Article

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

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

Preoperative components of ERAS

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

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

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

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

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

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

Continue to: Intraoperative components of ERAS...

Intraoperative components of ERAS

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

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

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

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

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

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

Postoperative components of ERAS

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

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

Early ambulation.

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

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

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

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

Auditing and reporting adherence with components of ERAS

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

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

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

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

Preoperative components of ERAS

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

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

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

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

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

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

Continue to: Intraoperative components of ERAS...

Intraoperative components of ERAS

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

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

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

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

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

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

Postoperative components of ERAS

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

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

Early ambulation.

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

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

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

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

Auditing and reporting adherence with components of ERAS

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

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

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

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

Preoperative components of ERAS

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

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

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

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

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

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

Continue to: Intraoperative components of ERAS...

Intraoperative components of ERAS

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

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

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

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

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

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

Postoperative components of ERAS

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

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

Early ambulation.

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

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

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

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

Auditing and reporting adherence with components of ERAS

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

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

CASE Pregnant woman with a suspected parasitic infection

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

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


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


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

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

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

How Chagas disease is transmitted and who is at risk

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

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

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

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

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

Continue to: Clinical manifestations of Chagas disease...

Clinical manifestations of Chagas disease

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

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

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

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

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

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

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

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

Continue to: Making the diagnosis...

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

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

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

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

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

Treatment options

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

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

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

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

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

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

Preventing infection

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

Other important preventive measures include:

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

Unique considerations in pregnancy

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

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

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

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

CASE Continue surveillance during pregnancy, treat after delivery

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

CASE Pregnant woman with a suspected parasitic infection

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

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


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


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

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

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

How Chagas disease is transmitted and who is at risk

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

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

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

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

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

Continue to: Clinical manifestations of Chagas disease...

Clinical manifestations of Chagas disease

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

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

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

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

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

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

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

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

Continue to: Making the diagnosis...

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

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

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

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

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

Treatment options

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

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

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

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

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

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

Preventing infection

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

Other important preventive measures include:

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

Unique considerations in pregnancy

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

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

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

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

CASE Continue surveillance during pregnancy, treat after delivery

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

CASE Pregnant woman with a suspected parasitic infection

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

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


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


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

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

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

How Chagas disease is transmitted and who is at risk

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

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

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

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

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

Continue to: Clinical manifestations of Chagas disease...

Clinical manifestations of Chagas disease

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

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

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

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

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

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

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

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

Continue to: Making the diagnosis...

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

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

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

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

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

Treatment options

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

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

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

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

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

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

Preventing infection

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

Other important preventive measures include:

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

Unique considerations in pregnancy

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

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

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

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

CASE Continue surveillance during pregnancy, treat after delivery

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

ILLUSTRATION: KATERYNA KON/SCIENCE PHOTO LIBRARY

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

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

Causative organisms

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

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

Why does VVC reoccur?

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

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

Clinical aspects and diagnosis of VVC

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

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

Diagnostic considerations

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

Treatment options

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

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

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

Fluconazole

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

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

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

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

Options for fluconazole-resistant C albicans infection

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

Options for non- albicans Candida species infection

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

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

Gentian violet

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

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

Lactobacilli probiotics and dietary changes

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

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

Behavioral therapy

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

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

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

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

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

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

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

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

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

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

ILLUSTRATION: KATERYNA KON/SCIENCE PHOTO LIBRARY

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

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

Causative organisms

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

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

Why does VVC reoccur?

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

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

Clinical aspects and diagnosis of VVC

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

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

Diagnostic considerations

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

Treatment options

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

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

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

Fluconazole

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

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

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

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

Options for fluconazole-resistant C albicans infection

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

Options for non- albicans Candida species infection

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

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

Gentian violet

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

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

Lactobacilli probiotics and dietary changes

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

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

Behavioral therapy

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

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

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

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

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

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

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

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

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

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

ILLUSTRATION: KATERYNA KON/SCIENCE PHOTO LIBRARY

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

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

Causative organisms

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

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

Why does VVC reoccur?

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

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

Clinical aspects and diagnosis of VVC

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

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

Diagnostic considerations

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

Treatment options

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

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

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

Fluconazole

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

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

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

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

Options for fluconazole-resistant C albicans infection

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

Options for non- albicans Candida species infection

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

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

Gentian violet

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

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

Lactobacilli probiotics and dietary changes

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

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

Behavioral therapy

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

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

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

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

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

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

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

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

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

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

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Perineuriomas are benign, slow-growing tumors derived from perineurial cells,¹ which form the structurally supportive perineurium that surrounds individual nerve fascicles.^2,3 Perineuriomas are classified into 2 main forms: intraneural or extraneural.⁴ Intraneural perineuriomas are found within the border of the peripheral nerve,⁵ while extraneural perineuriomas usually are found in soft tissue and skin. Extraneural perineuriomas can be further classified into variants based on their histologic appearance, including reticular, sclerosing, and plexiform subtypes. Extraneural perineuriomas usually present on the extremities or trunk of young to middle-aged adults as a well-circumscribed, painless, subcutaneous masses.¹ These tumors are especially unusual in children.⁴ We present 2 extraneural perineurioma cases in children, and we review the pertinent diagnostic features of perineurioma as well as the presentation in the pediatric population.

Case Reports

Patient 1—A 10-year-old boy with a history of cerebral palsy and related comorbidities presented to the clinic for evaluation of a lesion on the thigh with no associated pain, irritation, erythema, or drainage. Physical examination revealed a soft, pedunculated, mobile nodule on the right medial thigh. An elliptical excision was performed. Gross examination demonstrated a 2.0×2.0×1.8-cm polypoid nodule. Histologic examination showed a dermal-based proliferation of bland spindle cells (Figure 1). The cytomorphology was characterized by elongated tapering nuclei and many areas with delicate bipolar cytoplasmic processes. The constituent cells were arranged in a whorled pattern in a variably myxoid to collagenous stroma. The tumor cells were multifocally positive for CD34; focally positive for smooth muscle actin (SMA); and negative for S-100, epithelial membrane antigen (EMA), GLUT1, claudin-1, STAT6, and desmin. Rb protein was intact. The CD34 immunostain highlighted the cytoplasmic processes. Electron microscopy was performed because the immunohistochemical results were nonspecific despite the favorable histologic features for perineurioma and showed pinocytic vesicles with delicate cytoplasmic processes, characteristic of perineurioma (Figure 2). Follow-up visits were related to the management of multiple comorbidities; no known recurrence of the lesion was documented.

Patient 2—A 15-year-old adolescent boy with no notable medical history presented to the pediatric clinic for a bump on the right upper arm of 4 to 5 months’ duration. He did not recall an injury to the area and denied change in size, redness, bruising, or pain of the lesion. Ultrasonography demonstrated a 2.6×2.3×1.3-cm hypoechoic and slightly heterogeneous, well-circumscribed, subcutaneous mass with internal vascularity. The patient was then referred to a pediatric surgeon. The clinical differential included a lipoma, lymphadenopathy, or sebaceous cyst. An excision was performed. Gross inspection demonstrated a 7-g, 2.8×2.6×1.8-cm, homogeneous, tan-pink, rubbery nodule with minimal surrounding soft tissue. Histologic examination showed a bland proliferation of spindle cells with storiform and whorled patterns (Figure 3). No notable nuclear atypia or necrosis was identified. The tumor cells were focally positive for EMA (Figure 4), claudin-1, and CD34 and negative for S-100, SOX10, GLUT1, desmin, STAT6, pankeratin AE1/AE3, and SMA. The diagnosis of perineurioma was rendered. No recurrence of the lesion was appreciated clinically on a 6-month follow-up examination.

Comment

Characteristics of Perineuriomas—On gross evaluation, perineuriomas are firm, gray-white, and well circumscribed but not encapsulated. Histologically, perineuriomas can have a storiform, whorled, or lamellar pattern of spindle cells. Perivascular whorls can be a histologic clue. The spindle cells are bland appearing and typically are elongated and slender but can appear slightly ovoid and plump. The background stroma can be myxoid, collagenous, or mixed. There usually is no atypia, and mitotic figures are rare.^2,3,6,7 Intraneural perineuriomas vary architecturally in that they display a unique onion bulb–like appearance in which whorls of cytoplasmic material of variable sizes surround central axons.³

Diagnosis—The diagnosis of perineuriomas usually requires characteristic immunohistochemical and sometimes ultrastructural features. Perineuriomas are positive for EMA and GLUT1 and variable for CD34.⁶ Approximately 20% to 91% will be positive for claudin-1, a tight junction protein associated with perineuriomas.⁸ Of note, EMA and GLUT1 usually are positive in both neoplastic and nonneoplastic perineurial cells.^9,10 Occasionally, these tumors can be focally positive for SMA and negative for S-100 and glial fibrillary acidic protein. The bipolar, thin, delicate, cytoplasmic processes with long-tapering nuclei may be easier to appreciate on electron microscopy than on conventional light microscopy. In addition, the cells contain pinocytotic vesicles and a discontinuous external lamina, which may be helpful for diagnosis.¹⁰

Genetics—Genetic alterations in perineurioma continue to be elucidated. Although many soft tissue perineuriomas possess deletion of chromosome 22q material, this is not a consistent finding and is not pathognomonic. Notably, the NF2 tumor suppressor gene is found on chromosome 22.¹¹ For the sclerosing variant of perineurioma, rearrangements or deletions of chromosome 10q have been described. A study of 14 soft tissue/extraneural perineuriomas using whole-exome sequencing and single nucleotide polymorphism array showed 6 cases of recurrent chromosome 22q deletions containing the NF2 locus and 4 cases with a previously unreported finding of chromosome 17q deletions containing the NF1 locus that were mutually exclusive events in all but 1 case.¹² Although perineuriomas can harbor NF1 or NF2 mutations, perineuriomas are not considered to be associated with neurofibromatosis type 1 or 2 (NF1 or NF2, respectively). Patients with NF1 or NF2 and perineurioma are exceedingly rare. One pediatric patient with both soft tissue perineurioma and NF1 has been reported in the literature.¹³

Differential Diagnosis—Perineuriomas should be distinguished from other benign neural neoplasms of the skin and soft tissue. Commonly considered in the differential diagnosis is schwannoma and neurofibroma. Schwannomas are encapsulated epineurial nerve sheath tumors comprised of a neoplastic proliferation of Schwann cells. Schwannomas morphologically differ from perineuriomas because of the presence of the hypercellular Antoni A with Verocay bodies and the hypocellular myxoid Antoni B patterns of spindle cells with elongated wavy nuclei and tapered ends. Other features include hyalinized vessels, hemosiderin deposition, cystic degeneration, and/or degenerative atypia.^3,14 Importantly, the constituent cells of schwannomas are positive for S-100 and SOX10 and negative for EMA.³ Neurofibromas consist of fascicles and whorls of Schwann cells in a background myxoid stroma with scattered mast cells, lymphocytes, fibroblasts, and perineurial cells. Similar to schwannomas, neurofibromas also are positive for S-100 and negative for EMA.^3,14 Neurofibromas can have either a somatic or germline mutation of the biallelic NF1 gene on chromosome 17q11.2 with subsequent loss of protein neurofibromin activity.¹⁵ Less common but still a consideration are the hybrid peripheral nerve sheath tumors that may present with a biphasic or intermingled morphology. Combinations include neurofibroma-schwannoma, schwannoma-perineurioma, and neurofibroma-perineurioma. The hybrid schwannoma-perineurioma has a mixture of thin and plump spindle cells with tapered nuclei as well as patchy S-100 positivity corresponding to schwannian areas. Similarly, S-100 will highlight the wavy Schwann cells in neurofibroma-perineurioma as well as CD34-highlighting fibroblasts.^7,15 In both aforementioned hybrid tumors, EMA will be positive in the perineurial areas. Another potential diagnostic consideration that can occur in both pediatric and adult populations is dermatofibrosarcoma protuberans (DFSP), which is comprised of a dermal proliferation of monomorphic fusiform spindle cells. Although both perineuriomas and DFSP can have a storiform architecture, DFSP is more asymmetric and infiltrative. Dermatofibrosarcoma protuberans is recognized in areas of individual adipocyte trapping, referred to as honeycombing. Dermatofibrosarcoma protuberans typically does not express EMA, though the sclerosing variant of DFSP has been reported to sometimes demonstrate focal EMA reactivity.^11,14,16 For morphologically challenging cases, cytogenetic studies will show t(17;22) translocation fusing the COL1A1 and PDGFRB genes.¹⁶ Finally, for subcutaneous or deep-seated tumors, one also may consider other mesenchymal neoplasms, including solitary fibrous tumor, low-grade fibromyxoid sarcoma, or low-grade malignant peripheral nerve sheath tumor (MPNST).¹¹

Management—Perineuriomas are considered benign. The presence of mitotic figures, pleomorphism, and degenerative nuclear atypia akin to ancient change, as seen in ancient schwannoma, does not affect their benign clinical behavior. Treatment of a perineurioma typically is surgical excision with conservative margins and minimal chance of recurrence.^1,11 So-called malignant perineuriomas are better classified as MPNSTs with perineural differentiation or perineurial MPNST. They also are positive for EMA and may be distinguished from perineurioma by the presence of major atypia and an infiltrative growth pattern.^17,18

Considerations in the Pediatric Population—Few pediatric soft tissue perineuriomas have been reported. A clinicopathologic analysis by Hornick and Fletcher¹ of patients with soft tissue perineurioma showed that only 6 of 81 patients were younger than 20 years. The youngest reported case of perineurioma occurred as an extraneural perineurioma on the scalp in an infant.¹⁹ Only 1 soft tissue perineural MPNST has been reported in the pediatric population, arising on the face of an 11-year-old boy. In a case series of 11 pediatric perineuriomas, including extraneural and intraneural, there was no evidence of recurrence or metastasis at follow-up.⁴

Conclusion

Perineuriomas are rare benign peripheral nerve sheath tumors with unique histologic and immunohistochemical features. Soft tissue perineuriomas in the pediatric population are an important diagnostic consideration, especially for the pediatrician or dermatologist when encountering a well-circumscribed nodular soft tissue lesion of the extremity or when encountering a neural-appearing tumor in the subcutaneous tissue.

Acknowledgment—We would like to thank Christopher Fletcher, MD (Boston, Massachusetts), for his expertise in outside consultation for patient 1.

Perineuriomas are benign, slow-growing tumors derived from perineurial cells,¹ which form the structurally supportive perineurium that surrounds individual nerve fascicles.^2,3 Perineuriomas are classified into 2 main forms: intraneural or extraneural.⁴ Intraneural perineuriomas are found within the border of the peripheral nerve,⁵ while extraneural perineuriomas usually are found in soft tissue and skin. Extraneural perineuriomas can be further classified into variants based on their histologic appearance, including reticular, sclerosing, and plexiform subtypes. Extraneural perineuriomas usually present on the extremities or trunk of young to middle-aged adults as a well-circumscribed, painless, subcutaneous masses.¹ These tumors are especially unusual in children.⁴ We present 2 extraneural perineurioma cases in children, and we review the pertinent diagnostic features of perineurioma as well as the presentation in the pediatric population.

