. Pneumonia can be classified as community-acquired, hospital-acquired, or ventilator-associated. Another category, healthcare-associated pneumonia, was included in an earlier American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) guideline but was removed from the 2016 guideline because there was no clear evidence that patients diagnosed with healthcare-associated pneumonia were at higher risk for harboring multidrug-resistant pathogens [2]. In this article, we review the epidemiology, microbiology, predisposing factors, diagnosis, treatment, and prevention of community-acquired pneumonia (CAP).

Definition and Epidemiology

CAP is defined as an acute infection of the lungs that develops in patients who have not been hospitalized recently and have not had regular exposure to the health care system [3]. A previously ambulatory patient who is diagnosed with pneumonia within 48 hours after admission also meets the criteria for CAP. Approximately 4 to 5 million cases of CAP are diagnosed in the United States annually [4]. About 25% of CAP patients require hospitalization, and about 5% to 10% of these patients are admitted to the intensive care unit (ICU) [5]. In-hospital mortality is considerable (~10% in population-based studies) [6] and 30-day mortality was found to be as high as 23% in a review by File and Marrie [7]. CAP also confers a high risk of long-term morbidity and mortality compared with the general population who have never had CAP, irrespective of age [8].

Causative Organisms

Numerous microorganisms can cause CAP. Common causes and less common causes are delineated in Table 1. 

Predisposing Factors

Most people diagnosed with CAP have one or more predisposing factors [12,13] (Table 2). 

Clinical Signs and Symptoms

Symptoms of CAP include fever, chills, rigors, fatigue, anorexia, diaphoresis, dyspnea, cough (with or without sputum production), and pleuritic chest pain. There is no individual symptom or cluster of symptoms that can absolutely differentiate pneumonia from other acute respiratory diseases, including upper and lower respiratory infections. However, if a patient presents with the constellation of symptoms of fever ≥ 100⁰F (37.8⁰C), productive cough, and tachycardia, it is more suggestive of pneumonia [14]. Abnormal vital signs include fever, hypothermia, tachypnea, tachycardia, and oxygen desaturation. Auscultation of the chest reveals crackles or other adventitious breath sounds. Elderly patients with pneumonia report a significantly lower number of both respiratory and nonrespiratory symptoms compared with younger patients. Clinicians should be aware of this phenomenon so it does not lead to delayed diagnosis and treatment [15].

Imaging Evaluation

The presence of a pulmonary consolidation or an infiltrate on chest radiograph is required to diagnose CAP, and a chest radiograph should be obtained when CAP is suspected [16]. It should be noted that there is no pattern of radiographic abnormalities reliable enough to differentiate infectious pneumonia from noninfectious causes [17].

There are case reports and case series demonstrating false-negative plain chest radiographs existing in dehydrated patients [18] or in neutropenic state. However, animal studies have shown that dogs challenged with pneumococcus showed abnormal pulmonary shadow, suggestive of pneumonia, regardless of hydration status [19]. There is also no reliable scientific evidence to support the notion that severe neutropenia can cause false-negative radiographs because of the inability to develop an acute inflammatory reaction in the lungs [20].

A chest CT scan is more sensitive than a plain chest radiograph in detecting pneumonia. Therefore, a chest CT should be performed in a patient with negative plain chest radiograph when pneumonia is still highly suspected [21]. A chest CT scan is also more sensitive in detecting cavitation, adenopathy, interstitial disease and empyema. It also has the advantage of better defining anatomical changes than plain films [22].

Because improvement of pulmonary opacities in patients with CAP lags behind clinical improvement, repeating chest imaging studies is not recommended in patients who demonstrate clinical improvement. Sometimes clearing of pulmonary infiltrate or consolidation can take 6 weeks or longer [23].

Laboratory Evaluation

Generally the etiologic agent of CAP cannot be determined solely on the basis of clinical signs and symptoms or imaging studies. Although routine microbiological testing for patients suspicious for CAP is not necessary for empirical treatment, by determining the etiologic agent of the pneumonia, a clinician will be able to narrow the antibiotics from a broad-spectrum empirical regimen to specific pathogen-directed therapy. Determination of certain etiologic agents causing the pneumonia can have important public health implications (eg, Mycobacterium tuberculosis and influenza virus) [24].

Sputum Gram Stain and Culture

Sputum Gram stain is an inexpensive test that may identify pathogens that cause CAP (eg, S. pneumonia and Haemophilus influenzae). A quality specimen is required. A sputum sample must contain > 25 neutrophils and < 10 squamous epithelial cells/low power field on Gram stain to be considered suitable for culture.

The sensitivity and specificity of sputum Gram stain and culture are highly variable in different clinical settings (eg, outpatient setting, nursing home, ICU). Reed et al’s meta-analysis of patients diagnosed with CAP in the United States showed the sensitivity and specificity of sputum Gram stain (compared with sputum culture) ranged from 15% to 100% and 11% to 100%, respectively [24]. In cases of proven bacteremic pneumococcal pneumonia, positive cultures from sputum samples were positive less than 50% of the time [25].

For patients who cannot provide sputum samples or are intubated, a deep-suction aspirate or bronchoalveolar lavage through a bronchoscopic procedure might be necessary to obtain pulmonary secretion for Gram stain and culture. Besides bacterial culture, sputum samples can also be sent for fungal and mycobacterial cultures and acid-fast stain if deemed clinically necessary.

Blood Culture

Because the positivity rate of blood culture in patients who are suspected to have pneumonia but not exposed to antimicrobial agents is disappointingly low (5%–14%), blood cultures are no longer recommended in patients hospitalized for CAP. Another reason for not recommending blood culture is positive culture rarely leads to changes in antibiotic regimen in patients without underlying diseases [26]. However, high-risk patients, including patients with severe CAP or in immunocompromised patients (eg, patients with neutropenia, asplenia or complement deficiencies) should have a blood culture done [24].

A multinational study published in 2008 examined 125 patients with pneumococcal bacteremic CAP versus 1847 patients with non-bacteremic CAP [27]. Analysis of the data demonstrated no association of pneumococcal bacteremic CAP and time to clinical stability, length of hospital stay, all-cause mortality or CAP-related mortality. The authors concluded that pneumococcal bacteremia does not increase the risk of poor outcomes in patients with CAP compared to non-bacteremic patients, and the presence of pneumococcal bacteremia should not deter de-escalation of therapy in clinically stable patients.

Urinary Antigen Tests

Urinary antigen tests may assist clinicians in narrowing antibiotic therapy when test results are positive. There are 2 U.S. Food and Drug Administration–approved tests available to clinicians for detecting pneumococcal and Legionella antigen in urine. The test for Legionella pneumophila detects disease due to serogroup 1 only, which accounts for 80% of community-acquired Legionnaires disease. The sensitivity and specificity of the Legionella urine antigen test are 90% and 99%, respectively. The pneumococcal urine antigen test is less sensitive and specific than the Legionella urine antigen test (sensitivity 80% and specificity > 90%) [28,29].

Advantages of the urinary antigen tests are that they are easily performed, results are available in less than an hour if done in-house, and results are not affected by prior exposure to antibiotics. However, the tests do not meet Clinical Laboratory Improvements Amendments criteria for waiver and must be performed by a technician in the laboratory.

Polymerase Chain Reaction

There are several FDA-approved polymerase chain reaction (PCR) tests commercially available to assist clinicians in diagnosing pneumonia. PCR test of nasopharyngeal swabs for diagnosing influenza have become standard in many medical U.S. facilities. The great advantage of using PCR to diagnose influenza is its high sensitivity and specificity and rapid turnaround time. PCR can also be used to detect Legionella species, S. pneumonia, Mycoplasma pneumoniae, Chlamydophila pneumonia and mycobacterial species [24].

One limitation of using PCR tests on respiratory specimens is that specimens can be contaminated with oral or upper airway flora, so the results must be interpreted with caution, bearing in mind that some of the pathogens isolated may be colonizers of the oral or upper airway flora [30].

Biologic Markers

Two biologic markers—procalcitonin and C-reactive protein (CRP)—can be used in conjunction with history, physical examination, laboratory tests and imaging studies to assist in the diagnosis and treatment of CAP [24]. Procalcitonin is a peptide precursor of the hormone calcitonin that is released by parenchymal cells into the bloodstream resulting in increased serum level in patients with bacterial infections. In contrast, there is no remarkable proclacitonin level increase with viral or noninfectious inflammation. The reference value of procalcitonin in the blood of an adult individual without infection or inflammation is < 0.15 ng/mL. In the blood, procalcitonin has a half-life of 25 to 30 hours. The quantitative immunoluminometric method (LUMI test, Brahms PCT, Berlin, Germany ) is the preferred test to use because of its high sensitivity [31].

A 2012 Cochrane meta-analysis that involved 4221 patients with acute respiratory infections (with half of the patients diagnosed with CAP) from 14 prospective trials found the use of procalcitonin test for antibiotic use significantly decreased median antibiotic exposure from 8 to 4 days without an increase in treatment failure, mortality rates in any clinical setting (eg, outpatient clinic, emergency room), or length of hospitalization [32]. A prospective study conducted in France on 100 ICU patients showed that increased procalcitonin from day 1 to day 3 has a poor prognosis factor for severe CAP whereas decreasing procalcitonin levels is associated with a favorable outcome [33].

CRP is an acute phase protein produced by the liver. CRP level in the blood increases in response to acute infection or inflammation. Use of CRP in assisting diagnosis and guiding treatment of CAP is more limited in part due to its poor specificity. A prospective study conducted on 168 consecutive patients presented with cough showed that a CRP > 40 mg/L had a sensitivity and specificity of 70% and 90%, respectively [34].

Treatment

Site of Care Decision

For patients with CAP, the clinician must decide whether the patient will be treated in an outpatient or inpatient setting, and for those in the inpatient setting, whether they can safely be treated on the general medical ward or should be the ICU. Two common scoring systems that can be used to aid the clinician in determining severity of the infection and guiding site-of-care decisions are the Pneumonia Severity Index (PSI) and CURB-65 scores.

The PSI score uses 20 different parameters, including comorbidities, laboratory parameters and radiographic findings to stratify patients into 5 mortality risk classes [35]. On the basis of associated mortality rates, it has been suggested that risk class I and II patients should be treated as outpatients, risk class III patients should be treated in an observation unit or with a short hospitalization, and risk class IV and V patients should be treated as inpatients [35].

The CURB-65 method of risk stratification is based on 5 clinical parameters: confusion, urea level, respiratory rate, systolic blood pressure and age ≥ 65 (Table 3) [36].

Patients with CURB-65 scores of 4 or 5 are considered to have severe pneumonia and admission to the ICU should be considered. Aside from the CURB-65 score, anyone requiring vasopressor support or mechanical ventilation merits admission to the ICU [16]. IDSA/ATS guidelines also recommend the use of “minor criteria” for making ICU admission decisions; these include respiratory rate ≥ 30 breaths / minute, PaO2 fraction ≤ 250, multilobar infiltrates, confusion, blood urea nitrogen ≥ 20 mg/dL, leukopenia, thrombocytopenia, hypothermia and hypotension [16]. These factors are associated with increased mortality due to CAP and admission to an ICU is indicated if 3 of the minor criteria for severe CAP are present.

Similar to CURB-65, another clinical calculator that can be used for assessing severity of CAP is SMART-COP [39]. This scoring system uses 8 weighted criteria to predict which patients will require intensive respiratory or vasopressor support. SMART-COP has a sensitivity of 79% and specificity 64% in predicting ICU admission, whereas CURB-65 had a pooled sensitivity of 57.2% and specificity of 77.2% [40].

Antibiotic Therapy

Antibiotics are the mainstay of treatment for CAP, with the majority of patients with CAP treated empirically taking into account the site of care, likely pathogen, and antimicrobial resistance issues. Patients with pneumonia who are treated as outpatients usually respond well to empiric antibiotic treatment and a causative pathogen is not usually sought. Patients who are hospitalized for treatment of CAP usually receive empiric antibiotic on admission. Once the etiology has been determined by microbiologic or serologic means, antimicrobial therapy should be adjusted accordingly. As noted previously, a CDC study found that the burden of viral etiologies was higher than previously thought, with rhinovirus and influenza accounting for 15% of cases and S. pneumoniae for only 5% [9]. This study highlighted the fact that despite advances in molecular techniques, most patients with pneumonia have no pathogen identified [9]. Given the lack of discernable pathogens in the majority of cases, unless a nonbacterial etiology is found patients should continue to be treated with antibiotics.

Outpatients without comorbidities or risk factors for drug-resistant S. pneumoniae (Table 4)

As previously mentioned, antibiotic therapy is typically empiric; neither clinical features nor radiographic features are sufficient to include or exclude infectious etiologies. Epidemiologic risk factors should be considered and, in certain cases, expanded antimicrobial coverage to include those entities; for example, treatment of anaerobes in the setting of lung abscess and antipseudomonal antibiotics for patients with bronchiectasis.

Of concern in the treatment of CAP is the increased prevalence of antimicrobial resistance among S. pneumoniae. The IDSA guidelines report that drug-resistant S. pneumoniae is more common in persons aged < 2 or > 65 years, and those with ß-lactam therapy within the previous 3 months, alcoholism, medical comorbidities, immunosuppressive illness or therapy, or exposure to a child who attends a day care center [16].

S. aureus should be considered during influenza outbreaks, with either vancomycin or linezolid being the recommended agents in the setting of methicillin-resistant S. aureus (MRSA). In a study comparing vancomycin versus linezolid for nosocomial pneumonia, the all-cause 60-day mortality was similar for both agents [41]. Datpomycin is another agent used against MRSA; however, its use in the setting of pneumonia is not indicated as daptomycin binds to surfactant, yielding it ineffective in the treatment of pneumonia [42]. Ceftaroline is a newer cephalosporin with activity against MRSA; its role in treatment of community-acquired MRSA pneumonia has not been fully elucidated, but it appears to be a useful agent for this indication [43,44].

Antibiotic Therapy for Selected Pathogens

S. pneumoniae

Patients with pneumococcal pneumonia who have penicillin-susceptible strains can be treated with intravenous penicillin (2 or 3 million units every 4 hours) or ceftriaxone. Once a patient meets criteria of stability, they can then be transitioned to oral penicillin, amoxicillin, or clarithromycin. Those with strains with reduced susceptibility can still be treated with penicillin but at a higher dose (4 million units IV every 4 hours) or a third-generation cephalosporin. Those whose pneumococcal pneumonia is complicated by bacteremia will benefit from dual therapy if severely ill, requiring ICU monitoring. Those not severely ill can be treated with monotherapy [46].

S. aureus

S. aureus is more commonly associated with hospital-acquired pneumonia but may also be seen during the influenza season and in those with severe necrotizing CAP. Both linezolid and vancomycin can be used to treat MRSA CAP. As noted above, ceftaroline has activity against MRSA and is approved for treatment of CAP, but is not approved by the FDA for MRSA CAP treatment. Similarly, tigecycline is approved for CAP and has activity against MRSA, but is not approved for MRSA CAP. Moreover, the FDA has warned of increased risk of death with tigecycline and has a black box warning to that effect [47].

Legionella

Treatment of legionellosis can be achieved with tetra­cyclines, macrolides, or fluoroquinolones. For nonimmunosuppressed patients with mild pneumonia, any of the listed antibiotics is considered appropriate. However, patients with severe infection or those with immunosuppression should be treated with either levofloxacin or azithromycin for 7 to 10 days [48].

C. pneumoniae

As with other atypical organisms, C. pneumoniae can be treated with doxycycline, a macrolide, or respiratory fluoroquinolones. However, length of therapy varies by regimen used; whereas treating with doxycycline 100 mg twice daily generally requires 14–21 days, moxifloxacin 400 mg daily only requires 10 days [49].

M. pneumoniae

As with C. pneumoniae, length of therapy of M. pneumoniae varies by antimicrobial used. Shortest courses are seen with the use of macrolides for 5 days, whereas 14 days is considered standard for doxycycline or a respiratory fluoroquinolone [50]. It should be noted that there has been increasingly documented resistance to macrolides, with known resistance of 8.2% in the United States [51].

Duration of Treatment

Most patients with CAP respond within 72 hours to appropriate therapy. IDSA/ATS guidelines recommend that patients be treated for a minimum of 5 days, and before discontinuing antibiotics patients should be afebrile a minimum of 48-72 hours and be clinically stable (Table 6) [16]. 

Hospitalized patients do not need to be monitored for an additional day once they have reached clinical stability (Table 6), are able to maintain oral intake, and have normal mentation, provided that other comorbidities are stable and social needs have been met [16]. Patients discharged from the hospital with instability have higher risk of readmission or death [55].

Transition to Oral Therapy

IDSA/ATS guidelines [16] recommend that patients should be transitioned from IV to oral antibiotics when they are improving clinically, have stable vital signs, and are able to ingest food/fluids and medications.

Management of Nonresponders

Although the majority of patients respond to antibiotics within 72 hours, treatment failure occurs in up to 15% of patients [45]. Nonresponding pneumonia is generally seen in 2 patterns: worsening of clinical status despite empiric antibiotics OR delay in achieving clinical stability as defined in Table 5 after 72 hours of treatment [13]. Risk factors associated with nonresponding pneumonia [56] are:

• Radiographic: multilobar infiltrates, pleural effusion, cavitation
• Bacteriologic: MRSA, gram-negative or Legionella pneumonia
• Severity index: PSI > 90
• Pharmacologic: incorrect antibiotic choice based on susceptibility

Patients with acute deterioration of clinical status will prompt transfer to a higher level of care and may require mechanical ventilator support. In those with delay in achieving clinical stability, question centers on whether the same antibiotics can be continued while doing further radiographic/microbiologic workup and/or changing antibiotics.

History should be reviewed with particular attention to exposures, travel history, and microbiologic and radiographic data. Clinicians should recall that viral causes account for up to 20% of pneumonias and there are also noninfectious causes that can mimic pyogenic infections [57]. If adequate initial cultures were not obtained, they should be obtained; however, care must be taken in reviewing new sets of cultures while on antibiotics as they may reveal colonization selected out by antibiotics and not a true pathogen. If repeat evaluation is unrevealing, then further evaluation with CT scan and bronchoscopy with bronchoalveolar lavage and biopsy is warranted. CT scans can show pleural effusions, bronchial obstructions or pattern suggestive of cryptogenic pneumonia. A bronchoscopy might yield a microbiologic diagnosis and with biopsy can also evaluate for noninfectious causes.

As with other infections, if escalation of antibiotics is undertaken, clinicians should be mindful to ensure that efforts are being made to elucidate the reason for nonresponse. To simply broaden antimicrobial therapy without attempts at establishing a microbiologic or radiographic cause for nonresponse may lead to inappropriate treatment recurrence of infection. Aside from patients who have bacteremic pneumococcal pneumonia in an ICU setting, there are no published reports pointing to superiority of combination antibiotics [46].

Other Treatment

Because of the inflammatory response associated with pneumonia, several agents have been evaluated as adjunctive treatment of pneumonia to decrease this inflammatory state; namely, steroids, macrolide antibiotics and statins. To date, only the use of steroids (methylprednisolone 0.5 mg/kg every 12 hours for 5 days) in those with severe CAP and high initial anti-inflammatory response (CRP > 150) was shown to decrease treatment failure, decreased risk of ARDS, possibly reduce length of stay, duration of intravenous antibiotics and clinical stability, without effect on mortality or adverse side effects [58,59].

Other adjunctive methods have not been found to have significant impact [16].

Prevention of Pneumonia

Prevention of pneumococcal pneumonia is twofold: prevention of infection caused by S. pneumoniae and prevention of influenza infection. As influenza infection is a risk factor for bacterial infection, specifically with S. pneumoniae, influenza vaccination can prevent bacterial pneumonia [60]. In their most recent recommendations, the CDC continues to recommend routine influenza vaccination for all persons aged greater than 6 months, unless otherwise contraindicated [61].

There are 2 vaccines for prevention of pneumococcal disease: the pneumococcal polysaccharide vaccine (PPSV23) and a conjugate vaccine (PCV13). Following vaccination with PPSV23, 80% of adults develop antibodies against at least 18 of the 23 serotypes [62]. Despite this response, PPSV23 is reported to be protective against invasive pneumococcal infection; yet there is no consensus regarding PPSV23 leading to decreased rates of pneumonia [63]. On the other hand, PCV13 vaccination was associated with prevention of both invasive disease and community-acquired pneumonia in adults 65 years or older [64]. The CDC recommends that all children aged 2 or under receive PCV13, whereas those aged 65 or older should receive PCV13 followed by a dose of PPSV23 [65]. The dose of PPSV23 should be given ≥1 year following the dose of PCV13 [66].Persons < 65 years of age with immunocompromising and certain other conditions should also receive vaccination [67] (Table 7). Full details, many scenarios, and timing of vaccinations can be found at www.cdc.gov/vaccines/schedules/downloads/adult/adult-schedule.pdf.

Cigarette smoking increases the risk of respiratory infections as evidenced by smokers accounting for almost half of all patients with invasive pneumococcal disease [11]. As this is a modifiable risk factor it should be a goal of a comprehensive approach towards prevention of pneumonia.

Summary

CAP remains a leading cause of hospitalization and death in the 21st century. Traditionally, pneumococcus has been considered the major pathogen causing CAP; however, the 2015 EPIC study found that in only 5% of patients diagnosed with CAP was S. pneumoniae detected. Despite the new findings, it is still recommended that empiric treatment for CAP target common typical bacteria (pneumococcus, H. influenzae, Moraxella catarrhalis) and atypical bacteria (M. pneumonia, C. pneumoniae, L. pneumophila).

Because diagnosing pneumonia through history and clinical examination is less than 50% sensitive, a chest imaging study (a plain chest radiograph or a chest CT scan) is usually required to make the diagnosis. Laboratory tests, such as sputum Gram stain/culture, blood culture, urinary antigen tests, PCR test, procalcitonin, and CRP are important adjunctive diagnostic modalities to assist in the diagnosis and management of CAP. However, no single test is sensitive and specific enough to be a stand-alone test. They should be used in conjunction with history, physical examination, and imaging studies. Because vaccination (PPSV23, PCV13, and influenza vaccine) remains the most effective tool in preventing the development of CAP, clinicians, should strive for 100% vaccination rates in appropriate persons.

Corresponding author: Tze Shein Lo, MD, University of North Dakota, 1919 Elm Street, Fargo, ND 58102, [email protected].

Financial disclosures: None.

Author contributions: drafting of article, PM, TSL; critical revision of the article, PM, TSL.

From the University of North Dakota School of Medicine & Health Sciences, Fargo, ND.

Abstract

• Objective: To review the management of community-acquired pneumonia (CAP) in adults.
• Methods: Review of the literature.
• Results: Approximately 4 to 5 million cases of CAP are diagnosed in the United States annually, accounting for significant morbidity and mortality. While numerous studies have previously shown pneumococcus to be the most common causative pathogen, the 2015 EPIC study found that in nearly two-thirds of patients with CAP who required hospitalization, no pathogen was detected. Symptoms and signs of respiratory tract infection are useful in helping to diagnose pneumonia; however, they are less sensitive than chest imaging studies. Laboratory tests used in diagnosing pneumonia include sputum Gram stain and culture, blood culture, urinary antigen, polymerase chain reaction, and biologic markers. In empiric treatment of CAP, both the typical and atypical pathogens should be targeted. Influenza vaccine and pneumococcal polysaccharide and conjugate vaccines should be administered as recommended by the CDC to reduce risk of CAP.
• Conclusion: CAP is a common illness with high rates of morbidity and mortality. Treatment is for the most part empirical; diagnostic testing can be used to identify the causative organism and guide pathogen-specific therapy.

Key words: community-acquired pneumonia; adults; management; vaccines.

Despite advances in medical science, pneumonia remains a major cause of morbidity and mortality. In 2014, 50,620 patients in the United States died from the disease [1]. Pneumonia can be classified as community-acquired, hospital-acquired, or ventilator-associated. Another category, healthcare-associated pneumonia, was included in an earlier American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) guideline but was removed from the 2016 guideline because there was no clear evidence that patients diagnosed with healthcare-associated pneumonia were at higher risk for harboring multidrug-resistant pathogens [2]. In this article, we review the epidemiology, microbiology, predisposing factors, diagnosis, treatment, and prevention of community-acquired pneumonia (CAP).

Definition and Epidemiology

CAP is defined as an acute infection of the lungs that develops in patients who have not been hospitalized recently and have not had regular exposure to the health care system [3]. A previously ambulatory patient who is diagnosed with pneumonia within 48 hours after admission also meets the criteria for CAP. Approximately 4 to 5 million cases of CAP are diagnosed in the United States annually [4]. About 25% of CAP patients require hospitalization, and about 5% to 10% of these patients are admitted to the intensive care unit (ICU) [5]. In-hospital mortality is considerable (~10% in population-based studies) [6] and 30-day mortality was found to be as high as 23% in a review by File and Marrie [7]. CAP also confers a high risk of long-term morbidity and mortality compared with the general population who have never had CAP, irrespective of age [8].

Causative Organisms

Numerous microorganisms can cause CAP. Common causes and less common causes are delineated in Table 1. 

Predisposing Factors

Most people diagnosed with CAP have one or more predisposing factors [12,13] (Table 2). 

Clinical Signs and Symptoms

Symptoms of CAP include fever, chills, rigors, fatigue, anorexia, diaphoresis, dyspnea, cough (with or without sputum production), and pleuritic chest pain. There is no individual symptom or cluster of symptoms that can absolutely differentiate pneumonia from other acute respiratory diseases, including upper and lower respiratory infections. However, if a patient presents with the constellation of symptoms of fever ≥ 100⁰F (37.8⁰C), productive cough, and tachycardia, it is more suggestive of pneumonia [14]. Abnormal vital signs include fever, hypothermia, tachypnea, tachycardia, and oxygen desaturation. Auscultation of the chest reveals crackles or other adventitious breath sounds. Elderly patients with pneumonia report a significantly lower number of both respiratory and nonrespiratory symptoms compared with younger patients. Clinicians should be aware of this phenomenon so it does not lead to delayed diagnosis and treatment [15].

Imaging Evaluation

The presence of a pulmonary consolidation or an infiltrate on chest radiograph is required to diagnose CAP, and a chest radiograph should be obtained when CAP is suspected [16]. It should be noted that there is no pattern of radiographic abnormalities reliable enough to differentiate infectious pneumonia from noninfectious causes [17].

There are case reports and case series demonstrating false-negative plain chest radiographs existing in dehydrated patients [18] or in neutropenic state. However, animal studies have shown that dogs challenged with pneumococcus showed abnormal pulmonary shadow, suggestive of pneumonia, regardless of hydration status [19]. There is also no reliable scientific evidence to support the notion that severe neutropenia can cause false-negative radiographs because of the inability to develop an acute inflammatory reaction in the lungs [20].

A chest CT scan is more sensitive than a plain chest radiograph in detecting pneumonia. Therefore, a chest CT should be performed in a patient with negative plain chest radiograph when pneumonia is still highly suspected [21]. A chest CT scan is also more sensitive in detecting cavitation, adenopathy, interstitial disease and empyema. It also has the advantage of better defining anatomical changes than plain films [22].

Because improvement of pulmonary opacities in patients with CAP lags behind clinical improvement, repeating chest imaging studies is not recommended in patients who demonstrate clinical improvement. Sometimes clearing of pulmonary infiltrate or consolidation can take 6 weeks or longer [23].

Laboratory Evaluation

Generally the etiologic agent of CAP cannot be determined solely on the basis of clinical signs and symptoms or imaging studies. Although routine microbiological testing for patients suspicious for CAP is not necessary for empirical treatment, by determining the etiologic agent of the pneumonia, a clinician will be able to narrow the antibiotics from a broad-spectrum empirical regimen to specific pathogen-directed therapy. Determination of certain etiologic agents causing the pneumonia can have important public health implications (eg, Mycobacterium tuberculosis and influenza virus) [24].

Sputum Gram Stain and Culture

Sputum Gram stain is an inexpensive test that may identify pathogens that cause CAP (eg, S. pneumonia and Haemophilus influenzae). A quality specimen is required. A sputum sample must contain > 25 neutrophils and < 10 squamous epithelial cells/low power field on Gram stain to be considered suitable for culture.

The sensitivity and specificity of sputum Gram stain and culture are highly variable in different clinical settings (eg, outpatient setting, nursing home, ICU). Reed et al’s meta-analysis of patients diagnosed with CAP in the United States showed the sensitivity and specificity of sputum Gram stain (compared with sputum culture) ranged from 15% to 100% and 11% to 100%, respectively [24]. In cases of proven bacteremic pneumococcal pneumonia, positive cultures from sputum samples were positive less than 50% of the time [25].

For patients who cannot provide sputum samples or are intubated, a deep-suction aspirate or bronchoalveolar lavage through a bronchoscopic procedure might be necessary to obtain pulmonary secretion for Gram stain and culture. Besides bacterial culture, sputum samples can also be sent for fungal and mycobacterial cultures and acid-fast stain if deemed clinically necessary.

Blood Culture

Because the positivity rate of blood culture in patients who are suspected to have pneumonia but not exposed to antimicrobial agents is disappointingly low (5%–14%), blood cultures are no longer recommended in patients hospitalized for CAP. Another reason for not recommending blood culture is positive culture rarely leads to changes in antibiotic regimen in patients without underlying diseases [26]. However, high-risk patients, including patients with severe CAP or in immunocompromised patients (eg, patients with neutropenia, asplenia or complement deficiencies) should have a blood culture done [24].

A multinational study published in 2008 examined 125 patients with pneumococcal bacteremic CAP versus 1847 patients with non-bacteremic CAP [27]. Analysis of the data demonstrated no association of pneumococcal bacteremic CAP and time to clinical stability, length of hospital stay, all-cause mortality or CAP-related mortality. The authors concluded that pneumococcal bacteremia does not increase the risk of poor outcomes in patients with CAP compared to non-bacteremic patients, and the presence of pneumococcal bacteremia should not deter de-escalation of therapy in clinically stable patients.

Urinary Antigen Tests

Urinary antigen tests may assist clinicians in narrowing antibiotic therapy when test results are positive. There are 2 U.S. Food and Drug Administration–approved tests available to clinicians for detecting pneumococcal and Legionella antigen in urine. The test for Legionella pneumophila detects disease due to serogroup 1 only, which accounts for 80% of community-acquired Legionnaires disease. The sensitivity and specificity of the Legionella urine antigen test are 90% and 99%, respectively. The pneumococcal urine antigen test is less sensitive and specific than the Legionella urine antigen test (sensitivity 80% and specificity > 90%) [28,29].

Advantages of the urinary antigen tests are that they are easily performed, results are available in less than an hour if done in-house, and results are not affected by prior exposure to antibiotics. However, the tests do not meet Clinical Laboratory Improvements Amendments criteria for waiver and must be performed by a technician in the laboratory.

Polymerase Chain Reaction

There are several FDA-approved polymerase chain reaction (PCR) tests commercially available to assist clinicians in diagnosing pneumonia. PCR test of nasopharyngeal swabs for diagnosing influenza have become standard in many medical U.S. facilities. The great advantage of using PCR to diagnose influenza is its high sensitivity and specificity and rapid turnaround time. PCR can also be used to detect Legionella species, S. pneumonia, Mycoplasma pneumoniae, Chlamydophila pneumonia and mycobacterial species [24].

One limitation of using PCR tests on respiratory specimens is that specimens can be contaminated with oral or upper airway flora, so the results must be interpreted with caution, bearing in mind that some of the pathogens isolated may be colonizers of the oral or upper airway flora [30].

Biologic Markers

Two biologic markers—procalcitonin and C-reactive protein (CRP)—can be used in conjunction with history, physical examination, laboratory tests and imaging studies to assist in the diagnosis and treatment of CAP [24]. Procalcitonin is a peptide precursor of the hormone calcitonin that is released by parenchymal cells into the bloodstream resulting in increased serum level in patients with bacterial infections. In contrast, there is no remarkable proclacitonin level increase with viral or noninfectious inflammation. The reference value of procalcitonin in the blood of an adult individual without infection or inflammation is < 0.15 ng/mL. In the blood, procalcitonin has a half-life of 25 to 30 hours. The quantitative immunoluminometric method (LUMI test, Brahms PCT, Berlin, Germany ) is the preferred test to use because of its high sensitivity [31].

A 2012 Cochrane meta-analysis that involved 4221 patients with acute respiratory infections (with half of the patients diagnosed with CAP) from 14 prospective trials found the use of procalcitonin test for antibiotic use significantly decreased median antibiotic exposure from 8 to 4 days without an increase in treatment failure, mortality rates in any clinical setting (eg, outpatient clinic, emergency room), or length of hospitalization [32]. A prospective study conducted in France on 100 ICU patients showed that increased procalcitonin from day 1 to day 3 has a poor prognosis factor for severe CAP whereas decreasing procalcitonin levels is associated with a favorable outcome [33].

