CHICAGO – Systematic mortality-risk assessment of patients who presented to hospital emergency departments for acute heart failure led to better patient outcomes in a controlled Canadian trial with more than 5,000 patients.

Thirty days after patients presented, the incidence of death from any cause or hospitalization for cardiovascular causes – one of two primary endpoints in the COACH study – was 12.1% among patients who underwent acute risk assessment and 14.5% in control patients who did not undergo this assessment, which translated into an adjusted, significant 12% relative risk reduction for the patients who underwent systematic assessment, Douglas S. Lee, MD, PhD, said at the American Heart Association scientific sessions.

Mitchel L. Zoler/MDedge News

The study’s second primary endpoint, the incidence of the same combined outcome 20 months after initial presentation, was 54.4% among the 2,480 patients assessed with the risk-assessment tool and 56.2% in the 2,972 controls, a significant, adjusted relative risk reduction of 5%.

This benefit was primarily driven by reductions in cardiovascular hospitalizations, which fell by an adjusted 16% in the intervention group compared with controls, and more specifically by hospitalizations for heart failure, which tallied a relative 20% less with the intervention. Both were significant between-group differences.

The other portion of the combined endpoint, all-cause mortality, was not significantly different between the patients who underwent the systematic emergency department assessment and the controls who were managed using usual emergency-department protocols.

Simultaneous with the report, the results also appeared online in the New England Journal of Medicine.
 

A pathway for early discharge and improved outcomes

“Implementation of this approach may lead to a pathway for early discharge from the hospital or emergency department, and improved patient outcomes,” said Dr. Lee, a professor at the University of Toronto, and a senior core scientist at the ICES Cardiovascular Research Program in Toronto.

Mitchel L. Zoler/MDedge News

“The treatment effect on the primary process outcome – patients admitted or discharged – will add useful insights into how intervention may improve,” commented Harriette Van Spall, MD, who was designated discussant for the report. The findings “fill an important knowledge gap,” added Dr. Van Spall, a cardiologist at McMaster University in Hamilton, Ont. The results “have important implications for health resource utilization,” she said.

The risk assessment tool used in the study is called the Emergency Heart failure Mortality Risk Grade for 30-day mortality (EHMRG30-ST), which was devised and validated by Dr. Lee and his associates. The assessment tool uses 11 clinical variables that include age, systolic blood pressure, heart rate, oxygen saturation, potassium and creatinine levels, and presence of ST depression on a 12-lead ECG.

The study design recommended that patients be discharged early and receive standardized transitional care as outpatients if they had a low risk of death within 7 days and within 30 days as estimated by the EHMRG30-ST. The protocol recommended that patients scored as high risk should be admitted to the hospital, and that clinicians use their clinical judgment for intermediate-risk patients but favor admission for intermediate to high risk and discharge for low to intermediate risk. The study ran at 10 hospitals in Ontario. Initially, all 10 hospitals assessed patients by usual care, and then, over time, each hospital began using the tool so that by the end of the study all 10 hospitals employed it. Among the 2,480 patients seen during the active phase, 2,442 actually underwent assessment, with 24% rated as low risk, 32% rated as intermediate risk, and 44% judged to have high risk.

The researchers also ran risk assessments retrospectively on the controls, who showed a roughly similar risk distribution, with 18% low risk, 28% intermediate risk, and 54% high risk.

The patients averaged 78 years of age, 55% were men, about 40% had diabetes, and about 64% had a prior heart failure diagnosis.



Heart failure admissions have become ‘a big deal’

Emergency department clinicians and heart failure cardiologists “have worked together for a long time” when making decisions about which patients with acute heart failure need hospital admission, commented Mary N. Walsh, MD, medical director of the heart failure and cardiac transplantation programs at Ascension St. Vincent Heart Center in Indianapolis. These decisions “became a big deal” a decade ago when the U.S. Centers for Medicare & Medicaid Services launched the Hospital Readmissions Reduction Program that began to penalize hospitals for high rates of hospital readmissions for several conditions including heart failure, she said in an interview.

Mitchel L. Zoler/MDedge News

“If a heart failure patient is not admitted, they can’t be readmitted,” Dr. Walsh noted.

“Many risk-assessment tools exist for patients once they are hospitalized, but these tools have not been used in emergency departments. The take-home message is that we need to start risk assessment sooner, in the emergency department,” she said.

But the specific approach tested in the COACH trial needs more study and may need further tweaking to work in the United States, where it is not clear who would pay for a program like the one tested in the trial. Canada’s unified health care payment system makes the COACH approach more financially feasible, Dr. Walsh commented.

COACH received no commercial funding. Dr. Lee, Dr. Van Spall, and Dr. Walsh had no disclosures.

CHICAGO – Systematic mortality-risk assessment of patients who presented to hospital emergency departments for acute heart failure led to better patient outcomes in a controlled Canadian trial with more than 5,000 patients.

Thirty days after patients presented, the incidence of death from any cause or hospitalization for cardiovascular causes – one of two primary endpoints in the COACH study – was 12.1% among patients who underwent acute risk assessment and 14.5% in control patients who did not undergo this assessment, which translated into an adjusted, significant 12% relative risk reduction for the patients who underwent systematic assessment, Douglas S. Lee, MD, PhD, said at the American Heart Association scientific sessions.

Mitchel L. Zoler/MDedge News

The study’s second primary endpoint, the incidence of the same combined outcome 20 months after initial presentation, was 54.4% among the 2,480 patients assessed with the risk-assessment tool and 56.2% in the 2,972 controls, a significant, adjusted relative risk reduction of 5%.

This benefit was primarily driven by reductions in cardiovascular hospitalizations, which fell by an adjusted 16% in the intervention group compared with controls, and more specifically by hospitalizations for heart failure, which tallied a relative 20% less with the intervention. Both were significant between-group differences.

The other portion of the combined endpoint, all-cause mortality, was not significantly different between the patients who underwent the systematic emergency department assessment and the controls who were managed using usual emergency-department protocols.

Simultaneous with the report, the results also appeared online in the New England Journal of Medicine.
 

A pathway for early discharge and improved outcomes

“Implementation of this approach may lead to a pathway for early discharge from the hospital or emergency department, and improved patient outcomes,” said Dr. Lee, a professor at the University of Toronto, and a senior core scientist at the ICES Cardiovascular Research Program in Toronto.

Mitchel L. Zoler/MDedge News

“The treatment effect on the primary process outcome – patients admitted or discharged – will add useful insights into how intervention may improve,” commented Harriette Van Spall, MD, who was designated discussant for the report. The findings “fill an important knowledge gap,” added Dr. Van Spall, a cardiologist at McMaster University in Hamilton, Ont. The results “have important implications for health resource utilization,” she said.

The risk assessment tool used in the study is called the Emergency Heart failure Mortality Risk Grade for 30-day mortality (EHMRG30-ST), which was devised and validated by Dr. Lee and his associates. The assessment tool uses 11 clinical variables that include age, systolic blood pressure, heart rate, oxygen saturation, potassium and creatinine levels, and presence of ST depression on a 12-lead ECG.

The study design recommended that patients be discharged early and receive standardized transitional care as outpatients if they had a low risk of death within 7 days and within 30 days as estimated by the EHMRG30-ST. The protocol recommended that patients scored as high risk should be admitted to the hospital, and that clinicians use their clinical judgment for intermediate-risk patients but favor admission for intermediate to high risk and discharge for low to intermediate risk. The study ran at 10 hospitals in Ontario. Initially, all 10 hospitals assessed patients by usual care, and then, over time, each hospital began using the tool so that by the end of the study all 10 hospitals employed it. Among the 2,480 patients seen during the active phase, 2,442 actually underwent assessment, with 24% rated as low risk, 32% rated as intermediate risk, and 44% judged to have high risk.

The researchers also ran risk assessments retrospectively on the controls, who showed a roughly similar risk distribution, with 18% low risk, 28% intermediate risk, and 54% high risk.

The patients averaged 78 years of age, 55% were men, about 40% had diabetes, and about 64% had a prior heart failure diagnosis.



Heart failure admissions have become ‘a big deal’

Emergency department clinicians and heart failure cardiologists “have worked together for a long time” when making decisions about which patients with acute heart failure need hospital admission, commented Mary N. Walsh, MD, medical director of the heart failure and cardiac transplantation programs at Ascension St. Vincent Heart Center in Indianapolis. These decisions “became a big deal” a decade ago when the U.S. Centers for Medicare & Medicaid Services launched the Hospital Readmissions Reduction Program that began to penalize hospitals for high rates of hospital readmissions for several conditions including heart failure, she said in an interview.

Mitchel L. Zoler/MDedge News

“If a heart failure patient is not admitted, they can’t be readmitted,” Dr. Walsh noted.

“Many risk-assessment tools exist for patients once they are hospitalized, but these tools have not been used in emergency departments. The take-home message is that we need to start risk assessment sooner, in the emergency department,” she said.

But the specific approach tested in the COACH trial needs more study and may need further tweaking to work in the United States, where it is not clear who would pay for a program like the one tested in the trial. Canada’s unified health care payment system makes the COACH approach more financially feasible, Dr. Walsh commented.

COACH received no commercial funding. Dr. Lee, Dr. Van Spall, and Dr. Walsh had no disclosures.

CHICAGO – Systematic mortality-risk assessment of patients who presented to hospital emergency departments for acute heart failure led to better patient outcomes in a controlled Canadian trial with more than 5,000 patients.

Thirty days after patients presented, the incidence of death from any cause or hospitalization for cardiovascular causes – one of two primary endpoints in the COACH study – was 12.1% among patients who underwent acute risk assessment and 14.5% in control patients who did not undergo this assessment, which translated into an adjusted, significant 12% relative risk reduction for the patients who underwent systematic assessment, Douglas S. Lee, MD, PhD, said at the American Heart Association scientific sessions.

Mitchel L. Zoler/MDedge News

The study’s second primary endpoint, the incidence of the same combined outcome 20 months after initial presentation, was 54.4% among the 2,480 patients assessed with the risk-assessment tool and 56.2% in the 2,972 controls, a significant, adjusted relative risk reduction of 5%.

This benefit was primarily driven by reductions in cardiovascular hospitalizations, which fell by an adjusted 16% in the intervention group compared with controls, and more specifically by hospitalizations for heart failure, which tallied a relative 20% less with the intervention. Both were significant between-group differences.

The other portion of the combined endpoint, all-cause mortality, was not significantly different between the patients who underwent the systematic emergency department assessment and the controls who were managed using usual emergency-department protocols.

Simultaneous with the report, the results also appeared online in the New England Journal of Medicine.
 

A pathway for early discharge and improved outcomes

“Implementation of this approach may lead to a pathway for early discharge from the hospital or emergency department, and improved patient outcomes,” said Dr. Lee, a professor at the University of Toronto, and a senior core scientist at the ICES Cardiovascular Research Program in Toronto.

Mitchel L. Zoler/MDedge News

“The treatment effect on the primary process outcome – patients admitted or discharged – will add useful insights into how intervention may improve,” commented Harriette Van Spall, MD, who was designated discussant for the report. The findings “fill an important knowledge gap,” added Dr. Van Spall, a cardiologist at McMaster University in Hamilton, Ont. The results “have important implications for health resource utilization,” she said.

The risk assessment tool used in the study is called the Emergency Heart failure Mortality Risk Grade for 30-day mortality (EHMRG30-ST), which was devised and validated by Dr. Lee and his associates. The assessment tool uses 11 clinical variables that include age, systolic blood pressure, heart rate, oxygen saturation, potassium and creatinine levels, and presence of ST depression on a 12-lead ECG.

The study design recommended that patients be discharged early and receive standardized transitional care as outpatients if they had a low risk of death within 7 days and within 30 days as estimated by the EHMRG30-ST. The protocol recommended that patients scored as high risk should be admitted to the hospital, and that clinicians use their clinical judgment for intermediate-risk patients but favor admission for intermediate to high risk and discharge for low to intermediate risk. The study ran at 10 hospitals in Ontario. Initially, all 10 hospitals assessed patients by usual care, and then, over time, each hospital began using the tool so that by the end of the study all 10 hospitals employed it. Among the 2,480 patients seen during the active phase, 2,442 actually underwent assessment, with 24% rated as low risk, 32% rated as intermediate risk, and 44% judged to have high risk.

The researchers also ran risk assessments retrospectively on the controls, who showed a roughly similar risk distribution, with 18% low risk, 28% intermediate risk, and 54% high risk.

The patients averaged 78 years of age, 55% were men, about 40% had diabetes, and about 64% had a prior heart failure diagnosis.



Heart failure admissions have become ‘a big deal’

Emergency department clinicians and heart failure cardiologists “have worked together for a long time” when making decisions about which patients with acute heart failure need hospital admission, commented Mary N. Walsh, MD, medical director of the heart failure and cardiac transplantation programs at Ascension St. Vincent Heart Center in Indianapolis. These decisions “became a big deal” a decade ago when the U.S. Centers for Medicare & Medicaid Services launched the Hospital Readmissions Reduction Program that began to penalize hospitals for high rates of hospital readmissions for several conditions including heart failure, she said in an interview.

Mitchel L. Zoler/MDedge News

“If a heart failure patient is not admitted, they can’t be readmitted,” Dr. Walsh noted.

“Many risk-assessment tools exist for patients once they are hospitalized, but these tools have not been used in emergency departments. The take-home message is that we need to start risk assessment sooner, in the emergency department,” she said.

But the specific approach tested in the COACH trial needs more study and may need further tweaking to work in the United States, where it is not clear who would pay for a program like the one tested in the trial. Canada’s unified health care payment system makes the COACH approach more financially feasible, Dr. Walsh commented.

COACH received no commercial funding. Dr. Lee, Dr. Van Spall, and Dr. Walsh had no disclosures.

Cesarean birth is one of the most common major surgical procedures performed in developed countries¹ with over 1,170,000 cesarean births in the United States in 2021.² Many surgeons and anesthesiologists believe that Enhanced Recovery after Surgery (ERAS) pathways improve surgical outcomes.^3,4 Important goals of ERAS include setting patient expectations for the surgical procedure, accelerating patient recovery to full function, and minimizing perioperative complications such as severe nausea, aspiration, surgical site infection, wound complications, and perioperative anemia. The ERAS Society in 2018^5-7 and the Society for Obstetric Anesthesia and Perinatology (SOAP) in 2021⁸ proposed ERAS pathways for cesarean birth. Both societies recommended that obstetric units consider adopting an ERAS pathway compatible with local clinical resources. In addition, the American College of Obstetricians and Gynecologists (ACOG) has provided guidance for implementing ERAS pathways for gynecologic surgery.⁹ The consistent use of standardized protocols to improve surgical care in obstetrics should lead to a reduction in care variation and improve health equity outcomes.

The clinical interventions recommended for ERAS cesarean birth occur sequentially in the preoperative, intraoperative, and postoperative phases of care. The recommendations associated with each of these phases are reviewed below. It is important to note that each obstetric unit should use a multidisciplinary process to develop an ERAS pathway that best supports local practice given clinician preferences, patient characteristics, and resource availability.
 

Preoperative components of ERAS

Standardized patient education (SPE). SPE is an important component of ERAS, although evidence to support the recommendation is limited. At a minimum a written handout describing steps in the cesarean birth process, or a patient-education video should be part of patient education. The University of Michigan Medical Center has produced a 3-minute video for patients explaining ERAS cesarean birth.¹⁰ The University of Maryland Medical Center has produced a 2.5-minute video in English and Spanish, explaining ERAS cesarean birth for patients.¹¹ Some surgeons place a telephone call to patients the evening before surgery to help orient the patient to ERAS cesarean birth.

Breastfeeding education. An important goal of obstetric care is to optimize the rate of exclusive breastfeeding at birth. Breastfeeding education, including a commitment to support the initiation of breastfeeding within 1 hour of birth, may enhance the rate of exclusive breastfeeding. There are numerous videos available for patients about breastfeeding after cesarean birth (as an example, see: https://www.youtube.com/watch?v=9iOGn85NdTg).

Limit fasting. In the past, surgical guidelines recommended fasting after midnight prior to surgery. The ERAS Society recommends that patients should be encouraged to drink clear fluids up to 2 hours before surgery and may have a light meal up to 6 hours before surgery (Part 1).

Carbohydrate loading. Surgery causes a metabolic stress that is increased by fasting. Carbohydrate loading prior to surgery reduces the magnitude of the catabolic state caused by the combination of surgery and fasting.¹² SOAP and the ERAS Society recommend oral carbohydrate fluid supplementation 2 hours before surgery for nondiabetic patients. SOAP suggests 32 oz of Gatorade or 16 oz of clear apple juice as options for carbohydrate loading. For diabetic patients, the carbohydrate load can be omitted. In fasting pregnant patients at term, gastric emptying was near complete 2 hours after consumption of 400 mL of a carbohydrate drink.¹³ In one study, consumption of 400 mL of a carbohydrate drink 2 hours before cesarean resulted in a 7% increase in the newborn blood glucose level at 20 min after delivery.¹⁴

Minimize preoperative anemia. Approximately 50% of pregnant women are iron deficient and approximately 10% are anemic in the third trimester.^15,16 Cesarean birth is associated with significant blood loss necessitating the need to optimize red blood cell mass before surgery. Measuring ferritin to identify patients with iron deficiency and aggressive iron replacement, including intravenous iron if necessary, will reduce the prevalence of anemia prior to cesarean birth.¹⁷ Another cause of anemia in pregnancy is vitamin B12 (cobalamin) deficiency. Low vitamin B12 is especially common in pregnant patients who have previously had bariatric surgery. One study reported that, of 113 pregnant patients who were, on average, 3 years from a bariatric surgery procedure, 12% had vitamin B12 circulating levels < 130 pg/mL.¹⁸ Among pregnant patients who are anemic, and do not have a hemoglobinopathy, measuring ferritin, folic acid, and vitamin B12 will help identify the cause of anemia and guide treatment.¹⁹

Optimize preoperative physical condition. Improving healthy behaviors and reducing unhealthy behaviors preoperatively may enhance patient recovery to full function. In the weeks before scheduled cesarean birth, cessation of the use of tobacco products, optimizing activity and improving diet quality, including increasing protein intake, may best prepare patients for the metabolic stress of surgery.

Continue to: Intraoperative components of ERAS...

Intraoperative components of ERAS

Reduce the risk of surgical site infection (SSI) and wound complications. Bundles that include antibiotics, chlorhexidine (or an alternative antibacterial soap) and clippers have been shown to reduce SSI.²⁰ Routine administration of preoperative antibiotics is a consensus recommendation and there is high adherence with this recommendation in the United States. Chlorhexidine-alcohol is the preferred solution for skin preparation. Vaginal preparation with povidine-iodine or chlorhexidine may be considered.⁶

Surgical technique. Blunt extension of a transverse hysterotomy may reduce blood loss. Closure of the hysterotomy incision in 2 layers is recommended to reduce uterine scar dehiscence in a subsequent pregnancy. If the patient has ≥2 cm of subcutaneous tissue, this layer should be approximated with sutures. Skin closure should be with subcuticular suture.⁶

Optimize uterotonic administration. Routine use of uterotonics reduces the risk of blood loss, transfusion, and postoperative anemia. There is high adherence with the use of uterotonic administration after birth in the United States.^6,8

Ensure normothermia. Many patients become hypothermic during a cesarean birth. Active warming of the patient with an in-line IV fluid warmer and forced air warming over the patient’s body can reduce the risk of hypothermia.⁸

Initiate multimodal anesthesia. Anesthesiologists often use intrathecal or epidural morphine to enhance analgesia. Ketorolac administration prior to completion of the cesarean procedure and perioperative administration of acetaminophen may reduce postoperative pain.⁸ The use of preoperative antiemetics will reduce intraoperative and postoperative nausea and vomiting.

Initiate VTE prophylaxis. Pneumatic compression stockings are recommended. Anticoagulation should not be routinely used for VTE prophylaxis.⁶

Postoperative components of ERAS

Patient education to prepare for discharge home when ready. Patient education focused on home when ready is important in preparing the patient for discharge home.⁷ Completion of required newborn testing, lactation education, and contraception planning plus coordination of newborn pediatric follow-up is necessary before discharge.

Support early return of bowel function. Early return of bowel function is best supported by a multimodal approach including initiation of clear fluid intake immediately following surgery, encouraging consumption of a regular diet within 2⁷ to 4 hours⁸ following surgery. Gum chewing for at least 5 minutes 3 times daily accelerates return of bowel function.⁸ In a meta-analysis of 10 randomized studies examining the effect of gum chewing after cesarean, the investigators reported that gum chewing shortened the time to passage of flatus and defecation.²¹

Early ambulation.

Sequentially advanced activity, starting with sitting on the edge of the bed, sitting in a chair, and ambulation within 8 hours of surgery, is recommended to facilitate faster recovery, reduce rates of complications, and enable transition to home.⁸

Early removal of the urinary catheter. It is recommended that the urinary catheter be removed within 12 hours after cesarean birth.⁸ Early removal of the urinary catheter increases patient mobility and reduces the length of hospitalization. Early removal of the urinary catheter may be associated with postoperative urinary retention and recatheterization in a small number of patients.

Prescribe routinely scheduled acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) and ketorolac. A key component of ERAS cesarean birth is the standardized administration of nonopioid pain medicines, alternating doses of acetaminophen and an NSAID. ERAS cesarean birth is likely to result in a reduction in inpatient and postdischarge opioid use.^22-24

VTE prophylaxis. Pneumatic compression stockings are recommended. Anticoagulation should not be routinely used for VTE prophylaxis.⁸

Auditing and reporting adherence with components of ERAS

In clinical practice there may be a gap between a clinician’s subjective perception of their performance and an independent audit of their clinical performance. ERAS pathways should be implemented with a commitment to performing audits and providing quantitative feedback to clinicians. Consistent use of measurement, feedback, and coaching can improve performance and reduce variation among individual clinicians. As an example, in one study of the use of a surgical safety checklist, 99% of the surgeons reported that they routinely used a surgical safety checklist, but the audit showed that the checklist was used in only 60% of cases.²⁵ Gaps between self-reported performance and audited performance are common in clinical practice. Audits with feedback are critical to improving adherence with the components of an ERAS pathway.

Three independent systematic reviews and meta-analyses report that ERAS pathways reduce hospital length of stay without increasing the readmission rate.^26-28 One meta-analysis reported that ERAS may also reduce time to first mobilization and result in earlier removal of the urinary catheter.²⁶ ERAS pathways also may reduce postoperative complications, lower pain scores, and decrease opioid use.²⁷ The general consensus among quality and safety experts is that reducing variation through standardization of pathways is generally associated with improved quality and enhanced safety. ERAS pathways have been widely accepted in multiple surgical fields. ERAS pathways should become the standard for performing cesarean procedures.●

Cesarean birth is one of the most common major surgical procedures performed in developed countries¹ with over 1,170,000 cesarean births in the United States in 2021.² Many surgeons and anesthesiologists believe that Enhanced Recovery after Surgery (ERAS) pathways improve surgical outcomes.^3,4 Important goals of ERAS include setting patient expectations for the surgical procedure, accelerating patient recovery to full function, and minimizing perioperative complications such as severe nausea, aspiration, surgical site infection, wound complications, and perioperative anemia. The ERAS Society in 2018^5-7 and the Society for Obstetric Anesthesia and Perinatology (SOAP) in 2021⁸ proposed ERAS pathways for cesarean birth. Both societies recommended that obstetric units consider adopting an ERAS pathway compatible with local clinical resources. In addition, the American College of Obstetricians and Gynecologists (ACOG) has provided guidance for implementing ERAS pathways for gynecologic surgery.⁹ The consistent use of standardized protocols to improve surgical care in obstetrics should lead to a reduction in care variation and improve health equity outcomes.

The clinical interventions recommended for ERAS cesarean birth occur sequentially in the preoperative, intraoperative, and postoperative phases of care. The recommendations associated with each of these phases are reviewed below. It is important to note that each obstetric unit should use a multidisciplinary process to develop an ERAS pathway that best supports local practice given clinician preferences, patient characteristics, and resource availability.
 

Preoperative components of ERAS

Standardized patient education (SPE). SPE is an important component of ERAS, although evidence to support the recommendation is limited. At a minimum a written handout describing steps in the cesarean birth process, or a patient-education video should be part of patient education. The University of Michigan Medical Center has produced a 3-minute video for patients explaining ERAS cesarean birth.¹⁰ The University of Maryland Medical Center has produced a 2.5-minute video in English and Spanish, explaining ERAS cesarean birth for patients.¹¹ Some surgeons place a telephone call to patients the evening before surgery to help orient the patient to ERAS cesarean birth.

Breastfeeding education. An important goal of obstetric care is to optimize the rate of exclusive breastfeeding at birth. Breastfeeding education, including a commitment to support the initiation of breastfeeding within 1 hour of birth, may enhance the rate of exclusive breastfeeding. There are numerous videos available for patients about breastfeeding after cesarean birth (as an example, see: https://www.youtube.com/watch?v=9iOGn85NdTg).

Limit fasting. In the past, surgical guidelines recommended fasting after midnight prior to surgery. The ERAS Society recommends that patients should be encouraged to drink clear fluids up to 2 hours before surgery and may have a light meal up to 6 hours before surgery (Part 1).