Case Reports

Patient 1—A 10-year-old boy with a history of cerebral palsy and related comorbidities presented to the clinic for evaluation of a lesion on the thigh with no associated pain, irritation, erythema, or drainage. Physical examination revealed a soft, pedunculated, mobile nodule on the right medial thigh. An elliptical excision was performed. Gross examination demonstrated a 2.0×2.0×1.8-cm polypoid nodule. Histologic examination showed a dermal-based proliferation of bland spindle cells (Figure 1). The cytomorphology was characterized by elongated tapering nuclei and many areas with delicate bipolar cytoplasmic processes. The constituent cells were arranged in a whorled pattern in a variably myxoid to collagenous stroma. The tumor cells were multifocally positive for CD34; focally positive for smooth muscle actin (SMA); and negative for S-100, epithelial membrane antigen (EMA), GLUT1, claudin-1, STAT6, and desmin. Rb protein was intact. The CD34 immunostain highlighted the cytoplasmic processes. Electron microscopy was performed because the immunohistochemical results were nonspecific despite the favorable histologic features for perineurioma and showed pinocytic vesicles with delicate cytoplasmic processes, characteristic of perineurioma (Figure 2). Follow-up visits were related to the management of multiple comorbidities; no known recurrence of the lesion was documented.

Patient 2—A 15-year-old adolescent boy with no notable medical history presented to the pediatric clinic for a bump on the right upper arm of 4 to 5 months’ duration. He did not recall an injury to the area and denied change in size, redness, bruising, or pain of the lesion. Ultrasonography demonstrated a 2.6×2.3×1.3-cm hypoechoic and slightly heterogeneous, well-circumscribed, subcutaneous mass with internal vascularity. The patient was then referred to a pediatric surgeon. The clinical differential included a lipoma, lymphadenopathy, or sebaceous cyst. An excision was performed. Gross inspection demonstrated a 7-g, 2.8×2.6×1.8-cm, homogeneous, tan-pink, rubbery nodule with minimal surrounding soft tissue. Histologic examination showed a bland proliferation of spindle cells with storiform and whorled patterns (Figure 3). No notable nuclear atypia or necrosis was identified. The tumor cells were focally positive for EMA (Figure 4), claudin-1, and CD34 and negative for S-100, SOX10, GLUT1, desmin, STAT6, pankeratin AE1/AE3, and SMA. The diagnosis of perineurioma was rendered. No recurrence of the lesion was appreciated clinically on a 6-month follow-up examination.

Comment

Characteristics of Perineuriomas—On gross evaluation, perineuriomas are firm, gray-white, and well circumscribed but not encapsulated. Histologically, perineuriomas can have a storiform, whorled, or lamellar pattern of spindle cells. Perivascular whorls can be a histologic clue. The spindle cells are bland appearing and typically are elongated and slender but can appear slightly ovoid and plump. The background stroma can be myxoid, collagenous, or mixed. There usually is no atypia, and mitotic figures are rare.^2,3,6,7 Intraneural perineuriomas vary architecturally in that they display a unique onion bulb–like appearance in which whorls of cytoplasmic material of variable sizes surround central axons.³

Diagnosis—The diagnosis of perineuriomas usually requires characteristic immunohistochemical and sometimes ultrastructural features. Perineuriomas are positive for EMA and GLUT1 and variable for CD34.⁶ Approximately 20% to 91% will be positive for claudin-1, a tight junction protein associated with perineuriomas.⁸ Of note, EMA and GLUT1 usually are positive in both neoplastic and nonneoplastic perineurial cells.^9,10 Occasionally, these tumors can be focally positive for SMA and negative for S-100 and glial fibrillary acidic protein. The bipolar, thin, delicate, cytoplasmic processes with long-tapering nuclei may be easier to appreciate on electron microscopy than on conventional light microscopy. In addition, the cells contain pinocytotic vesicles and a discontinuous external lamina, which may be helpful for diagnosis.¹⁰

Genetics—Genetic alterations in perineurioma continue to be elucidated. Although many soft tissue perineuriomas possess deletion of chromosome 22q material, this is not a consistent finding and is not pathognomonic. Notably, the NF2 tumor suppressor gene is found on chromosome 22.¹¹ For the sclerosing variant of perineurioma, rearrangements or deletions of chromosome 10q have been described. A study of 14 soft tissue/extraneural perineuriomas using whole-exome sequencing and single nucleotide polymorphism array showed 6 cases of recurrent chromosome 22q deletions containing the NF2 locus and 4 cases with a previously unreported finding of chromosome 17q deletions containing the NF1 locus that were mutually exclusive events in all but 1 case.¹² Although perineuriomas can harbor NF1 or NF2 mutations, perineuriomas are not considered to be associated with neurofibromatosis type 1 or 2 (NF1 or NF2, respectively). Patients with NF1 or NF2 and perineurioma are exceedingly rare. One pediatric patient with both soft tissue perineurioma and NF1 has been reported in the literature.¹³

Differential Diagnosis—Perineuriomas should be distinguished from other benign neural neoplasms of the skin and soft tissue. Commonly considered in the differential diagnosis is schwannoma and neurofibroma. Schwannomas are encapsulated epineurial nerve sheath tumors comprised of a neoplastic proliferation of Schwann cells. Schwannomas morphologically differ from perineuriomas because of the presence of the hypercellular Antoni A with Verocay bodies and the hypocellular myxoid Antoni B patterns of spindle cells with elongated wavy nuclei and tapered ends. Other features include hyalinized vessels, hemosiderin deposition, cystic degeneration, and/or degenerative atypia.^3,14 Importantly, the constituent cells of schwannomas are positive for S-100 and SOX10 and negative for EMA.³ Neurofibromas consist of fascicles and whorls of Schwann cells in a background myxoid stroma with scattered mast cells, lymphocytes, fibroblasts, and perineurial cells. Similar to schwannomas, neurofibromas also are positive for S-100 and negative for EMA.^3,14 Neurofibromas can have either a somatic or germline mutation of the biallelic NF1 gene on chromosome 17q11.2 with subsequent loss of protein neurofibromin activity.¹⁵ Less common but still a consideration are the hybrid peripheral nerve sheath tumors that may present with a biphasic or intermingled morphology. Combinations include neurofibroma-schwannoma, schwannoma-perineurioma, and neurofibroma-perineurioma. The hybrid schwannoma-perineurioma has a mixture of thin and plump spindle cells with tapered nuclei as well as patchy S-100 positivity corresponding to schwannian areas. Similarly, S-100 will highlight the wavy Schwann cells in neurofibroma-perineurioma as well as CD34-highlighting fibroblasts.^7,15 In both aforementioned hybrid tumors, EMA will be positive in the perineurial areas. Another potential diagnostic consideration that can occur in both pediatric and adult populations is dermatofibrosarcoma protuberans (DFSP), which is comprised of a dermal proliferation of monomorphic fusiform spindle cells. Although both perineuriomas and DFSP can have a storiform architecture, DFSP is more asymmetric and infiltrative. Dermatofibrosarcoma protuberans is recognized in areas of individual adipocyte trapping, referred to as honeycombing. Dermatofibrosarcoma protuberans typically does not express EMA, though the sclerosing variant of DFSP has been reported to sometimes demonstrate focal EMA reactivity.^11,14,16 For morphologically challenging cases, cytogenetic studies will show t(17;22) translocation fusing the COL1A1 and PDGFRB genes.¹⁶ Finally, for subcutaneous or deep-seated tumors, one also may consider other mesenchymal neoplasms, including solitary fibrous tumor, low-grade fibromyxoid sarcoma, or low-grade malignant peripheral nerve sheath tumor (MPNST).¹¹

Management—Perineuriomas are considered benign. The presence of mitotic figures, pleomorphism, and degenerative nuclear atypia akin to ancient change, as seen in ancient schwannoma, does not affect their benign clinical behavior. Treatment of a perineurioma typically is surgical excision with conservative margins and minimal chance of recurrence.^1,11 So-called malignant perineuriomas are better classified as MPNSTs with perineural differentiation or perineurial MPNST. They also are positive for EMA and may be distinguished from perineurioma by the presence of major atypia and an infiltrative growth pattern.^17,18

Considerations in the Pediatric Population—Few pediatric soft tissue perineuriomas have been reported. A clinicopathologic analysis by Hornick and Fletcher¹ of patients with soft tissue perineurioma showed that only 6 of 81 patients were younger than 20 years. The youngest reported case of perineurioma occurred as an extraneural perineurioma on the scalp in an infant.¹⁹ Only 1 soft tissue perineural MPNST has been reported in the pediatric population, arising on the face of an 11-year-old boy. In a case series of 11 pediatric perineuriomas, including extraneural and intraneural, there was no evidence of recurrence or metastasis at follow-up.⁴

Conclusion

Perineuriomas are rare benign peripheral nerve sheath tumors with unique histologic and immunohistochemical features. Soft tissue perineuriomas in the pediatric population are an important diagnostic consideration, especially for the pediatrician or dermatologist when encountering a well-circumscribed nodular soft tissue lesion of the extremity or when encountering a neural-appearing tumor in the subcutaneous tissue.

Acknowledgment—We would like to thank Christopher Fletcher, MD (Boston, Massachusetts), for his expertise in outside consultation for patient 1.

Perineuriomas are benign, slow-growing tumors derived from perineurial cells,¹ which form the structurally supportive perineurium that surrounds individual nerve fascicles.^2,3 Perineuriomas are classified into 2 main forms: intraneural or extraneural.⁴ Intraneural perineuriomas are found within the border of the peripheral nerve,⁵ while extraneural perineuriomas usually are found in soft tissue and skin. Extraneural perineuriomas can be further classified into variants based on their histologic appearance, including reticular, sclerosing, and plexiform subtypes. Extraneural perineuriomas usually present on the extremities or trunk of young to middle-aged adults as a well-circumscribed, painless, subcutaneous masses.¹ These tumors are especially unusual in children.⁴ We present 2 extraneural perineurioma cases in children, and we review the pertinent diagnostic features of perineurioma as well as the presentation in the pediatric population.

Case Reports

Patient 1—A 10-year-old boy with a history of cerebral palsy and related comorbidities presented to the clinic for evaluation of a lesion on the thigh with no associated pain, irritation, erythema, or drainage. Physical examination revealed a soft, pedunculated, mobile nodule on the right medial thigh. An elliptical excision was performed. Gross examination demonstrated a 2.0×2.0×1.8-cm polypoid nodule. Histologic examination showed a dermal-based proliferation of bland spindle cells (Figure 1). The cytomorphology was characterized by elongated tapering nuclei and many areas with delicate bipolar cytoplasmic processes. The constituent cells were arranged in a whorled pattern in a variably myxoid to collagenous stroma. The tumor cells were multifocally positive for CD34; focally positive for smooth muscle actin (SMA); and negative for S-100, epithelial membrane antigen (EMA), GLUT1, claudin-1, STAT6, and desmin. Rb protein was intact. The CD34 immunostain highlighted the cytoplasmic processes. Electron microscopy was performed because the immunohistochemical results were nonspecific despite the favorable histologic features for perineurioma and showed pinocytic vesicles with delicate cytoplasmic processes, characteristic of perineurioma (Figure 2). Follow-up visits were related to the management of multiple comorbidities; no known recurrence of the lesion was documented.

Patient 2—A 15-year-old adolescent boy with no notable medical history presented to the pediatric clinic for a bump on the right upper arm of 4 to 5 months’ duration. He did not recall an injury to the area and denied change in size, redness, bruising, or pain of the lesion. Ultrasonography demonstrated a 2.6×2.3×1.3-cm hypoechoic and slightly heterogeneous, well-circumscribed, subcutaneous mass with internal vascularity. The patient was then referred to a pediatric surgeon. The clinical differential included a lipoma, lymphadenopathy, or sebaceous cyst. An excision was performed. Gross inspection demonstrated a 7-g, 2.8×2.6×1.8-cm, homogeneous, tan-pink, rubbery nodule with minimal surrounding soft tissue. Histologic examination showed a bland proliferation of spindle cells with storiform and whorled patterns (Figure 3). No notable nuclear atypia or necrosis was identified. The tumor cells were focally positive for EMA (Figure 4), claudin-1, and CD34 and negative for S-100, SOX10, GLUT1, desmin, STAT6, pankeratin AE1/AE3, and SMA. The diagnosis of perineurioma was rendered. No recurrence of the lesion was appreciated clinically on a 6-month follow-up examination.

Comment

Characteristics of Perineuriomas—On gross evaluation, perineuriomas are firm, gray-white, and well circumscribed but not encapsulated. Histologically, perineuriomas can have a storiform, whorled, or lamellar pattern of spindle cells. Perivascular whorls can be a histologic clue. The spindle cells are bland appearing and typically are elongated and slender but can appear slightly ovoid and plump. The background stroma can be myxoid, collagenous, or mixed. There usually is no atypia, and mitotic figures are rare.^2,3,6,7 Intraneural perineuriomas vary architecturally in that they display a unique onion bulb–like appearance in which whorls of cytoplasmic material of variable sizes surround central axons.³

Diagnosis—The diagnosis of perineuriomas usually requires characteristic immunohistochemical and sometimes ultrastructural features. Perineuriomas are positive for EMA and GLUT1 and variable for CD34.⁶ Approximately 20% to 91% will be positive for claudin-1, a tight junction protein associated with perineuriomas.⁸ Of note, EMA and GLUT1 usually are positive in both neoplastic and nonneoplastic perineurial cells.^9,10 Occasionally, these tumors can be focally positive for SMA and negative for S-100 and glial fibrillary acidic protein. The bipolar, thin, delicate, cytoplasmic processes with long-tapering nuclei may be easier to appreciate on electron microscopy than on conventional light microscopy. In addition, the cells contain pinocytotic vesicles and a discontinuous external lamina, which may be helpful for diagnosis.¹⁰

Genetics—Genetic alterations in perineurioma continue to be elucidated. Although many soft tissue perineuriomas possess deletion of chromosome 22q material, this is not a consistent finding and is not pathognomonic. Notably, the NF2 tumor suppressor gene is found on chromosome 22.¹¹ For the sclerosing variant of perineurioma, rearrangements or deletions of chromosome 10q have been described. A study of 14 soft tissue/extraneural perineuriomas using whole-exome sequencing and single nucleotide polymorphism array showed 6 cases of recurrent chromosome 22q deletions containing the NF2 locus and 4 cases with a previously unreported finding of chromosome 17q deletions containing the NF1 locus that were mutually exclusive events in all but 1 case.¹² Although perineuriomas can harbor NF1 or NF2 mutations, perineuriomas are not considered to be associated with neurofibromatosis type 1 or 2 (NF1 or NF2, respectively). Patients with NF1 or NF2 and perineurioma are exceedingly rare. One pediatric patient with both soft tissue perineurioma and NF1 has been reported in the literature.¹³