CRP is an acute phase protein produced by the liver. CRP level in the blood increases in response to acute infection or inflammation. Use of CRP in assisting diagnosis and guiding treatment of CAP is more limited in part due to its poor specificity. A prospective study conducted on 168 consecutive patients presented with cough showed that a CRP > 40 mg/L had a sensitivity and specificity of 70% and 90%, respectively [34].

Treatment

Site of Care Decision

For patients with CAP, the clinician must decide whether the patient will be treated in an outpatient or inpatient setting, and for those in the inpatient setting, whether they can safely be treated on the general medical ward or should be the ICU. Two common scoring systems that can be used to aid the clinician in determining severity of the infection and guiding site-of-care decisions are the Pneumonia Severity Index (PSI) and CURB-65 scores.

The PSI score uses 20 different parameters, including comorbidities, laboratory parameters and radiographic findings to stratify patients into 5 mortality risk classes [35]. On the basis of associated mortality rates, it has been suggested that risk class I and II patients should be treated as outpatients, risk class III patients should be treated in an observation unit or with a short hospitalization, and risk class IV and V patients should be treated as inpatients [35].

The CURB-65 method of risk stratification is based on 5 clinical parameters: confusion, urea level, respiratory rate, systolic blood pressure and age ≥ 65 (Table 3) [36].

Patients with CURB-65 scores of 4 or 5 are considered to have severe pneumonia and admission to the ICU should be considered. Aside from the CURB-65 score, anyone requiring vasopressor support or mechanical ventilation merits admission to the ICU [16]. IDSA/ATS guidelines also recommend the use of “minor criteria” for making ICU admission decisions; these include respiratory rate ≥ 30 breaths / minute, PaO2 fraction ≤ 250, multilobar infiltrates, confusion, blood urea nitrogen ≥ 20 mg/dL, leukopenia, thrombocytopenia, hypothermia and hypotension [16]. These factors are associated with increased mortality due to CAP and admission to an ICU is indicated if 3 of the minor criteria for severe CAP are present.

Similar to CURB-65, another clinical calculator that can be used for assessing severity of CAP is SMART-COP [39]. This scoring system uses 8 weighted criteria to predict which patients will require intensive respiratory or vasopressor support. SMART-COP has a sensitivity of 79% and specificity 64% in predicting ICU admission, whereas CURB-65 had a pooled sensitivity of 57.2% and specificity of 77.2% [40].

Antibiotic Therapy

Antibiotics are the mainstay of treatment for CAP, with the majority of patients with CAP treated empirically taking into account the site of care, likely pathogen, and antimicrobial resistance issues. Patients with pneumonia who are treated as outpatients usually respond well to empiric antibiotic treatment and a causative pathogen is not usually sought. Patients who are hospitalized for treatment of CAP usually receive empiric antibiotic on admission. Once the etiology has been determined by microbiologic or serologic means, antimicrobial therapy should be adjusted accordingly. As noted previously, a CDC study found that the burden of viral etiologies was higher than previously thought, with rhinovirus and influenza accounting for 15% of cases and S. pneumoniae for only 5% [9]. This study highlighted the fact that despite advances in molecular techniques, most patients with pneumonia have no pathogen identified [9]. Given the lack of discernable pathogens in the majority of cases, unless a nonbacterial etiology is found patients should continue to be treated with antibiotics.

Outpatients without comorbidities or risk factors for drug-resistant S. pneumoniae (Table 4)

As previously mentioned, antibiotic therapy is typically empiric; neither clinical features nor radiographic features are sufficient to include or exclude infectious etiologies. Epidemiologic risk factors should be considered and, in certain cases, expanded antimicrobial coverage to include those entities; for example, treatment of anaerobes in the setting of lung abscess and antipseudomonal antibiotics for patients with bronchiectasis.

Of concern in the treatment of CAP is the increased prevalence of antimicrobial resistance among S. pneumoniae. The IDSA guidelines report that drug-resistant S. pneumoniae is more common in persons aged < 2 or > 65 years, and those with ß-lactam therapy within the previous 3 months, alcoholism, medical comorbidities, immunosuppressive illness or therapy, or exposure to a child who attends a day care center [16].

S. aureus should be considered during influenza outbreaks, with either vancomycin or linezolid being the recommended agents in the setting of methicillin-resistant S. aureus (MRSA). In a study comparing vancomycin versus linezolid for nosocomial pneumonia, the all-cause 60-day mortality was similar for both agents [41]. Datpomycin is another agent used against MRSA; however, its use in the setting of pneumonia is not indicated as daptomycin binds to surfactant, yielding it ineffective in the treatment of pneumonia [42]. Ceftaroline is a newer cephalosporin with activity against MRSA; its role in treatment of community-acquired MRSA pneumonia has not been fully elucidated, but it appears to be a useful agent for this indication [43,44].

Antibiotic Therapy for Selected Pathogens

S. pneumoniae

Patients with pneumococcal pneumonia who have penicillin-susceptible strains can be treated with intravenous penicillin (2 or 3 million units every 4 hours) or ceftriaxone. Once a patient meets criteria of stability, they can then be transitioned to oral penicillin, amoxicillin, or clarithromycin. Those with strains with reduced susceptibility can still be treated with penicillin but at a higher dose (4 million units IV every 4 hours) or a third-generation cephalosporin. Those whose pneumococcal pneumonia is complicated by bacteremia will benefit from dual therapy if severely ill, requiring ICU monitoring. Those not severely ill can be treated with monotherapy [46].

S. aureus

S. aureus is more commonly associated with hospital-acquired pneumonia but may also be seen during the influenza season and in those with severe necrotizing CAP. Both linezolid and vancomycin can be used to treat MRSA CAP. As noted above, ceftaroline has activity against MRSA and is approved for treatment of CAP, but is not approved by the FDA for MRSA CAP treatment. Similarly, tigecycline is approved for CAP and has activity against MRSA, but is not approved for MRSA CAP. Moreover, the FDA has warned of increased risk of death with tigecycline and has a black box warning to that effect [47].

Legionella

Treatment of legionellosis can be achieved with tetra­cyclines, macrolides, or fluoroquinolones. For nonimmunosuppressed patients with mild pneumonia, any of the listed antibiotics is considered appropriate. However, patients with severe infection or those with immunosuppression should be treated with either levofloxacin or azithromycin for 7 to 10 days [48].

C. pneumoniae

As with other atypical organisms, C. pneumoniae can be treated with doxycycline, a macrolide, or respiratory fluoroquinolones. However, length of therapy varies by regimen used; whereas treating with doxycycline 100 mg twice daily generally requires 14–21 days, moxifloxacin 400 mg daily only requires 10 days [49].

M. pneumoniae

As with C. pneumoniae, length of therapy of M. pneumoniae varies by antimicrobial used. Shortest courses are seen with the use of macrolides for 5 days, whereas 14 days is considered standard for doxycycline or a respiratory fluoroquinolone [50]. It should be noted that there has been increasingly documented resistance to macrolides, with known resistance of 8.2% in the United States [51].

Duration of Treatment

Most patients with CAP respond within 72 hours to appropriate therapy. IDSA/ATS guidelines recommend that patients be treated for a minimum of 5 days, and before discontinuing antibiotics patients should be afebrile a minimum of 48-72 hours and be clinically stable (Table 6) [16]. 

Hospitalized patients do not need to be monitored for an additional day once they have reached clinical stability (Table 6), are able to maintain oral intake, and have normal mentation, provided that other comorbidities are stable and social needs have been met [16]. Patients discharged from the hospital with instability have higher risk of readmission or death [55].

Transition to Oral Therapy

IDSA/ATS guidelines [16] recommend that patients should be transitioned from IV to oral antibiotics when they are improving clinically, have stable vital signs, and are able to ingest food/fluids and medications.

Management of Nonresponders

Although the majority of patients respond to antibiotics within 72 hours, treatment failure occurs in up to 15% of patients [45]. Nonresponding pneumonia is generally seen in 2 patterns: worsening of clinical status despite empiric antibiotics OR delay in achieving clinical stability as defined in Table 5 after 72 hours of treatment [13]. Risk factors associated with nonresponding pneumonia [56] are:

• Radiographic: multilobar infiltrates, pleural effusion, cavitation
• Bacteriologic: MRSA, gram-negative or Legionella pneumonia
• Severity index: PSI > 90
• Pharmacologic: incorrect antibiotic choice based on susceptibility

Patients with acute deterioration of clinical status will prompt transfer to a higher level of care and may require mechanical ventilator support. In those with delay in achieving clinical stability, question centers on whether the same antibiotics can be continued while doing further radiographic/microbiologic workup and/or changing antibiotics.

History should be reviewed with particular attention to exposures, travel history, and microbiologic and radiographic data. Clinicians should recall that viral causes account for up to 20% of pneumonias and there are also noninfectious causes that can mimic pyogenic infections [57]. If adequate initial cultures were not obtained, they should be obtained; however, care must be taken in reviewing new sets of cultures while on antibiotics as they may reveal colonization selected out by antibiotics and not a true pathogen. If repeat evaluation is unrevealing, then further evaluation with CT scan and bronchoscopy with bronchoalveolar lavage and biopsy is warranted. CT scans can show pleural effusions, bronchial obstructions or pattern suggestive of cryptogenic pneumonia. A bronchoscopy might yield a microbiologic diagnosis and with biopsy can also evaluate for noninfectious causes.

As with other infections, if escalation of antibiotics is undertaken, clinicians should be mindful to ensure that efforts are being made to elucidate the reason for nonresponse. To simply broaden antimicrobial therapy without attempts at establishing a microbiologic or radiographic cause for nonresponse may lead to inappropriate treatment recurrence of infection. Aside from patients who have bacteremic pneumococcal pneumonia in an ICU setting, there are no published reports pointing to superiority of combination antibiotics [46].

Other Treatment

Because of the inflammatory response associated with pneumonia, several agents have been evaluated as adjunctive treatment of pneumonia to decrease this inflammatory state; namely, steroids, macrolide antibiotics and statins. To date, only the use of steroids (methylprednisolone 0.5 mg/kg every 12 hours for 5 days) in those with severe CAP and high initial anti-inflammatory response (CRP > 150) was shown to decrease treatment failure, decreased risk of ARDS, possibly reduce length of stay, duration of intravenous antibiotics and clinical stability, without effect on mortality or adverse side effects [58,59].

Other adjunctive methods have not been found to have significant impact [16].

Prevention of Pneumonia

Prevention of pneumococcal pneumonia is twofold: prevention of infection caused by S. pneumoniae and prevention of influenza infection. As influenza infection is a risk factor for bacterial infection, specifically with S. pneumoniae, influenza vaccination can prevent bacterial pneumonia [60]. In their most recent recommendations, the CDC continues to recommend routine influenza vaccination for all persons aged greater than 6 months, unless otherwise contraindicated [61].

There are 2 vaccines for prevention of pneumococcal disease: the pneumococcal polysaccharide vaccine (PPSV23) and a conjugate vaccine (PCV13). Following vaccination with PPSV23, 80% of adults develop antibodies against at least 18 of the 23 serotypes [62]. Despite this response, PPSV23 is reported to be protective against invasive pneumococcal infection; yet there is no consensus regarding PPSV23 leading to decreased rates of pneumonia [63]. On the other hand, PCV13 vaccination was associated with prevention of both invasive disease and community-acquired pneumonia in adults 65 years or older [64]. The CDC recommends that all children aged 2 or under receive PCV13, whereas those aged 65 or older should receive PCV13 followed by a dose of PPSV23 [65]. The dose of PPSV23 should be given ≥1 year following the dose of PCV13 [66].Persons < 65 years of age with immunocompromising and certain other conditions should also receive vaccination [67] (Table 7). Full details, many scenarios, and timing of vaccinations can be found at www.cdc.gov/vaccines/schedules/downloads/adult/adult-schedule.pdf.

Cigarette smoking increases the risk of respiratory infections as evidenced by smokers accounting for almost half of all patients with invasive pneumococcal disease [11]. As this is a modifiable risk factor it should be a goal of a comprehensive approach towards prevention of pneumonia.

Summary

CAP remains a leading cause of hospitalization and death in the 21st century. Traditionally, pneumococcus has been considered the major pathogen causing CAP; however, the 2015 EPIC study found that in only 5% of patients diagnosed with CAP was S. pneumoniae detected. Despite the new findings, it is still recommended that empiric treatment for CAP target common typical bacteria (pneumococcus, H. influenzae, Moraxella catarrhalis) and atypical bacteria (M. pneumonia, C. pneumoniae, L. pneumophila).

Because diagnosing pneumonia through history and clinical examination is less than 50% sensitive, a chest imaging study (a plain chest radiograph or a chest CT scan) is usually required to make the diagnosis. Laboratory tests, such as sputum Gram stain/culture, blood culture, urinary antigen tests, PCR test, procalcitonin, and CRP are important adjunctive diagnostic modalities to assist in the diagnosis and management of CAP. However, no single test is sensitive and specific enough to be a stand-alone test. They should be used in conjunction with history, physical examination, and imaging studies. Because vaccination (PPSV23, PCV13, and influenza vaccine) remains the most effective tool in preventing the development of CAP, clinicians, should strive for 100% vaccination rates in appropriate persons.

Corresponding author: Tze Shein Lo, MD, University of North Dakota, 1919 Elm Street, Fargo, ND 58102, [email protected].

Financial disclosures: None.

Author contributions: drafting of article, PM, TSL; critical revision of the article, PM, TSL.

From the University of North Dakota School of Medicine & Health Sciences, Fargo, ND.

Abstract

• Objective: To review the management of community-acquired pneumonia (CAP) in adults.
• Methods: Review of the literature.
• Results: Approximately 4 to 5 million cases of CAP are diagnosed in the United States annually, accounting for significant morbidity and mortality. While numerous studies have previously shown pneumococcus to be the most common causative pathogen, the 2015 EPIC study found that in nearly two-thirds of patients with CAP who required hospitalization, no pathogen was detected. Symptoms and signs of respiratory tract infection are useful in helping to diagnose pneumonia; however, they are less sensitive than chest imaging studies. Laboratory tests used in diagnosing pneumonia include sputum Gram stain and culture, blood culture, urinary antigen, polymerase chain reaction, and biologic markers. In empiric treatment of CAP, both the typical and atypical pathogens should be targeted. Influenza vaccine and pneumococcal polysaccharide and conjugate vaccines should be administered as recommended by the CDC to reduce risk of CAP.
• Conclusion: CAP is a common illness with high rates of morbidity and mortality. Treatment is for the most part empirical; diagnostic testing can be used to identify the causative organism and guide pathogen-specific therapy.

Key words: community-acquired pneumonia; adults; management; vaccines.

Despite advances in medical science, pneumonia remains a major cause of morbidity and mortality. In 2014, 50,620 patients in the United States died from the disease [1]. Pneumonia can be classified as community-acquired, hospital-acquired, or ventilator-associated. Another category, healthcare-associated pneumonia, was included in an earlier American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) guideline but was removed from the 2016 guideline because there was no clear evidence that patients diagnosed with healthcare-associated pneumonia were at higher risk for harboring multidrug-resistant pathogens [2]. In this article, we review the epidemiology, microbiology, predisposing factors, diagnosis, treatment, and prevention of community-acquired pneumonia (CAP).

Definition and Epidemiology

CAP is defined as an acute infection of the lungs that develops in patients who have not been hospitalized recently and have not had regular exposure to the health care system [3]. A previously ambulatory patient who is diagnosed with pneumonia within 48 hours after admission also meets the criteria for CAP. Approximately 4 to 5 million cases of CAP are diagnosed in the United States annually [4]. About 25% of CAP patients require hospitalization, and about 5% to 10% of these patients are admitted to the intensive care unit (ICU) [5]. In-hospital mortality is considerable (~10% in population-based studies) [6] and 30-day mortality was found to be as high as 23% in a review by File and Marrie [7]. CAP also confers a high risk of long-term morbidity and mortality compared with the general population who have never had CAP, irrespective of age [8].

Causative Organisms

Numerous microorganisms can cause CAP. Common causes and less common causes are delineated in Table 1. 

Predisposing Factors

Most people diagnosed with CAP have one or more predisposing factors [12,13] (Table 2). 

Clinical Signs and Symptoms

Symptoms of CAP include fever, chills, rigors, fatigue, anorexia, diaphoresis, dyspnea, cough (with or without sputum production), and pleuritic chest pain. There is no individual symptom or cluster of symptoms that can absolutely differentiate pneumonia from other acute respiratory diseases, including upper and lower respiratory infections. However, if a patient presents with the constellation of symptoms of fever ≥ 100⁰F (37.8⁰C), productive cough, and tachycardia, it is more suggestive of pneumonia [14]. Abnormal vital signs include fever, hypothermia, tachypnea, tachycardia, and oxygen desaturation. Auscultation of the chest reveals crackles or other adventitious breath sounds. Elderly patients with pneumonia report a significantly lower number of both respiratory and nonrespiratory symptoms compared with younger patients. Clinicians should be aware of this phenomenon so it does not lead to delayed diagnosis and treatment [15].

Imaging Evaluation

The presence of a pulmonary consolidation or an infiltrate on chest radiograph is required to diagnose CAP, and a chest radiograph should be obtained when CAP is suspected [16]. It should be noted that there is no pattern of radiographic abnormalities reliable enough to differentiate infectious pneumonia from noninfectious causes [17].

There are case reports and case series demonstrating false-negative plain chest radiographs existing in dehydrated patients [18] or in neutropenic state. However, animal studies have shown that dogs challenged with pneumococcus showed abnormal pulmonary shadow, suggestive of pneumonia, regardless of hydration status [19]. There is also no reliable scientific evidence to support the notion that severe neutropenia can cause false-negative radiographs because of the inability to develop an acute inflammatory reaction in the lungs [20].

A chest CT scan is more sensitive than a plain chest radiograph in detecting pneumonia. Therefore, a chest CT should be performed in a patient with negative plain chest radiograph when pneumonia is still highly suspected [21]. A chest CT scan is also more sensitive in detecting cavitation, adenopathy, interstitial disease and empyema. It also has the advantage of better defining anatomical changes than plain films [22].

Because improvement of pulmonary opacities in patients with CAP lags behind clinical improvement, repeating chest imaging studies is not recommended in patients who demonstrate clinical improvement. Sometimes clearing of pulmonary infiltrate or consolidation can take 6 weeks or longer [23].

Laboratory Evaluation

Generally the etiologic agent of CAP cannot be determined solely on the basis of clinical signs and symptoms or imaging studies. Although routine microbiological testing for patients suspicious for CAP is not necessary for empirical treatment, by determining the etiologic agent of the pneumonia, a clinician will be able to narrow the antibiotics from a broad-spectrum empirical regimen to specific pathogen-directed therapy. Determination of certain etiologic agents causing the pneumonia can have important public health implications (eg, Mycobacterium tuberculosis and influenza virus) [24].

Sputum Gram Stain and Culture

Sputum Gram stain is an inexpensive test that may identify pathogens that cause CAP (eg, S. pneumonia and Haemophilus influenzae). A quality specimen is required. A sputum sample must contain > 25 neutrophils and < 10 squamous epithelial cells/low power field on Gram stain to be considered suitable for culture.

The sensitivity and specificity of sputum Gram stain and culture are highly variable in different clinical settings (eg, outpatient setting, nursing home, ICU). Reed et al’s meta-analysis of patients diagnosed with CAP in the United States showed the sensitivity and specificity of sputum Gram stain (compared with sputum culture) ranged from 15% to 100% and 11% to 100%, respectively [24]. In cases of proven bacteremic pneumococcal pneumonia, positive cultures from sputum samples were positive less than 50% of the time [25].

For patients who cannot provide sputum samples or are intubated, a deep-suction aspirate or bronchoalveolar lavage through a bronchoscopic procedure might be necessary to obtain pulmonary secretion for Gram stain and culture. Besides bacterial culture, sputum samples can also be sent for fungal and mycobacterial cultures and acid-fast stain if deemed clinically necessary.

Blood Culture

Because the positivity rate of blood culture in patients who are suspected to have pneumonia but not exposed to antimicrobial agents is disappointingly low (5%–14%), blood cultures are no longer recommended in patients hospitalized for CAP. Another reason for not recommending blood culture is positive culture rarely leads to changes in antibiotic regimen in patients without underlying diseases [26]. However, high-risk patients, including patients with severe CAP or in immunocompromised patients (eg, patients with neutropenia, asplenia or complement deficiencies) should have a blood culture done [24].

A multinational study published in 2008 examined 125 patients with pneumococcal bacteremic CAP versus 1847 patients with non-bacteremic CAP [27]. Analysis of the data demonstrated no association of pneumococcal bacteremic CAP and time to clinical stability, length of hospital stay, all-cause mortality or CAP-related mortality. The authors concluded that pneumococcal bacteremia does not increase the risk of poor outcomes in patients with CAP compared to non-bacteremic patients, and the presence of pneumococcal bacteremia should not deter de-escalation of therapy in clinically stable patients.

Urinary Antigen Tests

Urinary antigen tests may assist clinicians in narrowing antibiotic therapy when test results are positive. There are 2 U.S. Food and Drug Administration–approved tests available to clinicians for detecting pneumococcal and Legionella antigen in urine. The test for Legionella pneumophila detects disease due to serogroup 1 only, which accounts for 80% of community-acquired Legionnaires disease. The sensitivity and specificity of the Legionella urine antigen test are 90% and 99%, respectively. The pneumococcal urine antigen test is less sensitive and specific than the Legionella urine antigen test (sensitivity 80% and specificity > 90%) [28,29].

Advantages of the urinary antigen tests are that they are easily performed, results are available in less than an hour if done in-house, and results are not affected by prior exposure to antibiotics. However, the tests do not meet Clinical Laboratory Improvements Amendments criteria for waiver and must be performed by a technician in the laboratory.

Polymerase Chain Reaction

There are several FDA-approved polymerase chain reaction (PCR) tests commercially available to assist clinicians in diagnosing pneumonia. PCR test of nasopharyngeal swabs for diagnosing influenza have become standard in many medical U.S. facilities. The great advantage of using PCR to diagnose influenza is its high sensitivity and specificity and rapid turnaround time. PCR can also be used to detect Legionella species, S. pneumonia, Mycoplasma pneumoniae, Chlamydophila pneumonia and mycobacterial species [24].

One limitation of using PCR tests on respiratory specimens is that specimens can be contaminated with oral or upper airway flora, so the results must be interpreted with caution, bearing in mind that some of the pathogens isolated may be colonizers of the oral or upper airway flora [30].

Biologic Markers

Two biologic markers—procalcitonin and C-reactive protein (CRP)—can be used in conjunction with history, physical examination, laboratory tests and imaging studies to assist in the diagnosis and treatment of CAP [24]. Procalcitonin is a peptide precursor of the hormone calcitonin that is released by parenchymal cells into the bloodstream resulting in increased serum level in patients with bacterial infections. In contrast, there is no remarkable proclacitonin level increase with viral or noninfectious inflammation. The reference value of procalcitonin in the blood of an adult individual without infection or inflammation is < 0.15 ng/mL. In the blood, procalcitonin has a half-life of 25 to 30 hours. The quantitative immunoluminometric method (LUMI test, Brahms PCT, Berlin, Germany ) is the preferred test to use because of its high sensitivity [31].

A 2012 Cochrane meta-analysis that involved 4221 patients with acute respiratory infections (with half of the patients diagnosed with CAP) from 14 prospective trials found the use of procalcitonin test for antibiotic use significantly decreased median antibiotic exposure from 8 to 4 days without an increase in treatment failure, mortality rates in any clinical setting (eg, outpatient clinic, emergency room), or length of hospitalization [32]. A prospective study conducted in France on 100 ICU patients showed that increased procalcitonin from day 1 to day 3 has a poor prognosis factor for severe CAP whereas decreasing procalcitonin levels is associated with a favorable outcome [33].

CRP is an acute phase protein produced by the liver. CRP level in the blood increases in response to acute infection or inflammation. Use of CRP in assisting diagnosis and guiding treatment of CAP is more limited in part due to its poor specificity. A prospective study conducted on 168 consecutive patients presented with cough showed that a CRP > 40 mg/L had a sensitivity and specificity of 70% and 90%, respectively [34].

Treatment

Site of Care Decision

For patients with CAP, the clinician must decide whether the patient will be treated in an outpatient or inpatient setting, and for those in the inpatient setting, whether they can safely be treated on the general medical ward or should be the ICU. Two common scoring systems that can be used to aid the clinician in determining severity of the infection and guiding site-of-care decisions are the Pneumonia Severity Index (PSI) and CURB-65 scores.

The PSI score uses 20 different parameters, including comorbidities, laboratory parameters and radiographic findings to stratify patients into 5 mortality risk classes [35]. On the basis of associated mortality rates, it has been suggested that risk class I and II patients should be treated as outpatients, risk class III patients should be treated in an observation unit or with a short hospitalization, and risk class IV and V patients should be treated as inpatients [35].

The CURB-65 method of risk stratification is based on 5 clinical parameters: confusion, urea level, respiratory rate, systolic blood pressure and age ≥ 65 (Table 3) [36].

Patients with CURB-65 scores of 4 or 5 are considered to have severe pneumonia and admission to the ICU should be considered. Aside from the CURB-65 score, anyone requiring vasopressor support or mechanical ventilation merits admission to the ICU [16]. IDSA/ATS guidelines also recommend the use of “minor criteria” for making ICU admission decisions; these include respiratory rate ≥ 30 breaths / minute, PaO2 fraction ≤ 250, multilobar infiltrates, confusion, blood urea nitrogen ≥ 20 mg/dL, leukopenia, thrombocytopenia, hypothermia and hypotension [16]. These factors are associated with increased mortality due to CAP and admission to an ICU is indicated if 3 of the minor criteria for severe CAP are present.

Similar to CURB-65, another clinical calculator that can be used for assessing severity of CAP is SMART-COP [39]. This scoring system uses 8 weighted criteria to predict which patients will require intensive respiratory or vasopressor support. SMART-COP has a sensitivity of 79% and specificity 64% in predicting ICU admission, whereas CURB-65 had a pooled sensitivity of 57.2% and specificity of 77.2% [40].

Antibiotic Therapy

Antibiotics are the mainstay of treatment for CAP, with the majority of patients with CAP treated empirically taking into account the site of care, likely pathogen, and antimicrobial resistance issues. Patients with pneumonia who are treated as outpatients usually respond well to empiric antibiotic treatment and a causative pathogen is not usually sought. Patients who are hospitalized for treatment of CAP usually receive empiric antibiotic on admission. Once the etiology has been determined by microbiologic or serologic means, antimicrobial therapy should be adjusted accordingly. As noted previously, a CDC study found that the burden of viral etiologies was higher than previously thought, with rhinovirus and influenza accounting for 15% of cases and S. pneumoniae for only 5% [9]. This study highlighted the fact that despite advances in molecular techniques, most patients with pneumonia have no pathogen identified [9]. Given the lack of discernable pathogens in the majority of cases, unless a nonbacterial etiology is found patients should continue to be treated with antibiotics.

Outpatients without comorbidities or risk factors for drug-resistant S. pneumoniae (Table 4)

As previously mentioned, antibiotic therapy is typically empiric; neither clinical features nor radiographic features are sufficient to include or exclude infectious etiologies. Epidemiologic risk factors should be considered and, in certain cases, expanded antimicrobial coverage to include those entities; for example, treatment of anaerobes in the setting of lung abscess and antipseudomonal antibiotics for patients with bronchiectasis.

Of concern in the treatment of CAP is the increased prevalence of antimicrobial resistance among S. pneumoniae. The IDSA guidelines report that drug-resistant S. pneumoniae is more common in persons aged < 2 or > 65 years, and those with ß-lactam therapy within the previous 3 months, alcoholism, medical comorbidities, immunosuppressive illness or therapy, or exposure to a child who attends a day care center [16].

S. aureus should be considered during influenza outbreaks, with either vancomycin or linezolid being the recommended agents in the setting of methicillin-resistant S. aureus (MRSA). In a study comparing vancomycin versus linezolid for nosocomial pneumonia, the all-cause 60-day mortality was similar for both agents [41]. Datpomycin is another agent used against MRSA; however, its use in the setting of pneumonia is not indicated as daptomycin binds to surfactant, yielding it ineffective in the treatment of pneumonia [42]. Ceftaroline is a newer cephalosporin with activity against MRSA; its role in treatment of community-acquired MRSA pneumonia has not been fully elucidated, but it appears to be a useful agent for this indication [43,44].

Antibiotic Therapy for Selected Pathogens

S. pneumoniae

Patients with pneumococcal pneumonia who have penicillin-susceptible strains can be treated with intravenous penicillin (2 or 3 million units every 4 hours) or ceftriaxone. Once a patient meets criteria of stability, they can then be transitioned to oral penicillin, amoxicillin, or clarithromycin. Those with strains with reduced susceptibility can still be treated with penicillin but at a higher dose (4 million units IV every 4 hours) or a third-generation cephalosporin. Those whose pneumococcal pneumonia is complicated by bacteremia will benefit from dual therapy if severely ill, requiring ICU monitoring. Those not severely ill can be treated with monotherapy [46].

S. aureus

S. aureus is more commonly associated with hospital-acquired pneumonia but may also be seen during the influenza season and in those with severe necrotizing CAP. Both linezolid and vancomycin can be used to treat MRSA CAP. As noted above, ceftaroline has activity against MRSA and is approved for treatment of CAP, but is not approved by the FDA for MRSA CAP treatment. Similarly, tigecycline is approved for CAP and has activity against MRSA, but is not approved for MRSA CAP. Moreover, the FDA has warned of increased risk of death with tigecycline and has a black box warning to that effect [47].

Legionella

Treatment of legionellosis can be achieved with tetra­cyclines, macrolides, or fluoroquinolones. For nonimmunosuppressed patients with mild pneumonia, any of the listed antibiotics is considered appropriate. However, patients with severe infection or those with immunosuppression should be treated with either levofloxacin or azithromycin for 7 to 10 days [48].

C. pneumoniae

As with other atypical organisms, C. pneumoniae can be treated with doxycycline, a macrolide, or respiratory fluoroquinolones. However, length of therapy varies by regimen used; whereas treating with doxycycline 100 mg twice daily generally requires 14–21 days, moxifloxacin 400 mg daily only requires 10 days [49].

M. pneumoniae

As with C. pneumoniae, length of therapy of M. pneumoniae varies by antimicrobial used. Shortest courses are seen with the use of macrolides for 5 days, whereas 14 days is considered standard for doxycycline or a respiratory fluoroquinolone [50]. It should be noted that there has been increasingly documented resistance to macrolides, with known resistance of 8.2% in the United States [51].

Duration of Treatment

Most patients with CAP respond within 72 hours to appropriate therapy. IDSA/ATS guidelines recommend that patients be treated for a minimum of 5 days, and before discontinuing antibiotics patients should be afebrile a minimum of 48-72 hours and be clinically stable (Table 6) [16]. 

Hospitalized patients do not need to be monitored for an additional day once they have reached clinical stability (Table 6), are able to maintain oral intake, and have normal mentation, provided that other comorbidities are stable and social needs have been met [16]. Patients discharged from the hospital with instability have higher risk of readmission or death [55].

Transition to Oral Therapy

IDSA/ATS guidelines [16] recommend that patients should be transitioned from IV to oral antibiotics when they are improving clinically, have stable vital signs, and are able to ingest food/fluids and medications.

Management of Nonresponders

Although the majority of patients respond to antibiotics within 72 hours, treatment failure occurs in up to 15% of patients [45]. Nonresponding pneumonia is generally seen in 2 patterns: worsening of clinical status despite empiric antibiotics OR delay in achieving clinical stability as defined in Table 5 after 72 hours of treatment [13]. Risk factors associated with nonresponding pneumonia [56] are:

• Radiographic: multilobar infiltrates, pleural effusion, cavitation
• Bacteriologic: MRSA, gram-negative or Legionella pneumonia
• Severity index: PSI > 90
• Pharmacologic: incorrect antibiotic choice based on susceptibility

Patients with acute deterioration of clinical status will prompt transfer to a higher level of care and may require mechanical ventilator support. In those with delay in achieving clinical stability, question centers on whether the same antibiotics can be continued while doing further radiographic/microbiologic workup and/or changing antibiotics.

