Infectious Diseases

Attendees at a public meeting on Nov. 4 gave the US Food and Drug Administration conflicting views on whether the agency should continue to allow a relatively loose regulatory environment for fecal microbiota transplants (FMT) – debating the limits of “enforcement discretion” the FDA now has in place.

The question is especially relevant as use of the procedure is growing, while safety data are not being rigorously collected in all cases. The death of an immunocompromised FMT patient earlier in 2018 from an invasive bacterial infection caused by drug-resistant Escherichia coli, as reported by Medscape Medical News, is seen by some as an example of the consequences of a loose policy.

Still, the American Gastroenterological Association (AGA) presented new, unpublished follow-up data at the meeting that showed that the majority of FMT patients in a national registry had no adverse events.

Some companies developing FMT-based products argued at the meeting that the agency should impose stricter requirements, while stool banks and clinicians offering the therapy outside of clinical trials said that the current policy – in place since 2013 – in which the FDA has exercised “enforcement discretion,” should be allowed to continue.

“Enforcement discretion has been successful in enabling and overcoming key barriers to access to treatment,” said Majdi Osman, MD, clinical program director at OpenBiome, a nonprofit stool bank based in Cambridge, Mass. Dr. Osman said that 98% of the U.S. population now lives within a 2-hour drive of an FMT provider.

Amanda Kabage, a researcher and donor program coordinator for the Microbiota Therapeutics program at the University of Minnesota in Minneapolis, and herself a former recipient of FMT, said she was in favor of continuing the FDA policy.

“If enforcement discretion were to go away, patients far sicker than I was will not have access. They’ll get sicker and they will die,” Ms. Kabage said.

But, she added, the FDA had missed an opportunity by not insisting on collecting outcomes and safety data. Minnesota has established a patient registry to do just that, and physicians cannot administer FMT unless they agree to participate, she said. In response, FDA panelists noted that the agency cannot mandate data collection under an enforcement policy.

Lee Jones, founder and chief executive officer of Rebiotix/Ferring, a biotech company focused on the development of microbiome-based therapeutics, argued for tighter restrictions, however, claiming that increased access – and the FDA policy – had led to a fourfold decrease in enrollment since the company began study of its lead FMT product, RBX2660, in 2013.

“We’re dealing with an orphan indication and the patients were hard to come by to begin with,” she said at the meeting. “Enforcement discretion has slowed our clinical development and delayed patient access to FDA-approved therapies by over 2 years.”

An investigator at the University of Texas Health Science Center at Houston, Herbert DuPont, MD, who has administered FMT and is conducting a trial for Rebiotix, said his center wanted the FDA policy to continue “allowing multiple groups to perform FMT for recurrent [Clostridium difficile], because of the incredible public health need.”

But, he added, “We’re very concerned about industry and ability to do clinical trials.”

Those trials are important, Dr. DuPont said. “I think we have to address very actively how industry can move these products through,” he said, “because all of us want to remove the F from FMT,” by isolating the necessary elements of the process while not having the risk sometimes associated with human stool.
 

Policy slow to evolve

“I’m frustrated that it’s taken over 6 years and three draft guidances to get us this far,” Christian John Lillis, executive director of the Peggy Lillis Foundation – a group dedicated to creating awareness about the dangers of C. difficile – said at the meeting.

Mr. Lillis said that probably several thousand deaths had been prevented through increased FMT access, but that it was time to create a concrete policy that advanced the therapy.

The FDA guidance issued in 2013 allowed physicians to provide FMT for recurrent or refractory C. difficile infection without filing an investigational new drug (IND) application.

Clinicians must obtain informed consent that includes a discussion of the risks, and a statement that FMT is investigational. In March 2016, the agency issued revised draft guidance that it was aiming to require stool banks to apply for INDs, as reported by Medscape Medical News.

OpenBiome has flourished under the current policy. It has provided more than 50,000 treatments to 1,200 hospitals and clinics, and has provided FMT for 49 clinical trials and for 16 single patients who received INDs, Dr. Osman said.

But requiring INDs for all centers is a bad idea, he said. “IND requirements are insurmountable for most health centers,” Dr. Osman said, noting that most of the FMT material OpenBiome produces is sent to community-based physicians.

“These requirements would likely mean restrictions in access for stool bank–provided FMT and potentially pushing patients to physician-directed FMT or discouraging physicians from using FMT at all,” he said.

Stacy Kahn, MD, FMT director at Boston Children’s Hospital in Massachusetts, said that having ready access from a stool bank was crucial.

“Universal donor FMT is much easier, much faster and much more cost effective than what we can do as clinicians,” she said.
 

New safety and efficacy data

One unpublished study showed that 75% of patients treated since 2011 had a sustained cure, noted Colleen Kelly, MD, a Brown University professor of medicine and principal investigator for the National Institutes of Health–funded national FMT registry (although the data in this study were not from the FMT registry).

The study, which was a collaboration between the Alpert Medical School of Brown University, Brigham and Women’s Hospital, and Indiana University School of Medicine, attempted follow-up on 533 patients; 208 were successfully contacted, and an additional 55 had died, none due to FMT.

Dr. Kelly also presented data from the FMT National Registry showing that at 1 month posttransplant, two (1%) of 253 patients had an infection possibly related to FMT; one with Bacteroides fragilis and one with enteropathogenic E. coli. Seven hospitalizations were deemed related or possibly related to FMT, including two recurrences of C. difficile.

At 6 months posttransplant, 8 (5%) of 152 patients had a serious infection, and 23 patients reported a diagnosis of a new condition, primarily diarrhea-predominant irritable bowel syndrome, which is common post FMT, said Dr. Kelly, who presented the data on behalf of AGA, which administers the registry.

The AGA supports a continuation of the enforcement discretion as a means to maintain patient access where the evidence supports the use of FMT, but the group does not back use of FMT outside medical supervision, Dr. Kelly said.
 

This article originally appeared on Medscape. For more news, follow Medscape on Facebook, Twitter, Instagram, and YouTube.

Attendees at a public meeting on Nov. 4 gave the US Food and Drug Administration conflicting views on whether the agency should continue to allow a relatively loose regulatory environment for fecal microbiota transplants (FMT) – debating the limits of “enforcement discretion” the FDA now has in place.

The question is especially relevant as use of the procedure is growing, while safety data are not being rigorously collected in all cases. The death of an immunocompromised FMT patient earlier in 2018 from an invasive bacterial infection caused by drug-resistant Escherichia coli, as reported by Medscape Medical News, is seen by some as an example of the consequences of a loose policy.

Still, the American Gastroenterological Association (AGA) presented new, unpublished follow-up data at the meeting that showed that the majority of FMT patients in a national registry had no adverse events.

Some companies developing FMT-based products argued at the meeting that the agency should impose stricter requirements, while stool banks and clinicians offering the therapy outside of clinical trials said that the current policy – in place since 2013 – in which the FDA has exercised “enforcement discretion,” should be allowed to continue.

“Enforcement discretion has been successful in enabling and overcoming key barriers to access to treatment,” said Majdi Osman, MD, clinical program director at OpenBiome, a nonprofit stool bank based in Cambridge, Mass. Dr. Osman said that 98% of the U.S. population now lives within a 2-hour drive of an FMT provider.

Amanda Kabage, a researcher and donor program coordinator for the Microbiota Therapeutics program at the University of Minnesota in Minneapolis, and herself a former recipient of FMT, said she was in favor of continuing the FDA policy.

“If enforcement discretion were to go away, patients far sicker than I was will not have access. They’ll get sicker and they will die,” Ms. Kabage said.

But, she added, the FDA had missed an opportunity by not insisting on collecting outcomes and safety data. Minnesota has established a patient registry to do just that, and physicians cannot administer FMT unless they agree to participate, she said. In response, FDA panelists noted that the agency cannot mandate data collection under an enforcement policy.

Lee Jones, founder and chief executive officer of Rebiotix/Ferring, a biotech company focused on the development of microbiome-based therapeutics, argued for tighter restrictions, however, claiming that increased access – and the FDA policy – had led to a fourfold decrease in enrollment since the company began study of its lead FMT product, RBX2660, in 2013.

“We’re dealing with an orphan indication and the patients were hard to come by to begin with,” she said at the meeting. “Enforcement discretion has slowed our clinical development and delayed patient access to FDA-approved therapies by over 2 years.”

An investigator at the University of Texas Health Science Center at Houston, Herbert DuPont, MD, who has administered FMT and is conducting a trial for Rebiotix, said his center wanted the FDA policy to continue “allowing multiple groups to perform FMT for recurrent [Clostridium difficile], because of the incredible public health need.”

But, he added, “We’re very concerned about industry and ability to do clinical trials.”

Those trials are important, Dr. DuPont said. “I think we have to address very actively how industry can move these products through,” he said, “because all of us want to remove the F from FMT,” by isolating the necessary elements of the process while not having the risk sometimes associated with human stool.
 

Policy slow to evolve

“I’m frustrated that it’s taken over 6 years and three draft guidances to get us this far,” Christian John Lillis, executive director of the Peggy Lillis Foundation – a group dedicated to creating awareness about the dangers of C. difficile – said at the meeting.

Mr. Lillis said that probably several thousand deaths had been prevented through increased FMT access, but that it was time to create a concrete policy that advanced the therapy.

The FDA guidance issued in 2013 allowed physicians to provide FMT for recurrent or refractory C. difficile infection without filing an investigational new drug (IND) application.

Clinicians must obtain informed consent that includes a discussion of the risks, and a statement that FMT is investigational. In March 2016, the agency issued revised draft guidance that it was aiming to require stool banks to apply for INDs, as reported by Medscape Medical News.

OpenBiome has flourished under the current policy. It has provided more than 50,000 treatments to 1,200 hospitals and clinics, and has provided FMT for 49 clinical trials and for 16 single patients who received INDs, Dr. Osman said.

But requiring INDs for all centers is a bad idea, he said. “IND requirements are insurmountable for most health centers,” Dr. Osman said, noting that most of the FMT material OpenBiome produces is sent to community-based physicians.

“These requirements would likely mean restrictions in access for stool bank–provided FMT and potentially pushing patients to physician-directed FMT or discouraging physicians from using FMT at all,” he said.

Stacy Kahn, MD, FMT director at Boston Children’s Hospital in Massachusetts, said that having ready access from a stool bank was crucial.

“Universal donor FMT is much easier, much faster and much more cost effective than what we can do as clinicians,” she said.
 

New safety and efficacy data

One unpublished study showed that 75% of patients treated since 2011 had a sustained cure, noted Colleen Kelly, MD, a Brown University professor of medicine and principal investigator for the National Institutes of Health–funded national FMT registry (although the data in this study were not from the FMT registry).