Differential Diagnosis—Perineuriomas should be distinguished from other benign neural neoplasms of the skin and soft tissue. Commonly considered in the differential diagnosis is schwannoma and neurofibroma. Schwannomas are encapsulated epineurial nerve sheath tumors comprised of a neoplastic proliferation of Schwann cells. Schwannomas morphologically differ from perineuriomas because of the presence of the hypercellular Antoni A with Verocay bodies and the hypocellular myxoid Antoni B patterns of spindle cells with elongated wavy nuclei and tapered ends. Other features include hyalinized vessels, hemosiderin deposition, cystic degeneration, and/or degenerative atypia.^3,14 Importantly, the constituent cells of schwannomas are positive for S-100 and SOX10 and negative for EMA.³ Neurofibromas consist of fascicles and whorls of Schwann cells in a background myxoid stroma with scattered mast cells, lymphocytes, fibroblasts, and perineurial cells. Similar to schwannomas, neurofibromas also are positive for S-100 and negative for EMA.^3,14 Neurofibromas can have either a somatic or germline mutation of the biallelic NF1 gene on chromosome 17q11.2 with subsequent loss of protein neurofibromin activity.¹⁵ Less common but still a consideration are the hybrid peripheral nerve sheath tumors that may present with a biphasic or intermingled morphology. Combinations include neurofibroma-schwannoma, schwannoma-perineurioma, and neurofibroma-perineurioma. The hybrid schwannoma-perineurioma has a mixture of thin and plump spindle cells with tapered nuclei as well as patchy S-100 positivity corresponding to schwannian areas. Similarly, S-100 will highlight the wavy Schwann cells in neurofibroma-perineurioma as well as CD34-highlighting fibroblasts.^7,15 In both aforementioned hybrid tumors, EMA will be positive in the perineurial areas. Another potential diagnostic consideration that can occur in both pediatric and adult populations is dermatofibrosarcoma protuberans (DFSP), which is comprised of a dermal proliferation of monomorphic fusiform spindle cells. Although both perineuriomas and DFSP can have a storiform architecture, DFSP is more asymmetric and infiltrative. Dermatofibrosarcoma protuberans is recognized in areas of individual adipocyte trapping, referred to as honeycombing. Dermatofibrosarcoma protuberans typically does not express EMA, though the sclerosing variant of DFSP has been reported to sometimes demonstrate focal EMA reactivity.^11,14,16 For morphologically challenging cases, cytogenetic studies will show t(17;22) translocation fusing the COL1A1 and PDGFRB genes.¹⁶ Finally, for subcutaneous or deep-seated tumors, one also may consider other mesenchymal neoplasms, including solitary fibrous tumor, low-grade fibromyxoid sarcoma, or low-grade malignant peripheral nerve sheath tumor (MPNST).¹¹

Management—Perineuriomas are considered benign. The presence of mitotic figures, pleomorphism, and degenerative nuclear atypia akin to ancient change, as seen in ancient schwannoma, does not affect their benign clinical behavior. Treatment of a perineurioma typically is surgical excision with conservative margins and minimal chance of recurrence.^1,11 So-called malignant perineuriomas are better classified as MPNSTs with perineural differentiation or perineurial MPNST. They also are positive for EMA and may be distinguished from perineurioma by the presence of major atypia and an infiltrative growth pattern.^17,18

Considerations in the Pediatric Population—Few pediatric soft tissue perineuriomas have been reported. A clinicopathologic analysis by Hornick and Fletcher¹ of patients with soft tissue perineurioma showed that only 6 of 81 patients were younger than 20 years. The youngest reported case of perineurioma occurred as an extraneural perineurioma on the scalp in an infant.¹⁹ Only 1 soft tissue perineural MPNST has been reported in the pediatric population, arising on the face of an 11-year-old boy. In a case series of 11 pediatric perineuriomas, including extraneural and intraneural, there was no evidence of recurrence or metastasis at follow-up.⁴

Conclusion

Perineuriomas are rare benign peripheral nerve sheath tumors with unique histologic and immunohistochemical features. Soft tissue perineuriomas in the pediatric population are an important diagnostic consideration, especially for the pediatrician or dermatologist when encountering a well-circumscribed nodular soft tissue lesion of the extremity or when encountering a neural-appearing tumor in the subcutaneous tissue.

Acknowledgment—We would like to thank Christopher Fletcher, MD (Boston, Massachusetts), for his expertise in outside consultation for patient 1.

Atopic dermatitis (AD), or eczema, is a common inflammatory skin disease notorious for its chronic, relapsing, and often frustrating disease course. Although as many as 25% of children in the United States are affected by this condition and its impact on the quality of life of affected patients and families is profound,^1-3 therapeutic advances in the pediatric population have been fairly limited until recently.

Over the last 10 years, there has been robust investigation into pediatric AD therapeutics, with many topical and systemic medications either recently approved or under clinical investigation. These developments are changing the landscape of the management of pediatric AD and raise a set of fascinating questions about how early and aggressive intervention might change the course of this disease. We discuss current limitations in the field that may be addressed with additional research.

New Topical Medications

In the last several years, there has been a rapid increase in efforts to develop new topical agents to manage AD. Until the beginning of the 21st century, the dermatologist’s arsenal was limited to topical corticosteroids (TCs). In the early 2000s, attention shifted to topical calcineurin inhibitors as nonsteroidal alternatives when the US Food and Drug Administration (FDA) approved topical tacrolimus and pimecrolimus for AD. In 2016, crisaborole (a phosphodiesterase-4 [PDE4] inhibitor) was approved by the FDA for use in mild to moderate AD in patients 2 years and older, marking a new age of development for topical AD therapies. In 2021, the FDA approved ruxolitinib (a topical Janus kinase [JAK] 1/2 inhibitor) for use in mild to moderate AD in patients 12 years and older.

Roflumilast (ARQ-151) and difamilast (OPA-15406)(members of the PDE4 inhibitor class) are undergoing investigation for pediatric AD. A phase 3 clinical trial for roflumilast for AD is underway (ClinicalTrial.gov Identifier: NCT04845620); it is already approved for psoriasis in patients 12 years and older. A phase 3 trial of difamilast (NCT03911401) was recently completed, with results supporting the drug’s safety and efficacy in AD management.⁴ Efforts to synthesize new better-targeted PDE4 inhibitors are ongoing.⁵

Tapinarof (a novel aryl hydrocarbon receptor-modulating agent) is approved for psoriasis in adults, and a phase 3 trial for management of pediatric AD is underway (NCT05032859) after phase 2 trials revealed promising results.⁶

Lastly, the microbiome is a target for AD topical therapies. A recently completed phase 1 trial of bacteriotherapy with Staphylococcus hominis A9 transplant lotion showed promising results (NCT03151148).⁷ Although this bacteriotherapy technique is early in development and has been studied only in adult patients, results are exciting because they represent a gateway to a largely unexplored realm of potential future therapies.

Standard of Care—How will these new topical therapies impact our standard of care for pediatric AD patients? Topical corticosteroids are still a pillar of topical AD therapy, but the potential for nonsteroidal topical agents as alternatives and used in combination therapeutic regimens has expanded exponentially. It is uncertain how we might individualize regimens tailored to patient-specific factors because the standard approach has been to test drugs as monotherapy, with vehicle comparisons or with reference medications in Europe.

Newer topical nonsteroidal agents may offer several opportunities. First, they may help avoid local and systemic adverse effects that often limit the use of current standard therapy.⁸ This capability may prove essential in bridging TC treatments and serving as long-term maintenance therapies to decrease the frequency of eczema flares. Second, they can alleviate the need for different medication strengths for different body regions, thereby allowing for simplification of regimens and potentially increased adherence and decreased disease burden—a boon to affected patients and caregivers.

Although the efficacy and long-term safety profile of these new drugs require further study, it does not seem unreasonable to look forward to achieving levels of optimization and individualization with topical regimens for AD in the near future that makes flares in patients with mild to moderate AD a phenomenon of the past.

Advances in Systemic Therapy

Systemic therapeutics in pediatric AD also recently entered an exciting era of development. Traditional systemic agents, including cyclosporine, methotrexate, azathioprine, and mycophenolate mofetil, have existed for decades but have not been widely utilized for moderate to severe AD in the United States, especially in the pediatric population, likely because these drugs lacked FDA approval and they can cause a range of adverse effects, including notable immunosuppression.⁹

Introduction and approval of dupilumab in 2017 by the FDA was revolutionary in this field. As a monoclonal antibody targeted against IL-4 and IL-13, dupilumab has consistently demonstrated strong long-term efficacy for pediatric AD and has an acceptable safety profile in children and adolescents.^10-14 Expansion of the label to include children as young as 6 months with moderate to severe AD seems an important milestone in pediatric AD care.

Since the approval of dupilumab for adolescents and children aged 6 to 12 years, global experience has supported expanded use of systemic agents for patients who have an inadequate response to TCs and previously approved nonsteroidal topical agents. How expansive the use of systemics will be in younger children depends on how their long-term use impacts the disease course, whether therapy is disease modifying, and whether early use can curb the development of comorbidities.

Investigations into targeted systemic therapeutics for eczematous dermatitis are not limited to dupilumab. In a study of adolescents as young as 12 years, tralokinumab (an IL-13 pathway inhibitor) demonstrated an Eczema Area Severity Index-75 of 27.8% to 28.6% and a mean decrease in the SCORing Atopic Dermatitis index of 27.5 to 29.1, with minimal adverse effects.¹⁵ Lebrikizumab, another biologic IL-13 inhibitor with strong published safety and efficacy data in adults, has completed short- and longer-term studies in adolescents (NCT04178967 and NCT04146363).¹⁶ The drug received FDA Fast Track designation for moderate to severe AD in patients 12 years and older after showing positive data.¹⁷

This push to targeted therapy stretches beyond monoclonal antibodies. In the last few years, oral JAK inhibitors have emerged as a new class of systemic therapy for eczematous dermatitis. Upadacitinib, a JAK1 selective inhibitor, was approved by the FDA in 2022 for patients 12 years and older with AD and has data that supports its efficacy in adolescents and adults.¹⁸ Other JAK inhibitors including the selective JAK1 inhibitor abrocitinib and the combined JAK1/2 inhibitor baricitinib are being studied for pediatric AD (NCT04564755, NCT03422822, and NCT03952559), with most evidence to date supporting their safety and efficacy, at least over the short-term.¹⁹

The study of these and other advanced systemic therapies for eczematous dermatitis is transforming the toolbox for pediatric AD care. Although long-term data are lacking for some of these medications, it is possible that newer agents may decrease reliance on older immunosuppressants, such as systemic corticosteroids, cyclosporine, and methotrexate. Unanswered questions include: How and which systemic medications may alter the course of the disease? What is the disease modification for AD? What is the impact on comorbidities over time?

What’s Missing?

The field of pediatric AD has experienced exciting new developments with the emergence of targeted therapeutics, but those new agents require more long-term study, though we already have longer-term data on crisaborole and dupilumab.^10-14,20 Studies of the long-term use of these new treatments on comorbidities of pediatric AD—mental health outcomes, cardiovascular disease, effects on the family, and other allergic conditions—are needed.²¹ Furthermore, clinical guidelines that address indications, timing of use, tapering, and discontinuation of new treatments depend on long-term experience and data collection.

Therefore, it is prudent that investigators, companies, payers, patients, and families support phase 4, long-term extension, and registry studies, which will expand our knowledge of AD medications and their impact on the disease over time.

Final Thoughts

Medications to treat AD are reaching a new level of advancement—from topical agents that target novel pathways to revolutionary biologics and systemic medications. Although there are knowledge gaps on these new therapeutics, the standard of care is already rapidly changing as the expectations of clinicians, patients, and families advance with each addition to the provider’s toolbox.

Atopic dermatitis (AD), or eczema, is a common inflammatory skin disease notorious for its chronic, relapsing, and often frustrating disease course. Although as many as 25% of children in the United States are affected by this condition and its impact on the quality of life of affected patients and families is profound,^1-3 therapeutic advances in the pediatric population have been fairly limited until recently.

Over the last 10 years, there has been robust investigation into pediatric AD therapeutics, with many topical and systemic medications either recently approved or under clinical investigation. These developments are changing the landscape of the management of pediatric AD and raise a set of fascinating questions about how early and aggressive intervention might change the course of this disease. We discuss current limitations in the field that may be addressed with additional research.

New Topical Medications

In the last several years, there has been a rapid increase in efforts to develop new topical agents to manage AD. Until the beginning of the 21st century, the dermatologist’s arsenal was limited to topical corticosteroids (TCs). In the early 2000s, attention shifted to topical calcineurin inhibitors as nonsteroidal alternatives when the US Food and Drug Administration (FDA) approved topical tacrolimus and pimecrolimus for AD. In 2016, crisaborole (a phosphodiesterase-4 [PDE4] inhibitor) was approved by the FDA for use in mild to moderate AD in patients 2 years and older, marking a new age of development for topical AD therapies. In 2021, the FDA approved ruxolitinib (a topical Janus kinase [JAK] 1/2 inhibitor) for use in mild to moderate AD in patients 12 years and older.

Roflumilast (ARQ-151) and difamilast (OPA-15406)(members of the PDE4 inhibitor class) are undergoing investigation for pediatric AD. A phase 3 clinical trial for roflumilast for AD is underway (ClinicalTrial.gov Identifier: NCT04845620); it is already approved for psoriasis in patients 12 years and older. A phase 3 trial of difamilast (NCT03911401) was recently completed, with results supporting the drug’s safety and efficacy in AD management.⁴ Efforts to synthesize new better-targeted PDE4 inhibitors are ongoing.⁵

Tapinarof (a novel aryl hydrocarbon receptor-modulating agent) is approved for psoriasis in adults, and a phase 3 trial for management of pediatric AD is underway (NCT05032859) after phase 2 trials revealed promising results.⁶

Lastly, the microbiome is a target for AD topical therapies. A recently completed phase 1 trial of bacteriotherapy with Staphylococcus hominis A9 transplant lotion showed promising results (NCT03151148).⁷ Although this bacteriotherapy technique is early in development and has been studied only in adult patients, results are exciting because they represent a gateway to a largely unexplored realm of potential future therapies.

Standard of Care—How will these new topical therapies impact our standard of care for pediatric AD patients? Topical corticosteroids are still a pillar of topical AD therapy, but the potential for nonsteroidal topical agents as alternatives and used in combination therapeutic regimens has expanded exponentially. It is uncertain how we might individualize regimens tailored to patient-specific factors because the standard approach has been to test drugs as monotherapy, with vehicle comparisons or with reference medications in Europe.

Newer topical nonsteroidal agents may offer several opportunities. First, they may help avoid local and systemic adverse effects that often limit the use of current standard therapy.⁸ This capability may prove essential in bridging TC treatments and serving as long-term maintenance therapies to decrease the frequency of eczema flares. Second, they can alleviate the need for different medication strengths for different body regions, thereby allowing for simplification of regimens and potentially increased adherence and decreased disease burden—a boon to affected patients and caregivers.

Although the efficacy and long-term safety profile of these new drugs require further study, it does not seem unreasonable to look forward to achieving levels of optimization and individualization with topical regimens for AD in the near future that makes flares in patients with mild to moderate AD a phenomenon of the past.

Advances in Systemic Therapy

Systemic therapeutics in pediatric AD also recently entered an exciting era of development. Traditional systemic agents, including cyclosporine, methotrexate, azathioprine, and mycophenolate mofetil, have existed for decades but have not been widely utilized for moderate to severe AD in the United States, especially in the pediatric population, likely because these drugs lacked FDA approval and they can cause a range of adverse effects, including notable immunosuppression.⁹

Introduction and approval of dupilumab in 2017 by the FDA was revolutionary in this field. As a monoclonal antibody targeted against IL-4 and IL-13, dupilumab has consistently demonstrated strong long-term efficacy for pediatric AD and has an acceptable safety profile in children and adolescents.^10-14 Expansion of the label to include children as young as 6 months with moderate to severe AD seems an important milestone in pediatric AD care.

Since the approval of dupilumab for adolescents and children aged 6 to 12 years, global experience has supported expanded use of systemic agents for patients who have an inadequate response to TCs and previously approved nonsteroidal topical agents. How expansive the use of systemics will be in younger children depends on how their long-term use impacts the disease course, whether therapy is disease modifying, and whether early use can curb the development of comorbidities.