History should be reviewed with particular attention to exposures, travel history, and microbiologic and radiographic data. Clinicians should recall that viral causes account for up to 20% of pneumonias and there are also noninfectious causes that can mimic pyogenic infections [57]. If adequate initial cultures were not obtained, they should be obtained; however, care must be taken in reviewing new sets of cultures while on antibiotics as they may reveal colonization selected out by antibiotics and not a true pathogen. If repeat evaluation is unrevealing, then further evaluation with CT scan and bronchoscopy with bronchoalveolar lavage and biopsy is warranted. CT scans can show pleural effusions, bronchial obstructions or pattern suggestive of cryptogenic pneumonia. A bronchoscopy might yield a microbiologic diagnosis and with biopsy can also evaluate for noninfectious causes.

As with other infections, if escalation of antibiotics is undertaken, clinicians should be mindful to ensure that efforts are being made to elucidate the reason for nonresponse. To simply broaden antimicrobial therapy without attempts at establishing a microbiologic or radiographic cause for nonresponse may lead to inappropriate treatment recurrence of infection. Aside from patients who have bacteremic pneumococcal pneumonia in an ICU setting, there are no published reports pointing to superiority of combination antibiotics [46].

Other Treatment

Because of the inflammatory response associated with pneumonia, several agents have been evaluated as adjunctive treatment of pneumonia to decrease this inflammatory state; namely, steroids, macrolide antibiotics and statins. To date, only the use of steroids (methylprednisolone 0.5 mg/kg every 12 hours for 5 days) in those with severe CAP and high initial anti-inflammatory response (CRP > 150) was shown to decrease treatment failure, decreased risk of ARDS, possibly reduce length of stay, duration of intravenous antibiotics and clinical stability, without effect on mortality or adverse side effects [58,59].

Other adjunctive methods have not been found to have significant impact [16].

Prevention of Pneumonia

Prevention of pneumococcal pneumonia is twofold: prevention of infection caused by S. pneumoniae and prevention of influenza infection. As influenza infection is a risk factor for bacterial infection, specifically with S. pneumoniae, influenza vaccination can prevent bacterial pneumonia [60]. In their most recent recommendations, the CDC continues to recommend routine influenza vaccination for all persons aged greater than 6 months, unless otherwise contraindicated [61].

There are 2 vaccines for prevention of pneumococcal disease: the pneumococcal polysaccharide vaccine (PPSV23) and a conjugate vaccine (PCV13). Following vaccination with PPSV23, 80% of adults develop antibodies against at least 18 of the 23 serotypes [62]. Despite this response, PPSV23 is reported to be protective against invasive pneumococcal infection; yet there is no consensus regarding PPSV23 leading to decreased rates of pneumonia [63]. On the other hand, PCV13 vaccination was associated with prevention of both invasive disease and community-acquired pneumonia in adults 65 years or older [64]. The CDC recommends that all children aged 2 or under receive PCV13, whereas those aged 65 or older should receive PCV13 followed by a dose of PPSV23 [65]. The dose of PPSV23 should be given ≥1 year following the dose of PCV13 [66].Persons < 65 years of age with immunocompromising and certain other conditions should also receive vaccination [67] (Table 7). Full details, many scenarios, and timing of vaccinations can be found at www.cdc.gov/vaccines/schedules/downloads/adult/adult-schedule.pdf.

Cigarette smoking increases the risk of respiratory infections as evidenced by smokers accounting for almost half of all patients with invasive pneumococcal disease [11]. As this is a modifiable risk factor it should be a goal of a comprehensive approach towards prevention of pneumonia.

Summary

CAP remains a leading cause of hospitalization and death in the 21st century. Traditionally, pneumococcus has been considered the major pathogen causing CAP; however, the 2015 EPIC study found that in only 5% of patients diagnosed with CAP was S. pneumoniae detected. Despite the new findings, it is still recommended that empiric treatment for CAP target common typical bacteria (pneumococcus, H. influenzae, Moraxella catarrhalis) and atypical bacteria (M. pneumonia, C. pneumoniae, L. pneumophila).

Because diagnosing pneumonia through history and clinical examination is less than 50% sensitive, a chest imaging study (a plain chest radiograph or a chest CT scan) is usually required to make the diagnosis. Laboratory tests, such as sputum Gram stain/culture, blood culture, urinary antigen tests, PCR test, procalcitonin, and CRP are important adjunctive diagnostic modalities to assist in the diagnosis and management of CAP. However, no single test is sensitive and specific enough to be a stand-alone test. They should be used in conjunction with history, physical examination, and imaging studies. Because vaccination (PPSV23, PCV13, and influenza vaccine) remains the most effective tool in preventing the development of CAP, clinicians, should strive for 100% vaccination rates in appropriate persons.

Corresponding author: Tze Shein Lo, MD, University of North Dakota, 1919 Elm Street, Fargo, ND 58102, [email protected].

Financial disclosures: None.

Author contributions: drafting of article, PM, TSL; critical revision of the article, PM, TSL.

From the Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (Dr. Marra), Division of Anesthesiology Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN (Dr. Hayhurst, Dr. Hughes, Dr. Pandharipande), Department of Clinical and Experimental Science, University of Brescia, Brescia, Italy (Dr. Marengoni), School of Medicine and Surgery,
University of Milano-Bicocca, Milan, Italy (Dr. Bellelli), and Rehabilitation and Aged Care Unit Hospital Ancelle, Cremona, Italy (Dr. Morandi).

Abstract

• Objective: To present an overview of the phenomenon of inappropriate medication prescription in older critically ill patients and examine possible strategies of intervention.
• Methods: Review of the literature.
• Results: Polypharmacy and inappropriate prescribing of medications in older persons may lead to a significant risk of adverse drug-related events and mortality. The intensive care unit (ICU) is often the place where potentially inappropriate medications (PIMs) are first prescribed. Common PIMs at ICU discharge are antipsychotics, benzodiazepines, opioids, anticholinergic medications, antidepressants, and drugs causing orthostatic hypotension. Different classes of medications, typically intended for short-term use, are sometimes inappropriately continued after discharge from the hospital. At admission, potential risk factors for PIM are multiple morbidities, polypharmacy, frailty and cognitive decline; at discharge, a high number of pre-admission PIMs, discharge to a location other than home, discharge from a surgical service, longer length of ICU and hospital stay, and mechanical ventilation. Inappropriate prescribing in older patients can be detected through either the use of explicit criteria, drug utilization reviews, and multidisciplinary teams, including a geriatrician and/or the involvement of a clinical pharmacist.
• Conclusion: Use of PIMs may be common in critical patients, both on admission and at discharge from ICU. Therapeutic reconciliation is recommended at every transition of care (eg, at hospital or ICU admission and discharge) in order to improve appropriateness of prescription.

Key words: elderly; intensive care unit; inappropriate medications; antipsychotics.

Since older persons are often affected by multiple chronic diseases and are prescribed several medications, the quality and safety of prescribing these medications has become a global health care issue [1–4]. Polypharmacy and inappropriate prescribing of medications among the elderly is receiving significant attention in the medical literature [5,6]. Inappropriate medications in the elderly can lead to falls, cognitive impairment and delirium, poorer health status, and higher mortality [7–10]. Medications are considered potentially inappropriate when (a) the risks of treatment outweigh the benefits [11], (b) they are prescribed for periods longer than clinically indicated or without any clear indication, (c) they are not prescribed when indicated [12], and (d) they are likely to interact with other drugs and diseases. Medications included in this category are often referred to as potentially inappropriate medications (PIMs), as in some situations their use is justified; however, if the risk of harm from the drug is judged to outweigh the potential clinical benefit after an individual patient’s clinical circumstances are considered, these drugs are considered “actually inappropriate medications” (AIMs) [6].

Advancing age is associated with substantial pharmacokinetic and pharmacodynamics changes, such as altered distribution volumes and altered permeability of the blood-brain barrier, impaired liver metabolism and renal capacity, up- and down-regulation of target receptors, transmitters, and signaling pathways changes, impaired homeostasis, and increased risk of adverse drug reactions (ADRs) that lead to increased mortality and morbidity and higher health care costs [2,11,13–19]. Studies show that ADRs cause approximately 5% of hospital admissions in the general population, but the percentage rises to 10% in older persons [20].

Avoiding PIMs represents a strategy aimed at reducing drug-related mortality and morbidity. This article provides an overview of the phenomenon of inappropriate medication prescription in older critically ill patients and examines available strategies of intervention.

Inappropriate Medications at ICU Discharge

Though PIMs and AIMs may be identified at the time of hospital discharge, the intensive care unit (ICU) is often the place where these medications are first prescribed [21]. Acute hospitalization may increase PIM prescribing because of newly prescribed medications, the presence of multiple prescribers, inadequate medication reconciliation, and a lack of care coordination among inpatient providers or in the transition back to outpatient care [22)].

A known complication of critical illness and ICU stay is a significant increase in psychological symptoms, sleep cycle alterations, delirium, and cognitive impairment, which may be associated with increased prescription of specific PIMs, such as antipsychotics or benzodiazepines [6,23,24]. Despite the lack of reliable evidence supporting their use in the ICU, antipsychotic agents are used routinely in ICU patients [25] to treat a variety of conditions, such as substance withdrawal, agitation not responding to other therapies, or delirium. Results from a multicenter study of 164,996 hospitalizations across 71 academic medical centers in the US showed that 1 out of 10 ICU patients received an antipsychotic during their hospital stay [25]. Jasiak et al estimated that one-third of patients initiated on an atypical antipsychotic therapy for ICU delirium received a hospital discharge prescription for these medications, with a potential annual outpatient medication cost of approximately $2255 per patient [26].

One potential consequence of antipsychotic use in the ICU is their continuation after the transition to other clinical settings, including discharge from the hospital [27] (Table 1). 

When examining the specific factors that may contribute to a patient being discharged on an antipsychotic, authors found that the specific antipsychotic used correlated with risk of continuation [27,30], with atypical antipsychotics having a greater likelihood of being continued than haloperidol [27,30]. Possible explanation for these results could be that physicians perceive less long-term risk from atypical agents, so may be more likely to continue them on discharge [30]. However, such an approach is not always safe. Indeed, although atypical antipsychotic agents tend to cause less tardive dyskinesia, they are known to be associated with similar rates of other adverse events compared with typical agents and have been linked to an increased risk of sudden cardiac death and pneumonia in the elderly [31,32].

Other factors independently associated with being discharged on a new antipsychotic medication were the severity of the acute illness as measured with the Acute Physiology and Chronic Health Evaluation II score at ICU admission (odds ratio [OR] 1 [95% confidence interval {CI}, 1.0–1.1]) and days treated with benzodiazepines (OR 1.1 [95% CI, 1.0–1.14]) [30]. Conversely, perhaps due to different practice patterns, Tomichek et al did not find an association between benzodiazepines administration and antipsychotic prescription at discharge in post hoc analyses [27].

Another possible reason for antipsychotic continuation may reside in the indication chosen [33]. Antipsychotic agents have sedative properties and they might be used to optimize sleep during hospitalization, despite the lack of evidence to support this indication [34]. Other factors potentially contributing to continuation of antipsychotics may include persistent delirium and agitation, newly diagnosed psychiatric illness, and difficulties experienced by physicians in deprescribing [35] with improper/incomplete medication reconciliation [33].

The continuation of antipsychotic therapy increased 30-day readmission rates in patients compared to those who had therapy stopped before discharge [33]. In addition to the well-described cardiac effects (prolonged QT interval), neuroleptic malignant syndrome and extrapyramidal symptoms may also occur, and longer-term use can predispose patients to metabolic disturbances, falls, and increase the risk of death in elderly patients with dementia [31].

Benzodiazepines and sedative hypnotics are commonly used to treat insomnia and agitation in older adults despite significant risk. Benzodiazepine administration was found to be an independent risk factor for a daily transition to delirium [36,37]. Pandharipande et al reported that every unit dose of lorazepam was associated with a higher risk for daily transition to delirium (OR 1.2, 95% CI 1.1–1.4, P = 0.003) [36] in critically ill patients. A more recent analysis found for every 5 mg of midazolam administered to a patient who is awake and without delirium, there is a 4% chance that this patient will develop delirium the next ICU day [37].

Given that the risk for benzodiazepine-associated delirium is dose-dependent, clinicians should use strategies known to reduce the daily number of benzodiazepines administered that often includes the use of a sedative associated with less delirium occurrence, such as dexmedetomidine or propofol [38]. Evidence has shown that long-term use of benzodiazepines has little benefit with many risks, including an increased susceptibility to spontaneous bacterial infection [39,40] and mortality in the setting of infection [41]. Nakafero et al showed that exposure to benzodiazepines was associated with increased occurrence of both influenza-like-illness–related pneumonia and mortality. Benzodiazepine use was associated also with increased occurrence of asthma exacerbation and with increased all-cause mortality during a median follow-up of 2 years in a cohort of asthmatic patients [42] as well with an increased risk of pneumonia and long-term mortality in patients with a prior diagnosis of community- acquired pneumonia [40]. Long-term use of benzodiazepines is also associated with increased risk of falls [43–45], cognitive impairment [46–48] and disability [49,50].

Other common types of PIMs at ICU discharge were opioids, anticholinergic medications, antidepressants, and drugs causing orthostatic hypotension [6]. Of the anticholinergic AIMs, H2 blockers (61%) and promethazine (15%) were the most common [6]. Only 16% of opioids, 23% of antidepressants, and 10% of drugs causing orthostatic hypotension were found to be actually inappropriate after the patient’s circumstances were considered (eg, postoperative pain control, a new diagnosis of major depressive disorder) [6].

Inappropriate Medications at Hospital Discharge

Medications typically intended for short-term use during acute illness are sometimes continued after discharge without documented indication [51]. Poudel et al found that in 206 patients 70 years of age and older discharged to residential aged care facilities from acute care, at least 1 PIM was identified in 112 (54.4%) patients on admission and 102 (49.5%) patients on discharge [11]. Commonly prescribed PIM categories, at both admission and discharge, were central nervous system, cardiovascular, gastrointestinal, and respiratory drugs and analgesics [6,11,52,53]. Of all medications prescribed at admission (1728), 10.8% were PIMs, and at discharge, of 1759 medications, 9.6% were PIMs. Of the total 187 PIMs on admission, 56 (30%) were stopped, and 131 (70%) were continued; 32 new PIMs were introduced [11].

Morandi et al in 2011 conducted a prospective cohort study including 120 patients age ≥ 60 who were discharged after receiving care in a medical, surgical, or cardiovascular ICU for shock or respiratory failure. The percentage of patients prescribed at least 1 PIM increased from 66% at pre-admission to 85% at discharge. The number of patients with 0 PIMs dropped from 34% at preadmission to 14% at discharge, and the number of patients with 3 or more PIMS increased from 16% at preadmission to 37% at discharge. While it is possible that these drugs may be appropriate when started during an acute illness in the ICU (eg, stress ulcer prophylaxis with H2-antagonists in mechanically ventilated patients), most should have been discontinued at ICU and/or hospital discharge [21].

Inappropriate prescriptions of proton pump inhibitors (PPIs) in hospital and primary care have been widely reported [54,55]. In a study conducted by Ahrens et al in 31 primary care practices, for 58% (263/506) of patients discharged from 35 hospitals with a PPI recommendation in hospital discharge letters, an appropriate indication was missing. In 57% of these cases general practitioners followed this recommendation and continued the prescription for more than 1 month [54]. The strongest factor associated with appropriate and inappropriate continuation of PPI after discharge was PPI prescription prior to hospitalization [54]. Although PPIs are safe, they can cause adverse effects. PPI intake has been found to have a significant association with risk of community-acquired pneumonia [56,57], hip fractures [58], Clostridium difficile-associated diarrhea [55,61,62], and to reduce the therapeutic effects of bisphosphonates [59] and low-dose aspirin [60].

Unintentional medication continuation is not a problem isolated to a single drug class or disease [63]. Scales et al evaluated rates of and risk factors for potentially unintentional medication continuation following hospitalization in a population of elderly patients (≥ 66 years) [51]. They created distinct cohorts by identifying seniors not previously receiving four classes of medications typically used to treat or prevent complications of acute illness: antipsychotic medications; gastric acid suppressants (ie, histamine-2 blockers and proton pump inhibitors); benzodiazepines; and inhaled bronchodilators and steroids [51]. Prescription without documented indication occurred across all medication classes, from 12,209 patients (1.4 %) for antipsychotic medications to 34,140 patients (6.1 %) for gastric acid suppressants [51].

Several potential risk factors were considered. The relationship between multimorbidity and polypharmacy is well described in the literature, and several studies have identified a positive association between the number of drugs and the use of PIMs [64–66]. Conversely, Poudel et al did not find any association between polypharmacy and PIM use [11]. Associations were found between the use of PIMs, frailty status, and cognitive decline of patients at admission and at discharge [11], while no association was observed with age, gender, in-hospital falls, delirium, and functional decline [11,67]. Other potential risk factors of a high number of PIMs at discharge were a high number of pre-admission PIMs, discharge to a location other than home, and discharge from a surgical service [1,6,68,69]. Length of ICU stay and mechanical ventilation had a positive influence on the number of PIMs used by acutely ill older patients [11,63,69]. In the study of Scales et al, the greatest absolute risk factor across all medication groups was longer hospitalization. The increased OR for medication continuation after a hospitalization lasting more than 7 days ranged from 2.03 (95% CI 1.94–2.11) for respiratory inhalers to 6.35 (95% CI 5.91–6.82) for antipsychotic medications [51].

Inappropriate Medications: Where and How to Intervene?

Early detection of PIMs may prevent adverse drug events and improve geriatric care in older adults [13,70]. PIM prevalence can often be a useful indicator of prescribing quality [2]. Appropriate interventions and an improved quality of prescribed medications require appropriate assessment tools to decrease the number of patients discharged on these medications [71,72]. Medication reconciliation is the process of avoiding inadvertent inconsistencies within a patient’s drug regimen, which can occur during transitions in different setting of care [73]. A multidisciplinary team should be involved in the medication reconciliation at each care transition to reevaluate medications use according to the clinical conditions, cognitive/functional status and the coexistence of geriatric syndromes (eg, dementia, malnutrition, delirium, urinary incontinence, frailty) (Figure).

Criteria for the Evaluation of Inappropriate Medications Prescription

Explicit criteria derived from expert reports or published reviews are available (Table 2).

Beers criteria PIMs have been found to be associated with poor health outcomes, including confusion, falls, and mortality [7,75,78]. The STOPP (Screening Tool of Older Person’s potentially inappropriate Prescriptions) and START (Screening Tool to Alert doctors to the Right Treatment) are evidence-based sets of criteria that were developed in Ireland and updated in October 2014, including some of the new criteria for direct oral anticoagulants, drugs affecting or affected by renal system and anti-muscarinic/anticholinergic agents [79]. 

Several other sets of criteria have been published to identify PIMs, such as the FORTA (Fit for the Aged) and the PRISCUS [86] criteria. FORTA allows a disease-related evaluation revealing over-treatment and under-treatment, and medications are graded as follows: A, indispensable drug, clear-cut benefit in terms of efficacy/safety ratio proven in elderly patients for a given indication; B, drugs with proven or obvious efficacy in the elderly, but limited extent of effect or safety concerns; C, drugs with questionable efficacy/safety profiles in the elderly which should be avoided or omitted in the presence of too many drugs or side effects; D, avoid in the elderly, omit first, refer also to negative listings. Negative lists such as PRISCUS, which provide an explicit listing of drugs, independent of the diagnosis, are easy to use. On the other hand, constant updates are needed, and such lists carry the risk of an assumption that drugs not listed would be appropriate in every case [87]. Both sets of criteria have in common that they refer to long-term medication and drugs frequently used during the inpatient stay, such as antibiotics, are hardly taken into account [87].

The Medication Appropriateness Index measures overall prescribing quality through 10 separate but interrelated domains [8]. Three components are used to detect PIMs: indication, effectiveness, and duplication. However, it does not give any precise guidance in relation to specific medicines and therefore has limited application for objectively defining PIMs.

Another prescribing quality assessment tool is the Inappropriate Prescribing in the Elderly Tool (IPET), which consists of a list of the 14 most prevalent prescription errors identified from an extensive list of inappropriate prescription instances drawn up by an expert Canadian Consensus Panel [88,89].

Another approach to assess the appropriateness of drugs prescribed for older people is the use of Drug Utilization Reviews (DURs) [16]. DURs use consensus opinion by drug therapy experts to define standards or explicit criteria for a single drug, class of drugs, or group of drugs [16]. DURs typically use retrospective information from large, nonclinical administrative databases to identify problems such as dosage range, duration, therapeutic duplication, and drug interactions [90, 91]. Monane et al [92] evaluated a program designed to decrease the use of PIMs among the elderly through a computerized online DUR database. Computer alerts triggered telephone calls to physicians by pharmacists to discuss a potential problem and any therapeutic substitution options. From a total of 43,007 telepharmacy calls generated by the alerts, they were able to reach 19,368 physicians regarding 24,266 alerts (56%). The rate of change to a more appropriate therapeutic agent was 24% (5860), but ranged from 40% for long half-life benzodiazepines to 2% to 7% for drugs that theoretically were contraindicated by patients’ self-reported history [92].

Computerized Support Systems to Reduce Inappropriate Prescribing in the Elderly

Other potential solutions for reducing inappropriate medications may include continuing medical education, electronic medical records surveillance, routine clinical evaluation, and/or improved hand-off communication between discharging and accepting providers. Incorporating this assessment of medication appropriateness into the medication reconciliation process when patients are discharged or transferred out of the ICU has the potential to enhance patient safety [21,93]. A randomized controlled trial conducted by Raebel et al [94] reported the effectiveness of a computerized pharmacy alert system plus collaboration between health care professionals for decreasing potentially inappropriate medication dispensing in elderly patients. Another study showed that computer-based access to complete drug profiles and alerts about potential prescribing problems reduced the occurrence of potentially inappropriate prescriptions [95]. A summary of these studies is shown in Table 3.

Interdisciplinary Teams to Reduce Inappropriate Prescribing in the Elderly

Some studies evaluated the effect of multidisciplinary teamwork in improving inappropriate medication prescribing in the elderly (Table 4).

Pharmacists in hospitals can play a significant role in the initiation of changes to patient’s therapy and management [11] (Table 5).

Mattison et al recently emphasized that studies of PIMs should determine scenarios in which it is appropriate to prescribe PIMs, moving beyond simply labeling some medications as “potentially inappropriate,” since some PIMs are appropriately prescribed in specific clinical situations [109]. Morandi et al showed that the positive predictive value (PPV) depends on the drug type. Thus, when developing a screening system, one cannot be concerned only with high negative predictive value (NPV), one must consider PPV as well [6]. Screening tools that include medication classes with low PPV will generate false positive “flags” or warnings, which could lead to misguided clinical decisions [6]. The fact that many PIMs are not AIMs also reveals the value of using a multidisciplinary team to identify AIMs from lists of PIMs generated when discharge medication lists are screened [6,110]. Thus, a multidisciplinary team is needed to consider the clinical context to distinguish PIMs from AIMs [6]. Of course, such a team is not available in some settings; when resources are limited, knowledge of which PIMs are most likely AIMs (ie, have high PPVs) could guide the development of computer-based decision support systems or other surveillance approaches that are efficient in that particular setting [6].

Approaches for optimizing prescribing in this population mainly depend on patient needs and comorbidities and most available data are derived from randomized controlled trials involving a single drug. Such trials do not take into account the confounding effects of multiple comorbidities and patient preferences. Therefore, approaches for optimizing prescription management that are available for and validated in younger patients are not applicable to elderly subjects [3,111].

Conclusion

Clinicians should seek to identify and discontinue AIMs at 3 important transitions during a critically ill elderly patient’s hospital course: at the time of hospital or ICU admission; at ICU discharge; and at hospital discharge. The patient’s clinical situation should be reviewed at every transition points, ideally by a multidisciplinary team of clinicians, to judge the appropriateness of each PIM [6]. After the hospital discharge, patient’s medications should be then reviewed by a multidisciplinary team and/or by the primary care physician according to the final discharge destination (ie, home, nursing home, rehabilitation) by using any of the validated tools. Regardless of the approach, it is clear that standardized care processes, including enhanced clinical decision support, are necessary to ensure that physicians do not continue exposing our patients to unnecessary medications and harm after discharge.

Corresponding author: Alessandro Morandi, MD, MPH, [email protected].

Funding/support: Dr. Pandiharipande is supported by National Institutes of Health HL111111 (Bethesda, MD) and by the VA Clinical Science Research and Development Service (Washington, DC) and the National Institutes of Health AG027472 and AG035117 (Bethesda, MD).

Financial disclosures: Dr. Pratik Pandharipande has received a research grant from Hospira Inc in collaboration with the NIH.

From the Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (Dr. Marra), Division of Anesthesiology Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN (Dr. Hayhurst, Dr. Hughes, Dr. Pandharipande), Department of Clinical and Experimental Science, University of Brescia, Brescia, Italy (Dr. Marengoni), School of Medicine and Surgery,
University of Milano-Bicocca, Milan, Italy (Dr. Bellelli), and Rehabilitation and Aged Care Unit Hospital Ancelle, Cremona, Italy (Dr. Morandi).

Abstract

• Objective: To present an overview of the phenomenon of inappropriate medication prescription in older critically ill patients and examine possible strategies of intervention.
• Methods: Review of the literature.
• Results: Polypharmacy and inappropriate prescribing of medications in older persons may lead to a significant risk of adverse drug-related events and mortality. The intensive care unit (ICU) is often the place where potentially inappropriate medications (PIMs) are first prescribed. Common PIMs at ICU discharge are antipsychotics, benzodiazepines, opioids, anticholinergic medications, antidepressants, and drugs causing orthostatic hypotension. Different classes of medications, typically intended for short-term use, are sometimes inappropriately continued after discharge from the hospital. At admission, potential risk factors for PIM are multiple morbidities, polypharmacy, frailty and cognitive decline; at discharge, a high number of pre-admission PIMs, discharge to a location other than home, discharge from a surgical service, longer length of ICU and hospital stay, and mechanical ventilation. Inappropriate prescribing in older patients can be detected through either the use of explicit criteria, drug utilization reviews, and multidisciplinary teams, including a geriatrician and/or the involvement of a clinical pharmacist.
• Conclusion: Use of PIMs may be common in critical patients, both on admission and at discharge from ICU. Therapeutic reconciliation is recommended at every transition of care (eg, at hospital or ICU admission and discharge) in order to improve appropriateness of prescription.

Key words: elderly; intensive care unit; inappropriate medications; antipsychotics.

Since older persons are often affected by multiple chronic diseases and are prescribed several medications, the quality and safety of prescribing these medications has become a global health care issue [1–4]. Polypharmacy and inappropriate prescribing of medications among the elderly is receiving significant attention in the medical literature [5,6]. Inappropriate medications in the elderly can lead to falls, cognitive impairment and delirium, poorer health status, and higher mortality [7–10]. Medications are considered potentially inappropriate when (a) the risks of treatment outweigh the benefits [11], (b) they are prescribed for periods longer than clinically indicated or without any clear indication, (c) they are not prescribed when indicated [12], and (d) they are likely to interact with other drugs and diseases. Medications included in this category are often referred to as potentially inappropriate medications (PIMs), as in some situations their use is justified; however, if the risk of harm from the drug is judged to outweigh the potential clinical benefit after an individual patient’s clinical circumstances are considered, these drugs are considered “actually inappropriate medications” (AIMs) [6].

Advancing age is associated with substantial pharmacokinetic and pharmacodynamics changes, such as altered distribution volumes and altered permeability of the blood-brain barrier, impaired liver metabolism and renal capacity, up- and down-regulation of target receptors, transmitters, and signaling pathways changes, impaired homeostasis, and increased risk of adverse drug reactions (ADRs) that lead to increased mortality and morbidity and higher health care costs [2,11,13–19]. Studies show that ADRs cause approximately 5% of hospital admissions in the general population, but the percentage rises to 10% in older persons [20].

Avoiding PIMs represents a strategy aimed at reducing drug-related mortality and morbidity. This article provides an overview of the phenomenon of inappropriate medication prescription in older critically ill patients and examines available strategies of intervention.

Inappropriate Medications at ICU Discharge

Though PIMs and AIMs may be identified at the time of hospital discharge, the intensive care unit (ICU) is often the place where these medications are first prescribed [21]. Acute hospitalization may increase PIM prescribing because of newly prescribed medications, the presence of multiple prescribers, inadequate medication reconciliation, and a lack of care coordination among inpatient providers or in the transition back to outpatient care [22)].

A known complication of critical illness and ICU stay is a significant increase in psychological symptoms, sleep cycle alterations, delirium, and cognitive impairment, which may be associated with increased prescription of specific PIMs, such as antipsychotics or benzodiazepines [6,23,24]. Despite the lack of reliable evidence supporting their use in the ICU, antipsychotic agents are used routinely in ICU patients [25] to treat a variety of conditions, such as substance withdrawal, agitation not responding to other therapies, or delirium. Results from a multicenter study of 164,996 hospitalizations across 71 academic medical centers in the US showed that 1 out of 10 ICU patients received an antipsychotic during their hospital stay [25]. Jasiak et al estimated that one-third of patients initiated on an atypical antipsychotic therapy for ICU delirium received a hospital discharge prescription for these medications, with a potential annual outpatient medication cost of approximately $2255 per patient [26].

One potential consequence of antipsychotic use in the ICU is their continuation after the transition to other clinical settings, including discharge from the hospital [27] (Table 1). 

When examining the specific factors that may contribute to a patient being discharged on an antipsychotic, authors found that the specific antipsychotic used correlated with risk of continuation [27,30], with atypical antipsychotics having a greater likelihood of being continued than haloperidol [27,30]. Possible explanation for these results could be that physicians perceive less long-term risk from atypical agents, so may be more likely to continue them on discharge [30]. However, such an approach is not always safe. Indeed, although atypical antipsychotic agents tend to cause less tardive dyskinesia, they are known to be associated with similar rates of other adverse events compared with typical agents and have been linked to an increased risk of sudden cardiac death and pneumonia in the elderly [31,32].

Other factors independently associated with being discharged on a new antipsychotic medication were the severity of the acute illness as measured with the Acute Physiology and Chronic Health Evaluation II score at ICU admission (odds ratio [OR] 1 [95% confidence interval {CI}, 1.0–1.1]) and days treated with benzodiazepines (OR 1.1 [95% CI, 1.0–1.14]) [30]. Conversely, perhaps due to different practice patterns, Tomichek et al did not find an association between benzodiazepines administration and antipsychotic prescription at discharge in post hoc analyses [27].

Another possible reason for antipsychotic continuation may reside in the indication chosen [33]. Antipsychotic agents have sedative properties and they might be used to optimize sleep during hospitalization, despite the lack of evidence to support this indication [34]. Other factors potentially contributing to continuation of antipsychotics may include persistent delirium and agitation, newly diagnosed psychiatric illness, and difficulties experienced by physicians in deprescribing [35] with improper/incomplete medication reconciliation [33].

The continuation of antipsychotic therapy increased 30-day readmission rates in patients compared to those who had therapy stopped before discharge [33]. In addition to the well-described cardiac effects (prolonged QT interval), neuroleptic malignant syndrome and extrapyramidal symptoms may also occur, and longer-term use can predispose patients to metabolic disturbances, falls, and increase the risk of death in elderly patients with dementia [31].

Benzodiazepines and sedative hypnotics are commonly used to treat insomnia and agitation in older adults despite significant risk. Benzodiazepine administration was found to be an independent risk factor for a daily transition to delirium [36,37]. Pandharipande et al reported that every unit dose of lorazepam was associated with a higher risk for daily transition to delirium (OR 1.2, 95% CI 1.1–1.4, P = 0.003) [36] in critically ill patients. A more recent analysis found for every 5 mg of midazolam administered to a patient who is awake and without delirium, there is a 4% chance that this patient will develop delirium the next ICU day [37].

Given that the risk for benzodiazepine-associated delirium is dose-dependent, clinicians should use strategies known to reduce the daily number of benzodiazepines administered that often includes the use of a sedative associated with less delirium occurrence, such as dexmedetomidine or propofol [38]. Evidence has shown that long-term use of benzodiazepines has little benefit with many risks, including an increased susceptibility to spontaneous bacterial infection [39,40] and mortality in the setting of infection [41]. Nakafero et al showed that exposure to benzodiazepines was associated with increased occurrence of both influenza-like-illness–related pneumonia and mortality. Benzodiazepine use was associated also with increased occurrence of asthma exacerbation and with increased all-cause mortality during a median follow-up of 2 years in a cohort of asthmatic patients [42] as well with an increased risk of pneumonia and long-term mortality in patients with a prior diagnosis of community- acquired pneumonia [40]. Long-term use of benzodiazepines is also associated with increased risk of falls [43–45], cognitive impairment [46–48] and disability [49,50].