The study, which was a collaboration between the Alpert Medical School of Brown University, Brigham and Women’s Hospital, and Indiana University School of Medicine, attempted follow-up on 533 patients; 208 were successfully contacted, and an additional 55 had died, none due to FMT.

Dr. Kelly also presented data from the FMT National Registry showing that at 1 month posttransplant, two (1%) of 253 patients had an infection possibly related to FMT; one with Bacteroides fragilis and one with enteropathogenic E. coli. Seven hospitalizations were deemed related or possibly related to FMT, including two recurrences of C. difficile.

At 6 months posttransplant, 8 (5%) of 152 patients had a serious infection, and 23 patients reported a diagnosis of a new condition, primarily diarrhea-predominant irritable bowel syndrome, which is common post FMT, said Dr. Kelly, who presented the data on behalf of AGA, which administers the registry.

The AGA supports a continuation of the enforcement discretion as a means to maintain patient access where the evidence supports the use of FMT, but the group does not back use of FMT outside medical supervision, Dr. Kelly said.
 

This article originally appeared on Medscape. For more news, follow Medscape on Facebook, Twitter, Instagram, and YouTube.

Attendees at a public meeting on Nov. 4 gave the US Food and Drug Administration conflicting views on whether the agency should continue to allow a relatively loose regulatory environment for fecal microbiota transplants (FMT) – debating the limits of “enforcement discretion” the FDA now has in place.

The question is especially relevant as use of the procedure is growing, while safety data are not being rigorously collected in all cases. The death of an immunocompromised FMT patient earlier in 2018 from an invasive bacterial infection caused by drug-resistant Escherichia coli, as reported by Medscape Medical News, is seen by some as an example of the consequences of a loose policy.

Still, the American Gastroenterological Association (AGA) presented new, unpublished follow-up data at the meeting that showed that the majority of FMT patients in a national registry had no adverse events.

Some companies developing FMT-based products argued at the meeting that the agency should impose stricter requirements, while stool banks and clinicians offering the therapy outside of clinical trials said that the current policy – in place since 2013 – in which the FDA has exercised “enforcement discretion,” should be allowed to continue.

“Enforcement discretion has been successful in enabling and overcoming key barriers to access to treatment,” said Majdi Osman, MD, clinical program director at OpenBiome, a nonprofit stool bank based in Cambridge, Mass. Dr. Osman said that 98% of the U.S. population now lives within a 2-hour drive of an FMT provider.

Amanda Kabage, a researcher and donor program coordinator for the Microbiota Therapeutics program at the University of Minnesota in Minneapolis, and herself a former recipient of FMT, said she was in favor of continuing the FDA policy.

“If enforcement discretion were to go away, patients far sicker than I was will not have access. They’ll get sicker and they will die,” Ms. Kabage said.

But, she added, the FDA had missed an opportunity by not insisting on collecting outcomes and safety data. Minnesota has established a patient registry to do just that, and physicians cannot administer FMT unless they agree to participate, she said. In response, FDA panelists noted that the agency cannot mandate data collection under an enforcement policy.

Lee Jones, founder and chief executive officer of Rebiotix/Ferring, a biotech company focused on the development of microbiome-based therapeutics, argued for tighter restrictions, however, claiming that increased access – and the FDA policy – had led to a fourfold decrease in enrollment since the company began study of its lead FMT product, RBX2660, in 2013.

“We’re dealing with an orphan indication and the patients were hard to come by to begin with,” she said at the meeting. “Enforcement discretion has slowed our clinical development and delayed patient access to FDA-approved therapies by over 2 years.”

An investigator at the University of Texas Health Science Center at Houston, Herbert DuPont, MD, who has administered FMT and is conducting a trial for Rebiotix, said his center wanted the FDA policy to continue “allowing multiple groups to perform FMT for recurrent [Clostridium difficile], because of the incredible public health need.”

But, he added, “We’re very concerned about industry and ability to do clinical trials.”

Those trials are important, Dr. DuPont said. “I think we have to address very actively how industry can move these products through,” he said, “because all of us want to remove the F from FMT,” by isolating the necessary elements of the process while not having the risk sometimes associated with human stool.
 

Policy slow to evolve

“I’m frustrated that it’s taken over 6 years and three draft guidances to get us this far,” Christian John Lillis, executive director of the Peggy Lillis Foundation – a group dedicated to creating awareness about the dangers of C. difficile – said at the meeting.

Mr. Lillis said that probably several thousand deaths had been prevented through increased FMT access, but that it was time to create a concrete policy that advanced the therapy.

The FDA guidance issued in 2013 allowed physicians to provide FMT for recurrent or refractory C. difficile infection without filing an investigational new drug (IND) application.

Clinicians must obtain informed consent that includes a discussion of the risks, and a statement that FMT is investigational. In March 2016, the agency issued revised draft guidance that it was aiming to require stool banks to apply for INDs, as reported by Medscape Medical News.

OpenBiome has flourished under the current policy. It has provided more than 50,000 treatments to 1,200 hospitals and clinics, and has provided FMT for 49 clinical trials and for 16 single patients who received INDs, Dr. Osman said.

But requiring INDs for all centers is a bad idea, he said. “IND requirements are insurmountable for most health centers,” Dr. Osman said, noting that most of the FMT material OpenBiome produces is sent to community-based physicians.

“These requirements would likely mean restrictions in access for stool bank–provided FMT and potentially pushing patients to physician-directed FMT or discouraging physicians from using FMT at all,” he said.

Stacy Kahn, MD, FMT director at Boston Children’s Hospital in Massachusetts, said that having ready access from a stool bank was crucial.

“Universal donor FMT is much easier, much faster and much more cost effective than what we can do as clinicians,” she said.
 

New safety and efficacy data

One unpublished study showed that 75% of patients treated since 2011 had a sustained cure, noted Colleen Kelly, MD, a Brown University professor of medicine and principal investigator for the National Institutes of Health–funded national FMT registry (although the data in this study were not from the FMT registry).

The study, which was a collaboration between the Alpert Medical School of Brown University, Brigham and Women’s Hospital, and Indiana University School of Medicine, attempted follow-up on 533 patients; 208 were successfully contacted, and an additional 55 had died, none due to FMT.

Dr. Kelly also presented data from the FMT National Registry showing that at 1 month posttransplant, two (1%) of 253 patients had an infection possibly related to FMT; one with Bacteroides fragilis and one with enteropathogenic E. coli. Seven hospitalizations were deemed related or possibly related to FMT, including two recurrences of C. difficile.

At 6 months posttransplant, 8 (5%) of 152 patients had a serious infection, and 23 patients reported a diagnosis of a new condition, primarily diarrhea-predominant irritable bowel syndrome, which is common post FMT, said Dr. Kelly, who presented the data on behalf of AGA, which administers the registry.

The AGA supports a continuation of the enforcement discretion as a means to maintain patient access where the evidence supports the use of FMT, but the group does not back use of FMT outside medical supervision, Dr. Kelly said.
 

This article originally appeared on Medscape. For more news, follow Medscape on Facebook, Twitter, Instagram, and YouTube.

WASHINGTON – Although severe, community-acquired sepsis in previously healthy U.S. adults is relatively uncommon, it occurs often enough to strike about 40,000 people annually, and when previously healthy people are hospitalized for severe sepsis, their rate of in-hospital mortality was double the rate in people with one or more comorbidities who have severe, community-acquired sepsis, based on a review of almost 7 million Americans hospitalized for sepsis.

The findings “underscore the importance of improving public awareness of sepsis and emphasizing early sepsis recognition and treatment in all patients,” including those without comorbidities, Chanu Rhee, MD, said at an annual scientific meeting on infectious diseases. He hypothesized that the increased sepsis mortality among previously healthy patients may have stemmed from factors such as delayed sepsis recognition resulting in hospitalization at a more advanced stage and less aggressive management.

In addition, “the findings provide context for high-profile reports about sepsis death in previously healthy people,” said Dr. Rhee, an infectious diseases and critical care physician at Brigham and Women’s Hospital in Boston. Dr. Rhee and associates found that, among patients hospitalized with what the researchers defined as “community-acquired” sepsis, 3% were judged previously healthy by having no identified major or minor comorbidity or pregnancy at the time of hospitalization, a percentage that – while small – still translates into roughly 40,000 such cases annually in the United States. That helps explain why every so often a headline appears about a famous person who died suddenly and unexpectedly from sepsis, he noted.

The study used data collected on hospitalized U.S. patients in the Cerner Health Facts, HCA Healthcare, and Institute for Health Metrics and Evaluation databases, which included about 6.7 million people total including 337,983 identified as having community-acquired sepsis, defined as patients who met the criteria for adult sepsis advanced by the Centers for Disease Control and Prevention within 2 days of their hospital admission. The researchers looked further into the hospital records of these patients and divided them into patients with one or more major comorbidities (96% of the cohort), patients who were pregnant or had a “minor” comorbidity such as a lipid disorder, benign neoplasm, or obesity (1% of the study group), or those with no chronic comorbidity (3%; the subgroup the researchers deemed previously healthy).

In a multivariate analysis that adjusted for patients’ age, sex, race, infection site, and illness severity at the time of hospital admission the researchers found that the rate of in-hospital death among the previously healthy patients was exactly twice the rate of those who had at least one major chronic comorbidity, Dr. Rhee reported. Differences in the treatment received by the previously-healthy patients or in their medical status compared with patients with a major comorbidity suggested that the previously health patients were sicker. They had a higher rate of mechanical ventilation, 30%, compared with about 18% for those with a comorbidity; a higher rate of acute kidney injury, about 43% in those previously healthy and 28% in those with a comorbidity; and a higher percentage had an elevated lactate level, about 41% among the previously healthy patients and about 22% among those with a comorbidity.

[email protected]

SOURCE: Alrawashdeh M et al. Open Forum Infect Dis. 2019 Oct 23;6. Abstract 891.

WASHINGTON – Although severe, community-acquired sepsis in previously healthy U.S. adults is relatively uncommon, it occurs often enough to strike about 40,000 people annually, and when previously healthy people are hospitalized for severe sepsis, their rate of in-hospital mortality was double the rate in people with one or more comorbidities who have severe, community-acquired sepsis, based on a review of almost 7 million Americans hospitalized for sepsis.

The findings “underscore the importance of improving public awareness of sepsis and emphasizing early sepsis recognition and treatment in all patients,” including those without comorbidities, Chanu Rhee, MD, said at an annual scientific meeting on infectious diseases. He hypothesized that the increased sepsis mortality among previously healthy patients may have stemmed from factors such as delayed sepsis recognition resulting in hospitalization at a more advanced stage and less aggressive management.

