Evidence summary

A 2014 meta-analysis of 4 RCTs including 71,683 patients with nonvalvular atrial fibrillation evaluated the NOACs dabigatran, rivaroxaban, apixaban, and edoxaban, for efficacy and safety compared with warfarin.¹ The RCTs analyzed 42,411 patients receiving NOACs and 29,272 patients receiving warfarin. All trials were designed to show noninferiority. Selection criteria for RCTs included all phase 3 trials of available NOACs (edoxaban isn’t available in the United States). Median follow-up was 1.8 to 2.8 years.

Pooled data demonstrated that NOACs were noninferior to warfarin in preventing stroke or systemic embolism (relative risk [RR]=0.81; 95% confidence interval [CI], 0.73-0.91; number needed to treat [NNT]=147). The main benefit was derived from the relatively large decrease in the rate of hemorrhagic stroke (RR=0.49; 95% CI, 0.38-0.64; NNT=97) compared with warfarin. All-cause mortality was lower with NOACs as well (RR=0.90; 95% CI, 0.85-0.95; NNT=128).

A significant increase in gastrointestinal bleeding occurred with NOACs compared with warfarin (RR=1.3; 95% CI, 1.1-1.6; number needed to harm=185), but NOACs were associated with a decrease in intracranial hemorrhage similar to the reduction in hemorrhagic stroke (RR=0.48; 95% CI, 0.39-0.59; NNT=132).

NOACs show no significant difference in bleeding complications vs warfarin

A 2013 meta-analysis of 5 RCTs including 51,895 patients with nonvalvular atrial fibrillation compared the efficacy and safety of the NOACs dabigatran, rivaroxaban, apixaban, and ximelagatran, with the efficacy and safety of warfarin.² This review included the 3 studies of dabigatran, rivaroxaban, and apixaban from the previously described review, as well as 2 trials of ximelagatran that were not included in the other review (presumably because ximelagatran was no longer available owing to liver toxicity). This review didn’t include the study of edoxaban that was published after the search dates of the literature review.

All trials were designed to show noninferiority. Selection criteria included a study population of at least 3000 patients and use of intention-to-treat analysis. Only 3 of the trials were double-blinded, and 2 were open-label. Mean follow-up was 16 months; median was 24 months.

NOACs were noninferior to vitamin K antagonists in the rate of stroke or systemic embolism (RR=0.82; 95% CI, 0.69-0.98; NNT=200), the rate of death from any cause (RR=0.91; 95% CI, 0.85-0.96; NNT=145), and the rate of hemorrhagic strokes (RR=0.51; 95% CI, 0.41-0.64). NOACs showed no significant difference in major bleeding compared with warfarin (RR=0.83; 95% CI, 0.69-1.0), and were noninferior for minor bleeding (RR=0.88; 95% CI, 0.80-0.97). There was no difference in ischemic stroke (RR=0.87; 95% CI, 0.75-1.06) and major noncerebral bleeding (RR=0.88; 95% CI, 0.73-1.08).

The ACCP weighs in

The American College of Chest Physicians’ 2012 clinical practice guidelines for antithrombotic therapy for atrial fibrillation recommend dabigatran 150 mg twice daily rather than adjusted-dose warfarin therapy for patients with nonvalvular atrial fibrillation requiring thromboembolism prophylaxis (Grade 2B, weak recommendation based on RCTs with important limitations).³

Evidence summary

A 2014 meta-analysis of 4 RCTs including 71,683 patients with nonvalvular atrial fibrillation evaluated the NOACs dabigatran, rivaroxaban, apixaban, and edoxaban, for efficacy and safety compared with warfarin.¹ The RCTs analyzed 42,411 patients receiving NOACs and 29,272 patients receiving warfarin. All trials were designed to show noninferiority. Selection criteria for RCTs included all phase 3 trials of available NOACs (edoxaban isn’t available in the United States). Median follow-up was 1.8 to 2.8 years.

Pooled data demonstrated that NOACs were noninferior to warfarin in preventing stroke or systemic embolism (relative risk [RR]=0.81; 95% confidence interval [CI], 0.73-0.91; number needed to treat [NNT]=147). The main benefit was derived from the relatively large decrease in the rate of hemorrhagic stroke (RR=0.49; 95% CI, 0.38-0.64; NNT=97) compared with warfarin. All-cause mortality was lower with NOACs as well (RR=0.90; 95% CI, 0.85-0.95; NNT=128).

A significant increase in gastrointestinal bleeding occurred with NOACs compared with warfarin (RR=1.3; 95% CI, 1.1-1.6; number needed to harm=185), but NOACs were associated with a decrease in intracranial hemorrhage similar to the reduction in hemorrhagic stroke (RR=0.48; 95% CI, 0.39-0.59; NNT=132).

NOACs show no significant difference in bleeding complications vs warfarin

A 2013 meta-analysis of 5 RCTs including 51,895 patients with nonvalvular atrial fibrillation compared the efficacy and safety of the NOACs dabigatran, rivaroxaban, apixaban, and ximelagatran, with the efficacy and safety of warfarin.² This review included the 3 studies of dabigatran, rivaroxaban, and apixaban from the previously described review, as well as 2 trials of ximelagatran that were not included in the other review (presumably because ximelagatran was no longer available owing to liver toxicity). This review didn’t include the study of edoxaban that was published after the search dates of the literature review.

All trials were designed to show noninferiority. Selection criteria included a study population of at least 3000 patients and use of intention-to-treat analysis. Only 3 of the trials were double-blinded, and 2 were open-label. Mean follow-up was 16 months; median was 24 months.

NOACs were noninferior to vitamin K antagonists in the rate of stroke or systemic embolism (RR=0.82; 95% CI, 0.69-0.98; NNT=200), the rate of death from any cause (RR=0.91; 95% CI, 0.85-0.96; NNT=145), and the rate of hemorrhagic strokes (RR=0.51; 95% CI, 0.41-0.64). NOACs showed no significant difference in major bleeding compared with warfarin (RR=0.83; 95% CI, 0.69-1.0), and were noninferior for minor bleeding (RR=0.88; 95% CI, 0.80-0.97). There was no difference in ischemic stroke (RR=0.87; 95% CI, 0.75-1.06) and major noncerebral bleeding (RR=0.88; 95% CI, 0.73-1.08).

The ACCP weighs in

The American College of Chest Physicians’ 2012 clinical practice guidelines for antithrombotic therapy for atrial fibrillation recommend dabigatran 150 mg twice daily rather than adjusted-dose warfarin therapy for patients with nonvalvular atrial fibrillation requiring thromboembolism prophylaxis (Grade 2B, weak recommendation based on RCTs with important limitations).³

Evidence summary

A 2014 meta-analysis of 4 RCTs including 71,683 patients with nonvalvular atrial fibrillation evaluated the NOACs dabigatran, rivaroxaban, apixaban, and edoxaban, for efficacy and safety compared with warfarin.¹ The RCTs analyzed 42,411 patients receiving NOACs and 29,272 patients receiving warfarin. All trials were designed to show noninferiority. Selection criteria for RCTs included all phase 3 trials of available NOACs (edoxaban isn’t available in the United States). Median follow-up was 1.8 to 2.8 years.

Pooled data demonstrated that NOACs were noninferior to warfarin in preventing stroke or systemic embolism (relative risk [RR]=0.81; 95% confidence interval [CI], 0.73-0.91; number needed to treat [NNT]=147). The main benefit was derived from the relatively large decrease in the rate of hemorrhagic stroke (RR=0.49; 95% CI, 0.38-0.64; NNT=97) compared with warfarin. All-cause mortality was lower with NOACs as well (RR=0.90; 95% CI, 0.85-0.95; NNT=128).

A significant increase in gastrointestinal bleeding occurred with NOACs compared with warfarin (RR=1.3; 95% CI, 1.1-1.6; number needed to harm=185), but NOACs were associated with a decrease in intracranial hemorrhage similar to the reduction in hemorrhagic stroke (RR=0.48; 95% CI, 0.39-0.59; NNT=132).

NOACs show no significant difference in bleeding complications vs warfarin

A 2013 meta-analysis of 5 RCTs including 51,895 patients with nonvalvular atrial fibrillation compared the efficacy and safety of the NOACs dabigatran, rivaroxaban, apixaban, and ximelagatran, with the efficacy and safety of warfarin.² This review included the 3 studies of dabigatran, rivaroxaban, and apixaban from the previously described review, as well as 2 trials of ximelagatran that were not included in the other review (presumably because ximelagatran was no longer available owing to liver toxicity). This review didn’t include the study of edoxaban that was published after the search dates of the literature review.

All trials were designed to show noninferiority. Selection criteria included a study population of at least 3000 patients and use of intention-to-treat analysis. Only 3 of the trials were double-blinded, and 2 were open-label. Mean follow-up was 16 months; median was 24 months.

NOACs were noninferior to vitamin K antagonists in the rate of stroke or systemic embolism (RR=0.82; 95% CI, 0.69-0.98; NNT=200), the rate of death from any cause (RR=0.91; 95% CI, 0.85-0.96; NNT=145), and the rate of hemorrhagic strokes (RR=0.51; 95% CI, 0.41-0.64). NOACs showed no significant difference in major bleeding compared with warfarin (RR=0.83; 95% CI, 0.69-1.0), and were noninferior for minor bleeding (RR=0.88; 95% CI, 0.80-0.97). There was no difference in ischemic stroke (RR=0.87; 95% CI, 0.75-1.06) and major noncerebral bleeding (RR=0.88; 95% CI, 0.73-1.08).

The ACCP weighs in

The American College of Chest Physicians’ 2012 clinical practice guidelines for antithrombotic therapy for atrial fibrillation recommend dabigatran 150 mg twice daily rather than adjusted-dose warfarin therapy for patients with nonvalvular atrial fibrillation requiring thromboembolism prophylaxis (Grade 2B, weak recommendation based on RCTs with important limitations).³

Roughly 1%-2% of pregnancies are complicated by an adnexal mass, and prenatal ultrasound for fetal evaluation has detected more asymptomatic ovarian masses as a result.

The differential diagnosis for adnexal mass is broad and includes follicular or corpus luteum cysts, mature teratoma, theca lutein cyst, hydrosalpinx, endometrioma, cystadenoma, pedunculated leiomyoma, luteoma, as well as malignant neoplasms of epithelial, germ cell, and sex cord–stromal origin (J Ultrasound Med. 2004 Jun;23[6]:805-19). Most masses will be benign neoplasms, with a fraction identified as malignancies.

In 2013, Baser et al. performed a retrospective study of 151 women who underwent surgery of an adnexal mass at time of cesarean delivery. Of the 151 cases reviewed, 148 (98%) of the masses were benign (Int J Gynaecol Obstet. 2013 Nov;123[2]:124-6). Additionally, if the patient presents with pain, diagnoses such as ectopic pregnancy, heterotopic pregnancy, degenerating fibroid, and torsion should also be considered.

Diagnostic evaluation and management

The majority of adnexal masses identified in pregnancy are benign simple cysts measuring less than 5 cm in diameter. Approximately 70% of cystic masses detected in the first trimester will spontaneously resolve by the second trimester (Clin Obstet Gynecol. 2006 Sep;49[3]:492-505). However, for some masses, surgical resection is warranted.

Masses present after the first trimester and that are (1) greater than 10cm in diameter or (2) are solid or contain solid and cystic areas or have septated or papillary areas, are generally managed surgically as these features increase the risk of malignancy or complications such as adnexal torsion, rupture, or labor dystocia (Gynecol Oncol. 2006 May;101(2):315-21).

Adnexal masses without these features often resolve during pregnancy and can be expectantly managed (Obstet Gynecol. 2005 May;105[5 Pt 1]:1098-103). The optimal time for surgical intervention is after the first trimester as organogenesis is largely complete, therefore minimizing the risk of drug-induced teratogenesis, and any necessary cystectomy or oophorectomy will not disrupt the required progesterone production of the corpus luteum as this has been replaced by the placenta.

Preoperative assessment

For most cases, imaging with ultrasound is adequate for preoperative evaluation; however, in some cases, further imaging is needed for appropriate characterization of the mass. In this situation, further imaging with MRI is preferred as this modality has good resolution for visualization of soft tissue pathology and does not expose the patient and fetus to ionizing radiation. Of note, Gadolinium-based contrast should be avoided as effects have not been well established in pregnancy (AJR Am J Roentgenol. 2008 Aug;191[2]:364-70).