Other common types of PIMs at ICU discharge were opioids, anticholinergic medications, antidepressants, and drugs causing orthostatic hypotension [6]. Of the anticholinergic AIMs, H2 blockers (61%) and promethazine (15%) were the most common [6]. Only 16% of opioids, 23% of antidepressants, and 10% of drugs causing orthostatic hypotension were found to be actually inappropriate after the patient’s circumstances were considered (eg, postoperative pain control, a new diagnosis of major depressive disorder) [6].

Inappropriate Medications at Hospital Discharge

Medications typically intended for short-term use during acute illness are sometimes continued after discharge without documented indication [51]. Poudel et al found that in 206 patients 70 years of age and older discharged to residential aged care facilities from acute care, at least 1 PIM was identified in 112 (54.4%) patients on admission and 102 (49.5%) patients on discharge [11]. Commonly prescribed PIM categories, at both admission and discharge, were central nervous system, cardiovascular, gastrointestinal, and respiratory drugs and analgesics [6,11,52,53]. Of all medications prescribed at admission (1728), 10.8% were PIMs, and at discharge, of 1759 medications, 9.6% were PIMs. Of the total 187 PIMs on admission, 56 (30%) were stopped, and 131 (70%) were continued; 32 new PIMs were introduced [11].

Morandi et al in 2011 conducted a prospective cohort study including 120 patients age ≥ 60 who were discharged after receiving care in a medical, surgical, or cardiovascular ICU for shock or respiratory failure. The percentage of patients prescribed at least 1 PIM increased from 66% at pre-admission to 85% at discharge. The number of patients with 0 PIMs dropped from 34% at preadmission to 14% at discharge, and the number of patients with 3 or more PIMS increased from 16% at preadmission to 37% at discharge. While it is possible that these drugs may be appropriate when started during an acute illness in the ICU (eg, stress ulcer prophylaxis with H2-antagonists in mechanically ventilated patients), most should have been discontinued at ICU and/or hospital discharge [21].

Inappropriate prescriptions of proton pump inhibitors (PPIs) in hospital and primary care have been widely reported [54,55]. In a study conducted by Ahrens et al in 31 primary care practices, for 58% (263/506) of patients discharged from 35 hospitals with a PPI recommendation in hospital discharge letters, an appropriate indication was missing. In 57% of these cases general practitioners followed this recommendation and continued the prescription for more than 1 month [54]. The strongest factor associated with appropriate and inappropriate continuation of PPI after discharge was PPI prescription prior to hospitalization [54]. Although PPIs are safe, they can cause adverse effects. PPI intake has been found to have a significant association with risk of community-acquired pneumonia [56,57], hip fractures [58], Clostridium difficile-associated diarrhea [55,61,62], and to reduce the therapeutic effects of bisphosphonates [59] and low-dose aspirin [60].

Unintentional medication continuation is not a problem isolated to a single drug class or disease [63]. Scales et al evaluated rates of and risk factors for potentially unintentional medication continuation following hospitalization in a population of elderly patients (≥ 66 years) [51]. They created distinct cohorts by identifying seniors not previously receiving four classes of medications typically used to treat or prevent complications of acute illness: antipsychotic medications; gastric acid suppressants (ie, histamine-2 blockers and proton pump inhibitors); benzodiazepines; and inhaled bronchodilators and steroids [51]. Prescription without documented indication occurred across all medication classes, from 12,209 patients (1.4 %) for antipsychotic medications to 34,140 patients (6.1 %) for gastric acid suppressants [51].

Several potential risk factors were considered. The relationship between multimorbidity and polypharmacy is well described in the literature, and several studies have identified a positive association between the number of drugs and the use of PIMs [64–66]. Conversely, Poudel et al did not find any association between polypharmacy and PIM use [11]. Associations were found between the use of PIMs, frailty status, and cognitive decline of patients at admission and at discharge [11], while no association was observed with age, gender, in-hospital falls, delirium, and functional decline [11,67]. Other potential risk factors of a high number of PIMs at discharge were a high number of pre-admission PIMs, discharge to a location other than home, and discharge from a surgical service [1,6,68,69]. Length of ICU stay and mechanical ventilation had a positive influence on the number of PIMs used by acutely ill older patients [11,63,69]. In the study of Scales et al, the greatest absolute risk factor across all medication groups was longer hospitalization. The increased OR for medication continuation after a hospitalization lasting more than 7 days ranged from 2.03 (95% CI 1.94–2.11) for respiratory inhalers to 6.35 (95% CI 5.91–6.82) for antipsychotic medications [51].

Inappropriate Medications: Where and How to Intervene?

Early detection of PIMs may prevent adverse drug events and improve geriatric care in older adults [13,70]. PIM prevalence can often be a useful indicator of prescribing quality [2]. Appropriate interventions and an improved quality of prescribed medications require appropriate assessment tools to decrease the number of patients discharged on these medications [71,72]. Medication reconciliation is the process of avoiding inadvertent inconsistencies within a patient’s drug regimen, which can occur during transitions in different setting of care [73]. A multidisciplinary team should be involved in the medication reconciliation at each care transition to reevaluate medications use according to the clinical conditions, cognitive/functional status and the coexistence of geriatric syndromes (eg, dementia, malnutrition, delirium, urinary incontinence, frailty) (Figure).

Criteria for the Evaluation of Inappropriate Medications Prescription

Explicit criteria derived from expert reports or published reviews are available (Table 2).

Beers criteria PIMs have been found to be associated with poor health outcomes, including confusion, falls, and mortality [7,75,78]. The STOPP (Screening Tool of Older Person’s potentially inappropriate Prescriptions) and START (Screening Tool to Alert doctors to the Right Treatment) are evidence-based sets of criteria that were developed in Ireland and updated in October 2014, including some of the new criteria for direct oral anticoagulants, drugs affecting or affected by renal system and anti-muscarinic/anticholinergic agents [79]. 

Several other sets of criteria have been published to identify PIMs, such as the FORTA (Fit for the Aged) and the PRISCUS [86] criteria. FORTA allows a disease-related evaluation revealing over-treatment and under-treatment, and medications are graded as follows: A, indispensable drug, clear-cut benefit in terms of efficacy/safety ratio proven in elderly patients for a given indication; B, drugs with proven or obvious efficacy in the elderly, but limited extent of effect or safety concerns; C, drugs with questionable efficacy/safety profiles in the elderly which should be avoided or omitted in the presence of too many drugs or side effects; D, avoid in the elderly, omit first, refer also to negative listings. Negative lists such as PRISCUS, which provide an explicit listing of drugs, independent of the diagnosis, are easy to use. On the other hand, constant updates are needed, and such lists carry the risk of an assumption that drugs not listed would be appropriate in every case [87]. Both sets of criteria have in common that they refer to long-term medication and drugs frequently used during the inpatient stay, such as antibiotics, are hardly taken into account [87].

The Medication Appropriateness Index measures overall prescribing quality through 10 separate but interrelated domains [8]. Three components are used to detect PIMs: indication, effectiveness, and duplication. However, it does not give any precise guidance in relation to specific medicines and therefore has limited application for objectively defining PIMs.

Another prescribing quality assessment tool is the Inappropriate Prescribing in the Elderly Tool (IPET), which consists of a list of the 14 most prevalent prescription errors identified from an extensive list of inappropriate prescription instances drawn up by an expert Canadian Consensus Panel [88,89].

Another approach to assess the appropriateness of drugs prescribed for older people is the use of Drug Utilization Reviews (DURs) [16]. DURs use consensus opinion by drug therapy experts to define standards or explicit criteria for a single drug, class of drugs, or group of drugs [16]. DURs typically use retrospective information from large, nonclinical administrative databases to identify problems such as dosage range, duration, therapeutic duplication, and drug interactions [90, 91]. Monane et al [92] evaluated a program designed to decrease the use of PIMs among the elderly through a computerized online DUR database. Computer alerts triggered telephone calls to physicians by pharmacists to discuss a potential problem and any therapeutic substitution options. From a total of 43,007 telepharmacy calls generated by the alerts, they were able to reach 19,368 physicians regarding 24,266 alerts (56%). The rate of change to a more appropriate therapeutic agent was 24% (5860), but ranged from 40% for long half-life benzodiazepines to 2% to 7% for drugs that theoretically were contraindicated by patients’ self-reported history [92].

Computerized Support Systems to Reduce Inappropriate Prescribing in the Elderly

Other potential solutions for reducing inappropriate medications may include continuing medical education, electronic medical records surveillance, routine clinical evaluation, and/or improved hand-off communication between discharging and accepting providers. Incorporating this assessment of medication appropriateness into the medication reconciliation process when patients are discharged or transferred out of the ICU has the potential to enhance patient safety [21,93]. A randomized controlled trial conducted by Raebel et al [94] reported the effectiveness of a computerized pharmacy alert system plus collaboration between health care professionals for decreasing potentially inappropriate medication dispensing in elderly patients. Another study showed that computer-based access to complete drug profiles and alerts about potential prescribing problems reduced the occurrence of potentially inappropriate prescriptions [95]. A summary of these studies is shown in Table 3.

Interdisciplinary Teams to Reduce Inappropriate Prescribing in the Elderly

Some studies evaluated the effect of multidisciplinary teamwork in improving inappropriate medication prescribing in the elderly (Table 4).

Pharmacists in hospitals can play a significant role in the initiation of changes to patient’s therapy and management [11] (Table 5).

Mattison et al recently emphasized that studies of PIMs should determine scenarios in which it is appropriate to prescribe PIMs, moving beyond simply labeling some medications as “potentially inappropriate,” since some PIMs are appropriately prescribed in specific clinical situations [109]. Morandi et al showed that the positive predictive value (PPV) depends on the drug type. Thus, when developing a screening system, one cannot be concerned only with high negative predictive value (NPV), one must consider PPV as well [6]. Screening tools that include medication classes with low PPV will generate false positive “flags” or warnings, which could lead to misguided clinical decisions [6]. The fact that many PIMs are not AIMs also reveals the value of using a multidisciplinary team to identify AIMs from lists of PIMs generated when discharge medication lists are screened [6,110]. Thus, a multidisciplinary team is needed to consider the clinical context to distinguish PIMs from AIMs [6]. Of course, such a team is not available in some settings; when resources are limited, knowledge of which PIMs are most likely AIMs (ie, have high PPVs) could guide the development of computer-based decision support systems or other surveillance approaches that are efficient in that particular setting [6].

Approaches for optimizing prescribing in this population mainly depend on patient needs and comorbidities and most available data are derived from randomized controlled trials involving a single drug. Such trials do not take into account the confounding effects of multiple comorbidities and patient preferences. Therefore, approaches for optimizing prescription management that are available for and validated in younger patients are not applicable to elderly subjects [3,111].

Conclusion

Clinicians should seek to identify and discontinue AIMs at 3 important transitions during a critically ill elderly patient’s hospital course: at the time of hospital or ICU admission; at ICU discharge; and at hospital discharge. The patient’s clinical situation should be reviewed at every transition points, ideally by a multidisciplinary team of clinicians, to judge the appropriateness of each PIM [6]. After the hospital discharge, patient’s medications should be then reviewed by a multidisciplinary team and/or by the primary care physician according to the final discharge destination (ie, home, nursing home, rehabilitation) by using any of the validated tools. Regardless of the approach, it is clear that standardized care processes, including enhanced clinical decision support, are necessary to ensure that physicians do not continue exposing our patients to unnecessary medications and harm after discharge.

Corresponding author: Alessandro Morandi, MD, MPH, [email protected].

Funding/support: Dr. Pandiharipande is supported by National Institutes of Health HL111111 (Bethesda, MD) and by the VA Clinical Science Research and Development Service (Washington, DC) and the National Institutes of Health AG027472 and AG035117 (Bethesda, MD).

Financial disclosures: Dr. Pratik Pandharipande has received a research grant from Hospira Inc in collaboration with the NIH.

From the Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (Dr. Marra), Division of Anesthesiology Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN (Dr. Hayhurst, Dr. Hughes, Dr. Pandharipande), Department of Clinical and Experimental Science, University of Brescia, Brescia, Italy (Dr. Marengoni), School of Medicine and Surgery,
University of Milano-Bicocca, Milan, Italy (Dr. Bellelli), and Rehabilitation and Aged Care Unit Hospital Ancelle, Cremona, Italy (Dr. Morandi).

Abstract

• Objective: To present an overview of the phenomenon of inappropriate medication prescription in older critically ill patients and examine possible strategies of intervention.
• Methods: Review of the literature.
• Results: Polypharmacy and inappropriate prescribing of medications in older persons may lead to a significant risk of adverse drug-related events and mortality. The intensive care unit (ICU) is often the place where potentially inappropriate medications (PIMs) are first prescribed. Common PIMs at ICU discharge are antipsychotics, benzodiazepines, opioids, anticholinergic medications, antidepressants, and drugs causing orthostatic hypotension. Different classes of medications, typically intended for short-term use, are sometimes inappropriately continued after discharge from the hospital. At admission, potential risk factors for PIM are multiple morbidities, polypharmacy, frailty and cognitive decline; at discharge, a high number of pre-admission PIMs, discharge to a location other than home, discharge from a surgical service, longer length of ICU and hospital stay, and mechanical ventilation. Inappropriate prescribing in older patients can be detected through either the use of explicit criteria, drug utilization reviews, and multidisciplinary teams, including a geriatrician and/or the involvement of a clinical pharmacist.
• Conclusion: Use of PIMs may be common in critical patients, both on admission and at discharge from ICU. Therapeutic reconciliation is recommended at every transition of care (eg, at hospital or ICU admission and discharge) in order to improve appropriateness of prescription.

Key words: elderly; intensive care unit; inappropriate medications; antipsychotics.

Since older persons are often affected by multiple chronic diseases and are prescribed several medications, the quality and safety of prescribing these medications has become a global health care issue [1–4]. Polypharmacy and inappropriate prescribing of medications among the elderly is receiving significant attention in the medical literature [5,6]. Inappropriate medications in the elderly can lead to falls, cognitive impairment and delirium, poorer health status, and higher mortality [7–10]. Medications are considered potentially inappropriate when (a) the risks of treatment outweigh the benefits [11], (b) they are prescribed for periods longer than clinically indicated or without any clear indication, (c) they are not prescribed when indicated [12], and (d) they are likely to interact with other drugs and diseases. Medications included in this category are often referred to as potentially inappropriate medications (PIMs), as in some situations their use is justified; however, if the risk of harm from the drug is judged to outweigh the potential clinical benefit after an individual patient’s clinical circumstances are considered, these drugs are considered “actually inappropriate medications” (AIMs) [6].

Advancing age is associated with substantial pharmacokinetic and pharmacodynamics changes, such as altered distribution volumes and altered permeability of the blood-brain barrier, impaired liver metabolism and renal capacity, up- and down-regulation of target receptors, transmitters, and signaling pathways changes, impaired homeostasis, and increased risk of adverse drug reactions (ADRs) that lead to increased mortality and morbidity and higher health care costs [2,11,13–19]. Studies show that ADRs cause approximately 5% of hospital admissions in the general population, but the percentage rises to 10% in older persons [20].

Avoiding PIMs represents a strategy aimed at reducing drug-related mortality and morbidity. This article provides an overview of the phenomenon of inappropriate medication prescription in older critically ill patients and examines available strategies of intervention.

Inappropriate Medications at ICU Discharge

Though PIMs and AIMs may be identified at the time of hospital discharge, the intensive care unit (ICU) is often the place where these medications are first prescribed [21]. Acute hospitalization may increase PIM prescribing because of newly prescribed medications, the presence of multiple prescribers, inadequate medication reconciliation, and a lack of care coordination among inpatient providers or in the transition back to outpatient care [22)].

A known complication of critical illness and ICU stay is a significant increase in psychological symptoms, sleep cycle alterations, delirium, and cognitive impairment, which may be associated with increased prescription of specific PIMs, such as antipsychotics or benzodiazepines [6,23,24]. Despite the lack of reliable evidence supporting their use in the ICU, antipsychotic agents are used routinely in ICU patients [25] to treat a variety of conditions, such as substance withdrawal, agitation not responding to other therapies, or delirium. Results from a multicenter study of 164,996 hospitalizations across 71 academic medical centers in the US showed that 1 out of 10 ICU patients received an antipsychotic during their hospital stay [25]. Jasiak et al estimated that one-third of patients initiated on an atypical antipsychotic therapy for ICU delirium received a hospital discharge prescription for these medications, with a potential annual outpatient medication cost of approximately $2255 per patient [26].

One potential consequence of antipsychotic use in the ICU is their continuation after the transition to other clinical settings, including discharge from the hospital [27] (Table 1). 

When examining the specific factors that may contribute to a patient being discharged on an antipsychotic, authors found that the specific antipsychotic used correlated with risk of continuation [27,30], with atypical antipsychotics having a greater likelihood of being continued than haloperidol [27,30]. Possible explanation for these results could be that physicians perceive less long-term risk from atypical agents, so may be more likely to continue them on discharge [30]. However, such an approach is not always safe. Indeed, although atypical antipsychotic agents tend to cause less tardive dyskinesia, they are known to be associated with similar rates of other adverse events compared with typical agents and have been linked to an increased risk of sudden cardiac death and pneumonia in the elderly [31,32].

Other factors independently associated with being discharged on a new antipsychotic medication were the severity of the acute illness as measured with the Acute Physiology and Chronic Health Evaluation II score at ICU admission (odds ratio [OR] 1 [95% confidence interval {CI}, 1.0–1.1]) and days treated with benzodiazepines (OR 1.1 [95% CI, 1.0–1.14]) [30]. Conversely, perhaps due to different practice patterns, Tomichek et al did not find an association between benzodiazepines administration and antipsychotic prescription at discharge in post hoc analyses [27].

Another possible reason for antipsychotic continuation may reside in the indication chosen [33]. Antipsychotic agents have sedative properties and they might be used to optimize sleep during hospitalization, despite the lack of evidence to support this indication [34]. Other factors potentially contributing to continuation of antipsychotics may include persistent delirium and agitation, newly diagnosed psychiatric illness, and difficulties experienced by physicians in deprescribing [35] with improper/incomplete medication reconciliation [33].

The continuation of antipsychotic therapy increased 30-day readmission rates in patients compared to those who had therapy stopped before discharge [33]. In addition to the well-described cardiac effects (prolonged QT interval), neuroleptic malignant syndrome and extrapyramidal symptoms may also occur, and longer-term use can predispose patients to metabolic disturbances, falls, and increase the risk of death in elderly patients with dementia [31].

Benzodiazepines and sedative hypnotics are commonly used to treat insomnia and agitation in older adults despite significant risk. Benzodiazepine administration was found to be an independent risk factor for a daily transition to delirium [36,37]. Pandharipande et al reported that every unit dose of lorazepam was associated with a higher risk for daily transition to delirium (OR 1.2, 95% CI 1.1–1.4, P = 0.003) [36] in critically ill patients. A more recent analysis found for every 5 mg of midazolam administered to a patient who is awake and without delirium, there is a 4% chance that this patient will develop delirium the next ICU day [37].

Given that the risk for benzodiazepine-associated delirium is dose-dependent, clinicians should use strategies known to reduce the daily number of benzodiazepines administered that often includes the use of a sedative associated with less delirium occurrence, such as dexmedetomidine or propofol [38]. Evidence has shown that long-term use of benzodiazepines has little benefit with many risks, including an increased susceptibility to spontaneous bacterial infection [39,40] and mortality in the setting of infection [41]. Nakafero et al showed that exposure to benzodiazepines was associated with increased occurrence of both influenza-like-illness–related pneumonia and mortality. Benzodiazepine use was associated also with increased occurrence of asthma exacerbation and with increased all-cause mortality during a median follow-up of 2 years in a cohort of asthmatic patients [42] as well with an increased risk of pneumonia and long-term mortality in patients with a prior diagnosis of community- acquired pneumonia [40]. Long-term use of benzodiazepines is also associated with increased risk of falls [43–45], cognitive impairment [46–48] and disability [49,50].

Other common types of PIMs at ICU discharge were opioids, anticholinergic medications, antidepressants, and drugs causing orthostatic hypotension [6]. Of the anticholinergic AIMs, H2 blockers (61%) and promethazine (15%) were the most common [6]. Only 16% of opioids, 23% of antidepressants, and 10% of drugs causing orthostatic hypotension were found to be actually inappropriate after the patient’s circumstances were considered (eg, postoperative pain control, a new diagnosis of major depressive disorder) [6].

Inappropriate Medications at Hospital Discharge

Medications typically intended for short-term use during acute illness are sometimes continued after discharge without documented indication [51]. Poudel et al found that in 206 patients 70 years of age and older discharged to residential aged care facilities from acute care, at least 1 PIM was identified in 112 (54.4%) patients on admission and 102 (49.5%) patients on discharge [11]. Commonly prescribed PIM categories, at both admission and discharge, were central nervous system, cardiovascular, gastrointestinal, and respiratory drugs and analgesics [6,11,52,53]. Of all medications prescribed at admission (1728), 10.8% were PIMs, and at discharge, of 1759 medications, 9.6% were PIMs. Of the total 187 PIMs on admission, 56 (30%) were stopped, and 131 (70%) were continued; 32 new PIMs were introduced [11].

Morandi et al in 2011 conducted a prospective cohort study including 120 patients age ≥ 60 who were discharged after receiving care in a medical, surgical, or cardiovascular ICU for shock or respiratory failure. The percentage of patients prescribed at least 1 PIM increased from 66% at pre-admission to 85% at discharge. The number of patients with 0 PIMs dropped from 34% at preadmission to 14% at discharge, and the number of patients with 3 or more PIMS increased from 16% at preadmission to 37% at discharge. While it is possible that these drugs may be appropriate when started during an acute illness in the ICU (eg, stress ulcer prophylaxis with H2-antagonists in mechanically ventilated patients), most should have been discontinued at ICU and/or hospital discharge [21].

Inappropriate prescriptions of proton pump inhibitors (PPIs) in hospital and primary care have been widely reported [54,55]. In a study conducted by Ahrens et al in 31 primary care practices, for 58% (263/506) of patients discharged from 35 hospitals with a PPI recommendation in hospital discharge letters, an appropriate indication was missing. In 57% of these cases general practitioners followed this recommendation and continued the prescription for more than 1 month [54]. The strongest factor associated with appropriate and inappropriate continuation of PPI after discharge was PPI prescription prior to hospitalization [54]. Although PPIs are safe, they can cause adverse effects. PPI intake has been found to have a significant association with risk of community-acquired pneumonia [56,57], hip fractures [58], Clostridium difficile-associated diarrhea [55,61,62], and to reduce the therapeutic effects of bisphosphonates [59] and low-dose aspirin [60].

Unintentional medication continuation is not a problem isolated to a single drug class or disease [63]. Scales et al evaluated rates of and risk factors for potentially unintentional medication continuation following hospitalization in a population of elderly patients (≥ 66 years) [51]. They created distinct cohorts by identifying seniors not previously receiving four classes of medications typically used to treat or prevent complications of acute illness: antipsychotic medications; gastric acid suppressants (ie, histamine-2 blockers and proton pump inhibitors); benzodiazepines; and inhaled bronchodilators and steroids [51]. Prescription without documented indication occurred across all medication classes, from 12,209 patients (1.4 %) for antipsychotic medications to 34,140 patients (6.1 %) for gastric acid suppressants [51].

Several potential risk factors were considered. The relationship between multimorbidity and polypharmacy is well described in the literature, and several studies have identified a positive association between the number of drugs and the use of PIMs [64–66]. Conversely, Poudel et al did not find any association between polypharmacy and PIM use [11]. Associations were found between the use of PIMs, frailty status, and cognitive decline of patients at admission and at discharge [11], while no association was observed with age, gender, in-hospital falls, delirium, and functional decline [11,67]. Other potential risk factors of a high number of PIMs at discharge were a high number of pre-admission PIMs, discharge to a location other than home, and discharge from a surgical service [1,6,68,69]. Length of ICU stay and mechanical ventilation had a positive influence on the number of PIMs used by acutely ill older patients [11,63,69]. In the study of Scales et al, the greatest absolute risk factor across all medication groups was longer hospitalization. The increased OR for medication continuation after a hospitalization lasting more than 7 days ranged from 2.03 (95% CI 1.94–2.11) for respiratory inhalers to 6.35 (95% CI 5.91–6.82) for antipsychotic medications [51].

Inappropriate Medications: Where and How to Intervene?

Early detection of PIMs may prevent adverse drug events and improve geriatric care in older adults [13,70]. PIM prevalence can often be a useful indicator of prescribing quality [2]. Appropriate interventions and an improved quality of prescribed medications require appropriate assessment tools to decrease the number of patients discharged on these medications [71,72]. Medication reconciliation is the process of avoiding inadvertent inconsistencies within a patient’s drug regimen, which can occur during transitions in different setting of care [73]. A multidisciplinary team should be involved in the medication reconciliation at each care transition to reevaluate medications use according to the clinical conditions, cognitive/functional status and the coexistence of geriatric syndromes (eg, dementia, malnutrition, delirium, urinary incontinence, frailty) (Figure).

Criteria for the Evaluation of Inappropriate Medications Prescription

Explicit criteria derived from expert reports or published reviews are available (Table 2).

Beers criteria PIMs have been found to be associated with poor health outcomes, including confusion, falls, and mortality [7,75,78]. The STOPP (Screening Tool of Older Person’s potentially inappropriate Prescriptions) and START (Screening Tool to Alert doctors to the Right Treatment) are evidence-based sets of criteria that were developed in Ireland and updated in October 2014, including some of the new criteria for direct oral anticoagulants, drugs affecting or affected by renal system and anti-muscarinic/anticholinergic agents [79]. 

Several other sets of criteria have been published to identify PIMs, such as the FORTA (Fit for the Aged) and the PRISCUS [86] criteria. FORTA allows a disease-related evaluation revealing over-treatment and under-treatment, and medications are graded as follows: A, indispensable drug, clear-cut benefit in terms of efficacy/safety ratio proven in elderly patients for a given indication; B, drugs with proven or obvious efficacy in the elderly, but limited extent of effect or safety concerns; C, drugs with questionable efficacy/safety profiles in the elderly which should be avoided or omitted in the presence of too many drugs or side effects; D, avoid in the elderly, omit first, refer also to negative listings. Negative lists such as PRISCUS, which provide an explicit listing of drugs, independent of the diagnosis, are easy to use. On the other hand, constant updates are needed, and such lists carry the risk of an assumption that drugs not listed would be appropriate in every case [87]. Both sets of criteria have in common that they refer to long-term medication and drugs frequently used during the inpatient stay, such as antibiotics, are hardly taken into account [87].

The Medication Appropriateness Index measures overall prescribing quality through 10 separate but interrelated domains [8]. Three components are used to detect PIMs: indication, effectiveness, and duplication. However, it does not give any precise guidance in relation to specific medicines and therefore has limited application for objectively defining PIMs.

Another prescribing quality assessment tool is the Inappropriate Prescribing in the Elderly Tool (IPET), which consists of a list of the 14 most prevalent prescription errors identified from an extensive list of inappropriate prescription instances drawn up by an expert Canadian Consensus Panel [88,89].

Another approach to assess the appropriateness of drugs prescribed for older people is the use of Drug Utilization Reviews (DURs) [16]. DURs use consensus opinion by drug therapy experts to define standards or explicit criteria for a single drug, class of drugs, or group of drugs [16]. DURs typically use retrospective information from large, nonclinical administrative databases to identify problems such as dosage range, duration, therapeutic duplication, and drug interactions [90, 91]. Monane et al [92] evaluated a program designed to decrease the use of PIMs among the elderly through a computerized online DUR database. Computer alerts triggered telephone calls to physicians by pharmacists to discuss a potential problem and any therapeutic substitution options. From a total of 43,007 telepharmacy calls generated by the alerts, they were able to reach 19,368 physicians regarding 24,266 alerts (56%). The rate of change to a more appropriate therapeutic agent was 24% (5860), but ranged from 40% for long half-life benzodiazepines to 2% to 7% for drugs that theoretically were contraindicated by patients’ self-reported history [92].

Computerized Support Systems to Reduce Inappropriate Prescribing in the Elderly

Other potential solutions for reducing inappropriate medications may include continuing medical education, electronic medical records surveillance, routine clinical evaluation, and/or improved hand-off communication between discharging and accepting providers. Incorporating this assessment of medication appropriateness into the medication reconciliation process when patients are discharged or transferred out of the ICU has the potential to enhance patient safety [21,93]. A randomized controlled trial conducted by Raebel et al [94] reported the effectiveness of a computerized pharmacy alert system plus collaboration between health care professionals for decreasing potentially inappropriate medication dispensing in elderly patients. Another study showed that computer-based access to complete drug profiles and alerts about potential prescribing problems reduced the occurrence of potentially inappropriate prescriptions [95]. A summary of these studies is shown in Table 3.

Interdisciplinary Teams to Reduce Inappropriate Prescribing in the Elderly

Some studies evaluated the effect of multidisciplinary teamwork in improving inappropriate medication prescribing in the elderly (Table 4).

Pharmacists in hospitals can play a significant role in the initiation of changes to patient’s therapy and management [11] (Table 5).

Mattison et al recently emphasized that studies of PIMs should determine scenarios in which it is appropriate to prescribe PIMs, moving beyond simply labeling some medications as “potentially inappropriate,” since some PIMs are appropriately prescribed in specific clinical situations [109]. Morandi et al showed that the positive predictive value (PPV) depends on the drug type. Thus, when developing a screening system, one cannot be concerned only with high negative predictive value (NPV), one must consider PPV as well [6]. Screening tools that include medication classes with low PPV will generate false positive “flags” or warnings, which could lead to misguided clinical decisions [6]. The fact that many PIMs are not AIMs also reveals the value of using a multidisciplinary team to identify AIMs from lists of PIMs generated when discharge medication lists are screened [6,110]. Thus, a multidisciplinary team is needed to consider the clinical context to distinguish PIMs from AIMs [6]. Of course, such a team is not available in some settings; when resources are limited, knowledge of which PIMs are most likely AIMs (ie, have high PPVs) could guide the development of computer-based decision support systems or other surveillance approaches that are efficient in that particular setting [6].

Approaches for optimizing prescribing in this population mainly depend on patient needs and comorbidities and most available data are derived from randomized controlled trials involving a single drug. Such trials do not take into account the confounding effects of multiple comorbidities and patient preferences. Therefore, approaches for optimizing prescription management that are available for and validated in younger patients are not applicable to elderly subjects [3,111].

Conclusion

Clinicians should seek to identify and discontinue AIMs at 3 important transitions during a critically ill elderly patient’s hospital course: at the time of hospital or ICU admission; at ICU discharge; and at hospital discharge. The patient’s clinical situation should be reviewed at every transition points, ideally by a multidisciplinary team of clinicians, to judge the appropriateness of each PIM [6]. After the hospital discharge, patient’s medications should be then reviewed by a multidisciplinary team and/or by the primary care physician according to the final discharge destination (ie, home, nursing home, rehabilitation) by using any of the validated tools. Regardless of the approach, it is clear that standardized care processes, including enhanced clinical decision support, are necessary to ensure that physicians do not continue exposing our patients to unnecessary medications and harm after discharge.

Corresponding author: Alessandro Morandi, MD, MPH, [email protected].

Funding/support: Dr. Pandiharipande is supported by National Institutes of Health HL111111 (Bethesda, MD) and by the VA Clinical Science Research and Development Service (Washington, DC) and the National Institutes of Health AG027472 and AG035117 (Bethesda, MD).

Financial disclosures: Dr. Pratik Pandharipande has received a research grant from Hospira Inc in collaboration with the NIH.

ABSTRACT

Complex glenoid bone deformities present the treating surgeon with a complex reconstructive challenge. Although glenoid bone loss can be encountered in the primary setting (degenerative, congenital, post-traumatic), severe glenoid bone loss is encountered in most revision total shoulder arthroplasties. Severe glenoid bone loss is treated with various techniques including hemiarthroplasty, eccentric reaming, and glenoid reconstruction with bone autografts and allografts. Despite encouraging short- to mid-term results reported with these reconstruction techniques, the clinical and radiographic outcomes remain inconsistent and the high number of complications is a concern. To overcome this problem, more recently augmented components and patient specific implants were introduced. Using the computer-aided design and computer-aided manufacturing technology patient-specific implants have been created to reconstruct the glenoid vault in cases of severe glenoid bone loss.

In this article we describe a patient specific glenoid implant, its indication, technical aspects and surgical technique, based on the author's experience as well as a review of the current literature on custom glenoid implants.

Continue to: Total shoulder arthroplasty...

Total shoulder arthroplasty (TSA) is an effective operation for providing pain relief and improving function in patients with end-stage degenerative shoulder disease that is nonresponsive to nonoperative treatments.^1-4 With the increasing number of arthroplasties performed, and the expanding indication for shoulder arthroplasty, the number of revision shoulder arthroplasties is also increasing.^5-14 Complex glenoid bone deformities present the treating surgeon with a complex reconstructive challenge. Although glenoid bone loss can be seen in the primary setting (degenerative, congenital, and post-traumatic), severe glenoid bone loss is encountered mostly in revision TSAs.