Carbohydrate loading. Surgery causes a metabolic stress that is increased by fasting. Carbohydrate loading prior to surgery reduces the magnitude of the catabolic state caused by the combination of surgery and fasting.¹² SOAP and the ERAS Society recommend oral carbohydrate fluid supplementation 2 hours before surgery for nondiabetic patients. SOAP suggests 32 oz of Gatorade or 16 oz of clear apple juice as options for carbohydrate loading. For diabetic patients, the carbohydrate load can be omitted. In fasting pregnant patients at term, gastric emptying was near complete 2 hours after consumption of 400 mL of a carbohydrate drink.¹³ In one study, consumption of 400 mL of a carbohydrate drink 2 hours before cesarean resulted in a 7% increase in the newborn blood glucose level at 20 min after delivery.¹⁴

Minimize preoperative anemia. Approximately 50% of pregnant women are iron deficient and approximately 10% are anemic in the third trimester.^15,16 Cesarean birth is associated with significant blood loss necessitating the need to optimize red blood cell mass before surgery. Measuring ferritin to identify patients with iron deficiency and aggressive iron replacement, including intravenous iron if necessary, will reduce the prevalence of anemia prior to cesarean birth.¹⁷ Another cause of anemia in pregnancy is vitamin B12 (cobalamin) deficiency. Low vitamin B12 is especially common in pregnant patients who have previously had bariatric surgery. One study reported that, of 113 pregnant patients who were, on average, 3 years from a bariatric surgery procedure, 12% had vitamin B12 circulating levels < 130 pg/mL.¹⁸ Among pregnant patients who are anemic, and do not have a hemoglobinopathy, measuring ferritin, folic acid, and vitamin B12 will help identify the cause of anemia and guide treatment.¹⁹

Optimize preoperative physical condition. Improving healthy behaviors and reducing unhealthy behaviors preoperatively may enhance patient recovery to full function. In the weeks before scheduled cesarean birth, cessation of the use of tobacco products, optimizing activity and improving diet quality, including increasing protein intake, may best prepare patients for the metabolic stress of surgery.

Continue to: Intraoperative components of ERAS...

Intraoperative components of ERAS

Reduce the risk of surgical site infection (SSI) and wound complications. Bundles that include antibiotics, chlorhexidine (or an alternative antibacterial soap) and clippers have been shown to reduce SSI.²⁰ Routine administration of preoperative antibiotics is a consensus recommendation and there is high adherence with this recommendation in the United States. Chlorhexidine-alcohol is the preferred solution for skin preparation. Vaginal preparation with povidine-iodine or chlorhexidine may be considered.⁶

Surgical technique. Blunt extension of a transverse hysterotomy may reduce blood loss. Closure of the hysterotomy incision in 2 layers is recommended to reduce uterine scar dehiscence in a subsequent pregnancy. If the patient has ≥2 cm of subcutaneous tissue, this layer should be approximated with sutures. Skin closure should be with subcuticular suture.⁶

Optimize uterotonic administration. Routine use of uterotonics reduces the risk of blood loss, transfusion, and postoperative anemia. There is high adherence with the use of uterotonic administration after birth in the United States.^6,8

Ensure normothermia. Many patients become hypothermic during a cesarean birth. Active warming of the patient with an in-line IV fluid warmer and forced air warming over the patient’s body can reduce the risk of hypothermia.⁸

Initiate multimodal anesthesia. Anesthesiologists often use intrathecal or epidural morphine to enhance analgesia. Ketorolac administration prior to completion of the cesarean procedure and perioperative administration of acetaminophen may reduce postoperative pain.⁸ The use of preoperative antiemetics will reduce intraoperative and postoperative nausea and vomiting.

Initiate VTE prophylaxis. Pneumatic compression stockings are recommended. Anticoagulation should not be routinely used for VTE prophylaxis.⁶

Postoperative components of ERAS

Patient education to prepare for discharge home when ready. Patient education focused on home when ready is important in preparing the patient for discharge home.⁷ Completion of required newborn testing, lactation education, and contraception planning plus coordination of newborn pediatric follow-up is necessary before discharge.

Support early return of bowel function. Early return of bowel function is best supported by a multimodal approach including initiation of clear fluid intake immediately following surgery, encouraging consumption of a regular diet within 2⁷ to 4 hours⁸ following surgery. Gum chewing for at least 5 minutes 3 times daily accelerates return of bowel function.⁸ In a meta-analysis of 10 randomized studies examining the effect of gum chewing after cesarean, the investigators reported that gum chewing shortened the time to passage of flatus and defecation.²¹

Early ambulation.

Sequentially advanced activity, starting with sitting on the edge of the bed, sitting in a chair, and ambulation within 8 hours of surgery, is recommended to facilitate faster recovery, reduce rates of complications, and enable transition to home.⁸

Early removal of the urinary catheter. It is recommended that the urinary catheter be removed within 12 hours after cesarean birth.⁸ Early removal of the urinary catheter increases patient mobility and reduces the length of hospitalization. Early removal of the urinary catheter may be associated with postoperative urinary retention and recatheterization in a small number of patients.

Prescribe routinely scheduled acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) and ketorolac. A key component of ERAS cesarean birth is the standardized administration of nonopioid pain medicines, alternating doses of acetaminophen and an NSAID. ERAS cesarean birth is likely to result in a reduction in inpatient and postdischarge opioid use.^22-24

VTE prophylaxis. Pneumatic compression stockings are recommended. Anticoagulation should not be routinely used for VTE prophylaxis.⁸

Auditing and reporting adherence with components of ERAS

In clinical practice there may be a gap between a clinician’s subjective perception of their performance and an independent audit of their clinical performance. ERAS pathways should be implemented with a commitment to performing audits and providing quantitative feedback to clinicians. Consistent use of measurement, feedback, and coaching can improve performance and reduce variation among individual clinicians. As an example, in one study of the use of a surgical safety checklist, 99% of the surgeons reported that they routinely used a surgical safety checklist, but the audit showed that the checklist was used in only 60% of cases.²⁵ Gaps between self-reported performance and audited performance are common in clinical practice. Audits with feedback are critical to improving adherence with the components of an ERAS pathway.

Three independent systematic reviews and meta-analyses report that ERAS pathways reduce hospital length of stay without increasing the readmission rate.^26-28 One meta-analysis reported that ERAS may also reduce time to first mobilization and result in earlier removal of the urinary catheter.²⁶ ERAS pathways also may reduce postoperative complications, lower pain scores, and decrease opioid use.²⁷ The general consensus among quality and safety experts is that reducing variation through standardization of pathways is generally associated with improved quality and enhanced safety. ERAS pathways have been widely accepted in multiple surgical fields. ERAS pathways should become the standard for performing cesarean procedures.●

Cesarean birth is one of the most common major surgical procedures performed in developed countries¹ with over 1,170,000 cesarean births in the United States in 2021.² Many surgeons and anesthesiologists believe that Enhanced Recovery after Surgery (ERAS) pathways improve surgical outcomes.^3,4 Important goals of ERAS include setting patient expectations for the surgical procedure, accelerating patient recovery to full function, and minimizing perioperative complications such as severe nausea, aspiration, surgical site infection, wound complications, and perioperative anemia. The ERAS Society in 2018^5-7 and the Society for Obstetric Anesthesia and Perinatology (SOAP) in 2021⁸ proposed ERAS pathways for cesarean birth. Both societies recommended that obstetric units consider adopting an ERAS pathway compatible with local clinical resources. In addition, the American College of Obstetricians and Gynecologists (ACOG) has provided guidance for implementing ERAS pathways for gynecologic surgery.⁹ The consistent use of standardized protocols to improve surgical care in obstetrics should lead to a reduction in care variation and improve health equity outcomes.

The clinical interventions recommended for ERAS cesarean birth occur sequentially in the preoperative, intraoperative, and postoperative phases of care. The recommendations associated with each of these phases are reviewed below. It is important to note that each obstetric unit should use a multidisciplinary process to develop an ERAS pathway that best supports local practice given clinician preferences, patient characteristics, and resource availability.
 

Preoperative components of ERAS

Standardized patient education (SPE). SPE is an important component of ERAS, although evidence to support the recommendation is limited. At a minimum a written handout describing steps in the cesarean birth process, or a patient-education video should be part of patient education. The University of Michigan Medical Center has produced a 3-minute video for patients explaining ERAS cesarean birth.¹⁰ The University of Maryland Medical Center has produced a 2.5-minute video in English and Spanish, explaining ERAS cesarean birth for patients.¹¹ Some surgeons place a telephone call to patients the evening before surgery to help orient the patient to ERAS cesarean birth.

Breastfeeding education. An important goal of obstetric care is to optimize the rate of exclusive breastfeeding at birth. Breastfeeding education, including a commitment to support the initiation of breastfeeding within 1 hour of birth, may enhance the rate of exclusive breastfeeding. There are numerous videos available for patients about breastfeeding after cesarean birth (as an example, see: https://www.youtube.com/watch?v=9iOGn85NdTg).

Limit fasting. In the past, surgical guidelines recommended fasting after midnight prior to surgery. The ERAS Society recommends that patients should be encouraged to drink clear fluids up to 2 hours before surgery and may have a light meal up to 6 hours before surgery (Part 1).

Carbohydrate loading. Surgery causes a metabolic stress that is increased by fasting. Carbohydrate loading prior to surgery reduces the magnitude of the catabolic state caused by the combination of surgery and fasting.¹² SOAP and the ERAS Society recommend oral carbohydrate fluid supplementation 2 hours before surgery for nondiabetic patients. SOAP suggests 32 oz of Gatorade or 16 oz of clear apple juice as options for carbohydrate loading. For diabetic patients, the carbohydrate load can be omitted. In fasting pregnant patients at term, gastric emptying was near complete 2 hours after consumption of 400 mL of a carbohydrate drink.¹³ In one study, consumption of 400 mL of a carbohydrate drink 2 hours before cesarean resulted in a 7% increase in the newborn blood glucose level at 20 min after delivery.¹⁴

Minimize preoperative anemia. Approximately 50% of pregnant women are iron deficient and approximately 10% are anemic in the third trimester.^15,16 Cesarean birth is associated with significant blood loss necessitating the need to optimize red blood cell mass before surgery. Measuring ferritin to identify patients with iron deficiency and aggressive iron replacement, including intravenous iron if necessary, will reduce the prevalence of anemia prior to cesarean birth.¹⁷ Another cause of anemia in pregnancy is vitamin B12 (cobalamin) deficiency. Low vitamin B12 is especially common in pregnant patients who have previously had bariatric surgery. One study reported that, of 113 pregnant patients who were, on average, 3 years from a bariatric surgery procedure, 12% had vitamin B12 circulating levels < 130 pg/mL.¹⁸ Among pregnant patients who are anemic, and do not have a hemoglobinopathy, measuring ferritin, folic acid, and vitamin B12 will help identify the cause of anemia and guide treatment.¹⁹

Optimize preoperative physical condition. Improving healthy behaviors and reducing unhealthy behaviors preoperatively may enhance patient recovery to full function. In the weeks before scheduled cesarean birth, cessation of the use of tobacco products, optimizing activity and improving diet quality, including increasing protein intake, may best prepare patients for the metabolic stress of surgery.

Continue to: Intraoperative components of ERAS...

Intraoperative components of ERAS

Reduce the risk of surgical site infection (SSI) and wound complications. Bundles that include antibiotics, chlorhexidine (or an alternative antibacterial soap) and clippers have been shown to reduce SSI.²⁰ Routine administration of preoperative antibiotics is a consensus recommendation and there is high adherence with this recommendation in the United States. Chlorhexidine-alcohol is the preferred solution for skin preparation. Vaginal preparation with povidine-iodine or chlorhexidine may be considered.⁶

Surgical technique. Blunt extension of a transverse hysterotomy may reduce blood loss. Closure of the hysterotomy incision in 2 layers is recommended to reduce uterine scar dehiscence in a subsequent pregnancy. If the patient has ≥2 cm of subcutaneous tissue, this layer should be approximated with sutures. Skin closure should be with subcuticular suture.⁶

Optimize uterotonic administration. Routine use of uterotonics reduces the risk of blood loss, transfusion, and postoperative anemia. There is high adherence with the use of uterotonic administration after birth in the United States.^6,8

Ensure normothermia. Many patients become hypothermic during a cesarean birth. Active warming of the patient with an in-line IV fluid warmer and forced air warming over the patient’s body can reduce the risk of hypothermia.⁸

Initiate multimodal anesthesia. Anesthesiologists often use intrathecal or epidural morphine to enhance analgesia. Ketorolac administration prior to completion of the cesarean procedure and perioperative administration of acetaminophen may reduce postoperative pain.⁸ The use of preoperative antiemetics will reduce intraoperative and postoperative nausea and vomiting.

Initiate VTE prophylaxis. Pneumatic compression stockings are recommended. Anticoagulation should not be routinely used for VTE prophylaxis.⁶

Postoperative components of ERAS

Patient education to prepare for discharge home when ready. Patient education focused on home when ready is important in preparing the patient for discharge home.⁷ Completion of required newborn testing, lactation education, and contraception planning plus coordination of newborn pediatric follow-up is necessary before discharge.

Support early return of bowel function. Early return of bowel function is best supported by a multimodal approach including initiation of clear fluid intake immediately following surgery, encouraging consumption of a regular diet within 2⁷ to 4 hours⁸ following surgery. Gum chewing for at least 5 minutes 3 times daily accelerates return of bowel function.⁸ In a meta-analysis of 10 randomized studies examining the effect of gum chewing after cesarean, the investigators reported that gum chewing shortened the time to passage of flatus and defecation.²¹

Early ambulation.

Sequentially advanced activity, starting with sitting on the edge of the bed, sitting in a chair, and ambulation within 8 hours of surgery, is recommended to facilitate faster recovery, reduce rates of complications, and enable transition to home.⁸

Early removal of the urinary catheter. It is recommended that the urinary catheter be removed within 12 hours after cesarean birth.⁸ Early removal of the urinary catheter increases patient mobility and reduces the length of hospitalization. Early removal of the urinary catheter may be associated with postoperative urinary retention and recatheterization in a small number of patients.

Prescribe routinely scheduled acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) and ketorolac. A key component of ERAS cesarean birth is the standardized administration of nonopioid pain medicines, alternating doses of acetaminophen and an NSAID. ERAS cesarean birth is likely to result in a reduction in inpatient and postdischarge opioid use.^22-24

VTE prophylaxis. Pneumatic compression stockings are recommended. Anticoagulation should not be routinely used for VTE prophylaxis.⁸

Auditing and reporting adherence with components of ERAS

In clinical practice there may be a gap between a clinician’s subjective perception of their performance and an independent audit of their clinical performance. ERAS pathways should be implemented with a commitment to performing audits and providing quantitative feedback to clinicians. Consistent use of measurement, feedback, and coaching can improve performance and reduce variation among individual clinicians. As an example, in one study of the use of a surgical safety checklist, 99% of the surgeons reported that they routinely used a surgical safety checklist, but the audit showed that the checklist was used in only 60% of cases.²⁵ Gaps between self-reported performance and audited performance are common in clinical practice. Audits with feedback are critical to improving adherence with the components of an ERAS pathway.

Three independent systematic reviews and meta-analyses report that ERAS pathways reduce hospital length of stay without increasing the readmission rate.^26-28 One meta-analysis reported that ERAS may also reduce time to first mobilization and result in earlier removal of the urinary catheter.²⁶ ERAS pathways also may reduce postoperative complications, lower pain scores, and decrease opioid use.²⁷ The general consensus among quality and safety experts is that reducing variation through standardization of pathways is generally associated with improved quality and enhanced safety. ERAS pathways have been widely accepted in multiple surgical fields. ERAS pathways should become the standard for performing cesarean procedures.●

CASE Pregnant woman with a suspected parasitic infection

A 20-year-old, previously healthy, primigravid woman at 24 weeks’ gestation immigrated from Bolivia to the United States 3 days ago. On the morning of her international flight, she awoke to discover a small insect bite just below her left eye. She sought medical evaluation because her eyelid is now significantly swollen, and she has a headache, anorexia, fatigue, and a fever of 38.4° C. The examining physician ordered a polymerase chain reaction (PCR) test for Trypanosoma cruzi, and the test is positive.

• How should this patient be treated during, and after, her delivery?


• Does this infection pose a risk to the newborn baby?


• What type of surveillance and treatment is indicated for the baby?

Chagas disease is common in South America, Central America, and Mexico and is well known to physicians in those countries. Clinicians who practice in the United States are much less familiar with the condition, but it is becoming increasingly common as a result of international travel within the Americas.

In this article, we review the interesting microbiology and epidemiology of Chagas disease, focus on its clinical manifestations, and discuss the most useful diagnostic tests for the illness. We conclude with a summary of preventive and treatment measures, with particular emphasis on managing the disease in pregnancy.

How Chagas disease is transmitted and who is at risk

Chagas disease was named in honor of a Brazilian physician, Carlos Chagas, who first described the condition in 1909. The disease is endemic in South America, Central America, and Mexico, and, recently, its prevalence has increased in the southern United States. Approximately 300,000 people in the United States are infected.^1,2

The illness is caused by the parasite Trypanosoma cruzi, and it is also known as American trypanosomiasis. The parasite is spread primarily by the bite of triatomine insects (“kissing bugs”). Approximately 60% of these insects are infected with the parasite. The insects live and thrive in the interspaces of mud walls (adobe homes) and thatched roofs. At night, the insects leave their darkened spaces and feed on the exposed skin of sleeping persons. They are particularly likely to bite the moist skin surfaces near the eye and mouth, and, as they do, they defecate and excrete the parasite into the blood vessels beneath the skin. Within the blood, the trypomastigotes invade various host cells. Inside the host cells, the organism transforms into an amastigote, which is the replicative form of the parasite. After several rounds of replication, the amastigote transforms back into a trypomastigote, bursts from the cell, and goes on to infect other host cells.¹

In addition to transmission by the insect vector, the parasite also can be transmitted by blood transfusion and organ donation. When contaminated blood is transfused, the risk of transmission is approximately 10% to 25% for each unit. Following implementation of effective screening programs by blood banks in Central America, South America, Mexico, and the United States, the risk of transmission from undetected infection is now approximately 1:200,000 per unit.

When a transplant procedure with an infected heart is performed, the risk of transmission is 75% to 100%. For liver transplants, the frequency of transmission is 0% to 29%; for kidney transplants, the risk of transmission is 0% to 19%.

Consumption of contaminated food or drink, particularly nonpasteurized items sold by street vendors, is also an important mechanism of transmission. In addition, transmission can occur as a result of laboratory exposure and by exposure to wild animals (racoons, opossums, marmosets, bats, armadillos) in forested areas. Finally, perinatal transmission now accounts for about 22% of infections. As effective vector control programs have been introduced in endemic areas, the proportion of cases caused by the insect vector has steadily decreased^1-3 (FIGURE 1).

Continue to: Clinical manifestations of Chagas disease...

Clinical manifestations of Chagas disease

Chagas disease occurs in 2 stages, acute and chronic.^1,2,4 In patients who are infected via an insect vector, the acute stage typically begins 1 to 2 weeks after the insect bite. This phase of the illness usually lasts 4 to 8 weeks and almost always resolves without treatment.

Some infected patients will be completely free of symptoms. Others will have manifestations such as:

• fever
• malaise
• headache
• hepatosplenomegaly
• lymphadenopathy
• swollen nodule at the site of infection

—Romaña’s sign, when the lesion is on the eyelid
—Chagoma, when the lesion is elsewhere on the skin.

Fortunately, less than 5% of patients will have severe illness, manifested by myocarditis, pericarditis, encephalitis, or meningitis.

People infected by ingestion of the parasite in food or drink often become more severely ill within 3 weeks. Their clinical manifestations include fever, vomiting, dyspnea, cough, chest pain, abdominal pain, and myalgias. Individuals infected through organ transplant or blood transfusion present more like those infected by the insect vector, but their illness may not develop until several weeks to 5 months after exposure.

In the absence of effective treatment, approximately 40% of patients with acute infection will develop chronic infection, often several decades later. The most common, and most ominous, feature of chronic illness is cardiac disease, experienced by about 30% of patients. Cardiac disease may be manifested as a serious arrhythmia, chest pain, congestive heart failure, or thromboembolism.

The other organ system that is likely to be adversely affected in patients with chronic disease is the gastrointestinal (GI) system, and approximately 10% of chronically infected patients experience this complication. Patients may develop a dilated esophagus, which leads to odynophagia and dysphagia. Diminished motility in other areas of the GI tract also may result in chronic constipation and even bowel obstruction. Chronically infected patients who are immunosuppressed due to HIV infection may become gravely ill as a result of encephalitis and brain abscesses. Cardiac and GI dysfunction is due to the parasite’s massive destruction of nerve endings.

Continue to: Making the diagnosis...

The diagnosis of Chagas disease begins with screening patients who have epidemiologic risk factors that place them at high risk for contracting the infection and at significantly increased risk for morbidity and mortality as a result of either the acute infection or the later chronic stage of infection. A thorough history is vital in the evaluation because the acute illness can have such vague clinical manifestations, and many patients remain asymptomatic until signs of chronic infection appear.

Risk factors that warrant screening include being born in a country endemic for Chagas disease, living in an endemic country for more than 6 months, living with someone who has a confirmed diagnosis, residing in a house made of natural materials (mud walls, thatched roof) in an endemic area, and a history of discovering the triatomine bug in the household.

Screening options include serology, microscopy, and PCR testing. Screening with a single, highly sensitive immunoglobulin G (IgG) serologic test is recommended for nonendemic clinical or community settings. In patients who were born in or who lived in an endemic area for more than 6 months, special consideration should be given to screening women of reproductive age, patients of all ages who were born to a mother with a confirmed diagnosis, individuals who were exposed to a triatomine insect, and people who are immunocompromised.⁵

A positive serologic test should be confirmed with a second assay based on a different antigen. Currently, 4 IgG tests have US Food and Drug Administration (FDA) approval for diagnosis. If a patient has 2 positive serologic tests, the diagnosis is confirmed, regardless of clinical presentation. Discordant results warrant a third test to differentiate between positive and negative results (FIGURE 2).⁵ All patients with a confirmed diagnosis should have an electrocardiogram, echocardiogram, and abdominal computed tomography (CT) scan to assess for cardiac or GI abnormalities.

Organ recipients merit special consideration because, in these individuals, the late stages of Chagas disease may be fatal. In these patients, the preferred diagnostic test is PCR. For transplant patients, monitoring should occur every week for 2 months, bimonthly for the third month, and monthly for 6 months after transplantation. Routine monitoring is not recommended in patients with HIV infection who show no clinical signs of Chagas disease and who are not from endemic areas.

Treatment options

No vaccine or hyperimmune globulin can be used to treat Chagas disease. At this time, 2 antiparasitic drugs are available to treat the condition. One is benznidazole, which inhibits DNA, RNA, and protein synthesis within the microorganism. The medication is given in a dose of 5 to 8 mg/kg per day, divided into 2 doses, for 60 days. Benznidazole is FDA approved for the treatment of individuals older than age 2. It has been used off-label in children younger than 2 years of age. The drug is commercially available at http://www.benznidazoletablets.com.

Benznidazole causes multiple minor side effects and several very serious adverse effects. The serious adverse effects include acute generalized exanthematous pustulosis, toxic epidermal necrolysis, peripheral neuropathy, marrow suppression, and hepatotoxicity. Benznidazole has been teratogenic and carcinogenic in animal studies and should not be used in pregnancy.^1,3,6

The second drug is nifurtimox. This drug is FDA approved for the treatment of Chagas disease in adults and for newborns and young children. It is commercially available for pharmacies to purchase from several drug wholesalers. Nifurtimox produces reactive oxygen species and toxic intermediates that induce DNA damage and cause cell death of the microorganism. The appropriate oral dose is 8 to 10 mg/kg per day, divided into 3 to 4 equal doses. The duration of treatment is 60 to 90 days, depending on the patient’s response. Like benznidazole, nifurtimox also is highly toxic. Severe adverse effects include a hypersensitivity reaction, anaphylaxis, angioedema, syncope, seizures, and psychosis. Nifurtimox also is teratogenic and is contraindicated in pregnancy.^1,3,6

Clinicians who have questions about the use of either of these medications should contact the Centers for Disease Control and Prevention, Division of Parasitic Diseases public inquiries telephone line at (404) 718-4745.

Potential for cure. When either benznidazole or nifurtimox is administered early in the course of a patient’s acute infection, the chance for complete cure is excellent. The same is true for early treatment of the infected neonate. When treatment is delayed, or if it cannot be completed because of intolerable adverse effects, the prognosis for complete cure is diminished.

In adults who have chronic disease, antiparasitic treatment is unlikely to be effective. In such a situation, secondary treatment is directed toward correction of heart failure, control of cardiac rhythm disturbances, and control of GI motility disorders. For both cardiac and GI conditions, medication and surgery may be indicated. Antiparasitic treatment is more effective in children with chronic disease but it is still not uniformly effective.^1,3,5,6

Preventing infection

Vector control is the key to preventing infection in areas where Chagas disease is endemic. One important, but often financially unaffordable, measure is construction of homes with building materials that do not support the growth of the triatomine insects that transmit the disease. A second critical preventive measure is the spraying of mud and thatched homes and surrounding areas with long-lasting insecticides. Pyrethroids are the preferred agents today. Alternative agents include fenitrothion and bendiocarb.¹

Other important preventive measures include:

• screening the blood supply for T cruzi and eliminating units contaminated with the parasite
• screening for the parasite in organs targeted for transplant
• screening infected women of reproductive age in endemic areas and treating those who are positive before they become pregnant; this measure may be almost 95% effective in preventing congenital infection
• using mosquito netting when housing is insecure and air conditioning is not available
• in endemic areas, avoiding unpasteurized fruit drinks and unwashed fruits and vegetables.

Unique considerations in pregnancy

Chagas disease does not cause specific anatomic birth defects. However, infected women are more likely to experience spontaneous abortion, preterm premature rupture of membranes, preterm labor, and fetal growth restriction. Overall, the risk of perinatal transmission is approximately 5%, but it may be higher in women who have a very high parasite load. Infected neonates who remain untreated are at risk for developing the serious sequelae of chronic infection. At least half of neonates who are infected will initially be asymptomatic. Therefore, screening of at-risk neonates is essential in order to implement effective treatment.^3,6

As noted earlier, the usual drugs used for treating Chagas disease should not be used in pregnancy. Nevertheless, it is still important to screen certain individuals for infection and, subsequently, target them and their neonates for treatment immediately following delivery. The following pregnant patients should be screened^5,6:

• women with clinical manifestations that suggest acute or chronic infection
• women from areas of the world in which Chagas disease is endemic, namely, from the southern United States to northern Chile and Argentina. Although the disease is endemic in 21 countries, the countries with the highest prevalence are Bolivia, Argentina, and Paraguay.
• newborns delivered to mothers who have been identified as infected.