In addition, “the findings provide context for high-profile reports about sepsis death in previously healthy people,” said Dr. Rhee, an infectious diseases and critical care physician at Brigham and Women’s Hospital in Boston. Dr. Rhee and associates found that, among patients hospitalized with what the researchers defined as “community-acquired” sepsis, 3% were judged previously healthy by having no identified major or minor comorbidity or pregnancy at the time of hospitalization, a percentage that – while small – still translates into roughly 40,000 such cases annually in the United States. That helps explain why every so often a headline appears about a famous person who died suddenly and unexpectedly from sepsis, he noted.

The study used data collected on hospitalized U.S. patients in the Cerner Health Facts, HCA Healthcare, and Institute for Health Metrics and Evaluation databases, which included about 6.7 million people total including 337,983 identified as having community-acquired sepsis, defined as patients who met the criteria for adult sepsis advanced by the Centers for Disease Control and Prevention within 2 days of their hospital admission. The researchers looked further into the hospital records of these patients and divided them into patients with one or more major comorbidities (96% of the cohort), patients who were pregnant or had a “minor” comorbidity such as a lipid disorder, benign neoplasm, or obesity (1% of the study group), or those with no chronic comorbidity (3%; the subgroup the researchers deemed previously healthy).

In a multivariate analysis that adjusted for patients’ age, sex, race, infection site, and illness severity at the time of hospital admission the researchers found that the rate of in-hospital death among the previously healthy patients was exactly twice the rate of those who had at least one major chronic comorbidity, Dr. Rhee reported. Differences in the treatment received by the previously-healthy patients or in their medical status compared with patients with a major comorbidity suggested that the previously health patients were sicker. They had a higher rate of mechanical ventilation, 30%, compared with about 18% for those with a comorbidity; a higher rate of acute kidney injury, about 43% in those previously healthy and 28% in those with a comorbidity; and a higher percentage had an elevated lactate level, about 41% among the previously healthy patients and about 22% among those with a comorbidity.

[email protected]

SOURCE: Alrawashdeh M et al. Open Forum Infect Dis. 2019 Oct 23;6. Abstract 891.

WASHINGTON – Although severe, community-acquired sepsis in previously healthy U.S. adults is relatively uncommon, it occurs often enough to strike about 40,000 people annually, and when previously healthy people are hospitalized for severe sepsis, their rate of in-hospital mortality was double the rate in people with one or more comorbidities who have severe, community-acquired sepsis, based on a review of almost 7 million Americans hospitalized for sepsis.

The findings “underscore the importance of improving public awareness of sepsis and emphasizing early sepsis recognition and treatment in all patients,” including those without comorbidities, Chanu Rhee, MD, said at an annual scientific meeting on infectious diseases. He hypothesized that the increased sepsis mortality among previously healthy patients may have stemmed from factors such as delayed sepsis recognition resulting in hospitalization at a more advanced stage and less aggressive management.

In addition, “the findings provide context for high-profile reports about sepsis death in previously healthy people,” said Dr. Rhee, an infectious diseases and critical care physician at Brigham and Women’s Hospital in Boston. Dr. Rhee and associates found that, among patients hospitalized with what the researchers defined as “community-acquired” sepsis, 3% were judged previously healthy by having no identified major or minor comorbidity or pregnancy at the time of hospitalization, a percentage that – while small – still translates into roughly 40,000 such cases annually in the United States. That helps explain why every so often a headline appears about a famous person who died suddenly and unexpectedly from sepsis, he noted.

The study used data collected on hospitalized U.S. patients in the Cerner Health Facts, HCA Healthcare, and Institute for Health Metrics and Evaluation databases, which included about 6.7 million people total including 337,983 identified as having community-acquired sepsis, defined as patients who met the criteria for adult sepsis advanced by the Centers for Disease Control and Prevention within 2 days of their hospital admission. The researchers looked further into the hospital records of these patients and divided them into patients with one or more major comorbidities (96% of the cohort), patients who were pregnant or had a “minor” comorbidity such as a lipid disorder, benign neoplasm, or obesity (1% of the study group), or those with no chronic comorbidity (3%; the subgroup the researchers deemed previously healthy).

In a multivariate analysis that adjusted for patients’ age, sex, race, infection site, and illness severity at the time of hospital admission the researchers found that the rate of in-hospital death among the previously healthy patients was exactly twice the rate of those who had at least one major chronic comorbidity, Dr. Rhee reported. Differences in the treatment received by the previously-healthy patients or in their medical status compared with patients with a major comorbidity suggested that the previously health patients were sicker. They had a higher rate of mechanical ventilation, 30%, compared with about 18% for those with a comorbidity; a higher rate of acute kidney injury, about 43% in those previously healthy and 28% in those with a comorbidity; and a higher percentage had an elevated lactate level, about 41% among the previously healthy patients and about 22% among those with a comorbidity.

[email protected]

SOURCE: Alrawashdeh M et al. Open Forum Infect Dis. 2019 Oct 23;6. Abstract 891.

A 68-year-old woman is admitted to the hospital with a diagnosis of community-acquired pneumonia. Should you add probiotics to her antibiotic regimen to prevent infection with Clostridium difficile?

Clostridium difficile infection (CDI) leads to significant morbidity, mortality, and treatment failures. In 2011, it culminated in a cost of $4.8 billion and 29,000 deaths.^2,3 Risk factors for infection include antibiotic use, hospitalization, older age, and medical comorbidities.² Probiotics have been proposed as one way to prevent CDI.

Several systematic reviews have demonstrated efficacy for probiotics in the prevention of CDI, although not all of them followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines or focused specifically on hospitalized patients, who are at increased risk.^4-6 The largest high-quality randomized controlled trial (RCT) on the use of probiotics to prevent CDI, the PLACIDE trial, found no difference in CDI incidence between inpatients (ages 65 and older) who did and those who did not receive probiotics in addition to their oral or parenteral antibiotics; however, this trial had a lower incidence of CDI than was assumed in the power calculations.⁷ Guidelines from the American College of Gastroenterology and the Society for Healthcare Epidemiology of America do not include a recommendation for the use of probiotics in CDI prevention.^8,9

Given the conflicting and poor-quality evidence and lack of recommendations, an additional systematic review and meta-analysis was performed, following PRISMA guidelines and focusing on studies conducted only in hospitalized adults.

STUDY SUMMARY

Probiotics prevent CDI in this population

This meta-analysis of 19 RCTs evaluated the efficacy of probiotics for the prevention of CDI in 6261 hospitalized adults taking antibiotics. All patients were 18 or older (mean age, 68-69) and received antibiotics orally, intravenously, or via both routes, for any medical indication.

Trials were included if the intervention was for CDI prevention and if the probiotic strains used were Lactobacillus, Saccharomyces, Bifidobacterium, or Streptococcus (alone or in combination). Probiotic doses ranged from 4 billion to 900 billion colony-forming U/d and were started from 1 to 7 days after the first antibiotic dose. Duration of probiotic use was either fixed at 14 to 21 days or varied based on the duration of antibiotics (extending 3-14 d after the last antibiotic dose).

Control groups received matching placebo in all but 2 trials; those 2 used usual care of no probiotics as the control. Exclusion criteria included pregnancy, immunocompromise, intensive care, a prosthetic heart valve, and pre-existing gastrointestinal disorders.

[polldaddy:10452484]

Continue to: The risk for CDI...

The risk for CDI was lower in the probiotic group (range 0%-11%) than in the control group (0%-40%), with no heterogeneity when the data from all 19 studies were pooled (relative risk [RR], 0.42). The median incidence of CDI in the control groups from all studies was 4%, which yielded a number needed to treat (NNT) of 43.

The researchers examined the NNT at varying incidence rates. If the CDI incidence was 1.2%, the NNT to prevent 1 case of CDI was 144; if the incidence was 7.4%, the NNT was 23. Compared with control groups, there was a significant reduction in CDI if probiotics were started within 1 to 2 days of antibiotic initiation (RR, 0.32), but not if they were started at 3 to 7 days (RR, 0.70). There was no significant difference in adverse events (ie, cramping, nausea, fever, soft stools, flatulence, taste disturbance) between probiotic and control groups (14% vs 16%).

WHAT’S NEW

Added benefit if probiotics taken sooner

This high-quality meta-analysis shows that administration of probiotics to hospitalized patients—particularly when started within 1 to 2 days of initiating antibiotic therapy—can prevent CDI.

CAVEATS

Limited applicability, lack of recommendations

Findings from this meta-analysis do not apply to patients who are pregnant; who have an immunocompromising condition, a prosthetic heart valve, or a pre-existing gastrointestinal disorder (eg, irritable bowel disease, pancreatitis); or who require intensive care. In addition, specific recommendations as to the optimal probiotic species, dose, formulation, and duration of use cannot be made based on this meta-analysis. Lastly, findings from this study do not apply to patients treated with antibiotics in the ambulatory care setting.

CHALLENGES TO IMPLEMENTATION

Limited availability in hospitals

The largest barrier to giving probiotics to hospitalized adults is their availability on local hospital formularies. Probiotics are not technically a medication; they are not regulated or FDA-approved, and thus, insurance coverage and availability for inpatient use are limited. Lastly, US cost-effectiveness data are lacking, although such data would likely be favorable, given the high costs associated with treating CDI.

Continue to: ACKNOWLEDGMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2019. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2019;68[6]:351-352,354).

A 68-year-old woman is admitted to the hospital with a diagnosis of community-acquired pneumonia. Should you add probiotics to her antibiotic regimen to prevent infection with Clostridium difficile?

Clostridium difficile infection (CDI) leads to significant morbidity, mortality, and treatment failures. In 2011, it culminated in a cost of $4.8 billion and 29,000 deaths.^2,3 Risk factors for infection include antibiotic use, hospitalization, older age, and medical comorbidities.² Probiotics have been proposed as one way to prevent CDI.

Several systematic reviews have demonstrated efficacy for probiotics in the prevention of CDI, although not all of them followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines or focused specifically on hospitalized patients, who are at increased risk.^4-6 The largest high-quality randomized controlled trial (RCT) on the use of probiotics to prevent CDI, the PLACIDE trial, found no difference in CDI incidence between inpatients (ages 65 and older) who did and those who did not receive probiotics in addition to their oral or parenteral antibiotics; however, this trial had a lower incidence of CDI than was assumed in the power calculations.⁷ Guidelines from the American College of Gastroenterology and the Society for Healthcare Epidemiology of America do not include a recommendation for the use of probiotics in CDI prevention.^8,9

Given the conflicting and poor-quality evidence and lack of recommendations, an additional systematic review and meta-analysis was performed, following PRISMA guidelines and focusing on studies conducted only in hospitalized adults.