If there is concern for malignancy during pregnancy, drawing serum tumor markers preoperatively is typically not suggested. Oncofetal antigens, including alpha fetoprotein (AFP), human chorionic gonadotropin (hCG), carcinoembryonic antigen (CEA), and cancer antigen 125 (CA-125), are elevated during gestation, making them poor markers for malignancy. If malignancy is ultimately diagnosed, then tumor markers can be obtained immediately postoperatively.

Surgical approach and prognosis

If there is low suspicion for malignancy, a laparoscopic approach is preferable and reasonable at all stages of pregnancy, although early second trimester is ideal. Entry at Palmer’s point in the left upper quadrant versus the umbilicus is preferable in order to minimize risk of uterine injury.

If malignancy is suspected, maximum exposure should be obtained with a midline vertical incision. Peritoneal washings should be obtained on immediate entry of the peritoneal cavity, and the contralateral ovary should also be adequately examined along with a general abdominopelvic survey. If the mass demonstrates concerning features, such as solid features or presence of ascites, then the specimen should be sent for intraoperative frozen pathology, and the pathologist should be made aware of the concurrent pregnancy. If malignancy is confirmed on frozen pathology, a full staging procedure should be performed and a gynecologic oncologist consulted.

Roughly three-quarters of invasive ovarian cancers diagnosed in pregnancy are early stage disease, and the 5-year survival of ovarian cancers associated with pregnancy is between 72% and 90% (Int J Gynecol Cancer. 2006 Jan-Feb;16[1]:8-15).

In a retrospective cohort study of 101 pregnant women, 31% of adnexal masses resected in pregnant women greater than 14 weeks gestation were teratomas. In total, 23% of masses were luteal cysts. Less commonly, patients were diagnosed with serous cystadenoma (14%), endometrioma (8%), mucinous cystadenoma (7%), benign cyst (6%), tumor of low malignant potential (5%), and paratubal cyst (3%).

In this study, approximately half of the women underwent minimally invasive surgery and half had surgery via laparotomy. There were more complications in the women undergoing laparotomy (ileus) and there were no differences between the groups with regards to pregnancy and neonatal outcomes (J Minim Invasive Gynecol. 2011 Nov-Dec;18[6]:720-5).

In general, characteristics that are favorable for spontaneous resolution include masses that are simple in nature by ultrasound and less than 5 cm to 6 cm in diameter.

For women with simple-appearing masses on ultrasound, reimaging can occur during the remainder of the pregnancy at the discretion of the physician or during the postpartum period. All women should be provided with torsion and rupture precautions during the pregnancy (Am J Obstet Gynecol. 2011 Aug;205[2]:97-102). For women with more concerning features on ultrasound, referral to a gynecologic oncologist is warranted. If the decision for surgical management is made, minimally invasive surgery should be strongly considered due to minimal maternal and perinatal morbidity.

Dr. Staley is a resident physician in the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill. Dr. Gehrig is professor and director of gynecologic oncology at the university. They reported having no relevant financial disclosures.

Roughly 1%-2% of pregnancies are complicated by an adnexal mass, and prenatal ultrasound for fetal evaluation has detected more asymptomatic ovarian masses as a result.

The differential diagnosis for adnexal mass is broad and includes follicular or corpus luteum cysts, mature teratoma, theca lutein cyst, hydrosalpinx, endometrioma, cystadenoma, pedunculated leiomyoma, luteoma, as well as malignant neoplasms of epithelial, germ cell, and sex cord–stromal origin (J Ultrasound Med. 2004 Jun;23[6]:805-19). Most masses will be benign neoplasms, with a fraction identified as malignancies.

In 2013, Baser et al. performed a retrospective study of 151 women who underwent surgery of an adnexal mass at time of cesarean delivery. Of the 151 cases reviewed, 148 (98%) of the masses were benign (Int J Gynaecol Obstet. 2013 Nov;123[2]:124-6). Additionally, if the patient presents with pain, diagnoses such as ectopic pregnancy, heterotopic pregnancy, degenerating fibroid, and torsion should also be considered.

Diagnostic evaluation and management

The majority of adnexal masses identified in pregnancy are benign simple cysts measuring less than 5 cm in diameter. Approximately 70% of cystic masses detected in the first trimester will spontaneously resolve by the second trimester (Clin Obstet Gynecol. 2006 Sep;49[3]:492-505). However, for some masses, surgical resection is warranted.

Masses present after the first trimester and that are (1) greater than 10cm in diameter or (2) are solid or contain solid and cystic areas or have septated or papillary areas, are generally managed surgically as these features increase the risk of malignancy or complications such as adnexal torsion, rupture, or labor dystocia (Gynecol Oncol. 2006 May;101(2):315-21).

Adnexal masses without these features often resolve during pregnancy and can be expectantly managed (Obstet Gynecol. 2005 May;105[5 Pt 1]:1098-103). The optimal time for surgical intervention is after the first trimester as organogenesis is largely complete, therefore minimizing the risk of drug-induced teratogenesis, and any necessary cystectomy or oophorectomy will not disrupt the required progesterone production of the corpus luteum as this has been replaced by the placenta.

Preoperative assessment

For most cases, imaging with ultrasound is adequate for preoperative evaluation; however, in some cases, further imaging is needed for appropriate characterization of the mass. In this situation, further imaging with MRI is preferred as this modality has good resolution for visualization of soft tissue pathology and does not expose the patient and fetus to ionizing radiation. Of note, Gadolinium-based contrast should be avoided as effects have not been well established in pregnancy (AJR Am J Roentgenol. 2008 Aug;191[2]:364-70).

If there is concern for malignancy during pregnancy, drawing serum tumor markers preoperatively is typically not suggested. Oncofetal antigens, including alpha fetoprotein (AFP), human chorionic gonadotropin (hCG), carcinoembryonic antigen (CEA), and cancer antigen 125 (CA-125), are elevated during gestation, making them poor markers for malignancy. If malignancy is ultimately diagnosed, then tumor markers can be obtained immediately postoperatively.

Surgical approach and prognosis

If there is low suspicion for malignancy, a laparoscopic approach is preferable and reasonable at all stages of pregnancy, although early second trimester is ideal. Entry at Palmer’s point in the left upper quadrant versus the umbilicus is preferable in order to minimize risk of uterine injury.

If malignancy is suspected, maximum exposure should be obtained with a midline vertical incision. Peritoneal washings should be obtained on immediate entry of the peritoneal cavity, and the contralateral ovary should also be adequately examined along with a general abdominopelvic survey. If the mass demonstrates concerning features, such as solid features or presence of ascites, then the specimen should be sent for intraoperative frozen pathology, and the pathologist should be made aware of the concurrent pregnancy. If malignancy is confirmed on frozen pathology, a full staging procedure should be performed and a gynecologic oncologist consulted.

Roughly three-quarters of invasive ovarian cancers diagnosed in pregnancy are early stage disease, and the 5-year survival of ovarian cancers associated with pregnancy is between 72% and 90% (Int J Gynecol Cancer. 2006 Jan-Feb;16[1]:8-15).

In a retrospective cohort study of 101 pregnant women, 31% of adnexal masses resected in pregnant women greater than 14 weeks gestation were teratomas. In total, 23% of masses were luteal cysts. Less commonly, patients were diagnosed with serous cystadenoma (14%), endometrioma (8%), mucinous cystadenoma (7%), benign cyst (6%), tumor of low malignant potential (5%), and paratubal cyst (3%).

In this study, approximately half of the women underwent minimally invasive surgery and half had surgery via laparotomy. There were more complications in the women undergoing laparotomy (ileus) and there were no differences between the groups with regards to pregnancy and neonatal outcomes (J Minim Invasive Gynecol. 2011 Nov-Dec;18[6]:720-5).

In general, characteristics that are favorable for spontaneous resolution include masses that are simple in nature by ultrasound and less than 5 cm to 6 cm in diameter.

For women with simple-appearing masses on ultrasound, reimaging can occur during the remainder of the pregnancy at the discretion of the physician or during the postpartum period. All women should be provided with torsion and rupture precautions during the pregnancy (Am J Obstet Gynecol. 2011 Aug;205[2]:97-102). For women with more concerning features on ultrasound, referral to a gynecologic oncologist is warranted. If the decision for surgical management is made, minimally invasive surgery should be strongly considered due to minimal maternal and perinatal morbidity.

Dr. Staley is a resident physician in the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill. Dr. Gehrig is professor and director of gynecologic oncology at the university. They reported having no relevant financial disclosures.

Roughly 1%-2% of pregnancies are complicated by an adnexal mass, and prenatal ultrasound for fetal evaluation has detected more asymptomatic ovarian masses as a result.

The differential diagnosis for adnexal mass is broad and includes follicular or corpus luteum cysts, mature teratoma, theca lutein cyst, hydrosalpinx, endometrioma, cystadenoma, pedunculated leiomyoma, luteoma, as well as malignant neoplasms of epithelial, germ cell, and sex cord–stromal origin (J Ultrasound Med. 2004 Jun;23[6]:805-19). Most masses will be benign neoplasms, with a fraction identified as malignancies.

In 2013, Baser et al. performed a retrospective study of 151 women who underwent surgery of an adnexal mass at time of cesarean delivery. Of the 151 cases reviewed, 148 (98%) of the masses were benign (Int J Gynaecol Obstet. 2013 Nov;123[2]:124-6). Additionally, if the patient presents with pain, diagnoses such as ectopic pregnancy, heterotopic pregnancy, degenerating fibroid, and torsion should also be considered.

Diagnostic evaluation and management

The majority of adnexal masses identified in pregnancy are benign simple cysts measuring less than 5 cm in diameter. Approximately 70% of cystic masses detected in the first trimester will spontaneously resolve by the second trimester (Clin Obstet Gynecol. 2006 Sep;49[3]:492-505). However, for some masses, surgical resection is warranted.

Masses present after the first trimester and that are (1) greater than 10cm in diameter or (2) are solid or contain solid and cystic areas or have septated or papillary areas, are generally managed surgically as these features increase the risk of malignancy or complications such as adnexal torsion, rupture, or labor dystocia (Gynecol Oncol. 2006 May;101(2):315-21).

Adnexal masses without these features often resolve during pregnancy and can be expectantly managed (Obstet Gynecol. 2005 May;105[5 Pt 1]:1098-103). The optimal time for surgical intervention is after the first trimester as organogenesis is largely complete, therefore minimizing the risk of drug-induced teratogenesis, and any necessary cystectomy or oophorectomy will not disrupt the required progesterone production of the corpus luteum as this has been replaced by the placenta.

Preoperative assessment

For most cases, imaging with ultrasound is adequate for preoperative evaluation; however, in some cases, further imaging is needed for appropriate characterization of the mass. In this situation, further imaging with MRI is preferred as this modality has good resolution for visualization of soft tissue pathology and does not expose the patient and fetus to ionizing radiation. Of note, Gadolinium-based contrast should be avoided as effects have not been well established in pregnancy (AJR Am J Roentgenol. 2008 Aug;191[2]:364-70).

If there is concern for malignancy during pregnancy, drawing serum tumor markers preoperatively is typically not suggested. Oncofetal antigens, including alpha fetoprotein (AFP), human chorionic gonadotropin (hCG), carcinoembryonic antigen (CEA), and cancer antigen 125 (CA-125), are elevated during gestation, making them poor markers for malignancy. If malignancy is ultimately diagnosed, then tumor markers can be obtained immediately postoperatively.

Surgical approach and prognosis

If there is low suspicion for malignancy, a laparoscopic approach is preferable and reasonable at all stages of pregnancy, although early second trimester is ideal. Entry at Palmer’s point in the left upper quadrant versus the umbilicus is preferable in order to minimize risk of uterine injury.

If malignancy is suspected, maximum exposure should be obtained with a midline vertical incision. Peritoneal washings should be obtained on immediate entry of the peritoneal cavity, and the contralateral ovary should also be adequately examined along with a general abdominopelvic survey. If the mass demonstrates concerning features, such as solid features or presence of ascites, then the specimen should be sent for intraoperative frozen pathology, and the pathologist should be made aware of the concurrent pregnancy. If malignancy is confirmed on frozen pathology, a full staging procedure should be performed and a gynecologic oncologist consulted.

Roughly three-quarters of invasive ovarian cancers diagnosed in pregnancy are early stage disease, and the 5-year survival of ovarian cancers associated with pregnancy is between 72% and 90% (Int J Gynecol Cancer. 2006 Jan-Feb;16[1]:8-15).