As mentioned, several tests are available for screening: PCR, antibody assays, and examination of peripheral blood smears. At least 2 test results should be positive to confirm the diagnosis of infection. Neonates should be followed for 9 to 12 months after delivery to determine if perinatal transmission has occurred. Treatment with antiparasitic drugs is indicated for all infected children.⁵

CASE Continue surveillance during pregnancy, treat after delivery

This patient should not be treated during pregnancy because the 2 major antiparasitic drugs are teratogenic. Antenatally, she should be followed for evidence of preterm labor and fetal growth restriction. She also should have an electrocardiogram and echocardiogram to evaluate for cardiac disease. Immediately after delivery, the patient should be treated with benznidazole for 60 days. Breastfeeding is acceptable. Her neonate should be screened for infection for up to 9 months, following the algorithm outlined earlier (FIGURE 3), and treated if the surveillance tests are positive. ●

CASE Pregnant woman with a suspected parasitic infection

A 20-year-old, previously healthy, primigravid woman at 24 weeks’ gestation immigrated from Bolivia to the United States 3 days ago. On the morning of her international flight, she awoke to discover a small insect bite just below her left eye. She sought medical evaluation because her eyelid is now significantly swollen, and she has a headache, anorexia, fatigue, and a fever of 38.4° C. The examining physician ordered a polymerase chain reaction (PCR) test for Trypanosoma cruzi, and the test is positive.

• How should this patient be treated during, and after, her delivery?


• Does this infection pose a risk to the newborn baby?


• What type of surveillance and treatment is indicated for the baby?

Chagas disease is common in South America, Central America, and Mexico and is well known to physicians in those countries. Clinicians who practice in the United States are much less familiar with the condition, but it is becoming increasingly common as a result of international travel within the Americas.

In this article, we review the interesting microbiology and epidemiology of Chagas disease, focus on its clinical manifestations, and discuss the most useful diagnostic tests for the illness. We conclude with a summary of preventive and treatment measures, with particular emphasis on managing the disease in pregnancy.

How Chagas disease is transmitted and who is at risk

Chagas disease was named in honor of a Brazilian physician, Carlos Chagas, who first described the condition in 1909. The disease is endemic in South America, Central America, and Mexico, and, recently, its prevalence has increased in the southern United States. Approximately 300,000 people in the United States are infected.^1,2

The illness is caused by the parasite Trypanosoma cruzi, and it is also known as American trypanosomiasis. The parasite is spread primarily by the bite of triatomine insects (“kissing bugs”). Approximately 60% of these insects are infected with the parasite. The insects live and thrive in the interspaces of mud walls (adobe homes) and thatched roofs. At night, the insects leave their darkened spaces and feed on the exposed skin of sleeping persons. They are particularly likely to bite the moist skin surfaces near the eye and mouth, and, as they do, they defecate and excrete the parasite into the blood vessels beneath the skin. Within the blood, the trypomastigotes invade various host cells. Inside the host cells, the organism transforms into an amastigote, which is the replicative form of the parasite. After several rounds of replication, the amastigote transforms back into a trypomastigote, bursts from the cell, and goes on to infect other host cells.¹

In addition to transmission by the insect vector, the parasite also can be transmitted by blood transfusion and organ donation. When contaminated blood is transfused, the risk of transmission is approximately 10% to 25% for each unit. Following implementation of effective screening programs by blood banks in Central America, South America, Mexico, and the United States, the risk of transmission from undetected infection is now approximately 1:200,000 per unit.

When a transplant procedure with an infected heart is performed, the risk of transmission is 75% to 100%. For liver transplants, the frequency of transmission is 0% to 29%; for kidney transplants, the risk of transmission is 0% to 19%.

Consumption of contaminated food or drink, particularly nonpasteurized items sold by street vendors, is also an important mechanism of transmission. In addition, transmission can occur as a result of laboratory exposure and by exposure to wild animals (racoons, opossums, marmosets, bats, armadillos) in forested areas. Finally, perinatal transmission now accounts for about 22% of infections. As effective vector control programs have been introduced in endemic areas, the proportion of cases caused by the insect vector has steadily decreased^1-3 (FIGURE 1).

Continue to: Clinical manifestations of Chagas disease...

Clinical manifestations of Chagas disease

Chagas disease occurs in 2 stages, acute and chronic.^1,2,4 In patients who are infected via an insect vector, the acute stage typically begins 1 to 2 weeks after the insect bite. This phase of the illness usually lasts 4 to 8 weeks and almost always resolves without treatment.

Some infected patients will be completely free of symptoms. Others will have manifestations such as:

• fever
• malaise
• headache
• hepatosplenomegaly
• lymphadenopathy
• swollen nodule at the site of infection

—Romaña’s sign, when the lesion is on the eyelid
—Chagoma, when the lesion is elsewhere on the skin.

Fortunately, less than 5% of patients will have severe illness, manifested by myocarditis, pericarditis, encephalitis, or meningitis.

People infected by ingestion of the parasite in food or drink often become more severely ill within 3 weeks. Their clinical manifestations include fever, vomiting, dyspnea, cough, chest pain, abdominal pain, and myalgias. Individuals infected through organ transplant or blood transfusion present more like those infected by the insect vector, but their illness may not develop until several weeks to 5 months after exposure.

In the absence of effective treatment, approximately 40% of patients with acute infection will develop chronic infection, often several decades later. The most common, and most ominous, feature of chronic illness is cardiac disease, experienced by about 30% of patients. Cardiac disease may be manifested as a serious arrhythmia, chest pain, congestive heart failure, or thromboembolism.

The other organ system that is likely to be adversely affected in patients with chronic disease is the gastrointestinal (GI) system, and approximately 10% of chronically infected patients experience this complication. Patients may develop a dilated esophagus, which leads to odynophagia and dysphagia. Diminished motility in other areas of the GI tract also may result in chronic constipation and even bowel obstruction. Chronically infected patients who are immunosuppressed due to HIV infection may become gravely ill as a result of encephalitis and brain abscesses. Cardiac and GI dysfunction is due to the parasite’s massive destruction of nerve endings.

Continue to: Making the diagnosis...

The diagnosis of Chagas disease begins with screening patients who have epidemiologic risk factors that place them at high risk for contracting the infection and at significantly increased risk for morbidity and mortality as a result of either the acute infection or the later chronic stage of infection. A thorough history is vital in the evaluation because the acute illness can have such vague clinical manifestations, and many patients remain asymptomatic until signs of chronic infection appear.

Risk factors that warrant screening include being born in a country endemic for Chagas disease, living in an endemic country for more than 6 months, living with someone who has a confirmed diagnosis, residing in a house made of natural materials (mud walls, thatched roof) in an endemic area, and a history of discovering the triatomine bug in the household.

Screening options include serology, microscopy, and PCR testing. Screening with a single, highly sensitive immunoglobulin G (IgG) serologic test is recommended for nonendemic clinical or community settings. In patients who were born in or who lived in an endemic area for more than 6 months, special consideration should be given to screening women of reproductive age, patients of all ages who were born to a mother with a confirmed diagnosis, individuals who were exposed to a triatomine insect, and people who are immunocompromised.⁵

A positive serologic test should be confirmed with a second assay based on a different antigen. Currently, 4 IgG tests have US Food and Drug Administration (FDA) approval for diagnosis. If a patient has 2 positive serologic tests, the diagnosis is confirmed, regardless of clinical presentation. Discordant results warrant a third test to differentiate between positive and negative results (FIGURE 2).⁵ All patients with a confirmed diagnosis should have an electrocardiogram, echocardiogram, and abdominal computed tomography (CT) scan to assess for cardiac or GI abnormalities.

Organ recipients merit special consideration because, in these individuals, the late stages of Chagas disease may be fatal. In these patients, the preferred diagnostic test is PCR. For transplant patients, monitoring should occur every week for 2 months, bimonthly for the third month, and monthly for 6 months after transplantation. Routine monitoring is not recommended in patients with HIV infection who show no clinical signs of Chagas disease and who are not from endemic areas.

Treatment options

No vaccine or hyperimmune globulin can be used to treat Chagas disease. At this time, 2 antiparasitic drugs are available to treat the condition. One is benznidazole, which inhibits DNA, RNA, and protein synthesis within the microorganism. The medication is given in a dose of 5 to 8 mg/kg per day, divided into 2 doses, for 60 days. Benznidazole is FDA approved for the treatment of individuals older than age 2. It has been used off-label in children younger than 2 years of age. The drug is commercially available at http://www.benznidazoletablets.com.

Benznidazole causes multiple minor side effects and several very serious adverse effects. The serious adverse effects include acute generalized exanthematous pustulosis, toxic epidermal necrolysis, peripheral neuropathy, marrow suppression, and hepatotoxicity. Benznidazole has been teratogenic and carcinogenic in animal studies and should not be used in pregnancy.^1,3,6

The second drug is nifurtimox. This drug is FDA approved for the treatment of Chagas disease in adults and for newborns and young children. It is commercially available for pharmacies to purchase from several drug wholesalers. Nifurtimox produces reactive oxygen species and toxic intermediates that induce DNA damage and cause cell death of the microorganism. The appropriate oral dose is 8 to 10 mg/kg per day, divided into 3 to 4 equal doses. The duration of treatment is 60 to 90 days, depending on the patient’s response. Like benznidazole, nifurtimox also is highly toxic. Severe adverse effects include a hypersensitivity reaction, anaphylaxis, angioedema, syncope, seizures, and psychosis. Nifurtimox also is teratogenic and is contraindicated in pregnancy.^1,3,6

Clinicians who have questions about the use of either of these medications should contact the Centers for Disease Control and Prevention, Division of Parasitic Diseases public inquiries telephone line at (404) 718-4745.

Potential for cure. When either benznidazole or nifurtimox is administered early in the course of a patient’s acute infection, the chance for complete cure is excellent. The same is true for early treatment of the infected neonate. When treatment is delayed, or if it cannot be completed because of intolerable adverse effects, the prognosis for complete cure is diminished.

In adults who have chronic disease, antiparasitic treatment is unlikely to be effective. In such a situation, secondary treatment is directed toward correction of heart failure, control of cardiac rhythm disturbances, and control of GI motility disorders. For both cardiac and GI conditions, medication and surgery may be indicated. Antiparasitic treatment is more effective in children with chronic disease but it is still not uniformly effective.^1,3,5,6

Preventing infection

Vector control is the key to preventing infection in areas where Chagas disease is endemic. One important, but often financially unaffordable, measure is construction of homes with building materials that do not support the growth of the triatomine insects that transmit the disease. A second critical preventive measure is the spraying of mud and thatched homes and surrounding areas with long-lasting insecticides. Pyrethroids are the preferred agents today. Alternative agents include fenitrothion and bendiocarb.¹

Other important preventive measures include:

• screening the blood supply for T cruzi and eliminating units contaminated with the parasite
• screening for the parasite in organs targeted for transplant
• screening infected women of reproductive age in endemic areas and treating those who are positive before they become pregnant; this measure may be almost 95% effective in preventing congenital infection
• using mosquito netting when housing is insecure and air conditioning is not available
• in endemic areas, avoiding unpasteurized fruit drinks and unwashed fruits and vegetables.

Unique considerations in pregnancy

Chagas disease does not cause specific anatomic birth defects. However, infected women are more likely to experience spontaneous abortion, preterm premature rupture of membranes, preterm labor, and fetal growth restriction. Overall, the risk of perinatal transmission is approximately 5%, but it may be higher in women who have a very high parasite load. Infected neonates who remain untreated are at risk for developing the serious sequelae of chronic infection. At least half of neonates who are infected will initially be asymptomatic. Therefore, screening of at-risk neonates is essential in order to implement effective treatment.^3,6

As noted earlier, the usual drugs used for treating Chagas disease should not be used in pregnancy. Nevertheless, it is still important to screen certain individuals for infection and, subsequently, target them and their neonates for treatment immediately following delivery. The following pregnant patients should be screened^5,6:

• women with clinical manifestations that suggest acute or chronic infection
• women from areas of the world in which Chagas disease is endemic, namely, from the southern United States to northern Chile and Argentina. Although the disease is endemic in 21 countries, the countries with the highest prevalence are Bolivia, Argentina, and Paraguay.
• newborns delivered to mothers who have been identified as infected.

As mentioned, several tests are available for screening: PCR, antibody assays, and examination of peripheral blood smears. At least 2 test results should be positive to confirm the diagnosis of infection. Neonates should be followed for 9 to 12 months after delivery to determine if perinatal transmission has occurred. Treatment with antiparasitic drugs is indicated for all infected children.⁵

CASE Continue surveillance during pregnancy, treat after delivery

This patient should not be treated during pregnancy because the 2 major antiparasitic drugs are teratogenic. Antenatally, she should be followed for evidence of preterm labor and fetal growth restriction. She also should have an electrocardiogram and echocardiogram to evaluate for cardiac disease. Immediately after delivery, the patient should be treated with benznidazole for 60 days. Breastfeeding is acceptable. Her neonate should be screened for infection for up to 9 months, following the algorithm outlined earlier (FIGURE 3), and treated if the surveillance tests are positive. ●

CASE Pregnant woman with a suspected parasitic infection

A 20-year-old, previously healthy, primigravid woman at 24 weeks’ gestation immigrated from Bolivia to the United States 3 days ago. On the morning of her international flight, she awoke to discover a small insect bite just below her left eye. She sought medical evaluation because her eyelid is now significantly swollen, and she has a headache, anorexia, fatigue, and a fever of 38.4° C. The examining physician ordered a polymerase chain reaction (PCR) test for Trypanosoma cruzi, and the test is positive.

• How should this patient be treated during, and after, her delivery?


• Does this infection pose a risk to the newborn baby?


• What type of surveillance and treatment is indicated for the baby?

Chagas disease is common in South America, Central America, and Mexico and is well known to physicians in those countries. Clinicians who practice in the United States are much less familiar with the condition, but it is becoming increasingly common as a result of international travel within the Americas.

In this article, we review the interesting microbiology and epidemiology of Chagas disease, focus on its clinical manifestations, and discuss the most useful diagnostic tests for the illness. We conclude with a summary of preventive and treatment measures, with particular emphasis on managing the disease in pregnancy.

How Chagas disease is transmitted and who is at risk

Chagas disease was named in honor of a Brazilian physician, Carlos Chagas, who first described the condition in 1909. The disease is endemic in South America, Central America, and Mexico, and, recently, its prevalence has increased in the southern United States. Approximately 300,000 people in the United States are infected.^1,2

The illness is caused by the parasite Trypanosoma cruzi, and it is also known as American trypanosomiasis. The parasite is spread primarily by the bite of triatomine insects (“kissing bugs”). Approximately 60% of these insects are infected with the parasite. The insects live and thrive in the interspaces of mud walls (adobe homes) and thatched roofs. At night, the insects leave their darkened spaces and feed on the exposed skin of sleeping persons. They are particularly likely to bite the moist skin surfaces near the eye and mouth, and, as they do, they defecate and excrete the parasite into the blood vessels beneath the skin. Within the blood, the trypomastigotes invade various host cells. Inside the host cells, the organism transforms into an amastigote, which is the replicative form of the parasite. After several rounds of replication, the amastigote transforms back into a trypomastigote, bursts from the cell, and goes on to infect other host cells.¹

In addition to transmission by the insect vector, the parasite also can be transmitted by blood transfusion and organ donation. When contaminated blood is transfused, the risk of transmission is approximately 10% to 25% for each unit. Following implementation of effective screening programs by blood banks in Central America, South America, Mexico, and the United States, the risk of transmission from undetected infection is now approximately 1:200,000 per unit.

When a transplant procedure with an infected heart is performed, the risk of transmission is 75% to 100%. For liver transplants, the frequency of transmission is 0% to 29%; for kidney transplants, the risk of transmission is 0% to 19%.

Consumption of contaminated food or drink, particularly nonpasteurized items sold by street vendors, is also an important mechanism of transmission. In addition, transmission can occur as a result of laboratory exposure and by exposure to wild animals (racoons, opossums, marmosets, bats, armadillos) in forested areas. Finally, perinatal transmission now accounts for about 22% of infections. As effective vector control programs have been introduced in endemic areas, the proportion of cases caused by the insect vector has steadily decreased^1-3 (FIGURE 1).

Continue to: Clinical manifestations of Chagas disease...

Clinical manifestations of Chagas disease

Chagas disease occurs in 2 stages, acute and chronic.^1,2,4 In patients who are infected via an insect vector, the acute stage typically begins 1 to 2 weeks after the insect bite. This phase of the illness usually lasts 4 to 8 weeks and almost always resolves without treatment.

Some infected patients will be completely free of symptoms. Others will have manifestations such as:

• fever
• malaise
• headache
• hepatosplenomegaly
• lymphadenopathy
• swollen nodule at the site of infection

—Romaña’s sign, when the lesion is on the eyelid
—Chagoma, when the lesion is elsewhere on the skin.

Fortunately, less than 5% of patients will have severe illness, manifested by myocarditis, pericarditis, encephalitis, or meningitis.

People infected by ingestion of the parasite in food or drink often become more severely ill within 3 weeks. Their clinical manifestations include fever, vomiting, dyspnea, cough, chest pain, abdominal pain, and myalgias. Individuals infected through organ transplant or blood transfusion present more like those infected by the insect vector, but their illness may not develop until several weeks to 5 months after exposure.

In the absence of effective treatment, approximately 40% of patients with acute infection will develop chronic infection, often several decades later. The most common, and most ominous, feature of chronic illness is cardiac disease, experienced by about 30% of patients. Cardiac disease may be manifested as a serious arrhythmia, chest pain, congestive heart failure, or thromboembolism.

The other organ system that is likely to be adversely affected in patients with chronic disease is the gastrointestinal (GI) system, and approximately 10% of chronically infected patients experience this complication. Patients may develop a dilated esophagus, which leads to odynophagia and dysphagia. Diminished motility in other areas of the GI tract also may result in chronic constipation and even bowel obstruction. Chronically infected patients who are immunosuppressed due to HIV infection may become gravely ill as a result of encephalitis and brain abscesses. Cardiac and GI dysfunction is due to the parasite’s massive destruction of nerve endings.

Continue to: Making the diagnosis...

The diagnosis of Chagas disease begins with screening patients who have epidemiologic risk factors that place them at high risk for contracting the infection and at significantly increased risk for morbidity and mortality as a result of either the acute infection or the later chronic stage of infection. A thorough history is vital in the evaluation because the acute illness can have such vague clinical manifestations, and many patients remain asymptomatic until signs of chronic infection appear.

Risk factors that warrant screening include being born in a country endemic for Chagas disease, living in an endemic country for more than 6 months, living with someone who has a confirmed diagnosis, residing in a house made of natural materials (mud walls, thatched roof) in an endemic area, and a history of discovering the triatomine bug in the household.

Screening options include serology, microscopy, and PCR testing. Screening with a single, highly sensitive immunoglobulin G (IgG) serologic test is recommended for nonendemic clinical or community settings. In patients who were born in or who lived in an endemic area for more than 6 months, special consideration should be given to screening women of reproductive age, patients of all ages who were born to a mother with a confirmed diagnosis, individuals who were exposed to a triatomine insect, and people who are immunocompromised.⁵

A positive serologic test should be confirmed with a second assay based on a different antigen. Currently, 4 IgG tests have US Food and Drug Administration (FDA) approval for diagnosis. If a patient has 2 positive serologic tests, the diagnosis is confirmed, regardless of clinical presentation. Discordant results warrant a third test to differentiate between positive and negative results (FIGURE 2).⁵ All patients with a confirmed diagnosis should have an electrocardiogram, echocardiogram, and abdominal computed tomography (CT) scan to assess for cardiac or GI abnormalities.

Organ recipients merit special consideration because, in these individuals, the late stages of Chagas disease may be fatal. In these patients, the preferred diagnostic test is PCR. For transplant patients, monitoring should occur every week for 2 months, bimonthly for the third month, and monthly for 6 months after transplantation. Routine monitoring is not recommended in patients with HIV infection who show no clinical signs of Chagas disease and who are not from endemic areas.

Treatment options

No vaccine or hyperimmune globulin can be used to treat Chagas disease. At this time, 2 antiparasitic drugs are available to treat the condition. One is benznidazole, which inhibits DNA, RNA, and protein synthesis within the microorganism. The medication is given in a dose of 5 to 8 mg/kg per day, divided into 2 doses, for 60 days. Benznidazole is FDA approved for the treatment of individuals older than age 2. It has been used off-label in children younger than 2 years of age. The drug is commercially available at http://www.benznidazoletablets.com.

Benznidazole causes multiple minor side effects and several very serious adverse effects. The serious adverse effects include acute generalized exanthematous pustulosis, toxic epidermal necrolysis, peripheral neuropathy, marrow suppression, and hepatotoxicity. Benznidazole has been teratogenic and carcinogenic in animal studies and should not be used in pregnancy.^1,3,6

The second drug is nifurtimox. This drug is FDA approved for the treatment of Chagas disease in adults and for newborns and young children. It is commercially available for pharmacies to purchase from several drug wholesalers. Nifurtimox produces reactive oxygen species and toxic intermediates that induce DNA damage and cause cell death of the microorganism. The appropriate oral dose is 8 to 10 mg/kg per day, divided into 3 to 4 equal doses. The duration of treatment is 60 to 90 days, depending on the patient’s response. Like benznidazole, nifurtimox also is highly toxic. Severe adverse effects include a hypersensitivity reaction, anaphylaxis, angioedema, syncope, seizures, and psychosis. Nifurtimox also is teratogenic and is contraindicated in pregnancy.^1,3,6

Clinicians who have questions about the use of either of these medications should contact the Centers for Disease Control and Prevention, Division of Parasitic Diseases public inquiries telephone line at (404) 718-4745.

Potential for cure. When either benznidazole or nifurtimox is administered early in the course of a patient’s acute infection, the chance for complete cure is excellent. The same is true for early treatment of the infected neonate. When treatment is delayed, or if it cannot be completed because of intolerable adverse effects, the prognosis for complete cure is diminished.

In adults who have chronic disease, antiparasitic treatment is unlikely to be effective. In such a situation, secondary treatment is directed toward correction of heart failure, control of cardiac rhythm disturbances, and control of GI motility disorders. For both cardiac and GI conditions, medication and surgery may be indicated. Antiparasitic treatment is more effective in children with chronic disease but it is still not uniformly effective.^1,3,5,6

Preventing infection

Vector control is the key to preventing infection in areas where Chagas disease is endemic. One important, but often financially unaffordable, measure is construction of homes with building materials that do not support the growth of the triatomine insects that transmit the disease. A second critical preventive measure is the spraying of mud and thatched homes and surrounding areas with long-lasting insecticides. Pyrethroids are the preferred agents today. Alternative agents include fenitrothion and bendiocarb.¹

Other important preventive measures include:

• screening the blood supply for T cruzi and eliminating units contaminated with the parasite
• screening for the parasite in organs targeted for transplant
• screening infected women of reproductive age in endemic areas and treating those who are positive before they become pregnant; this measure may be almost 95% effective in preventing congenital infection
• using mosquito netting when housing is insecure and air conditioning is not available
• in endemic areas, avoiding unpasteurized fruit drinks and unwashed fruits and vegetables.

Unique considerations in pregnancy

Chagas disease does not cause specific anatomic birth defects. However, infected women are more likely to experience spontaneous abortion, preterm premature rupture of membranes, preterm labor, and fetal growth restriction. Overall, the risk of perinatal transmission is approximately 5%, but it may be higher in women who have a very high parasite load. Infected neonates who remain untreated are at risk for developing the serious sequelae of chronic infection. At least half of neonates who are infected will initially be asymptomatic. Therefore, screening of at-risk neonates is essential in order to implement effective treatment.^3,6

As noted earlier, the usual drugs used for treating Chagas disease should not be used in pregnancy. Nevertheless, it is still important to screen certain individuals for infection and, subsequently, target them and their neonates for treatment immediately following delivery. The following pregnant patients should be screened^5,6:

• women with clinical manifestations that suggest acute or chronic infection
• women from areas of the world in which Chagas disease is endemic, namely, from the southern United States to northern Chile and Argentina. Although the disease is endemic in 21 countries, the countries with the highest prevalence are Bolivia, Argentina, and Paraguay.
• newborns delivered to mothers who have been identified as infected.

As mentioned, several tests are available for screening: PCR, antibody assays, and examination of peripheral blood smears. At least 2 test results should be positive to confirm the diagnosis of infection. Neonates should be followed for 9 to 12 months after delivery to determine if perinatal transmission has occurred. Treatment with antiparasitic drugs is indicated for all infected children.⁵

CASE Continue surveillance during pregnancy, treat after delivery

This patient should not be treated during pregnancy because the 2 major antiparasitic drugs are teratogenic. Antenatally, she should be followed for evidence of preterm labor and fetal growth restriction. She also should have an electrocardiogram and echocardiogram to evaluate for cardiac disease. Immediately after delivery, the patient should be treated with benznidazole for 60 days. Breastfeeding is acceptable. Her neonate should be screened for infection for up to 9 months, following the algorithm outlined earlier (FIGURE 3), and treated if the surveillance tests are positive. ●

ILLUSTRATION: KATERYNA KON/SCIENCE PHOTO LIBRARY

Recurrent vulvovaginal candidiasis (RVVC) is a common cause of vaginitis and gynecologic morbidity in the United States and globally.¹ RVVC is defined as at least 3 laboratory-confirmed (for example, culture, nucleic acid amplification test [NAAT]) symptomatic episodes in the previous 12 months.² Common symptoms include vulvar pruritus, erythema, local skin and mucosal irritation, and abnormal discharge that may be thick and white or thin and watery.