Investigations into targeted systemic therapeutics for eczematous dermatitis are not limited to dupilumab. In a study of adolescents as young as 12 years, tralokinumab (an IL-13 pathway inhibitor) demonstrated an Eczema Area Severity Index-75 of 27.8% to 28.6% and a mean decrease in the SCORing Atopic Dermatitis index of 27.5 to 29.1, with minimal adverse effects.¹⁵ Lebrikizumab, another biologic IL-13 inhibitor with strong published safety and efficacy data in adults, has completed short- and longer-term studies in adolescents (NCT04178967 and NCT04146363).¹⁶ The drug received FDA Fast Track designation for moderate to severe AD in patients 12 years and older after showing positive data.¹⁷

This push to targeted therapy stretches beyond monoclonal antibodies. In the last few years, oral JAK inhibitors have emerged as a new class of systemic therapy for eczematous dermatitis. Upadacitinib, a JAK1 selective inhibitor, was approved by the FDA in 2022 for patients 12 years and older with AD and has data that supports its efficacy in adolescents and adults.¹⁸ Other JAK inhibitors including the selective JAK1 inhibitor abrocitinib and the combined JAK1/2 inhibitor baricitinib are being studied for pediatric AD (NCT04564755, NCT03422822, and NCT03952559), with most evidence to date supporting their safety and efficacy, at least over the short-term.¹⁹

The study of these and other advanced systemic therapies for eczematous dermatitis is transforming the toolbox for pediatric AD care. Although long-term data are lacking for some of these medications, it is possible that newer agents may decrease reliance on older immunosuppressants, such as systemic corticosteroids, cyclosporine, and methotrexate. Unanswered questions include: How and which systemic medications may alter the course of the disease? What is the disease modification for AD? What is the impact on comorbidities over time?

What’s Missing?

The field of pediatric AD has experienced exciting new developments with the emergence of targeted therapeutics, but those new agents require more long-term study, though we already have longer-term data on crisaborole and dupilumab.^10-14,20 Studies of the long-term use of these new treatments on comorbidities of pediatric AD—mental health outcomes, cardiovascular disease, effects on the family, and other allergic conditions—are needed.²¹ Furthermore, clinical guidelines that address indications, timing of use, tapering, and discontinuation of new treatments depend on long-term experience and data collection.

Therefore, it is prudent that investigators, companies, payers, patients, and families support phase 4, long-term extension, and registry studies, which will expand our knowledge of AD medications and their impact on the disease over time.

Final Thoughts

Medications to treat AD are reaching a new level of advancement—from topical agents that target novel pathways to revolutionary biologics and systemic medications. Although there are knowledge gaps on these new therapeutics, the standard of care is already rapidly changing as the expectations of clinicians, patients, and families advance with each addition to the provider’s toolbox.

Atopic dermatitis (AD), or eczema, is a common inflammatory skin disease notorious for its chronic, relapsing, and often frustrating disease course. Although as many as 25% of children in the United States are affected by this condition and its impact on the quality of life of affected patients and families is profound,^1-3 therapeutic advances in the pediatric population have been fairly limited until recently.

Over the last 10 years, there has been robust investigation into pediatric AD therapeutics, with many topical and systemic medications either recently approved or under clinical investigation. These developments are changing the landscape of the management of pediatric AD and raise a set of fascinating questions about how early and aggressive intervention might change the course of this disease. We discuss current limitations in the field that may be addressed with additional research.

New Topical Medications

In the last several years, there has been a rapid increase in efforts to develop new topical agents to manage AD. Until the beginning of the 21st century, the dermatologist’s arsenal was limited to topical corticosteroids (TCs). In the early 2000s, attention shifted to topical calcineurin inhibitors as nonsteroidal alternatives when the US Food and Drug Administration (FDA) approved topical tacrolimus and pimecrolimus for AD. In 2016, crisaborole (a phosphodiesterase-4 [PDE4] inhibitor) was approved by the FDA for use in mild to moderate AD in patients 2 years and older, marking a new age of development for topical AD therapies. In 2021, the FDA approved ruxolitinib (a topical Janus kinase [JAK] 1/2 inhibitor) for use in mild to moderate AD in patients 12 years and older.

Roflumilast (ARQ-151) and difamilast (OPA-15406)(members of the PDE4 inhibitor class) are undergoing investigation for pediatric AD. A phase 3 clinical trial for roflumilast for AD is underway (ClinicalTrial.gov Identifier: NCT04845620); it is already approved for psoriasis in patients 12 years and older. A phase 3 trial of difamilast (NCT03911401) was recently completed, with results supporting the drug’s safety and efficacy in AD management.⁴ Efforts to synthesize new better-targeted PDE4 inhibitors are ongoing.⁵

Tapinarof (a novel aryl hydrocarbon receptor-modulating agent) is approved for psoriasis in adults, and a phase 3 trial for management of pediatric AD is underway (NCT05032859) after phase 2 trials revealed promising results.⁶

Lastly, the microbiome is a target for AD topical therapies. A recently completed phase 1 trial of bacteriotherapy with Staphylococcus hominis A9 transplant lotion showed promising results (NCT03151148).⁷ Although this bacteriotherapy technique is early in development and has been studied only in adult patients, results are exciting because they represent a gateway to a largely unexplored realm of potential future therapies.

Standard of Care—How will these new topical therapies impact our standard of care for pediatric AD patients? Topical corticosteroids are still a pillar of topical AD therapy, but the potential for nonsteroidal topical agents as alternatives and used in combination therapeutic regimens has expanded exponentially. It is uncertain how we might individualize regimens tailored to patient-specific factors because the standard approach has been to test drugs as monotherapy, with vehicle comparisons or with reference medications in Europe.

Newer topical nonsteroidal agents may offer several opportunities. First, they may help avoid local and systemic adverse effects that often limit the use of current standard therapy.⁸ This capability may prove essential in bridging TC treatments and serving as long-term maintenance therapies to decrease the frequency of eczema flares. Second, they can alleviate the need for different medication strengths for different body regions, thereby allowing for simplification of regimens and potentially increased adherence and decreased disease burden—a boon to affected patients and caregivers.

Although the efficacy and long-term safety profile of these new drugs require further study, it does not seem unreasonable to look forward to achieving levels of optimization and individualization with topical regimens for AD in the near future that makes flares in patients with mild to moderate AD a phenomenon of the past.

Advances in Systemic Therapy

Systemic therapeutics in pediatric AD also recently entered an exciting era of development. Traditional systemic agents, including cyclosporine, methotrexate, azathioprine, and mycophenolate mofetil, have existed for decades but have not been widely utilized for moderate to severe AD in the United States, especially in the pediatric population, likely because these drugs lacked FDA approval and they can cause a range of adverse effects, including notable immunosuppression.⁹

Introduction and approval of dupilumab in 2017 by the FDA was revolutionary in this field. As a monoclonal antibody targeted against IL-4 and IL-13, dupilumab has consistently demonstrated strong long-term efficacy for pediatric AD and has an acceptable safety profile in children and adolescents.^10-14 Expansion of the label to include children as young as 6 months with moderate to severe AD seems an important milestone in pediatric AD care.

Since the approval of dupilumab for adolescents and children aged 6 to 12 years, global experience has supported expanded use of systemic agents for patients who have an inadequate response to TCs and previously approved nonsteroidal topical agents. How expansive the use of systemics will be in younger children depends on how their long-term use impacts the disease course, whether therapy is disease modifying, and whether early use can curb the development of comorbidities.

Investigations into targeted systemic therapeutics for eczematous dermatitis are not limited to dupilumab. In a study of adolescents as young as 12 years, tralokinumab (an IL-13 pathway inhibitor) demonstrated an Eczema Area Severity Index-75 of 27.8% to 28.6% and a mean decrease in the SCORing Atopic Dermatitis index of 27.5 to 29.1, with minimal adverse effects.¹⁵ Lebrikizumab, another biologic IL-13 inhibitor with strong published safety and efficacy data in adults, has completed short- and longer-term studies in adolescents (NCT04178967 and NCT04146363).¹⁶ The drug received FDA Fast Track designation for moderate to severe AD in patients 12 years and older after showing positive data.¹⁷

This push to targeted therapy stretches beyond monoclonal antibodies. In the last few years, oral JAK inhibitors have emerged as a new class of systemic therapy for eczematous dermatitis. Upadacitinib, a JAK1 selective inhibitor, was approved by the FDA in 2022 for patients 12 years and older with AD and has data that supports its efficacy in adolescents and adults.¹⁸ Other JAK inhibitors including the selective JAK1 inhibitor abrocitinib and the combined JAK1/2 inhibitor baricitinib are being studied for pediatric AD (NCT04564755, NCT03422822, and NCT03952559), with most evidence to date supporting their safety and efficacy, at least over the short-term.¹⁹

The study of these and other advanced systemic therapies for eczematous dermatitis is transforming the toolbox for pediatric AD care. Although long-term data are lacking for some of these medications, it is possible that newer agents may decrease reliance on older immunosuppressants, such as systemic corticosteroids, cyclosporine, and methotrexate. Unanswered questions include: How and which systemic medications may alter the course of the disease? What is the disease modification for AD? What is the impact on comorbidities over time?

What’s Missing?

The field of pediatric AD has experienced exciting new developments with the emergence of targeted therapeutics, but those new agents require more long-term study, though we already have longer-term data on crisaborole and dupilumab.^10-14,20 Studies of the long-term use of these new treatments on comorbidities of pediatric AD—mental health outcomes, cardiovascular disease, effects on the family, and other allergic conditions—are needed.²¹ Furthermore, clinical guidelines that address indications, timing of use, tapering, and discontinuation of new treatments depend on long-term experience and data collection.

Therefore, it is prudent that investigators, companies, payers, patients, and families support phase 4, long-term extension, and registry studies, which will expand our knowledge of AD medications and their impact on the disease over time.

Final Thoughts

Medications to treat AD are reaching a new level of advancement—from topical agents that target novel pathways to revolutionary biologics and systemic medications. Although there are knowledge gaps on these new therapeutics, the standard of care is already rapidly changing as the expectations of clinicians, patients, and families advance with each addition to the provider’s toolbox.

Acrodermatitis enteropathica (AE) is a rare disorder of zinc metabolism that typically presents in infancy.¹ Although it is clinically characterized by acral and periorificial dermatitis, alopecia, and diarrhea, only 20% of cases present with this triad.² Zinc deficiency in AE can either be acquired or inborn (congenital). Acquired forms can occur from dietary inadequacy or malabsorption, whereas genetic causes are related to an autosomal-recessive disorder affecting zinc transporters.¹ We report a case of a 3-month-old female infant with acquired AE who was successfully treated with zinc supplementation over the course of 3 weeks.

Case Report

A 3-month-old female infant presented to the emergency department with a rash of 2 weeks’ duration. She was born full term with no birth complications. The patient’s mother reported that the rash started on the cheeks, then enlarged and spread to the neck, back, and perineum. The patient also had been having diarrhea during this time. She previously had received mupirocin and cephalexin with no response to treatment. Maternal history was negative for lupus, and the mother’s diet consisted of a variety of foods but not many vegetables. The patient was exclusively breastfed, and there was no pertinent history of similar rashes occurring in other family members.

Physical examination revealed the patient had annular and polycyclic, hyperkeratotic, crusted papules and plaques on the cheeks, neck, back, and axillae, as well as the perineum/groin and perianal regions (Figure 1). The differential diagnosis at the time included neonatal lupus, zinc deficiency, and syphilis. Relevant laboratory testing and a shave biopsy of the left axilla were obtained.

Comment

Etiology of AE—Acrodermatitis enteropathica was first identified in 1942 as an acral rash associated with diarrhea³; in 1973, Barnes and Moynahan⁴ discovered zinc deficiency as a causal agent for these findings. The causes of AE are further subclassified as either an acquired or inborn etiology. Congenital causes commonly are seen in infants within the first few months of life, whereas acquired forms are seen at any age. Acquired forms in infants can occur from failure of the mother to secrete zinc in breast milk, low maternal serum zinc levels, or other reasons causing low nutritional intake. A single mutation in the SLC30A2 gene has been found to markedly reduce zinc concentrations in breast milk, thus causing zinc deficiency in breastfed infants.⁵ Other acquired forms can be caused by malabsorption, sometimes after surgery such as intestinal bypass or from intravenous nutrition without sufficient zinc.¹ The congenital form of AE is an autosomal-recessive disorder occurring from mutations in the SLC39A4 gene located on band 8q24.3. Affected individuals have a decreased ability to absorb zinc in the small intestine because of defects in zinc transporters ZIP and ZnT.⁶ Based on our patient’s laboratory findings and history, it is believed that the zinc deficiency was acquired, as the condition normalized with repletion and has not required any supplementation in the year of follow-up. In addition, the absence of a pertinent family history supported an acquired diagnosis, which has various etiologies, whereas the congenital form primarily is a genetic disease.

Diagnosis of AE—The characteristic clinical features of AE include erythematous, dry, scaly papules and plaques that may evolve into crusted, erosive, pustular lesions. These lesions typically are distributed in a periorificial and acral pattern.^1,2 Although AE includes the clinical triad of acral and periorificial dermatitis, alopecia, and diarrhea, most cases present with only partial features of this syndrome, as seen in our patient, who presented with only 2 symptoms—dermatitis and diarrhea. The diagnosis of AE is based on clinical and laboratory abnormalities, especially a low serum zinc level. Low levels of zinc-dependent enzymes, such as alkaline phosphatase, may support the diagnosis, as seen in our patient. Histologic evaluation is characteristic but is not diagnostic, as the same findings can be seen in other nutritional disorders. Such findings include confluent parakeratosis associated with a reduced granular layer in early lesions and subsequent ballooning of subcorneal keratinocytes, upper epidermal pallor, and intraepidermal clefts. Late lesions exhibit psoriasiform hyperplasia of the epidermis with less epidermal pallor.⁷

Acrodermatitis enteropathica (AE) is a rare disorder of zinc metabolism that typically presents in infancy.¹ Although it is clinically characterized by acral and periorificial dermatitis, alopecia, and diarrhea, only 20% of cases present with this triad.² Zinc deficiency in AE can either be acquired or inborn (congenital). Acquired forms can occur from dietary inadequacy or malabsorption, whereas genetic causes are related to an autosomal-recessive disorder affecting zinc transporters.¹ We report a case of a 3-month-old female infant with acquired AE who was successfully treated with zinc supplementation over the course of 3 weeks.

Case Report

A 3-month-old female infant presented to the emergency department with a rash of 2 weeks’ duration. She was born full term with no birth complications. The patient’s mother reported that the rash started on the cheeks, then enlarged and spread to the neck, back, and perineum. The patient also had been having diarrhea during this time. She previously had received mupirocin and cephalexin with no response to treatment. Maternal history was negative for lupus, and the mother’s diet consisted of a variety of foods but not many vegetables. The patient was exclusively breastfed, and there was no pertinent history of similar rashes occurring in other family members.

Physical examination revealed the patient had annular and polycyclic, hyperkeratotic, crusted papules and plaques on the cheeks, neck, back, and axillae, as well as the perineum/groin and perianal regions (Figure 1). The differential diagnosis at the time included neonatal lupus, zinc deficiency, and syphilis. Relevant laboratory testing and a shave biopsy of the left axilla were obtained.