In a retrospective cohort study of 101 pregnant women, 31% of adnexal masses resected in pregnant women greater than 14 weeks gestation were teratomas. In total, 23% of masses were luteal cysts. Less commonly, patients were diagnosed with serous cystadenoma (14%), endometrioma (8%), mucinous cystadenoma (7%), benign cyst (6%), tumor of low malignant potential (5%), and paratubal cyst (3%).

In this study, approximately half of the women underwent minimally invasive surgery and half had surgery via laparotomy. There were more complications in the women undergoing laparotomy (ileus) and there were no differences between the groups with regards to pregnancy and neonatal outcomes (J Minim Invasive Gynecol. 2011 Nov-Dec;18[6]:720-5).

In general, characteristics that are favorable for spontaneous resolution include masses that are simple in nature by ultrasound and less than 5 cm to 6 cm in diameter.

For women with simple-appearing masses on ultrasound, reimaging can occur during the remainder of the pregnancy at the discretion of the physician or during the postpartum period. All women should be provided with torsion and rupture precautions during the pregnancy (Am J Obstet Gynecol. 2011 Aug;205[2]:97-102). For women with more concerning features on ultrasound, referral to a gynecologic oncologist is warranted. If the decision for surgical management is made, minimally invasive surgery should be strongly considered due to minimal maternal and perinatal morbidity.

Dr. Staley is a resident physician in the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill. Dr. Gehrig is professor and director of gynecologic oncology at the university. They reported having no relevant financial disclosures.

STREPTOCOCCUS PNEUMONIAE (the “pneumococcus”) causes a variety of clinical syndromes that range from otitis media to bacteremia, meningitis, and pneumonia. Hardest hit are immunocompromised people and those at the extremes of age. Therefore, preventing disease through pneumococcal vaccination is very important in these groups.

This review summarizes the current guidelines from the Advisory Committee on Immunization Practices (ACIP) of the US Centers for Disease Control and Prevention (CDC) for pneumococcal immunization in adults.

STRIKES THE VERY YOUNG, VERY OLD, AND IMMUNOCOMPROMISED

Invasive pneumococcal disease is defined as infection in which S pneumoniae can be found in a normally sterile site such as the cerebrospinal fluid or blood, and it includes bacteremic pneumonia.¹ By far the most common type of pneumococcal disease is pneumonia, followed by bacteremia and meningitis (Figure 1);^2,3 about 25% of patients with pneumococcal pneumonia also have bacteremia.²

Invasive pneumococcal disease most often occurs in children age 2 and younger, adults age 65 and older, and people who are immunocompromised. In 2010, the incidence was 3.8 per 100,000 in people ages 18 to 34 but was 10 times higher in the elderly and those with compromised immunity.¹

Even now that vaccines are available, invasive pneumococcal disease continues to cause 4,000 deaths per year in the United States.¹

TWO INACTIVATED VACCINES

S pneumoniae is a gram-positive coccus with an outer capsule composed of polysaccharides that protect the bacterium from being ingested and killed by host phagocytic cells. Some 91 serotypes of this organism have been identified on the basis of genetic differences in capsular polysaccharide composition.

Currently, two inactivated vaccines are available that elicit antibody responses to the most common pneumococcal serotypes that infect humans.

• PPSV23 (pneumococcal polysaccharide vaccine-23, or Pneumovax 23) contains purified capsular polysaccharides from 23 pneumococcal serotypes.
• PCV13 (pneumococcal conjugate vaccine-13, or Prevnar 13) contains purified capsular polysaccharides from 13 serotypes that are covalently bound to (conjugated with) a carrier protein.

PPSV23 AND PCV13 ARE NOT THE SAME

Apart from the number of serotypes covered, the two vaccines differ in important ways. Both of them elicit a B-cell-mediated immune response, but only PCV13 produces a T-cell-dependent response, which is essential for maturation of the B-cell response and development of immune memory.

PPSV23 generally provides 3 to 5 years of immunity, and repeat doses do not offer additive or “boosted” protection. It is ineffective in children under 2 years of age.

Pneumococcal conjugate vaccine has been available since 2000 for children starting at 2 months of age. Since then it has directly reduced the incidence of invasive pneumococcal disease in children and indirectly in adults. The impact on pneumococcal disease rates in adults has probably been related to reduction in rates of pneumococcal nasopharyngeal carriage in children, another unique benefit of conjugated vaccines.³

In December 2011, the US Food and Drug Administration (FDA) approved PCV13 for adults on the basis of immunologic studies and anticipation that clinical efficacy would be similar to that observed in children.

HOW EFFECTIVE ARE THEY?

The efficacy and safety of PPSV23 and PCV13 have been studied in a variety of patient populations. Though antibody responses to PCV13 were similar to or better than those with PPSV23, no studies of specific correlations between immunologic responses and disease outcomes are available.^4,5

In large studies in healthy adults, both vaccines reduced the incidence of invasive pneumococcal disease. A study in more than 47,000 adults age 65 and older showed a significant reduction in pneumococcal bacteremia (hazard ratio 0.56, 95% confidence interval 0.33–0.93) in those who received PPSV23 compared with those who received placebo.⁶ However, PPSV23 was not effective in preventing nonbacteremic and noninvasive pneumococcal community-acquired pneumonia when all bacterial serotypes were considered.⁶

In a placebo-controlled trial in more than 84,000 people age 65 and older, PCV13 prevented both nonbacteremic and bacteremic community-acquired pneumococcal pneumonia due to serotypes included in the vaccine (relative risk reduction 45%, P < .007) and overall invasive pneumococcal disease due to serotypes included in the vaccine (relative risk reduction 70%, P < .001).⁷

Both vaccines have also demonstrated efficacy in immunocompromised adults. Several studies showed an equivalent or superior antibody response to a seven-valent pneumococcal conjugate vaccine (PCV7, which has been replaced by PCV13) compared with PPSV23 in adults with human immunodeficiency virus (HIV) infection.^8,9 While specific clinical studies of the efficacy of PCV13 among immunocompromised people are not available, a study of vaccination with PCV7 in 496 people in Malawi, of whom 88% were infected with HIV, found that the vaccine was effective in preventing invasive pneumococcal disease (hazard ratio 26%, 95% confidence interval 0.10–0.70).¹⁰

AT-RISK PATIENT POPULATIONS

Since both PPSV23 and PCV13 are approved for use in adults, it is important to understand appropriate indications for their use. The ACIP recommends pneumococcal vaccination in adults at an increased risk of invasive pneumococcal disease: ie, people age 65 and older, at-risk people ages 19 to 64, and people who are immunocompromised or asplenic.

A more robust antibody response has been shown with PCV13 compared to PPSV23 in healthy people.⁵ Of note, when PPSV23 is given before PCV13, there is a diminished immune response to PCV13.^11,12 Therefore, unvaccinated people who will receive both PCV13 and PPSV23 should be given the conjugate vaccine PCV13 first. (See Commonly asked questions.)

ADULTS AGE 65 AND OLDER: ONE DOSE EACH OF PCV13 AND PPSV23

Before September 2014, the ACIP recommended one dose of PPSV23 for adults age 65 and older to prevent invasive pneumococcal disease.¹³ With evidence that PCV13 also produces an antibody response and is clinically effective against pneumococcal pneumonia in older people, the ACIP now recommends that all adults age 65 and older receive one dose of PCV13 and one dose of PPSV23.^3,14

Based on antibody studies, the ACIP recommends giving PCV13 first and PPSV23 12 months after.^11,12 Patients who received PPSV23 at age 65 or older should receive PCV13 at least 1 year after PPSV23 (Figure 2).^3,14 Patients who had previously received one dose of PPSV23 before age 65 who are now age 65 or older should receive one dose of PCV13 at least 1 year after PPSV23 and an additional dose of PPSV23 at least 5 years after the first dose of PPSV23 and at least 1 year after the dose of PCV13.³ Patients who received a dose of PCV13 before age 65 do not need an additional dose after age 65.

The Centers for Medicare and Medicaid Services have updated the reimbursement for pneumococcal vaccines to include both PCV13 and PPSV23. Patients can receive one dose of pneumococcal vaccine followed by a different, second pneumococcal vaccine at least 11 full months after the month in which the first pneumococcal vaccine was administered.¹⁵

AT-RISK PATIENTS AGES 19 TO 64

Before 2012, the ACIP recommended that patients at risk, including immunocompromised patients and those without a spleen, with cerebrospinal fluid leaks, or with cochlear implants, receive only PPSV23 before age 65.¹³ In 2010, 50% of cases of invasive pneumococcal disease in immunocompromised adults were due to serotypes contained in PCV13.¹⁶ Additionally, according to CDC data from 2013, in adults ages 19 to 64 at risk of pneumococcal disease, only 21.2% had received pneumococcal vaccine.¹⁷ With information on epidemiology, safety, and efficacy, as well as expanded FDA approval of PCV13 for adults in 2011, the ACIP updated its guidelines for pneumococcal immunization of adults with immunocompromising conditions in October 2012.¹⁶ The updated guidelines now include giving PCV13 to adults at increased risk of invasive pneumococcal disease.¹⁶

Adults under age 65 at risk of invasive pneumococcal disease can be further divided into those who are immunocompetent with comorbid conditions, and those with cochlear implants or cerebrospinal fluid leak (Table 1).¹⁶

Patients with cochlear implants or cerebrospinal fluid leaks should receive one dose of PCV13 followed by one dose of PPSV23 8 weeks later. If PPSV23 is given first in this group, PCV13 can be given 1 year later.

Immunocompetent patients with comorbid conditions, including cigarette smoking, chronic heart, liver, or lung disease, asthma, cirrhosis, and diabetes mellitus, should receive one dose of PPSV23 before age 65 (Table 1).¹⁶

IMMUNOCOMPROMISED AND ASPLENIC PATIENTS

Immunocompromised patients at risk for invasive pneumococcal disease include patients with functional or anatomic asplenia or immunocompromising conditions such as HIV infection, chronic renal failure, generalized malignancy, solid organ transplant, iatrogenic immunosuppression (eg, due to corticosteroid therapy), and other immunocompromising conditions.¹⁶ Patients on corticosteroid therapy are considered immunosuppressed if they take 20 mg or more of prednisone daily (or an equivalent corticosteroid dose) for at least 14 days.¹⁶ These immunocompromised patients should receive one dose of PCV13, followed by a PPSV23 dose 8 weeks later and a second PPSV23 dose 5 years after the first.¹⁶

The time between vaccinations is also important. If PCV13 is given first, PPSV23 can be given after at least 8 weeks. If PPSV23 is given first, PCV13 should be given after 12 months. The time between PPSV23 doses is 5 years (Figure 3).¹⁶

ADDRESSING BARRIERS TO PNEUMOCOCCAL VACCINATION

In 2013, only 59.7% of adults age 65 and older and 21.1% of younger, at-risk adults with immunocompromising conditions had received pneumococcal vaccination.¹⁷ Healthcare providers have the opportunity to improve pneumococcal vaccination rates. The National Foundation for Infectious Diseases (www.nfid.org) summarized challenges in vaccinating at-risk patients and recommended strategies to overcome barriers.¹⁸

Challenges include the cost of vaccine coverage, limited time (with competing priorities during office appointments or hospitalizations), patient refusal, and knowledge gaps.

Strategies to overcome barriers include incorporating vaccination into protocols and procedures; educating healthcare providers and patients about pneumococcal disease, vaccines, costs, and reimbursement; engaging nonclinical staff members; and monitoring local vaccination rates. However, the most important factor affecting whether adults are vaccinated is whether the healthcare provider recommends it.

AN OPPORTUNITY TO IMPROVE

In the last 30 years, great strides have been made in recognizing and preventing pneumococcal disease, but challenges remain. Adherence to the new ACIP guidelines for pneumococcal vaccination in immunocompromised, at risk and elderly patients is important in reducing invasive pneumococcal disease.

Healthcare providers have the opportunity to improve pneumococcal vaccination rates at outpatient appointments to decrease the burden of invasive pneumococcal disease in at-risk populations. A comprehensive understanding of the guideline recommendations for pneumococcal vaccination can aid the provider in identifying patients who are eligible for vaccination.

Adult pneumococcal immunization rates are low due to missed opportunities. Healthcare providers can improve these rates by viewing every patient encounter as a chance to provide vaccination.

TAKE THE POST-TEST AND COMPLETE THE CME PROCESS

STREPTOCOCCUS PNEUMONIAE (the “pneumococcus”) causes a variety of clinical syndromes that range from otitis media to bacteremia, meningitis, and pneumonia. Hardest hit are immunocompromised people and those at the extremes of age. Therefore, preventing disease through pneumococcal vaccination is very important in these groups.