STUDY SUMMARY

Probiotics prevent CDI in this population

This meta-analysis of 19 RCTs evaluated the efficacy of probiotics for the prevention of CDI in 6261 hospitalized adults taking antibiotics. All patients were 18 or older (mean age, 68-69) and received antibiotics orally, intravenously, or via both routes, for any medical indication.

Trials were included if the intervention was for CDI prevention and if the probiotic strains used were Lactobacillus, Saccharomyces, Bifidobacterium, or Streptococcus (alone or in combination). Probiotic doses ranged from 4 billion to 900 billion colony-forming U/d and were started from 1 to 7 days after the first antibiotic dose. Duration of probiotic use was either fixed at 14 to 21 days or varied based on the duration of antibiotics (extending 3-14 d after the last antibiotic dose).

Control groups received matching placebo in all but 2 trials; those 2 used usual care of no probiotics as the control. Exclusion criteria included pregnancy, immunocompromise, intensive care, a prosthetic heart valve, and pre-existing gastrointestinal disorders.

[polldaddy:10452484]

Continue to: The risk for CDI...

The risk for CDI was lower in the probiotic group (range 0%-11%) than in the control group (0%-40%), with no heterogeneity when the data from all 19 studies were pooled (relative risk [RR], 0.42). The median incidence of CDI in the control groups from all studies was 4%, which yielded a number needed to treat (NNT) of 43.

The researchers examined the NNT at varying incidence rates. If the CDI incidence was 1.2%, the NNT to prevent 1 case of CDI was 144; if the incidence was 7.4%, the NNT was 23. Compared with control groups, there was a significant reduction in CDI if probiotics were started within 1 to 2 days of antibiotic initiation (RR, 0.32), but not if they were started at 3 to 7 days (RR, 0.70). There was no significant difference in adverse events (ie, cramping, nausea, fever, soft stools, flatulence, taste disturbance) between probiotic and control groups (14% vs 16%).

WHAT’S NEW

Added benefit if probiotics taken sooner

This high-quality meta-analysis shows that administration of probiotics to hospitalized patients—particularly when started within 1 to 2 days of initiating antibiotic therapy—can prevent CDI.

CAVEATS

Limited applicability, lack of recommendations

Findings from this meta-analysis do not apply to patients who are pregnant; who have an immunocompromising condition, a prosthetic heart valve, or a pre-existing gastrointestinal disorder (eg, irritable bowel disease, pancreatitis); or who require intensive care. In addition, specific recommendations as to the optimal probiotic species, dose, formulation, and duration of use cannot be made based on this meta-analysis. Lastly, findings from this study do not apply to patients treated with antibiotics in the ambulatory care setting.

CHALLENGES TO IMPLEMENTATION

Limited availability in hospitals

The largest barrier to giving probiotics to hospitalized adults is their availability on local hospital formularies. Probiotics are not technically a medication; they are not regulated or FDA-approved, and thus, insurance coverage and availability for inpatient use are limited. Lastly, US cost-effectiveness data are lacking, although such data would likely be favorable, given the high costs associated with treating CDI.

Continue to: ACKNOWLEDGMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2019. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2019;68[6]:351-352,354).

A 68-year-old woman is admitted to the hospital with a diagnosis of community-acquired pneumonia. Should you add probiotics to her antibiotic regimen to prevent infection with Clostridium difficile?

Clostridium difficile infection (CDI) leads to significant morbidity, mortality, and treatment failures. In 2011, it culminated in a cost of $4.8 billion and 29,000 deaths.^2,3 Risk factors for infection include antibiotic use, hospitalization, older age, and medical comorbidities.² Probiotics have been proposed as one way to prevent CDI.

Several systematic reviews have demonstrated efficacy for probiotics in the prevention of CDI, although not all of them followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines or focused specifically on hospitalized patients, who are at increased risk.^4-6 The largest high-quality randomized controlled trial (RCT) on the use of probiotics to prevent CDI, the PLACIDE trial, found no difference in CDI incidence between inpatients (ages 65 and older) who did and those who did not receive probiotics in addition to their oral or parenteral antibiotics; however, this trial had a lower incidence of CDI than was assumed in the power calculations.⁷ Guidelines from the American College of Gastroenterology and the Society for Healthcare Epidemiology of America do not include a recommendation for the use of probiotics in CDI prevention.^8,9

Given the conflicting and poor-quality evidence and lack of recommendations, an additional systematic review and meta-analysis was performed, following PRISMA guidelines and focusing on studies conducted only in hospitalized adults.

STUDY SUMMARY

Probiotics prevent CDI in this population

This meta-analysis of 19 RCTs evaluated the efficacy of probiotics for the prevention of CDI in 6261 hospitalized adults taking antibiotics. All patients were 18 or older (mean age, 68-69) and received antibiotics orally, intravenously, or via both routes, for any medical indication.

Trials were included if the intervention was for CDI prevention and if the probiotic strains used were Lactobacillus, Saccharomyces, Bifidobacterium, or Streptococcus (alone or in combination). Probiotic doses ranged from 4 billion to 900 billion colony-forming U/d and were started from 1 to 7 days after the first antibiotic dose. Duration of probiotic use was either fixed at 14 to 21 days or varied based on the duration of antibiotics (extending 3-14 d after the last antibiotic dose).

Control groups received matching placebo in all but 2 trials; those 2 used usual care of no probiotics as the control. Exclusion criteria included pregnancy, immunocompromise, intensive care, a prosthetic heart valve, and pre-existing gastrointestinal disorders.

[polldaddy:10452484]

Continue to: The risk for CDI...

The risk for CDI was lower in the probiotic group (range 0%-11%) than in the control group (0%-40%), with no heterogeneity when the data from all 19 studies were pooled (relative risk [RR], 0.42). The median incidence of CDI in the control groups from all studies was 4%, which yielded a number needed to treat (NNT) of 43.

The researchers examined the NNT at varying incidence rates. If the CDI incidence was 1.2%, the NNT to prevent 1 case of CDI was 144; if the incidence was 7.4%, the NNT was 23. Compared with control groups, there was a significant reduction in CDI if probiotics were started within 1 to 2 days of antibiotic initiation (RR, 0.32), but not if they were started at 3 to 7 days (RR, 0.70). There was no significant difference in adverse events (ie, cramping, nausea, fever, soft stools, flatulence, taste disturbance) between probiotic and control groups (14% vs 16%).

WHAT’S NEW

Added benefit if probiotics taken sooner

This high-quality meta-analysis shows that administration of probiotics to hospitalized patients—particularly when started within 1 to 2 days of initiating antibiotic therapy—can prevent CDI.

CAVEATS

Limited applicability, lack of recommendations

Findings from this meta-analysis do not apply to patients who are pregnant; who have an immunocompromising condition, a prosthetic heart valve, or a pre-existing gastrointestinal disorder (eg, irritable bowel disease, pancreatitis); or who require intensive care. In addition, specific recommendations as to the optimal probiotic species, dose, formulation, and duration of use cannot be made based on this meta-analysis. Lastly, findings from this study do not apply to patients treated with antibiotics in the ambulatory care setting.

CHALLENGES TO IMPLEMENTATION

Limited availability in hospitals

The largest barrier to giving probiotics to hospitalized adults is their availability on local hospital formularies. Probiotics are not technically a medication; they are not regulated or FDA-approved, and thus, insurance coverage and availability for inpatient use are limited. Lastly, US cost-effectiveness data are lacking, although such data would likely be favorable, given the high costs associated with treating CDI.

Continue to: ACKNOWLEDGMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2019. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2019;68[6]:351-352,354).

Requests for crowd diagnosis of sexually transmitted diseases were frequent on a social media website, new research found.

The social media website Reddit, which currently has 330 million monthly active users, is home to more than 230 health-related subreddits, including r/STD, a forum that allows users to publicly share “stories, concerns, and questions” about “anything and everything STD related,” Alicia L. Nobles, PhD, of the department of medicine at the University of California, San Diego, and associates wrote in a research letter published in JAMA.

Dr. Noble and associates conducted an analysis of all posts published to r/STD from the subreddit’s inception during November 2010–February 2019, a total of 16,979 posts. Three coauthors independently coded each post, recording whether or not a post requested a crowd diagnosis, and if so, whether that request was made to obtain a second opinion after a visit to a health care professional.

About 58% of posts requested a crowd diagnosis, 31% of which included an image of the physical signs. One-fifth of the requests for a crowd diagnosis were seeking a second opinion after a previous diagnosis by a health care professional. Nearly 90% of all crowd-diagnosis requests received at least one reply (mean responses, 1.7), with a median response time of 3.04 hours. About 80% of requests were answered in less than 1 day.

While crowd diagnoses do seem to be popular and have the benefits of anonymity, rapid response, and multiple opinions, the accuracy of crowd diagnoses is unknown given the limited information responders operate with and the potential lack of responder medical training, the study authors noted. Misdiagnosis could allow further disease transmission, and third parties viewing posts could incorrectly self-diagnose their own condition.

“Health care professionals could partner with social media outlets to promote the potential benefits of crowd diagnosis while suppressing potential harms, for example by having trained professionals respond to posts to better diagnose and make referrals to health care centers,” Dr. Nobles and associates concluded.

One coauthor reported receiving personal fees from Bloomberg and Good Analytics, and another reported receiving grants from the National Institutes of Health; no other disclosures were reported.

[email protected]

SOURCE: Nobles AL et al. JAMA. 2019 Nov 5;322(17):1712-3.

Requests for crowd diagnosis of sexually transmitted diseases were frequent on a social media website, new research found.

The social media website Reddit, which currently has 330 million monthly active users, is home to more than 230 health-related subreddits, including r/STD, a forum that allows users to publicly share “stories, concerns, and questions” about “anything and everything STD related,” Alicia L. Nobles, PhD, of the department of medicine at the University of California, San Diego, and associates wrote in a research letter published in JAMA.

Dr. Noble and associates conducted an analysis of all posts published to r/STD from the subreddit’s inception during November 2010–February 2019, a total of 16,979 posts. Three coauthors independently coded each post, recording whether or not a post requested a crowd diagnosis, and if so, whether that request was made to obtain a second opinion after a visit to a health care professional.