Historically, patients with severe glenoid bone loss were treated with a hemiarthroplasty.^15-17 However, due to inferior outcomes associated with the use of shoulder hemiarthroplasties compared with TSA in these cases,^18-20 various techniques were developed with the aim of realigning the glenoid axis and securing the implants into the deficient glenoid vault.^21-25 Options have included eccentric reaming, glenoid reconstruction with bone autografts and allografts, and more recently augmented components and patient-specific implants. Studies with eccentric reaming and reconstruction with bone graft during complex shoulder arthroplasty have reported encouraging short- to mid-term results, but the clinical and radiographic outcomes remain inconsistent, and the high number of complications is a concern.^25-28

Complications with these techniques include component loosening, graft resorption, nonunion, failure of graft incorporation, infection, and instability.^25-28

Computer-aided design and computer-aided manufacturing (CAD/CAM) of patient-specific implants have been used successfully by hip arthroplasty surgeons to deal with complex acetabular reconstructions in the setting of severe bone loss. More recently, the same technology has been used to reconstruct the glenoid vault in cases of severe glenoid bone loss.

In this article, we describe a patient-specific glenoid implant, its indication, and both technical aspects and the surgical technique, based on the authors’ experience as well as a review of the current literature on custom glenoid implants.

Continue to: PATIENT-SPECIFIC GLENOID COMPONENT

The Vault Reconstruction System ([VRS], Zimmer Biomet) is a patient-specific glenoid vault reconstruction system developed with the use of CAD/CAM to address severe glenoid bone loss encountered during shoulder arthroplasty. For several years, the VRS was available only as a custom implant according to the US Food and Drug Administration rules, and therefore its use was limited to a few cases per year. Recently, a 510(k) envelope clearance was granted to use the VRS in reverse TSA to address significant glenoid bone defects.

The VRS is made of porous plasma spray titanium to provide high strength and flexibility, and allows for biologic fixation. This system can accommodate a restricted bone loss envelope of about 50 mm × 50 mm × 35 mm according to the previous experience of the manufacturer in the custom scenario, covering 96% of defects previously addressed. One 6.5-mm nonlocking central screw and a minimum of four 4.75-mm nonlocking or locking peripheral screws are required for optimal fixation of the implant in the native scapula. A custom boss can be added in to enhance fixation in the native scapula when the bone is sufficient. To facilitate the surgical procedure, a trial implant, a bone model of the scapula, and a custom boss reaming guide are 3-dimensional (3-D) and printed in sterilizable material. These are all provided as single-use disposable instruments and can be available for surgeons during both the initial plan review and surgery.

PREOPERATIVE PLANNING

Patients undergo a preoperative fine-cut 2-dimensional computed tomography scan of the scapula and adjacent humerus following a predefined protocol with a slice thickness of 2 mm to 3 mm. An accurate 3-D bone model of the scapula is obtained using a 3-D image processing software system (Figure 1). The 3-D scapular model is used to create a patient-specific glenoid implant proposal that is approved by the surgeon (Figure 2). Implant position, orientation, size, screw trajectory, and recommended bone removal, if necessary, are determined to create a more normal glenohumeral center of rotation and to secure a glenoid implant in severely deficient glenoid bone (Figure 3). Once the implant design is approved by the surgeon, the final patient-specific implant is manufactured.

SURGICAL TECHNIQUE

The exposure of the glenoid is a critical step for the successful implantation of the patient-specific glenoid implant. Soft tissue and scar tissue around the glenoid must be removed to allow for optimal fit of the custom-made reaming guide. Also, removal of the entire capsulolabral complex on the anteroinferior rim of the glenoid is essential to both enhance glenoid exposure and to allow a perfect fit of the guide to the pathologic bone stock. Attention should be paid during débridement and/or implant removal in case of revision, to make sure that no excessive bone is removed because the patient-specific guide is referenced to this anatomy. Excessive bone removal can change the orientation of the patient-specific guide and ultimately the fixation of the implant. Once the custom-made patient-specific guide is positioned, a 3.2-mm Steinmann pin is placed through the inserter for temporary fixation. The pin should engage or perforate the medial cortical wall to ensure that the subsequent reamer has a stable cannula over which to ream. After the glenoid is reamed, the final implant can be placed in the ideal position according to the preoperative planning. A central 6.5-mm nonlocking central screw and 4.75-mm nonlocking or locking peripheral screws are required to complete the fixation of the implant in the native scapula. Once the patient-specific glenoid component is positioned and strongly fixed to the bone, the glenosphere can be positioned according to the preoperative planning, and the reverse shoulder arthroplasty can be completed in the usual fashion.

CASE EXAMPLES

A 68-year-old woman underwent a TSA for end-stage osteoarthritis in 2000. The implant failed due to a cuff failure. The patient underwent several surgeries, including an open cuff repair, with no success. She had no active elevation preoperatively. Because of the significant glenoid bone loss, a patient-specific glenoid reconstruction was planned. Within 24 months after this surgery, the patient was able to get her hand to her head and elevate to 90º (Figures 4A-4F).

Continue to: In October 2013...

In October 2013, a 68-year-old man underwent a TSA for end-stage osteoarthritis. After 18 months, the implant failed due to active Propionibacterium acnes infection, which required excisional arthroplasty with insertion of an antibiotic spacer. Significant glenoid bone loss (Figure 5) and global soft-tissue deficiency caused substantial disability and led to an indication for a reverse TSA with a patient-specific glenoid vault reconstruction (Figures 6A-6D) after infection eradication. Within 20 months after this surgery, the patient had resumed a satisfactory range of motion (130º forward elevation, 20º external rotation) and outcome.

DISCUSSION

Although glenoid bone loss is often seen in the primary setting (degenerative, congenital, and post-traumatic), severe glenoid bone loss is encountered in most revision TSAs. The best treatment method for massive glenoid bone defects during complex shoulder arthroplasty remains uncertain. Options have included eccentric reaming, glenoid reconstruction with bone allograft and autograft, and more recently augmented components and patient-specific implants.^21-25 The advent and availability of CAD/CAM technology have enabled shoulder surgeons to create patient-specific metal solutions to these challenging cases. Currently, only a few reports exist in the literature on patient-specific glenoid components in the setting of severe bone loss.^29-32

Chammaa and colleagues²⁹ reported the outcomes of 37 patients with a hip-inspired glenoid component (Total Shoulder Replacement, Stanmore Implants Worldwide). The 5-year results with this implant were promising, with a 16% revision rate and only 1 case of glenoid loosening.

Stoffelen and colleagues³⁰ recently described the successful use of a patient-specific anatomic metal-backed glenoid component for the management of severe glenoid bone loss with excellent results at 2.5 years of follow-up. A different approach was pursued by Gunther and Lynch,³¹ who reported on 7 patients with a custom inset glenoid implant for deficient glenoid vaults. These circular anatomic, custom-made glenoid components were created with the intention of placing the implants partially inside the glenoid vault and relying partially on sclerotic cortical bone. Despite excellent results at 3 years of follow-up, their use is limited to specific defect geometries and cannot be used in cases of extreme bone loss.

CONCLUSION

We have described the use of a patient-specific glenoid component in 2 patients with severe glenoid bone loss. Despite the satisfactory clinical and short-term radiographic results, we acknowledge that longer-term follow-up is needed to confirm the efficacy of this type of reconstruction. We believe that patient-specific glenoid components represent a valuable addition to the armamentarium of shoulder surgeons who address complex glenoid bone deformities.

ABSTRACT

Complex glenoid bone deformities present the treating surgeon with a complex reconstructive challenge. Although glenoid bone loss can be encountered in the primary setting (degenerative, congenital, post-traumatic), severe glenoid bone loss is encountered in most revision total shoulder arthroplasties. Severe glenoid bone loss is treated with various techniques including hemiarthroplasty, eccentric reaming, and glenoid reconstruction with bone autografts and allografts. Despite encouraging short- to mid-term results reported with these reconstruction techniques, the clinical and radiographic outcomes remain inconsistent and the high number of complications is a concern. To overcome this problem, more recently augmented components and patient specific implants were introduced. Using the computer-aided design and computer-aided manufacturing technology patient-specific implants have been created to reconstruct the glenoid vault in cases of severe glenoid bone loss.

In this article we describe a patient specific glenoid implant, its indication, technical aspects and surgical technique, based on the author's experience as well as a review of the current literature on custom glenoid implants.

Continue to: Total shoulder arthroplasty...

Total shoulder arthroplasty (TSA) is an effective operation for providing pain relief and improving function in patients with end-stage degenerative shoulder disease that is nonresponsive to nonoperative treatments.^1-4 With the increasing number of arthroplasties performed, and the expanding indication for shoulder arthroplasty, the number of revision shoulder arthroplasties is also increasing.^5-14 Complex glenoid bone deformities present the treating surgeon with a complex reconstructive challenge. Although glenoid bone loss can be seen in the primary setting (degenerative, congenital, and post-traumatic), severe glenoid bone loss is encountered mostly in revision TSAs.

Historically, patients with severe glenoid bone loss were treated with a hemiarthroplasty.^15-17 However, due to inferior outcomes associated with the use of shoulder hemiarthroplasties compared with TSA in these cases,^18-20 various techniques were developed with the aim of realigning the glenoid axis and securing the implants into the deficient glenoid vault.^21-25 Options have included eccentric reaming, glenoid reconstruction with bone autografts and allografts, and more recently augmented components and patient-specific implants. Studies with eccentric reaming and reconstruction with bone graft during complex shoulder arthroplasty have reported encouraging short- to mid-term results, but the clinical and radiographic outcomes remain inconsistent, and the high number of complications is a concern.^25-28

Complications with these techniques include component loosening, graft resorption, nonunion, failure of graft incorporation, infection, and instability.^25-28

Computer-aided design and computer-aided manufacturing (CAD/CAM) of patient-specific implants have been used successfully by hip arthroplasty surgeons to deal with complex acetabular reconstructions in the setting of severe bone loss. More recently, the same technology has been used to reconstruct the glenoid vault in cases of severe glenoid bone loss.

In this article, we describe a patient-specific glenoid implant, its indication, and both technical aspects and the surgical technique, based on the authors’ experience as well as a review of the current literature on custom glenoid implants.

Continue to: PATIENT-SPECIFIC GLENOID COMPONENT

The Vault Reconstruction System ([VRS], Zimmer Biomet) is a patient-specific glenoid vault reconstruction system developed with the use of CAD/CAM to address severe glenoid bone loss encountered during shoulder arthroplasty. For several years, the VRS was available only as a custom implant according to the US Food and Drug Administration rules, and therefore its use was limited to a few cases per year. Recently, a 510(k) envelope clearance was granted to use the VRS in reverse TSA to address significant glenoid bone defects.

The VRS is made of porous plasma spray titanium to provide high strength and flexibility, and allows for biologic fixation. This system can accommodate a restricted bone loss envelope of about 50 mm × 50 mm × 35 mm according to the previous experience of the manufacturer in the custom scenario, covering 96% of defects previously addressed. One 6.5-mm nonlocking central screw and a minimum of four 4.75-mm nonlocking or locking peripheral screws are required for optimal fixation of the implant in the native scapula. A custom boss can be added in to enhance fixation in the native scapula when the bone is sufficient. To facilitate the surgical procedure, a trial implant, a bone model of the scapula, and a custom boss reaming guide are 3-dimensional (3-D) and printed in sterilizable material. These are all provided as single-use disposable instruments and can be available for surgeons during both the initial plan review and surgery.

PREOPERATIVE PLANNING

Patients undergo a preoperative fine-cut 2-dimensional computed tomography scan of the scapula and adjacent humerus following a predefined protocol with a slice thickness of 2 mm to 3 mm. An accurate 3-D bone model of the scapula is obtained using a 3-D image processing software system (Figure 1). The 3-D scapular model is used to create a patient-specific glenoid implant proposal that is approved by the surgeon (Figure 2). Implant position, orientation, size, screw trajectory, and recommended bone removal, if necessary, are determined to create a more normal glenohumeral center of rotation and to secure a glenoid implant in severely deficient glenoid bone (Figure 3). Once the implant design is approved by the surgeon, the final patient-specific implant is manufactured.

SURGICAL TECHNIQUE

The exposure of the glenoid is a critical step for the successful implantation of the patient-specific glenoid implant. Soft tissue and scar tissue around the glenoid must be removed to allow for optimal fit of the custom-made reaming guide. Also, removal of the entire capsulolabral complex on the anteroinferior rim of the glenoid is essential to both enhance glenoid exposure and to allow a perfect fit of the guide to the pathologic bone stock. Attention should be paid during débridement and/or implant removal in case of revision, to make sure that no excessive bone is removed because the patient-specific guide is referenced to this anatomy. Excessive bone removal can change the orientation of the patient-specific guide and ultimately the fixation of the implant. Once the custom-made patient-specific guide is positioned, a 3.2-mm Steinmann pin is placed through the inserter for temporary fixation. The pin should engage or perforate the medial cortical wall to ensure that the subsequent reamer has a stable cannula over which to ream. After the glenoid is reamed, the final implant can be placed in the ideal position according to the preoperative planning. A central 6.5-mm nonlocking central screw and 4.75-mm nonlocking or locking peripheral screws are required to complete the fixation of the implant in the native scapula. Once the patient-specific glenoid component is positioned and strongly fixed to the bone, the glenosphere can be positioned according to the preoperative planning, and the reverse shoulder arthroplasty can be completed in the usual fashion.

CASE EXAMPLES

A 68-year-old woman underwent a TSA for end-stage osteoarthritis in 2000. The implant failed due to a cuff failure. The patient underwent several surgeries, including an open cuff repair, with no success. She had no active elevation preoperatively. Because of the significant glenoid bone loss, a patient-specific glenoid reconstruction was planned. Within 24 months after this surgery, the patient was able to get her hand to her head and elevate to 90º (Figures 4A-4F).

Continue to: In October 2013...

In October 2013, a 68-year-old man underwent a TSA for end-stage osteoarthritis. After 18 months, the implant failed due to active Propionibacterium acnes infection, which required excisional arthroplasty with insertion of an antibiotic spacer. Significant glenoid bone loss (Figure 5) and global soft-tissue deficiency caused substantial disability and led to an indication for a reverse TSA with a patient-specific glenoid vault reconstruction (Figures 6A-6D) after infection eradication. Within 20 months after this surgery, the patient had resumed a satisfactory range of motion (130º forward elevation, 20º external rotation) and outcome.

DISCUSSION

Although glenoid bone loss is often seen in the primary setting (degenerative, congenital, and post-traumatic), severe glenoid bone loss is encountered in most revision TSAs. The best treatment method for massive glenoid bone defects during complex shoulder arthroplasty remains uncertain. Options have included eccentric reaming, glenoid reconstruction with bone allograft and autograft, and more recently augmented components and patient-specific implants.^21-25 The advent and availability of CAD/CAM technology have enabled shoulder surgeons to create patient-specific metal solutions to these challenging cases. Currently, only a few reports exist in the literature on patient-specific glenoid components in the setting of severe bone loss.^29-32

Chammaa and colleagues²⁹ reported the outcomes of 37 patients with a hip-inspired glenoid component (Total Shoulder Replacement, Stanmore Implants Worldwide). The 5-year results with this implant were promising, with a 16% revision rate and only 1 case of glenoid loosening.

Stoffelen and colleagues³⁰ recently described the successful use of a patient-specific anatomic metal-backed glenoid component for the management of severe glenoid bone loss with excellent results at 2.5 years of follow-up. A different approach was pursued by Gunther and Lynch,³¹ who reported on 7 patients with a custom inset glenoid implant for deficient glenoid vaults. These circular anatomic, custom-made glenoid components were created with the intention of placing the implants partially inside the glenoid vault and relying partially on sclerotic cortical bone. Despite excellent results at 3 years of follow-up, their use is limited to specific defect geometries and cannot be used in cases of extreme bone loss.

CONCLUSION

We have described the use of a patient-specific glenoid component in 2 patients with severe glenoid bone loss. Despite the satisfactory clinical and short-term radiographic results, we acknowledge that longer-term follow-up is needed to confirm the efficacy of this type of reconstruction. We believe that patient-specific glenoid components represent a valuable addition to the armamentarium of shoulder surgeons who address complex glenoid bone deformities.

ABSTRACT

Complex glenoid bone deformities present the treating surgeon with a complex reconstructive challenge. Although glenoid bone loss can be encountered in the primary setting (degenerative, congenital, post-traumatic), severe glenoid bone loss is encountered in most revision total shoulder arthroplasties. Severe glenoid bone loss is treated with various techniques including hemiarthroplasty, eccentric reaming, and glenoid reconstruction with bone autografts and allografts. Despite encouraging short- to mid-term results reported with these reconstruction techniques, the clinical and radiographic outcomes remain inconsistent and the high number of complications is a concern. To overcome this problem, more recently augmented components and patient specific implants were introduced. Using the computer-aided design and computer-aided manufacturing technology patient-specific implants have been created to reconstruct the glenoid vault in cases of severe glenoid bone loss.

In this article we describe a patient specific glenoid implant, its indication, technical aspects and surgical technique, based on the author's experience as well as a review of the current literature on custom glenoid implants.

Continue to: Total shoulder arthroplasty...

Total shoulder arthroplasty (TSA) is an effective operation for providing pain relief and improving function in patients with end-stage degenerative shoulder disease that is nonresponsive to nonoperative treatments.^1-4 With the increasing number of arthroplasties performed, and the expanding indication for shoulder arthroplasty, the number of revision shoulder arthroplasties is also increasing.^5-14 Complex glenoid bone deformities present the treating surgeon with a complex reconstructive challenge. Although glenoid bone loss can be seen in the primary setting (degenerative, congenital, and post-traumatic), severe glenoid bone loss is encountered mostly in revision TSAs.

Historically, patients with severe glenoid bone loss were treated with a hemiarthroplasty.^15-17 However, due to inferior outcomes associated with the use of shoulder hemiarthroplasties compared with TSA in these cases,^18-20 various techniques were developed with the aim of realigning the glenoid axis and securing the implants into the deficient glenoid vault.^21-25 Options have included eccentric reaming, glenoid reconstruction with bone autografts and allografts, and more recently augmented components and patient-specific implants. Studies with eccentric reaming and reconstruction with bone graft during complex shoulder arthroplasty have reported encouraging short- to mid-term results, but the clinical and radiographic outcomes remain inconsistent, and the high number of complications is a concern.^25-28

Complications with these techniques include component loosening, graft resorption, nonunion, failure of graft incorporation, infection, and instability.^25-28

Computer-aided design and computer-aided manufacturing (CAD/CAM) of patient-specific implants have been used successfully by hip arthroplasty surgeons to deal with complex acetabular reconstructions in the setting of severe bone loss. More recently, the same technology has been used to reconstruct the glenoid vault in cases of severe glenoid bone loss.

In this article, we describe a patient-specific glenoid implant, its indication, and both technical aspects and the surgical technique, based on the authors’ experience as well as a review of the current literature on custom glenoid implants.

Continue to: PATIENT-SPECIFIC GLENOID COMPONENT

The Vault Reconstruction System ([VRS], Zimmer Biomet) is a patient-specific glenoid vault reconstruction system developed with the use of CAD/CAM to address severe glenoid bone loss encountered during shoulder arthroplasty. For several years, the VRS was available only as a custom implant according to the US Food and Drug Administration rules, and therefore its use was limited to a few cases per year. Recently, a 510(k) envelope clearance was granted to use the VRS in reverse TSA to address significant glenoid bone defects.

The VRS is made of porous plasma spray titanium to provide high strength and flexibility, and allows for biologic fixation. This system can accommodate a restricted bone loss envelope of about 50 mm × 50 mm × 35 mm according to the previous experience of the manufacturer in the custom scenario, covering 96% of defects previously addressed. One 6.5-mm nonlocking central screw and a minimum of four 4.75-mm nonlocking or locking peripheral screws are required for optimal fixation of the implant in the native scapula. A custom boss can be added in to enhance fixation in the native scapula when the bone is sufficient. To facilitate the surgical procedure, a trial implant, a bone model of the scapula, and a custom boss reaming guide are 3-dimensional (3-D) and printed in sterilizable material. These are all provided as single-use disposable instruments and can be available for surgeons during both the initial plan review and surgery.

PREOPERATIVE PLANNING

Patients undergo a preoperative fine-cut 2-dimensional computed tomography scan of the scapula and adjacent humerus following a predefined protocol with a slice thickness of 2 mm to 3 mm. An accurate 3-D bone model of the scapula is obtained using a 3-D image processing software system (Figure 1). The 3-D scapular model is used to create a patient-specific glenoid implant proposal that is approved by the surgeon (Figure 2). Implant position, orientation, size, screw trajectory, and recommended bone removal, if necessary, are determined to create a more normal glenohumeral center of rotation and to secure a glenoid implant in severely deficient glenoid bone (Figure 3). Once the implant design is approved by the surgeon, the final patient-specific implant is manufactured.

SURGICAL TECHNIQUE

The exposure of the glenoid is a critical step for the successful implantation of the patient-specific glenoid implant. Soft tissue and scar tissue around the glenoid must be removed to allow for optimal fit of the custom-made reaming guide. Also, removal of the entire capsulolabral complex on the anteroinferior rim of the glenoid is essential to both enhance glenoid exposure and to allow a perfect fit of the guide to the pathologic bone stock. Attention should be paid during débridement and/or implant removal in case of revision, to make sure that no excessive bone is removed because the patient-specific guide is referenced to this anatomy. Excessive bone removal can change the orientation of the patient-specific guide and ultimately the fixation of the implant. Once the custom-made patient-specific guide is positioned, a 3.2-mm Steinmann pin is placed through the inserter for temporary fixation. The pin should engage or perforate the medial cortical wall to ensure that the subsequent reamer has a stable cannula over which to ream. After the glenoid is reamed, the final implant can be placed in the ideal position according to the preoperative planning. A central 6.5-mm nonlocking central screw and 4.75-mm nonlocking or locking peripheral screws are required to complete the fixation of the implant in the native scapula. Once the patient-specific glenoid component is positioned and strongly fixed to the bone, the glenosphere can be positioned according to the preoperative planning, and the reverse shoulder arthroplasty can be completed in the usual fashion.

CASE EXAMPLES

A 68-year-old woman underwent a TSA for end-stage osteoarthritis in 2000. The implant failed due to a cuff failure. The patient underwent several surgeries, including an open cuff repair, with no success. She had no active elevation preoperatively. Because of the significant glenoid bone loss, a patient-specific glenoid reconstruction was planned. Within 24 months after this surgery, the patient was able to get her hand to her head and elevate to 90º (Figures 4A-4F).

Continue to: In October 2013...

In October 2013, a 68-year-old man underwent a TSA for end-stage osteoarthritis. After 18 months, the implant failed due to active Propionibacterium acnes infection, which required excisional arthroplasty with insertion of an antibiotic spacer. Significant glenoid bone loss (Figure 5) and global soft-tissue deficiency caused substantial disability and led to an indication for a reverse TSA with a patient-specific glenoid vault reconstruction (Figures 6A-6D) after infection eradication. Within 20 months after this surgery, the patient had resumed a satisfactory range of motion (130º forward elevation, 20º external rotation) and outcome.

DISCUSSION

Although glenoid bone loss is often seen in the primary setting (degenerative, congenital, and post-traumatic), severe glenoid bone loss is encountered in most revision TSAs. The best treatment method for massive glenoid bone defects during complex shoulder arthroplasty remains uncertain. Options have included eccentric reaming, glenoid reconstruction with bone allograft and autograft, and more recently augmented components and patient-specific implants.^21-25 The advent and availability of CAD/CAM technology have enabled shoulder surgeons to create patient-specific metal solutions to these challenging cases. Currently, only a few reports exist in the literature on patient-specific glenoid components in the setting of severe bone loss.^29-32

Chammaa and colleagues²⁹ reported the outcomes of 37 patients with a hip-inspired glenoid component (Total Shoulder Replacement, Stanmore Implants Worldwide). The 5-year results with this implant were promising, with a 16% revision rate and only 1 case of glenoid loosening.

Stoffelen and colleagues³⁰ recently described the successful use of a patient-specific anatomic metal-backed glenoid component for the management of severe glenoid bone loss with excellent results at 2.5 years of follow-up. A different approach was pursued by Gunther and Lynch,³¹ who reported on 7 patients with a custom inset glenoid implant for deficient glenoid vaults. These circular anatomic, custom-made glenoid components were created with the intention of placing the implants partially inside the glenoid vault and relying partially on sclerotic cortical bone. Despite excellent results at 3 years of follow-up, their use is limited to specific defect geometries and cannot be used in cases of extreme bone loss.

CONCLUSION

We have described the use of a patient-specific glenoid component in 2 patients with severe glenoid bone loss. Despite the satisfactory clinical and short-term radiographic results, we acknowledge that longer-term follow-up is needed to confirm the efficacy of this type of reconstruction. We believe that patient-specific glenoid components represent a valuable addition to the armamentarium of shoulder surgeons who address complex glenoid bone deformities.

Introduction

Biliary tract carcinoma (BTC) is the term for a heterogeneous group of rare gastrointestinal malignancies¹ that includes both carcinoma arising from the gallbladder and cholangiocarcinoma, which refers to diverse aggressive epithelial cancers involving the intrahepatic, perihilar, and distal biliary tree.^1–3 In this article, we review the epidemiology, clinical features, and diagnostic approach to BTC, with a focus on current evidence-based treatment strategies for localized, locally advanced, and metastatic BTC.

Epidemiology

In the United States, BTC is rare and accounts for approximately 4% of all gastrointestinal malignancies, with an estimated 6000 to 7000 cases of carcinoma of the gallbladder and 3000 to 4000 cases of carcinoma of the bile duct diagnosed annually.⁴ Among women, there is a 26-fold variation in BTC mortality worldwide, ranging from 0.8 deaths per 100,000 in South Africa to 21.2 per 100,000 in Chile.^1,5 Interestingly, for American Indians in New Mexico, gallbladder cancer mortality rates (8.9 per 100,000) surpass those for breast and pancreatic cancers.⁶ The incidence of anatomical cholangiocarcinoma subtypes also varies regionally, reflecting disparities in genetic and environmental predisposing factors.^2,7 In a large, single-center study in the United States, intrahepatic cholangiocarcinoma accounted for less than 10% of cases, perihilar accounted for 50%, and distal accounted for the remaining 40%.⁸ Importantly, intrahepatic cholangiocarcinoma is the second most common primary malignancy of the liver, and its incidence seems to be rising in many western countries. In the United States, there has been an estimated 128% rise over the past 40 years.^4,9

BTC is associated with high mortality rates.¹⁰ Median overall survival (OS) for cholangiocarcinoma is 20 to 28 months and 5-year survival is around 25%.¹⁰ Most cholangiocarcinomas are diagnosed at advanced stages with unresectable tumors.¹⁰ Furthermore, outcomes following resection with curative intent are poor—median disease-free survival (DFS) of 12 to 36 months has been reported.^11,12 Patients with intrahepatic disease have a better prognosis when compared with patients who have extrahepatic tumors.¹² Gallbladder cancer, likewise, carries a poor overall prognosis; median OS is 32 months and 5-year survival is as low as 13%.⁶

Risk factors for BTC include intrinsic and extrinsic elements.⁶ Incidence of BTC increases with age, and diagnosis typically occurs in the sixth to eighth decade of life.^5,6,13 In contrast to gallbladder cancer, the incidence of cholangiocarcinoma is slightly higher in men.⁹ Obesity, diabetes, and consumption of sweetened drinks also increase the risk for BTC.^14–16 Cholelithiasis is the most prevalent risk factor for gallbladder cancer, and the risk is greater for larger stones.⁵ Around 1 in 5 patients with porcelain gallbladder will develop gallbladder carcinoma.¹⁷ Primary sclerosing cholangitis (PSC), chronic calculi of the bile duct, choledochal cysts, cirrhosis, hepatitis C, and liver fluke infections are well established risk factors for cholangiocarcinoma.^7,12,18 PSC is one of the best described entities among these predisposing conditions. Lifetime prevalence of cholangiocarcinoma among patients with PSC ranges from 5% to 10%.^18,19 These patients also present at a younger age; in one series, the median age at diagnosis for BTC arising from PSC was 39 years.¹⁸ It is important to recognize, however, that in most patients diagnosed with cholangiocarcinoma, no predisposing factors are identified.⁸

Diagnosis

Clinical Presentation

Clinical presentation of BTC depends upon anatomic location.²⁰ Patients with early invasive gallbladder cancer are most often asymptomatic.²¹ When symptoms occur, they may be nonspecific and mimic cholelithiasis.²¹ The most common clinical presentations include jaundice, weight loss, and abdominal pain.²¹ Prior to widespread availability of imaging studies, the preoperative diagnosis rate for gallbladder cancer was as low as 10%.²² However, the accuracy of computed tomography (CT) has changed this scenario, with sensitivity ranging from 73% to 87% and specificity from 88% to 100%.²¹ As a result of its silent clinical character, cholangiocarcinoma is frequently difficult to diagnose.²³ Perihilar and distal cholangiocarcinoma characteristically present with signs of biliary obstruction, and imaging and laboratory data can corroborate the presence of cholestasis.²⁴ On examination, patients with extrahepatic cholangiocarcinoma may present with jaundice, hepatomegaly, and a palpable right upper quadrant mass.²⁵ A palpable gallbladder (Courvoisier sign) can also be present.²⁵ Intrahepatic cholangiocarcinoma presents differently, and patients are less likely to be jaundiced.²³ Typical clinical features are nonspecific and include dull right upper quadrant pain, weight loss, and an elevated alkaline phosphatase level.²³ Alternatively, asymptomatic patients can present with incidentally detected lesions, when imaging is obtained as part of the workup for other causes or during screening for hepatocellular carcinoma in patients with viral hepatitis or cirrhosis.^23,26 Uncommonly, BTC patients present because of signs or symptoms related to metastatic disease or evidence of metastatic disease on imaging.

Pathology and Grading

The majority of BTCs are adenocarcinomas, corresponding to 90% of cholangiocarcinomas and 99% of gallbladder cancers.^27,28 They are graded as well, moderately, or poorly differentiated.² Adenosquamous and squamous cell carcinoma are responsible for most of the remaining cases.^2,29 Cholangiocarcinomas are divided into 3 types, defined by the Liver Cancer Study Group of Japan: (1) mass-forming, (2) periductal-infiltrating, and (3) intraductal-growing.^30,31 Mass-forming intrahepatic cholangiocarcinomas are characterized morphologically by a homogeneous gray-yellow mass with frequent satellite nodules and irregular but well-defined margins.^17,30 Central necrosis and fibrosis are also common.³⁰ In the periductal-infiltrating type, tumor typically grows along the bile duct wall without mass formation, resulting in concentric mural thickening and proximal biliary dilation.³⁰ Intraductal-growing papillary cholangiocarcinoma is characterized by the presence of intraluminal papillary or tubular polypoid tumors of the intra- or extrahepatic bile ducts, with partial obstruction and proximal biliary dilation.³⁰

Cholangiocarcinoma

Case Presentation

A previously healthy 59-year-old man presents to his primary care physician with a 3-month history of dull right upper quadrant pain associated with weight loss. The patient is markedly cachectic and abdominal examination reveals upper quadrant tenderness. Laboratory exams are significant for elevated alkaline phosphatase (500 U/L; reference range 45–115 U/L), cancer antigen 19-9 (CA 19-9, 73 U/mL; reference range ≤ 37 U/mL), and carcinoembryonic antigen (CEA , 20 ng/mL; reference range for nonsmokers ≤ 3.0 ng/mL). Aspartate aminotransferase, alanine aminotransferase, total bilirubin, and coagulation studies are within normal range. Ultrasound demonstrates a homogeneous mass with irregular borders in the right lobe of the liver. Triphasic contrast-enhanced CT scan demonstrates a tumor with ragged rim enhancement at the periphery, and portal venous phase shows gradual centripetal enhancement of the tumor with capsular retraction. No abdominal lymph nodes or extrahepatic tumors are noted (Figure 1, Image A).

• What are the next diagnostic steps?

The most critical differential diagnosis of solid liver mass in patients without cirrhosis is cholangiocarcinoma and metastases from another primary site.³² Alternatively, when an intrahepatic lesion is noted on an imaging study in the setting of cirrhosis, the next diagnostic step is differentiation between cholangiocarcinoma and hepatocellular carcinoma (HCC).³² Triphasic contrast-enhanced CT and dynamic magnetic resonance imaging (MRI) are key diagnostic procedures.^32,33 In the appropriate setting, classical imaging features in the arterial phase with washout in portal venous or delayed phase can be diagnostic of HCC and may obviate the need for a biopsy (Figure 2).