This review summarizes the current guidelines from the Advisory Committee on Immunization Practices (ACIP) of the US Centers for Disease Control and Prevention (CDC) for pneumococcal immunization in adults.

STRIKES THE VERY YOUNG, VERY OLD, AND IMMUNOCOMPROMISED

Invasive pneumococcal disease is defined as infection in which S pneumoniae can be found in a normally sterile site such as the cerebrospinal fluid or blood, and it includes bacteremic pneumonia.¹ By far the most common type of pneumococcal disease is pneumonia, followed by bacteremia and meningitis (Figure 1);^2,3 about 25% of patients with pneumococcal pneumonia also have bacteremia.²

Invasive pneumococcal disease most often occurs in children age 2 and younger, adults age 65 and older, and people who are immunocompromised. In 2010, the incidence was 3.8 per 100,000 in people ages 18 to 34 but was 10 times higher in the elderly and those with compromised immunity.¹

Even now that vaccines are available, invasive pneumococcal disease continues to cause 4,000 deaths per year in the United States.¹

TWO INACTIVATED VACCINES

S pneumoniae is a gram-positive coccus with an outer capsule composed of polysaccharides that protect the bacterium from being ingested and killed by host phagocytic cells. Some 91 serotypes of this organism have been identified on the basis of genetic differences in capsular polysaccharide composition.

Currently, two inactivated vaccines are available that elicit antibody responses to the most common pneumococcal serotypes that infect humans.

• PPSV23 (pneumococcal polysaccharide vaccine-23, or Pneumovax 23) contains purified capsular polysaccharides from 23 pneumococcal serotypes.
• PCV13 (pneumococcal conjugate vaccine-13, or Prevnar 13) contains purified capsular polysaccharides from 13 serotypes that are covalently bound to (conjugated with) a carrier protein.

PPSV23 AND PCV13 ARE NOT THE SAME

Apart from the number of serotypes covered, the two vaccines differ in important ways. Both of them elicit a B-cell-mediated immune response, but only PCV13 produces a T-cell-dependent response, which is essential for maturation of the B-cell response and development of immune memory.

PPSV23 generally provides 3 to 5 years of immunity, and repeat doses do not offer additive or “boosted” protection. It is ineffective in children under 2 years of age.

Pneumococcal conjugate vaccine has been available since 2000 for children starting at 2 months of age. Since then it has directly reduced the incidence of invasive pneumococcal disease in children and indirectly in adults. The impact on pneumococcal disease rates in adults has probably been related to reduction in rates of pneumococcal nasopharyngeal carriage in children, another unique benefit of conjugated vaccines.³

In December 2011, the US Food and Drug Administration (FDA) approved PCV13 for adults on the basis of immunologic studies and anticipation that clinical efficacy would be similar to that observed in children.

HOW EFFECTIVE ARE THEY?

The efficacy and safety of PPSV23 and PCV13 have been studied in a variety of patient populations. Though antibody responses to PCV13 were similar to or better than those with PPSV23, no studies of specific correlations between immunologic responses and disease outcomes are available.^4,5

In large studies in healthy adults, both vaccines reduced the incidence of invasive pneumococcal disease. A study in more than 47,000 adults age 65 and older showed a significant reduction in pneumococcal bacteremia (hazard ratio 0.56, 95% confidence interval 0.33–0.93) in those who received PPSV23 compared with those who received placebo.⁶ However, PPSV23 was not effective in preventing nonbacteremic and noninvasive pneumococcal community-acquired pneumonia when all bacterial serotypes were considered.⁶

In a placebo-controlled trial in more than 84,000 people age 65 and older, PCV13 prevented both nonbacteremic and bacteremic community-acquired pneumococcal pneumonia due to serotypes included in the vaccine (relative risk reduction 45%, P < .007) and overall invasive pneumococcal disease due to serotypes included in the vaccine (relative risk reduction 70%, P < .001).⁷

Both vaccines have also demonstrated efficacy in immunocompromised adults. Several studies showed an equivalent or superior antibody response to a seven-valent pneumococcal conjugate vaccine (PCV7, which has been replaced by PCV13) compared with PPSV23 in adults with human immunodeficiency virus (HIV) infection.^8,9 While specific clinical studies of the efficacy of PCV13 among immunocompromised people are not available, a study of vaccination with PCV7 in 496 people in Malawi, of whom 88% were infected with HIV, found that the vaccine was effective in preventing invasive pneumococcal disease (hazard ratio 26%, 95% confidence interval 0.10–0.70).¹⁰

AT-RISK PATIENT POPULATIONS

Since both PPSV23 and PCV13 are approved for use in adults, it is important to understand appropriate indications for their use. The ACIP recommends pneumococcal vaccination in adults at an increased risk of invasive pneumococcal disease: ie, people age 65 and older, at-risk people ages 19 to 64, and people who are immunocompromised or asplenic.

A more robust antibody response has been shown with PCV13 compared to PPSV23 in healthy people.⁵ Of note, when PPSV23 is given before PCV13, there is a diminished immune response to PCV13.^11,12 Therefore, unvaccinated people who will receive both PCV13 and PPSV23 should be given the conjugate vaccine PCV13 first. (See Commonly asked questions.)

ADULTS AGE 65 AND OLDER: ONE DOSE EACH OF PCV13 AND PPSV23

Before September 2014, the ACIP recommended one dose of PPSV23 for adults age 65 and older to prevent invasive pneumococcal disease.¹³ With evidence that PCV13 also produces an antibody response and is clinically effective against pneumococcal pneumonia in older people, the ACIP now recommends that all adults age 65 and older receive one dose of PCV13 and one dose of PPSV23.^3,14

Based on antibody studies, the ACIP recommends giving PCV13 first and PPSV23 12 months after.^11,12 Patients who received PPSV23 at age 65 or older should receive PCV13 at least 1 year after PPSV23 (Figure 2).^3,14 Patients who had previously received one dose of PPSV23 before age 65 who are now age 65 or older should receive one dose of PCV13 at least 1 year after PPSV23 and an additional dose of PPSV23 at least 5 years after the first dose of PPSV23 and at least 1 year after the dose of PCV13.³ Patients who received a dose of PCV13 before age 65 do not need an additional dose after age 65.

The Centers for Medicare and Medicaid Services have updated the reimbursement for pneumococcal vaccines to include both PCV13 and PPSV23. Patients can receive one dose of pneumococcal vaccine followed by a different, second pneumococcal vaccine at least 11 full months after the month in which the first pneumococcal vaccine was administered.¹⁵

AT-RISK PATIENTS AGES 19 TO 64

Before 2012, the ACIP recommended that patients at risk, including immunocompromised patients and those without a spleen, with cerebrospinal fluid leaks, or with cochlear implants, receive only PPSV23 before age 65.¹³ In 2010, 50% of cases of invasive pneumococcal disease in immunocompromised adults were due to serotypes contained in PCV13.¹⁶ Additionally, according to CDC data from 2013, in adults ages 19 to 64 at risk of pneumococcal disease, only 21.2% had received pneumococcal vaccine.¹⁷ With information on epidemiology, safety, and efficacy, as well as expanded FDA approval of PCV13 for adults in 2011, the ACIP updated its guidelines for pneumococcal immunization of adults with immunocompromising conditions in October 2012.¹⁶ The updated guidelines now include giving PCV13 to adults at increased risk of invasive pneumococcal disease.¹⁶

Adults under age 65 at risk of invasive pneumococcal disease can be further divided into those who are immunocompetent with comorbid conditions, and those with cochlear implants or cerebrospinal fluid leak (Table 1).¹⁶

Patients with cochlear implants or cerebrospinal fluid leaks should receive one dose of PCV13 followed by one dose of PPSV23 8 weeks later. If PPSV23 is given first in this group, PCV13 can be given 1 year later.

Immunocompetent patients with comorbid conditions, including cigarette smoking, chronic heart, liver, or lung disease, asthma, cirrhosis, and diabetes mellitus, should receive one dose of PPSV23 before age 65 (Table 1).¹⁶

IMMUNOCOMPROMISED AND ASPLENIC PATIENTS

Immunocompromised patients at risk for invasive pneumococcal disease include patients with functional or anatomic asplenia or immunocompromising conditions such as HIV infection, chronic renal failure, generalized malignancy, solid organ transplant, iatrogenic immunosuppression (eg, due to corticosteroid therapy), and other immunocompromising conditions.¹⁶ Patients on corticosteroid therapy are considered immunosuppressed if they take 20 mg or more of prednisone daily (or an equivalent corticosteroid dose) for at least 14 days.¹⁶ These immunocompromised patients should receive one dose of PCV13, followed by a PPSV23 dose 8 weeks later and a second PPSV23 dose 5 years after the first.¹⁶

The time between vaccinations is also important. If PCV13 is given first, PPSV23 can be given after at least 8 weeks. If PPSV23 is given first, PCV13 should be given after 12 months. The time between PPSV23 doses is 5 years (Figure 3).¹⁶

ADDRESSING BARRIERS TO PNEUMOCOCCAL VACCINATION

In 2013, only 59.7% of adults age 65 and older and 21.1% of younger, at-risk adults with immunocompromising conditions had received pneumococcal vaccination.¹⁷ Healthcare providers have the opportunity to improve pneumococcal vaccination rates. The National Foundation for Infectious Diseases (www.nfid.org) summarized challenges in vaccinating at-risk patients and recommended strategies to overcome barriers.¹⁸

Challenges include the cost of vaccine coverage, limited time (with competing priorities during office appointments or hospitalizations), patient refusal, and knowledge gaps.

Strategies to overcome barriers include incorporating vaccination into protocols and procedures; educating healthcare providers and patients about pneumococcal disease, vaccines, costs, and reimbursement; engaging nonclinical staff members; and monitoring local vaccination rates. However, the most important factor affecting whether adults are vaccinated is whether the healthcare provider recommends it.

AN OPPORTUNITY TO IMPROVE

In the last 30 years, great strides have been made in recognizing and preventing pneumococcal disease, but challenges remain. Adherence to the new ACIP guidelines for pneumococcal vaccination in immunocompromised, at risk and elderly patients is important in reducing invasive pneumococcal disease.

Healthcare providers have the opportunity to improve pneumococcal vaccination rates at outpatient appointments to decrease the burden of invasive pneumococcal disease in at-risk populations. A comprehensive understanding of the guideline recommendations for pneumococcal vaccination can aid the provider in identifying patients who are eligible for vaccination.

Adult pneumococcal immunization rates are low due to missed opportunities. Healthcare providers can improve these rates by viewing every patient encounter as a chance to provide vaccination.

TAKE THE POST-TEST AND COMPLETE THE CME PROCESS

STREPTOCOCCUS PNEUMONIAE (the “pneumococcus”) causes a variety of clinical syndromes that range from otitis media to bacteremia, meningitis, and pneumonia. Hardest hit are immunocompromised people and those at the extremes of age. Therefore, preventing disease through pneumococcal vaccination is very important in these groups.

This review summarizes the current guidelines from the Advisory Committee on Immunization Practices (ACIP) of the US Centers for Disease Control and Prevention (CDC) for pneumococcal immunization in adults.

STRIKES THE VERY YOUNG, VERY OLD, AND IMMUNOCOMPROMISED

Invasive pneumococcal disease is defined as infection in which S pneumoniae can be found in a normally sterile site such as the cerebrospinal fluid or blood, and it includes bacteremic pneumonia.¹ By far the most common type of pneumococcal disease is pneumonia, followed by bacteremia and meningitis (Figure 1);^2,3 about 25% of patients with pneumococcal pneumonia also have bacteremia.²

Invasive pneumococcal disease most often occurs in children age 2 and younger, adults age 65 and older, and people who are immunocompromised. In 2010, the incidence was 3.8 per 100,000 in people ages 18 to 34 but was 10 times higher in the elderly and those with compromised immunity.¹

Even now that vaccines are available, invasive pneumococcal disease continues to cause 4,000 deaths per year in the United States.¹

TWO INACTIVATED VACCINES

S pneumoniae is a gram-positive coccus with an outer capsule composed of polysaccharides that protect the bacterium from being ingested and killed by host phagocytic cells. Some 91 serotypes of this organism have been identified on the basis of genetic differences in capsular polysaccharide composition.

Currently, two inactivated vaccines are available that elicit antibody responses to the most common pneumococcal serotypes that infect humans.