Comment

Etiology of AE—Acrodermatitis enteropathica was first identified in 1942 as an acral rash associated with diarrhea³; in 1973, Barnes and Moynahan⁴ discovered zinc deficiency as a causal agent for these findings. The causes of AE are further subclassified as either an acquired or inborn etiology. Congenital causes commonly are seen in infants within the first few months of life, whereas acquired forms are seen at any age. Acquired forms in infants can occur from failure of the mother to secrete zinc in breast milk, low maternal serum zinc levels, or other reasons causing low nutritional intake. A single mutation in the SLC30A2 gene has been found to markedly reduce zinc concentrations in breast milk, thus causing zinc deficiency in breastfed infants.⁵ Other acquired forms can be caused by malabsorption, sometimes after surgery such as intestinal bypass or from intravenous nutrition without sufficient zinc.¹ The congenital form of AE is an autosomal-recessive disorder occurring from mutations in the SLC39A4 gene located on band 8q24.3. Affected individuals have a decreased ability to absorb zinc in the small intestine because of defects in zinc transporters ZIP and ZnT.⁶ Based on our patient’s laboratory findings and history, it is believed that the zinc deficiency was acquired, as the condition normalized with repletion and has not required any supplementation in the year of follow-up. In addition, the absence of a pertinent family history supported an acquired diagnosis, which has various etiologies, whereas the congenital form primarily is a genetic disease.

Diagnosis of AE—The characteristic clinical features of AE include erythematous, dry, scaly papules and plaques that may evolve into crusted, erosive, pustular lesions. These lesions typically are distributed in a periorificial and acral pattern.^1,2 Although AE includes the clinical triad of acral and periorificial dermatitis, alopecia, and diarrhea, most cases present with only partial features of this syndrome, as seen in our patient, who presented with only 2 symptoms—dermatitis and diarrhea. The diagnosis of AE is based on clinical and laboratory abnormalities, especially a low serum zinc level. Low levels of zinc-dependent enzymes, such as alkaline phosphatase, may support the diagnosis, as seen in our patient. Histologic evaluation is characteristic but is not diagnostic, as the same findings can be seen in other nutritional disorders. Such findings include confluent parakeratosis associated with a reduced granular layer in early lesions and subsequent ballooning of subcorneal keratinocytes, upper epidermal pallor, and intraepidermal clefts. Late lesions exhibit psoriasiform hyperplasia of the epidermis with less epidermal pallor.⁷

Acrodermatitis enteropathica (AE) is a rare disorder of zinc metabolism that typically presents in infancy.¹ Although it is clinically characterized by acral and periorificial dermatitis, alopecia, and diarrhea, only 20% of cases present with this triad.² Zinc deficiency in AE can either be acquired or inborn (congenital). Acquired forms can occur from dietary inadequacy or malabsorption, whereas genetic causes are related to an autosomal-recessive disorder affecting zinc transporters.¹ We report a case of a 3-month-old female infant with acquired AE who was successfully treated with zinc supplementation over the course of 3 weeks.

Case Report

A 3-month-old female infant presented to the emergency department with a rash of 2 weeks’ duration. She was born full term with no birth complications. The patient’s mother reported that the rash started on the cheeks, then enlarged and spread to the neck, back, and perineum. The patient also had been having diarrhea during this time. She previously had received mupirocin and cephalexin with no response to treatment. Maternal history was negative for lupus, and the mother’s diet consisted of a variety of foods but not many vegetables. The patient was exclusively breastfed, and there was no pertinent history of similar rashes occurring in other family members.

Physical examination revealed the patient had annular and polycyclic, hyperkeratotic, crusted papules and plaques on the cheeks, neck, back, and axillae, as well as the perineum/groin and perianal regions (Figure 1). The differential diagnosis at the time included neonatal lupus, zinc deficiency, and syphilis. Relevant laboratory testing and a shave biopsy of the left axilla were obtained.

Comment

Etiology of AE—Acrodermatitis enteropathica was first identified in 1942 as an acral rash associated with diarrhea³; in 1973, Barnes and Moynahan⁴ discovered zinc deficiency as a causal agent for these findings. The causes of AE are further subclassified as either an acquired or inborn etiology. Congenital causes commonly are seen in infants within the first few months of life, whereas acquired forms are seen at any age. Acquired forms in infants can occur from failure of the mother to secrete zinc in breast milk, low maternal serum zinc levels, or other reasons causing low nutritional intake. A single mutation in the SLC30A2 gene has been found to markedly reduce zinc concentrations in breast milk, thus causing zinc deficiency in breastfed infants.⁵ Other acquired forms can be caused by malabsorption, sometimes after surgery such as intestinal bypass or from intravenous nutrition without sufficient zinc.¹ The congenital form of AE is an autosomal-recessive disorder occurring from mutations in the SLC39A4 gene located on band 8q24.3. Affected individuals have a decreased ability to absorb zinc in the small intestine because of defects in zinc transporters ZIP and ZnT.⁶ Based on our patient’s laboratory findings and history, it is believed that the zinc deficiency was acquired, as the condition normalized with repletion and has not required any supplementation in the year of follow-up. In addition, the absence of a pertinent family history supported an acquired diagnosis, which has various etiologies, whereas the congenital form primarily is a genetic disease.

Diagnosis of AE—The characteristic clinical features of AE include erythematous, dry, scaly papules and plaques that may evolve into crusted, erosive, pustular lesions. These lesions typically are distributed in a periorificial and acral pattern.^1,2 Although AE includes the clinical triad of acral and periorificial dermatitis, alopecia, and diarrhea, most cases present with only partial features of this syndrome, as seen in our patient, who presented with only 2 symptoms—dermatitis and diarrhea. The diagnosis of AE is based on clinical and laboratory abnormalities, especially a low serum zinc level. Low levels of zinc-dependent enzymes, such as alkaline phosphatase, may support the diagnosis, as seen in our patient. Histologic evaluation is characteristic but is not diagnostic, as the same findings can be seen in other nutritional disorders. Such findings include confluent parakeratosis associated with a reduced granular layer in early lesions and subsequent ballooning of subcorneal keratinocytes, upper epidermal pallor, and intraepidermal clefts. Late lesions exhibit psoriasiform hyperplasia of the epidermis with less epidermal pallor.⁷

Photoallergic contact dermatitis (PACD), a subtype of allergic contact dermatitis that occurs because of the specific combination of exposure to an exogenous chemical applied topically to the skin and UV radiation, may be more common than was once thought.¹ Although the incidence in the general population is unknown, current research points to approximately 20% to 40% of patients with suspected photosensitivity having a PACD diagnosis.² Recently, the North American Contact Dermatitis Group (NACDG) reported that 21% of 373 patients undergoing photopatch testing (PPT) were diagnosed with PACD²; however, PPT is not routinely performed, which may contribute to underdiagnosis.

Mechanism of Disease

Similar to allergic contact dermatitis, PACD is a delayed type IV hypersensitivity reaction; however, it only occurs when an exogenous chemical is applied topically to the skin with concomitant exposure to UV radiation, usually in the UVA range (315–400 nm).^3,4 When exposed to UV radiation, it is thought that the exogenous chemical combines with a protein in the skin and transforms into a photoantigen. In the sensitization phase, the photoantigen is taken up by antigen-presenting cells in the epidermis and transported to local lymph nodes where antigen-specific T cells are generated.⁵ In the elicitation phase, the inflammatory reaction of PACD occurs upon subsequent exposure to the same chemical plus UV radiation.⁴ Development of PACD does not necessarily depend on the dose of the chemical or the amount of UV radiation.⁶ Why certain individuals may be more susceptible is unknown, though major histocompatibility complex haplotypes could be influential.^7,8

Clinical Manifestations

Photoallergic contact dermatitis primarily presents in sun-exposed areas of the skin (eg, face, neck, V area of the chest, dorsal upper extremities) with sparing of naturally photoprotected sites, such as the upper eyelids and nasolabial and retroauricular folds. Other than its characteristic photodistribution, PACD often is clinically indistinguishable from routine allergic contact dermatitis. It manifests as a pruritic, poorly demarcated, eczematous or sometimes vesiculobullous eruption that develops in a delayed fashion—24 to 72 hours after sun exposure. The dermatitis may extend to other parts of the body either through spread of the chemical agent by the hands or clothing or due to the systemic nature of the immune response. The severity of the presentation can vary depending on multiple factors, such as concentration and absorption of the agent, length of exposure, intensity and duration of UV radiation exposure, and individual susceptibility.⁴ Chronic PACD may become lichenified. Generally, rashes resolve after discontinuation of the causative agent; however, long-term exposure may lead to development of chronic actinic dermatitis, with persistent photodistributed eczema regardless of contact with the initial inciting agent.⁹

Differential Diagnosis

The differential diagnosis for patients presenting with photodistributed dermatitis is broad; therefore, taking a thorough history is important. Considerations include age of onset, timing and persistence of reactions, use of topical and systemic medications (both prescription and over-the-counter [OTC]), personal care products, occupation, and hobbies, as well as a thorough review of systems.

It is important to distinguish PACD from phototoxic contact dermatitis (PTCD)(also known as photoirritant contact dermatitis)(Table). Asking about the onset and timing of the eruption may be critical for distinction, as PTCD can occur within minutes to hours of the first exposure to a chemical and UV radiation, while there is a sensitization delay in PACD.⁶ Phytophotodermatitis is a well-known type of PTCD caused by exposure to furocoumarin-containing plants, most commonly limes.¹⁰ Other causes of PTCD include tar products and certain medications.¹¹ Importantly, PPT to a known phototoxic chemical should never be performed because it will cause a strong reaction in anyone tested, regardless of exposure history.

Diagnosis

Histologically, PACD presents similarly to allergic contact dermatitis with spongiotic dermatitis; therefore, biopsy cannot be relied upon to make the diagnosis.⁶ Photopatch testing is required for definitive diagnosis. It is reasonable to perform PPT in any patient with chronic dermatitis primarily affecting sun-exposed areas without a clear alternative diagnosis.^14,15 Of note, at present there are no North American consensus guidelines for PPT, but typically duplicate sets of photoallergens are applied to both sides of the patient’s back and one side is exposed to UVA radiation. The reactions are compared after 48 to 96 hours.¹⁵ A positive reaction only at the irradiated site is consistent with photoallergy, while a reaction of equal strength at both the irradiated and nonirradiated sites indicates regular contact allergy. The case of a reaction occurring at both sites with a stronger response at the irradiated site is known as photoaggravated contact allergy, which can be thought of as allergic contact dermatitis that worsens but does not solely occur with exposure to sunlight.

Although PPT is necessary for the accurate diagnosis of PACD, it is infrequently used. Two surveys of 112 and 117 American Contact Dermatitis Society members, respectively, have revealed that only around half performed PPT, most of them testing fewer than 20 times per year.^16,17 Additionally, there was variability in the test methodology and allergens employed. Nevertheless, most respondents tested sunscreens, nonsteroidal anti-inflammatory drugs (NSAIDs), fragrances, and their patients’ own products.^16,17 The most common reasons for not performing PPT were lack of equipment, insufficient skills, rare clinical suspicion, and cost. Dermatologists at academic centers performed more PPT than those in other practice settings, including multispecialty group practices and private offices.¹⁶ These findings highlight multiple factors that may contribute to reduced patient access to PPT and thus potential underdiagnosis of PACD.

Common Photoallergens

The most common photoallergens change over time in response to market trends; for example, fragrance was once a top photoallergen in the United States in the 1970s and 1980s but declined in prominence after musk ambrette—the primary allergen associated with PACD at the time—was removed as an ingredient in fragrances.¹⁸

In the largest and most recent PPT series from North America (1999-2009),² sunscreens comprised 7 of the top 10 most common photoallergens, which is consistent with other studies showing sunscreens to be the most common North American photoallergens.^19-22 The frequency of PACD due to sunscreens likely relates to their increasing use worldwide as awareness of photocarcinogenesis and photoaging grows, as well as the common use of UV filters in nonsunscreen personal care products, ranging from lip balms to perfumes and bodywashes. Chemical (organic) UV filters—in particular oxybenzone (benzophenone-3) and avobenzone (butyl methoxydibenzoylmethane)—are the most common sunscreen photoallergens.^2,23 Para-aminobenzoic acid was once a common photoallergen, but it is no longer used in US sunscreens due to safety concerns.^19,20 The physical (inorganic) UV filters zinc oxide and titanium dioxide are not known photosensitizers.

Methylisothiazolinone (MI) is a highly allergenic preservative commonly used in a wide array of personal care products, including sunscreens.²⁴ In the most recent NACDG patch test data, MI was the second most common contact allergen.²⁵ Allergic contact dermatitis caused by MI in sunscreen can mimic PACD.²⁶ In addition, MI can cause photoaggravated contact dermatitis, with some affected patients experiencing ongoing photosensitivity even after avoiding this allergen.^26-30 The European Union and Canada have introduced restrictions on the use of MI in personal care products, but no such regulatory measures have been taken in the United States to date.^25,31,32

After sunscreens, another common cause of PACD are topical NSAIDs, which are frequently used for musculoskeletal pain relief. These are of particular concern in Europe, where a variety of formulations are widely available OTC.³³ Ketoprofen and etofenamate are responsible for the largest number of PACD reactions in Europe.^2,34,35 Meanwhile, the only OTC topical NSAID available in the United States is diclofenac gel, which was approved in 2020. Cases of PACD due to use of diclofenac gel have been reported in the literature, but testing in larger populations is needed.^36-39

Notably, ketoprofen may co- or cross-react with certain UV filters—oxybenzone and octocrylene—and the lipid-lowering agent fenofibrate due to chemical similarities.^40-43 Despite the relatively high number of photoallergic reactions to ketoprofen in the NACDG photopatch series, only 25% (5/20) were considered clinically relevant (ie, the allergen could not be verified as present in the known skin contactants of the patient, and the patient was not exposed to circumstances in which contact with materials known to contain the allergen would likely occur), which suggests that they likely represented cross-reactions in patients sensitized to sunscreens.²

Other agents that may cause PACD include antimicrobials, plants and plant derivatives, and pesticides.^2,4,18 The antimicrobial fentichlor is a common cause of positive PPT reactions, but it rarely is clinically relevant.⁴⁴

Treatment

The primary management of PACD centers on identification of the causative photoallergen to avoid future exposure. Patients should be educated on the various names by which the causative allergen can be identified on product labels and should be given a list of safe products that are free from relevant allergens and cross-reacting chemicals.⁴⁵ Additionally, sun protection education should be provided. Exposure to UVA radiation can occur through windows, making the use of broad-spectrum sunscreens and protective clothing crucial. In cases of sunscreen-induced PACD, the responsible chemical UV filter(s) should be avoided, or alternatively, patients may use physical sunscreens containing only zinc oxide and/or titanium dioxide as active ingredients, as these are not known to cause PACD.⁴

When avoidance alone is insufficient, topical corticosteroids are the usual first-line treatment for localized PACD. When steroid-sparing treatments are preferred, topical calcineurin inhibitors such as tacrolimus and pimecrolimus may be used. If PACD is more widespread and severe, systemic therapy using steroids or steroid-sparing agents may be necessary to provide symptomatic relief.⁴

Final Interpretation

Photoallergic contact dermatitis is not uncommon, particularly among photosensitive patients. Most cases are due to sunscreens or topical NSAIDs. Consideration of PPT should be given in any patient with a chronic photodistributed dermatitis to evaluate for the possibility of PACD.

Photoallergic contact dermatitis (PACD), a subtype of allergic contact dermatitis that occurs because of the specific combination of exposure to an exogenous chemical applied topically to the skin and UV radiation, may be more common than was once thought.¹ Although the incidence in the general population is unknown, current research points to approximately 20% to 40% of patients with suspected photosensitivity having a PACD diagnosis.² Recently, the North American Contact Dermatitis Group (NACDG) reported that 21% of 373 patients undergoing photopatch testing (PPT) were diagnosed with PACD²; however, PPT is not routinely performed, which may contribute to underdiagnosis.