Typical radiographic features of cholangiocarcinoma include a hypodense hepatic lesion that can be either well-defined or infiltrative and is frequently associated with biliary dilatation (Figure 1, Image A).³³ The dense fibrotic nature of the tumor may cause capsular retraction, which is seen in up to 20% of cases.¹⁷ This finding is highly suggestive of cholangiocarcinoma and is rarely present in HCC.³³ Following contrast administration, there is peripheral (rim) enhancement throughout both arterial and venous phases.^32–34 However, these classic features were present in only 70% of cases in one study.³⁵ Although intrahepatic cholangiocarcinomas are most commonly hypovascular, small mass-forming intrahepatic cholangiocarcinomas can often be arterially hyperenhancing and mimic HCC.³³ Tumor enhancement on delayed CT imaging has been correlated with survival. Asayama et al demonstrated that tumors that exhibited delayed enhancement on CT in more than two-thirds of their volume were associated with a worse prognosis.³⁶

Patients without cirrhosis who present with a localized lesion of the liver should undergo extensive evaluation for a primary cancer site.³⁷ CT of the chest, abdomen, and pelvis with contrast should be obtained.³⁷ Additionally, mammogram and endoscopic evaluation with esophagogastroduodenoscopy (EGD) and colonoscopy should be included in the work-up.³⁷

Preoperative tumor markers are also included in the work-up. All patients with a solid liver lesion should have serum alpha-fetoprotein (AFP) levels checked. AFP is a serum glycoprotein recognized as a marker for HCC and is reported to detect preclinical HCC.³⁸ However, serum concentrations are normal in up to 40% of small HCCs.³⁸ Although no specific marker for cholangiocarcinoma has yet been identified, the presence of certain tumor markers in the serum of patients may be of diagnostic value, especially in patients with PSC. CA 19-9 and CEA are the best studied. Elevated levels of CA 19-9 prior to treatment are associated with a poorer prognosis, and CA 19-9 concentrations greater than 1000 U/mL are consistent with advanced disease.^39,40 One large series evaluated the diagnostic value of serum CEA levels in 333 patients with PSC, 13% of whom were diagnosed with cholangiocarcinoma.³⁴ A serum CEA level greater than 5.2 ng/mL had a sensitivity of 68.0% and specificity of 81.5%.³⁸

If a biopsy is obtained, appropriate immunohistochemistry (IHC) can facilitate the diagnosis. BTC is strongly positive for CK-7 and CK-19.⁴¹ CK-7 positivity is not specific and is also common among metastatic cancers of the lung and breast; therefore, in some cases cholangiocarcinoma may be a diagnosis of exclusion. Immunostaining for monoclonal CEA is diffusely positive in up to 75% of cases.⁴¹ An IHC panel consisting of Hep Par-1, arginase-1, monoclonal CEA, CK-7, CK-20, TTF-1, MOC-31, and CDX-2 has been proposed to optimize the differential diagnosis of HCC, metastatic adenocarcinoma, and cholangiocarcinoma.⁴¹

Case Continued

CT of the chest, abdomen, and pelvis reveals no concerns for metastasis and no evidence of primary cancer elsewhere. EGD and colonoscopy are clear. AFP levels are within normal limits (2 ng/mL). Biopsy is performed and demonstrates adenocarcinoma. IHC studies demonstrate cells positive for monoclonal CEA, CK-7, CK-19, and MOC-31, and negative for Napsin A, TTF-1, and CK-20.

• How is cholangiocarcinoma staged and classified?

The purpose of the staging system is to provide information on prognosis and guidance for therapy. Prognostic factors and the therapeutic approaches for BTC differ depending upon their location in the biliary tree. Accordingly, TNM classification systems for intrahepatic, hilar, and distal cholangiocarcinoma and gallbladder cancer have been separated (Table 1 and Table 2).²³

The Bismuth-Corlette classification is used to further classify perihilar cholangiocarcinoma according to patterns of hepatic duct involvement. Type I tumors are located below the confluence of the left and right hepatic ducts.⁴² Type II reach the confluence of the hepatic ducts.⁴² Type III occlude the common hepatic duct and either the right or left hepatic duct (IIIa and IIIb, respectively).⁴² Finally, type IV are multicentric, or involve the confluence and both the right and left hepatic ducts.⁴² Tumors that involve the common hepatic duct bifurcation are named Klatskin tumors.⁴²

• What is the first-line treatment for localized cholangiocarcinomas?

Surgical resection is the only potentially curative treatment for localized cholangiocarcinoma, although fewer than 20% of patients are suitable for curative treatment, due to the presence of advanced disease at diagnosis.^43,44 Available evidence supports the recommendation that resection with negative margins, regardless of extent, should be the goal of therapy for patients with potentially resectable disease.⁴⁴ Extensive hepatic resections are often necessary to achieve clear margins since the majority of patients present with large masses. Substantial evidence corroborates that R0 resection is associated with better survival, whereas the benefit of wide compared to narrow (< 5–10 mm) margins is unclear.⁴⁵ A recent analysis of 96 patients suggests that the proximal resection margin has more prognostic implications than distal margins.⁴⁵

Surgical options and resectability criteria depend upon tumor location. Extent of tumor in the bile duct is one of the most important factors that determine resectability.¹⁷ Although multifocal liver tumors (including satellite lesions), lymph node metastases to the porta hepatis, and distant metastases are considered relative contraindications to surgery, surgical approaches can be considered in selected patients.⁴³ Patient selection for surgery is facilitated by careful preoperative staging, which may include laparoscopy. Laparoscopic staging prior to resection may prevent unnecessary laparotomy in 30% to 45% of patients.^42,46

• Is there a role for adjuvant treatment?

Recurrence following complete resection is a primary limitation for cure in BTC, which provides a rationale for the use of adjuvant therapy.^47,48 In a sample of 79 patients with extrahepatic cholangiocarcinoma who underwent curative resection, the cumulative recurrence rate after 4 years was 56%.⁴⁷ Initial recurrence at a distant site occurs in 40% to 50% of patients.⁴⁸

Lymphovascular and perineural invasion, lymph node metastasis, and tumor size ≥ 5 cm have been reported as independent predictors of recurrence and mortality following resection.⁴⁹ A 2017 meta-analysis which included 30 studies involving more than 22,499 patients reported a 41% reduction in the risk of death with adjuvant chemotherapy, which translated to a mean OS benefit of 4 months in an unselected population.⁴⁹ Moreover, this study revealed inferior OS in patients given adjuvant radiation therapy (RT) in combination with chemotherapy.⁴⁹ These results are in line with the previous meta-analysis by Horgan et al, which demonstrated that adjuvant RT seems to benefit only patients with R1 resections, with a possible detrimental effect in R0 disease.⁵⁰ Therefore, adjuvant chemoradiation cannot be viewed as a standard practice following R0 resection, and should be reserved for those patients with positive margins (R1/ 2) to reduce local progression.

In the phase 3 BILCAP trial presented at ASCO 2017, 447 patients with completely resected cholangiocarcinoma or gallbladder cancer with adequate biliary drainage and Eastern Cooperative Oncology Group (ECOG) performance score ≤ 2 were randomly assigned to observation or capecitabine (1250 mg/m² twice daily for days 1–14 every 21 days for 8 cycles).⁵¹ Surgical treatment achieved R0 resection in 62% of patients and 46% were node-negative. Median OS was 51 months for the capecitabine group and 36 months for the control arm (hazard ratio [HR] 0.80, 95% CI 0.63 to 1.04, P = 0.097). Analyses with adjustment for nodal status, grade of disease, and gender indicated a HR of 0.71 (P < 0.01). Median DFS was 25 months versus 18 months favoring the capecitabine group, and rates of grade 3 or 4 toxicity were less than anticipated. Following the results of this trial, adjuvant capecitabine should become the new standard of care.

• What is the treatment for locally advanced cholangiocarcinoma?

The optimal approach to patients with locally advanced unresectable cholangiocarcinoma has not been established. The prognosis for patients with either locally unresectable or locally recurrent disease is typically measured in months. Goals of palliative therapy are relief of symptoms and improvement in quality of life, and there is no role for surgical debulking.

Liver transplantation is a potentially curative option for selected patients with hilar or intrahepatic cholangiocarcinoma. Patients with lymph node-negative, non-disseminated, locally advanced hilar cholangiocarcinomas have 5-year survival rates ranging from 25% to 42% following transplantation.⁵² Retrospective data suggests that neoadjuvant chemoradiation followed by liver transplantation is highly effective for selected patients with hilar cholangiocarcinoma.⁵² However, these results require confirmation from prospective clinical evidence. It is important to recognize that liver transplantation plays no role in the management of distal cholangiocarcinoma or gallbladder cancer.

Rarely, patients with borderline resectable intrahepatic cholangiocarcinoma will have a sufficient response to chemotherapy to permit later resection, and, in such cases, starting with chemotherapy and then restaging to evaluate resectability is appropriate.⁵⁴ A single-center, retrospective analysis including 186 patients by Le Roy et al evaluated survival in patients with locally advanced, unresectable intrahepatic cholangiocarcinoma who received primary chemotherapy, followed by surgery in those with secondary resectability.⁵⁴ After a median of 6 cycles of chemotherapy, 53% of patients achieved resectability and underwent surgery with curative intent. These patients had similar short- and long-term results compared to patients with initially resectable intrahepatic cholangiocarcinoma who had surgery alone, with median OS reaching 24 months.⁵⁴

Ablative radiotherapy is an additional option for localized inoperable intrahepatic cholangiocarcinoma. Tao and colleagues evaluated 79 consecutive patients with inoperable intrahepatic cholangiocarcinoma treated with definitive RT.⁵⁵ Median tumor size was 7.9 cm and 89% of patients received chemotherapy before RT. Median OS was 30 months and 3-year OS was 44%. Radiation dose was the single most important prognostic factor, and higher doses correlated with improved local control and OS. A biologic equivalent dose (BED) greater than 80.5 Gy was identified as an ablative dose of RT for large intrahepatic cholangiocarcinomas. The 3-year OS for patients receiving BED greater than 80.5 Gy was 73% versus 38% for those receiving lower doses.

Case Continued

The patient is deemed to have resectable disease and undergoes surgical resection followed by adjuvant capecitabine for 8 cycles. Unfortunately, after 1 year, follow-up imaging identifies bilateral enlarging lung nodules. Biopsy is performed and confirms metastatic cholangiocarcinoma.

• What is the treatment for metastatic BTC?

The prognosis of patients with advanced BTC is poor and OS for those undergoing supportive care alone is short. A benefit of chemotherapy over best supportive care for cholangiocarcinoma was demonstrated in an early phase 3 trial that randomly assigned 90 patients with advanced pancreatic or biliary cancer (37 with bile duct cancer) to receive either fluorouracil (FU) -based systemic chemotherapy or best supportive care. Results showed that chemotherapy significantly improved OS (6 months versus 2.5 months).⁵⁶ Chemotherapy is also beneficial for patients with unresectable gallbladder cancer. In a single-center randomized study including 81 patients with unresectable gallbladder cancer, gemcitabine and oxaliplatin (GEMOX) improved progression-free survival (PFS) and OS compared to best supportive care.⁵⁷ Treatment for metastatic cholangiocarcinoma and gallbladder cancer follows the same algorithm.

In 2010, cisplatin plus gemcitabine was established as a reference regimen for first-line therapy by the ABC-02 study, in which 410 patients with locally advanced or metastatic bile duct, gallbladder, or ampullary cancer were randomly assigned to 6 courses of cisplatin (25 mg/m²) plus gemcitabine (1000 mg/m² on days 1 and 8, every 21 days) or gemcitabine alone (1000 mg/m² days 1, 8, 15, every 28 days).⁵⁸ OS was significantly greater with combination therapy (11.7 versus 8.1 months), and PFS also favored the combination arm (8 versus 5 months). Toxicity was comparable in both groups, with the exception of significantly higher rates of grade 3 or 4 neutropenia with gemcitabine plus cisplatin (25% versus 17%), and higher rates of grade 3 or 4 abnormal liver function with gemcitabine alone (27% versus 17%). Most quality-of-life scales showed a trend favoring combined therapy.⁵⁸ A smaller, identically designed Japanese phase 3 randomized trial achieved similar results, demonstrating greater OS with cisplatin plus gemcitabine compared to gemcitabine alone (11.2 versus 7.7 months).⁵⁹

The gemcitabine plus cisplatin combination has not been directly compared with other gemcitabine combinations in phase 3 trials. A pooled analysis of 104 trials of a variety of chemotherapy regimens in advanced biliary cancer concluded that the gemcitabine plus cisplatin regimen offered the highest rates of objective response and tumor control compared with either gemcitabine-free or cisplatin-free regimens.⁶⁰ However, this did not translate into significant benefit in terms of either time to tumor progression or median OS. It is important to note that this analysis did not include results of the subsequent ABC-02 trial.

There is no standard treatment for patients with cholangiocarcinoma for whom first-line gemcitabine-based therapy fails. There are no completed prospective phase 3 trials supporting the use of second-line chemotherapy after failure of first-line chemotherapy in BTC, and the selection of candidates for second-line therapy as well as the optimal regimen are not established.⁶¹ The ongoing phase 2 multicenter ABC-06 trial is evaluating oxaliplatin plus short-term infusional FU and leucovorin (FOLFOX) versus best supportive care for second-line therapy. In a systematic review including 23 studies (14 phase 2 clinical trials and 9 retrospective studies) with 761 patients with BTC, the median OS was 7.2 months.

The optimal selection of candidates for second-line chemotherapy is not established. Two independent studies suggest that patients who have a good performance status (0 or 1), disease control with the first-line chemotherapy, low CA 19-9 level, and possibly previous surgery on their primary tumor, have the longest survival with second-line chemotherapy. However, whether these characteristics predict for chemotherapy responsiveness or more favorable biologic behavior is not clear.^62,63 No particular regimen has proved superior to any other, and the choice of second-line regimen remains empiric.

For patients with adequate performance status, examples of other conventional chemotherapy regimens with demonstrated activity that could be considered for second-line therapy include: FOLFOX or capecitabine, gemcitabine plus capecitabine, capecitabine plus cisplatin, or irinotecan plus short-term infusional FU and leucovorin (FOLFIRI) with or without bevacizumab.⁶⁴ For selected patients, second-line molecularly targeted therapy using erlotinib plus bevacizumab may be considered. However, this regimen is very costly.⁶⁴ Examples of other regimens with demonstrated activity in phase 2 trials include GEMOX, gemcitabine plus fluoropyrimidine, and fluoropyrimidine plus oxaliplatin or cisplatin.⁶⁴

There is promising data from studies of targeted therapy for specific molecular subgroups. A recent phase 2 trial evaluated the activity of BGJ398, an orally bioavailable, selective, ATP-competitive pan inhibitor of human fibroblast growth factor receptor (FGFR) kinase, in patients with FGFR-altered advanced cholangiocarcinoma.⁶⁵ The overall response rate was 14.8% (18.8% FGFR2 fusions only) and disease control rate was 75.4% (83.3% FGFR2 fusions only). All responsive tumors contained FGFR2 fusions. Adverse events were manageable, and grade 3 or 4 treatment-related adverse events occurred in 25 patients (41%). Those included hyperphosphatemia, stomatitis, and palmar-plantar erythrodysesthesia. Javle and colleagues also identified HER2/neu blockade as a promising treatment strategy for gallbladder cancer patients with this gene amplification.⁶⁶ This retrospective analysis included 9 patients with gallbladder cancer and 5 patients with cholangiocarcinoma who received HER2/neu-directed therapy (trastuzumab, lapatinib, or pertuzumab). In the gallbladder cancer group, HER2/neu gene amplification or overexpression was detected in 8 cases. These patients experienced disease stability (n = 3), partial response (n = 4), or complete response (n = 1) with HER2/neu–directed therapy. Median duration of response was 40 weeks. The cholangiocarcinoma cases treated in this series had no radiological responses despite HER2/neu mutations or amplification.

Gallbladder Cancer

Case Presentation

A 57-year-old woman from Chile presents with a 3-week history of progressive right upper quadrant abdominal pain. She denies nausea, vomiting, dysphagia, odynophagia, alterations in bowel habits, fever, or jaundice. Her past medical history is significant for obesity and hypertension. She has no history of smoking, alcohol, or illicit drug use. Laboratory studies show marked leukocytosis (23,800/µL) with neutrophilia (91%). Liver function test results are within normal limits. Ultrasound of the abdomen reveals gallbladder wall thickening and cholelithiasis.

The patient undergoes an uneventful laparoscopic cholecystectomy and is discharged from the hospital after 48 hours. Pathology report reveals a moderately differentiated adenocarcinoma of the gallbladder invading the perimuscular connective tissue (T2). No lymph nodes are identified in the specimen.

• What is the appropriate surgical management of gallbladder cancer?

Gallbladder cancer can be diagnosed preoperatively or can be found incidentally by intraoperative or pathological findings. In one large series, gallbladder cancer was incidentally found during 0.25% of laparoscopic cholecystectomies.⁶⁷

For patients who are diagnosed with previously unsuspected gallbladder cancer by pathology findings, the extent of tumor invasion (T stage) indicates the need for re-resection (Figure 3).⁶⁴

Alternatively, when gallbladder cancer is documented or suspected preoperatively, adequate imaging is important to identify patients with absolute contraindications to resection. Contraindications to surgery include metastasis, extensive involvement of the hepatoduodenal ligament, encasement of major vessels, and involvement of celiac, peripancreatic, periduodenal, or superior mesenteric nodes.⁷² Notwithstanding, retrospective series suggest individual patients may benefit, and surgical indications in advanced disease should be determined on an individual basis.⁷³ Staging imaging should be obtained using multiphasic contrast-enhanced CT or MRI of the chest, abdomen, and pelvis. PET-scan can be used in selected cases where metastatic disease is suspected.⁶⁴ Laparoscopic diagnostic staging should be considered prior to resection.⁶⁴ This procedure can identify previously unknown contraindications to tumor resection in as much as 23% of patients, and the yield is significantly higher in locally advanced tumors.⁷³

Patients with a diagnosis of potentially resectable, localized gallbladder cancer should be offered definitive surgery. Extended cholecystectomy is recommended for patients stage T2 or above. This procedure involves wedge resection of the gallbladder bed or a segmentectomy IVb/V and lymph node dissection, which should include the cystic duct, common bile duct, posterior superior pancreaticoduodenal lymph nodes, and those around the hepatoduodenal ligament.⁷² Bile duct excision should be performed if there is malignant involvement.⁶⁴

Conclusion

BTCs are anatomically and clinically heterogeneous tumors. Prognostic factors and therapeutic approaches for BTCs differ depending upon their location in the biliary tree and, accordingly, TNM classification systems for intrahepatic, hilar, and distal cholangiocarcinoma and gallbladder cancer have been separated. Surgical resection is the only potentially curative treatment for localized BTC. However, recurrence following complete resection is a primary limitation for cure, which provides a rationale for the use of adjuvant therapy. The prognosis of patients with advanced BTC is poor and OS for those undergoing supportive care alone is short. Multiple randomized clinical trials have demonstrated a benefit of chemotherapy for metastatic disease. For patients with adequate performance status, second-line therapy can be considered, and data from studies that evaluated targeted therapy for specific molecular subgroups is promising.

Introduction

Biliary tract carcinoma (BTC) is the term for a heterogeneous group of rare gastrointestinal malignancies¹ that includes both carcinoma arising from the gallbladder and cholangiocarcinoma, which refers to diverse aggressive epithelial cancers involving the intrahepatic, perihilar, and distal biliary tree.^1–3 In this article, we review the epidemiology, clinical features, and diagnostic approach to BTC, with a focus on current evidence-based treatment strategies for localized, locally advanced, and metastatic BTC.

Epidemiology

In the United States, BTC is rare and accounts for approximately 4% of all gastrointestinal malignancies, with an estimated 6000 to 7000 cases of carcinoma of the gallbladder and 3000 to 4000 cases of carcinoma of the bile duct diagnosed annually.⁴ Among women, there is a 26-fold variation in BTC mortality worldwide, ranging from 0.8 deaths per 100,000 in South Africa to 21.2 per 100,000 in Chile.^1,5 Interestingly, for American Indians in New Mexico, gallbladder cancer mortality rates (8.9 per 100,000) surpass those for breast and pancreatic cancers.⁶ The incidence of anatomical cholangiocarcinoma subtypes also varies regionally, reflecting disparities in genetic and environmental predisposing factors.^2,7 In a large, single-center study in the United States, intrahepatic cholangiocarcinoma accounted for less than 10% of cases, perihilar accounted for 50%, and distal accounted for the remaining 40%.⁸ Importantly, intrahepatic cholangiocarcinoma is the second most common primary malignancy of the liver, and its incidence seems to be rising in many western countries. In the United States, there has been an estimated 128% rise over the past 40 years.^4,9

BTC is associated with high mortality rates.¹⁰ Median overall survival (OS) for cholangiocarcinoma is 20 to 28 months and 5-year survival is around 25%.¹⁰ Most cholangiocarcinomas are diagnosed at advanced stages with unresectable tumors.¹⁰ Furthermore, outcomes following resection with curative intent are poor—median disease-free survival (DFS) of 12 to 36 months has been reported.^11,12 Patients with intrahepatic disease have a better prognosis when compared with patients who have extrahepatic tumors.¹² Gallbladder cancer, likewise, carries a poor overall prognosis; median OS is 32 months and 5-year survival is as low as 13%.⁶

Risk factors for BTC include intrinsic and extrinsic elements.⁶ Incidence of BTC increases with age, and diagnosis typically occurs in the sixth to eighth decade of life.^5,6,13 In contrast to gallbladder cancer, the incidence of cholangiocarcinoma is slightly higher in men.⁹ Obesity, diabetes, and consumption of sweetened drinks also increase the risk for BTC.^14–16 Cholelithiasis is the most prevalent risk factor for gallbladder cancer, and the risk is greater for larger stones.⁵ Around 1 in 5 patients with porcelain gallbladder will develop gallbladder carcinoma.¹⁷ Primary sclerosing cholangitis (PSC), chronic calculi of the bile duct, choledochal cysts, cirrhosis, hepatitis C, and liver fluke infections are well established risk factors for cholangiocarcinoma.^7,12,18 PSC is one of the best described entities among these predisposing conditions. Lifetime prevalence of cholangiocarcinoma among patients with PSC ranges from 5% to 10%.^18,19 These patients also present at a younger age; in one series, the median age at diagnosis for BTC arising from PSC was 39 years.¹⁸ It is important to recognize, however, that in most patients diagnosed with cholangiocarcinoma, no predisposing factors are identified.⁸

Diagnosis

Clinical Presentation

Clinical presentation of BTC depends upon anatomic location.²⁰ Patients with early invasive gallbladder cancer are most often asymptomatic.²¹ When symptoms occur, they may be nonspecific and mimic cholelithiasis.²¹ The most common clinical presentations include jaundice, weight loss, and abdominal pain.²¹ Prior to widespread availability of imaging studies, the preoperative diagnosis rate for gallbladder cancer was as low as 10%.²² However, the accuracy of computed tomography (CT) has changed this scenario, with sensitivity ranging from 73% to 87% and specificity from 88% to 100%.²¹ As a result of its silent clinical character, cholangiocarcinoma is frequently difficult to diagnose.²³ Perihilar and distal cholangiocarcinoma characteristically present with signs of biliary obstruction, and imaging and laboratory data can corroborate the presence of cholestasis.²⁴ On examination, patients with extrahepatic cholangiocarcinoma may present with jaundice, hepatomegaly, and a palpable right upper quadrant mass.²⁵ A palpable gallbladder (Courvoisier sign) can also be present.²⁵ Intrahepatic cholangiocarcinoma presents differently, and patients are less likely to be jaundiced.²³ Typical clinical features are nonspecific and include dull right upper quadrant pain, weight loss, and an elevated alkaline phosphatase level.²³ Alternatively, asymptomatic patients can present with incidentally detected lesions, when imaging is obtained as part of the workup for other causes or during screening for hepatocellular carcinoma in patients with viral hepatitis or cirrhosis.^23,26 Uncommonly, BTC patients present because of signs or symptoms related to metastatic disease or evidence of metastatic disease on imaging.

Pathology and Grading

The majority of BTCs are adenocarcinomas, corresponding to 90% of cholangiocarcinomas and 99% of gallbladder cancers.^27,28 They are graded as well, moderately, or poorly differentiated.² Adenosquamous and squamous cell carcinoma are responsible for most of the remaining cases.^2,29 Cholangiocarcinomas are divided into 3 types, defined by the Liver Cancer Study Group of Japan: (1) mass-forming, (2) periductal-infiltrating, and (3) intraductal-growing.^30,31 Mass-forming intrahepatic cholangiocarcinomas are characterized morphologically by a homogeneous gray-yellow mass with frequent satellite nodules and irregular but well-defined margins.^17,30 Central necrosis and fibrosis are also common.³⁰ In the periductal-infiltrating type, tumor typically grows along the bile duct wall without mass formation, resulting in concentric mural thickening and proximal biliary dilation.³⁰ Intraductal-growing papillary cholangiocarcinoma is characterized by the presence of intraluminal papillary or tubular polypoid tumors of the intra- or extrahepatic bile ducts, with partial obstruction and proximal biliary dilation.³⁰

Cholangiocarcinoma

Case Presentation

A previously healthy 59-year-old man presents to his primary care physician with a 3-month history of dull right upper quadrant pain associated with weight loss. The patient is markedly cachectic and abdominal examination reveals upper quadrant tenderness. Laboratory exams are significant for elevated alkaline phosphatase (500 U/L; reference range 45–115 U/L), cancer antigen 19-9 (CA 19-9, 73 U/mL; reference range ≤ 37 U/mL), and carcinoembryonic antigen (CEA , 20 ng/mL; reference range for nonsmokers ≤ 3.0 ng/mL). Aspartate aminotransferase, alanine aminotransferase, total bilirubin, and coagulation studies are within normal range. Ultrasound demonstrates a homogeneous mass with irregular borders in the right lobe of the liver. Triphasic contrast-enhanced CT scan demonstrates a tumor with ragged rim enhancement at the periphery, and portal venous phase shows gradual centripetal enhancement of the tumor with capsular retraction. No abdominal lymph nodes or extrahepatic tumors are noted (Figure 1, Image A).

• What are the next diagnostic steps?

The most critical differential diagnosis of solid liver mass in patients without cirrhosis is cholangiocarcinoma and metastases from another primary site.³² Alternatively, when an intrahepatic lesion is noted on an imaging study in the setting of cirrhosis, the next diagnostic step is differentiation between cholangiocarcinoma and hepatocellular carcinoma (HCC).³² Triphasic contrast-enhanced CT and dynamic magnetic resonance imaging (MRI) are key diagnostic procedures.^32,33 In the appropriate setting, classical imaging features in the arterial phase with washout in portal venous or delayed phase can be diagnostic of HCC and may obviate the need for a biopsy (Figure 2).

Typical radiographic features of cholangiocarcinoma include a hypodense hepatic lesion that can be either well-defined or infiltrative and is frequently associated with biliary dilatation (Figure 1, Image A).³³ The dense fibrotic nature of the tumor may cause capsular retraction, which is seen in up to 20% of cases.¹⁷ This finding is highly suggestive of cholangiocarcinoma and is rarely present in HCC.³³ Following contrast administration, there is peripheral (rim) enhancement throughout both arterial and venous phases.^32–34 However, these classic features were present in only 70% of cases in one study.³⁵ Although intrahepatic cholangiocarcinomas are most commonly hypovascular, small mass-forming intrahepatic cholangiocarcinomas can often be arterially hyperenhancing and mimic HCC.³³ Tumor enhancement on delayed CT imaging has been correlated with survival. Asayama et al demonstrated that tumors that exhibited delayed enhancement on CT in more than two-thirds of their volume were associated with a worse prognosis.³⁶

Patients without cirrhosis who present with a localized lesion of the liver should undergo extensive evaluation for a primary cancer site.³⁷ CT of the chest, abdomen, and pelvis with contrast should be obtained.³⁷ Additionally, mammogram and endoscopic evaluation with esophagogastroduodenoscopy (EGD) and colonoscopy should be included in the work-up.³⁷

Preoperative tumor markers are also included in the work-up. All patients with a solid liver lesion should have serum alpha-fetoprotein (AFP) levels checked. AFP is a serum glycoprotein recognized as a marker for HCC and is reported to detect preclinical HCC.³⁸ However, serum concentrations are normal in up to 40% of small HCCs.³⁸ Although no specific marker for cholangiocarcinoma has yet been identified, the presence of certain tumor markers in the serum of patients may be of diagnostic value, especially in patients with PSC. CA 19-9 and CEA are the best studied. Elevated levels of CA 19-9 prior to treatment are associated with a poorer prognosis, and CA 19-9 concentrations greater than 1000 U/mL are consistent with advanced disease.^39,40 One large series evaluated the diagnostic value of serum CEA levels in 333 patients with PSC, 13% of whom were diagnosed with cholangiocarcinoma.³⁴ A serum CEA level greater than 5.2 ng/mL had a sensitivity of 68.0% and specificity of 81.5%.³⁸

If a biopsy is obtained, appropriate immunohistochemistry (IHC) can facilitate the diagnosis. BTC is strongly positive for CK-7 and CK-19.⁴¹ CK-7 positivity is not specific and is also common among metastatic cancers of the lung and breast; therefore, in some cases cholangiocarcinoma may be a diagnosis of exclusion. Immunostaining for monoclonal CEA is diffusely positive in up to 75% of cases.⁴¹ An IHC panel consisting of Hep Par-1, arginase-1, monoclonal CEA, CK-7, CK-20, TTF-1, MOC-31, and CDX-2 has been proposed to optimize the differential diagnosis of HCC, metastatic adenocarcinoma, and cholangiocarcinoma.⁴¹

Case Continued

CT of the chest, abdomen, and pelvis reveals no concerns for metastasis and no evidence of primary cancer elsewhere. EGD and colonoscopy are clear. AFP levels are within normal limits (2 ng/mL). Biopsy is performed and demonstrates adenocarcinoma. IHC studies demonstrate cells positive for monoclonal CEA, CK-7, CK-19, and MOC-31, and negative for Napsin A, TTF-1, and CK-20.

• How is cholangiocarcinoma staged and classified?

The purpose of the staging system is to provide information on prognosis and guidance for therapy. Prognostic factors and the therapeutic approaches for BTC differ depending upon their location in the biliary tree. Accordingly, TNM classification systems for intrahepatic, hilar, and distal cholangiocarcinoma and gallbladder cancer have been separated (Table 1 and Table 2).²³

The Bismuth-Corlette classification is used to further classify perihilar cholangiocarcinoma according to patterns of hepatic duct involvement. Type I tumors are located below the confluence of the left and right hepatic ducts.⁴² Type II reach the confluence of the hepatic ducts.⁴² Type III occlude the common hepatic duct and either the right or left hepatic duct (IIIa and IIIb, respectively).⁴² Finally, type IV are multicentric, or involve the confluence and both the right and left hepatic ducts.⁴² Tumors that involve the common hepatic duct bifurcation are named Klatskin tumors.⁴²

• What is the first-line treatment for localized cholangiocarcinomas?

Surgical resection is the only potentially curative treatment for localized cholangiocarcinoma, although fewer than 20% of patients are suitable for curative treatment, due to the presence of advanced disease at diagnosis.^43,44 Available evidence supports the recommendation that resection with negative margins, regardless of extent, should be the goal of therapy for patients with potentially resectable disease.⁴⁴ Extensive hepatic resections are often necessary to achieve clear margins since the majority of patients present with large masses. Substantial evidence corroborates that R0 resection is associated with better survival, whereas the benefit of wide compared to narrow (< 5–10 mm) margins is unclear.⁴⁵ A recent analysis of 96 patients suggests that the proximal resection margin has more prognostic implications than distal margins.⁴⁵

Surgical options and resectability criteria depend upon tumor location. Extent of tumor in the bile duct is one of the most important factors that determine resectability.¹⁷ Although multifocal liver tumors (including satellite lesions), lymph node metastases to the porta hepatis, and distant metastases are considered relative contraindications to surgery, surgical approaches can be considered in selected patients.⁴³ Patient selection for surgery is facilitated by careful preoperative staging, which may include laparoscopy. Laparoscopic staging prior to resection may prevent unnecessary laparotomy in 30% to 45% of patients.^42,46

• Is there a role for adjuvant treatment?