• PPSV23 (pneumococcal polysaccharide vaccine-23, or Pneumovax 23) contains purified capsular polysaccharides from 23 pneumococcal serotypes.
• PCV13 (pneumococcal conjugate vaccine-13, or Prevnar 13) contains purified capsular polysaccharides from 13 serotypes that are covalently bound to (conjugated with) a carrier protein.

PPSV23 AND PCV13 ARE NOT THE SAME

Apart from the number of serotypes covered, the two vaccines differ in important ways. Both of them elicit a B-cell-mediated immune response, but only PCV13 produces a T-cell-dependent response, which is essential for maturation of the B-cell response and development of immune memory.

PPSV23 generally provides 3 to 5 years of immunity, and repeat doses do not offer additive or “boosted” protection. It is ineffective in children under 2 years of age.

Pneumococcal conjugate vaccine has been available since 2000 for children starting at 2 months of age. Since then it has directly reduced the incidence of invasive pneumococcal disease in children and indirectly in adults. The impact on pneumococcal disease rates in adults has probably been related to reduction in rates of pneumococcal nasopharyngeal carriage in children, another unique benefit of conjugated vaccines.³

In December 2011, the US Food and Drug Administration (FDA) approved PCV13 for adults on the basis of immunologic studies and anticipation that clinical efficacy would be similar to that observed in children.

HOW EFFECTIVE ARE THEY?

The efficacy and safety of PPSV23 and PCV13 have been studied in a variety of patient populations. Though antibody responses to PCV13 were similar to or better than those with PPSV23, no studies of specific correlations between immunologic responses and disease outcomes are available.^4,5

In large studies in healthy adults, both vaccines reduced the incidence of invasive pneumococcal disease. A study in more than 47,000 adults age 65 and older showed a significant reduction in pneumococcal bacteremia (hazard ratio 0.56, 95% confidence interval 0.33–0.93) in those who received PPSV23 compared with those who received placebo.⁶ However, PPSV23 was not effective in preventing nonbacteremic and noninvasive pneumococcal community-acquired pneumonia when all bacterial serotypes were considered.⁶

In a placebo-controlled trial in more than 84,000 people age 65 and older, PCV13 prevented both nonbacteremic and bacteremic community-acquired pneumococcal pneumonia due to serotypes included in the vaccine (relative risk reduction 45%, P < .007) and overall invasive pneumococcal disease due to serotypes included in the vaccine (relative risk reduction 70%, P < .001).⁷

Both vaccines have also demonstrated efficacy in immunocompromised adults. Several studies showed an equivalent or superior antibody response to a seven-valent pneumococcal conjugate vaccine (PCV7, which has been replaced by PCV13) compared with PPSV23 in adults with human immunodeficiency virus (HIV) infection.^8,9 While specific clinical studies of the efficacy of PCV13 among immunocompromised people are not available, a study of vaccination with PCV7 in 496 people in Malawi, of whom 88% were infected with HIV, found that the vaccine was effective in preventing invasive pneumococcal disease (hazard ratio 26%, 95% confidence interval 0.10–0.70).¹⁰

AT-RISK PATIENT POPULATIONS

Since both PPSV23 and PCV13 are approved for use in adults, it is important to understand appropriate indications for their use. The ACIP recommends pneumococcal vaccination in adults at an increased risk of invasive pneumococcal disease: ie, people age 65 and older, at-risk people ages 19 to 64, and people who are immunocompromised or asplenic.

A more robust antibody response has been shown with PCV13 compared to PPSV23 in healthy people.⁵ Of note, when PPSV23 is given before PCV13, there is a diminished immune response to PCV13.^11,12 Therefore, unvaccinated people who will receive both PCV13 and PPSV23 should be given the conjugate vaccine PCV13 first. (See Commonly asked questions.)

ADULTS AGE 65 AND OLDER: ONE DOSE EACH OF PCV13 AND PPSV23

Before September 2014, the ACIP recommended one dose of PPSV23 for adults age 65 and older to prevent invasive pneumococcal disease.¹³ With evidence that PCV13 also produces an antibody response and is clinically effective against pneumococcal pneumonia in older people, the ACIP now recommends that all adults age 65 and older receive one dose of PCV13 and one dose of PPSV23.^3,14

Based on antibody studies, the ACIP recommends giving PCV13 first and PPSV23 12 months after.^11,12 Patients who received PPSV23 at age 65 or older should receive PCV13 at least 1 year after PPSV23 (Figure 2).^3,14 Patients who had previously received one dose of PPSV23 before age 65 who are now age 65 or older should receive one dose of PCV13 at least 1 year after PPSV23 and an additional dose of PPSV23 at least 5 years after the first dose of PPSV23 and at least 1 year after the dose of PCV13.³ Patients who received a dose of PCV13 before age 65 do not need an additional dose after age 65.

The Centers for Medicare and Medicaid Services have updated the reimbursement for pneumococcal vaccines to include both PCV13 and PPSV23. Patients can receive one dose of pneumococcal vaccine followed by a different, second pneumococcal vaccine at least 11 full months after the month in which the first pneumococcal vaccine was administered.¹⁵

AT-RISK PATIENTS AGES 19 TO 64

Before 2012, the ACIP recommended that patients at risk, including immunocompromised patients and those without a spleen, with cerebrospinal fluid leaks, or with cochlear implants, receive only PPSV23 before age 65.¹³ In 2010, 50% of cases of invasive pneumococcal disease in immunocompromised adults were due to serotypes contained in PCV13.¹⁶ Additionally, according to CDC data from 2013, in adults ages 19 to 64 at risk of pneumococcal disease, only 21.2% had received pneumococcal vaccine.¹⁷ With information on epidemiology, safety, and efficacy, as well as expanded FDA approval of PCV13 for adults in 2011, the ACIP updated its guidelines for pneumococcal immunization of adults with immunocompromising conditions in October 2012.¹⁶ The updated guidelines now include giving PCV13 to adults at increased risk of invasive pneumococcal disease.¹⁶

Adults under age 65 at risk of invasive pneumococcal disease can be further divided into those who are immunocompetent with comorbid conditions, and those with cochlear implants or cerebrospinal fluid leak (Table 1).¹⁶

Patients with cochlear implants or cerebrospinal fluid leaks should receive one dose of PCV13 followed by one dose of PPSV23 8 weeks later. If PPSV23 is given first in this group, PCV13 can be given 1 year later.

Immunocompetent patients with comorbid conditions, including cigarette smoking, chronic heart, liver, or lung disease, asthma, cirrhosis, and diabetes mellitus, should receive one dose of PPSV23 before age 65 (Table 1).¹⁶

IMMUNOCOMPROMISED AND ASPLENIC PATIENTS

Immunocompromised patients at risk for invasive pneumococcal disease include patients with functional or anatomic asplenia or immunocompromising conditions such as HIV infection, chronic renal failure, generalized malignancy, solid organ transplant, iatrogenic immunosuppression (eg, due to corticosteroid therapy), and other immunocompromising conditions.¹⁶ Patients on corticosteroid therapy are considered immunosuppressed if they take 20 mg or more of prednisone daily (or an equivalent corticosteroid dose) for at least 14 days.¹⁶ These immunocompromised patients should receive one dose of PCV13, followed by a PPSV23 dose 8 weeks later and a second PPSV23 dose 5 years after the first.¹⁶

The time between vaccinations is also important. If PCV13 is given first, PPSV23 can be given after at least 8 weeks. If PPSV23 is given first, PCV13 should be given after 12 months. The time between PPSV23 doses is 5 years (Figure 3).¹⁶

ADDRESSING BARRIERS TO PNEUMOCOCCAL VACCINATION

In 2013, only 59.7% of adults age 65 and older and 21.1% of younger, at-risk adults with immunocompromising conditions had received pneumococcal vaccination.¹⁷ Healthcare providers have the opportunity to improve pneumococcal vaccination rates. The National Foundation for Infectious Diseases (www.nfid.org) summarized challenges in vaccinating at-risk patients and recommended strategies to overcome barriers.¹⁸

Challenges include the cost of vaccine coverage, limited time (with competing priorities during office appointments or hospitalizations), patient refusal, and knowledge gaps.

Strategies to overcome barriers include incorporating vaccination into protocols and procedures; educating healthcare providers and patients about pneumococcal disease, vaccines, costs, and reimbursement; engaging nonclinical staff members; and monitoring local vaccination rates. However, the most important factor affecting whether adults are vaccinated is whether the healthcare provider recommends it.

AN OPPORTUNITY TO IMPROVE

In the last 30 years, great strides have been made in recognizing and preventing pneumococcal disease, but challenges remain. Adherence to the new ACIP guidelines for pneumococcal vaccination in immunocompromised, at risk and elderly patients is important in reducing invasive pneumococcal disease.

Healthcare providers have the opportunity to improve pneumococcal vaccination rates at outpatient appointments to decrease the burden of invasive pneumococcal disease in at-risk populations. A comprehensive understanding of the guideline recommendations for pneumococcal vaccination can aid the provider in identifying patients who are eligible for vaccination.

Adult pneumococcal immunization rates are low due to missed opportunities. Healthcare providers can improve these rates by viewing every patient encounter as a chance to provide vaccination.

TAKE THE POST-TEST AND COMPLETE THE CME PROCESS

• Reenergize and focus your practice with the latest research, best practices, and newest innovations in the field that can immediately be applied to improving patient care.
• Learn from the “best of the best,” including nationally renowned leaders in the field of hospital medicine.
• Connect and collaborate with a vibrant community of hospital medicine professionals.

It’s not too early to register! Sign up now and save at www.hospitalmedicine2017.org.

• Reenergize and focus your practice with the latest research, best practices, and newest innovations in the field that can immediately be applied to improving patient care.
• Learn from the “best of the best,” including nationally renowned leaders in the field of hospital medicine.
• Connect and collaborate with a vibrant community of hospital medicine professionals.

It’s not too early to register! Sign up now and save at www.hospitalmedicine2017.org.

• Reenergize and focus your practice with the latest research, best practices, and newest innovations in the field that can immediately be applied to improving patient care.
• Learn from the “best of the best,” including nationally renowned leaders in the field of hospital medicine.
• Connect and collaborate with a vibrant community of hospital medicine professionals.

It’s not too early to register! Sign up now and save at www.hospitalmedicine2017.org.

A successful hospitalist program requires strong leadership from the unit to the C-suite. SHM’s Leadership Academy (www.shmleadershipacademy.org) prepares clinical and academic leaders with vital skills traditionally not taught in medical school or typical residency programs. This year’s meeting will be held from October 24 to 27 at Disney’s BoardWalk Inn in Lake Buena Vista, Fla. Courses offered include:

• Leadership Foundations: Evaluate your personal leadership strengths and weaknesses, understand key hospital drivers, and more.
• Advanced Leadership: Influential Management: Learn the skills needed to drive culture change through specific leadership behaviors and actions as well as financial storytelling.

  (Prerequisite: Leadership Foundations or an advanced management degree upon course director approval.)

• Advanced Leadership: Mastering Teamwork: Learn to critically assess program growth opportunities, lead and motivate teams, and design effective communication strategies. (Prerequisite: Leadership Foundations or an advanced management degree upon course director approval.)

A successful hospitalist program requires strong leadership from the unit to the C-suite. SHM’s Leadership Academy (www.shmleadershipacademy.org) prepares clinical and academic leaders with vital skills traditionally not taught in medical school or typical residency programs. This year’s meeting will be held from October 24 to 27 at Disney’s BoardWalk Inn in Lake Buena Vista, Fla. Courses offered include:

• Leadership Foundations: Evaluate your personal leadership strengths and weaknesses, understand key hospital drivers, and more.
• Advanced Leadership: Influential Management: Learn the skills needed to drive culture change through specific leadership behaviors and actions as well as financial storytelling.

  (Prerequisite: Leadership Foundations or an advanced management degree upon course director approval.)

• Advanced Leadership: Mastering Teamwork: Learn to critically assess program growth opportunities, lead and motivate teams, and design effective communication strategies. (Prerequisite: Leadership Foundations or an advanced management degree upon course director approval.)

A successful hospitalist program requires strong leadership from the unit to the C-suite. SHM’s Leadership Academy (www.shmleadershipacademy.org) prepares clinical and academic leaders with vital skills traditionally not taught in medical school or typical residency programs. This year’s meeting will be held from October 24 to 27 at Disney’s BoardWalk Inn in Lake Buena Vista, Fla. Courses offered include:

• Leadership Foundations: Evaluate your personal leadership strengths and weaknesses, understand key hospital drivers, and more.
• Advanced Leadership: Influential Management: Learn the skills needed to drive culture change through specific leadership behaviors and actions as well as financial storytelling.