About 58% of posts requested a crowd diagnosis, 31% of which included an image of the physical signs. One-fifth of the requests for a crowd diagnosis were seeking a second opinion after a previous diagnosis by a health care professional. Nearly 90% of all crowd-diagnosis requests received at least one reply (mean responses, 1.7), with a median response time of 3.04 hours. About 80% of requests were answered in less than 1 day.

While crowd diagnoses do seem to be popular and have the benefits of anonymity, rapid response, and multiple opinions, the accuracy of crowd diagnoses is unknown given the limited information responders operate with and the potential lack of responder medical training, the study authors noted. Misdiagnosis could allow further disease transmission, and third parties viewing posts could incorrectly self-diagnose their own condition.

“Health care professionals could partner with social media outlets to promote the potential benefits of crowd diagnosis while suppressing potential harms, for example by having trained professionals respond to posts to better diagnose and make referrals to health care centers,” Dr. Nobles and associates concluded.

One coauthor reported receiving personal fees from Bloomberg and Good Analytics, and another reported receiving grants from the National Institutes of Health; no other disclosures were reported.

[email protected]

SOURCE: Nobles AL et al. JAMA. 2019 Nov 5;322(17):1712-3.

Requests for crowd diagnosis of sexually transmitted diseases were frequent on a social media website, new research found.

The social media website Reddit, which currently has 330 million monthly active users, is home to more than 230 health-related subreddits, including r/STD, a forum that allows users to publicly share “stories, concerns, and questions” about “anything and everything STD related,” Alicia L. Nobles, PhD, of the department of medicine at the University of California, San Diego, and associates wrote in a research letter published in JAMA.

Dr. Noble and associates conducted an analysis of all posts published to r/STD from the subreddit’s inception during November 2010–February 2019, a total of 16,979 posts. Three coauthors independently coded each post, recording whether or not a post requested a crowd diagnosis, and if so, whether that request was made to obtain a second opinion after a visit to a health care professional.

About 58% of posts requested a crowd diagnosis, 31% of which included an image of the physical signs. One-fifth of the requests for a crowd diagnosis were seeking a second opinion after a previous diagnosis by a health care professional. Nearly 90% of all crowd-diagnosis requests received at least one reply (mean responses, 1.7), with a median response time of 3.04 hours. About 80% of requests were answered in less than 1 day.

While crowd diagnoses do seem to be popular and have the benefits of anonymity, rapid response, and multiple opinions, the accuracy of crowd diagnoses is unknown given the limited information responders operate with and the potential lack of responder medical training, the study authors noted. Misdiagnosis could allow further disease transmission, and third parties viewing posts could incorrectly self-diagnose their own condition.

“Health care professionals could partner with social media outlets to promote the potential benefits of crowd diagnosis while suppressing potential harms, for example by having trained professionals respond to posts to better diagnose and make referrals to health care centers,” Dr. Nobles and associates concluded.

One coauthor reported receiving personal fees from Bloomberg and Good Analytics, and another reported receiving grants from the National Institutes of Health; no other disclosures were reported.

[email protected]

SOURCE: Nobles AL et al. JAMA. 2019 Nov 5;322(17):1712-3.

Classically, eczema herpeticum is associated with atopic dermatitis (AD), but it also has been previously reported in the setting of pemphigus vulgaris, Darier disease, ichthyosis vulgaris, burns, psoriasis, and irritant contact dermatitis.^1,2 Descriptions of cutaneous herpes simplex virus (HSV) in the setting of seborrheic dermatitis are lacking.

Case Report

A 2-month-old infant boy who was otherwise healthy presented to the emergency department with a new rash on the scalp. Initially there were a few clusters of small fluid-filled lesions that evolved over several days into diffuse clusters covering the scalp and extending onto the forehead and upper chest (Figure). The patient’s medical history was notable for infantile seborrheic dermatitis and a family history of AD. His grandmother, who was his primary caretaker, had a recent history of herpes labialis.

Physical examination revealed numerous discrete, erythematous, and punched-out erosions diffusely on the scalp. There were fewer similar erosions on the forehead and upper chest. There were no oral or periocular lesions. There were no areas of lichenification or eczematous plaques on the remainder of the trunk or extremities. Laboratory testing was positive for HSV type 1 polymerase chain reaction and positive for HSV type 1 viral culture. Liver enzymes were elevated with alanine aminotransferase at 107 U/L (reference range, 7–52 U/L) and aspartate aminotransferase at 94 U/L (reference range, 13–39 U/L).

The patient was admitted to the hospital and was treated by the dermatology and infectious disease services. Intravenous acyclovir 60 mg/kg daily was administered for 3 days until all lesions had crusted over. On the day of discharge, the patient was transitioned to oral valacyclovir 20 mg/kg daily for 7 days with resolution. One month later he developed a recurrence that was within his existing seborrheic dermatitis. After a repeat 7-day course of oral valacyclovir 20 mg/kg daily, he was placed on prophylaxis therapy of oral acyclovir 10 mg/kg daily. Gentle skin care precautions also were recommended.

Comment

Eczema herpeticum refers to disseminated cutaneous infection with HSV types 1 or 2 in the setting of underlying dermatosis.² Although it is classically associated with AD, it has been reported in a number of other chronic skin disorders and can lead to serious complications, including hepatitis, keratoconjunctivitis, and meningitis. In those with AD who develop HSV, presentation may occur in active dermatitis locations because of skin barrier disruption, which may lead to increased susceptibility to viral infection.³

Herpes simplex virus in a background of seborrheic dermatitis has not been well described. Although the pathogenesis of seborrheic dermatitis has not been fully reported, several gene mutations and protein deficiencies have been identified in patients and animal models that are associated with immune response or epidermal differentiation.⁴ Therefore, it is possible that, as with AD, a disruption in the skin barrier increases susceptibility to viral infection.

It also has been suggested that infantile seborrheic dermatitis and AD represent the same spectrum of disease.⁵ Given our patient’s family history of AD, it is possible his presentation represents early underlying AD. Providers should be aware that cutaneous HSV can be confined to a seborrheic distribution and may represent underlying epidermal dysfunction secondary to seborrheic dermatitis.

Classically, eczema herpeticum is associated with atopic dermatitis (AD), but it also has been previously reported in the setting of pemphigus vulgaris, Darier disease, ichthyosis vulgaris, burns, psoriasis, and irritant contact dermatitis.^1,2 Descriptions of cutaneous herpes simplex virus (HSV) in the setting of seborrheic dermatitis are lacking.

Case Report

A 2-month-old infant boy who was otherwise healthy presented to the emergency department with a new rash on the scalp. Initially there were a few clusters of small fluid-filled lesions that evolved over several days into diffuse clusters covering the scalp and extending onto the forehead and upper chest (Figure). The patient’s medical history was notable for infantile seborrheic dermatitis and a family history of AD. His grandmother, who was his primary caretaker, had a recent history of herpes labialis.

Physical examination revealed numerous discrete, erythematous, and punched-out erosions diffusely on the scalp. There were fewer similar erosions on the forehead and upper chest. There were no oral or periocular lesions. There were no areas of lichenification or eczematous plaques on the remainder of the trunk or extremities. Laboratory testing was positive for HSV type 1 polymerase chain reaction and positive for HSV type 1 viral culture. Liver enzymes were elevated with alanine aminotransferase at 107 U/L (reference range, 7–52 U/L) and aspartate aminotransferase at 94 U/L (reference range, 13–39 U/L).

The patient was admitted to the hospital and was treated by the dermatology and infectious disease services. Intravenous acyclovir 60 mg/kg daily was administered for 3 days until all lesions had crusted over. On the day of discharge, the patient was transitioned to oral valacyclovir 20 mg/kg daily for 7 days with resolution. One month later he developed a recurrence that was within his existing seborrheic dermatitis. After a repeat 7-day course of oral valacyclovir 20 mg/kg daily, he was placed on prophylaxis therapy of oral acyclovir 10 mg/kg daily. Gentle skin care precautions also were recommended.

Comment

Eczema herpeticum refers to disseminated cutaneous infection with HSV types 1 or 2 in the setting of underlying dermatosis.² Although it is classically associated with AD, it has been reported in a number of other chronic skin disorders and can lead to serious complications, including hepatitis, keratoconjunctivitis, and meningitis. In those with AD who develop HSV, presentation may occur in active dermatitis locations because of skin barrier disruption, which may lead to increased susceptibility to viral infection.³

Herpes simplex virus in a background of seborrheic dermatitis has not been well described. Although the pathogenesis of seborrheic dermatitis has not been fully reported, several gene mutations and protein deficiencies have been identified in patients and animal models that are associated with immune response or epidermal differentiation.⁴ Therefore, it is possible that, as with AD, a disruption in the skin barrier increases susceptibility to viral infection.

It also has been suggested that infantile seborrheic dermatitis and AD represent the same spectrum of disease.⁵ Given our patient’s family history of AD, it is possible his presentation represents early underlying AD. Providers should be aware that cutaneous HSV can be confined to a seborrheic distribution and may represent underlying epidermal dysfunction secondary to seborrheic dermatitis.

Classically, eczema herpeticum is associated with atopic dermatitis (AD), but it also has been previously reported in the setting of pemphigus vulgaris, Darier disease, ichthyosis vulgaris, burns, psoriasis, and irritant contact dermatitis.^1,2 Descriptions of cutaneous herpes simplex virus (HSV) in the setting of seborrheic dermatitis are lacking.

Case Report

A 2-month-old infant boy who was otherwise healthy presented to the emergency department with a new rash on the scalp. Initially there were a few clusters of small fluid-filled lesions that evolved over several days into diffuse clusters covering the scalp and extending onto the forehead and upper chest (Figure). The patient’s medical history was notable for infantile seborrheic dermatitis and a family history of AD. His grandmother, who was his primary caretaker, had a recent history of herpes labialis.

Physical examination revealed numerous discrete, erythematous, and punched-out erosions diffusely on the scalp. There were fewer similar erosions on the forehead and upper chest. There were no oral or periocular lesions. There were no areas of lichenification or eczematous plaques on the remainder of the trunk or extremities. Laboratory testing was positive for HSV type 1 polymerase chain reaction and positive for HSV type 1 viral culture. Liver enzymes were elevated with alanine aminotransferase at 107 U/L (reference range, 7–52 U/L) and aspartate aminotransferase at 94 U/L (reference range, 13–39 U/L).

The patient was admitted to the hospital and was treated by the dermatology and infectious disease services. Intravenous acyclovir 60 mg/kg daily was administered for 3 days until all lesions had crusted over. On the day of discharge, the patient was transitioned to oral valacyclovir 20 mg/kg daily for 7 days with resolution. One month later he developed a recurrence that was within his existing seborrheic dermatitis. After a repeat 7-day course of oral valacyclovir 20 mg/kg daily, he was placed on prophylaxis therapy of oral acyclovir 10 mg/kg daily. Gentle skin care precautions also were recommended.