Recurrence following complete resection is a primary limitation for cure in BTC, which provides a rationale for the use of adjuvant therapy.^47,48 In a sample of 79 patients with extrahepatic cholangiocarcinoma who underwent curative resection, the cumulative recurrence rate after 4 years was 56%.⁴⁷ Initial recurrence at a distant site occurs in 40% to 50% of patients.⁴⁸

Lymphovascular and perineural invasion, lymph node metastasis, and tumor size ≥ 5 cm have been reported as independent predictors of recurrence and mortality following resection.⁴⁹ A 2017 meta-analysis which included 30 studies involving more than 22,499 patients reported a 41% reduction in the risk of death with adjuvant chemotherapy, which translated to a mean OS benefit of 4 months in an unselected population.⁴⁹ Moreover, this study revealed inferior OS in patients given adjuvant radiation therapy (RT) in combination with chemotherapy.⁴⁹ These results are in line with the previous meta-analysis by Horgan et al, which demonstrated that adjuvant RT seems to benefit only patients with R1 resections, with a possible detrimental effect in R0 disease.⁵⁰ Therefore, adjuvant chemoradiation cannot be viewed as a standard practice following R0 resection, and should be reserved for those patients with positive margins (R1/ 2) to reduce local progression.

In the phase 3 BILCAP trial presented at ASCO 2017, 447 patients with completely resected cholangiocarcinoma or gallbladder cancer with adequate biliary drainage and Eastern Cooperative Oncology Group (ECOG) performance score ≤ 2 were randomly assigned to observation or capecitabine (1250 mg/m² twice daily for days 1–14 every 21 days for 8 cycles).⁵¹ Surgical treatment achieved R0 resection in 62% of patients and 46% were node-negative. Median OS was 51 months for the capecitabine group and 36 months for the control arm (hazard ratio [HR] 0.80, 95% CI 0.63 to 1.04, P = 0.097). Analyses with adjustment for nodal status, grade of disease, and gender indicated a HR of 0.71 (P < 0.01). Median DFS was 25 months versus 18 months favoring the capecitabine group, and rates of grade 3 or 4 toxicity were less than anticipated. Following the results of this trial, adjuvant capecitabine should become the new standard of care.

• What is the treatment for locally advanced cholangiocarcinoma?

The optimal approach to patients with locally advanced unresectable cholangiocarcinoma has not been established. The prognosis for patients with either locally unresectable or locally recurrent disease is typically measured in months. Goals of palliative therapy are relief of symptoms and improvement in quality of life, and there is no role for surgical debulking.

Liver transplantation is a potentially curative option for selected patients with hilar or intrahepatic cholangiocarcinoma. Patients with lymph node-negative, non-disseminated, locally advanced hilar cholangiocarcinomas have 5-year survival rates ranging from 25% to 42% following transplantation.⁵² Retrospective data suggests that neoadjuvant chemoradiation followed by liver transplantation is highly effective for selected patients with hilar cholangiocarcinoma.⁵² However, these results require confirmation from prospective clinical evidence. It is important to recognize that liver transplantation plays no role in the management of distal cholangiocarcinoma or gallbladder cancer.

Rarely, patients with borderline resectable intrahepatic cholangiocarcinoma will have a sufficient response to chemotherapy to permit later resection, and, in such cases, starting with chemotherapy and then restaging to evaluate resectability is appropriate.⁵⁴ A single-center, retrospective analysis including 186 patients by Le Roy et al evaluated survival in patients with locally advanced, unresectable intrahepatic cholangiocarcinoma who received primary chemotherapy, followed by surgery in those with secondary resectability.⁵⁴ After a median of 6 cycles of chemotherapy, 53% of patients achieved resectability and underwent surgery with curative intent. These patients had similar short- and long-term results compared to patients with initially resectable intrahepatic cholangiocarcinoma who had surgery alone, with median OS reaching 24 months.⁵⁴

Ablative radiotherapy is an additional option for localized inoperable intrahepatic cholangiocarcinoma. Tao and colleagues evaluated 79 consecutive patients with inoperable intrahepatic cholangiocarcinoma treated with definitive RT.⁵⁵ Median tumor size was 7.9 cm and 89% of patients received chemotherapy before RT. Median OS was 30 months and 3-year OS was 44%. Radiation dose was the single most important prognostic factor, and higher doses correlated with improved local control and OS. A biologic equivalent dose (BED) greater than 80.5 Gy was identified as an ablative dose of RT for large intrahepatic cholangiocarcinomas. The 3-year OS for patients receiving BED greater than 80.5 Gy was 73% versus 38% for those receiving lower doses.

Case Continued

The patient is deemed to have resectable disease and undergoes surgical resection followed by adjuvant capecitabine for 8 cycles. Unfortunately, after 1 year, follow-up imaging identifies bilateral enlarging lung nodules. Biopsy is performed and confirms metastatic cholangiocarcinoma.

• What is the treatment for metastatic BTC?

The prognosis of patients with advanced BTC is poor and OS for those undergoing supportive care alone is short. A benefit of chemotherapy over best supportive care for cholangiocarcinoma was demonstrated in an early phase 3 trial that randomly assigned 90 patients with advanced pancreatic or biliary cancer (37 with bile duct cancer) to receive either fluorouracil (FU) -based systemic chemotherapy or best supportive care. Results showed that chemotherapy significantly improved OS (6 months versus 2.5 months).⁵⁶ Chemotherapy is also beneficial for patients with unresectable gallbladder cancer. In a single-center randomized study including 81 patients with unresectable gallbladder cancer, gemcitabine and oxaliplatin (GEMOX) improved progression-free survival (PFS) and OS compared to best supportive care.⁵⁷ Treatment for metastatic cholangiocarcinoma and gallbladder cancer follows the same algorithm.

In 2010, cisplatin plus gemcitabine was established as a reference regimen for first-line therapy by the ABC-02 study, in which 410 patients with locally advanced or metastatic bile duct, gallbladder, or ampullary cancer were randomly assigned to 6 courses of cisplatin (25 mg/m²) plus gemcitabine (1000 mg/m² on days 1 and 8, every 21 days) or gemcitabine alone (1000 mg/m² days 1, 8, 15, every 28 days).⁵⁸ OS was significantly greater with combination therapy (11.7 versus 8.1 months), and PFS also favored the combination arm (8 versus 5 months). Toxicity was comparable in both groups, with the exception of significantly higher rates of grade 3 or 4 neutropenia with gemcitabine plus cisplatin (25% versus 17%), and higher rates of grade 3 or 4 abnormal liver function with gemcitabine alone (27% versus 17%). Most quality-of-life scales showed a trend favoring combined therapy.⁵⁸ A smaller, identically designed Japanese phase 3 randomized trial achieved similar results, demonstrating greater OS with cisplatin plus gemcitabine compared to gemcitabine alone (11.2 versus 7.7 months).⁵⁹

The gemcitabine plus cisplatin combination has not been directly compared with other gemcitabine combinations in phase 3 trials. A pooled analysis of 104 trials of a variety of chemotherapy regimens in advanced biliary cancer concluded that the gemcitabine plus cisplatin regimen offered the highest rates of objective response and tumor control compared with either gemcitabine-free or cisplatin-free regimens.⁶⁰ However, this did not translate into significant benefit in terms of either time to tumor progression or median OS. It is important to note that this analysis did not include results of the subsequent ABC-02 trial.

There is no standard treatment for patients with cholangiocarcinoma for whom first-line gemcitabine-based therapy fails. There are no completed prospective phase 3 trials supporting the use of second-line chemotherapy after failure of first-line chemotherapy in BTC, and the selection of candidates for second-line therapy as well as the optimal regimen are not established.⁶¹ The ongoing phase 2 multicenter ABC-06 trial is evaluating oxaliplatin plus short-term infusional FU and leucovorin (FOLFOX) versus best supportive care for second-line therapy. In a systematic review including 23 studies (14 phase 2 clinical trials and 9 retrospective studies) with 761 patients with BTC, the median OS was 7.2 months.

The optimal selection of candidates for second-line chemotherapy is not established. Two independent studies suggest that patients who have a good performance status (0 or 1), disease control with the first-line chemotherapy, low CA 19-9 level, and possibly previous surgery on their primary tumor, have the longest survival with second-line chemotherapy. However, whether these characteristics predict for chemotherapy responsiveness or more favorable biologic behavior is not clear.^62,63 No particular regimen has proved superior to any other, and the choice of second-line regimen remains empiric.

For patients with adequate performance status, examples of other conventional chemotherapy regimens with demonstrated activity that could be considered for second-line therapy include: FOLFOX or capecitabine, gemcitabine plus capecitabine, capecitabine plus cisplatin, or irinotecan plus short-term infusional FU and leucovorin (FOLFIRI) with or without bevacizumab.⁶⁴ For selected patients, second-line molecularly targeted therapy using erlotinib plus bevacizumab may be considered. However, this regimen is very costly.⁶⁴ Examples of other regimens with demonstrated activity in phase 2 trials include GEMOX, gemcitabine plus fluoropyrimidine, and fluoropyrimidine plus oxaliplatin or cisplatin.⁶⁴

There is promising data from studies of targeted therapy for specific molecular subgroups. A recent phase 2 trial evaluated the activity of BGJ398, an orally bioavailable, selective, ATP-competitive pan inhibitor of human fibroblast growth factor receptor (FGFR) kinase, in patients with FGFR-altered advanced cholangiocarcinoma.⁶⁵ The overall response rate was 14.8% (18.8% FGFR2 fusions only) and disease control rate was 75.4% (83.3% FGFR2 fusions only). All responsive tumors contained FGFR2 fusions. Adverse events were manageable, and grade 3 or 4 treatment-related adverse events occurred in 25 patients (41%). Those included hyperphosphatemia, stomatitis, and palmar-plantar erythrodysesthesia. Javle and colleagues also identified HER2/neu blockade as a promising treatment strategy for gallbladder cancer patients with this gene amplification.⁶⁶ This retrospective analysis included 9 patients with gallbladder cancer and 5 patients with cholangiocarcinoma who received HER2/neu-directed therapy (trastuzumab, lapatinib, or pertuzumab). In the gallbladder cancer group, HER2/neu gene amplification or overexpression was detected in 8 cases. These patients experienced disease stability (n = 3), partial response (n = 4), or complete response (n = 1) with HER2/neu–directed therapy. Median duration of response was 40 weeks. The cholangiocarcinoma cases treated in this series had no radiological responses despite HER2/neu mutations or amplification.

Gallbladder Cancer

Case Presentation

A 57-year-old woman from Chile presents with a 3-week history of progressive right upper quadrant abdominal pain. She denies nausea, vomiting, dysphagia, odynophagia, alterations in bowel habits, fever, or jaundice. Her past medical history is significant for obesity and hypertension. She has no history of smoking, alcohol, or illicit drug use. Laboratory studies show marked leukocytosis (23,800/µL) with neutrophilia (91%). Liver function test results are within normal limits. Ultrasound of the abdomen reveals gallbladder wall thickening and cholelithiasis.

The patient undergoes an uneventful laparoscopic cholecystectomy and is discharged from the hospital after 48 hours. Pathology report reveals a moderately differentiated adenocarcinoma of the gallbladder invading the perimuscular connective tissue (T2). No lymph nodes are identified in the specimen.

• What is the appropriate surgical management of gallbladder cancer?

Gallbladder cancer can be diagnosed preoperatively or can be found incidentally by intraoperative or pathological findings. In one large series, gallbladder cancer was incidentally found during 0.25% of laparoscopic cholecystectomies.⁶⁷

For patients who are diagnosed with previously unsuspected gallbladder cancer by pathology findings, the extent of tumor invasion (T stage) indicates the need for re-resection (Figure 3).⁶⁴

Alternatively, when gallbladder cancer is documented or suspected preoperatively, adequate imaging is important to identify patients with absolute contraindications to resection. Contraindications to surgery include metastasis, extensive involvement of the hepatoduodenal ligament, encasement of major vessels, and involvement of celiac, peripancreatic, periduodenal, or superior mesenteric nodes.⁷² Notwithstanding, retrospective series suggest individual patients may benefit, and surgical indications in advanced disease should be determined on an individual basis.⁷³ Staging imaging should be obtained using multiphasic contrast-enhanced CT or MRI of the chest, abdomen, and pelvis. PET-scan can be used in selected cases where metastatic disease is suspected.⁶⁴ Laparoscopic diagnostic staging should be considered prior to resection.⁶⁴ This procedure can identify previously unknown contraindications to tumor resection in as much as 23% of patients, and the yield is significantly higher in locally advanced tumors.⁷³

Patients with a diagnosis of potentially resectable, localized gallbladder cancer should be offered definitive surgery. Extended cholecystectomy is recommended for patients stage T2 or above. This procedure involves wedge resection of the gallbladder bed or a segmentectomy IVb/V and lymph node dissection, which should include the cystic duct, common bile duct, posterior superior pancreaticoduodenal lymph nodes, and those around the hepatoduodenal ligament.⁷² Bile duct excision should be performed if there is malignant involvement.⁶⁴

Conclusion

BTCs are anatomically and clinically heterogeneous tumors. Prognostic factors and therapeutic approaches for BTCs differ depending upon their location in the biliary tree and, accordingly, TNM classification systems for intrahepatic, hilar, and distal cholangiocarcinoma and gallbladder cancer have been separated. Surgical resection is the only potentially curative treatment for localized BTC. However, recurrence following complete resection is a primary limitation for cure, which provides a rationale for the use of adjuvant therapy. The prognosis of patients with advanced BTC is poor and OS for those undergoing supportive care alone is short. Multiple randomized clinical trials have demonstrated a benefit of chemotherapy for metastatic disease. For patients with adequate performance status, second-line therapy can be considered, and data from studies that evaluated targeted therapy for specific molecular subgroups is promising.

Introduction

Biliary tract carcinoma (BTC) is the term for a heterogeneous group of rare gastrointestinal malignancies¹ that includes both carcinoma arising from the gallbladder and cholangiocarcinoma, which refers to diverse aggressive epithelial cancers involving the intrahepatic, perihilar, and distal biliary tree.^1–3 In this article, we review the epidemiology, clinical features, and diagnostic approach to BTC, with a focus on current evidence-based treatment strategies for localized, locally advanced, and metastatic BTC.

Epidemiology

In the United States, BTC is rare and accounts for approximately 4% of all gastrointestinal malignancies, with an estimated 6000 to 7000 cases of carcinoma of the gallbladder and 3000 to 4000 cases of carcinoma of the bile duct diagnosed annually.⁴ Among women, there is a 26-fold variation in BTC mortality worldwide, ranging from 0.8 deaths per 100,000 in South Africa to 21.2 per 100,000 in Chile.^1,5 Interestingly, for American Indians in New Mexico, gallbladder cancer mortality rates (8.9 per 100,000) surpass those for breast and pancreatic cancers.⁶ The incidence of anatomical cholangiocarcinoma subtypes also varies regionally, reflecting disparities in genetic and environmental predisposing factors.^2,7 In a large, single-center study in the United States, intrahepatic cholangiocarcinoma accounted for less than 10% of cases, perihilar accounted for 50%, and distal accounted for the remaining 40%.⁸ Importantly, intrahepatic cholangiocarcinoma is the second most common primary malignancy of the liver, and its incidence seems to be rising in many western countries. In the United States, there has been an estimated 128% rise over the past 40 years.^4,9

BTC is associated with high mortality rates.¹⁰ Median overall survival (OS) for cholangiocarcinoma is 20 to 28 months and 5-year survival is around 25%.¹⁰ Most cholangiocarcinomas are diagnosed at advanced stages with unresectable tumors.¹⁰ Furthermore, outcomes following resection with curative intent are poor—median disease-free survival (DFS) of 12 to 36 months has been reported.^11,12 Patients with intrahepatic disease have a better prognosis when compared with patients who have extrahepatic tumors.¹² Gallbladder cancer, likewise, carries a poor overall prognosis; median OS is 32 months and 5-year survival is as low as 13%.⁶

Risk factors for BTC include intrinsic and extrinsic elements.⁶ Incidence of BTC increases with age, and diagnosis typically occurs in the sixth to eighth decade of life.^5,6,13 In contrast to gallbladder cancer, the incidence of cholangiocarcinoma is slightly higher in men.⁹ Obesity, diabetes, and consumption of sweetened drinks also increase the risk for BTC.^14–16 Cholelithiasis is the most prevalent risk factor for gallbladder cancer, and the risk is greater for larger stones.⁵ Around 1 in 5 patients with porcelain gallbladder will develop gallbladder carcinoma.¹⁷ Primary sclerosing cholangitis (PSC), chronic calculi of the bile duct, choledochal cysts, cirrhosis, hepatitis C, and liver fluke infections are well established risk factors for cholangiocarcinoma.^7,12,18 PSC is one of the best described entities among these predisposing conditions. Lifetime prevalence of cholangiocarcinoma among patients with PSC ranges from 5% to 10%.^18,19 These patients also present at a younger age; in one series, the median age at diagnosis for BTC arising from PSC was 39 years.¹⁸ It is important to recognize, however, that in most patients diagnosed with cholangiocarcinoma, no predisposing factors are identified.⁸

Diagnosis

Clinical Presentation

Clinical presentation of BTC depends upon anatomic location.²⁰ Patients with early invasive gallbladder cancer are most often asymptomatic.²¹ When symptoms occur, they may be nonspecific and mimic cholelithiasis.²¹ The most common clinical presentations include jaundice, weight loss, and abdominal pain.²¹ Prior to widespread availability of imaging studies, the preoperative diagnosis rate for gallbladder cancer was as low as 10%.²² However, the accuracy of computed tomography (CT) has changed this scenario, with sensitivity ranging from 73% to 87% and specificity from 88% to 100%.²¹ As a result of its silent clinical character, cholangiocarcinoma is frequently difficult to diagnose.²³ Perihilar and distal cholangiocarcinoma characteristically present with signs of biliary obstruction, and imaging and laboratory data can corroborate the presence of cholestasis.²⁴ On examination, patients with extrahepatic cholangiocarcinoma may present with jaundice, hepatomegaly, and a palpable right upper quadrant mass.²⁵ A palpable gallbladder (Courvoisier sign) can also be present.²⁵ Intrahepatic cholangiocarcinoma presents differently, and patients are less likely to be jaundiced.²³ Typical clinical features are nonspecific and include dull right upper quadrant pain, weight loss, and an elevated alkaline phosphatase level.²³ Alternatively, asymptomatic patients can present with incidentally detected lesions, when imaging is obtained as part of the workup for other causes or during screening for hepatocellular carcinoma in patients with viral hepatitis or cirrhosis.^23,26 Uncommonly, BTC patients present because of signs or symptoms related to metastatic disease or evidence of metastatic disease on imaging.

Pathology and Grading

The majority of BTCs are adenocarcinomas, corresponding to 90% of cholangiocarcinomas and 99% of gallbladder cancers.^27,28 They are graded as well, moderately, or poorly differentiated.² Adenosquamous and squamous cell carcinoma are responsible for most of the remaining cases.^2,29 Cholangiocarcinomas are divided into 3 types, defined by the Liver Cancer Study Group of Japan: (1) mass-forming, (2) periductal-infiltrating, and (3) intraductal-growing.^30,31 Mass-forming intrahepatic cholangiocarcinomas are characterized morphologically by a homogeneous gray-yellow mass with frequent satellite nodules and irregular but well-defined margins.^17,30 Central necrosis and fibrosis are also common.³⁰ In the periductal-infiltrating type, tumor typically grows along the bile duct wall without mass formation, resulting in concentric mural thickening and proximal biliary dilation.³⁰ Intraductal-growing papillary cholangiocarcinoma is characterized by the presence of intraluminal papillary or tubular polypoid tumors of the intra- or extrahepatic bile ducts, with partial obstruction and proximal biliary dilation.³⁰

Cholangiocarcinoma

Case Presentation

A previously healthy 59-year-old man presents to his primary care physician with a 3-month history of dull right upper quadrant pain associated with weight loss. The patient is markedly cachectic and abdominal examination reveals upper quadrant tenderness. Laboratory exams are significant for elevated alkaline phosphatase (500 U/L; reference range 45–115 U/L), cancer antigen 19-9 (CA 19-9, 73 U/mL; reference range ≤ 37 U/mL), and carcinoembryonic antigen (CEA , 20 ng/mL; reference range for nonsmokers ≤ 3.0 ng/mL). Aspartate aminotransferase, alanine aminotransferase, total bilirubin, and coagulation studies are within normal range. Ultrasound demonstrates a homogeneous mass with irregular borders in the right lobe of the liver. Triphasic contrast-enhanced CT scan demonstrates a tumor with ragged rim enhancement at the periphery, and portal venous phase shows gradual centripetal enhancement of the tumor with capsular retraction. No abdominal lymph nodes or extrahepatic tumors are noted (Figure 1, Image A).

• What are the next diagnostic steps?

The most critical differential diagnosis of solid liver mass in patients without cirrhosis is cholangiocarcinoma and metastases from another primary site.³² Alternatively, when an intrahepatic lesion is noted on an imaging study in the setting of cirrhosis, the next diagnostic step is differentiation between cholangiocarcinoma and hepatocellular carcinoma (HCC).³² Triphasic contrast-enhanced CT and dynamic magnetic resonance imaging (MRI) are key diagnostic procedures.^32,33 In the appropriate setting, classical imaging features in the arterial phase with washout in portal venous or delayed phase can be diagnostic of HCC and may obviate the need for a biopsy (Figure 2).

Typical radiographic features of cholangiocarcinoma include a hypodense hepatic lesion that can be either well-defined or infiltrative and is frequently associated with biliary dilatation (Figure 1, Image A).³³ The dense fibrotic nature of the tumor may cause capsular retraction, which is seen in up to 20% of cases.¹⁷ This finding is highly suggestive of cholangiocarcinoma and is rarely present in HCC.³³ Following contrast administration, there is peripheral (rim) enhancement throughout both arterial and venous phases.^32–34 However, these classic features were present in only 70% of cases in one study.³⁵ Although intrahepatic cholangiocarcinomas are most commonly hypovascular, small mass-forming intrahepatic cholangiocarcinomas can often be arterially hyperenhancing and mimic HCC.³³ Tumor enhancement on delayed CT imaging has been correlated with survival. Asayama et al demonstrated that tumors that exhibited delayed enhancement on CT in more than two-thirds of their volume were associated with a worse prognosis.³⁶

Patients without cirrhosis who present with a localized lesion of the liver should undergo extensive evaluation for a primary cancer site.³⁷ CT of the chest, abdomen, and pelvis with contrast should be obtained.³⁷ Additionally, mammogram and endoscopic evaluation with esophagogastroduodenoscopy (EGD) and colonoscopy should be included in the work-up.³⁷

Preoperative tumor markers are also included in the work-up. All patients with a solid liver lesion should have serum alpha-fetoprotein (AFP) levels checked. AFP is a serum glycoprotein recognized as a marker for HCC and is reported to detect preclinical HCC.³⁸ However, serum concentrations are normal in up to 40% of small HCCs.³⁸ Although no specific marker for cholangiocarcinoma has yet been identified, the presence of certain tumor markers in the serum of patients may be of diagnostic value, especially in patients with PSC. CA 19-9 and CEA are the best studied. Elevated levels of CA 19-9 prior to treatment are associated with a poorer prognosis, and CA 19-9 concentrations greater than 1000 U/mL are consistent with advanced disease.^39,40 One large series evaluated the diagnostic value of serum CEA levels in 333 patients with PSC, 13% of whom were diagnosed with cholangiocarcinoma.³⁴ A serum CEA level greater than 5.2 ng/mL had a sensitivity of 68.0% and specificity of 81.5%.³⁸

If a biopsy is obtained, appropriate immunohistochemistry (IHC) can facilitate the diagnosis. BTC is strongly positive for CK-7 and CK-19.⁴¹ CK-7 positivity is not specific and is also common among metastatic cancers of the lung and breast; therefore, in some cases cholangiocarcinoma may be a diagnosis of exclusion. Immunostaining for monoclonal CEA is diffusely positive in up to 75% of cases.⁴¹ An IHC panel consisting of Hep Par-1, arginase-1, monoclonal CEA, CK-7, CK-20, TTF-1, MOC-31, and CDX-2 has been proposed to optimize the differential diagnosis of HCC, metastatic adenocarcinoma, and cholangiocarcinoma.⁴¹

Case Continued

CT of the chest, abdomen, and pelvis reveals no concerns for metastasis and no evidence of primary cancer elsewhere. EGD and colonoscopy are clear. AFP levels are within normal limits (2 ng/mL). Biopsy is performed and demonstrates adenocarcinoma. IHC studies demonstrate cells positive for monoclonal CEA, CK-7, CK-19, and MOC-31, and negative for Napsin A, TTF-1, and CK-20.

• How is cholangiocarcinoma staged and classified?

The purpose of the staging system is to provide information on prognosis and guidance for therapy. Prognostic factors and the therapeutic approaches for BTC differ depending upon their location in the biliary tree. Accordingly, TNM classification systems for intrahepatic, hilar, and distal cholangiocarcinoma and gallbladder cancer have been separated (Table 1 and Table 2).²³

The Bismuth-Corlette classification is used to further classify perihilar cholangiocarcinoma according to patterns of hepatic duct involvement. Type I tumors are located below the confluence of the left and right hepatic ducts.⁴² Type II reach the confluence of the hepatic ducts.⁴² Type III occlude the common hepatic duct and either the right or left hepatic duct (IIIa and IIIb, respectively).⁴² Finally, type IV are multicentric, or involve the confluence and both the right and left hepatic ducts.⁴² Tumors that involve the common hepatic duct bifurcation are named Klatskin tumors.⁴²

• What is the first-line treatment for localized cholangiocarcinomas?

Surgical resection is the only potentially curative treatment for localized cholangiocarcinoma, although fewer than 20% of patients are suitable for curative treatment, due to the presence of advanced disease at diagnosis.^43,44 Available evidence supports the recommendation that resection with negative margins, regardless of extent, should be the goal of therapy for patients with potentially resectable disease.⁴⁴ Extensive hepatic resections are often necessary to achieve clear margins since the majority of patients present with large masses. Substantial evidence corroborates that R0 resection is associated with better survival, whereas the benefit of wide compared to narrow (< 5–10 mm) margins is unclear.⁴⁵ A recent analysis of 96 patients suggests that the proximal resection margin has more prognostic implications than distal margins.⁴⁵

Surgical options and resectability criteria depend upon tumor location. Extent of tumor in the bile duct is one of the most important factors that determine resectability.¹⁷ Although multifocal liver tumors (including satellite lesions), lymph node metastases to the porta hepatis, and distant metastases are considered relative contraindications to surgery, surgical approaches can be considered in selected patients.⁴³ Patient selection for surgery is facilitated by careful preoperative staging, which may include laparoscopy. Laparoscopic staging prior to resection may prevent unnecessary laparotomy in 30% to 45% of patients.^42,46

• Is there a role for adjuvant treatment?

Recurrence following complete resection is a primary limitation for cure in BTC, which provides a rationale for the use of adjuvant therapy.^47,48 In a sample of 79 patients with extrahepatic cholangiocarcinoma who underwent curative resection, the cumulative recurrence rate after 4 years was 56%.⁴⁷ Initial recurrence at a distant site occurs in 40% to 50% of patients.⁴⁸

Lymphovascular and perineural invasion, lymph node metastasis, and tumor size ≥ 5 cm have been reported as independent predictors of recurrence and mortality following resection.⁴⁹ A 2017 meta-analysis which included 30 studies involving more than 22,499 patients reported a 41% reduction in the risk of death with adjuvant chemotherapy, which translated to a mean OS benefit of 4 months in an unselected population.⁴⁹ Moreover, this study revealed inferior OS in patients given adjuvant radiation therapy (RT) in combination with chemotherapy.⁴⁹ These results are in line with the previous meta-analysis by Horgan et al, which demonstrated that adjuvant RT seems to benefit only patients with R1 resections, with a possible detrimental effect in R0 disease.⁵⁰ Therefore, adjuvant chemoradiation cannot be viewed as a standard practice following R0 resection, and should be reserved for those patients with positive margins (R1/ 2) to reduce local progression.

In the phase 3 BILCAP trial presented at ASCO 2017, 447 patients with completely resected cholangiocarcinoma or gallbladder cancer with adequate biliary drainage and Eastern Cooperative Oncology Group (ECOG) performance score ≤ 2 were randomly assigned to observation or capecitabine (1250 mg/m² twice daily for days 1–14 every 21 days for 8 cycles).⁵¹ Surgical treatment achieved R0 resection in 62% of patients and 46% were node-negative. Median OS was 51 months for the capecitabine group and 36 months for the control arm (hazard ratio [HR] 0.80, 95% CI 0.63 to 1.04, P = 0.097). Analyses with adjustment for nodal status, grade of disease, and gender indicated a HR of 0.71 (P < 0.01). Median DFS was 25 months versus 18 months favoring the capecitabine group, and rates of grade 3 or 4 toxicity were less than anticipated. Following the results of this trial, adjuvant capecitabine should become the new standard of care.

• What is the treatment for locally advanced cholangiocarcinoma?

The optimal approach to patients with locally advanced unresectable cholangiocarcinoma has not been established. The prognosis for patients with either locally unresectable or locally recurrent disease is typically measured in months. Goals of palliative therapy are relief of symptoms and improvement in quality of life, and there is no role for surgical debulking.

Liver transplantation is a potentially curative option for selected patients with hilar or intrahepatic cholangiocarcinoma. Patients with lymph node-negative, non-disseminated, locally advanced hilar cholangiocarcinomas have 5-year survival rates ranging from 25% to 42% following transplantation.⁵² Retrospective data suggests that neoadjuvant chemoradiation followed by liver transplantation is highly effective for selected patients with hilar cholangiocarcinoma.⁵² However, these results require confirmation from prospective clinical evidence. It is important to recognize that liver transplantation plays no role in the management of distal cholangiocarcinoma or gallbladder cancer.

Rarely, patients with borderline resectable intrahepatic cholangiocarcinoma will have a sufficient response to chemotherapy to permit later resection, and, in such cases, starting with chemotherapy and then restaging to evaluate resectability is appropriate.⁵⁴ A single-center, retrospective analysis including 186 patients by Le Roy et al evaluated survival in patients with locally advanced, unresectable intrahepatic cholangiocarcinoma who received primary chemotherapy, followed by surgery in those with secondary resectability.⁵⁴ After a median of 6 cycles of chemotherapy, 53% of patients achieved resectability and underwent surgery with curative intent. These patients had similar short- and long-term results compared to patients with initially resectable intrahepatic cholangiocarcinoma who had surgery alone, with median OS reaching 24 months.⁵⁴

Ablative radiotherapy is an additional option for localized inoperable intrahepatic cholangiocarcinoma. Tao and colleagues evaluated 79 consecutive patients with inoperable intrahepatic cholangiocarcinoma treated with definitive RT.⁵⁵ Median tumor size was 7.9 cm and 89% of patients received chemotherapy before RT. Median OS was 30 months and 3-year OS was 44%. Radiation dose was the single most important prognostic factor, and higher doses correlated with improved local control and OS. A biologic equivalent dose (BED) greater than 80.5 Gy was identified as an ablative dose of RT for large intrahepatic cholangiocarcinomas. The 3-year OS for patients receiving BED greater than 80.5 Gy was 73% versus 38% for those receiving lower doses.

Case Continued

The patient is deemed to have resectable disease and undergoes surgical resection followed by adjuvant capecitabine for 8 cycles. Unfortunately, after 1 year, follow-up imaging identifies bilateral enlarging lung nodules. Biopsy is performed and confirms metastatic cholangiocarcinoma.

• What is the treatment for metastatic BTC?

The prognosis of patients with advanced BTC is poor and OS for those undergoing supportive care alone is short. A benefit of chemotherapy over best supportive care for cholangiocarcinoma was demonstrated in an early phase 3 trial that randomly assigned 90 patients with advanced pancreatic or biliary cancer (37 with bile duct cancer) to receive either fluorouracil (FU) -based systemic chemotherapy or best supportive care. Results showed that chemotherapy significantly improved OS (6 months versus 2.5 months).⁵⁶ Chemotherapy is also beneficial for patients with unresectable gallbladder cancer. In a single-center randomized study including 81 patients with unresectable gallbladder cancer, gemcitabine and oxaliplatin (GEMOX) improved progression-free survival (PFS) and OS compared to best supportive care.⁵⁷ Treatment for metastatic cholangiocarcinoma and gallbladder cancer follows the same algorithm.