The true incidence of RVVC is difficult to determine due to clinical diagnostic inaccuracy that results in over- and underdiagnosis of VVC and the general availability of over-the-counter topical antifungal medications that individuals who self-diagnose use to treat VVC.³

Causative organisms

Vulvovaginal yeast infections are caused by Candida species, a family of ubiquitous fungi that are a part of normal genitourinary and gastrointestinal flora.⁴ As such, these infections are commonly termed VVC. The presence of Candida species in the vagina without evidence of inflammation is not considered an infection but rather is more consistent with vaginal colonization. Inflammation in the setting of Candida species is what characterizes a true VVC infection.⁴

Candida albicans is responsible for the vast majority of VVC cases in the United States, with Candida glabrata accounting for most of the remaining infections.⁵ The majority of RVVC infections that are caused by C albicans are due to azole-sensitive strains (85%–95% of infections).²C glabrata, by contrast, is intrinsically resistant to azoles, which is thought primarily to be due to overexpression of drug efflux pumps that remove active drug from the cell.^6,7

Why does VVC reoccur?

The pathogenesis of RVVC is not well understood. Predisposing factors may include frequent or recent antibiotic use, poorly controlled diabetes, immunodeficiency, and other host factors. However, many cases of RVVC are idiopathic and no predisposing or underlying conditions are identified.⁷

The role of genetic factors in predisposing to or triggering RVVC is unclear and is an area of ongoing investigation.² Longitudinal DNA-typing studies suggest that recurrent disease is usually due to relapse from a persistent vaginal reservoir of organisms (that is, vaginal colonization) or endogenous reinfection with identical strains of susceptible C albicans.^8,9 Symptomatic VVC likely results when the symbiotic balance between yeast and the normal vaginal microbiota is disrupted (by either Candida species overgrowth or changes in host immune factors).² Less commonly, “recurrent” infections may in fact be due to azole-resistant Candida and non-Candida species.²

Clinical aspects and diagnosis of VVC

Signs and symptoms suggestive of VVC include vulvovaginal erythema, edema, vaginal discharge, vulvovaginal pruritus, and irritation. Given the lack of specificity of individual clinical findings in diagnosing VVC, or for distinguishing between other common causes of vaginitis (such as bacterial vaginosis and trichomoniasis), laboratory testing (that is, microscopy) should be performed in combination with a clinical exam in order to make a confident diagnosis of VVC.¹⁰ Self-diagnosis of VVC is inaccurate and is not recommended, as misdiagnosis and inappropriate treatment is cost ineffective, delays accurate diagnoses, and may contribute to growing azole resistance.

In patients with signs and symptoms of VVC, saline and potassium hydroxide microscopy should be performed.⁷ TABLE 1 summarizes other major diagnostic techniques for VVC.

Diagnostic considerations

Non-albicans Candida species, such as C glabrata, may be associated with minimally symptomatic or completely asymptomatic infections and may not be identified easily on wet mount as it does not form pseudohyphae or hyphae.¹¹ Therefore, culture and susceptibility or NAAT testing is highly recommended for patients who remain symptomatic and/or have a nondiagnostic microscopy and a normal vaginal pH.⁷

Treatment options

Prior to May 2022, there had been no drugs approved by the US Food and Drug Administration (FDA) to treat RVVC. The mainstay of treatment is long-term maintenance therapy to achieve mycologic remission (TABLE 2).

In general, recurrent episodes of VVC should be treated with a longer duration of therapy (for example, oral fluconazole 150 mg every 72 hours for a total of 3 doses or topical azole for 7–14 days).⁷ If recurrent maintenance/suppressive therapy is started, the induction phase should be longer as well, at least 10 to 14 days with a topical or oral azole followed by a 6-month or longer course of weekly oral or topical azole therapy (such as 6–12 months).^12,13

Patients with underlying immunodeficiency (such as poorly controlled diabetes, chronic corticosteroid treatment) may need prolonged courses of therapy. Correction of modifiable conditions and optimization of comorbidities should be prioritized—for example, optimized glucose control, weight loss, durable viral suppression, and so on. Of note, symptomatic VVC is more frequent among individuals with HIV and correlates with severity of immunodeficiency. Pharmacologic options for RVVC for individuals with HIV do not differ from standard recommendations.¹⁴

Fluconazole

Fluconazole is a safe, affordable, and convenient prescription oral medication that can be used for initial and maintenance/suppressive therapy.² Fluconazole levels in vaginal secretions remain at therapeutic concentrations for at least 72 hours after a 150-mg dose.¹⁵ Induction therapy consists of oral fluconazole 150 mg every 72 hours for a total of 3 doses, followed by a maintenance regimen of a once-weekly dose of oral fluconazole 150 mg for a total of 6 months. Unfortunately, up to 55% of patients will experience a relapse in symptoms.¹²

Routine liver function test monitoring is not indicated for fluconazole maintenance therapy, but it should be performed if patients are treated with daily or long-term alternative oral azole medications, such as ketoconazole and itraconazole.

During pregnancy, only topical azole therapy is recommended for use, given the potential risk for adverse fetal outcomes, such as spontaneous abortion and congenital malformations, with fetal exposure to oral fluconazole ingested by the pregnant person.¹⁶ Fluconazole is present in breast milk, but it is safe to use during lactation when used at recommended doses.¹⁷

Continue to: Options for fluconazole-resistant C albicans infection...

Options for fluconazole-resistant C albicans infection

Patients who have RVVC with frequent and/or prolonged use of fluconazole are at risk for developing azole-resistant isolates of C albicans.¹² For patients found to have azole-resistant infections, treatment options include increasing the azole dose based on isolate minimal inhibitory concentrations (MIC) to various antifungals, therapy with a non-fluconazole azole regimen, or switching to a different therapeutic drug class altogether.⁷

Options for non- albicans Candida species infection

Given the intrinsic resistance to azole therapy in some non-albicans Candida species (specifically C glabrata and Candida krusei), boric acid or nystatin regimens can be used. An induction course of vaginal boric acid is given as 600 mg per vagina daily for up to 14 days and is associated with a 70% rate of mycologic control.⁷ Boric acid is known to cause local irritation and dermatitis for both the patient and any sexual partners. If ingested orally, boric acid is associated with significant toxicity and even death.⁷

Vaginal nystatin also may be considered, with an induction course of 100,000 U for 14 days, with a similar regimen recommended for maintenance therapy. However, data are limited on maintenance regimens for RVVC due to non-albicans Candida species.²

Gentian violet

Gentian violet is a topical antiseptic agent that is available over the counter. Use of this agent is uncommon given the availability of highly effective azole-based therapy. Although useful due to its antipruritic properties, gentian violet can be messy to use and tends to stain clothing permanently.

Gentian violet use may be considered in cases of refractory RVVC with or without azole-resistant infections; it is applied as a 1% or 2% solution directly to affected areas for 10 to 14 days.¹⁸

Lactobacilli probiotics and dietary changes

Data that support the oral and/or vaginal use of probiotics that contain live lactobacilli are conflicting. In the absence of conclusive evidence to support probiotic use to treat and prevent RVVC, as well as variable quality of available products, use of these agents is not recommended.¹⁹

No controlled studies have evaluated the role of various diets in preventing RVVC; thus, no specific dietary changes are recommended.

Behavioral therapy

Available evidence does not support the treatment of sexual partners of patients with RVVC.⁷

Continue to: What’s new in treatment?...

Until recently, the main standard of care for RVVC has been oral fluconazole-based therapy. For patients whose symptoms do not respond to oral fluconazole therapy, oteseconazole is now available as a noninferior treatment option to fluconazole for both induction and maintenance therapy. Like other azoles, oteseconazole works by inhibiting a fungal enzyme (CYP51) that is essential in fungal cell membrane integrity and fungal growth.²⁰ Oteseconazole is a more selective inhibitor of the fungal CYP51 enzyme and has demonstrated excellent potency against Candida species in in vitro pharmacologic studies.²¹

In a phase 3 study that evaluated the safety and efficacy of oteseconazole in the treatment and prevention of RVVC, oteseconazole was found to be both safe and efficacious in both the induction and maintenance phases of treatment for RVVC.²⁰ In this trial, induction and maintenance with oteseconazole was compared with induction with fluconazole and placebo maintenance. Among the 185 participants with culture-verified RVVC, the oteseconazole regimen (n = 123) was associated with fewer recurrences of culture-verified VVC infections than was the fluconazole induction/placebo maintenance regimen (n = 62) during the 48-week maintenance phase of therapy (5% vs 42%).²⁰

Single- and dual-drug dosing regimens of oteseconazole are recommended based on previous trial data that compared safety and efficacy of oteseconazole versus fluconazole induction therapy and oteseconazole versus placebo maintenance therapy.²² However, widespread use of oteseconazole regimens are limited due to its higher costs and limited access to the drug outside of a research setting.²⁰

Single-drug induction therapy with oteseconazole consists of a single 600-mg oral dose on day 1 followed by a second dose of 450 mg orally on day 2. Starting on day 14, maintenance therapy starts with a single oral dose of 150 mg and is continued weekly for 11 weeks.²²

Dual-drug induction therapy consists of oral fluconazole 150 mg on days 1, 4, and 7 followed by daily dosing of oral oteseconazole 150 mg on days 14 through 20. Then, starting on day 28, weekly dosing of oral oteseconazole 150 mg is continued for 11 weeks.²²

Effects on pregnancy and lactation. Concerns of oteseconazole’s fetal teratogenicity are based on animal reproduction studies that reported ocular abnormalities from in utero exposure. Human data are insufficient to determine if oteseconazole is excreted in breast milk or what its effects are on milk production. Among breastfed infants whose mothers were exposed to oteseconazole during lactation, no adverse outcomes were reported, but follow up of oteseconazole-exposed infants was limited. ²² Therefore, use of oteseconazole among pregnant and/or lactating persons with RVVC is contraindicated at this time. The long-half life (approximately 138 days) of oteseconazole may preclude use among persons attempting pregnancy. ²²

Other therapies. The other common classes of antifungal therapy used in the treatment of RVVC include the polyenes (for example, amphotericin B) and echinocandins (such as caspofungin) drug classes. Emerging azole-resistance among Candida species has been recognized as a significant concern from the Centers for Disease Control and Prevention. ⁷ Echinocandins, which are generally better tolerated and have a lower adverse side effect profile than polyenes, are a promising therapeutic class, but currently they are limited to intravenous options. SCY-078, a novel oral echinocandin in development, has shown in vitro fungicidal activity against multiple albicans and non-albicans Candida species in pharmacokinetic/pharmacodynamic studies.²³

Continued development of alternative, non-azole-based therapies for Candida species is needed.●

ILLUSTRATION: KATERYNA KON/SCIENCE PHOTO LIBRARY

Recurrent vulvovaginal candidiasis (RVVC) is a common cause of vaginitis and gynecologic morbidity in the United States and globally.¹ RVVC is defined as at least 3 laboratory-confirmed (for example, culture, nucleic acid amplification test [NAAT]) symptomatic episodes in the previous 12 months.² Common symptoms include vulvar pruritus, erythema, local skin and mucosal irritation, and abnormal discharge that may be thick and white or thin and watery.

The true incidence of RVVC is difficult to determine due to clinical diagnostic inaccuracy that results in over- and underdiagnosis of VVC and the general availability of over-the-counter topical antifungal medications that individuals who self-diagnose use to treat VVC.³

Causative organisms

Vulvovaginal yeast infections are caused by Candida species, a family of ubiquitous fungi that are a part of normal genitourinary and gastrointestinal flora.⁴ As such, these infections are commonly termed VVC. The presence of Candida species in the vagina without evidence of inflammation is not considered an infection but rather is more consistent with vaginal colonization. Inflammation in the setting of Candida species is what characterizes a true VVC infection.⁴

Candida albicans is responsible for the vast majority of VVC cases in the United States, with Candida glabrata accounting for most of the remaining infections.⁵ The majority of RVVC infections that are caused by C albicans are due to azole-sensitive strains (85%–95% of infections).²C glabrata, by contrast, is intrinsically resistant to azoles, which is thought primarily to be due to overexpression of drug efflux pumps that remove active drug from the cell.^6,7

Why does VVC reoccur?

The pathogenesis of RVVC is not well understood. Predisposing factors may include frequent or recent antibiotic use, poorly controlled diabetes, immunodeficiency, and other host factors. However, many cases of RVVC are idiopathic and no predisposing or underlying conditions are identified.⁷

The role of genetic factors in predisposing to or triggering RVVC is unclear and is an area of ongoing investigation.² Longitudinal DNA-typing studies suggest that recurrent disease is usually due to relapse from a persistent vaginal reservoir of organisms (that is, vaginal colonization) or endogenous reinfection with identical strains of susceptible C albicans.^8,9 Symptomatic VVC likely results when the symbiotic balance between yeast and the normal vaginal microbiota is disrupted (by either Candida species overgrowth or changes in host immune factors).² Less commonly, “recurrent” infections may in fact be due to azole-resistant Candida and non-Candida species.²

Clinical aspects and diagnosis of VVC

Signs and symptoms suggestive of VVC include vulvovaginal erythema, edema, vaginal discharge, vulvovaginal pruritus, and irritation. Given the lack of specificity of individual clinical findings in diagnosing VVC, or for distinguishing between other common causes of vaginitis (such as bacterial vaginosis and trichomoniasis), laboratory testing (that is, microscopy) should be performed in combination with a clinical exam in order to make a confident diagnosis of VVC.¹⁰ Self-diagnosis of VVC is inaccurate and is not recommended, as misdiagnosis and inappropriate treatment is cost ineffective, delays accurate diagnoses, and may contribute to growing azole resistance.

In patients with signs and symptoms of VVC, saline and potassium hydroxide microscopy should be performed.⁷ TABLE 1 summarizes other major diagnostic techniques for VVC.

Diagnostic considerations

Non-albicans Candida species, such as C glabrata, may be associated with minimally symptomatic or completely asymptomatic infections and may not be identified easily on wet mount as it does not form pseudohyphae or hyphae.¹¹ Therefore, culture and susceptibility or NAAT testing is highly recommended for patients who remain symptomatic and/or have a nondiagnostic microscopy and a normal vaginal pH.⁷

Treatment options

Prior to May 2022, there had been no drugs approved by the US Food and Drug Administration (FDA) to treat RVVC. The mainstay of treatment is long-term maintenance therapy to achieve mycologic remission (TABLE 2).

In general, recurrent episodes of VVC should be treated with a longer duration of therapy (for example, oral fluconazole 150 mg every 72 hours for a total of 3 doses or topical azole for 7–14 days).⁷ If recurrent maintenance/suppressive therapy is started, the induction phase should be longer as well, at least 10 to 14 days with a topical or oral azole followed by a 6-month or longer course of weekly oral or topical azole therapy (such as 6–12 months).^12,13

Patients with underlying immunodeficiency (such as poorly controlled diabetes, chronic corticosteroid treatment) may need prolonged courses of therapy. Correction of modifiable conditions and optimization of comorbidities should be prioritized—for example, optimized glucose control, weight loss, durable viral suppression, and so on. Of note, symptomatic VVC is more frequent among individuals with HIV and correlates with severity of immunodeficiency. Pharmacologic options for RVVC for individuals with HIV do not differ from standard recommendations.¹⁴

Fluconazole

Fluconazole is a safe, affordable, and convenient prescription oral medication that can be used for initial and maintenance/suppressive therapy.² Fluconazole levels in vaginal secretions remain at therapeutic concentrations for at least 72 hours after a 150-mg dose.¹⁵ Induction therapy consists of oral fluconazole 150 mg every 72 hours for a total of 3 doses, followed by a maintenance regimen of a once-weekly dose of oral fluconazole 150 mg for a total of 6 months. Unfortunately, up to 55% of patients will experience a relapse in symptoms.¹²

Routine liver function test monitoring is not indicated for fluconazole maintenance therapy, but it should be performed if patients are treated with daily or long-term alternative oral azole medications, such as ketoconazole and itraconazole.

During pregnancy, only topical azole therapy is recommended for use, given the potential risk for adverse fetal outcomes, such as spontaneous abortion and congenital malformations, with fetal exposure to oral fluconazole ingested by the pregnant person.¹⁶ Fluconazole is present in breast milk, but it is safe to use during lactation when used at recommended doses.¹⁷

Continue to: Options for fluconazole-resistant C albicans infection...

Options for fluconazole-resistant C albicans infection

Patients who have RVVC with frequent and/or prolonged use of fluconazole are at risk for developing azole-resistant isolates of C albicans.¹² For patients found to have azole-resistant infections, treatment options include increasing the azole dose based on isolate minimal inhibitory concentrations (MIC) to various antifungals, therapy with a non-fluconazole azole regimen, or switching to a different therapeutic drug class altogether.⁷

Options for non- albicans Candida species infection

Given the intrinsic resistance to azole therapy in some non-albicans Candida species (specifically C glabrata and Candida krusei), boric acid or nystatin regimens can be used. An induction course of vaginal boric acid is given as 600 mg per vagina daily for up to 14 days and is associated with a 70% rate of mycologic control.⁷ Boric acid is known to cause local irritation and dermatitis for both the patient and any sexual partners. If ingested orally, boric acid is associated with significant toxicity and even death.⁷

Vaginal nystatin also may be considered, with an induction course of 100,000 U for 14 days, with a similar regimen recommended for maintenance therapy. However, data are limited on maintenance regimens for RVVC due to non-albicans Candida species.²

Gentian violet

Gentian violet is a topical antiseptic agent that is available over the counter. Use of this agent is uncommon given the availability of highly effective azole-based therapy. Although useful due to its antipruritic properties, gentian violet can be messy to use and tends to stain clothing permanently.

Gentian violet use may be considered in cases of refractory RVVC with or without azole-resistant infections; it is applied as a 1% or 2% solution directly to affected areas for 10 to 14 days.¹⁸

Lactobacilli probiotics and dietary changes

Data that support the oral and/or vaginal use of probiotics that contain live lactobacilli are conflicting. In the absence of conclusive evidence to support probiotic use to treat and prevent RVVC, as well as variable quality of available products, use of these agents is not recommended.¹⁹

No controlled studies have evaluated the role of various diets in preventing RVVC; thus, no specific dietary changes are recommended.

Behavioral therapy

Available evidence does not support the treatment of sexual partners of patients with RVVC.⁷

Continue to: What’s new in treatment?...

Until recently, the main standard of care for RVVC has been oral fluconazole-based therapy. For patients whose symptoms do not respond to oral fluconazole therapy, oteseconazole is now available as a noninferior treatment option to fluconazole for both induction and maintenance therapy. Like other azoles, oteseconazole works by inhibiting a fungal enzyme (CYP51) that is essential in fungal cell membrane integrity and fungal growth.²⁰ Oteseconazole is a more selective inhibitor of the fungal CYP51 enzyme and has demonstrated excellent potency against Candida species in in vitro pharmacologic studies.²¹

In a phase 3 study that evaluated the safety and efficacy of oteseconazole in the treatment and prevention of RVVC, oteseconazole was found to be both safe and efficacious in both the induction and maintenance phases of treatment for RVVC.²⁰ In this trial, induction and maintenance with oteseconazole was compared with induction with fluconazole and placebo maintenance. Among the 185 participants with culture-verified RVVC, the oteseconazole regimen (n = 123) was associated with fewer recurrences of culture-verified VVC infections than was the fluconazole induction/placebo maintenance regimen (n = 62) during the 48-week maintenance phase of therapy (5% vs 42%).²⁰

Single- and dual-drug dosing regimens of oteseconazole are recommended based on previous trial data that compared safety and efficacy of oteseconazole versus fluconazole induction therapy and oteseconazole versus placebo maintenance therapy.²² However, widespread use of oteseconazole regimens are limited due to its higher costs and limited access to the drug outside of a research setting.²⁰

Single-drug induction therapy with oteseconazole consists of a single 600-mg oral dose on day 1 followed by a second dose of 450 mg orally on day 2. Starting on day 14, maintenance therapy starts with a single oral dose of 150 mg and is continued weekly for 11 weeks.²²

Dual-drug induction therapy consists of oral fluconazole 150 mg on days 1, 4, and 7 followed by daily dosing of oral oteseconazole 150 mg on days 14 through 20. Then, starting on day 28, weekly dosing of oral oteseconazole 150 mg is continued for 11 weeks.²²

Effects on pregnancy and lactation. Concerns of oteseconazole’s fetal teratogenicity are based on animal reproduction studies that reported ocular abnormalities from in utero exposure. Human data are insufficient to determine if oteseconazole is excreted in breast milk or what its effects are on milk production. Among breastfed infants whose mothers were exposed to oteseconazole during lactation, no adverse outcomes were reported, but follow up of oteseconazole-exposed infants was limited. ²² Therefore, use of oteseconazole among pregnant and/or lactating persons with RVVC is contraindicated at this time. The long-half life (approximately 138 days) of oteseconazole may preclude use among persons attempting pregnancy. ²²

Other therapies. The other common classes of antifungal therapy used in the treatment of RVVC include the polyenes (for example, amphotericin B) and echinocandins (such as caspofungin) drug classes. Emerging azole-resistance among Candida species has been recognized as a significant concern from the Centers for Disease Control and Prevention. ⁷ Echinocandins, which are generally better tolerated and have a lower adverse side effect profile than polyenes, are a promising therapeutic class, but currently they are limited to intravenous options. SCY-078, a novel oral echinocandin in development, has shown in vitro fungicidal activity against multiple albicans and non-albicans Candida species in pharmacokinetic/pharmacodynamic studies.²³

Continued development of alternative, non-azole-based therapies for Candida species is needed.●

ILLUSTRATION: KATERYNA KON/SCIENCE PHOTO LIBRARY

Recurrent vulvovaginal candidiasis (RVVC) is a common cause of vaginitis and gynecologic morbidity in the United States and globally.¹ RVVC is defined as at least 3 laboratory-confirmed (for example, culture, nucleic acid amplification test [NAAT]) symptomatic episodes in the previous 12 months.² Common symptoms include vulvar pruritus, erythema, local skin and mucosal irritation, and abnormal discharge that may be thick and white or thin and watery.

The true incidence of RVVC is difficult to determine due to clinical diagnostic inaccuracy that results in over- and underdiagnosis of VVC and the general availability of over-the-counter topical antifungal medications that individuals who self-diagnose use to treat VVC.³

Causative organisms

Vulvovaginal yeast infections are caused by Candida species, a family of ubiquitous fungi that are a part of normal genitourinary and gastrointestinal flora.⁴ As such, these infections are commonly termed VVC. The presence of Candida species in the vagina without evidence of inflammation is not considered an infection but rather is more consistent with vaginal colonization. Inflammation in the setting of Candida species is what characterizes a true VVC infection.⁴

Candida albicans is responsible for the vast majority of VVC cases in the United States, with Candida glabrata accounting for most of the remaining infections.⁵ The majority of RVVC infections that are caused by C albicans are due to azole-sensitive strains (85%–95% of infections).²C glabrata, by contrast, is intrinsically resistant to azoles, which is thought primarily to be due to overexpression of drug efflux pumps that remove active drug from the cell.^6,7

Why does VVC reoccur?

The pathogenesis of RVVC is not well understood. Predisposing factors may include frequent or recent antibiotic use, poorly controlled diabetes, immunodeficiency, and other host factors. However, many cases of RVVC are idiopathic and no predisposing or underlying conditions are identified.⁷

The role of genetic factors in predisposing to or triggering RVVC is unclear and is an area of ongoing investigation.² Longitudinal DNA-typing studies suggest that recurrent disease is usually due to relapse from a persistent vaginal reservoir of organisms (that is, vaginal colonization) or endogenous reinfection with identical strains of susceptible C albicans.^8,9 Symptomatic VVC likely results when the symbiotic balance between yeast and the normal vaginal microbiota is disrupted (by either Candida species overgrowth or changes in host immune factors).² Less commonly, “recurrent” infections may in fact be due to azole-resistant Candida and non-Candida species.²

Clinical aspects and diagnosis of VVC

Signs and symptoms suggestive of VVC include vulvovaginal erythema, edema, vaginal discharge, vulvovaginal pruritus, and irritation. Given the lack of specificity of individual clinical findings in diagnosing VVC, or for distinguishing between other common causes of vaginitis (such as bacterial vaginosis and trichomoniasis), laboratory testing (that is, microscopy) should be performed in combination with a clinical exam in order to make a confident diagnosis of VVC.¹⁰ Self-diagnosis of VVC is inaccurate and is not recommended, as misdiagnosis and inappropriate treatment is cost ineffective, delays accurate diagnoses, and may contribute to growing azole resistance.

In patients with signs and symptoms of VVC, saline and potassium hydroxide microscopy should be performed.⁷ TABLE 1 summarizes other major diagnostic techniques for VVC.

Diagnostic considerations

Non-albicans Candida species, such as C glabrata, may be associated with minimally symptomatic or completely asymptomatic infections and may not be identified easily on wet mount as it does not form pseudohyphae or hyphae.¹¹ Therefore, culture and susceptibility or NAAT testing is highly recommended for patients who remain symptomatic and/or have a nondiagnostic microscopy and a normal vaginal pH.⁷

Treatment options

Prior to May 2022, there had been no drugs approved by the US Food and Drug Administration (FDA) to treat RVVC. The mainstay of treatment is long-term maintenance therapy to achieve mycologic remission (TABLE 2).

In general, recurrent episodes of VVC should be treated with a longer duration of therapy (for example, oral fluconazole 150 mg every 72 hours for a total of 3 doses or topical azole for 7–14 days).⁷ If recurrent maintenance/suppressive therapy is started, the induction phase should be longer as well, at least 10 to 14 days with a topical or oral azole followed by a 6-month or longer course of weekly oral or topical azole therapy (such as 6–12 months).^12,13

Patients with underlying immunodeficiency (such as poorly controlled diabetes, chronic corticosteroid treatment) may need prolonged courses of therapy. Correction of modifiable conditions and optimization of comorbidities should be prioritized—for example, optimized glucose control, weight loss, durable viral suppression, and so on. Of note, symptomatic VVC is more frequent among individuals with HIV and correlates with severity of immunodeficiency. Pharmacologic options for RVVC for individuals with HIV do not differ from standard recommendations.¹⁴

Fluconazole

Fluconazole is a safe, affordable, and convenient prescription oral medication that can be used for initial and maintenance/suppressive therapy.² Fluconazole levels in vaginal secretions remain at therapeutic concentrations for at least 72 hours after a 150-mg dose.¹⁵ Induction therapy consists of oral fluconazole 150 mg every 72 hours for a total of 3 doses, followed by a maintenance regimen of a once-weekly dose of oral fluconazole 150 mg for a total of 6 months. Unfortunately, up to 55% of patients will experience a relapse in symptoms.¹²

Routine liver function test monitoring is not indicated for fluconazole maintenance therapy, but it should be performed if patients are treated with daily or long-term alternative oral azole medications, such as ketoconazole and itraconazole.