Comment

Eczema herpeticum refers to disseminated cutaneous infection with HSV types 1 or 2 in the setting of underlying dermatosis.² Although it is classically associated with AD, it has been reported in a number of other chronic skin disorders and can lead to serious complications, including hepatitis, keratoconjunctivitis, and meningitis. In those with AD who develop HSV, presentation may occur in active dermatitis locations because of skin barrier disruption, which may lead to increased susceptibility to viral infection.³

Herpes simplex virus in a background of seborrheic dermatitis has not been well described. Although the pathogenesis of seborrheic dermatitis has not been fully reported, several gene mutations and protein deficiencies have been identified in patients and animal models that are associated with immune response or epidermal differentiation.⁴ Therefore, it is possible that, as with AD, a disruption in the skin barrier increases susceptibility to viral infection.

It also has been suggested that infantile seborrheic dermatitis and AD represent the same spectrum of disease.⁵ Given our patient’s family history of AD, it is possible his presentation represents early underlying AD. Providers should be aware that cutaneous HSV can be confined to a seborrheic distribution and may represent underlying epidermal dysfunction secondary to seborrheic dermatitis.

Molluscum contagiosum virus (MCV) infection causes the cutaneous lesions we call molluscum. Molluscum has become common in the last 30 years. Deciding the best course of therapy requires some fundamental understanding about how MCV relates to the following factors: epidemiology, childhood immunity and vaccination, clinical features, comorbidities, and quality of life. Treatment depends on many factors, including presence or absence of atopic dermatitis (AD) and/or pruritus, other symptoms, cosmetic location, and the child’s concern about the lesions. Therapeutics include destructive and immunologic therapies, the latter geared toward increasing immune response.

Epidemiology

Molluscum contagiosum virus is the solo member of the Molluscipoxvirus genus. Infection with MCV causes benign growth or tumors in the skin (ie, molluscum). The infection is slow to clear because the virus reduces the host’s immunity.^1,2 Molluscum contagiosum virus is a double-stranded DNA virus that affects keratinocytes and genetically carries the tools for its own replication (ie, DNA-dependent RNA polymerase). The virus has a few subtypes—I/Ia, II, III, and IV—with MCV-I predominating in children and healthy humans and MCV-II in patients with human immunodeficiency virus.^1,2 Typing is experimental and is not standardly performed in clinical practice. Molluscum contagiosum virus produces a variety of factors that block the host’s immune response, prolonging infection and preventing erythema and inflammatory response.³

Molluscum contagiosum virus is transmitted through skin-to-skin contact and fomites, including shared towels, bathtubs, spas, bath sponges, and pool equipment.^2,4,5 Transmission from household contact and bathing together has been noted in pediatric patients with MCV. Based on the data it can be posited that the lesions are softer when wet and more readily release viral particles or fomites, and fomites may be left on surfaces, especially when a child is wet.^6,7 Propensity for infection occurs in patients with AD and in immunosuppressed hosts, including children with human immunodeficiency virus and iatrogenic immunosuppression caused by chemotherapy.^1,2,8 Contact sports can increase the risk of transmission, and outbreaks have occurred in pools,^5,9 day-care facilities,¹⁰ and sports settings.¹¹ Cases of congenital and vertically transmitted molluscum have been documented.^12,13 Sexual transmission of MCV may be seen in adolescents who are sexually active. Although child-to-child transmission can occur in the groin area from shared equipment, transmission via sexual abuse also is possible.¹⁴ Bargman¹⁵ has mentioned the isolated genital location and lack of contact with other infected children as concerning features. Latency of new lesion appearance is anywhere from 1 to 50 days from the date of inoculation; therefore, new lesions are possible and expected even after therapy has been effective in eradicating visible lesions.¹⁰ Although clearance has been reported in 6 to 12 months, one pediatric study demonstrated 70% clearance by 1.5 years, suggesting the disease often is more prolonged.¹⁶ One-third of children will experience signs of inflammation, such as pruritus and/or erythema. Rare side effects include bacterial superinfection and hypersensitivity.²

One Dutch study from 1994, the largest database survey of children to date, cited a 17% cumulative incidence of molluscum in children by reviewing the data from 103 general practices.¹⁷ In a survey and review of molluscum by Braue et al,¹⁸ annual rates in populations vary but seem to maximize at approximately 6% to 7%. Sturt et al¹⁹ reviewed the prevalence in the indigenous West Sepik section of New Guinea and noted annual incidence rates of 6% in children younger than 10 years (range, 1.8%–10.9%). Epidemics occur and can produce large numbers of cases in a short time period.¹⁸ The cumulative prevalence in early childhood may be as high as 22%, as Sturt et al¹⁹ observed in children younger than 10 years.

Rising incidence and therefore rising lifetime prevalence appear to have been an issue in the last few decades. Data from the Indian Health Service have demonstrated increases in MCV in Native American children between 2001 and 2005.²⁰ In adults, the data support a steady increase of molluscum from 1988-2007, with a 3-fold increase from 1988-1997 to 1998-2007 in a Spanish study.²¹ Better population-based data are needed.

Childhood Immunity and Vaccination

Sequence homology between MC133L, a protein of MCV, with vaccinia virus suggests overlapping genes.²² Therefore, it is conceptually possible that the rise in incidence of MCV since the 1980s relates to the loss of herd immunity to variola due to lack of vaccination for smallpox, which has not been offered in the United States since 1972.²³ Childhood immunity to MCV varies among studies, but it appears that children do develop antibodies to molluscum in the setting of forming an immune response. Because the rise in molluscum incidence began after the smallpox vaccine was discontinued, the factors appear related; however, the scientific data do not support the theory of a relationship. Mitchell²⁴ has shown that a patient can develop antibodies in response to ground molluscum bodies inoculated into the skin; however, vaccination against molluscum and natural infection do not appear to produce antibodies that would cross-react and protect against other poxviruses, including vaccinia or fowl pox infections.²⁵ Cell-mediated immunity also is required to clear MCV and may account for the inflammatory appearance of lesions as they resolve.²⁶

Demonstrated factors that account for the rise in MCV incidence, aside from alterations in vaccination practices, include spread through sports,⁹ swimming,¹¹ and AD,⁷ which have become more commonplace in the United States in the last few decades, supporting the theory that they may be the cause of the increase in childhood MCV infections. Another cause may be the ability of MCV to create factors that stem host immune response.¹

Clinical Features

Molluscum lesions have a typical appearance of pearly papules with a central dell. These lesions are lighter to flesh colored and measure 1 to 3 mm.^2,4,5 The lesions cluster in the axillae and extremities and average from 10 to 20 per child.⁶ Lesions clear spontaneously, but new ones will continue to form until immunity is developed. Specific clinical appearances of lesions that are not pearly papules are not infrequent. Table 1 contains a short list of the manifold clinical appearances of molluscum lesions in children.^1,2,7,27-35 In particular, certain clinical appearances should be considered. In small children, head and neck lesions resembling milia are not uncommon. Giant or wartlike lesions can appear on the head, neck, or gluteal region in children and are clinical mimics of condyloma or other warts (Figure 1). Giant lesions also can grow in the subcutaneous space and mimic a cyst or abscess.²⁷ Erosive lesions mimicking eczema vaccinatum can be seen (Figure 2), but dermoscopy may demonstrate central dells in some lesions. Other viral processes mimicked include Gianotti Crosti–like lesions (Figure 3) that appear when a papular id reaction forms over the extremities or a localized version in the axilla, mimicking unilateral laterothoracic exanthema.^2,36,37 Hypersensitivity reactions are commonly noted with clearance and can be papular or demonstrate swelling and erythema, termed the beginning-of-the-end sign.³⁸

Pruritus, erythema, and swelling can occur with clearance but do not appear in all patients. Addressing pruritus is important to prevent disease spread, as patients are likely to inoculate other areas of the skin with virus when they scratch, and lesion number is reduced with dermatitis interventions.³⁶

Comorbidities

Molluscum lesions can occur in any child; however, the impaired immunologic status and skin barrier in patients with AD is ripe for the extensive spread of lesions that is associated with higher lesion count.³⁶ Children with molluscum infection can experience new-onset dermatitis or triggering of AD flares, especially on the extremities, such as the antecubital and popliteal regions.⁷ A study of children with MCV infection demonstrated that treatment of active dermatitis reduced spread. The authors mentioned autoinoculation as the mechanism; however, these data also suggest supporting barrier state as a factor in disease spread.³⁶ Superinfection can occur prior to⁶ or after therapy for lesions,³⁷ but it is unclear if this relates to the underlying atopic diathesis. Children with molluscum have been described to have warts, psoriasis, family history of atopy, diabetes mellitus, and pityriasis alba,⁷ while immunosuppression of any kind is associated with molluscum and high lesion count or prolonged disease in childhood.^1,2

Quality of Life

Children with molluscum who have higher lesion counts appear to be at risk for severe effects on their quality of life. Approximately 10% of children with MCV infection have been documented to have severe impairments on quality of life.³⁹ In my practice, quality of life in children with MCV appears to be affected by many factors (Table 2).^7,18,39

Treatments

Proper Skin Care and Treatment of AD
Therapy for AD and/or pruritus appears to limit lesion number in children with MCV and rashes or itch.^7,36 I recommend barrier repair agents, including emollients and syndet bar cleansers, to prevent small breaks in the skin that occur with xerosis and AD and that increase itch and risk of spread. Therapy for AD and molluscum dermatitis is similar and overlapping. There is always a concern about the spread of MCV when using topical calcineurin inhibitors. I, therefore, focus the dermatitis therapeutics on topical corticosteroid–based care.^6,40

Prevention of Spread
Prevention of spread begins with hygiene interventions. Cobathing is common in children with MCV and should be held off when possible. It is important for the child with MCV to avoid sharing bath towels and equipment²³ and having bare skin come in contact with mats in sports. I request that children with MCV wear bathing suits that cover the areas affected.

Reassurance
The most important therapy is reassurance.⁴¹ Many parents/guardians are truly unaware that the MCV infection can last for more than a year and therefore worry over normal disease course. When counseled as to the benign course of illness and given instructions on proper skin care, the parent/guardian of a child with MCV will often opt against therapy of uncomplicated cases. On the other hand, there are medical reasons for treatment, and they support the need for intervention (Table 3). Seventy percent of lesions resolve in 1.5 years; however, of the residual infections, some may last as long as 4 years.¹⁶ It is not recommended to stop children from attending school because of MCV.