In 2010, cisplatin plus gemcitabine was established as a reference regimen for first-line therapy by the ABC-02 study, in which 410 patients with locally advanced or metastatic bile duct, gallbladder, or ampullary cancer were randomly assigned to 6 courses of cisplatin (25 mg/m²) plus gemcitabine (1000 mg/m² on days 1 and 8, every 21 days) or gemcitabine alone (1000 mg/m² days 1, 8, 15, every 28 days).⁵⁸ OS was significantly greater with combination therapy (11.7 versus 8.1 months), and PFS also favored the combination arm (8 versus 5 months). Toxicity was comparable in both groups, with the exception of significantly higher rates of grade 3 or 4 neutropenia with gemcitabine plus cisplatin (25% versus 17%), and higher rates of grade 3 or 4 abnormal liver function with gemcitabine alone (27% versus 17%). Most quality-of-life scales showed a trend favoring combined therapy.⁵⁸ A smaller, identically designed Japanese phase 3 randomized trial achieved similar results, demonstrating greater OS with cisplatin plus gemcitabine compared to gemcitabine alone (11.2 versus 7.7 months).⁵⁹

The gemcitabine plus cisplatin combination has not been directly compared with other gemcitabine combinations in phase 3 trials. A pooled analysis of 104 trials of a variety of chemotherapy regimens in advanced biliary cancer concluded that the gemcitabine plus cisplatin regimen offered the highest rates of objective response and tumor control compared with either gemcitabine-free or cisplatin-free regimens.⁶⁰ However, this did not translate into significant benefit in terms of either time to tumor progression or median OS. It is important to note that this analysis did not include results of the subsequent ABC-02 trial.

There is no standard treatment for patients with cholangiocarcinoma for whom first-line gemcitabine-based therapy fails. There are no completed prospective phase 3 trials supporting the use of second-line chemotherapy after failure of first-line chemotherapy in BTC, and the selection of candidates for second-line therapy as well as the optimal regimen are not established.⁶¹ The ongoing phase 2 multicenter ABC-06 trial is evaluating oxaliplatin plus short-term infusional FU and leucovorin (FOLFOX) versus best supportive care for second-line therapy. In a systematic review including 23 studies (14 phase 2 clinical trials and 9 retrospective studies) with 761 patients with BTC, the median OS was 7.2 months.

The optimal selection of candidates for second-line chemotherapy is not established. Two independent studies suggest that patients who have a good performance status (0 or 1), disease control with the first-line chemotherapy, low CA 19-9 level, and possibly previous surgery on their primary tumor, have the longest survival with second-line chemotherapy. However, whether these characteristics predict for chemotherapy responsiveness or more favorable biologic behavior is not clear.^62,63 No particular regimen has proved superior to any other, and the choice of second-line regimen remains empiric.

For patients with adequate performance status, examples of other conventional chemotherapy regimens with demonstrated activity that could be considered for second-line therapy include: FOLFOX or capecitabine, gemcitabine plus capecitabine, capecitabine plus cisplatin, or irinotecan plus short-term infusional FU and leucovorin (FOLFIRI) with or without bevacizumab.⁶⁴ For selected patients, second-line molecularly targeted therapy using erlotinib plus bevacizumab may be considered. However, this regimen is very costly.⁶⁴ Examples of other regimens with demonstrated activity in phase 2 trials include GEMOX, gemcitabine plus fluoropyrimidine, and fluoropyrimidine plus oxaliplatin or cisplatin.⁶⁴

There is promising data from studies of targeted therapy for specific molecular subgroups. A recent phase 2 trial evaluated the activity of BGJ398, an orally bioavailable, selective, ATP-competitive pan inhibitor of human fibroblast growth factor receptor (FGFR) kinase, in patients with FGFR-altered advanced cholangiocarcinoma.⁶⁵ The overall response rate was 14.8% (18.8% FGFR2 fusions only) and disease control rate was 75.4% (83.3% FGFR2 fusions only). All responsive tumors contained FGFR2 fusions. Adverse events were manageable, and grade 3 or 4 treatment-related adverse events occurred in 25 patients (41%). Those included hyperphosphatemia, stomatitis, and palmar-plantar erythrodysesthesia. Javle and colleagues also identified HER2/neu blockade as a promising treatment strategy for gallbladder cancer patients with this gene amplification.⁶⁶ This retrospective analysis included 9 patients with gallbladder cancer and 5 patients with cholangiocarcinoma who received HER2/neu-directed therapy (trastuzumab, lapatinib, or pertuzumab). In the gallbladder cancer group, HER2/neu gene amplification or overexpression was detected in 8 cases. These patients experienced disease stability (n = 3), partial response (n = 4), or complete response (n = 1) with HER2/neu–directed therapy. Median duration of response was 40 weeks. The cholangiocarcinoma cases treated in this series had no radiological responses despite HER2/neu mutations or amplification.

Gallbladder Cancer

Case Presentation

A 57-year-old woman from Chile presents with a 3-week history of progressive right upper quadrant abdominal pain. She denies nausea, vomiting, dysphagia, odynophagia, alterations in bowel habits, fever, or jaundice. Her past medical history is significant for obesity and hypertension. She has no history of smoking, alcohol, or illicit drug use. Laboratory studies show marked leukocytosis (23,800/µL) with neutrophilia (91%). Liver function test results are within normal limits. Ultrasound of the abdomen reveals gallbladder wall thickening and cholelithiasis.

The patient undergoes an uneventful laparoscopic cholecystectomy and is discharged from the hospital after 48 hours. Pathology report reveals a moderately differentiated adenocarcinoma of the gallbladder invading the perimuscular connective tissue (T2). No lymph nodes are identified in the specimen.

• What is the appropriate surgical management of gallbladder cancer?

Gallbladder cancer can be diagnosed preoperatively or can be found incidentally by intraoperative or pathological findings. In one large series, gallbladder cancer was incidentally found during 0.25% of laparoscopic cholecystectomies.⁶⁷

For patients who are diagnosed with previously unsuspected gallbladder cancer by pathology findings, the extent of tumor invasion (T stage) indicates the need for re-resection (Figure 3).⁶⁴

Alternatively, when gallbladder cancer is documented or suspected preoperatively, adequate imaging is important to identify patients with absolute contraindications to resection. Contraindications to surgery include metastasis, extensive involvement of the hepatoduodenal ligament, encasement of major vessels, and involvement of celiac, peripancreatic, periduodenal, or superior mesenteric nodes.⁷² Notwithstanding, retrospective series suggest individual patients may benefit, and surgical indications in advanced disease should be determined on an individual basis.⁷³ Staging imaging should be obtained using multiphasic contrast-enhanced CT or MRI of the chest, abdomen, and pelvis. PET-scan can be used in selected cases where metastatic disease is suspected.⁶⁴ Laparoscopic diagnostic staging should be considered prior to resection.⁶⁴ This procedure can identify previously unknown contraindications to tumor resection in as much as 23% of patients, and the yield is significantly higher in locally advanced tumors.⁷³

Patients with a diagnosis of potentially resectable, localized gallbladder cancer should be offered definitive surgery. Extended cholecystectomy is recommended for patients stage T2 or above. This procedure involves wedge resection of the gallbladder bed or a segmentectomy IVb/V and lymph node dissection, which should include the cystic duct, common bile duct, posterior superior pancreaticoduodenal lymph nodes, and those around the hepatoduodenal ligament.⁷² Bile duct excision should be performed if there is malignant involvement.⁶⁴

Conclusion

BTCs are anatomically and clinically heterogeneous tumors. Prognostic factors and therapeutic approaches for BTCs differ depending upon their location in the biliary tree and, accordingly, TNM classification systems for intrahepatic, hilar, and distal cholangiocarcinoma and gallbladder cancer have been separated. Surgical resection is the only potentially curative treatment for localized BTC. However, recurrence following complete resection is a primary limitation for cure, which provides a rationale for the use of adjuvant therapy. The prognosis of patients with advanced BTC is poor and OS for those undergoing supportive care alone is short. Multiple randomized clinical trials have demonstrated a benefit of chemotherapy for metastatic disease. For patients with adequate performance status, second-line therapy can be considered, and data from studies that evaluated targeted therapy for specific molecular subgroups is promising.

Introduction

Polycythemia vera (PV) and essential thrombocythemia (ET), along with primary myelofibrosis (PMF), belong to the group of Philadelphia-negative myeloproliferative neoplasms (MPN). All these malignancies arise from the clonal proliferation of an aberrant hematopoietic stem cell, but are characterized by distinct clinical phenotypes.^1,2 Although the clinical course of PV and ET is indolent, it can be complicated by thrombohemorrhagic episodes and/or evolution into myelofibrosis and/or acute myeloid leukemia (AML).³ Since vascular events are the most frequent life-threatening complications of PV and ET, therapeutic strategies are aimed at reducing this risk. Treatment may also help control other disease-associated symptoms.⁴ No therapy has been shown to prevent evolution of PV or ET into myelofibrosis or AML. The discovery of the Janus kinase 2 (JAK2)/V617F mutation in most patients with PV and over half of those with ET (and PMF)^5,6 has opened new avenues of research and led to the development of targeted therapies, such as the JAK1/2 inhibitor ruxolitinib, for patients with MPN.^7,8

Epidemiology

PV and ET are typically diagnosed in the fifth to seventh decade of life.⁹ Although these disorders are generally associated with a long clinical course, survival of patients with PV or ET may be shorter than that of the general population.^10–13 Estimating the incidence and prevalence of MPN is a challenge because most patients remain asymptomatic for long periods of time and do not seek medical attention.¹³ The annual incidence rates of PV and ET are estimated at 0.01 to 2.61 and 0.21 to 2.53 per 100,000, respectively. PV occurs slightly more frequently in males, whereas ET has a predilection for females.¹⁴ Given the long course and low mortality associated with these disorders, the prevalence of PV and ET are significantly higher than the respective incidence: up to 47 and 57 per 100,000, respectively.^15–17

Molecular Pathogenesis

In 2005 researchers discovered a gain-of-function mutation of the JAK2 gene in nearly all patients with PV and more than half of those with ET and PMF.^5,6,18,19 JAK2 is a non-receptor tyrosine kinase that plays a central role in normal hematopoiesis. Substitution of a valine for a phenylalanine at codon 617 (ie, V617F) leads to its constitutive activation and signaling through the JAK-STAT pathway.^5,6,18,19 More rarely (and exclusively in patients with PV), JAK2 mutations involve exon 12.^20–22 The vast majority of JAK2-negative ET patients harbor mutations in either the myeloproliferative leukemia (MPL) gene, which encodes the thrombopoietin receptor,^23–25 or the calreticulin (CALR) gene,^26,27 which encodes for a chaperone protein that plays a role in cellular proliferation, differentiation, and apoptosis.²⁸ Both the MPL and CALR mutations ultimately result in the constitutive activation of the JAK-STAT pathway. Thus, JAK2, MPL, and CALR alterations are collectively referred to as driver mutations. Moreover, because these mutations affect the same oncogenic pathway (ie, JAK-STAT), they are almost always mutually exclusive in a given patient. Patients with ET (or myelofibrosis) who are wild-type for JAK2, MPL, and CALR are referred to as having “triple-negative” disease. Many recurrent non-driver mutations are also found in patients with MPN that are not exclusive of each other (ie, patients may have many at the same time), and involve for example ten-eleven translocation-2 (TET2), additional sex combs like 1 (ASXL1), enhancer of zeste homolog 2 (EZH2), isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 (IDH1/2), and DNA methyltransferase 3A (DNMT3A) genes, among others.²⁹ The biologic and prognostic significance of these non-driver alterations remain to be fully defined in ET and PV.

Diagnosis and Risk Assessment

Case Presentations

Patient A is a 68-year-old man with a history of gouty arthritis who presents with a 6-month history of recurrent headaches and itching that increases after a hot shower. Over the past 2 months, he has also noticed worsening fatigue and redness of his face. He is a nonsmoker. Physical exam reveals erythromelalgia (ie, erythema, edema, and warmth) of the upper and lower extremities, scattered scratch marks, and splenomegaly 4 cm below the costal margin. Complete blood count (CBC) shows a white blood cell (WBC) count of 8100/µL, hemoglobin 194 g/L, and platelets 582 × 10³/µL. Serum erythropoietin level is decreased at 2 mU/mL. Peripheral blood testing reveals a JAK2V617F mutation.

Patient B is a 51-year-old woman with a history of severe depression treated with sertraline and hypertension controlled with lisinopril and amlodipine who presents to her primary care physician for her “50-year-old physical.” She denies symptoms and is a nonsmoker. Physical exam is unrevealing. CBC shows a WBC count of 7400/µL (normal differential), hemoglobin 135 g/L, and platelets 1282 × 10³/µL. A bone marrow biopsy shows normal cellularity with clusters of large, hyperlobulated megakaryocytes. Reverse transcriptase-polymerase chain reaction fails to reveal a BCR-ABL fusion product. The patient is diagnosed with ET.

Diagnostic Criteria

Diagnostic criteria for PV and ET according to the World Health Organization (WHO) classification³⁰ are summarized in Table 1. Criteria for the diagnosis of prefibrotic myelofibrosis are included as well since this entity was formally recognized as separate from ET and part of the PMF spectrum in the 2016 WHO classification of myeloid tumors.³⁰

Risk Stratification

Thrombohemorrhagic events, evolution into myelofibrosis, and leukemic transformation are the most serious complications in the course of PV or ET. Only thrombohemorrhagic events are, at least partially, preventable. Arterial or venous thrombotic complications are observed at rates of 1.8 to 10.9 per 100 patient-years in PV (arterial thrombosis being more common than venous) and 0.74 to 7.7 per 100 patient-years in ET, depending on the risk group³⁵ and the presence of other factors (see below).

Thrombosis Risk Stratification in PV

The risk stratification of patients with PV is based on 2 factors: age ≥ 60 years and prior history of thrombosis. If either is present the patient is assigned to the high-risk category, whereas if none is present the patient is considered at low risk.³⁶ In addition, high hematocrit³⁷ and high WBC,³⁸ but not thrombocytosis, have been associated with the development of vascular complications. In one study, the risk of new arterial thrombosis was increased by the presence of leukoerythroblastosis, hypertension, and prior arterial thrombosis, while karyotypic abnormalities and prior venous thrombosis were predictors of new venous thrombosis.³⁹ Another emerging risk factor for thrombosis in patients with PV is high JAK2 allele burden (ie, the normal-to-mutated gene product ratio), although the evidence supporting this conclusion is equivocal.⁴⁰

Thrombosis Risk Stratification in ET

Traditionally, in ET patients, thrombotic risk was assessed using the same 2 factors (age ≥ 60 years and prior history of thrombosis), separating patients into low- and high-risk groups. However, the prognostication of ET patients has been refined recently with the identification of new relevant factors. In particular, the impact of JAK2 mutations on thrombotic risk has been thoroughly studied. Clinically, the presence of JAK2V617F is associated with older age, higher hemoglobin and hematocrit, lower platelet counts, more frequent need for cytoreductive treatment, and greater tendency to evolve into PV (a rare event).^41,42 Many,^41,43–46 but not all,^47–51 studies suggested a correlation between JAK2 mutation and risk of both arterial and venous thrombosis. Although infrequent, a JAK2V617F homozygous state (ie, the mutation is present in both alleles) might confer an even higher thrombotic risk.⁵² Moreover, the impact of the JAK2 mutation on vascular events persists over time,⁵³ particularly in patients with high or unstable mutation burden.⁵⁴ Based on JAK2V617F’s influence on the thrombotic risk of ET patients, a new prognostic score was proposed, the International Prognostic Score for ET (IPSET)-thrombosis (Table 2). The revised version of this model is currently endorsed by the National Comprehensive Cancer Network and divides patients into 4 risk groups: high, intermediate, low, and very low. Treatment recommendations vary according to the risk group (as described below).⁵⁵

Other thrombotic risk factors have been identified, but deemed not significant enough to be included in the model. Cardiovascular risk factors (hypercholesterolemia, hypertension, smoking, diabetes mellitus) can increase the risk of vascular events,^56–59 as can splenomegaly⁶⁰ and baseline or persistent leukocytosis.^61–63 Thrombocytosis has been correlated with thrombotic risk in some studies,^64–68 whereas others did not support this conclusion and/or suggested a lower rate of thrombosis and, in some cases, increased risk of bleeding in ET patients with platelet counts greater than 1000 × 10³/µL (due to acquired von Willebrand syndrome).^{56,61,63,68,69}

CALR mutations tend to occur in younger males with lower hemoglobin and WBC count, higher platelet count, and greater marrow megakaryocytic predominance as compared to JAK2 mutations.^{26,27,70–72} The associated incidence of thrombosis was less than 10% at 15 years in patients with CALR mutations, lower than the incidence reported for ET patients with JAK2V617F mutations.⁷³ The presence of the mutation per se does not appear to affect the thrombotic risk.^74–76 Information on the thrombotic risk associated with MPL mutations or a triple-negative state is scarce. In both instances, however, the risk appears to be lower than with the JAK2 mutation.^73,77–79

Venous thromboembolism in patients with PV or ET may occur at unusual sites, such as the splanchnic or cerebral venous systems.⁸⁰ Risk factors for unusual venous thromboembolism include younger age,⁸¹ female gender (especially with concomitant use of oral contraceptive pills),⁸² and splenomegaly/splenectomy.⁸³JAK2 mutation has also been associated with thrombosis at unusual sites. However, the prevalence of MPN or JAK2V617F in patients presenting with splanchnic venous thromboembolism has varied.⁸⁰ In addition, MPN may be occult (ie, no clinical or laboratory abnormalities) in around 15% of patients.⁸⁴ Screening for JAK2V617F and underlying MPN is recommended in patients presenting with isolated unexplained splanchnic venous thromboembolism. Treatment entails long-term anticoagulation therapy. JAK2V617F screening in patients with nonsplanchnic venous thromboembolism is not recommended, as its prevalence in this group is low (< 3%).^85,86

Treatment

Cases Continued

Patient A is diagnosed with PV based on the presence of 2 major criteria (elevated hemoglobin and presence of the JAK2V617F mutation) and 1 minor criterion (low erythropoietin level). Given his age, he belongs to the high-risk disease category. He is now seeking advice regarding the management of his newly diagnosed PV.

Patient B presents to the emergency department with right lower extremity swelling and is found to have deep femoral thrombosis extending to the iliac vein. Five days after being discharged from the emergency department, she presents for follow-up. She is taking warfarin compliantly and her INR is within therapeutic range. The patient now has high-risk ET and would like to know more about thrombosis in her condition and how to best manage her risk.

Risk-Adapted Therapy

Low-Risk PV

All patients with PV should receive counseling to mitigate cardiovascular risk factors, including smoking cessation, lifestyle modifications, and lipid-lowering therapy, as indicated. Furthermore, all PV patients should receive acetylsalicylic acid (ASA) to decrease their risk for thrombosis and control vasomotor symptoms.^55,87 Aspirin 81 to 100 mg daily is the preferred regimen because it provides adequate antithrombotic effect without the associated bleeding risk of higher-dose aspirin.⁸⁸ Low-risk PV patients should also receive periodic phlebotomies to reduce and maintain their hematocrit below 45%. This recommendation is based on the results of the Cytoreductive Therapy in Polycythemia Vera (CYTO PV) randomized controlled trial. In the CYTO PV study, patients receiving more intense therapy to maintain the hematocrit below 45% had a lower incidence of cardiovascular-related deaths or major thrombotic events than those with hematocrit goals of 45% to 50% (2.7% versus 9.8%).⁸⁹ Cytoreduction is an option for low-risk patients who do not tolerate phlebotomy or require frequent phlebotomy, or who have disease-related bleeding, severe symptoms, symptomatic splenomegaly, or progressive leukocytosis.³⁸

High-Risk PV

Patients older than 60 years and/or with a history of thrombosis should be considered for cytoreductive therapy in addition to the above measures. Front-line cytoreductive therapies include hydroxyurea or interferon (IFN)- alfa.⁸⁷ Hydroxyurea is a potent ribonucleotide reductase inhibitor that interferes with DNA repair and is the treatment of choice for most high-risk patients with PV.⁹⁰ In a small trial hydroxyurea reduced the risk of thrombosis compared with historical controls treated with phlebotomy alone.⁹¹ Hydroxyurea is generally well tolerated; common side effects include cytopenias, nail changes, and mucosal and/or skin ulcers. Although never formally proven to be leukemogenic, this agent should be used with caution in younger patients.⁸⁷ Indeed, in the original study, the rates of transformation were 5.9% and 1.5% for patients receiving hydroxyurea and phlebotomy alone,⁹² respectively, although an independent role for hydroxyurea in leukemic transformation was not supported in the much larger European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) study.⁹³ About 70% of patients will have a sustained response to hydroxyurea,⁹⁴ while the remaining patients become resistant to or intolerant of the drug. Resistant individuals have a higher risk of progression to acute leukemia and death.⁹⁵

IFN alfa is a pleiotropic antitumor agent that has found application in many types of malignancies⁹⁶ and is sometimes employed as treatment for patients with newly diagnosed high-risk PV. Early studies showed responses in up to 100% of cases,^97,98 albeit at the expense of a high discontinuation rate due to adverse events, such as flu-like symptoms, fatigue, and neuropsychiatric manifestations.⁹⁹ A newer formulation of the drug obtained by adding a polyethylene glycol (PEG) moiety to the native IFN alfa molecule (PEG-IFN alfa) was shown to have a longer half-life, greater stability, less immunogenicity, and, potentially, better tolerability.¹⁰⁰ Pilot phase 2 trials of PEG-IFN alfa-2a demonstrated its remarkable activity, with symptomatic and hematologic responses seen in the majority of patients (which, in some cases, persisted beyond discontinuation), and reasonable tolerability, with long-term discontinuation rates of around 20% to 30%.^101–103 In some patients JAK2V617F became undetectable over time.¹⁰⁴ Results of 2 ongoing trials, MDP-RC111 (single-arm study, PEG-IFN alfa-2a in high-risk PV or ET [NCT01259817]) and MPD-RC112 (randomized controlled trial, PEG-IFN alfa-2a versus hydroxyurea in the same population [NCT01258856]), will shed light on the role of PEG-IFN alfa in the management of patients with high-risk PV or ET. In 2 phase 2 studies of PEG-IFN alfa-2b, complete responses were seen in 70% to 100% of patients and discontinuation occurred in around a third of cases.^105,106 A new, longer-acting formulation of PEG-IFN alfa-2a (peg-proline INF alfa-2b, AOP2014) is also undergoing clinical development.^107,108

The approach to treatment of PV based on thrombotic risk level is illustrated in Figure 1.

Very Low- and Low-Risk ET

Like patients with PV, individuals with ET should undergo rigorous cardiovascular risk management and generally receive ASA to decrease their thrombotic risk and improve symptom control. Antiplatelet therapy may not be warranted in patients with documented acquired von Willebrand syndrome, with or without extreme thrombocytosis, or in those in the very low-risk category according to the IPSET-thrombosis model.^55,87 The risk/benefit ratio of antiplatelet agents in patients with ET at different thrombotic risk levels was assessed in poor-quality studies and thus remains highly uncertain. Platelet-lowering agents are sometimes recommended in patients with low-risk disease who have platelet counts ≥ 1500 × 10³/µL, due to the potential risk of acquired von Willebrand syndrome and a risk of bleeding (this would require stopping ASA).¹⁰⁹ Cytoreduction may also be used in low-risk patients with progressive symptoms despite ASA, symptomatic or progressive splenomegaly, and progressive leukocytosis.

Intermediate-Risk ET

This category includes patients older than 60 years but without thrombosis or JAK2 mutations. These individuals would have been considered high risk (and thus candidates for cytoreductive therapy) according to the traditional risk stratification. Guidelines currently recommend ASA as the sole therapy for these patients, while reserving cytoreduction for those who experience thrombosis (ie, become high-risk) or have uncontrolled vasomotor or general symptoms, symptomatic splenomegaly, symptomatic thrombocytosis, or progressive leukocytosis.

High-Risk ET

For patients with ET in need of cytoreductive therapy (ie, those with prior thrombosis or older than 60 years with a JAK2V617F mutation), first-line options include hydroxyurea, IFN, and anagrelide. Hydroxyurea remains the treatment of choice in the majority of patients.¹¹⁰ In a seminal study, 114 patients with ET were randomly assigned to either observation or hydroxyurea treatment with the goal of maintaining the platelet count below 600 × 10³/µL. At a median follow-up of 27 months, patients in the hydroxyurea group had a lower thrombosis rate (3.6% versus 24%, P = 0.003) and longer thrombosis-free survival, regardless of the use of antiplatelet drugs.⁶⁴

Anagrelide, a selective inhibitor of megakaryocytic differentiation and proliferation, was compared with hydroxyurea in patients with ET in 2 randomized trials. In the first (N = 809), the group receiving anagrelide had a higher risk of arterial thrombosis, major bleeding, and fibrotic evolution, but lower incidence of venous thrombosis. Hydroxyurea was better tolerated, mainly due to anagrelide-related cardiovascular adverse events.¹¹¹ As a result of this study, hydroxyurea is often preferred to anagrelide as front-line therapy for patients with newly diagnosed high-risk ET. In the second, more recent study (N = 259), however, the 2 agents proved equivalent in terms of major or minor arterial or venous thrombosis, as well as discontinuation rate.¹¹² The discrepancy between the 2 trials may be partly explained by the different ET diagnostic criteria used, with the latter only enrolling patients with WHO-defined true ET, while the former utilized Polycythemia Vera Study Group-ET diagnostic criteria that included patients with increases in other blood counts or varying degrees of marrow fibrosis.

Interferons were studied in ET in parallel with PV. PEG-IFN alfa-2a proved effective in patients with ET, with responses observed in 80% of patients.¹⁰³ PEG-IFN alfa-2b produced similar results, with responses in 70% to 90% of patients in small studies and discontinuation observed in 20% to 38% of cases.^105,106,113 Because the very long-term leukemogenic potential of hydroxyurea has remained somewhat uncertain, anagrelide or IFN might be preferable choices in younger patients.

The approach to treatment of ET based on thrombotic risk level is illustrated in Figure 2.

Assessing Response to Therapy

For both patients with PV and ET the endpoint of treatment set forth for clinical trials has been the achievement of a clinicohematologic response. However, studies have failed to show a correlation between response and reduction of the thrombohemorrhagic risk.¹¹⁴ Therefore, proposed clinical trial response criteria were revised to include absence of hemorrhagic or thrombotic events as part of the definition of response (Table 3).⁹⁴

Cases Continued

Patient A was initially treated with phlebotomies and his blood counts were subsequently controlled with hydroxyurea, which he took uninterruptedly at an average dose of 2.5 g daily. He also took ASA daily throughout. Now, 18 months after the start of therapy, he presents with a complaint of fatigue for the past 3 months, which more recently has been associated with recurrent itching. A repeat CBC shows a WBC count of 17,200/µL, hemoglobin 181 g/L, and platelets 940 × 10³/µL.

Patient B presents for scheduled follow-up. She has had no further thrombotic episodes. However, she spontaneously discontinued hydroxyurea 1 month ago because of worsening mouth ulcers that impaired her ability to eat even small meals. She seeks recommendations for further treatment options.

Approach to Patients Refractory to or Intolerant of First-Line Therapy

According to the European LeukemiaNet recommendations, an inadequate response to hydroxyurea in patients with PV (or myelofibrosis) is defined as a need for phlebotomy to maintain hematocrit below < 45%, platelet count > 400 × 10³/µL, and a WBC count > 10,000/µL, or failure to reduce splenomegaly > 10 cm by > 50% at a dose of ≥ 2 g/day or maximum tolerated dose. Historically, treatment options for patients with PV or ET who failed first-line therapy (most commonly hydroxyurea) have included alkylating agents, such as busulfan, chlorambucil, or pipobroman, and phosphorus (P)-32. However, the use of these drugs is limited by the associated risk of leukemic transformation.^93,115,116 The use of IFN (or anagrelide for ET) is often considered in patients previously treated with hydroxyurea, and vice versa.

Ruxolitinib is a JAK1 and JAK2 inhibitor currently approved for the treatment of PV patients refractory to or intolerant of hydroxyurea.⁷ Following promising results of a phase 2 trial,¹¹⁷ ruxolitinib 10 mg twice daily was compared with best available therapy in the pivotal RESPONSE trial (N = 222). Ruxolitinib proved superior in achieving hematocrit control, reduction of spleen volume, and improvement of symptoms. Grade 3-4 hematologic toxicity was infrequent and similar in the 2 arms.¹¹⁸ In addition, longer follow-up of that study suggested a lower rate of thrombotic events in patients receiving ruxolitinib (1.8 versus 8.2 per 100 patient-years).¹¹⁹ In a similarly designed randomized phase 3 study in PV patients without splenomegaly (RESPONSE-2), more patients in the ruxolitinib arm had hematocrit reduction without an increase in toxicity. Based on the results of the above studies, ruxolitinib can be considered a standard of care for second-line therapy in this post-hydroxyurea patient population.¹²⁰

Ruxolitinib is also being tested in patients with high-risk ET who have become resistant to, or were intolerant of hydroxyurea, but currently has no approved indication in this setting.^121,122 Common side effects of ruxolitinib include cytopenias (especially anemia), increased risk of infections, hyperlipidemia, and increased risk of non-melanoma skin cancer.

Novel Agents

Novel agents that have been studied in patients with PV and ET are histone deacetylase inhibitors, murine double minute 2 (MDM2, or HDM2 for their human counterpart) inhibitors (which restore the function of p53), Bcl-2 homology domain 3 mimetics such as navitoclax and venetoclax, and, for patients with ET, the telomerase inhibitor imetelstat.¹²³

Disease Evolution

Cases Continued

Patient A’s PV has been well controlled with PEG-IFN alfa-2a 90 μg subcutaneously weekly. However, he now presents with a complaint of worsening fatigue and early satiety. On exam the patient appears ill and splenomegaly is appreciated 12 cm below the costal margin. CBC shows a WBC count of 2600/µL, hemoglobin 73 g/L, and platelets 122 × 10³/µL. Peripheral blood smear reveals leukoerythroblastosis and dacro­cytosis. CBC 6 months ago was normal. A bone marrow biopsy is consistent with myelofibrosis.

After discontinuing hydroxyurea, patient B’s ET has been well controlled with anagrelide. However, for the past 4 weeks she has complained of severe fatigue and easy bruising. Physical exam reveals a pale, ill-appearing woman with scattered bruises. CBC shows a WBC count of 14,600/µL with 44% myeloblasts, hemoglobin 73 g/L, and platelets 22 × 10³/µL. CBC 6 months ago was normal. A bone marrow biopsy is consistent with leukemic transformation of ET.

Post-PV/Post-ET Myelofibrosis

Diagnostic criteria for post-PV and post-ET myelofibrosis are outlined in Table 4.

Leukemic Transformation

The presence of more than 20% blasts in peripheral blood or bone marrow in a patient with MPN defines leukemic transformation. This occurs in up to 5% to 10% of patients and may or may not be preceded by a myelofibrosis phase.¹²⁶ In cases of extramedullary transformation, a lower percentage of blasts can be seen in the bone marrow compared to the peripheral blood. The pathogenesis of leukemic transformation has remained elusive, but it is believed to be associated with genetic instability, which facilitates the acquisition of additional mutations, including those of TET2, ASXL1, EZH2 and DNMT3, IDH1/2, and TP53.¹²⁷

Clinical risk factors for leukemic transformation include advanced age, karyotypic abnormalities, prior therapy with alkylating agents or P-32, splenectomy, increased peripheral blood or bone marrow blasts, leukocytosis, anemia, thrombocytopenia, and cytogenetic abnormalities. Hydroxyurea, interferon, and ruxolitinib have not been shown to have leukemogenic potential thus far. Prognosis of leukemic transformation is uniformly poor and patient survival rarely exceeds 6 months.

There is no standard of care for leukemic transformation of MPN (MPN-LT). Treatment options range from low-intensity regimens to more aggressive AML-type induction chemotherapy. No strategy appears clearly superior to others.¹²⁸ Hematopoietic stem cell transplantation is the only therapy that provides clinically meaningful benefit to patients,¹²⁹ but it is applicable only to a minority of patients with chemosensitive disease and good performance status.¹³⁰ Notable experimental approaches to MPN–LT include hypomethylating agents, such as decitabine¹³¹ or azacitidine,¹³² with or without ruxolitinib.^133-135

Conclusion

PV and ET are rare, chronic myeloid disorders. Patients typically experience a long clinical course and enjoy near-normal quality of life if properly managed. The 2 most important life-limiting complications of PV and ET are thrombohemorrhagic events and myelofibrosis/AML transformation. Vascular events are at least in part preventable with counseling on risk factors, phlebotomy (for patients with PV), antiplatelet therapy, and cytoreduction with hydroxyurea, IFNs, or anagrelide (for patients with ET). In addition, ruxolitinib was recently approved for PV patients after hydroxyurea failure. PV/ET transformation in myelofibrosis or AML is part of the natural history of the disease and no therapy has been shown to prevent it. Treatment follows recommendations set forth for PMF and AML, but results are generally poorer and novel strategies are needed to improve patients’ outcomes.