During pregnancy, only topical azole therapy is recommended for use, given the potential risk for adverse fetal outcomes, such as spontaneous abortion and congenital malformations, with fetal exposure to oral fluconazole ingested by the pregnant person.¹⁶ Fluconazole is present in breast milk, but it is safe to use during lactation when used at recommended doses.¹⁷

Continue to: Options for fluconazole-resistant C albicans infection...

Options for fluconazole-resistant C albicans infection

Patients who have RVVC with frequent and/or prolonged use of fluconazole are at risk for developing azole-resistant isolates of C albicans.¹² For patients found to have azole-resistant infections, treatment options include increasing the azole dose based on isolate minimal inhibitory concentrations (MIC) to various antifungals, therapy with a non-fluconazole azole regimen, or switching to a different therapeutic drug class altogether.⁷

Options for non- albicans Candida species infection

Given the intrinsic resistance to azole therapy in some non-albicans Candida species (specifically C glabrata and Candida krusei), boric acid or nystatin regimens can be used. An induction course of vaginal boric acid is given as 600 mg per vagina daily for up to 14 days and is associated with a 70% rate of mycologic control.⁷ Boric acid is known to cause local irritation and dermatitis for both the patient and any sexual partners. If ingested orally, boric acid is associated with significant toxicity and even death.⁷

Vaginal nystatin also may be considered, with an induction course of 100,000 U for 14 days, with a similar regimen recommended for maintenance therapy. However, data are limited on maintenance regimens for RVVC due to non-albicans Candida species.²

Gentian violet

Gentian violet is a topical antiseptic agent that is available over the counter. Use of this agent is uncommon given the availability of highly effective azole-based therapy. Although useful due to its antipruritic properties, gentian violet can be messy to use and tends to stain clothing permanently.

Gentian violet use may be considered in cases of refractory RVVC with or without azole-resistant infections; it is applied as a 1% or 2% solution directly to affected areas for 10 to 14 days.¹⁸

Lactobacilli probiotics and dietary changes

Data that support the oral and/or vaginal use of probiotics that contain live lactobacilli are conflicting. In the absence of conclusive evidence to support probiotic use to treat and prevent RVVC, as well as variable quality of available products, use of these agents is not recommended.¹⁹

No controlled studies have evaluated the role of various diets in preventing RVVC; thus, no specific dietary changes are recommended.

Behavioral therapy

Available evidence does not support the treatment of sexual partners of patients with RVVC.⁷

Continue to: What’s new in treatment?...

Until recently, the main standard of care for RVVC has been oral fluconazole-based therapy. For patients whose symptoms do not respond to oral fluconazole therapy, oteseconazole is now available as a noninferior treatment option to fluconazole for both induction and maintenance therapy. Like other azoles, oteseconazole works by inhibiting a fungal enzyme (CYP51) that is essential in fungal cell membrane integrity and fungal growth.²⁰ Oteseconazole is a more selective inhibitor of the fungal CYP51 enzyme and has demonstrated excellent potency against Candida species in in vitro pharmacologic studies.²¹

In a phase 3 study that evaluated the safety and efficacy of oteseconazole in the treatment and prevention of RVVC, oteseconazole was found to be both safe and efficacious in both the induction and maintenance phases of treatment for RVVC.²⁰ In this trial, induction and maintenance with oteseconazole was compared with induction with fluconazole and placebo maintenance. Among the 185 participants with culture-verified RVVC, the oteseconazole regimen (n = 123) was associated with fewer recurrences of culture-verified VVC infections than was the fluconazole induction/placebo maintenance regimen (n = 62) during the 48-week maintenance phase of therapy (5% vs 42%).²⁰

Single- and dual-drug dosing regimens of oteseconazole are recommended based on previous trial data that compared safety and efficacy of oteseconazole versus fluconazole induction therapy and oteseconazole versus placebo maintenance therapy.²² However, widespread use of oteseconazole regimens are limited due to its higher costs and limited access to the drug outside of a research setting.²⁰

Single-drug induction therapy with oteseconazole consists of a single 600-mg oral dose on day 1 followed by a second dose of 450 mg orally on day 2. Starting on day 14, maintenance therapy starts with a single oral dose of 150 mg and is continued weekly for 11 weeks.²²

Dual-drug induction therapy consists of oral fluconazole 150 mg on days 1, 4, and 7 followed by daily dosing of oral oteseconazole 150 mg on days 14 through 20. Then, starting on day 28, weekly dosing of oral oteseconazole 150 mg is continued for 11 weeks.²²

Effects on pregnancy and lactation. Concerns of oteseconazole’s fetal teratogenicity are based on animal reproduction studies that reported ocular abnormalities from in utero exposure. Human data are insufficient to determine if oteseconazole is excreted in breast milk or what its effects are on milk production. Among breastfed infants whose mothers were exposed to oteseconazole during lactation, no adverse outcomes were reported, but follow up of oteseconazole-exposed infants was limited. ²² Therefore, use of oteseconazole among pregnant and/or lactating persons with RVVC is contraindicated at this time. The long-half life (approximately 138 days) of oteseconazole may preclude use among persons attempting pregnancy. ²²

Other therapies. The other common classes of antifungal therapy used in the treatment of RVVC include the polyenes (for example, amphotericin B) and echinocandins (such as caspofungin) drug classes. Emerging azole-resistance among Candida species has been recognized as a significant concern from the Centers for Disease Control and Prevention. ⁷ Echinocandins, which are generally better tolerated and have a lower adverse side effect profile than polyenes, are a promising therapeutic class, but currently they are limited to intravenous options. SCY-078, a novel oral echinocandin in development, has shown in vitro fungicidal activity against multiple albicans and non-albicans Candida species in pharmacokinetic/pharmacodynamic studies.²³

Continued development of alternative, non-azole-based therapies for Candida species is needed.●

CHICAGO – With more than 15 years of follow-up from two related trials, the best conduit for the second most important target vessel in coronary artery bypass grafting (CABG) appears to be resolved.

The radial artery (RA) graft is linked with a lower risk of major adverse cardiac events (MACE) relative to a saphenous vein (SV) or the free right internal thoracic artery (FRITA).

On the basis of these findings, “a radial artery graft should be considered in all isolated CABG operations unless there are contraindications,” reported David L. Hare, MBBS, director of research in the department of cardiology, University of Melbourne.

For the primary graft, there is general agreement that the left internal thoracic artery (LITA) is the first choice for the left anterior descending vessel, but the optimal graft for the second most important target has never been established, according to Dr. Hare.

Almost 25 years ago, two randomized controlled trials called RAPCO-RITA and RAPCO-SV were initiated to address the question. There is now 15 years of follow-up for both of the RAPCO (Radial Artery Patency and Clinical Outcomes) trials, which were presented together at the American Heart Association scientific sessions.
 

Two trials conducted simultaneously

The RAPCO-RITA trial randomized CABG patients less than 70 years of age (less than 60 years in those with diabetes) to grafting of the second target vessel with an RA or FRITA graft. The RAPCO-SV trial randomized those 70 years or older (60 years or older with diabetes) to an RA or SV graft.

The two primary endpoints were graft patency at 10 years and a composite MACE at 10 years. The assessment of the MACE endpoint, which consisted of cardiovascular mortality, acute myocardial infarction, and coronary revascularization, was later amended to include a comparison at 15 years.

Ten-year patency results, favoring the RA in both studies, were previously published in Circulation. In the new data presented at the meeting, the RA was associated with a significant reduction in MACE relative to the comparator graft in both studies.

“The main driver was a reduction in all-cause mortality,” Dr. Hare reported.

In RAPCO-RITA, 394 patients were randomized with follow-up data available for all but 1 patient at 15 years. Similarly, only 1 patient was lost to follow-up among the 225 randomized in RAPCO-SV. In both studies, baseline characteristics were well balanced.

MACE curves separate at 5 years

In RAPCO-RITA, the MACE survival curves began to separate at about 5 years and then gradually widened. By 15 years, the lower rate of MACE in the RA group (38% vs. 48%) translated into a 26% relative reduction (hazard ratio, 0.74; P = .04).

In RAPCO-SV, the pattern was similar, by 15 years, the rates of MACE were 60% and 73% for the RA and SV groups, respectively, translating into a 29% relative reduction (HR, 0.71; P = .04).

There was no heterogeneity in benefit across prespecified subgroups such as presence or absence of diabetes, gender, or age. In RAPCO-RITA, there was 8% absolute and 31% relative reduction in all-cause mortality. In RAPCO-SV, the absolute and relative reductions were 11% and 26%.

When the trial was initiated, Dr. Hare hypothesized that RITA would prove more durable than RA, so the outcome was not anticipated.

“This is the first randomized controlled trial program to address the question,” said Dr. Hare, who noted that there have been numerous retrospective and case control analyses that have produced mixed results in the past.
 

Discussant praises trial quality

The AHA-invited discussant, Marc Ruel, MD, chair of cardiac surgery, University of Ottawa (Ont.) Heart Institute, called these data “important,” and he congratulated Dr. Hare for conducting the first randomized trial to address the question about second graft durability.

However, he noted that, although the study was randomized, it was not blinded, and he questioned whether postoperative care, in particular, was similar. He also pointed out that the MACE rate seemed high, particularly among the older patients randomized in RAPCO-SV.

“All of the patients were referred to an independently run CABG rehab program that was quite separate from the trial but that provided identical mandated care,” Dr. Hare responded, indicating that there was no opportunity for differences in postprocedural management.

In the United States, the SV graft is often preferred on the basis of easy harvesting and handling characteristics, according to Dr. Hare, who estimated that fewer than 10% of the 200,000 CABG procedures performed in the United States employ the RA conduit for second target vessels. He believes the RAPCO trials data support a change.

“My personal view is [that, on the basis of] this data, given that it is from a controlled trial rather than from patient-level meta-analyses, all isolated CABG operations should be using a radial graft if it is suitable,” Dr. Hare said.

Dr. Hare reports financial relationships with Abbott, Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, CSL-Biotherapies, Lundbeck, Menarini, Merck, Novartis, Pfizer, Regeneron, Sanofi, Servier, and Vifor. Dr. Ruel reports financial relationships with Cryolife, Edwards, and Medtronic.

CHICAGO – With more than 15 years of follow-up from two related trials, the best conduit for the second most important target vessel in coronary artery bypass grafting (CABG) appears to be resolved.

The radial artery (RA) graft is linked with a lower risk of major adverse cardiac events (MACE) relative to a saphenous vein (SV) or the free right internal thoracic artery (FRITA).

On the basis of these findings, “a radial artery graft should be considered in all isolated CABG operations unless there are contraindications,” reported David L. Hare, MBBS, director of research in the department of cardiology, University of Melbourne.

For the primary graft, there is general agreement that the left internal thoracic artery (LITA) is the first choice for the left anterior descending vessel, but the optimal graft for the second most important target has never been established, according to Dr. Hare.

Almost 25 years ago, two randomized controlled trials called RAPCO-RITA and RAPCO-SV were initiated to address the question. There is now 15 years of follow-up for both of the RAPCO (Radial Artery Patency and Clinical Outcomes) trials, which were presented together at the American Heart Association scientific sessions.
 

Two trials conducted simultaneously

The RAPCO-RITA trial randomized CABG patients less than 70 years of age (less than 60 years in those with diabetes) to grafting of the second target vessel with an RA or FRITA graft. The RAPCO-SV trial randomized those 70 years or older (60 years or older with diabetes) to an RA or SV graft.

The two primary endpoints were graft patency at 10 years and a composite MACE at 10 years. The assessment of the MACE endpoint, which consisted of cardiovascular mortality, acute myocardial infarction, and coronary revascularization, was later amended to include a comparison at 15 years.

Ten-year patency results, favoring the RA in both studies, were previously published in Circulation. In the new data presented at the meeting, the RA was associated with a significant reduction in MACE relative to the comparator graft in both studies.

“The main driver was a reduction in all-cause mortality,” Dr. Hare reported.

In RAPCO-RITA, 394 patients were randomized with follow-up data available for all but 1 patient at 15 years. Similarly, only 1 patient was lost to follow-up among the 225 randomized in RAPCO-SV. In both studies, baseline characteristics were well balanced.

MACE curves separate at 5 years

In RAPCO-RITA, the MACE survival curves began to separate at about 5 years and then gradually widened. By 15 years, the lower rate of MACE in the RA group (38% vs. 48%) translated into a 26% relative reduction (hazard ratio, 0.74; P = .04).

In RAPCO-SV, the pattern was similar, by 15 years, the rates of MACE were 60% and 73% for the RA and SV groups, respectively, translating into a 29% relative reduction (HR, 0.71; P = .04).

There was no heterogeneity in benefit across prespecified subgroups such as presence or absence of diabetes, gender, or age. In RAPCO-RITA, there was 8% absolute and 31% relative reduction in all-cause mortality. In RAPCO-SV, the absolute and relative reductions were 11% and 26%.

When the trial was initiated, Dr. Hare hypothesized that RITA would prove more durable than RA, so the outcome was not anticipated.

“This is the first randomized controlled trial program to address the question,” said Dr. Hare, who noted that there have been numerous retrospective and case control analyses that have produced mixed results in the past.
 

Discussant praises trial quality

The AHA-invited discussant, Marc Ruel, MD, chair of cardiac surgery, University of Ottawa (Ont.) Heart Institute, called these data “important,” and he congratulated Dr. Hare for conducting the first randomized trial to address the question about second graft durability.

However, he noted that, although the study was randomized, it was not blinded, and he questioned whether postoperative care, in particular, was similar. He also pointed out that the MACE rate seemed high, particularly among the older patients randomized in RAPCO-SV.

“All of the patients were referred to an independently run CABG rehab program that was quite separate from the trial but that provided identical mandated care,” Dr. Hare responded, indicating that there was no opportunity for differences in postprocedural management.

In the United States, the SV graft is often preferred on the basis of easy harvesting and handling characteristics, according to Dr. Hare, who estimated that fewer than 10% of the 200,000 CABG procedures performed in the United States employ the RA conduit for second target vessels. He believes the RAPCO trials data support a change.

“My personal view is [that, on the basis of] this data, given that it is from a controlled trial rather than from patient-level meta-analyses, all isolated CABG operations should be using a radial graft if it is suitable,” Dr. Hare said.

Dr. Hare reports financial relationships with Abbott, Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, CSL-Biotherapies, Lundbeck, Menarini, Merck, Novartis, Pfizer, Regeneron, Sanofi, Servier, and Vifor. Dr. Ruel reports financial relationships with Cryolife, Edwards, and Medtronic.

CHICAGO – With more than 15 years of follow-up from two related trials, the best conduit for the second most important target vessel in coronary artery bypass grafting (CABG) appears to be resolved.

The radial artery (RA) graft is linked with a lower risk of major adverse cardiac events (MACE) relative to a saphenous vein (SV) or the free right internal thoracic artery (FRITA).

On the basis of these findings, “a radial artery graft should be considered in all isolated CABG operations unless there are contraindications,” reported David L. Hare, MBBS, director of research in the department of cardiology, University of Melbourne.

For the primary graft, there is general agreement that the left internal thoracic artery (LITA) is the first choice for the left anterior descending vessel, but the optimal graft for the second most important target has never been established, according to Dr. Hare.

Almost 25 years ago, two randomized controlled trials called RAPCO-RITA and RAPCO-SV were initiated to address the question. There is now 15 years of follow-up for both of the RAPCO (Radial Artery Patency and Clinical Outcomes) trials, which were presented together at the American Heart Association scientific sessions.
 

Two trials conducted simultaneously

The RAPCO-RITA trial randomized CABG patients less than 70 years of age (less than 60 years in those with diabetes) to grafting of the second target vessel with an RA or FRITA graft. The RAPCO-SV trial randomized those 70 years or older (60 years or older with diabetes) to an RA or SV graft.

The two primary endpoints were graft patency at 10 years and a composite MACE at 10 years. The assessment of the MACE endpoint, which consisted of cardiovascular mortality, acute myocardial infarction, and coronary revascularization, was later amended to include a comparison at 15 years.

Ten-year patency results, favoring the RA in both studies, were previously published in Circulation. In the new data presented at the meeting, the RA was associated with a significant reduction in MACE relative to the comparator graft in both studies.

“The main driver was a reduction in all-cause mortality,” Dr. Hare reported.

In RAPCO-RITA, 394 patients were randomized with follow-up data available for all but 1 patient at 15 years. Similarly, only 1 patient was lost to follow-up among the 225 randomized in RAPCO-SV. In both studies, baseline characteristics were well balanced.

MACE curves separate at 5 years

In RAPCO-RITA, the MACE survival curves began to separate at about 5 years and then gradually widened. By 15 years, the lower rate of MACE in the RA group (38% vs. 48%) translated into a 26% relative reduction (hazard ratio, 0.74; P = .04).

In RAPCO-SV, the pattern was similar, by 15 years, the rates of MACE were 60% and 73% for the RA and SV groups, respectively, translating into a 29% relative reduction (HR, 0.71; P = .04).

There was no heterogeneity in benefit across prespecified subgroups such as presence or absence of diabetes, gender, or age. In RAPCO-RITA, there was 8% absolute and 31% relative reduction in all-cause mortality. In RAPCO-SV, the absolute and relative reductions were 11% and 26%.

When the trial was initiated, Dr. Hare hypothesized that RITA would prove more durable than RA, so the outcome was not anticipated.

“This is the first randomized controlled trial program to address the question,” said Dr. Hare, who noted that there have been numerous retrospective and case control analyses that have produced mixed results in the past.
 

Discussant praises trial quality

The AHA-invited discussant, Marc Ruel, MD, chair of cardiac surgery, University of Ottawa (Ont.) Heart Institute, called these data “important,” and he congratulated Dr. Hare for conducting the first randomized trial to address the question about second graft durability.

However, he noted that, although the study was randomized, it was not blinded, and he questioned whether postoperative care, in particular, was similar. He also pointed out that the MACE rate seemed high, particularly among the older patients randomized in RAPCO-SV.

“All of the patients were referred to an independently run CABG rehab program that was quite separate from the trial but that provided identical mandated care,” Dr. Hare responded, indicating that there was no opportunity for differences in postprocedural management.

In the United States, the SV graft is often preferred on the basis of easy harvesting and handling characteristics, according to Dr. Hare, who estimated that fewer than 10% of the 200,000 CABG procedures performed in the United States employ the RA conduit for second target vessels. He believes the RAPCO trials data support a change.

“My personal view is [that, on the basis of] this data, given that it is from a controlled trial rather than from patient-level meta-analyses, all isolated CABG operations should be using a radial graft if it is suitable,” Dr. Hare said.

Dr. Hare reports financial relationships with Abbott, Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, CSL-Biotherapies, Lundbeck, Menarini, Merck, Novartis, Pfizer, Regeneron, Sanofi, Servier, and Vifor. Dr. Ruel reports financial relationships with Cryolife, Edwards, and Medtronic.

In the first transplant of a genetically altered pig heart into a human in January, initial unexpected, prolonged ECG readings apparently did not affect the heart’s function, although the organ suddenly began to fail at day 50.

A study of these ECG changes, scheduled for presentation by Calvin Kagan, MD, and colleagues at the American Heart Association scientific sessions, offers insight into this novel operation.

As widely reported, the patient, 57-year-old David Bennett of Maryland, had end-stage heart disease and was a poor candidate for a ventricular assist device and was ineligible for a human heart, when he consented to be the first human to be transplanted with a pig heart that had a number of genes added or subtracted with the goal, in part, to prevent rejection.

University of Maryland Medical Center

The heart initially performed well after it was transplanted in an operation at the University of Maryland School of Medicine (UMSOM) in Baltimore on Jan. 7, but failed in the second month, and Mr. Bennett died on March 9.

The Food and Drug Administration had granted emergency authorization for the surgery through its expanded access (compassionate use) program, coauthor Muhammad Mohiuddin, MD, said in an interview.

“We have learned a lot and hope we can do more,” said Dr. Mohiuddin, scientific and program director of the cardiac xenotransplantation program at UMSOM.

“Suddenly on day 50, the heart started to get thicker and was not relaxing enough,” explained senior author Timm-Michael Dickfeld, MD, PhD, director of electrophysiology research at UMSOM. A biopsy revealed substantial buildup of interstitial fluid that restricted movement. The fluid was replaced by fibrous tissue, leading to irreversible damage.

Persistent, prolonged ECG parameters

In the heart from a genetically modified pig, three genes associated with antibody-mediated rejection and a gene associated with pig heart tissue growth had been inactivated and six human genes associated with immune acceptance had been added. The donor pig was supplied by Revivicor (Blacksburg, Va.).

The patient’s immunosuppressant therapy included an experimental antirejection medication (Kiniksa Pharmaceuticals; Lexington, Mass.).  

The patient had daily 12-lead ECGs after the transplant.

In prior research using a pig heart transplanted into a pig body, ECG readings showed a short PR interval (50-120 ms), short QRS duration (70-90 ms) and short QT intervals (260-380 ms).

However, in the transplanted xenograft heart, the initial ECG readings showed a longer PR interval of 190 ms, QRS duration of 138 ms, and QT of 538 ms.

Prolonged intrinsic PR intervals remained stable during the postoperative course (210 ms, range 142-246 ms).

QRS duration also remained prolonged (145 ms, range 116-192 ms), but shortened during the postoperative course (days 21-40 vs. 41-60: 148 ms vs. 132 ms; P < .001).

Increased QT persisted (509 ms, range 384-650 ms) with dynamic fluctuations. The shortest QT duration was observed on day 14 (P < .001).

“In a human heart, when those parameters get longer, this can indicate signs of electrical or myocardial disease,” Dr. Dickfeld explained in a press release from the AHA.

“The QRS duration may prolong when, for example, the muscle and the electrical system itself is diseased, and that is why it takes a long time for electricity to travel from cell to cell and travel from one side of the heart to the other,” he said.

“In the human heart, the QT duration is correlated with an increased risk of abnormal heart rhythms,” he noted. “In our patient, it was concerning that the QT measure was prolonged. While we saw some fluctuations, the QT measure remained prolonged during the whole 61 days.”
 

‘Interesting study’

Two experts who were not involved with this research weighed in on the findings for this news organization.

“This very interesting study reinforces the difficulties in xenotransplantation, and the need for more research to be able to safely monitor recipients, as baseline values are unknown,” said Edward Vigmond, PhD.

Dr. Vigmond, from the Electrophysiology and Heart Modeling Institute at the University of Bordeaux in France, published a related study about a model of translation of pig to human electrophysiology.

The ECG is sensitive to the electrical activation pattern of the heart, along with the cellular and tissue electrical properties, he noted.

“Although pigs and humans may be similar in size, there are many differences between them,” Dr. Vigmond observed, including “the extent of the rapid conduction system of the heart, the number of nuclei in the muscle cells, the proteins in the cell membrane which control electrical activity, the orientation of the heart and thorax, and the handling of calcium inside the cell.”

“On top of this,” he continued, “donor hearts are denervated, so they no longer respond to nervous modulation, and circulating compounds in the blood which affect heart function vary between species.

“With all these differences, it is not surprising that the ECG of a pig heart transplanted into a human resembles neither that of a human nor that of a pig,” Dr. Vigmond said.

“It is interesting to note that the humanized-gene-edited porcine heart exhibited abnormal electrical conduction parameters from the outset,” said Mandeep R. Mehra, MD.

“Whether these changes were due to the gene modifications (i.e., already inherent in the pig ECG prior to transplant) or a result of the transplant operation challenges (such as the ischemia reperfusion injury and early immunological interactions) is uncertain and should be clarified,” said Dr. Mehra, of Harvard Medical School and Brigham and Women’s Medicine in Boston.

“Knowledge of these changes is important to determine whether a simple ECG parameter may be useful to identify changes that could indicate developing pathology,” Dr. Mehra added.

“In the older days of human transplantation, we often used ECG parameters such as a change in voltage amplitude to identify signals for rejection,” he continued. “Whether such changes occurred in this case could be another interesting aspect to explore as changes occurred in cardiac performance in response to the physiological and pathological challenges that were encountered in this sentinel case.”

The study authors reported having no outside sources of funding.
 

A version of this article first appeared on Medscape.com.

In the first transplant of a genetically altered pig heart into a human in January, initial unexpected, prolonged ECG readings apparently did not affect the heart’s function, although the organ suddenly began to fail at day 50.

A study of these ECG changes, scheduled for presentation by Calvin Kagan, MD, and colleagues at the American Heart Association scientific sessions, offers insight into this novel operation.

As widely reported, the patient, 57-year-old David Bennett of Maryland, had end-stage heart disease and was a poor candidate for a ventricular assist device and was ineligible for a human heart, when he consented to be the first human to be transplanted with a pig heart that had a number of genes added or subtracted with the goal, in part, to prevent rejection.

University of Maryland Medical Center

The heart initially performed well after it was transplanted in an operation at the University of Maryland School of Medicine (UMSOM) in Baltimore on Jan. 7, but failed in the second month, and Mr. Bennett died on March 9.

The Food and Drug Administration had granted emergency authorization for the surgery through its expanded access (compassionate use) program, coauthor Muhammad Mohiuddin, MD, said in an interview.

“We have learned a lot and hope we can do more,” said Dr. Mohiuddin, scientific and program director of the cardiac xenotransplantation program at UMSOM.