Conclusion

Molluscum is a cutaneous viral infection that is common in children and has associated morbidities, including AD, pruritus, poor quality of life in some cases, and risk of contagion. Addressing the disease includes understanding its natural history and explaining it to parents/guardians. Therapeutics can be offered in cases where need is demonstrated, such as with lesions that spread and cause discomfort. Choice of therapeutics depends on the practitioner’s experience, the child’s clinical appearance, availability of therapy, and review of options with the parents/guardians. When avoidance of intervention is desired, barrier enhancement and treatment of symptomatic dermatitis are still beneficial, as are household (eg, not sharing towels) and activity (eg, adhesive bandages over active lesions) interventions to reduce transmission.

Molluscum contagiosum virus (MCV) infection causes the cutaneous lesions we call molluscum. Molluscum has become common in the last 30 years. Deciding the best course of therapy requires some fundamental understanding about how MCV relates to the following factors: epidemiology, childhood immunity and vaccination, clinical features, comorbidities, and quality of life. Treatment depends on many factors, including presence or absence of atopic dermatitis (AD) and/or pruritus, other symptoms, cosmetic location, and the child’s concern about the lesions. Therapeutics include destructive and immunologic therapies, the latter geared toward increasing immune response.

Epidemiology

Molluscum contagiosum virus is the solo member of the Molluscipoxvirus genus. Infection with MCV causes benign growth or tumors in the skin (ie, molluscum). The infection is slow to clear because the virus reduces the host’s immunity.^1,2 Molluscum contagiosum virus is a double-stranded DNA virus that affects keratinocytes and genetically carries the tools for its own replication (ie, DNA-dependent RNA polymerase). The virus has a few subtypes—I/Ia, II, III, and IV—with MCV-I predominating in children and healthy humans and MCV-II in patients with human immunodeficiency virus.^1,2 Typing is experimental and is not standardly performed in clinical practice. Molluscum contagiosum virus produces a variety of factors that block the host’s immune response, prolonging infection and preventing erythema and inflammatory response.³

Molluscum contagiosum virus is transmitted through skin-to-skin contact and fomites, including shared towels, bathtubs, spas, bath sponges, and pool equipment.^2,4,5 Transmission from household contact and bathing together has been noted in pediatric patients with MCV. Based on the data it can be posited that the lesions are softer when wet and more readily release viral particles or fomites, and fomites may be left on surfaces, especially when a child is wet.^6,7 Propensity for infection occurs in patients with AD and in immunosuppressed hosts, including children with human immunodeficiency virus and iatrogenic immunosuppression caused by chemotherapy.^1,2,8 Contact sports can increase the risk of transmission, and outbreaks have occurred in pools,^5,9 day-care facilities,¹⁰ and sports settings.¹¹ Cases of congenital and vertically transmitted molluscum have been documented.^12,13 Sexual transmission of MCV may be seen in adolescents who are sexually active. Although child-to-child transmission can occur in the groin area from shared equipment, transmission via sexual abuse also is possible.¹⁴ Bargman¹⁵ has mentioned the isolated genital location and lack of contact with other infected children as concerning features. Latency of new lesion appearance is anywhere from 1 to 50 days from the date of inoculation; therefore, new lesions are possible and expected even after therapy has been effective in eradicating visible lesions.¹⁰ Although clearance has been reported in 6 to 12 months, one pediatric study demonstrated 70% clearance by 1.5 years, suggesting the disease often is more prolonged.¹⁶ One-third of children will experience signs of inflammation, such as pruritus and/or erythema. Rare side effects include bacterial superinfection and hypersensitivity.²

One Dutch study from 1994, the largest database survey of children to date, cited a 17% cumulative incidence of molluscum in children by reviewing the data from 103 general practices.¹⁷ In a survey and review of molluscum by Braue et al,¹⁸ annual rates in populations vary but seem to maximize at approximately 6% to 7%. Sturt et al¹⁹ reviewed the prevalence in the indigenous West Sepik section of New Guinea and noted annual incidence rates of 6% in children younger than 10 years (range, 1.8%–10.9%). Epidemics occur and can produce large numbers of cases in a short time period.¹⁸ The cumulative prevalence in early childhood may be as high as 22%, as Sturt et al¹⁹ observed in children younger than 10 years.

Rising incidence and therefore rising lifetime prevalence appear to have been an issue in the last few decades. Data from the Indian Health Service have demonstrated increases in MCV in Native American children between 2001 and 2005.²⁰ In adults, the data support a steady increase of molluscum from 1988-2007, with a 3-fold increase from 1988-1997 to 1998-2007 in a Spanish study.²¹ Better population-based data are needed.

Childhood Immunity and Vaccination

Sequence homology between MC133L, a protein of MCV, with vaccinia virus suggests overlapping genes.²² Therefore, it is conceptually possible that the rise in incidence of MCV since the 1980s relates to the loss of herd immunity to variola due to lack of vaccination for smallpox, which has not been offered in the United States since 1972.²³ Childhood immunity to MCV varies among studies, but it appears that children do develop antibodies to molluscum in the setting of forming an immune response. Because the rise in molluscum incidence began after the smallpox vaccine was discontinued, the factors appear related; however, the scientific data do not support the theory of a relationship. Mitchell²⁴ has shown that a patient can develop antibodies in response to ground molluscum bodies inoculated into the skin; however, vaccination against molluscum and natural infection do not appear to produce antibodies that would cross-react and protect against other poxviruses, including vaccinia or fowl pox infections.²⁵ Cell-mediated immunity also is required to clear MCV and may account for the inflammatory appearance of lesions as they resolve.²⁶

Demonstrated factors that account for the rise in MCV incidence, aside from alterations in vaccination practices, include spread through sports,⁹ swimming,¹¹ and AD,⁷ which have become more commonplace in the United States in the last few decades, supporting the theory that they may be the cause of the increase in childhood MCV infections. Another cause may be the ability of MCV to create factors that stem host immune response.¹

Clinical Features

Molluscum lesions have a typical appearance of pearly papules with a central dell. These lesions are lighter to flesh colored and measure 1 to 3 mm.^2,4,5 The lesions cluster in the axillae and extremities and average from 10 to 20 per child.⁶ Lesions clear spontaneously, but new ones will continue to form until immunity is developed. Specific clinical appearances of lesions that are not pearly papules are not infrequent. Table 1 contains a short list of the manifold clinical appearances of molluscum lesions in children.^1,2,7,27-35 In particular, certain clinical appearances should be considered. In small children, head and neck lesions resembling milia are not uncommon. Giant or wartlike lesions can appear on the head, neck, or gluteal region in children and are clinical mimics of condyloma or other warts (Figure 1). Giant lesions also can grow in the subcutaneous space and mimic a cyst or abscess.²⁷ Erosive lesions mimicking eczema vaccinatum can be seen (Figure 2), but dermoscopy may demonstrate central dells in some lesions. Other viral processes mimicked include Gianotti Crosti–like lesions (Figure 3) that appear when a papular id reaction forms over the extremities or a localized version in the axilla, mimicking unilateral laterothoracic exanthema.^2,36,37 Hypersensitivity reactions are commonly noted with clearance and can be papular or demonstrate swelling and erythema, termed the beginning-of-the-end sign.³⁸

Pruritus, erythema, and swelling can occur with clearance but do not appear in all patients. Addressing pruritus is important to prevent disease spread, as patients are likely to inoculate other areas of the skin with virus when they scratch, and lesion number is reduced with dermatitis interventions.³⁶

Comorbidities

Molluscum lesions can occur in any child; however, the impaired immunologic status and skin barrier in patients with AD is ripe for the extensive spread of lesions that is associated with higher lesion count.³⁶ Children with molluscum infection can experience new-onset dermatitis or triggering of AD flares, especially on the extremities, such as the antecubital and popliteal regions.⁷ A study of children with MCV infection demonstrated that treatment of active dermatitis reduced spread. The authors mentioned autoinoculation as the mechanism; however, these data also suggest supporting barrier state as a factor in disease spread.³⁶ Superinfection can occur prior to⁶ or after therapy for lesions,³⁷ but it is unclear if this relates to the underlying atopic diathesis. Children with molluscum have been described to have warts, psoriasis, family history of atopy, diabetes mellitus, and pityriasis alba,⁷ while immunosuppression of any kind is associated with molluscum and high lesion count or prolonged disease in childhood.^1,2

Quality of Life

Children with molluscum who have higher lesion counts appear to be at risk for severe effects on their quality of life. Approximately 10% of children with MCV infection have been documented to have severe impairments on quality of life.³⁹ In my practice, quality of life in children with MCV appears to be affected by many factors (Table 2).^7,18,39

Treatments

Proper Skin Care and Treatment of AD
Therapy for AD and/or pruritus appears to limit lesion number in children with MCV and rashes or itch.^7,36 I recommend barrier repair agents, including emollients and syndet bar cleansers, to prevent small breaks in the skin that occur with xerosis and AD and that increase itch and risk of spread. Therapy for AD and molluscum dermatitis is similar and overlapping. There is always a concern about the spread of MCV when using topical calcineurin inhibitors. I, therefore, focus the dermatitis therapeutics on topical corticosteroid–based care.^6,40

Prevention of Spread
Prevention of spread begins with hygiene interventions. Cobathing is common in children with MCV and should be held off when possible. It is important for the child with MCV to avoid sharing bath towels and equipment²³ and having bare skin come in contact with mats in sports. I request that children with MCV wear bathing suits that cover the areas affected.

Reassurance
The most important therapy is reassurance.⁴¹ Many parents/guardians are truly unaware that the MCV infection can last for more than a year and therefore worry over normal disease course. When counseled as to the benign course of illness and given instructions on proper skin care, the parent/guardian of a child with MCV will often opt against therapy of uncomplicated cases. On the other hand, there are medical reasons for treatment, and they support the need for intervention (Table 3). Seventy percent of lesions resolve in 1.5 years; however, of the residual infections, some may last as long as 4 years.¹⁶ It is not recommended to stop children from attending school because of MCV.

Conclusion

Molluscum is a cutaneous viral infection that is common in children and has associated morbidities, including AD, pruritus, poor quality of life in some cases, and risk of contagion. Addressing the disease includes understanding its natural history and explaining it to parents/guardians. Therapeutics can be offered in cases where need is demonstrated, such as with lesions that spread and cause discomfort. Choice of therapeutics depends on the practitioner’s experience, the child’s clinical appearance, availability of therapy, and review of options with the parents/guardians. When avoidance of intervention is desired, barrier enhancement and treatment of symptomatic dermatitis are still beneficial, as are household (eg, not sharing towels) and activity (eg, adhesive bandages over active lesions) interventions to reduce transmission.