Mechanism of Disease

Similar to allergic contact dermatitis, PACD is a delayed type IV hypersensitivity reaction; however, it only occurs when an exogenous chemical is applied topically to the skin with concomitant exposure to UV radiation, usually in the UVA range (315–400 nm).^3,4 When exposed to UV radiation, it is thought that the exogenous chemical combines with a protein in the skin and transforms into a photoantigen. In the sensitization phase, the photoantigen is taken up by antigen-presenting cells in the epidermis and transported to local lymph nodes where antigen-specific T cells are generated.⁵ In the elicitation phase, the inflammatory reaction of PACD occurs upon subsequent exposure to the same chemical plus UV radiation.⁴ Development of PACD does not necessarily depend on the dose of the chemical or the amount of UV radiation.⁶ Why certain individuals may be more susceptible is unknown, though major histocompatibility complex haplotypes could be influential.^7,8

Clinical Manifestations

Photoallergic contact dermatitis primarily presents in sun-exposed areas of the skin (eg, face, neck, V area of the chest, dorsal upper extremities) with sparing of naturally photoprotected sites, such as the upper eyelids and nasolabial and retroauricular folds. Other than its characteristic photodistribution, PACD often is clinically indistinguishable from routine allergic contact dermatitis. It manifests as a pruritic, poorly demarcated, eczematous or sometimes vesiculobullous eruption that develops in a delayed fashion—24 to 72 hours after sun exposure. The dermatitis may extend to other parts of the body either through spread of the chemical agent by the hands or clothing or due to the systemic nature of the immune response. The severity of the presentation can vary depending on multiple factors, such as concentration and absorption of the agent, length of exposure, intensity and duration of UV radiation exposure, and individual susceptibility.⁴ Chronic PACD may become lichenified. Generally, rashes resolve after discontinuation of the causative agent; however, long-term exposure may lead to development of chronic actinic dermatitis, with persistent photodistributed eczema regardless of contact with the initial inciting agent.⁹

Differential Diagnosis

The differential diagnosis for patients presenting with photodistributed dermatitis is broad; therefore, taking a thorough history is important. Considerations include age of onset, timing and persistence of reactions, use of topical and systemic medications (both prescription and over-the-counter [OTC]), personal care products, occupation, and hobbies, as well as a thorough review of systems.

It is important to distinguish PACD from phototoxic contact dermatitis (PTCD)(also known as photoirritant contact dermatitis)(Table). Asking about the onset and timing of the eruption may be critical for distinction, as PTCD can occur within minutes to hours of the first exposure to a chemical and UV radiation, while there is a sensitization delay in PACD.⁶ Phytophotodermatitis is a well-known type of PTCD caused by exposure to furocoumarin-containing plants, most commonly limes.¹⁰ Other causes of PTCD include tar products and certain medications.¹¹ Importantly, PPT to a known phototoxic chemical should never be performed because it will cause a strong reaction in anyone tested, regardless of exposure history.

Diagnosis

Histologically, PACD presents similarly to allergic contact dermatitis with spongiotic dermatitis; therefore, biopsy cannot be relied upon to make the diagnosis.⁶ Photopatch testing is required for definitive diagnosis. It is reasonable to perform PPT in any patient with chronic dermatitis primarily affecting sun-exposed areas without a clear alternative diagnosis.^14,15 Of note, at present there are no North American consensus guidelines for PPT, but typically duplicate sets of photoallergens are applied to both sides of the patient’s back and one side is exposed to UVA radiation. The reactions are compared after 48 to 96 hours.¹⁵ A positive reaction only at the irradiated site is consistent with photoallergy, while a reaction of equal strength at both the irradiated and nonirradiated sites indicates regular contact allergy. The case of a reaction occurring at both sites with a stronger response at the irradiated site is known as photoaggravated contact allergy, which can be thought of as allergic contact dermatitis that worsens but does not solely occur with exposure to sunlight.

Although PPT is necessary for the accurate diagnosis of PACD, it is infrequently used. Two surveys of 112 and 117 American Contact Dermatitis Society members, respectively, have revealed that only around half performed PPT, most of them testing fewer than 20 times per year.^16,17 Additionally, there was variability in the test methodology and allergens employed. Nevertheless, most respondents tested sunscreens, nonsteroidal anti-inflammatory drugs (NSAIDs), fragrances, and their patients’ own products.^16,17 The most common reasons for not performing PPT were lack of equipment, insufficient skills, rare clinical suspicion, and cost. Dermatologists at academic centers performed more PPT than those in other practice settings, including multispecialty group practices and private offices.¹⁶ These findings highlight multiple factors that may contribute to reduced patient access to PPT and thus potential underdiagnosis of PACD.

Common Photoallergens

The most common photoallergens change over time in response to market trends; for example, fragrance was once a top photoallergen in the United States in the 1970s and 1980s but declined in prominence after musk ambrette—the primary allergen associated with PACD at the time—was removed as an ingredient in fragrances.¹⁸

In the largest and most recent PPT series from North America (1999-2009),² sunscreens comprised 7 of the top 10 most common photoallergens, which is consistent with other studies showing sunscreens to be the most common North American photoallergens.^19-22 The frequency of PACD due to sunscreens likely relates to their increasing use worldwide as awareness of photocarcinogenesis and photoaging grows, as well as the common use of UV filters in nonsunscreen personal care products, ranging from lip balms to perfumes and bodywashes. Chemical (organic) UV filters—in particular oxybenzone (benzophenone-3) and avobenzone (butyl methoxydibenzoylmethane)—are the most common sunscreen photoallergens.^2,23 Para-aminobenzoic acid was once a common photoallergen, but it is no longer used in US sunscreens due to safety concerns.^19,20 The physical (inorganic) UV filters zinc oxide and titanium dioxide are not known photosensitizers.

Methylisothiazolinone (MI) is a highly allergenic preservative commonly used in a wide array of personal care products, including sunscreens.²⁴ In the most recent NACDG patch test data, MI was the second most common contact allergen.²⁵ Allergic contact dermatitis caused by MI in sunscreen can mimic PACD.²⁶ In addition, MI can cause photoaggravated contact dermatitis, with some affected patients experiencing ongoing photosensitivity even after avoiding this allergen.^26-30 The European Union and Canada have introduced restrictions on the use of MI in personal care products, but no such regulatory measures have been taken in the United States to date.^25,31,32

After sunscreens, another common cause of PACD are topical NSAIDs, which are frequently used for musculoskeletal pain relief. These are of particular concern in Europe, where a variety of formulations are widely available OTC.³³ Ketoprofen and etofenamate are responsible for the largest number of PACD reactions in Europe.^2,34,35 Meanwhile, the only OTC topical NSAID available in the United States is diclofenac gel, which was approved in 2020. Cases of PACD due to use of diclofenac gel have been reported in the literature, but testing in larger populations is needed.^36-39

Notably, ketoprofen may co- or cross-react with certain UV filters—oxybenzone and octocrylene—and the lipid-lowering agent fenofibrate due to chemical similarities.^40-43 Despite the relatively high number of photoallergic reactions to ketoprofen in the NACDG photopatch series, only 25% (5/20) were considered clinically relevant (ie, the allergen could not be verified as present in the known skin contactants of the patient, and the patient was not exposed to circumstances in which contact with materials known to contain the allergen would likely occur), which suggests that they likely represented cross-reactions in patients sensitized to sunscreens.²

Other agents that may cause PACD include antimicrobials, plants and plant derivatives, and pesticides.^2,4,18 The antimicrobial fentichlor is a common cause of positive PPT reactions, but it rarely is clinically relevant.⁴⁴

Treatment

The primary management of PACD centers on identification of the causative photoallergen to avoid future exposure. Patients should be educated on the various names by which the causative allergen can be identified on product labels and should be given a list of safe products that are free from relevant allergens and cross-reacting chemicals.⁴⁵ Additionally, sun protection education should be provided. Exposure to UVA radiation can occur through windows, making the use of broad-spectrum sunscreens and protective clothing crucial. In cases of sunscreen-induced PACD, the responsible chemical UV filter(s) should be avoided, or alternatively, patients may use physical sunscreens containing only zinc oxide and/or titanium dioxide as active ingredients, as these are not known to cause PACD.⁴

When avoidance alone is insufficient, topical corticosteroids are the usual first-line treatment for localized PACD. When steroid-sparing treatments are preferred, topical calcineurin inhibitors such as tacrolimus and pimecrolimus may be used. If PACD is more widespread and severe, systemic therapy using steroids or steroid-sparing agents may be necessary to provide symptomatic relief.⁴

Final Interpretation

Photoallergic contact dermatitis is not uncommon, particularly among photosensitive patients. Most cases are due to sunscreens or topical NSAIDs. Consideration of PPT should be given in any patient with a chronic photodistributed dermatitis to evaluate for the possibility of PACD.

Photoallergic contact dermatitis (PACD), a subtype of allergic contact dermatitis that occurs because of the specific combination of exposure to an exogenous chemical applied topically to the skin and UV radiation, may be more common than was once thought.¹ Although the incidence in the general population is unknown, current research points to approximately 20% to 40% of patients with suspected photosensitivity having a PACD diagnosis.² Recently, the North American Contact Dermatitis Group (NACDG) reported that 21% of 373 patients undergoing photopatch testing (PPT) were diagnosed with PACD²; however, PPT is not routinely performed, which may contribute to underdiagnosis.

Mechanism of Disease

Similar to allergic contact dermatitis, PACD is a delayed type IV hypersensitivity reaction; however, it only occurs when an exogenous chemical is applied topically to the skin with concomitant exposure to UV radiation, usually in the UVA range (315–400 nm).^3,4 When exposed to UV radiation, it is thought that the exogenous chemical combines with a protein in the skin and transforms into a photoantigen. In the sensitization phase, the photoantigen is taken up by antigen-presenting cells in the epidermis and transported to local lymph nodes where antigen-specific T cells are generated.⁵ In the elicitation phase, the inflammatory reaction of PACD occurs upon subsequent exposure to the same chemical plus UV radiation.⁴ Development of PACD does not necessarily depend on the dose of the chemical or the amount of UV radiation.⁶ Why certain individuals may be more susceptible is unknown, though major histocompatibility complex haplotypes could be influential.^7,8

Clinical Manifestations

Photoallergic contact dermatitis primarily presents in sun-exposed areas of the skin (eg, face, neck, V area of the chest, dorsal upper extremities) with sparing of naturally photoprotected sites, such as the upper eyelids and nasolabial and retroauricular folds. Other than its characteristic photodistribution, PACD often is clinically indistinguishable from routine allergic contact dermatitis. It manifests as a pruritic, poorly demarcated, eczematous or sometimes vesiculobullous eruption that develops in a delayed fashion—24 to 72 hours after sun exposure. The dermatitis may extend to other parts of the body either through spread of the chemical agent by the hands or clothing or due to the systemic nature of the immune response. The severity of the presentation can vary depending on multiple factors, such as concentration and absorption of the agent, length of exposure, intensity and duration of UV radiation exposure, and individual susceptibility.⁴ Chronic PACD may become lichenified. Generally, rashes resolve after discontinuation of the causative agent; however, long-term exposure may lead to development of chronic actinic dermatitis, with persistent photodistributed eczema regardless of contact with the initial inciting agent.⁹

Differential Diagnosis

The differential diagnosis for patients presenting with photodistributed dermatitis is broad; therefore, taking a thorough history is important. Considerations include age of onset, timing and persistence of reactions, use of topical and systemic medications (both prescription and over-the-counter [OTC]), personal care products, occupation, and hobbies, as well as a thorough review of systems.

It is important to distinguish PACD from phototoxic contact dermatitis (PTCD)(also known as photoirritant contact dermatitis)(Table). Asking about the onset and timing of the eruption may be critical for distinction, as PTCD can occur within minutes to hours of the first exposure to a chemical and UV radiation, while there is a sensitization delay in PACD.⁶ Phytophotodermatitis is a well-known type of PTCD caused by exposure to furocoumarin-containing plants, most commonly limes.¹⁰ Other causes of PTCD include tar products and certain medications.¹¹ Importantly, PPT to a known phototoxic chemical should never be performed because it will cause a strong reaction in anyone tested, regardless of exposure history.

Diagnosis

Histologically, PACD presents similarly to allergic contact dermatitis with spongiotic dermatitis; therefore, biopsy cannot be relied upon to make the diagnosis.⁶ Photopatch testing is required for definitive diagnosis. It is reasonable to perform PPT in any patient with chronic dermatitis primarily affecting sun-exposed areas without a clear alternative diagnosis.^14,15 Of note, at present there are no North American consensus guidelines for PPT, but typically duplicate sets of photoallergens are applied to both sides of the patient’s back and one side is exposed to UVA radiation. The reactions are compared after 48 to 96 hours.¹⁵ A positive reaction only at the irradiated site is consistent with photoallergy, while a reaction of equal strength at both the irradiated and nonirradiated sites indicates regular contact allergy. The case of a reaction occurring at both sites with a stronger response at the irradiated site is known as photoaggravated contact allergy, which can be thought of as allergic contact dermatitis that worsens but does not solely occur with exposure to sunlight.

Although PPT is necessary for the accurate diagnosis of PACD, it is infrequently used. Two surveys of 112 and 117 American Contact Dermatitis Society members, respectively, have revealed that only around half performed PPT, most of them testing fewer than 20 times per year.^16,17 Additionally, there was variability in the test methodology and allergens employed. Nevertheless, most respondents tested sunscreens, nonsteroidal anti-inflammatory drugs (NSAIDs), fragrances, and their patients’ own products.^16,17 The most common reasons for not performing PPT were lack of equipment, insufficient skills, rare clinical suspicion, and cost. Dermatologists at academic centers performed more PPT than those in other practice settings, including multispecialty group practices and private offices.¹⁶ These findings highlight multiple factors that may contribute to reduced patient access to PPT and thus potential underdiagnosis of PACD.

Common Photoallergens

The most common photoallergens change over time in response to market trends; for example, fragrance was once a top photoallergen in the United States in the 1970s and 1980s but declined in prominence after musk ambrette—the primary allergen associated with PACD at the time—was removed as an ingredient in fragrances.¹⁸

In the largest and most recent PPT series from North America (1999-2009),² sunscreens comprised 7 of the top 10 most common photoallergens, which is consistent with other studies showing sunscreens to be the most common North American photoallergens.^19-22 The frequency of PACD due to sunscreens likely relates to their increasing use worldwide as awareness of photocarcinogenesis and photoaging grows, as well as the common use of UV filters in nonsunscreen personal care products, ranging from lip balms to perfumes and bodywashes. Chemical (organic) UV filters—in particular oxybenzone (benzophenone-3) and avobenzone (butyl methoxydibenzoylmethane)—are the most common sunscreen photoallergens.^2,23 Para-aminobenzoic acid was once a common photoallergen, but it is no longer used in US sunscreens due to safety concerns.^19,20 The physical (inorganic) UV filters zinc oxide and titanium dioxide are not known photosensitizers.