“Suddenly on day 50, the heart started to get thicker and was not relaxing enough,” explained senior author Timm-Michael Dickfeld, MD, PhD, director of electrophysiology research at UMSOM. A biopsy revealed substantial buildup of interstitial fluid that restricted movement. The fluid was replaced by fibrous tissue, leading to irreversible damage.

Persistent, prolonged ECG parameters

In the heart from a genetically modified pig, three genes associated with antibody-mediated rejection and a gene associated with pig heart tissue growth had been inactivated and six human genes associated with immune acceptance had been added. The donor pig was supplied by Revivicor (Blacksburg, Va.).

The patient’s immunosuppressant therapy included an experimental antirejection medication (Kiniksa Pharmaceuticals; Lexington, Mass.).  

The patient had daily 12-lead ECGs after the transplant.

In prior research using a pig heart transplanted into a pig body, ECG readings showed a short PR interval (50-120 ms), short QRS duration (70-90 ms) and short QT intervals (260-380 ms).

However, in the transplanted xenograft heart, the initial ECG readings showed a longer PR interval of 190 ms, QRS duration of 138 ms, and QT of 538 ms.

Prolonged intrinsic PR intervals remained stable during the postoperative course (210 ms, range 142-246 ms).

QRS duration also remained prolonged (145 ms, range 116-192 ms), but shortened during the postoperative course (days 21-40 vs. 41-60: 148 ms vs. 132 ms; P < .001).

Increased QT persisted (509 ms, range 384-650 ms) with dynamic fluctuations. The shortest QT duration was observed on day 14 (P < .001).

“In a human heart, when those parameters get longer, this can indicate signs of electrical or myocardial disease,” Dr. Dickfeld explained in a press release from the AHA.

“The QRS duration may prolong when, for example, the muscle and the electrical system itself is diseased, and that is why it takes a long time for electricity to travel from cell to cell and travel from one side of the heart to the other,” he said.

“In the human heart, the QT duration is correlated with an increased risk of abnormal heart rhythms,” he noted. “In our patient, it was concerning that the QT measure was prolonged. While we saw some fluctuations, the QT measure remained prolonged during the whole 61 days.”
 

‘Interesting study’

Two experts who were not involved with this research weighed in on the findings for this news organization.

“This very interesting study reinforces the difficulties in xenotransplantation, and the need for more research to be able to safely monitor recipients, as baseline values are unknown,” said Edward Vigmond, PhD.

Dr. Vigmond, from the Electrophysiology and Heart Modeling Institute at the University of Bordeaux in France, published a related study about a model of translation of pig to human electrophysiology.

The ECG is sensitive to the electrical activation pattern of the heart, along with the cellular and tissue electrical properties, he noted.

“Although pigs and humans may be similar in size, there are many differences between them,” Dr. Vigmond observed, including “the extent of the rapid conduction system of the heart, the number of nuclei in the muscle cells, the proteins in the cell membrane which control electrical activity, the orientation of the heart and thorax, and the handling of calcium inside the cell.”

“On top of this,” he continued, “donor hearts are denervated, so they no longer respond to nervous modulation, and circulating compounds in the blood which affect heart function vary between species.

“With all these differences, it is not surprising that the ECG of a pig heart transplanted into a human resembles neither that of a human nor that of a pig,” Dr. Vigmond said.

“It is interesting to note that the humanized-gene-edited porcine heart exhibited abnormal electrical conduction parameters from the outset,” said Mandeep R. Mehra, MD.

“Whether these changes were due to the gene modifications (i.e., already inherent in the pig ECG prior to transplant) or a result of the transplant operation challenges (such as the ischemia reperfusion injury and early immunological interactions) is uncertain and should be clarified,” said Dr. Mehra, of Harvard Medical School and Brigham and Women’s Medicine in Boston.

“Knowledge of these changes is important to determine whether a simple ECG parameter may be useful to identify changes that could indicate developing pathology,” Dr. Mehra added.

“In the older days of human transplantation, we often used ECG parameters such as a change in voltage amplitude to identify signals for rejection,” he continued. “Whether such changes occurred in this case could be another interesting aspect to explore as changes occurred in cardiac performance in response to the physiological and pathological challenges that were encountered in this sentinel case.”

The study authors reported having no outside sources of funding.
 

A version of this article first appeared on Medscape.com.

In the first transplant of a genetically altered pig heart into a human in January, initial unexpected, prolonged ECG readings apparently did not affect the heart’s function, although the organ suddenly began to fail at day 50.

A study of these ECG changes, scheduled for presentation by Calvin Kagan, MD, and colleagues at the American Heart Association scientific sessions, offers insight into this novel operation.

As widely reported, the patient, 57-year-old David Bennett of Maryland, had end-stage heart disease and was a poor candidate for a ventricular assist device and was ineligible for a human heart, when he consented to be the first human to be transplanted with a pig heart that had a number of genes added or subtracted with the goal, in part, to prevent rejection.

University of Maryland Medical Center

The heart initially performed well after it was transplanted in an operation at the University of Maryland School of Medicine (UMSOM) in Baltimore on Jan. 7, but failed in the second month, and Mr. Bennett died on March 9.

The Food and Drug Administration had granted emergency authorization for the surgery through its expanded access (compassionate use) program, coauthor Muhammad Mohiuddin, MD, said in an interview.

“We have learned a lot and hope we can do more,” said Dr. Mohiuddin, scientific and program director of the cardiac xenotransplantation program at UMSOM.

“Suddenly on day 50, the heart started to get thicker and was not relaxing enough,” explained senior author Timm-Michael Dickfeld, MD, PhD, director of electrophysiology research at UMSOM. A biopsy revealed substantial buildup of interstitial fluid that restricted movement. The fluid was replaced by fibrous tissue, leading to irreversible damage.

Persistent, prolonged ECG parameters

In the heart from a genetically modified pig, three genes associated with antibody-mediated rejection and a gene associated with pig heart tissue growth had been inactivated and six human genes associated with immune acceptance had been added. The donor pig was supplied by Revivicor (Blacksburg, Va.).

The patient’s immunosuppressant therapy included an experimental antirejection medication (Kiniksa Pharmaceuticals; Lexington, Mass.).  

The patient had daily 12-lead ECGs after the transplant.

In prior research using a pig heart transplanted into a pig body, ECG readings showed a short PR interval (50-120 ms), short QRS duration (70-90 ms) and short QT intervals (260-380 ms).

However, in the transplanted xenograft heart, the initial ECG readings showed a longer PR interval of 190 ms, QRS duration of 138 ms, and QT of 538 ms.

Prolonged intrinsic PR intervals remained stable during the postoperative course (210 ms, range 142-246 ms).

QRS duration also remained prolonged (145 ms, range 116-192 ms), but shortened during the postoperative course (days 21-40 vs. 41-60: 148 ms vs. 132 ms; P < .001).

Increased QT persisted (509 ms, range 384-650 ms) with dynamic fluctuations. The shortest QT duration was observed on day 14 (P < .001).

“In a human heart, when those parameters get longer, this can indicate signs of electrical or myocardial disease,” Dr. Dickfeld explained in a press release from the AHA.

“The QRS duration may prolong when, for example, the muscle and the electrical system itself is diseased, and that is why it takes a long time for electricity to travel from cell to cell and travel from one side of the heart to the other,” he said.

“In the human heart, the QT duration is correlated with an increased risk of abnormal heart rhythms,” he noted. “In our patient, it was concerning that the QT measure was prolonged. While we saw some fluctuations, the QT measure remained prolonged during the whole 61 days.”
 

‘Interesting study’

Two experts who were not involved with this research weighed in on the findings for this news organization.

“This very interesting study reinforces the difficulties in xenotransplantation, and the need for more research to be able to safely monitor recipients, as baseline values are unknown,” said Edward Vigmond, PhD.

Dr. Vigmond, from the Electrophysiology and Heart Modeling Institute at the University of Bordeaux in France, published a related study about a model of translation of pig to human electrophysiology.

The ECG is sensitive to the electrical activation pattern of the heart, along with the cellular and tissue electrical properties, he noted.

“Although pigs and humans may be similar in size, there are many differences between them,” Dr. Vigmond observed, including “the extent of the rapid conduction system of the heart, the number of nuclei in the muscle cells, the proteins in the cell membrane which control electrical activity, the orientation of the heart and thorax, and the handling of calcium inside the cell.”

“On top of this,” he continued, “donor hearts are denervated, so they no longer respond to nervous modulation, and circulating compounds in the blood which affect heart function vary between species.

“With all these differences, it is not surprising that the ECG of a pig heart transplanted into a human resembles neither that of a human nor that of a pig,” Dr. Vigmond said.

“It is interesting to note that the humanized-gene-edited porcine heart exhibited abnormal electrical conduction parameters from the outset,” said Mandeep R. Mehra, MD.

“Whether these changes were due to the gene modifications (i.e., already inherent in the pig ECG prior to transplant) or a result of the transplant operation challenges (such as the ischemia reperfusion injury and early immunological interactions) is uncertain and should be clarified,” said Dr. Mehra, of Harvard Medical School and Brigham and Women’s Medicine in Boston.

“Knowledge of these changes is important to determine whether a simple ECG parameter may be useful to identify changes that could indicate developing pathology,” Dr. Mehra added.

“In the older days of human transplantation, we often used ECG parameters such as a change in voltage amplitude to identify signals for rejection,” he continued. “Whether such changes occurred in this case could be another interesting aspect to explore as changes occurred in cardiac performance in response to the physiological and pathological challenges that were encountered in this sentinel case.”

The study authors reported having no outside sources of funding.
 

A version of this article first appeared on Medscape.com.

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

OBG Management Board Member Linda Bradley, MD, recently attended the Global Congress on Hysteroscopy in Malaga, Spain, May 26-27, 2022, organized by the Global Community on Hysteroscopy, and co-authored the article, “Implementation of office hysteroscopy for the evaluation and treatment of intrauterine pathology” in Obstetrics and Gynecology.¹ She is the Director of the Center for Menstrual Disorders, Fibroids and Hysteroscopic Services at Cleveland Clinic in Cleveland, Ohio. OBG Management recently caught up with her to ask about her perspectives on the expanded use of hysteroscopy in obstetrics and gynecology, and her call to “end blind endometrial sampling.”

OBG Management: What are the drawbacks of dilation and curettage?

Linda Bradley, MD: The standard in ObGyn for many years has been our reliance on the blind dilation and curettage (D&C)—it has been the mainstay for evaluation of the endometrial cavity. We know that it has risks, but most importantly, the procedure has low sensitivity for detecting focal pathology. This basic lack of confirmation of lesions makes a diagnosis impossible and patients are challenged in getting adequate treatment, and will not, since they may not know what options they have for the treatment of intrauterine pathology. 

Because it is a “blind procedure,” done without looking, we don’t know the endpoints, such as when is the procedure completed, how do we know we removed all of the lesions? Let’s look at our colleagues, like GI and colorectal physicians. If a patient presents with rectal bleeding, we would perform an exam, followed by either a colonoscopy or sigmoidoscopy. If a patient were vomiting up blood, a gastroenterologist would perform an upper endoscopy, look with a tube to see if there is an ulcer or something else as a source of the bleeding. If a patient were bleeding from the bladder, a urologist would use  a cystoscope for direct inspection. 

Unfortunately for gynecologists, only about 15% to 25% of us will use hysteroscopy as a diagnostic method²—a method that has excellent sensitivity in detecting endocervical disease, intrauterine disease, and proximal tubal pathology. Compared with blind curettage, we can visualize the cavity; we can sample the cavity directly; we can determine what the patient has and determine the proper surgical procedure, medical therapy, or reassurance that a patient may be offered. We often are looking at focal lesions, lesions in the uterine cavity that could be cancer, so we can make a diagnosis. Or we may be looking at small things, like endometrial hyperplasia, endocervical or endometrial polyps, retained products of conception, or fibroids. We can look at uterine pathology as well as anatomic issues and malformations—such as bicornuate or septate uterus. 

I actually say, “My hysteroscope is my stethoscope” because it allows us to evaluate for many things. The beauty of the new office hysteroscopes is that they are miniaturized. Doctors now have the ability to use reusable devices that are as small as 3 millimeters. There are disposable ones that are up to  3.5 to 4 millimeters in size. Gynecologists have the options to choose from reusuable rigid or flexible hysteroscopes or completely disposable devices. So, truly, we now should not have an excuse for evaluating a woman’s anatomy, especially for bleeding. We should no longer rely, as we have for the last century or more, just on blind sampling, because we miss focal lesions. 

OBG Management: When was the hysteroscope first introduced into the field?

Dr. Bradley: The technology employed in hysteroscopy has been around really since the last 150+ years, introduced by Dr. Pantaleoni. We just have not embraced its usefulness in our clinical practice for many years. Today, about 15% to 25% of gynecologists practicing in the United States are performing hysteroscopy in the office.¹

OBG Management: How does using hysteroscopy contribute to better patient outcomes?

Dr. Bradley: We can get a more accurate diagnosis—fewer false-negatives and a high degree of sensitivity in detecting focal lesions. With D&C, much focal pathology can be left behind. In a 2001 study, 105 symptomatic postmenopausal women with bleeding and thickened lining of the uterus greater than  5 mm on ultrasound underwent blind D&C. They found that 80% of the women had intracavitary lesions and 90% had focal lesions. In fact, 87% of the patients with focal lesions still had residual pathology after the blind D&C.³ The D&C procedure missed 58% of polyps, 50% of endometrial hyperplasia, 60% of cases of complex atypical hyperplasia, and even 11% of endometrial cancers. So these numbers are just not very good. Direct inspection of the uterus, with uninterrupted visualization through hysteroscopy, with removal of lesions under direct visualization, should be our goal. 

Blind sampling also poses greater risk for things like perforation. In addition, you not only can miss lesions by just scraping the endometrium, D&C also can leave lesions just floating around in the uterine cavity, with those lesions never retrieved. With office hysteroscopy, the physician can be more successful in treating a condition because once you see what is going on in the uterine cavity, you can say, “Okay, I can fix this with a surgical procedure. What instruments do I need? How much time is it going to take? Is this a straightforward case? Is it more complicated? Do I let an intern do the case? Is this for a more senior resident or fellow?” So I think it helps to direct the next steps for surgical management and even medical management, which also could be what we call “one-stop shopping.” For instance, for directed biopsies for removal of small polyps, for patients that can tolerate the procedure a little longer, the diagnostic hysteroscopy then becomes a management, an operative procedure, that really, for myself, can be done in the office. Removal of larger fibroids, because of fluid management and other concerns, would not be done in the office. Most patients tolerate office procedures, but it also depends on a patient’s weight, and her ability to relax during the procedure. 

The ultimate goal for hysteroscopy is a minimum of diagnosis, meaning in less than 2, 3 minutes, you can look inside the uterus. Our devices are 3 millimeters in size; I tell my patients, it’s the size of “a piece of spaghetti or pasta,” and we will just take a look. If we see a polyp, okay, if your office is not equipped, because then you need a different type of equipment for removal, then take her to the operating room. The patient would be under brief anesthesia and go home an hour or 2 later. So really, for physicians, we just need to embrace the technology to make a diagnosis, just look, and then from there decide what is next.

OBG Management: What techniques do you use to minimize or eliminate patient discomfort during hysteroscopy?...

OBG Management: What techniques do you use to minimize or eliminate patient discomfort during hysteroscopy?

Dr. Bradley: I think first is always be patient-centric. Let patients be prepared for the procedure. We have reading materials; our nurses explain the procedure. In the office, I try to prepare the patient for success. I let her know what is going on. A friend, family member can be with her. We have a nurse that understands the procedure; she explains it well. We have a type of bed that allows the patients’ legs to rest more comfortably in the stirrups—a leg rest kind of stirrup. We use a heating pad. Some patients like to hear music. Some patients like to have aromatherapy. We are quick and efficient, and typically just talk to the patient throughout the procedure. Although some patients don’t like this explanatory, “talkative” approach—they say, “Dr. Bradley, just do the procedure. I don’t want to know you are touching the cervix. I don’t want to know that you’re prepping. Just do it.” 

But I like what we called it when I was growing up: vocal-local (talk to your patient and explain as you proceed). It’s like local anesthesia. For these procedures in the office you usually do not have to use numbing medicine or a paracervical block. Look at the patient’s age, number of years in menopause, whether or not  she has delivered vaginally, and what her cervix looks like. Does she have a sexually transmitted infection or pelvic inflammatory disease? Sometimes we will use misoprostol, my personal preference is oral, but there are data to suggest that vaginal can be of help.⁴ We suggest Motrin, Tylenol an hour or 2 before, and we always want patients to not come in on an empty stomach. There is also the option of primrose oil, a supplement, that patients buy at the drug store in the vitamin section. It’s used for cervical softening. It is taken orally.^5-7

If they want, patients can watch a video—similar to watching childbirth videos when I used to deliver babies. At some point we started putting mirrors where women could see their efforts of pushing a baby out, as it might give them more willpower to push harder. Some people don’t want to look. But the majority of women will do well in this setting. I do have a small number of women that just say, “I can’t do this in the office,” and so in those cases, they can go to the operating room. But the main idea is, even in an operating room, you are not just doing a D&C. You are still going to look inside with a hysteroscope and have a great panoramic view of what is going on, and remove a lesion with an instrument while you watch. Not a process of looking with the hysteroscope, scraping with a curettage, and thinking that you are complete. Targeted removal of focal lesions under continuous visualization is the goal.

OBG Management: Can you describe the goals of the consensus document on ending blind sampling co-created by the European Society of Gynecologic Endoscopy, AAGL, and the Global Community on Hysteroscopy? 

Dr. Bradley: Our goal for this year is to get a systematic review and guidelines paper written that speaks to what we have just talked about. We want to have as many articles about why blind sampling is not beneficial, with too many misses, and now we have new technology available. We want to speak to physicians to solve the conundrum of bleeding, with equivocal ultrasounds, equivocal saline infusion, sonograms, equivocal MRIs—be able to take a look. Let’s come up to speed like our other colleagues in other specialties that “look.” A systematic review guideline document will provide the evidence that blind  D&C is fraught with problems and how often we miss disease and its inherent risk.

We need to, by itself, for most of our patients, abandon D&C because we have too many missed diagnoses. As doctors we have to be lifelong learners. There was no robot back in the day. We were not able to do laparoscopic hysterectomies, there were no MRIs. I remember in our city, there was one CT scan. We just did not have a lot of technology. The half-life of medical knowledge used to be decades—you graduated in the ‘60s, you could be a great gynecologist for the next  30 years because there was not that much going on. When I finished in the mid to late ‘80s, there was no hysteroscopy training. But I have come to see its value, the science  behind it.

So what I say to doctors is, “We learn so many new things, we shouldn’t get stuck in just saying, ‘I didn’t do this when I was in training.’” And if your thought is, “Oh, in my practice, I don’t have that many cases,” you still need to be able to know who in your community can be a resource to your patients. As Maya Angelou says, “When you know better, you should do better.” And that’s where I am now—to be a lifelong learner, and just  do it.

Lastly, patient influence is very important. If patients ask, “How are you going to do the procedure?” it’s a driver for change. By utilizing hysteroscopy in the evaluation of the intrauterine cavity, we have the opportunity to change the face of evaluation and treatment for abnormal uterine bleeding.●

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

OBG Management Board Member Linda Bradley, MD, recently attended the Global Congress on Hysteroscopy in Malaga, Spain, May 26-27, 2022, organized by the Global Community on Hysteroscopy, and co-authored the article, “Implementation of office hysteroscopy for the evaluation and treatment of intrauterine pathology” in Obstetrics and Gynecology.¹ She is the Director of the Center for Menstrual Disorders, Fibroids and Hysteroscopic Services at Cleveland Clinic in Cleveland, Ohio. OBG Management recently caught up with her to ask about her perspectives on the expanded use of hysteroscopy in obstetrics and gynecology, and her call to “end blind endometrial sampling.”

OBG Management: What are the drawbacks of dilation and curettage?

Linda Bradley, MD: The standard in ObGyn for many years has been our reliance on the blind dilation and curettage (D&C)—it has been the mainstay for evaluation of the endometrial cavity. We know that it has risks, but most importantly, the procedure has low sensitivity for detecting focal pathology. This basic lack of confirmation of lesions makes a diagnosis impossible and patients are challenged in getting adequate treatment, and will not, since they may not know what options they have for the treatment of intrauterine pathology. 

Because it is a “blind procedure,” done without looking, we don’t know the endpoints, such as when is the procedure completed, how do we know we removed all of the lesions? Let’s look at our colleagues, like GI and colorectal physicians. If a patient presents with rectal bleeding, we would perform an exam, followed by either a colonoscopy or sigmoidoscopy. If a patient were vomiting up blood, a gastroenterologist would perform an upper endoscopy, look with a tube to see if there is an ulcer or something else as a source of the bleeding. If a patient were bleeding from the bladder, a urologist would use  a cystoscope for direct inspection. 

Unfortunately for gynecologists, only about 15% to 25% of us will use hysteroscopy as a diagnostic method²—a method that has excellent sensitivity in detecting endocervical disease, intrauterine disease, and proximal tubal pathology. Compared with blind curettage, we can visualize the cavity; we can sample the cavity directly; we can determine what the patient has and determine the proper surgical procedure, medical therapy, or reassurance that a patient may be offered. We often are looking at focal lesions, lesions in the uterine cavity that could be cancer, so we can make a diagnosis. Or we may be looking at small things, like endometrial hyperplasia, endocervical or endometrial polyps, retained products of conception, or fibroids. We can look at uterine pathology as well as anatomic issues and malformations—such as bicornuate or septate uterus. 

I actually say, “My hysteroscope is my stethoscope” because it allows us to evaluate for many things. The beauty of the new office hysteroscopes is that they are miniaturized. Doctors now have the ability to use reusable devices that are as small as 3 millimeters. There are disposable ones that are up to  3.5 to 4 millimeters in size. Gynecologists have the options to choose from reusuable rigid or flexible hysteroscopes or completely disposable devices. So, truly, we now should not have an excuse for evaluating a woman’s anatomy, especially for bleeding. We should no longer rely, as we have for the last century or more, just on blind sampling, because we miss focal lesions. 

OBG Management: When was the hysteroscope first introduced into the field?

Dr. Bradley: The technology employed in hysteroscopy has been around really since the last 150+ years, introduced by Dr. Pantaleoni. We just have not embraced its usefulness in our clinical practice for many years. Today, about 15% to 25% of gynecologists practicing in the United States are performing hysteroscopy in the office.¹

OBG Management: How does using hysteroscopy contribute to better patient outcomes?

Dr. Bradley: We can get a more accurate diagnosis—fewer false-negatives and a high degree of sensitivity in detecting focal lesions. With D&C, much focal pathology can be left behind. In a 2001 study, 105 symptomatic postmenopausal women with bleeding and thickened lining of the uterus greater than  5 mm on ultrasound underwent blind D&C. They found that 80% of the women had intracavitary lesions and 90% had focal lesions. In fact, 87% of the patients with focal lesions still had residual pathology after the blind D&C.³ The D&C procedure missed 58% of polyps, 50% of endometrial hyperplasia, 60% of cases of complex atypical hyperplasia, and even 11% of endometrial cancers. So these numbers are just not very good. Direct inspection of the uterus, with uninterrupted visualization through hysteroscopy, with removal of lesions under direct visualization, should be our goal. 

Blind sampling also poses greater risk for things like perforation. In addition, you not only can miss lesions by just scraping the endometrium, D&C also can leave lesions just floating around in the uterine cavity, with those lesions never retrieved. With office hysteroscopy, the physician can be more successful in treating a condition because once you see what is going on in the uterine cavity, you can say, “Okay, I can fix this with a surgical procedure. What instruments do I need? How much time is it going to take? Is this a straightforward case? Is it more complicated? Do I let an intern do the case? Is this for a more senior resident or fellow?” So I think it helps to direct the next steps for surgical management and even medical management, which also could be what we call “one-stop shopping.” For instance, for directed biopsies for removal of small polyps, for patients that can tolerate the procedure a little longer, the diagnostic hysteroscopy then becomes a management, an operative procedure, that really, for myself, can be done in the office. Removal of larger fibroids, because of fluid management and other concerns, would not be done in the office. Most patients tolerate office procedures, but it also depends on a patient’s weight, and her ability to relax during the procedure. 

The ultimate goal for hysteroscopy is a minimum of diagnosis, meaning in less than 2, 3 minutes, you can look inside the uterus. Our devices are 3 millimeters in size; I tell my patients, it’s the size of “a piece of spaghetti or pasta,” and we will just take a look. If we see a polyp, okay, if your office is not equipped, because then you need a different type of equipment for removal, then take her to the operating room. The patient would be under brief anesthesia and go home an hour or 2 later. So really, for physicians, we just need to embrace the technology to make a diagnosis, just look, and then from there decide what is next.

OBG Management: What techniques do you use to minimize or eliminate patient discomfort during hysteroscopy?...

OBG Management: What techniques do you use to minimize or eliminate patient discomfort during hysteroscopy?

Dr. Bradley: I think first is always be patient-centric. Let patients be prepared for the procedure. We have reading materials; our nurses explain the procedure. In the office, I try to prepare the patient for success. I let her know what is going on. A friend, family member can be with her. We have a nurse that understands the procedure; she explains it well. We have a type of bed that allows the patients’ legs to rest more comfortably in the stirrups—a leg rest kind of stirrup. We use a heating pad. Some patients like to hear music. Some patients like to have aromatherapy. We are quick and efficient, and typically just talk to the patient throughout the procedure. Although some patients don’t like this explanatory, “talkative” approach—they say, “Dr. Bradley, just do the procedure. I don’t want to know you are touching the cervix. I don’t want to know that you’re prepping. Just do it.” 