  (Prerequisite: Leadership Foundations or an advanced management degree upon course director approval.)

• Advanced Leadership: Mastering Teamwork: Learn to critically assess program growth opportunities, lead and motivate teams, and design effective communication strategies. (Prerequisite: Leadership Foundations or an advanced management degree upon course director approval.)

Blood sample collection

Photo by Jeremy L. Grisham

The Centers for Disease Control and Prevention (CDC) has issued an interim guidance on how to interpret results of the Zika virus antibody test.

Over the past few weeks, the FDA has authorized the use of new Zika tests, including RealStar® Zika Virus RT-PCR Kit U.S., Zika Virus RNA Qualitative Real-Time RT-PCR test, and the Trioplex Real-time RT-PCR Assay.

The CDC is now updating its guidance, since a negative real time reverse transcription-polymerase chain reaction (rRT-PCR) test does not necessarily rule out Zika infection.

In these cases, the CDC recommends immunoglobulin (Ig) M and neutralizing antibody testing, which can identify additional recent Zika virus infections.

The Zika antibody test, however, is difficult to interpret because of cross-reactivity with other flaviviruses. Zika is a mosquito-borne flavivirus that is closely related to dengue, West Nile, Japanese encephalitis, and yellow fever viruses.

The cross-reactivity can preclude identification of the specific infecting virus, particularly if a person was previously infected with or vaccinated against a related flavivirus. And appropriate clinical management is dependent upon proper identification of the virus.

If IgM test results are positive, equivocal, or inconclusive, the CDC recommends performing a plaque reduction neutralization test (PRNT) to confirm the diagnosis.

However, in people who have been previously infected with or vaccinated against a related flavivirus, even a 4-fold higher titer by PRNT may not be able to discriminate between anti-Zika virus antibodies and cross-reacting antibodies.

Therefore, the CDC now recommends an even more conservative approach to interpreting PRNT results to reduce the possibility of missing the diagnosis of either Zika or dengue virus infection.

The US Food and Drug Administration issued in February an Emergency Use Authorization for the CDC Zika IgM Antibody Capture Enzyme-Linked Immunosorbent Assay (Zika MAC-ELISA) for antibody testing.

It is used to detect Zika virus IgM antibodies in serum or cerebrospinal fluid from people with suspect Zika virus disease.

Presumptive positive results should be confirmed with PRNT against Zika, dengue, and other flaviviruses.

Equivocal and inconclusive results that are not resolved by re-testing should also have PRNT performed to rule out false-positive results.

For more information on interpretation of the Zika virus antibody test results, see the CDC’s Interim Guidance published as part of the Morbidity and Mortality Weekly Report for 31 May 2016.

Blood sample collection

Photo by Jeremy L. Grisham

The Centers for Disease Control and Prevention (CDC) has issued an interim guidance on how to interpret results of the Zika virus antibody test.

Over the past few weeks, the FDA has authorized the use of new Zika tests, including RealStar® Zika Virus RT-PCR Kit U.S., Zika Virus RNA Qualitative Real-Time RT-PCR test, and the Trioplex Real-time RT-PCR Assay.

The CDC is now updating its guidance, since a negative real time reverse transcription-polymerase chain reaction (rRT-PCR) test does not necessarily rule out Zika infection.

In these cases, the CDC recommends immunoglobulin (Ig) M and neutralizing antibody testing, which can identify additional recent Zika virus infections.

The Zika antibody test, however, is difficult to interpret because of cross-reactivity with other flaviviruses. Zika is a mosquito-borne flavivirus that is closely related to dengue, West Nile, Japanese encephalitis, and yellow fever viruses.

The cross-reactivity can preclude identification of the specific infecting virus, particularly if a person was previously infected with or vaccinated against a related flavivirus. And appropriate clinical management is dependent upon proper identification of the virus.

If IgM test results are positive, equivocal, or inconclusive, the CDC recommends performing a plaque reduction neutralization test (PRNT) to confirm the diagnosis.

However, in people who have been previously infected with or vaccinated against a related flavivirus, even a 4-fold higher titer by PRNT may not be able to discriminate between anti-Zika virus antibodies and cross-reacting antibodies.

Therefore, the CDC now recommends an even more conservative approach to interpreting PRNT results to reduce the possibility of missing the diagnosis of either Zika or dengue virus infection.

The US Food and Drug Administration issued in February an Emergency Use Authorization for the CDC Zika IgM Antibody Capture Enzyme-Linked Immunosorbent Assay (Zika MAC-ELISA) for antibody testing.

It is used to detect Zika virus IgM antibodies in serum or cerebrospinal fluid from people with suspect Zika virus disease.

Presumptive positive results should be confirmed with PRNT against Zika, dengue, and other flaviviruses.

Equivocal and inconclusive results that are not resolved by re-testing should also have PRNT performed to rule out false-positive results.

For more information on interpretation of the Zika virus antibody test results, see the CDC’s Interim Guidance published as part of the Morbidity and Mortality Weekly Report for 31 May 2016.

Blood sample collection

Photo by Jeremy L. Grisham

The Centers for Disease Control and Prevention (CDC) has issued an interim guidance on how to interpret results of the Zika virus antibody test.

Over the past few weeks, the FDA has authorized the use of new Zika tests, including RealStar® Zika Virus RT-PCR Kit U.S., Zika Virus RNA Qualitative Real-Time RT-PCR test, and the Trioplex Real-time RT-PCR Assay.

The CDC is now updating its guidance, since a negative real time reverse transcription-polymerase chain reaction (rRT-PCR) test does not necessarily rule out Zika infection.

In these cases, the CDC recommends immunoglobulin (Ig) M and neutralizing antibody testing, which can identify additional recent Zika virus infections.

The Zika antibody test, however, is difficult to interpret because of cross-reactivity with other flaviviruses. Zika is a mosquito-borne flavivirus that is closely related to dengue, West Nile, Japanese encephalitis, and yellow fever viruses.

The cross-reactivity can preclude identification of the specific infecting virus, particularly if a person was previously infected with or vaccinated against a related flavivirus. And appropriate clinical management is dependent upon proper identification of the virus.

If IgM test results are positive, equivocal, or inconclusive, the CDC recommends performing a plaque reduction neutralization test (PRNT) to confirm the diagnosis.

However, in people who have been previously infected with or vaccinated against a related flavivirus, even a 4-fold higher titer by PRNT may not be able to discriminate between anti-Zika virus antibodies and cross-reacting antibodies.

Therefore, the CDC now recommends an even more conservative approach to interpreting PRNT results to reduce the possibility of missing the diagnosis of either Zika or dengue virus infection.

The US Food and Drug Administration issued in February an Emergency Use Authorization for the CDC Zika IgM Antibody Capture Enzyme-Linked Immunosorbent Assay (Zika MAC-ELISA) for antibody testing.

It is used to detect Zika virus IgM antibodies in serum or cerebrospinal fluid from people with suspect Zika virus disease.

Presumptive positive results should be confirmed with PRNT against Zika, dengue, and other flaviviruses.

Equivocal and inconclusive results that are not resolved by re-testing should also have PRNT performed to rule out false-positive results.

For more information on interpretation of the Zika virus antibody test results, see the CDC’s Interim Guidance published as part of the Morbidity and Mortality Weekly Report for 31 May 2016.

Pregnant woman
Photo by Nina Matthews

A blood test developed to diagnose a rare genetic blood cell disorder, atypical hemolytic uremic syndrome (aHUS), may also aid in the diagnosis of HELLP syndrome, a life-threatening high blood pressure condition that affects 1% of all pregnant women.

The study, based on blood samples from a small number of women, suggests that aHUS has similar underlying biochemistry to HELLP, which affects hemolysis, elevates liver enzymes, and causes a low platelet count. Both conditions have over activation of the alternative pathway of complement.

At present, no diagnostic blood or biomarker test exists to diagnose HELLP, which is thought to be a severe form of preeclampsia. The condition is diagnosed only by its symptoms.

Senior study author Robert Brodsky, MD, of Johns Hopkins, and his team developed the modified Ham test to diagnose aHUS, a genetic disorder in which abnormal blood clots form in small blood vessels in the kidneys. They published that work last year in Blood.
 
The two conditions share a number of traits, such as hemolysis, elevated liver enzymes, a low platelet count, kidney dysfunction, high blood pressure, and seizures. This led the investigators to believe that the modified Ham test could also help identify women with HELLP syndrome.

"The clinical implications from an obstetric point of view are potentially huge," said lead study author Arthur Vaught, MD, also of Johns Hopkins. "If this works, we can reduce pre-term deliveries, stays in the neonatal intensive care unit, and other complications for mothers and their babies."

The team analyzed serum samples from 14 women with classic or atypical HELLP syndrome, 7 with severe preeclampsia, 11 women with normal pregnancies, and 8 healthy nonpregnant women. All pregnant women were at least 23 weeks’ gestation, the point at which HELLP symptoms start to arise.

The team evaluated patient sera using terminal product of complement activation (C5b-9). They observed that women with classic or atypical HELLP had increased complement activation compared to nonpregnant controls.

Women with classic HELLP had an average cell killing of 34.3% compared with 26% in women with atypical HELLP, 5% in women with normal pregnancies, and3.3% in women who were not pregnant.

The investigators then added eculizumab to HELLP sera to see whether the agent could inhibit complement activation. They found that mixing HELLP serum with eculizumab-containing serum significantly decreased cell killing compared with HELLP serum alone.

The kill rate in women with classic or atypical HELLP decreased from 34% to 5% with eculizumab.

Eculizumab (Soliris), manufactured by Alexion Pharmaceuticals, is a monoclonal antibody approved by the US Food and Drug Administration for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and aHUS.

Further investigation is required to confirm these findings, but thus far, the investigators believe the modified Ham assay may assist in diagnosing the HELLP syndrome and corroborate its relationship to aHUS.

The current study by Vaught et al is published in Experimental Hematology.

Pregnant woman
Photo by Nina Matthews

A blood test developed to diagnose a rare genetic blood cell disorder, atypical hemolytic uremic syndrome (aHUS), may also aid in the diagnosis of HELLP syndrome, a life-threatening high blood pressure condition that affects 1% of all pregnant women.

The study, based on blood samples from a small number of women, suggests that aHUS has similar underlying biochemistry to HELLP, which affects hemolysis, elevates liver enzymes, and causes a low platelet count. Both conditions have over activation of the alternative pathway of complement.

At present, no diagnostic blood or biomarker test exists to diagnose HELLP, which is thought to be a severe form of preeclampsia. The condition is diagnosed only by its symptoms.

Senior study author Robert Brodsky, MD, of Johns Hopkins, and his team developed the modified Ham test to diagnose aHUS, a genetic disorder in which abnormal blood clots form in small blood vessels in the kidneys. They published that work last year in Blood.
 
The two conditions share a number of traits, such as hemolysis, elevated liver enzymes, a low platelet count, kidney dysfunction, high blood pressure, and seizures. This led the investigators to believe that the modified Ham test could also help identify women with HELLP syndrome.

"The clinical implications from an obstetric point of view are potentially huge," said lead study author Arthur Vaught, MD, also of Johns Hopkins. "If this works, we can reduce pre-term deliveries, stays in the neonatal intensive care unit, and other complications for mothers and their babies."

The team analyzed serum samples from 14 women with classic or atypical HELLP syndrome, 7 with severe preeclampsia, 11 women with normal pregnancies, and 8 healthy nonpregnant women. All pregnant women were at least 23 weeks’ gestation, the point at which HELLP symptoms start to arise.

The team evaluated patient sera using terminal product of complement activation (C5b-9). They observed that women with classic or atypical HELLP had increased complement activation compared to nonpregnant controls.

Women with classic HELLP had an average cell killing of 34.3% compared with 26% in women with atypical HELLP, 5% in women with normal pregnancies, and3.3% in women who were not pregnant.

The investigators then added eculizumab to HELLP sera to see whether the agent could inhibit complement activation. They found that mixing HELLP serum with eculizumab-containing serum significantly decreased cell killing compared with HELLP serum alone.

The kill rate in women with classic or atypical HELLP decreased from 34% to 5% with eculizumab.

Eculizumab (Soliris), manufactured by Alexion Pharmaceuticals, is a monoclonal antibody approved by the US Food and Drug Administration for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and aHUS.