Methylisothiazolinone (MI) is a highly allergenic preservative commonly used in a wide array of personal care products, including sunscreens.²⁴ In the most recent NACDG patch test data, MI was the second most common contact allergen.²⁵ Allergic contact dermatitis caused by MI in sunscreen can mimic PACD.²⁶ In addition, MI can cause photoaggravated contact dermatitis, with some affected patients experiencing ongoing photosensitivity even after avoiding this allergen.^26-30 The European Union and Canada have introduced restrictions on the use of MI in personal care products, but no such regulatory measures have been taken in the United States to date.^25,31,32

After sunscreens, another common cause of PACD are topical NSAIDs, which are frequently used for musculoskeletal pain relief. These are of particular concern in Europe, where a variety of formulations are widely available OTC.³³ Ketoprofen and etofenamate are responsible for the largest number of PACD reactions in Europe.^2,34,35 Meanwhile, the only OTC topical NSAID available in the United States is diclofenac gel, which was approved in 2020. Cases of PACD due to use of diclofenac gel have been reported in the literature, but testing in larger populations is needed.^36-39

Notably, ketoprofen may co- or cross-react with certain UV filters—oxybenzone and octocrylene—and the lipid-lowering agent fenofibrate due to chemical similarities.^40-43 Despite the relatively high number of photoallergic reactions to ketoprofen in the NACDG photopatch series, only 25% (5/20) were considered clinically relevant (ie, the allergen could not be verified as present in the known skin contactants of the patient, and the patient was not exposed to circumstances in which contact with materials known to contain the allergen would likely occur), which suggests that they likely represented cross-reactions in patients sensitized to sunscreens.²

Other agents that may cause PACD include antimicrobials, plants and plant derivatives, and pesticides.^2,4,18 The antimicrobial fentichlor is a common cause of positive PPT reactions, but it rarely is clinically relevant.⁴⁴

Treatment

The primary management of PACD centers on identification of the causative photoallergen to avoid future exposure. Patients should be educated on the various names by which the causative allergen can be identified on product labels and should be given a list of safe products that are free from relevant allergens and cross-reacting chemicals.⁴⁵ Additionally, sun protection education should be provided. Exposure to UVA radiation can occur through windows, making the use of broad-spectrum sunscreens and protective clothing crucial. In cases of sunscreen-induced PACD, the responsible chemical UV filter(s) should be avoided, or alternatively, patients may use physical sunscreens containing only zinc oxide and/or titanium dioxide as active ingredients, as these are not known to cause PACD.⁴

When avoidance alone is insufficient, topical corticosteroids are the usual first-line treatment for localized PACD. When steroid-sparing treatments are preferred, topical calcineurin inhibitors such as tacrolimus and pimecrolimus may be used. If PACD is more widespread and severe, systemic therapy using steroids or steroid-sparing agents may be necessary to provide symptomatic relief.⁴

Final Interpretation

Photoallergic contact dermatitis is not uncommon, particularly among photosensitive patients. Most cases are due to sunscreens or topical NSAIDs. Consideration of PPT should be given in any patient with a chronic photodistributed dermatitis to evaluate for the possibility of PACD.

Tinea capitis (TC) most often is caused by Trichophyton tonsurans and Microsporum canis. The peak incidence is between 3 and 7 years of age. Noninflammatory TC typically presents as fine scaling with single or multiple scaly patches of circular alopecia (grey patches); diffuse or patchy, fine, white, adherent scaling of the scalp resembling generalized dandruff with subtle hair loss; or single or multiple patches of well-demarcated areas of alopecia with fine scale studded with broken-off hairs at the scalp surface, resulting in a black dot appearance. Inflammatory variants of TC include kerion and favus.¹ Herein, updates on diagnosis, treatment, and monitoring of TC are provided, as well as a discussion of changes in the fungal microbiome associated with TC. Lastly, insights to some queries that practitioners may encounter when treating children with TC are provided.

Genetic Susceptibility

Molecular techniques have identified a number of macrophage regulator, leukocyte activation and migration, and cutaneous permeability genes associated with susceptibility to TC. These findings indicate that genetically determined deficiency in adaptive immune responses may affect the predisposition to dermatophyte infections.²

Clinical Varieties of Infection

Dermatophytes causing ringworm are capable of invading the hair shafts and can simultaneously invade smooth or glabrous skin (eg, T tonsurans, Trichophyton schoenleinii, Trichophyton violaceum). Some causative dermatophytes can even penetrate the nails (eg, Trichophyton soudanense). The clinical presentation is dependent on 3 main patterns of hair invasion³:

• Ectothrix: A mid-follicular pattern of invasion with hyphae growing down to the hair bulb that commonly is caused by Microsporum species. It clinically presents with scaling and inflammation with hair shafts breaking 2 to 3 mm above the scalp level.

• Endothrix: This pattern is nonfluorescent on Wood lamp examination, and hairs often break at the scalp level (black dot type). Trichophyton tonsurans, T soudanense, Trichophyton rubrum, and T violaceum are common causes.

• Favus: In this pattern, T schoenleinii is a common cause, and hairs grow to considerable lengths above the scalp with less damage than the other patterns. The hair shafts present with characteristic air spaces, and hyphae form clusters at the level of the epidermis.

Diagnosis

Optimal treatment of TC relies on proper identification of the causative agent. Fungal culture remains the gold standard of mycologic diagnosis regardless of its delayed results, which may take up to 4 weeks for proper identification of the fungal colonies and require ample expertise to interpret the morphologic features of the grown colonies.⁴

Other tests such as the potassium hydroxide preparation are nonspecific and do not identify the dermatophyte species. Although this method has been reported to have 5% to 15% false-negative results in routine practice depending on the skill of the observer and the quality of sampling, microscopic examination is essential, as it may allow the clinician to start treatment sooner pending culture results. The use of a Wood lamp is not suitable for definitive species identification, as this technique primarily is useful for observing fluorescence in ectothrix infection caused by Microsporum species, with the exception of T schoenleinii; otherwise, Trichophyton species, which cause endothrix infections, do not fluoresce.⁵Polymerase chain reaction is a sensitive technique that can help identify both the genus and species of common dermatophytes. Common target sequences include the ribosomal internal transcribed spacer and translation elongation factor 1α. The use of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry also has become popular for dermatophyte identification.⁶Trichoscopic diagnosis of TC, which is simple and noninvasive, is becoming increasingly popular. Features such as short, broken, black dot, comma, corkscrew, and/or zigzag hairs, as well as perifollicular scaling, are helpful for diagnosing TC (Figure). Moreover, trichoscopy can be useful for differentiating other common causes of hair loss, such as trichotillomania and alopecia areata. It had been reported that the trichoscopic features of TC can be seen as early as 2 weeks after starting treatment and therefore this can be a reliable period in which to follow-up with the patient to evaluate progress. The disappearance of black dots and comma hairs can be appreciated from 2 weeks onwards by trichoscopic evaluation.⁴

Treatment

The common recommendation for first-line treatment of TC is the use of systemic antifungals with the use of a topical agent as an adjuvant to prevent the spread of fungal spores. For almost 6 decades, griseofulvin had been the gold-standard fungistatic used for treating TC in patients older than 2 years until the 2007 US Food and Drug Administration (FDA) approval of terbinafine fungicidal oral granules for treatment of TC in patients older than 4 years.⁷

Meta-analyses have demonstrated comparable efficacy for a 4-week course of terbinafine compared to 6 weeks of griseofulvin for TC based on the infectious organism. Terbinafine demonstrated superiority in treating T tonsurans and a similar efficacy in treating T violaceum, while griseofulvin was superior in treating M canis and other Microsporum species.^8,9

The off-label use of fluconazole and itraconazole to treat TC is gaining popularity, with limited trials showing increased evidence of their effectiveness. There is not much clinical evidence to support the use of other oral antifungals, including the newer azoles such as voriconazole or posaconazole.⁹

Newer limited evidence has shown the off-label use of photodynamic therapy to be a promising alternative to systemic antifungal therapy in treating TC, pending validation by larger sample trials.¹⁰In my practice, I have found that severe cases of TC demonstrating inflammation or possible widespread id reactions are better treated with oral steroids. Ketoconazole shampoo or selenium sulfide used 2 to 3 times weekly to prevent spread in the early phases of therapy is a good adjunct to systemic treatment. Cases with kerions should be assessed for the possibility of a coexisting bacterial infection under the crusts, and if confirmed, antibiotics should be started.⁹The commonly used systemic antifungals generally are safe with a low side-effect profile, but there is a risk for hepatotoxicity. The FDA recommends that baseline alanine transaminase and aspartate transaminase levels should be obtained prior to beginning a terbinafine-based treatment regimen.¹¹ The American Academy of Pediatrics has specifically stated that laboratory testing of serum hepatic enzymes is not a requirement if a griseofulvin-based regimen does not exceed 8 weeks; however, transaminase levels (alanine transaminase and aspartate transaminase) should be considered in patients using terbinafine at baseline or if treatment is prolonged beyond 4 to 6 weeks.¹² In agreement with the FDA guidelines, the Canadian Pediatric Society has suggested that liver enzymes should be periodically monitored in patients being treated with terbinafine beyond 4 to 6 weeks.¹³

Changes in the Fungal Microbiome

Research has shown that changes in the fungal microbiome were associated with an altered bacterial community in patients with TC. During fungal infection, the relative abundances of Cutibacterium and Corynebacterium increased, and the relative abundance of Streptococcus decreased. In addition, some uncommon bacterial genera such as Herbaspirillum and Methylorubrum were detected on the scalp in TC.¹⁴

Carrier State

Carrier state is determined for those siblings and contacts of cases with a clinically normal scalp that are positive on culture. Those individuals could represent a potential reservoir responsible for contamination (or recontamination) of the patient as well as treatment failure. Opinions remain divided as to whether to use oral antifungal therapy in these carriers or maintain therapy on antifungal shampoos containing ketoconazole or povidone-iodine. Due to the paucity of available data, my experience has shown that it is sufficient to use antifungal shampoos for such carriers. In zoophilic infections, it is important to identify and treat the animal source.^6-9

Final Thoughts

Successful treatment of TC requires accurate identification of the pathogen, which commonly is achieved via fungal culture. Despite its practical value, the conventional identification of dermatophytes based on morphologic features can be highly challenging due to the low positive rate and delayed results. Trichoscopy is a quick, handy, and noninvasive tool that can better indicate the diagnosis and also is helpful for follow-up on treatment progress. Due to better understanding of the immunology and genetic susceptibility associated with TC spread, the current treatment pipeline holds more insight into better control of this condition. Increased surveillance, prompt diagnosis, and early onset of systemic treatment are the key to proper prevention of spread of TC.

Tinea capitis (TC) most often is caused by Trichophyton tonsurans and Microsporum canis. The peak incidence is between 3 and 7 years of age. Noninflammatory TC typically presents as fine scaling with single or multiple scaly patches of circular alopecia (grey patches); diffuse or patchy, fine, white, adherent scaling of the scalp resembling generalized dandruff with subtle hair loss; or single or multiple patches of well-demarcated areas of alopecia with fine scale studded with broken-off hairs at the scalp surface, resulting in a black dot appearance. Inflammatory variants of TC include kerion and favus.¹ Herein, updates on diagnosis, treatment, and monitoring of TC are provided, as well as a discussion of changes in the fungal microbiome associated with TC. Lastly, insights to some queries that practitioners may encounter when treating children with TC are provided.

Genetic Susceptibility

Molecular techniques have identified a number of macrophage regulator, leukocyte activation and migration, and cutaneous permeability genes associated with susceptibility to TC. These findings indicate that genetically determined deficiency in adaptive immune responses may affect the predisposition to dermatophyte infections.²

Clinical Varieties of Infection

Dermatophytes causing ringworm are capable of invading the hair shafts and can simultaneously invade smooth or glabrous skin (eg, T tonsurans, Trichophyton schoenleinii, Trichophyton violaceum). Some causative dermatophytes can even penetrate the nails (eg, Trichophyton soudanense). The clinical presentation is dependent on 3 main patterns of hair invasion³:

• Ectothrix: A mid-follicular pattern of invasion with hyphae growing down to the hair bulb that commonly is caused by Microsporum species. It clinically presents with scaling and inflammation with hair shafts breaking 2 to 3 mm above the scalp level.

• Endothrix: This pattern is nonfluorescent on Wood lamp examination, and hairs often break at the scalp level (black dot type). Trichophyton tonsurans, T soudanense, Trichophyton rubrum, and T violaceum are common causes.

• Favus: In this pattern, T schoenleinii is a common cause, and hairs grow to considerable lengths above the scalp with less damage than the other patterns. The hair shafts present with characteristic air spaces, and hyphae form clusters at the level of the epidermis.

Diagnosis

Optimal treatment of TC relies on proper identification of the causative agent. Fungal culture remains the gold standard of mycologic diagnosis regardless of its delayed results, which may take up to 4 weeks for proper identification of the fungal colonies and require ample expertise to interpret the morphologic features of the grown colonies.⁴

Other tests such as the potassium hydroxide preparation are nonspecific and do not identify the dermatophyte species. Although this method has been reported to have 5% to 15% false-negative results in routine practice depending on the skill of the observer and the quality of sampling, microscopic examination is essential, as it may allow the clinician to start treatment sooner pending culture results. The use of a Wood lamp is not suitable for definitive species identification, as this technique primarily is useful for observing fluorescence in ectothrix infection caused by Microsporum species, with the exception of T schoenleinii; otherwise, Trichophyton species, which cause endothrix infections, do not fluoresce.⁵Polymerase chain reaction is a sensitive technique that can help identify both the genus and species of common dermatophytes. Common target sequences include the ribosomal internal transcribed spacer and translation elongation factor 1α. The use of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry also has become popular for dermatophyte identification.⁶Trichoscopic diagnosis of TC, which is simple and noninvasive, is becoming increasingly popular. Features such as short, broken, black dot, comma, corkscrew, and/or zigzag hairs, as well as perifollicular scaling, are helpful for diagnosing TC (Figure). Moreover, trichoscopy can be useful for differentiating other common causes of hair loss, such as trichotillomania and alopecia areata. It had been reported that the trichoscopic features of TC can be seen as early as 2 weeks after starting treatment and therefore this can be a reliable period in which to follow-up with the patient to evaluate progress. The disappearance of black dots and comma hairs can be appreciated from 2 weeks onwards by trichoscopic evaluation.⁴

Treatment

The common recommendation for first-line treatment of TC is the use of systemic antifungals with the use of a topical agent as an adjuvant to prevent the spread of fungal spores. For almost 6 decades, griseofulvin had been the gold-standard fungistatic used for treating TC in patients older than 2 years until the 2007 US Food and Drug Administration (FDA) approval of terbinafine fungicidal oral granules for treatment of TC in patients older than 4 years.⁷

Meta-analyses have demonstrated comparable efficacy for a 4-week course of terbinafine compared to 6 weeks of griseofulvin for TC based on the infectious organism. Terbinafine demonstrated superiority in treating T tonsurans and a similar efficacy in treating T violaceum, while griseofulvin was superior in treating M canis and other Microsporum species.^8,9

The off-label use of fluconazole and itraconazole to treat TC is gaining popularity, with limited trials showing increased evidence of their effectiveness. There is not much clinical evidence to support the use of other oral antifungals, including the newer azoles such as voriconazole or posaconazole.⁹

Newer limited evidence has shown the off-label use of photodynamic therapy to be a promising alternative to systemic antifungal therapy in treating TC, pending validation by larger sample trials.¹⁰In my practice, I have found that severe cases of TC demonstrating inflammation or possible widespread id reactions are better treated with oral steroids. Ketoconazole shampoo or selenium sulfide used 2 to 3 times weekly to prevent spread in the early phases of therapy is a good adjunct to systemic treatment. Cases with kerions should be assessed for the possibility of a coexisting bacterial infection under the crusts, and if confirmed, antibiotics should be started.⁹The commonly used systemic antifungals generally are safe with a low side-effect profile, but there is a risk for hepatotoxicity. The FDA recommends that baseline alanine transaminase and aspartate transaminase levels should be obtained prior to beginning a terbinafine-based treatment regimen.¹¹ The American Academy of Pediatrics has specifically stated that laboratory testing of serum hepatic enzymes is not a requirement if a griseofulvin-based regimen does not exceed 8 weeks; however, transaminase levels (alanine transaminase and aspartate transaminase) should be considered in patients using terbinafine at baseline or if treatment is prolonged beyond 4 to 6 weeks.¹² In agreement with the FDA guidelines, the Canadian Pediatric Society has suggested that liver enzymes should be periodically monitored in patients being treated with terbinafine beyond 4 to 6 weeks.¹³

Changes in the Fungal Microbiome

Research has shown that changes in the fungal microbiome were associated with an altered bacterial community in patients with TC. During fungal infection, the relative abundances of Cutibacterium and Corynebacterium increased, and the relative abundance of Streptococcus decreased. In addition, some uncommon bacterial genera such as Herbaspirillum and Methylorubrum were detected on the scalp in TC.¹⁴

Carrier State

Carrier state is determined for those siblings and contacts of cases with a clinically normal scalp that are positive on culture. Those individuals could represent a potential reservoir responsible for contamination (or recontamination) of the patient as well as treatment failure. Opinions remain divided as to whether to use oral antifungal therapy in these carriers or maintain therapy on antifungal shampoos containing ketoconazole or povidone-iodine. Due to the paucity of available data, my experience has shown that it is sufficient to use antifungal shampoos for such carriers. In zoophilic infections, it is important to identify and treat the animal source.^6-9

Final Thoughts

Successful treatment of TC requires accurate identification of the pathogen, which commonly is achieved via fungal culture. Despite its practical value, the conventional identification of dermatophytes based on morphologic features can be highly challenging due to the low positive rate and delayed results. Trichoscopy is a quick, handy, and noninvasive tool that can better indicate the diagnosis and also is helpful for follow-up on treatment progress. Due to better understanding of the immunology and genetic susceptibility associated with TC spread, the current treatment pipeline holds more insight into better control of this condition. Increased surveillance, prompt diagnosis, and early onset of systemic treatment are the key to proper prevention of spread of TC.