But I like what we called it when I was growing up: vocal-local (talk to your patient and explain as you proceed). It’s like local anesthesia. For these procedures in the office you usually do not have to use numbing medicine or a paracervical block. Look at the patient’s age, number of years in menopause, whether or not  she has delivered vaginally, and what her cervix looks like. Does she have a sexually transmitted infection or pelvic inflammatory disease? Sometimes we will use misoprostol, my personal preference is oral, but there are data to suggest that vaginal can be of help.⁴ We suggest Motrin, Tylenol an hour or 2 before, and we always want patients to not come in on an empty stomach. There is also the option of primrose oil, a supplement, that patients buy at the drug store in the vitamin section. It’s used for cervical softening. It is taken orally.^5-7

If they want, patients can watch a video—similar to watching childbirth videos when I used to deliver babies. At some point we started putting mirrors where women could see their efforts of pushing a baby out, as it might give them more willpower to push harder. Some people don’t want to look. But the majority of women will do well in this setting. I do have a small number of women that just say, “I can’t do this in the office,” and so in those cases, they can go to the operating room. But the main idea is, even in an operating room, you are not just doing a D&C. You are still going to look inside with a hysteroscope and have a great panoramic view of what is going on, and remove a lesion with an instrument while you watch. Not a process of looking with the hysteroscope, scraping with a curettage, and thinking that you are complete. Targeted removal of focal lesions under continuous visualization is the goal.

OBG Management: Can you describe the goals of the consensus document on ending blind sampling co-created by the European Society of Gynecologic Endoscopy, AAGL, and the Global Community on Hysteroscopy? 

Dr. Bradley: Our goal for this year is to get a systematic review and guidelines paper written that speaks to what we have just talked about. We want to have as many articles about why blind sampling is not beneficial, with too many misses, and now we have new technology available. We want to speak to physicians to solve the conundrum of bleeding, with equivocal ultrasounds, equivocal saline infusion, sonograms, equivocal MRIs—be able to take a look. Let’s come up to speed like our other colleagues in other specialties that “look.” A systematic review guideline document will provide the evidence that blind  D&C is fraught with problems and how often we miss disease and its inherent risk.

We need to, by itself, for most of our patients, abandon D&C because we have too many missed diagnoses. As doctors we have to be lifelong learners. There was no robot back in the day. We were not able to do laparoscopic hysterectomies, there were no MRIs. I remember in our city, there was one CT scan. We just did not have a lot of technology. The half-life of medical knowledge used to be decades—you graduated in the ‘60s, you could be a great gynecologist for the next  30 years because there was not that much going on. When I finished in the mid to late ‘80s, there was no hysteroscopy training. But I have come to see its value, the science  behind it.

So what I say to doctors is, “We learn so many new things, we shouldn’t get stuck in just saying, ‘I didn’t do this when I was in training.’” And if your thought is, “Oh, in my practice, I don’t have that many cases,” you still need to be able to know who in your community can be a resource to your patients. As Maya Angelou says, “When you know better, you should do better.” And that’s where I am now—to be a lifelong learner, and just  do it.

Lastly, patient influence is very important. If patients ask, “How are you going to do the procedure?” it’s a driver for change. By utilizing hysteroscopy in the evaluation of the intrauterine cavity, we have the opportunity to change the face of evaluation and treatment for abnormal uterine bleeding.●

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

OBG Management Board Member Linda Bradley, MD, recently attended the Global Congress on Hysteroscopy in Malaga, Spain, May 26-27, 2022, organized by the Global Community on Hysteroscopy, and co-authored the article, “Implementation of office hysteroscopy for the evaluation and treatment of intrauterine pathology” in Obstetrics and Gynecology.¹ She is the Director of the Center for Menstrual Disorders, Fibroids and Hysteroscopic Services at Cleveland Clinic in Cleveland, Ohio. OBG Management recently caught up with her to ask about her perspectives on the expanded use of hysteroscopy in obstetrics and gynecology, and her call to “end blind endometrial sampling.”

OBG Management: What are the drawbacks of dilation and curettage?

Linda Bradley, MD: The standard in ObGyn for many years has been our reliance on the blind dilation and curettage (D&C)—it has been the mainstay for evaluation of the endometrial cavity. We know that it has risks, but most importantly, the procedure has low sensitivity for detecting focal pathology. This basic lack of confirmation of lesions makes a diagnosis impossible and patients are challenged in getting adequate treatment, and will not, since they may not know what options they have for the treatment of intrauterine pathology. 

Because it is a “blind procedure,” done without looking, we don’t know the endpoints, such as when is the procedure completed, how do we know we removed all of the lesions? Let’s look at our colleagues, like GI and colorectal physicians. If a patient presents with rectal bleeding, we would perform an exam, followed by either a colonoscopy or sigmoidoscopy. If a patient were vomiting up blood, a gastroenterologist would perform an upper endoscopy, look with a tube to see if there is an ulcer or something else as a source of the bleeding. If a patient were bleeding from the bladder, a urologist would use  a cystoscope for direct inspection. 

Unfortunately for gynecologists, only about 15% to 25% of us will use hysteroscopy as a diagnostic method²—a method that has excellent sensitivity in detecting endocervical disease, intrauterine disease, and proximal tubal pathology. Compared with blind curettage, we can visualize the cavity; we can sample the cavity directly; we can determine what the patient has and determine the proper surgical procedure, medical therapy, or reassurance that a patient may be offered. We often are looking at focal lesions, lesions in the uterine cavity that could be cancer, so we can make a diagnosis. Or we may be looking at small things, like endometrial hyperplasia, endocervical or endometrial polyps, retained products of conception, or fibroids. We can look at uterine pathology as well as anatomic issues and malformations—such as bicornuate or septate uterus. 

I actually say, “My hysteroscope is my stethoscope” because it allows us to evaluate for many things. The beauty of the new office hysteroscopes is that they are miniaturized. Doctors now have the ability to use reusable devices that are as small as 3 millimeters. There are disposable ones that are up to  3.5 to 4 millimeters in size. Gynecologists have the options to choose from reusuable rigid or flexible hysteroscopes or completely disposable devices. So, truly, we now should not have an excuse for evaluating a woman’s anatomy, especially for bleeding. We should no longer rely, as we have for the last century or more, just on blind sampling, because we miss focal lesions. 

OBG Management: When was the hysteroscope first introduced into the field?

Dr. Bradley: The technology employed in hysteroscopy has been around really since the last 150+ years, introduced by Dr. Pantaleoni. We just have not embraced its usefulness in our clinical practice for many years. Today, about 15% to 25% of gynecologists practicing in the United States are performing hysteroscopy in the office.¹

OBG Management: How does using hysteroscopy contribute to better patient outcomes?

Dr. Bradley: We can get a more accurate diagnosis—fewer false-negatives and a high degree of sensitivity in detecting focal lesions. With D&C, much focal pathology can be left behind. In a 2001 study, 105 symptomatic postmenopausal women with bleeding and thickened lining of the uterus greater than  5 mm on ultrasound underwent blind D&C. They found that 80% of the women had intracavitary lesions and 90% had focal lesions. In fact, 87% of the patients with focal lesions still had residual pathology after the blind D&C.³ The D&C procedure missed 58% of polyps, 50% of endometrial hyperplasia, 60% of cases of complex atypical hyperplasia, and even 11% of endometrial cancers. So these numbers are just not very good. Direct inspection of the uterus, with uninterrupted visualization through hysteroscopy, with removal of lesions under direct visualization, should be our goal. 

Blind sampling also poses greater risk for things like perforation. In addition, you not only can miss lesions by just scraping the endometrium, D&C also can leave lesions just floating around in the uterine cavity, with those lesions never retrieved. With office hysteroscopy, the physician can be more successful in treating a condition because once you see what is going on in the uterine cavity, you can say, “Okay, I can fix this with a surgical procedure. What instruments do I need? How much time is it going to take? Is this a straightforward case? Is it more complicated? Do I let an intern do the case? Is this for a more senior resident or fellow?” So I think it helps to direct the next steps for surgical management and even medical management, which also could be what we call “one-stop shopping.” For instance, for directed biopsies for removal of small polyps, for patients that can tolerate the procedure a little longer, the diagnostic hysteroscopy then becomes a management, an operative procedure, that really, for myself, can be done in the office. Removal of larger fibroids, because of fluid management and other concerns, would not be done in the office. Most patients tolerate office procedures, but it also depends on a patient’s weight, and her ability to relax during the procedure. 

The ultimate goal for hysteroscopy is a minimum of diagnosis, meaning in less than 2, 3 minutes, you can look inside the uterus. Our devices are 3 millimeters in size; I tell my patients, it’s the size of “a piece of spaghetti or pasta,” and we will just take a look. If we see a polyp, okay, if your office is not equipped, because then you need a different type of equipment for removal, then take her to the operating room. The patient would be under brief anesthesia and go home an hour or 2 later. So really, for physicians, we just need to embrace the technology to make a diagnosis, just look, and then from there decide what is next.

OBG Management: What techniques do you use to minimize or eliminate patient discomfort during hysteroscopy?...

OBG Management: What techniques do you use to minimize or eliminate patient discomfort during hysteroscopy?

Dr. Bradley: I think first is always be patient-centric. Let patients be prepared for the procedure. We have reading materials; our nurses explain the procedure. In the office, I try to prepare the patient for success. I let her know what is going on. A friend, family member can be with her. We have a nurse that understands the procedure; she explains it well. We have a type of bed that allows the patients’ legs to rest more comfortably in the stirrups—a leg rest kind of stirrup. We use a heating pad. Some patients like to hear music. Some patients like to have aromatherapy. We are quick and efficient, and typically just talk to the patient throughout the procedure. Although some patients don’t like this explanatory, “talkative” approach—they say, “Dr. Bradley, just do the procedure. I don’t want to know you are touching the cervix. I don’t want to know that you’re prepping. Just do it.” 

But I like what we called it when I was growing up: vocal-local (talk to your patient and explain as you proceed). It’s like local anesthesia. For these procedures in the office you usually do not have to use numbing medicine or a paracervical block. Look at the patient’s age, number of years in menopause, whether or not  she has delivered vaginally, and what her cervix looks like. Does she have a sexually transmitted infection or pelvic inflammatory disease? Sometimes we will use misoprostol, my personal preference is oral, but there are data to suggest that vaginal can be of help.⁴ We suggest Motrin, Tylenol an hour or 2 before, and we always want patients to not come in on an empty stomach. There is also the option of primrose oil, a supplement, that patients buy at the drug store in the vitamin section. It’s used for cervical softening. It is taken orally.^5-7

If they want, patients can watch a video—similar to watching childbirth videos when I used to deliver babies. At some point we started putting mirrors where women could see their efforts of pushing a baby out, as it might give them more willpower to push harder. Some people don’t want to look. But the majority of women will do well in this setting. I do have a small number of women that just say, “I can’t do this in the office,” and so in those cases, they can go to the operating room. But the main idea is, even in an operating room, you are not just doing a D&C. You are still going to look inside with a hysteroscope and have a great panoramic view of what is going on, and remove a lesion with an instrument while you watch. Not a process of looking with the hysteroscope, scraping with a curettage, and thinking that you are complete. Targeted removal of focal lesions under continuous visualization is the goal.

OBG Management: Can you describe the goals of the consensus document on ending blind sampling co-created by the European Society of Gynecologic Endoscopy, AAGL, and the Global Community on Hysteroscopy? 

Dr. Bradley: Our goal for this year is to get a systematic review and guidelines paper written that speaks to what we have just talked about. We want to have as many articles about why blind sampling is not beneficial, with too many misses, and now we have new technology available. We want to speak to physicians to solve the conundrum of bleeding, with equivocal ultrasounds, equivocal saline infusion, sonograms, equivocal MRIs—be able to take a look. Let’s come up to speed like our other colleagues in other specialties that “look.” A systematic review guideline document will provide the evidence that blind  D&C is fraught with problems and how often we miss disease and its inherent risk.

We need to, by itself, for most of our patients, abandon D&C because we have too many missed diagnoses. As doctors we have to be lifelong learners. There was no robot back in the day. We were not able to do laparoscopic hysterectomies, there were no MRIs. I remember in our city, there was one CT scan. We just did not have a lot of technology. The half-life of medical knowledge used to be decades—you graduated in the ‘60s, you could be a great gynecologist for the next  30 years because there was not that much going on. When I finished in the mid to late ‘80s, there was no hysteroscopy training. But I have come to see its value, the science  behind it.

So what I say to doctors is, “We learn so many new things, we shouldn’t get stuck in just saying, ‘I didn’t do this when I was in training.’” And if your thought is, “Oh, in my practice, I don’t have that many cases,” you still need to be able to know who in your community can be a resource to your patients. As Maya Angelou says, “When you know better, you should do better.” And that’s where I am now—to be a lifelong learner, and just  do it.

Lastly, patient influence is very important. If patients ask, “How are you going to do the procedure?” it’s a driver for change. By utilizing hysteroscopy in the evaluation of the intrauterine cavity, we have the opportunity to change the face of evaluation and treatment for abnormal uterine bleeding.●

There was no difference in major cardiovascular outcomes with the use of two different diuretics – chlorthalidone or hydrochlorothiazide – in the treatment of hypertension in a new large randomized real-world study.

The Diuretic Comparison Project (DCP), which was conducted in more than 13,500 U.S. veterans age 65 years or over, showed almost identical rates of the primary composite endpoint, including myocardial infarction (MI), stroke, noncancer death, hospitalization for acute heart failure, or urgent revascularization, after a median of 2.4 years of follow-up.

There was no difference in any of the individual endpoints or other secondary cardiovascular outcomes.

However, in the subgroup of patients who had a history of MI or stroke (who made up about 10% of the study population), there was a significant reduction in the primary endpoint with chlorthalidone, whereas those without a history of MI or stroke appeared to have an increased risk for primary outcome events while receiving chlorthalidone compared with those receiving hydrochlorothiazide.

The DCP trial was presented at the American Heart Association scientific sessions by Areef Ishani, MD, director of the Minneapolis Primary Care and Specialty Care Integrated Care Community and director of the Veterans Affairs (VA) Midwest Health Care Network.

Asked how to interpret the result for clinical practice, Dr. Ishani said, “I think we can now say that either of these two drugs is appropriate to use for the treatment of hypertension.”

But he added that the decision on what to do with the subgroup of patients with previous MI or stroke was more “challenging.”

“We saw a highly significant benefit in this subgroup, but this was in the context of an overall negative trial,” he noted. “I think this is a discussion with the patients on how they want to hedge their bets. Because these two drugs are so similar, if they wanted to take one or the other because of this subgroup result I think that is a conversation to have, but I think we now need to conduct another trial specifically in this subgroup of patients to see if chlorthalidone really is of benefit in that group.”

Dr. Ishani explained that both chlorthalidone and hydrochlorothiazide have been around for more than 50 years and are considered first-line treatments for hypertension. Early studies suggested better cardiovascular outcomes and 24-hour blood pressure control with chlorthalidone, but recent observational studies have not shown more benefit with chlorthalidone. These studies have suggested that chlorthalidone may be associated with an increase in adverse events, such as hypokalemia, acute kidney injury, and chronic kidney disease.
 

Pragmatic study

The DCP trial was conducted to try to definitively answer this question of whether chlorthalidone is superior to hydrochlorothiazide. The pragmatic study had a “point-of-care” design that allowed participants and health care professionals to know which medication was being prescribed and to administer the medication in a real-world setting.

“Patients can continue with their normal care with their usual care team because we integrated this trial into primary care clinics,” Dr. Ishani said. “We followed participant results using their electronic health record. This study was nonintrusive, cost-effective, and inexpensive. Plus, we were able to recruit a large rural population, which is unusual for large, randomized trials, where we usually rely on big academic medical centers.”

Using VA electronic medical records, the investigators recruited primary care physicians who identified patients older than age 65 years who were receiving hydrochlorothiazide (25 mg or 50 mg) for hypertension. These patients (97% of whom were male) were then randomly assigned to continue receiving hydrochlorothiazide or to switch to an equivalent dose of chlorthalidone. Patients were followed through the electronic medical record as well as Medicare claims and the National Death Index.

Results after a median follow-up of 2.4 years showed no difference in blood pressure control between the two groups.

In terms of clinical events, the primary composite outcome of MI, stroke, noncancer death, hospitalization for acute heart failure, or urgent revascularization occurred in 10.4% of the chlorthalidone group and in 10.0% of the hydrochlorothiazide group (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.94-1.16; P = .4).

There was no difference in any individual components of the primary endpoint or the secondary outcomes of all-cause mortality, any revascularization, or erectile dysfunction.

In terms of adverse events, chlorthalidone was associated with an increase in hypokalemia (6% vs. 4.4%; HR, 1.38), but there was no difference in hospitalization for acute kidney injury.
 

Benefit in MI, stroke subgroup?

In the subgroup analysis, patients with a history of MI or stroke who were receiving chlorthalidone had a significant 27% reduction in the primary endpoint (HR, 0.73; 95% CI, 0.57-0.94). Conversely, patients without a history of MI or stroke appeared to do worse while taking chlorthalidone (HR, 1.12; 95% CI, 1.00-1.26).

“We were surprised by these results,” Dr. Ishani said. “We expected chlorthalidone to be more effective overall. However, learning about these differences in patients who have a history of cardiovascular disease may affect patient care. It’s best for people to talk with their health care clinicians about which of these medications is better for their individual needs.”

He added: “More research is needed to explore these results further because we don’t know how they may fit into treating the general population.”

Dr. Ishani noted that a limitations of this study was that most patients were receiving the low dose of chlorthalidone, and previous studies that suggested benefits with chlorthalidone used the higher dose.

“But the world has voted – we had 4,000 clinicians involved in this study, and the vast majority are using the low dose of hydrochlorothiazide. And this is a definitively negative study,” he said. “The world has also voted in that 10 times more patients were on hydrochlorothiazide than on chlorthalidone.”

Commenting on the study at an AHA press conference, Biykem Bozkurt, MD, PhD, Baylor College of Medicine, Houston, pointed out that in all of the landmark National Institutes of Health hypertension trials, there was a signal for benefit with chlorthalidone compared with other antihypertensives.

Catherine Hackett/MDedge News

“We’ve always had this concept that chlorthalidone is better,” she said. “But this study shows no difference in major cardiovascular endpoints. There was more hypokalemia with chlorthalidone, but that’s recognizable as chlorthalidone is a more potent diuretic.”

Other limitations of the DCP trial are its open-label design, which could interject some bias; the enduring effects of hydrochlorothiazide – most of these patients were receiving this agent as background therapy; and inability to look at the effectiveness of decongestion of the agents in such a pragmatic study, Dr. Bozkurt noted.

She said she would like to see more analysis in the subgroup of patients with previous MI or stroke. “Does this result mean that chlorthalidone is better for sicker patients or is this result just due to chance?” she asked.

“While this study demonstrates equal effectiveness of these two diuretics in the targeted population, the question of subgroups of patients for which we use a more potent diuretic I think remains unanswered,” she concluded.

Designated discussant of the DCP trial at the late-breaking trial session, Daniel Levy, MD, director of the Framingham Heart Study at the National Heart, Lung, and Blood Institute, reminded attendees that chlorthalidone had shown impressive results in previous important hypertension studies including SHEP and ALLHAT.

He said the current DCP was a pragmatic study addressing a knowledge gap that “would never have been performed by industry.”

Dr. Levy concluded that the results showing no difference in outcomes between the two diuretics were “compelling,” although a few questions remain.

These include a possible bias toward hydrochlorothiazide – patients were selected who were already taking that drug and so would have already had a favorable response to it. In addition, because the trial was conducted in an older male population, he questioned whether the results could be generalized to women and younger patients.

The DCP study was funded by the VA Cooperative Studies Program. Dr. Ishani reported no disclosures.

A version of this article first appeared on Medscape.com.

There was no difference in major cardiovascular outcomes with the use of two different diuretics – chlorthalidone or hydrochlorothiazide – in the treatment of hypertension in a new large randomized real-world study.

The Diuretic Comparison Project (DCP), which was conducted in more than 13,500 U.S. veterans age 65 years or over, showed almost identical rates of the primary composite endpoint, including myocardial infarction (MI), stroke, noncancer death, hospitalization for acute heart failure, or urgent revascularization, after a median of 2.4 years of follow-up.

There was no difference in any of the individual endpoints or other secondary cardiovascular outcomes.

However, in the subgroup of patients who had a history of MI or stroke (who made up about 10% of the study population), there was a significant reduction in the primary endpoint with chlorthalidone, whereas those without a history of MI or stroke appeared to have an increased risk for primary outcome events while receiving chlorthalidone compared with those receiving hydrochlorothiazide.

The DCP trial was presented at the American Heart Association scientific sessions by Areef Ishani, MD, director of the Minneapolis Primary Care and Specialty Care Integrated Care Community and director of the Veterans Affairs (VA) Midwest Health Care Network.

Asked how to interpret the result for clinical practice, Dr. Ishani said, “I think we can now say that either of these two drugs is appropriate to use for the treatment of hypertension.”

But he added that the decision on what to do with the subgroup of patients with previous MI or stroke was more “challenging.”

“We saw a highly significant benefit in this subgroup, but this was in the context of an overall negative trial,” he noted. “I think this is a discussion with the patients on how they want to hedge their bets. Because these two drugs are so similar, if they wanted to take one or the other because of this subgroup result I think that is a conversation to have, but I think we now need to conduct another trial specifically in this subgroup of patients to see if chlorthalidone really is of benefit in that group.”

Dr. Ishani explained that both chlorthalidone and hydrochlorothiazide have been around for more than 50 years and are considered first-line treatments for hypertension. Early studies suggested better cardiovascular outcomes and 24-hour blood pressure control with chlorthalidone, but recent observational studies have not shown more benefit with chlorthalidone. These studies have suggested that chlorthalidone may be associated with an increase in adverse events, such as hypokalemia, acute kidney injury, and chronic kidney disease.
 

Pragmatic study

The DCP trial was conducted to try to definitively answer this question of whether chlorthalidone is superior to hydrochlorothiazide. The pragmatic study had a “point-of-care” design that allowed participants and health care professionals to know which medication was being prescribed and to administer the medication in a real-world setting.

“Patients can continue with their normal care with their usual care team because we integrated this trial into primary care clinics,” Dr. Ishani said. “We followed participant results using their electronic health record. This study was nonintrusive, cost-effective, and inexpensive. Plus, we were able to recruit a large rural population, which is unusual for large, randomized trials, where we usually rely on big academic medical centers.”

Using VA electronic medical records, the investigators recruited primary care physicians who identified patients older than age 65 years who were receiving hydrochlorothiazide (25 mg or 50 mg) for hypertension. These patients (97% of whom were male) were then randomly assigned to continue receiving hydrochlorothiazide or to switch to an equivalent dose of chlorthalidone. Patients were followed through the electronic medical record as well as Medicare claims and the National Death Index.

Results after a median follow-up of 2.4 years showed no difference in blood pressure control between the two groups.

In terms of clinical events, the primary composite outcome of MI, stroke, noncancer death, hospitalization for acute heart failure, or urgent revascularization occurred in 10.4% of the chlorthalidone group and in 10.0% of the hydrochlorothiazide group (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.94-1.16; P = .4).

There was no difference in any individual components of the primary endpoint or the secondary outcomes of all-cause mortality, any revascularization, or erectile dysfunction.

In terms of adverse events, chlorthalidone was associated with an increase in hypokalemia (6% vs. 4.4%; HR, 1.38), but there was no difference in hospitalization for acute kidney injury.
 

Benefit in MI, stroke subgroup?

In the subgroup analysis, patients with a history of MI or stroke who were receiving chlorthalidone had a significant 27% reduction in the primary endpoint (HR, 0.73; 95% CI, 0.57-0.94). Conversely, patients without a history of MI or stroke appeared to do worse while taking chlorthalidone (HR, 1.12; 95% CI, 1.00-1.26).

“We were surprised by these results,” Dr. Ishani said. “We expected chlorthalidone to be more effective overall. However, learning about these differences in patients who have a history of cardiovascular disease may affect patient care. It’s best for people to talk with their health care clinicians about which of these medications is better for their individual needs.”

He added: “More research is needed to explore these results further because we don’t know how they may fit into treating the general population.”

Dr. Ishani noted that a limitations of this study was that most patients were receiving the low dose of chlorthalidone, and previous studies that suggested benefits with chlorthalidone used the higher dose.

“But the world has voted – we had 4,000 clinicians involved in this study, and the vast majority are using the low dose of hydrochlorothiazide. And this is a definitively negative study,” he said. “The world has also voted in that 10 times more patients were on hydrochlorothiazide than on chlorthalidone.”

Commenting on the study at an AHA press conference, Biykem Bozkurt, MD, PhD, Baylor College of Medicine, Houston, pointed out that in all of the landmark National Institutes of Health hypertension trials, there was a signal for benefit with chlorthalidone compared with other antihypertensives.

Catherine Hackett/MDedge News

“We’ve always had this concept that chlorthalidone is better,” she said. “But this study shows no difference in major cardiovascular endpoints. There was more hypokalemia with chlorthalidone, but that’s recognizable as chlorthalidone is a more potent diuretic.”

Other limitations of the DCP trial are its open-label design, which could interject some bias; the enduring effects of hydrochlorothiazide – most of these patients were receiving this agent as background therapy; and inability to look at the effectiveness of decongestion of the agents in such a pragmatic study, Dr. Bozkurt noted.

She said she would like to see more analysis in the subgroup of patients with previous MI or stroke. “Does this result mean that chlorthalidone is better for sicker patients or is this result just due to chance?” she asked.

“While this study demonstrates equal effectiveness of these two diuretics in the targeted population, the question of subgroups of patients for which we use a more potent diuretic I think remains unanswered,” she concluded.

Designated discussant of the DCP trial at the late-breaking trial session, Daniel Levy, MD, director of the Framingham Heart Study at the National Heart, Lung, and Blood Institute, reminded attendees that chlorthalidone had shown impressive results in previous important hypertension studies including SHEP and ALLHAT.

He said the current DCP was a pragmatic study addressing a knowledge gap that “would never have been performed by industry.”

Dr. Levy concluded that the results showing no difference in outcomes between the two diuretics were “compelling,” although a few questions remain.