Further investigation is required to confirm these findings, but thus far, the investigators believe the modified Ham assay may assist in diagnosing the HELLP syndrome and corroborate its relationship to aHUS.

The current study by Vaught et al is published in Experimental Hematology.

Pregnant woman
Photo by Nina Matthews

A blood test developed to diagnose a rare genetic blood cell disorder, atypical hemolytic uremic syndrome (aHUS), may also aid in the diagnosis of HELLP syndrome, a life-threatening high blood pressure condition that affects 1% of all pregnant women.

The study, based on blood samples from a small number of women, suggests that aHUS has similar underlying biochemistry to HELLP, which affects hemolysis, elevates liver enzymes, and causes a low platelet count. Both conditions have over activation of the alternative pathway of complement.

At present, no diagnostic blood or biomarker test exists to diagnose HELLP, which is thought to be a severe form of preeclampsia. The condition is diagnosed only by its symptoms.

Senior study author Robert Brodsky, MD, of Johns Hopkins, and his team developed the modified Ham test to diagnose aHUS, a genetic disorder in which abnormal blood clots form in small blood vessels in the kidneys. They published that work last year in Blood.
 
The two conditions share a number of traits, such as hemolysis, elevated liver enzymes, a low platelet count, kidney dysfunction, high blood pressure, and seizures. This led the investigators to believe that the modified Ham test could also help identify women with HELLP syndrome.

"The clinical implications from an obstetric point of view are potentially huge," said lead study author Arthur Vaught, MD, also of Johns Hopkins. "If this works, we can reduce pre-term deliveries, stays in the neonatal intensive care unit, and other complications for mothers and their babies."

The team analyzed serum samples from 14 women with classic or atypical HELLP syndrome, 7 with severe preeclampsia, 11 women with normal pregnancies, and 8 healthy nonpregnant women. All pregnant women were at least 23 weeks’ gestation, the point at which HELLP symptoms start to arise.

The team evaluated patient sera using terminal product of complement activation (C5b-9). They observed that women with classic or atypical HELLP had increased complement activation compared to nonpregnant controls.

Women with classic HELLP had an average cell killing of 34.3% compared with 26% in women with atypical HELLP, 5% in women with normal pregnancies, and3.3% in women who were not pregnant.

The investigators then added eculizumab to HELLP sera to see whether the agent could inhibit complement activation. They found that mixing HELLP serum with eculizumab-containing serum significantly decreased cell killing compared with HELLP serum alone.

The kill rate in women with classic or atypical HELLP decreased from 34% to 5% with eculizumab.

Eculizumab (Soliris), manufactured by Alexion Pharmaceuticals, is a monoclonal antibody approved by the US Food and Drug Administration for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and aHUS.

Further investigation is required to confirm these findings, but thus far, the investigators believe the modified Ham assay may assist in diagnosing the HELLP syndrome and corroborate its relationship to aHUS.

The current study by Vaught et al is published in Experimental Hematology.

Table of Contents

• Discrimination, Dignity, and Duty
• Survival After Long-Term Residence in an Intensive Care Unit
• Disease-Modifying Therapies in Multiple Sclerosis: Overview and Treatment Considerations
• The Relationship Between Male Patients’ Antihypertensive Medication Beliefs and Erectile Function
• A Physician With Thigh Pain
• Shared Medical Appointments for Glycemic Management in Rural Veterans

Table of Contents

• Discrimination, Dignity, and Duty
• Survival After Long-Term Residence in an Intensive Care Unit
• Disease-Modifying Therapies in Multiple Sclerosis: Overview and Treatment Considerations
• The Relationship Between Male Patients’ Antihypertensive Medication Beliefs and Erectile Function
• A Physician With Thigh Pain
• Shared Medical Appointments for Glycemic Management in Rural Veterans

Table of Contents

• Discrimination, Dignity, and Duty
• Survival After Long-Term Residence in an Intensive Care Unit
• Disease-Modifying Therapies in Multiple Sclerosis: Overview and Treatment Considerations
• The Relationship Between Male Patients’ Antihypertensive Medication Beliefs and Erectile Function
• A Physician With Thigh Pain
• Shared Medical Appointments for Glycemic Management in Rural Veterans

A 12-week regimen achieved sustained viral response for 90% of patients with genotype 1 hepatitis C virus (HCV) infection and stage 4 or 5 chronic kidney disease (CKD), researchers reported in the April issue of Gastroenterology.

“The regimen is well tolerated, though ribavirin use may require a reduction or interruption to manage anemia,” said Dr. Paul Pockros at Scripps Clinic and Scripps Translational Science Institute in La Jolla, Calif., and his associates. The second phase of the study will evaluate the regimen in treatment-experienced CKD patients and those with compensated cirrhosis, they said.

©picsfive/Fotolia

The regimen contained ombitasvir, paritaprevir, ritonavir, and dasabuvir.

Between 8% and 44% of hemodialysis patients are HCV positive, and CKD is known to heighten the risk of HCV-associated cirrhosis, hepatocellular carcinoma, and liver-related death, the researchers noted. While sofosbuvir is cleared renally, ombitasvir, paritaprevir, ritonavir, and dasabuvir undergo hepatic metabolism and needed no dose adjustment in phase I studies of patients with mild, moderate, or severe renal impairment. To further investigate the safety and efficacy of these direct-acting antivirals in patients with severe kidney disease, the researchers performed a single-arm, open-label, multicenter study of 20 treatment-naive, noncirrhotic, HCV-infected adults with stage 4 CKD (estimated glomerular filtration rate, 15-30 mL/min per 1.73 m²) or stage 5 (eGFR, less than 15 mL/min per 1.73 m² or requiring hemodialysis). Patients received once-daily ombitasvir (25 mg), paritaprevir (150 mg), and ritonavir (100 mg) plus dasabuvir (250 mg) for 12 weeks. The 13 patients with genotype 1a infections also received once-daily ribavirin (200 mg). Most patients were black men with stage 5 CKD, and 14 were on hemodialysis, the researchers said (Gastroenterology. 2016 Apr 16. doi: 10.1053/j.gastro.2016.02.078).

All 20 patients completed treatment, and 18 (90%) achieved sustained viral response (SVR) at posttreatment week 12 (SVR12; 95% confidence interval, 70%-97%). No patients developed hepatic decompensation, the researchers said. The most common adverse effects were anemia (45%), fatigue (35%), diarrhea (25%), and nausea (25%). Anemia developed only in patients receiving ribavirin and was more pronounced than in phase III studies of this regimen, the researchers said. Hemoglobin levels dropped an average of 1.38 plus or minus 1.54 g/dL among patients who received ribavirin, compared with 0.02 plus or minus 0.9 g/dL among patients who did not receive ribavirin. There was one case of grade 3 anemia related to incorrect dosing of ribavirin; the lowest measured hemoglobin level was 7.0 g/dL, which improved to more than 10 g/dL after stopping ribavirin and starting erythropoietin treatment. This patient also achieved SVR12. The other eight patients who developed anemia also stopped ribavirin, although three were able to resume it after their hemoglobin levels improved.

Of the two patients who did not achieve SVR12, one relapsed 4 weeks after treatment, and one died of cardiac arrest 14 days after treatment. The patient who died had a history of hypertension; his hemoglobin level was stable (9-11 g/dL) during the last 6 weeks of treatment, and was 10 g/dL at admission, suggesting that ribavirin-induced anemia did not cause the cardiac event, the investigators said.

“The results of this study are important for hepatologists, gastroenterologists, and infectious disease specialists who are accustomed to treating HCV-infected patients with DAA [direct-acting antiviral] therapy but who may not yet have seen sufficient data to initiate DAA therapy in patients with ESRD [end-stage renal disease],” the researchers concluded. “Nephrologists, who may not be accustomed to treating HCV, should also be aware that treatment options may now be available that can help prevent the end-stage sequelae of HCV. How treatment of HCV infection affects early or intermediate stages of CKD and how achievement of SVR impacts strategies for kidney transplantation in patients with ESRD require more study.”

AbbVie makes the regimen and sponsored the study. Dr. Pockros and six coinvestigators disclosed financial relationships with AbbVie and numerous other pharmaceutical companies. Seven coinvestigators reported being employed by AbbVie.

A 12-week regimen achieved sustained viral response for 90% of patients with genotype 1 hepatitis C virus (HCV) infection and stage 4 or 5 chronic kidney disease (CKD), researchers reported in the April issue of Gastroenterology.

“The regimen is well tolerated, though ribavirin use may require a reduction or interruption to manage anemia,” said Dr. Paul Pockros at Scripps Clinic and Scripps Translational Science Institute in La Jolla, Calif., and his associates. The second phase of the study will evaluate the regimen in treatment-experienced CKD patients and those with compensated cirrhosis, they said.

©picsfive/Fotolia

The regimen contained ombitasvir, paritaprevir, ritonavir, and dasabuvir.

Between 8% and 44% of hemodialysis patients are HCV positive, and CKD is known to heighten the risk of HCV-associated cirrhosis, hepatocellular carcinoma, and liver-related death, the researchers noted. While sofosbuvir is cleared renally, ombitasvir, paritaprevir, ritonavir, and dasabuvir undergo hepatic metabolism and needed no dose adjustment in phase I studies of patients with mild, moderate, or severe renal impairment. To further investigate the safety and efficacy of these direct-acting antivirals in patients with severe kidney disease, the researchers performed a single-arm, open-label, multicenter study of 20 treatment-naive, noncirrhotic, HCV-infected adults with stage 4 CKD (estimated glomerular filtration rate, 15-30 mL/min per 1.73 m²) or stage 5 (eGFR, less than 15 mL/min per 1.73 m² or requiring hemodialysis). Patients received once-daily ombitasvir (25 mg), paritaprevir (150 mg), and ritonavir (100 mg) plus dasabuvir (250 mg) for 12 weeks. The 13 patients with genotype 1a infections also received once-daily ribavirin (200 mg). Most patients were black men with stage 5 CKD, and 14 were on hemodialysis, the researchers said (Gastroenterology. 2016 Apr 16. doi: 10.1053/j.gastro.2016.02.078).

All 20 patients completed treatment, and 18 (90%) achieved sustained viral response (SVR) at posttreatment week 12 (SVR12; 95% confidence interval, 70%-97%). No patients developed hepatic decompensation, the researchers said. The most common adverse effects were anemia (45%), fatigue (35%), diarrhea (25%), and nausea (25%). Anemia developed only in patients receiving ribavirin and was more pronounced than in phase III studies of this regimen, the researchers said. Hemoglobin levels dropped an average of 1.38 plus or minus 1.54 g/dL among patients who received ribavirin, compared with 0.02 plus or minus 0.9 g/dL among patients who did not receive ribavirin. There was one case of grade 3 anemia related to incorrect dosing of ribavirin; the lowest measured hemoglobin level was 7.0 g/dL, which improved to more than 10 g/dL after stopping ribavirin and starting erythropoietin treatment. This patient also achieved SVR12. The other eight patients who developed anemia also stopped ribavirin, although three were able to resume it after their hemoglobin levels improved.

Of the two patients who did not achieve SVR12, one relapsed 4 weeks after treatment, and one died of cardiac arrest 14 days after treatment. The patient who died had a history of hypertension; his hemoglobin level was stable (9-11 g/dL) during the last 6 weeks of treatment, and was 10 g/dL at admission, suggesting that ribavirin-induced anemia did not cause the cardiac event, the investigators said.

“The results of this study are important for hepatologists, gastroenterologists, and infectious disease specialists who are accustomed to treating HCV-infected patients with DAA [direct-acting antiviral] therapy but who may not yet have seen sufficient data to initiate DAA therapy in patients with ESRD [end-stage renal disease],” the researchers concluded. “Nephrologists, who may not be accustomed to treating HCV, should also be aware that treatment options may now be available that can help prevent the end-stage sequelae of HCV. How treatment of HCV infection affects early or intermediate stages of CKD and how achievement of SVR impacts strategies for kidney transplantation in patients with ESRD require more study.”

AbbVie makes the regimen and sponsored the study. Dr. Pockros and six coinvestigators disclosed financial relationships with AbbVie and numerous other pharmaceutical companies. Seven coinvestigators reported being employed by AbbVie.

A 12-week regimen achieved sustained viral response for 90% of patients with genotype 1 hepatitis C virus (HCV) infection and stage 4 or 5 chronic kidney disease (CKD), researchers reported in the April issue of Gastroenterology.