Tinea capitis (TC) most often is caused by Trichophyton tonsurans and Microsporum canis. The peak incidence is between 3 and 7 years of age. Noninflammatory TC typically presents as fine scaling with single or multiple scaly patches of circular alopecia (grey patches); diffuse or patchy, fine, white, adherent scaling of the scalp resembling generalized dandruff with subtle hair loss; or single or multiple patches of well-demarcated areas of alopecia with fine scale studded with broken-off hairs at the scalp surface, resulting in a black dot appearance. Inflammatory variants of TC include kerion and favus.¹ Herein, updates on diagnosis, treatment, and monitoring of TC are provided, as well as a discussion of changes in the fungal microbiome associated with TC. Lastly, insights to some queries that practitioners may encounter when treating children with TC are provided.

Genetic Susceptibility

Molecular techniques have identified a number of macrophage regulator, leukocyte activation and migration, and cutaneous permeability genes associated with susceptibility to TC. These findings indicate that genetically determined deficiency in adaptive immune responses may affect the predisposition to dermatophyte infections.²

Clinical Varieties of Infection

Dermatophytes causing ringworm are capable of invading the hair shafts and can simultaneously invade smooth or glabrous skin (eg, T tonsurans, Trichophyton schoenleinii, Trichophyton violaceum). Some causative dermatophytes can even penetrate the nails (eg, Trichophyton soudanense). The clinical presentation is dependent on 3 main patterns of hair invasion³:

• Ectothrix: A mid-follicular pattern of invasion with hyphae growing down to the hair bulb that commonly is caused by Microsporum species. It clinically presents with scaling and inflammation with hair shafts breaking 2 to 3 mm above the scalp level.

• Endothrix: This pattern is nonfluorescent on Wood lamp examination, and hairs often break at the scalp level (black dot type). Trichophyton tonsurans, T soudanense, Trichophyton rubrum, and T violaceum are common causes.

• Favus: In this pattern, T schoenleinii is a common cause, and hairs grow to considerable lengths above the scalp with less damage than the other patterns. The hair shafts present with characteristic air spaces, and hyphae form clusters at the level of the epidermis.

Diagnosis

Optimal treatment of TC relies on proper identification of the causative agent. Fungal culture remains the gold standard of mycologic diagnosis regardless of its delayed results, which may take up to 4 weeks for proper identification of the fungal colonies and require ample expertise to interpret the morphologic features of the grown colonies.⁴

Other tests such as the potassium hydroxide preparation are nonspecific and do not identify the dermatophyte species. Although this method has been reported to have 5% to 15% false-negative results in routine practice depending on the skill of the observer and the quality of sampling, microscopic examination is essential, as it may allow the clinician to start treatment sooner pending culture results. The use of a Wood lamp is not suitable for definitive species identification, as this technique primarily is useful for observing fluorescence in ectothrix infection caused by Microsporum species, with the exception of T schoenleinii; otherwise, Trichophyton species, which cause endothrix infections, do not fluoresce.⁵Polymerase chain reaction is a sensitive technique that can help identify both the genus and species of common dermatophytes. Common target sequences include the ribosomal internal transcribed spacer and translation elongation factor 1α. The use of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry also has become popular for dermatophyte identification.⁶Trichoscopic diagnosis of TC, which is simple and noninvasive, is becoming increasingly popular. Features such as short, broken, black dot, comma, corkscrew, and/or zigzag hairs, as well as perifollicular scaling, are helpful for diagnosing TC (Figure). Moreover, trichoscopy can be useful for differentiating other common causes of hair loss, such as trichotillomania and alopecia areata. It had been reported that the trichoscopic features of TC can be seen as early as 2 weeks after starting treatment and therefore this can be a reliable period in which to follow-up with the patient to evaluate progress. The disappearance of black dots and comma hairs can be appreciated from 2 weeks onwards by trichoscopic evaluation.⁴

Treatment

The common recommendation for first-line treatment of TC is the use of systemic antifungals with the use of a topical agent as an adjuvant to prevent the spread of fungal spores. For almost 6 decades, griseofulvin had been the gold-standard fungistatic used for treating TC in patients older than 2 years until the 2007 US Food and Drug Administration (FDA) approval of terbinafine fungicidal oral granules for treatment of TC in patients older than 4 years.⁷

Meta-analyses have demonstrated comparable efficacy for a 4-week course of terbinafine compared to 6 weeks of griseofulvin for TC based on the infectious organism. Terbinafine demonstrated superiority in treating T tonsurans and a similar efficacy in treating T violaceum, while griseofulvin was superior in treating M canis and other Microsporum species.^8,9

The off-label use of fluconazole and itraconazole to treat TC is gaining popularity, with limited trials showing increased evidence of their effectiveness. There is not much clinical evidence to support the use of other oral antifungals, including the newer azoles such as voriconazole or posaconazole.⁹

Newer limited evidence has shown the off-label use of photodynamic therapy to be a promising alternative to systemic antifungal therapy in treating TC, pending validation by larger sample trials.¹⁰In my practice, I have found that severe cases of TC demonstrating inflammation or possible widespread id reactions are better treated with oral steroids. Ketoconazole shampoo or selenium sulfide used 2 to 3 times weekly to prevent spread in the early phases of therapy is a good adjunct to systemic treatment. Cases with kerions should be assessed for the possibility of a coexisting bacterial infection under the crusts, and if confirmed, antibiotics should be started.⁹The commonly used systemic antifungals generally are safe with a low side-effect profile, but there is a risk for hepatotoxicity. The FDA recommends that baseline alanine transaminase and aspartate transaminase levels should be obtained prior to beginning a terbinafine-based treatment regimen.¹¹ The American Academy of Pediatrics has specifically stated that laboratory testing of serum hepatic enzymes is not a requirement if a griseofulvin-based regimen does not exceed 8 weeks; however, transaminase levels (alanine transaminase and aspartate transaminase) should be considered in patients using terbinafine at baseline or if treatment is prolonged beyond 4 to 6 weeks.¹² In agreement with the FDA guidelines, the Canadian Pediatric Society has suggested that liver enzymes should be periodically monitored in patients being treated with terbinafine beyond 4 to 6 weeks.¹³

Changes in the Fungal Microbiome

Research has shown that changes in the fungal microbiome were associated with an altered bacterial community in patients with TC. During fungal infection, the relative abundances of Cutibacterium and Corynebacterium increased, and the relative abundance of Streptococcus decreased. In addition, some uncommon bacterial genera such as Herbaspirillum and Methylorubrum were detected on the scalp in TC.¹⁴

Carrier State

Carrier state is determined for those siblings and contacts of cases with a clinically normal scalp that are positive on culture. Those individuals could represent a potential reservoir responsible for contamination (or recontamination) of the patient as well as treatment failure. Opinions remain divided as to whether to use oral antifungal therapy in these carriers or maintain therapy on antifungal shampoos containing ketoconazole or povidone-iodine. Due to the paucity of available data, my experience has shown that it is sufficient to use antifungal shampoos for such carriers. In zoophilic infections, it is important to identify and treat the animal source.^6-9

Final Thoughts

Successful treatment of TC requires accurate identification of the pathogen, which commonly is achieved via fungal culture. Despite its practical value, the conventional identification of dermatophytes based on morphologic features can be highly challenging due to the low positive rate and delayed results. Trichoscopy is a quick, handy, and noninvasive tool that can better indicate the diagnosis and also is helpful for follow-up on treatment progress. Due to better understanding of the immunology and genetic susceptibility associated with TC spread, the current treatment pipeline holds more insight into better control of this condition. Increased surveillance, prompt diagnosis, and early onset of systemic treatment are the key to proper prevention of spread of TC.

Black veterans hospitalized with COVID-19 were less likely to be treated with evidence-based treatments, in a study conducted in 130 US Department of Veterans Affairs (VA) medical centers between March 1, 2020, and February 28, 2022.

The study involved 12,135 Black veterans and 40,717 White veterans. Most patients hospitalized during period 1 (March-September 2020) were Black veterans and the proportion of White patients increased over time. The latter 3 periods, which included the Delta- and Omicron-predominant periods, saw the most admissions.

Controlling for the site of treatment, Black patients were equally likely to be admitted to the intensive care unit (40% vs 43%). However, they were less likely to receive steroids, remdesivir, or immunomodulatory drugs.

The researchers say their data confirm other findings from 41 US health care systems participating in the National Patient-Centered Clinical Research Network (PCORNet), which found lower use of monoclonal antibody treatment for COVID infection for patients who identified as Asian, Black, Hispanic, American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, or multiple races.

The researchers did not observe consistent differences in clinical outcomes between Black and White patients. After adjusting for demographics, chronic health conditions, severity of acute illness, and receipt of COVID-19–specific treatments, there was no association of Black race with hospital mortality or 30-day readmission. Black and White patients had a similar burden of preexisting health conditions. Of 38,782 patients discharged, 14% were readmitted within 30 days; the median time to readmission for both groups was 9 days.

Differences in care were partially explained by within- and between-hospital differences, the researchers say. They also cite research that demonstrated a poorer quality of care for hospitals with higher monthly COVID-19 discharges and hospital size.

The study results contradict the assumptions that differences in inpatient treatment by race and ethnicity may be due to differences in clinical indications for medication use based on age and comorbidities, such as chronic kidney or liver disease, the researchers say. For one thing, the VA issued a systemwide COVID-19 response plan that included specific treatment guidelines and distribution plans. But they also point to recent reports that have suggested that occult hypoxemia not detected by pulse oximetry occurs “far more often in Black patients than White patients,” which could result in delayed or missed opportunities to treat patients with COVID-19.

Black veterans hospitalized with COVID-19 were less likely to be treated with evidence-based treatments, in a study conducted in 130 US Department of Veterans Affairs (VA) medical centers between March 1, 2020, and February 28, 2022.

The study involved 12,135 Black veterans and 40,717 White veterans. Most patients hospitalized during period 1 (March-September 2020) were Black veterans and the proportion of White patients increased over time. The latter 3 periods, which included the Delta- and Omicron-predominant periods, saw the most admissions.

Controlling for the site of treatment, Black patients were equally likely to be admitted to the intensive care unit (40% vs 43%). However, they were less likely to receive steroids, remdesivir, or immunomodulatory drugs.

The researchers say their data confirm other findings from 41 US health care systems participating in the National Patient-Centered Clinical Research Network (PCORNet), which found lower use of monoclonal antibody treatment for COVID infection for patients who identified as Asian, Black, Hispanic, American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, or multiple races.

The researchers did not observe consistent differences in clinical outcomes between Black and White patients. After adjusting for demographics, chronic health conditions, severity of acute illness, and receipt of COVID-19–specific treatments, there was no association of Black race with hospital mortality or 30-day readmission. Black and White patients had a similar burden of preexisting health conditions. Of 38,782 patients discharged, 14% were readmitted within 30 days; the median time to readmission for both groups was 9 days.

Differences in care were partially explained by within- and between-hospital differences, the researchers say. They also cite research that demonstrated a poorer quality of care for hospitals with higher monthly COVID-19 discharges and hospital size.

The study results contradict the assumptions that differences in inpatient treatment by race and ethnicity may be due to differences in clinical indications for medication use based on age and comorbidities, such as chronic kidney or liver disease, the researchers say. For one thing, the VA issued a systemwide COVID-19 response plan that included specific treatment guidelines and distribution plans. But they also point to recent reports that have suggested that occult hypoxemia not detected by pulse oximetry occurs “far more often in Black patients than White patients,” which could result in delayed or missed opportunities to treat patients with COVID-19.

Black veterans hospitalized with COVID-19 were less likely to be treated with evidence-based treatments, in a study conducted in 130 US Department of Veterans Affairs (VA) medical centers between March 1, 2020, and February 28, 2022.

The study involved 12,135 Black veterans and 40,717 White veterans. Most patients hospitalized during period 1 (March-September 2020) were Black veterans and the proportion of White patients increased over time. The latter 3 periods, which included the Delta- and Omicron-predominant periods, saw the most admissions.

Controlling for the site of treatment, Black patients were equally likely to be admitted to the intensive care unit (40% vs 43%). However, they were less likely to receive steroids, remdesivir, or immunomodulatory drugs.

The researchers say their data confirm other findings from 41 US health care systems participating in the National Patient-Centered Clinical Research Network (PCORNet), which found lower use of monoclonal antibody treatment for COVID infection for patients who identified as Asian, Black, Hispanic, American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, or multiple races.

The researchers did not observe consistent differences in clinical outcomes between Black and White patients. After adjusting for demographics, chronic health conditions, severity of acute illness, and receipt of COVID-19–specific treatments, there was no association of Black race with hospital mortality or 30-day readmission. Black and White patients had a similar burden of preexisting health conditions. Of 38,782 patients discharged, 14% were readmitted within 30 days; the median time to readmission for both groups was 9 days.

Differences in care were partially explained by within- and between-hospital differences, the researchers say. They also cite research that demonstrated a poorer quality of care for hospitals with higher monthly COVID-19 discharges and hospital size.

The study results contradict the assumptions that differences in inpatient treatment by race and ethnicity may be due to differences in clinical indications for medication use based on age and comorbidities, such as chronic kidney or liver disease, the researchers say. For one thing, the VA issued a systemwide COVID-19 response plan that included specific treatment guidelines and distribution plans. But they also point to recent reports that have suggested that occult hypoxemia not detected by pulse oximetry occurs “far more often in Black patients than White patients,” which could result in delayed or missed opportunities to treat patients with COVID-19.