These include a possible bias toward hydrochlorothiazide – patients were selected who were already taking that drug and so would have already had a favorable response to it. In addition, because the trial was conducted in an older male population, he questioned whether the results could be generalized to women and younger patients.

The DCP study was funded by the VA Cooperative Studies Program. Dr. Ishani reported no disclosures.

A version of this article first appeared on Medscape.com.

There was no difference in major cardiovascular outcomes with the use of two different diuretics – chlorthalidone or hydrochlorothiazide – in the treatment of hypertension in a new large randomized real-world study.

The Diuretic Comparison Project (DCP), which was conducted in more than 13,500 U.S. veterans age 65 years or over, showed almost identical rates of the primary composite endpoint, including myocardial infarction (MI), stroke, noncancer death, hospitalization for acute heart failure, or urgent revascularization, after a median of 2.4 years of follow-up.

There was no difference in any of the individual endpoints or other secondary cardiovascular outcomes.

However, in the subgroup of patients who had a history of MI or stroke (who made up about 10% of the study population), there was a significant reduction in the primary endpoint with chlorthalidone, whereas those without a history of MI or stroke appeared to have an increased risk for primary outcome events while receiving chlorthalidone compared with those receiving hydrochlorothiazide.

The DCP trial was presented at the American Heart Association scientific sessions by Areef Ishani, MD, director of the Minneapolis Primary Care and Specialty Care Integrated Care Community and director of the Veterans Affairs (VA) Midwest Health Care Network.

Asked how to interpret the result for clinical practice, Dr. Ishani said, “I think we can now say that either of these two drugs is appropriate to use for the treatment of hypertension.”

But he added that the decision on what to do with the subgroup of patients with previous MI or stroke was more “challenging.”

“We saw a highly significant benefit in this subgroup, but this was in the context of an overall negative trial,” he noted. “I think this is a discussion with the patients on how they want to hedge their bets. Because these two drugs are so similar, if they wanted to take one or the other because of this subgroup result I think that is a conversation to have, but I think we now need to conduct another trial specifically in this subgroup of patients to see if chlorthalidone really is of benefit in that group.”

Dr. Ishani explained that both chlorthalidone and hydrochlorothiazide have been around for more than 50 years and are considered first-line treatments for hypertension. Early studies suggested better cardiovascular outcomes and 24-hour blood pressure control with chlorthalidone, but recent observational studies have not shown more benefit with chlorthalidone. These studies have suggested that chlorthalidone may be associated with an increase in adverse events, such as hypokalemia, acute kidney injury, and chronic kidney disease.
 

Pragmatic study

The DCP trial was conducted to try to definitively answer this question of whether chlorthalidone is superior to hydrochlorothiazide. The pragmatic study had a “point-of-care” design that allowed participants and health care professionals to know which medication was being prescribed and to administer the medication in a real-world setting.

“Patients can continue with their normal care with their usual care team because we integrated this trial into primary care clinics,” Dr. Ishani said. “We followed participant results using their electronic health record. This study was nonintrusive, cost-effective, and inexpensive. Plus, we were able to recruit a large rural population, which is unusual for large, randomized trials, where we usually rely on big academic medical centers.”

Using VA electronic medical records, the investigators recruited primary care physicians who identified patients older than age 65 years who were receiving hydrochlorothiazide (25 mg or 50 mg) for hypertension. These patients (97% of whom were male) were then randomly assigned to continue receiving hydrochlorothiazide or to switch to an equivalent dose of chlorthalidone. Patients were followed through the electronic medical record as well as Medicare claims and the National Death Index.

Results after a median follow-up of 2.4 years showed no difference in blood pressure control between the two groups.

In terms of clinical events, the primary composite outcome of MI, stroke, noncancer death, hospitalization for acute heart failure, or urgent revascularization occurred in 10.4% of the chlorthalidone group and in 10.0% of the hydrochlorothiazide group (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.94-1.16; P = .4).

There was no difference in any individual components of the primary endpoint or the secondary outcomes of all-cause mortality, any revascularization, or erectile dysfunction.

In terms of adverse events, chlorthalidone was associated with an increase in hypokalemia (6% vs. 4.4%; HR, 1.38), but there was no difference in hospitalization for acute kidney injury.
 

Benefit in MI, stroke subgroup?

In the subgroup analysis, patients with a history of MI or stroke who were receiving chlorthalidone had a significant 27% reduction in the primary endpoint (HR, 0.73; 95% CI, 0.57-0.94). Conversely, patients without a history of MI or stroke appeared to do worse while taking chlorthalidone (HR, 1.12; 95% CI, 1.00-1.26).

“We were surprised by these results,” Dr. Ishani said. “We expected chlorthalidone to be more effective overall. However, learning about these differences in patients who have a history of cardiovascular disease may affect patient care. It’s best for people to talk with their health care clinicians about which of these medications is better for their individual needs.”

He added: “More research is needed to explore these results further because we don’t know how they may fit into treating the general population.”

Dr. Ishani noted that a limitations of this study was that most patients were receiving the low dose of chlorthalidone, and previous studies that suggested benefits with chlorthalidone used the higher dose.

“But the world has voted – we had 4,000 clinicians involved in this study, and the vast majority are using the low dose of hydrochlorothiazide. And this is a definitively negative study,” he said. “The world has also voted in that 10 times more patients were on hydrochlorothiazide than on chlorthalidone.”

Commenting on the study at an AHA press conference, Biykem Bozkurt, MD, PhD, Baylor College of Medicine, Houston, pointed out that in all of the landmark National Institutes of Health hypertension trials, there was a signal for benefit with chlorthalidone compared with other antihypertensives.

Catherine Hackett/MDedge News

“We’ve always had this concept that chlorthalidone is better,” she said. “But this study shows no difference in major cardiovascular endpoints. There was more hypokalemia with chlorthalidone, but that’s recognizable as chlorthalidone is a more potent diuretic.”

Other limitations of the DCP trial are its open-label design, which could interject some bias; the enduring effects of hydrochlorothiazide – most of these patients were receiving this agent as background therapy; and inability to look at the effectiveness of decongestion of the agents in such a pragmatic study, Dr. Bozkurt noted.

She said she would like to see more analysis in the subgroup of patients with previous MI or stroke. “Does this result mean that chlorthalidone is better for sicker patients or is this result just due to chance?” she asked.

“While this study demonstrates equal effectiveness of these two diuretics in the targeted population, the question of subgroups of patients for which we use a more potent diuretic I think remains unanswered,” she concluded.

Designated discussant of the DCP trial at the late-breaking trial session, Daniel Levy, MD, director of the Framingham Heart Study at the National Heart, Lung, and Blood Institute, reminded attendees that chlorthalidone had shown impressive results in previous important hypertension studies including SHEP and ALLHAT.

He said the current DCP was a pragmatic study addressing a knowledge gap that “would never have been performed by industry.”

Dr. Levy concluded that the results showing no difference in outcomes between the two diuretics were “compelling,” although a few questions remain.

These include a possible bias toward hydrochlorothiazide – patients were selected who were already taking that drug and so would have already had a favorable response to it. In addition, because the trial was conducted in an older male population, he questioned whether the results could be generalized to women and younger patients.

The DCP study was funded by the VA Cooperative Studies Program. Dr. Ishani reported no disclosures.

A version of this article first appeared on Medscape.com.

CHICAGO – Despite a 25% reduction in triglycerides (TGs) along with similar reductions in very-low-density lipoprotein (VLDL), and remnant cholesterol, a novel agent failed to provide any protection in a multinational trial against a composite endpoint of major adverse cardiovascular events (MACE) in patients with type 2 diabetes.

“Our data further highlight the complexity of lipid mediators of residual risk among patients with insulin resistance who are receiving statin therapy,” reported Aruna Das Pradhan, MD, of Harvard Medical School, Boston, and Queen Mary University, London.

Ted Bosworth/MDedge News

No benefit from fibrates seen in statin era

“We have not seen a significant cardiovascular event reduction with a fibrate in the statin era,” according to Karol Watson, MD, PhD, director of the UCLA Women’s Cardiovascular Health Center, Los Angeles.

Ted Bosworth/MDedge News

Lipid profile improved as predicted

Yet, in regard to an improvement in the lipid profile, pemafibrate performed as predicted. When compared to placebo 4 months into the trial, pemafibrate was associated with median reductions of 26.2% in TGs, 25.8% in VLDL, and 25.6% in remnant cholesterol, which is cholesterol transported in TG-rich lipoproteins after lipolysis and lipoprotein remodeling.

Furthermore, pemafibrate was associated with a median 27.6% reduction relative to placebo in apolipoprotein C-III and a median 4.8% reduction in apolipoprotein E, all of which would be expected to reduce CV risk.

The findings of PROMINENT were published online in the New England Journal of Medicine immediately after their presentation.

The findings of this study do not eliminate any hope for lowering residual CV risk with TG reductions, but they do suggest the relationship with other lipid subfractions is complex, according to Salim S. Virani, MD, PhD, a professor of cardiology at Baylor College of Medicine, Houston.

“I think that the lack of efficacy despite TG lowering may be largely due to a lack of an overall decrease in the apolipoprotein B level,” speculated Dr. Virani, who wrote an editorial that accompanied publication of the PROMINENT results.

He noted that pemafibrate is implicated in converting remnant cholesterol to LDL cholesterol, which might be one reason for a counterproductive effect on CV risk.

“In order for therapies that lower TG levels to be effective, they probably have to have mechanisms to increase clearance of TG-rich remnant lipoprotein cholesterol particles rather than just converting remnant lipoproteins to LDL,” Dr. Virani explained in an attempt to unravel the interplay of these variables.

Although this study enrolled patients “who would be predicted to have the most benefit from a TG-lowering strategy,” Dr. Watson agreed that these results do not necessarily extend to other means of lowering TG. However, it might draw into question the value of pemafibrate and perhaps other drugs in this class for treatment of hypertriglyceridemia. In addition to a lack of CV benefit, treatment was not without risks, including a higher rate of thromboembolism and adverse renal events.

Dr. Das Pradhan reported financial relationships with Denka, Medtelligence, Optum, Novo Nordisk, and Kowa, which provided funding for this trial. Dr. Watson reported financial relationships with Amarin, Amgen, Boehringer-Ingelheim, and Esperion.

CHICAGO – Despite a 25% reduction in triglycerides (TGs) along with similar reductions in very-low-density lipoprotein (VLDL), and remnant cholesterol, a novel agent failed to provide any protection in a multinational trial against a composite endpoint of major adverse cardiovascular events (MACE) in patients with type 2 diabetes.

“Our data further highlight the complexity of lipid mediators of residual risk among patients with insulin resistance who are receiving statin therapy,” reported Aruna Das Pradhan, MD, of Harvard Medical School, Boston, and Queen Mary University, London.

Ted Bosworth/MDedge News

No benefit from fibrates seen in statin era

“We have not seen a significant cardiovascular event reduction with a fibrate in the statin era,” according to Karol Watson, MD, PhD, director of the UCLA Women’s Cardiovascular Health Center, Los Angeles.

Ted Bosworth/MDedge News

Lipid profile improved as predicted

Yet, in regard to an improvement in the lipid profile, pemafibrate performed as predicted. When compared to placebo 4 months into the trial, pemafibrate was associated with median reductions of 26.2% in TGs, 25.8% in VLDL, and 25.6% in remnant cholesterol, which is cholesterol transported in TG-rich lipoproteins after lipolysis and lipoprotein remodeling.

Furthermore, pemafibrate was associated with a median 27.6% reduction relative to placebo in apolipoprotein C-III and a median 4.8% reduction in apolipoprotein E, all of which would be expected to reduce CV risk.

The findings of PROMINENT were published online in the New England Journal of Medicine immediately after their presentation.

The findings of this study do not eliminate any hope for lowering residual CV risk with TG reductions, but they do suggest the relationship with other lipid subfractions is complex, according to Salim S. Virani, MD, PhD, a professor of cardiology at Baylor College of Medicine, Houston.

“I think that the lack of efficacy despite TG lowering may be largely due to a lack of an overall decrease in the apolipoprotein B level,” speculated Dr. Virani, who wrote an editorial that accompanied publication of the PROMINENT results.

He noted that pemafibrate is implicated in converting remnant cholesterol to LDL cholesterol, which might be one reason for a counterproductive effect on CV risk.

“In order for therapies that lower TG levels to be effective, they probably have to have mechanisms to increase clearance of TG-rich remnant lipoprotein cholesterol particles rather than just converting remnant lipoproteins to LDL,” Dr. Virani explained in an attempt to unravel the interplay of these variables.

Although this study enrolled patients “who would be predicted to have the most benefit from a TG-lowering strategy,” Dr. Watson agreed that these results do not necessarily extend to other means of lowering TG. However, it might draw into question the value of pemafibrate and perhaps other drugs in this class for treatment of hypertriglyceridemia. In addition to a lack of CV benefit, treatment was not without risks, including a higher rate of thromboembolism and adverse renal events.

Dr. Das Pradhan reported financial relationships with Denka, Medtelligence, Optum, Novo Nordisk, and Kowa, which provided funding for this trial. Dr. Watson reported financial relationships with Amarin, Amgen, Boehringer-Ingelheim, and Esperion.

CHICAGO – Despite a 25% reduction in triglycerides (TGs) along with similar reductions in very-low-density lipoprotein (VLDL), and remnant cholesterol, a novel agent failed to provide any protection in a multinational trial against a composite endpoint of major adverse cardiovascular events (MACE) in patients with type 2 diabetes.

“Our data further highlight the complexity of lipid mediators of residual risk among patients with insulin resistance who are receiving statin therapy,” reported Aruna Das Pradhan, MD, of Harvard Medical School, Boston, and Queen Mary University, London.

Ted Bosworth/MDedge News

No benefit from fibrates seen in statin era

“We have not seen a significant cardiovascular event reduction with a fibrate in the statin era,” according to Karol Watson, MD, PhD, director of the UCLA Women’s Cardiovascular Health Center, Los Angeles.

Ted Bosworth/MDedge News

Lipid profile improved as predicted

Yet, in regard to an improvement in the lipid profile, pemafibrate performed as predicted. When compared to placebo 4 months into the trial, pemafibrate was associated with median reductions of 26.2% in TGs, 25.8% in VLDL, and 25.6% in remnant cholesterol, which is cholesterol transported in TG-rich lipoproteins after lipolysis and lipoprotein remodeling.

Furthermore, pemafibrate was associated with a median 27.6% reduction relative to placebo in apolipoprotein C-III and a median 4.8% reduction in apolipoprotein E, all of which would be expected to reduce CV risk.

The findings of PROMINENT were published online in the New England Journal of Medicine immediately after their presentation.

The findings of this study do not eliminate any hope for lowering residual CV risk with TG reductions, but they do suggest the relationship with other lipid subfractions is complex, according to Salim S. Virani, MD, PhD, a professor of cardiology at Baylor College of Medicine, Houston.

“I think that the lack of efficacy despite TG lowering may be largely due to a lack of an overall decrease in the apolipoprotein B level,” speculated Dr. Virani, who wrote an editorial that accompanied publication of the PROMINENT results.

He noted that pemafibrate is implicated in converting remnant cholesterol to LDL cholesterol, which might be one reason for a counterproductive effect on CV risk.

“In order for therapies that lower TG levels to be effective, they probably have to have mechanisms to increase clearance of TG-rich remnant lipoprotein cholesterol particles rather than just converting remnant lipoproteins to LDL,” Dr. Virani explained in an attempt to unravel the interplay of these variables.

Although this study enrolled patients “who would be predicted to have the most benefit from a TG-lowering strategy,” Dr. Watson agreed that these results do not necessarily extend to other means of lowering TG. However, it might draw into question the value of pemafibrate and perhaps other drugs in this class for treatment of hypertriglyceridemia. In addition to a lack of CV benefit, treatment was not without risks, including a higher rate of thromboembolism and adverse renal events.

Dr. Das Pradhan reported financial relationships with Denka, Medtelligence, Optum, Novo Nordisk, and Kowa, which provided funding for this trial. Dr. Watson reported financial relationships with Amarin, Amgen, Boehringer-Ingelheim, and Esperion.

When compared with the general population, hairdressers experience an excess risk of contact allergy linked to hair cosmetic ingredients, a systematic review suggests.

“Research has shown that up to 70% of hairdressers suffer from work-related skin damage, mostly hand dermatitis, at some point during their career,” write Wolfgang Uter of Friedrich-Alexander University Erlangen-Nürnberg and coauthors. In general, they write, occupational skin diseases such as hand dermatitis represent up to 35% of reported occupational diseases. The study was published online in Contact Dermatitis.

Wet work and skin contact with detergents and hairdressing chemicals are top risk factors for developing occupational skin disease in this population, according to the researchers.

To further understand the burden of occupational contact allergy in hairdressers, the investigators gathered evidence published since 2000 on contact allergies to hair cosmetic chemicals. They searched the literature for nine substances selected beforehand by experts and stakeholders. The researchers also examined the prevalence of sensitization between hairdressers and other individuals given skin patch tests.
 

Substance by substance

Common potentially sensitizing cosmetic ingredients reported across studies included p-phenylenediamine (PPD), persulfates (mostly ammonium persulfate [APS]), glyceryl thioglycolate (GMTG), and ammonium thioglycolate (ATG).

In a pooled analysis, the overall prevalence of contact allergy to PPD was 4.3% in consecutively patch-tested patients, but in hairdressers specifically, the overall prevalence of contact allergy to this ingredient was 28.6%, reviewers reported.

The pooled prevalence of contact allergy to APS was 5.5% in consumers and 17.2% in hairdressers. In other review studies, contact allergy risks to APS, GMTG, and ATG were also elevated in hairdressers compared with all controls.

The calculated relative risk (RR) of contact allergy to PPD was approximately 5.4 higher for hairdressers, while the RR for ATG sensitization was 3.4 in hairdressers compared with consumers.

Commenting on these findings, James A. Yiannias, MD, professor of dermatology at the Mayo Medical School, Phoenix, told this news organization in an email that many providers and patients are concerned only about hair dye molecules such as PPD and aminophenol, as well as permanent, wave, and straightening chemicals such as GMTG.

“Although these are common allergens in hairdressers, allergens such as fragrances and some preservatives found in daily hair care products such as shampoos, conditioners, and hair sprays are also common causes of contact dermatitis,” said Dr. Yiannias, who wasn’t involved in the research.

Consequences of exposure

Dr. Yiannias explained that progressive worsening of the dermatitis can occur with ongoing allergen exposure and, if not properly mitigated, can lead to bigger issues. “Initial nuisances of mild irritation and hyperkeratosis can evolve to a state of fissuring with the risk of bleeding and significant pain,” he said.

But once severe and untreated dermatitis occurs, Dr. Yiannias said that hairdressers “may need to change careers” or at least face short- or long-term unemployment.

The researchers suggest reducing exposure to the allergen is key for prevention of symptoms, adding that adequate guidance on the safe use of new products is needed. Also, the researchers suggested that vocational schools should more rigorously implement education for hairdressers that addresses how to protect the skin appropriately at work.

“Hairdressers are taught during their training to be cautious about allergen exposure by avoiding touching high-risk ingredients such as hair dyes,” Dr. Yiannias added. “However, in practice, this is very difficult since the wearing of gloves can impair the tactile sensations that hairdressers often feel is essential in performing their job.”

The study received no industry funding. Dr. Yiannias reports no relevant financial relationships.

A version of this article first appeared on Medscape.com.

When compared with the general population, hairdressers experience an excess risk of contact allergy linked to hair cosmetic ingredients, a systematic review suggests.

“Research has shown that up to 70% of hairdressers suffer from work-related skin damage, mostly hand dermatitis, at some point during their career,” write Wolfgang Uter of Friedrich-Alexander University Erlangen-Nürnberg and coauthors. In general, they write, occupational skin diseases such as hand dermatitis represent up to 35% of reported occupational diseases. The study was published online in Contact Dermatitis.

Wet work and skin contact with detergents and hairdressing chemicals are top risk factors for developing occupational skin disease in this population, according to the researchers.

To further understand the burden of occupational contact allergy in hairdressers, the investigators gathered evidence published since 2000 on contact allergies to hair cosmetic chemicals. They searched the literature for nine substances selected beforehand by experts and stakeholders. The researchers also examined the prevalence of sensitization between hairdressers and other individuals given skin patch tests.
 

Substance by substance

Common potentially sensitizing cosmetic ingredients reported across studies included p-phenylenediamine (PPD), persulfates (mostly ammonium persulfate [APS]), glyceryl thioglycolate (GMTG), and ammonium thioglycolate (ATG).

In a pooled analysis, the overall prevalence of contact allergy to PPD was 4.3% in consecutively patch-tested patients, but in hairdressers specifically, the overall prevalence of contact allergy to this ingredient was 28.6%, reviewers reported.

The pooled prevalence of contact allergy to APS was 5.5% in consumers and 17.2% in hairdressers. In other review studies, contact allergy risks to APS, GMTG, and ATG were also elevated in hairdressers compared with all controls.

The calculated relative risk (RR) of contact allergy to PPD was approximately 5.4 higher for hairdressers, while the RR for ATG sensitization was 3.4 in hairdressers compared with consumers.

Commenting on these findings, James A. Yiannias, MD, professor of dermatology at the Mayo Medical School, Phoenix, told this news organization in an email that many providers and patients are concerned only about hair dye molecules such as PPD and aminophenol, as well as permanent, wave, and straightening chemicals such as GMTG.

“Although these are common allergens in hairdressers, allergens such as fragrances and some preservatives found in daily hair care products such as shampoos, conditioners, and hair sprays are also common causes of contact dermatitis,” said Dr. Yiannias, who wasn’t involved in the research.

Consequences of exposure

Dr. Yiannias explained that progressive worsening of the dermatitis can occur with ongoing allergen exposure and, if not properly mitigated, can lead to bigger issues. “Initial nuisances of mild irritation and hyperkeratosis can evolve to a state of fissuring with the risk of bleeding and significant pain,” he said.

But once severe and untreated dermatitis occurs, Dr. Yiannias said that hairdressers “may need to change careers” or at least face short- or long-term unemployment.

The researchers suggest reducing exposure to the allergen is key for prevention of symptoms, adding that adequate guidance on the safe use of new products is needed. Also, the researchers suggested that vocational schools should more rigorously implement education for hairdressers that addresses how to protect the skin appropriately at work.

“Hairdressers are taught during their training to be cautious about allergen exposure by avoiding touching high-risk ingredients such as hair dyes,” Dr. Yiannias added. “However, in practice, this is very difficult since the wearing of gloves can impair the tactile sensations that hairdressers often feel is essential in performing their job.”

The study received no industry funding. Dr. Yiannias reports no relevant financial relationships.

A version of this article first appeared on Medscape.com.

When compared with the general population, hairdressers experience an excess risk of contact allergy linked to hair cosmetic ingredients, a systematic review suggests.

“Research has shown that up to 70% of hairdressers suffer from work-related skin damage, mostly hand dermatitis, at some point during their career,” write Wolfgang Uter of Friedrich-Alexander University Erlangen-Nürnberg and coauthors. In general, they write, occupational skin diseases such as hand dermatitis represent up to 35% of reported occupational diseases. The study was published online in Contact Dermatitis.

Wet work and skin contact with detergents and hairdressing chemicals are top risk factors for developing occupational skin disease in this population, according to the researchers.

To further understand the burden of occupational contact allergy in hairdressers, the investigators gathered evidence published since 2000 on contact allergies to hair cosmetic chemicals. They searched the literature for nine substances selected beforehand by experts and stakeholders. The researchers also examined the prevalence of sensitization between hairdressers and other individuals given skin patch tests.
 

Substance by substance

Common potentially sensitizing cosmetic ingredients reported across studies included p-phenylenediamine (PPD), persulfates (mostly ammonium persulfate [APS]), glyceryl thioglycolate (GMTG), and ammonium thioglycolate (ATG).

In a pooled analysis, the overall prevalence of contact allergy to PPD was 4.3% in consecutively patch-tested patients, but in hairdressers specifically, the overall prevalence of contact allergy to this ingredient was 28.6%, reviewers reported.

The pooled prevalence of contact allergy to APS was 5.5% in consumers and 17.2% in hairdressers. In other review studies, contact allergy risks to APS, GMTG, and ATG were also elevated in hairdressers compared with all controls.

The calculated relative risk (RR) of contact allergy to PPD was approximately 5.4 higher for hairdressers, while the RR for ATG sensitization was 3.4 in hairdressers compared with consumers.

Commenting on these findings, James A. Yiannias, MD, professor of dermatology at the Mayo Medical School, Phoenix, told this news organization in an email that many providers and patients are concerned only about hair dye molecules such as PPD and aminophenol, as well as permanent, wave, and straightening chemicals such as GMTG.

“Although these are common allergens in hairdressers, allergens such as fragrances and some preservatives found in daily hair care products such as shampoos, conditioners, and hair sprays are also common causes of contact dermatitis,” said Dr. Yiannias, who wasn’t involved in the research.

Consequences of exposure

Dr. Yiannias explained that progressive worsening of the dermatitis can occur with ongoing allergen exposure and, if not properly mitigated, can lead to bigger issues. “Initial nuisances of mild irritation and hyperkeratosis can evolve to a state of fissuring with the risk of bleeding and significant pain,” he said.

But once severe and untreated dermatitis occurs, Dr. Yiannias said that hairdressers “may need to change careers” or at least face short- or long-term unemployment.

The researchers suggest reducing exposure to the allergen is key for prevention of symptoms, adding that adequate guidance on the safe use of new products is needed. Also, the researchers suggested that vocational schools should more rigorously implement education for hairdressers that addresses how to protect the skin appropriately at work.

“Hairdressers are taught during their training to be cautious about allergen exposure by avoiding touching high-risk ingredients such as hair dyes,” Dr. Yiannias added. “However, in practice, this is very difficult since the wearing of gloves can impair the tactile sensations that hairdressers often feel is essential in performing their job.”

The study received no industry funding. Dr. Yiannias reports no relevant financial relationships.

A version of this article first appeared on Medscape.com.