“The regimen is well tolerated, though ribavirin use may require a reduction or interruption to manage anemia,” said Dr. Paul Pockros at Scripps Clinic and Scripps Translational Science Institute in La Jolla, Calif., and his associates. The second phase of the study will evaluate the regimen in treatment-experienced CKD patients and those with compensated cirrhosis, they said.

©picsfive/Fotolia

The regimen contained ombitasvir, paritaprevir, ritonavir, and dasabuvir.

Between 8% and 44% of hemodialysis patients are HCV positive, and CKD is known to heighten the risk of HCV-associated cirrhosis, hepatocellular carcinoma, and liver-related death, the researchers noted. While sofosbuvir is cleared renally, ombitasvir, paritaprevir, ritonavir, and dasabuvir undergo hepatic metabolism and needed no dose adjustment in phase I studies of patients with mild, moderate, or severe renal impairment. To further investigate the safety and efficacy of these direct-acting antivirals in patients with severe kidney disease, the researchers performed a single-arm, open-label, multicenter study of 20 treatment-naive, noncirrhotic, HCV-infected adults with stage 4 CKD (estimated glomerular filtration rate, 15-30 mL/min per 1.73 m²) or stage 5 (eGFR, less than 15 mL/min per 1.73 m² or requiring hemodialysis). Patients received once-daily ombitasvir (25 mg), paritaprevir (150 mg), and ritonavir (100 mg) plus dasabuvir (250 mg) for 12 weeks. The 13 patients with genotype 1a infections also received once-daily ribavirin (200 mg). Most patients were black men with stage 5 CKD, and 14 were on hemodialysis, the researchers said (Gastroenterology. 2016 Apr 16. doi: 10.1053/j.gastro.2016.02.078).

All 20 patients completed treatment, and 18 (90%) achieved sustained viral response (SVR) at posttreatment week 12 (SVR12; 95% confidence interval, 70%-97%). No patients developed hepatic decompensation, the researchers said. The most common adverse effects were anemia (45%), fatigue (35%), diarrhea (25%), and nausea (25%). Anemia developed only in patients receiving ribavirin and was more pronounced than in phase III studies of this regimen, the researchers said. Hemoglobin levels dropped an average of 1.38 plus or minus 1.54 g/dL among patients who received ribavirin, compared with 0.02 plus or minus 0.9 g/dL among patients who did not receive ribavirin. There was one case of grade 3 anemia related to incorrect dosing of ribavirin; the lowest measured hemoglobin level was 7.0 g/dL, which improved to more than 10 g/dL after stopping ribavirin and starting erythropoietin treatment. This patient also achieved SVR12. The other eight patients who developed anemia also stopped ribavirin, although three were able to resume it after their hemoglobin levels improved.

Of the two patients who did not achieve SVR12, one relapsed 4 weeks after treatment, and one died of cardiac arrest 14 days after treatment. The patient who died had a history of hypertension; his hemoglobin level was stable (9-11 g/dL) during the last 6 weeks of treatment, and was 10 g/dL at admission, suggesting that ribavirin-induced anemia did not cause the cardiac event, the investigators said.

“The results of this study are important for hepatologists, gastroenterologists, and infectious disease specialists who are accustomed to treating HCV-infected patients with DAA [direct-acting antiviral] therapy but who may not yet have seen sufficient data to initiate DAA therapy in patients with ESRD [end-stage renal disease],” the researchers concluded. “Nephrologists, who may not be accustomed to treating HCV, should also be aware that treatment options may now be available that can help prevent the end-stage sequelae of HCV. How treatment of HCV infection affects early or intermediate stages of CKD and how achievement of SVR impacts strategies for kidney transplantation in patients with ESRD require more study.”

AbbVie makes the regimen and sponsored the study. Dr. Pockros and six coinvestigators disclosed financial relationships with AbbVie and numerous other pharmaceutical companies. Seven coinvestigators reported being employed by AbbVie.

Only 1% of adults with asymptomatic neoplastic pancreatic cysts developed invasive pancreatic adenocarcinoma after more than 5 years of follow-up, according to a multicenter retrospective study reported in the June issue of Clinical Gastroenterology and Hepatology.

©iStock / ThinkStockPhotos.com

Furthermore, there were no malignant conversions among patients lacking American Gastroenterological Association high-risk features – that is, mural nodules, dilated pancreatic ducts, or cysts measuring more than 3 cm, said Dr. Wilson Kwong at the University of California San Diego Health Sciences in La Jolla. “There is a very low risk of malignant transformation of asymptomatic neoplastic pancreatic cysts after 5 years,” he and his associates wrote.

Up to 20% of cross-sectional imaging studies reveal incidental pancreatic cysts, the researchers noted. Cysts with neoplastic features are recommended for indefinite surveillance, even though there is little or no data on their natural history and malignant potential beyond 5- 10 years, they added. Therefore, they studied 310 patients who underwent endoscopic ultrasound of pancreatic cysts at an academic medical center, a Veterans’ Affairs hospital, and two community health care systems in California between 2002 and 2010. The most common age at enrollment was 66 years, 60% of patients were women, and the median follow-up period was 87 months (range, 60 to 189 months). A total of 90% of patients were followed for 5-10 years, while 10% were followed for more than 10 years (Clin Gastroenterol Hepatol. 2016 Feb 10. doi: 10.1016/j.cgh.2015.11.013).

Source: American Gastroenterological Association

In all, three patients developed invasive pancreatic malignancies after 6, 8, and 11 years of follow-up, for an overall conversion rate of 1%. Conversion rates by subgroup were 0% for patients with no high-risk AGA features, 1% (one case) for patients with one high-risk feature, and 15% (two cases) for patients with two high-risk features. “Because the risk of malignant transformation beyond 5 years is lower than the 1.4% mortality risk of pancreatic resection at high-volume centers, the argument can be made that discontinuing surveillance after 5 years is justified,” the researchers said. Specifically, surveillance could be discontinued after 5 years for neoplastic pancreatic cysts with up to one high-risk feature, particularly if patients have significant comorbidities that increase their risk of imminent death from other causes, they added. In contrast, healthy patients in their 60s and 70s might benefit from long-term surveillance given their longer life expectancy, they said. “Among patients with two high-risk features who remain surgically fit, discussion of surgery or surveillance beyond 5 years should be considered,” they emphasized.

A total of two patients developed high-grade dysplasia – a risk factor for invasive pancreatic cancer – but even so, the aggregate rate of cancer and high-grade dysplasia was 1.6%, only slightly higher than the fatality rate associated with pancreatic resection, the researchers noted. By excluding patients with recent acute pancreatitis (because of the likelihood of pseudocysts), they might have inadvertently excluded “a small number” of patients with pancreatic intraductal papillary mucinous neoplasms, they added.

The University of California San Diego Health Care System supported the study. The investigators had no disclosures.

Only 1% of adults with asymptomatic neoplastic pancreatic cysts developed invasive pancreatic adenocarcinoma after more than 5 years of follow-up, according to a multicenter retrospective study reported in the June issue of Clinical Gastroenterology and Hepatology.

©iStock / ThinkStockPhotos.com

Furthermore, there were no malignant conversions among patients lacking American Gastroenterological Association high-risk features – that is, mural nodules, dilated pancreatic ducts, or cysts measuring more than 3 cm, said Dr. Wilson Kwong at the University of California San Diego Health Sciences in La Jolla. “There is a very low risk of malignant transformation of asymptomatic neoplastic pancreatic cysts after 5 years,” he and his associates wrote.

Up to 20% of cross-sectional imaging studies reveal incidental pancreatic cysts, the researchers noted. Cysts with neoplastic features are recommended for indefinite surveillance, even though there is little or no data on their natural history and malignant potential beyond 5- 10 years, they added. Therefore, they studied 310 patients who underwent endoscopic ultrasound of pancreatic cysts at an academic medical center, a Veterans’ Affairs hospital, and two community health care systems in California between 2002 and 2010. The most common age at enrollment was 66 years, 60% of patients were women, and the median follow-up period was 87 months (range, 60 to 189 months). A total of 90% of patients were followed for 5-10 years, while 10% were followed for more than 10 years (Clin Gastroenterol Hepatol. 2016 Feb 10. doi: 10.1016/j.cgh.2015.11.013).

Source: American Gastroenterological Association

In all, three patients developed invasive pancreatic malignancies after 6, 8, and 11 years of follow-up, for an overall conversion rate of 1%. Conversion rates by subgroup were 0% for patients with no high-risk AGA features, 1% (one case) for patients with one high-risk feature, and 15% (two cases) for patients with two high-risk features. “Because the risk of malignant transformation beyond 5 years is lower than the 1.4% mortality risk of pancreatic resection at high-volume centers, the argument can be made that discontinuing surveillance after 5 years is justified,” the researchers said. Specifically, surveillance could be discontinued after 5 years for neoplastic pancreatic cysts with up to one high-risk feature, particularly if patients have significant comorbidities that increase their risk of imminent death from other causes, they added. In contrast, healthy patients in their 60s and 70s might benefit from long-term surveillance given their longer life expectancy, they said. “Among patients with two high-risk features who remain surgically fit, discussion of surgery or surveillance beyond 5 years should be considered,” they emphasized.

A total of two patients developed high-grade dysplasia – a risk factor for invasive pancreatic cancer – but even so, the aggregate rate of cancer and high-grade dysplasia was 1.6%, only slightly higher than the fatality rate associated with pancreatic resection, the researchers noted. By excluding patients with recent acute pancreatitis (because of the likelihood of pseudocysts), they might have inadvertently excluded “a small number” of patients with pancreatic intraductal papillary mucinous neoplasms, they added.

The University of California San Diego Health Care System supported the study. The investigators had no disclosures.

Only 1% of adults with asymptomatic neoplastic pancreatic cysts developed invasive pancreatic adenocarcinoma after more than 5 years of follow-up, according to a multicenter retrospective study reported in the June issue of Clinical Gastroenterology and Hepatology.

©iStock / ThinkStockPhotos.com

Furthermore, there were no malignant conversions among patients lacking American Gastroenterological Association high-risk features – that is, mural nodules, dilated pancreatic ducts, or cysts measuring more than 3 cm, said Dr. Wilson Kwong at the University of California San Diego Health Sciences in La Jolla. “There is a very low risk of malignant transformation of asymptomatic neoplastic pancreatic cysts after 5 years,” he and his associates wrote.

Up to 20% of cross-sectional imaging studies reveal incidental pancreatic cysts, the researchers noted. Cysts with neoplastic features are recommended for indefinite surveillance, even though there is little or no data on their natural history and malignant potential beyond 5- 10 years, they added. Therefore, they studied 310 patients who underwent endoscopic ultrasound of pancreatic cysts at an academic medical center, a Veterans’ Affairs hospital, and two community health care systems in California between 2002 and 2010. The most common age at enrollment was 66 years, 60% of patients were women, and the median follow-up period was 87 months (range, 60 to 189 months). A total of 90% of patients were followed for 5-10 years, while 10% were followed for more than 10 years (Clin Gastroenterol Hepatol. 2016 Feb 10. doi: 10.1016/j.cgh.2015.11.013).

Source: American Gastroenterological Association

In all, three patients developed invasive pancreatic malignancies after 6, 8, and 11 years of follow-up, for an overall conversion rate of 1%. Conversion rates by subgroup were 0% for patients with no high-risk AGA features, 1% (one case) for patients with one high-risk feature, and 15% (two cases) for patients with two high-risk features. “Because the risk of malignant transformation beyond 5 years is lower than the 1.4% mortality risk of pancreatic resection at high-volume centers, the argument can be made that discontinuing surveillance after 5 years is justified,” the researchers said. Specifically, surveillance could be discontinued after 5 years for neoplastic pancreatic cysts with up to one high-risk feature, particularly if patients have significant comorbidities that increase their risk of imminent death from other causes, they added. In contrast, healthy patients in their 60s and 70s might benefit from long-term surveillance given their longer life expectancy, they said. “Among patients with two high-risk features who remain surgically fit, discussion of surgery or surveillance beyond 5 years should be considered,” they emphasized.

A total of two patients developed high-grade dysplasia – a risk factor for invasive pancreatic cancer – but even so, the aggregate rate of cancer and high-grade dysplasia was 1.6%, only slightly higher than the fatality rate associated with pancreatic resection, the researchers noted. By excluding patients with recent acute pancreatitis (because of the likelihood of pseudocysts), they might have inadvertently excluded “a small number” of patients with pancreatic intraductal papillary mucinous neoplasms, they added.

The University of California San Diego Health Care System supported the study. The investigators had no disclosures.