Molluscum contagiosum virus (MCV) infection causes the cutaneous lesions we call molluscum. Molluscum has become common in the last 30 years. Deciding the best course of therapy requires some fundamental understanding about how MCV relates to the following factors: epidemiology, childhood immunity and vaccination, clinical features, comorbidities, and quality of life. Treatment depends on many factors, including presence or absence of atopic dermatitis (AD) and/or pruritus, other symptoms, cosmetic location, and the child’s concern about the lesions. Therapeutics include destructive and immunologic therapies, the latter geared toward increasing immune response.

Epidemiology

Molluscum contagiosum virus is the solo member of the Molluscipoxvirus genus. Infection with MCV causes benign growth or tumors in the skin (ie, molluscum). The infection is slow to clear because the virus reduces the host’s immunity.^1,2 Molluscum contagiosum virus is a double-stranded DNA virus that affects keratinocytes and genetically carries the tools for its own replication (ie, DNA-dependent RNA polymerase). The virus has a few subtypes—I/Ia, II, III, and IV—with MCV-I predominating in children and healthy humans and MCV-II in patients with human immunodeficiency virus.^1,2 Typing is experimental and is not standardly performed in clinical practice. Molluscum contagiosum virus produces a variety of factors that block the host’s immune response, prolonging infection and preventing erythema and inflammatory response.³

Molluscum contagiosum virus is transmitted through skin-to-skin contact and fomites, including shared towels, bathtubs, spas, bath sponges, and pool equipment.^2,4,5 Transmission from household contact and bathing together has been noted in pediatric patients with MCV. Based on the data it can be posited that the lesions are softer when wet and more readily release viral particles or fomites, and fomites may be left on surfaces, especially when a child is wet.^6,7 Propensity for infection occurs in patients with AD and in immunosuppressed hosts, including children with human immunodeficiency virus and iatrogenic immunosuppression caused by chemotherapy.^1,2,8 Contact sports can increase the risk of transmission, and outbreaks have occurred in pools,^5,9 day-care facilities,¹⁰ and sports settings.¹¹ Cases of congenital and vertically transmitted molluscum have been documented.^12,13 Sexual transmission of MCV may be seen in adolescents who are sexually active. Although child-to-child transmission can occur in the groin area from shared equipment, transmission via sexual abuse also is possible.¹⁴ Bargman¹⁵ has mentioned the isolated genital location and lack of contact with other infected children as concerning features. Latency of new lesion appearance is anywhere from 1 to 50 days from the date of inoculation; therefore, new lesions are possible and expected even after therapy has been effective in eradicating visible lesions.¹⁰ Although clearance has been reported in 6 to 12 months, one pediatric study demonstrated 70% clearance by 1.5 years, suggesting the disease often is more prolonged.¹⁶ One-third of children will experience signs of inflammation, such as pruritus and/or erythema. Rare side effects include bacterial superinfection and hypersensitivity.²

One Dutch study from 1994, the largest database survey of children to date, cited a 17% cumulative incidence of molluscum in children by reviewing the data from 103 general practices.¹⁷ In a survey and review of molluscum by Braue et al,¹⁸ annual rates in populations vary but seem to maximize at approximately 6% to 7%. Sturt et al¹⁹ reviewed the prevalence in the indigenous West Sepik section of New Guinea and noted annual incidence rates of 6% in children younger than 10 years (range, 1.8%–10.9%). Epidemics occur and can produce large numbers of cases in a short time period.¹⁸ The cumulative prevalence in early childhood may be as high as 22%, as Sturt et al¹⁹ observed in children younger than 10 years.

Rising incidence and therefore rising lifetime prevalence appear to have been an issue in the last few decades. Data from the Indian Health Service have demonstrated increases in MCV in Native American children between 2001 and 2005.²⁰ In adults, the data support a steady increase of molluscum from 1988-2007, with a 3-fold increase from 1988-1997 to 1998-2007 in a Spanish study.²¹ Better population-based data are needed.

Childhood Immunity and Vaccination

Sequence homology between MC133L, a protein of MCV, with vaccinia virus suggests overlapping genes.²² Therefore, it is conceptually possible that the rise in incidence of MCV since the 1980s relates to the loss of herd immunity to variola due to lack of vaccination for smallpox, which has not been offered in the United States since 1972.²³ Childhood immunity to MCV varies among studies, but it appears that children do develop antibodies to molluscum in the setting of forming an immune response. Because the rise in molluscum incidence began after the smallpox vaccine was discontinued, the factors appear related; however, the scientific data do not support the theory of a relationship. Mitchell²⁴ has shown that a patient can develop antibodies in response to ground molluscum bodies inoculated into the skin; however, vaccination against molluscum and natural infection do not appear to produce antibodies that would cross-react and protect against other poxviruses, including vaccinia or fowl pox infections.²⁵ Cell-mediated immunity also is required to clear MCV and may account for the inflammatory appearance of lesions as they resolve.²⁶

Demonstrated factors that account for the rise in MCV incidence, aside from alterations in vaccination practices, include spread through sports,⁹ swimming,¹¹ and AD,⁷ which have become more commonplace in the United States in the last few decades, supporting the theory that they may be the cause of the increase in childhood MCV infections. Another cause may be the ability of MCV to create factors that stem host immune response.¹

Clinical Features

Molluscum lesions have a typical appearance of pearly papules with a central dell. These lesions are lighter to flesh colored and measure 1 to 3 mm.^2,4,5 The lesions cluster in the axillae and extremities and average from 10 to 20 per child.⁶ Lesions clear spontaneously, but new ones will continue to form until immunity is developed. Specific clinical appearances of lesions that are not pearly papules are not infrequent. Table 1 contains a short list of the manifold clinical appearances of molluscum lesions in children.^1,2,7,27-35 In particular, certain clinical appearances should be considered. In small children, head and neck lesions resembling milia are not uncommon. Giant or wartlike lesions can appear on the head, neck, or gluteal region in children and are clinical mimics of condyloma or other warts (Figure 1). Giant lesions also can grow in the subcutaneous space and mimic a cyst or abscess.²⁷ Erosive lesions mimicking eczema vaccinatum can be seen (Figure 2), but dermoscopy may demonstrate central dells in some lesions. Other viral processes mimicked include Gianotti Crosti–like lesions (Figure 3) that appear when a papular id reaction forms over the extremities or a localized version in the axilla, mimicking unilateral laterothoracic exanthema.^2,36,37 Hypersensitivity reactions are commonly noted with clearance and can be papular or demonstrate swelling and erythema, termed the beginning-of-the-end sign.³⁸

Pruritus, erythema, and swelling can occur with clearance but do not appear in all patients. Addressing pruritus is important to prevent disease spread, as patients are likely to inoculate other areas of the skin with virus when they scratch, and lesion number is reduced with dermatitis interventions.³⁶

Comorbidities

Molluscum lesions can occur in any child; however, the impaired immunologic status and skin barrier in patients with AD is ripe for the extensive spread of lesions that is associated with higher lesion count.³⁶ Children with molluscum infection can experience new-onset dermatitis or triggering of AD flares, especially on the extremities, such as the antecubital and popliteal regions.⁷ A study of children with MCV infection demonstrated that treatment of active dermatitis reduced spread. The authors mentioned autoinoculation as the mechanism; however, these data also suggest supporting barrier state as a factor in disease spread.³⁶ Superinfection can occur prior to⁶ or after therapy for lesions,³⁷ but it is unclear if this relates to the underlying atopic diathesis. Children with molluscum have been described to have warts, psoriasis, family history of atopy, diabetes mellitus, and pityriasis alba,⁷ while immunosuppression of any kind is associated with molluscum and high lesion count or prolonged disease in childhood.^1,2

Quality of Life

Children with molluscum who have higher lesion counts appear to be at risk for severe effects on their quality of life. Approximately 10% of children with MCV infection have been documented to have severe impairments on quality of life.³⁹ In my practice, quality of life in children with MCV appears to be affected by many factors (Table 2).^7,18,39

Treatments

Proper Skin Care and Treatment of AD
Therapy for AD and/or pruritus appears to limit lesion number in children with MCV and rashes or itch.^7,36 I recommend barrier repair agents, including emollients and syndet bar cleansers, to prevent small breaks in the skin that occur with xerosis and AD and that increase itch and risk of spread. Therapy for AD and molluscum dermatitis is similar and overlapping. There is always a concern about the spread of MCV when using topical calcineurin inhibitors. I, therefore, focus the dermatitis therapeutics on topical corticosteroid–based care.^6,40

Prevention of Spread
Prevention of spread begins with hygiene interventions. Cobathing is common in children with MCV and should be held off when possible. It is important for the child with MCV to avoid sharing bath towels and equipment²³ and having bare skin come in contact with mats in sports. I request that children with MCV wear bathing suits that cover the areas affected.

Reassurance
The most important therapy is reassurance.⁴¹ Many parents/guardians are truly unaware that the MCV infection can last for more than a year and therefore worry over normal disease course. When counseled as to the benign course of illness and given instructions on proper skin care, the parent/guardian of a child with MCV will often opt against therapy of uncomplicated cases. On the other hand, there are medical reasons for treatment, and they support the need for intervention (Table 3). Seventy percent of lesions resolve in 1.5 years; however, of the residual infections, some may last as long as 4 years.¹⁶ It is not recommended to stop children from attending school because of MCV.

Conclusion

Molluscum is a cutaneous viral infection that is common in children and has associated morbidities, including AD, pruritus, poor quality of life in some cases, and risk of contagion. Addressing the disease includes understanding its natural history and explaining it to parents/guardians. Therapeutics can be offered in cases where need is demonstrated, such as with lesions that spread and cause discomfort. Choice of therapeutics depends on the practitioner’s experience, the child’s clinical appearance, availability of therapy, and review of options with the parents/guardians. When avoidance of intervention is desired, barrier enhancement and treatment of symptomatic dermatitis are still beneficial, as are household (eg, not sharing towels) and activity (eg, adhesive bandages over active lesions) interventions to reduce transmission.

Treating Clostridioides difficile infection with fecal microbiota transplantation is associated with a lower risk of bloodstream infection and recurrence than treatment with antibiotics, new research has found.

A paper published in Annals of Internal Medicine presents outcomes of a prospective cohort study in 290 inpatients with recurrent C. difficile infection, 109 of whom were treated with fecal microbiota transplantation (FMT); the remainder were treated with antibiotics including metronidazole, vancomycin, and fidaxomicin.

While the FMT group had a higher mean number of previous C. difficile infections than the antibiotics group (2.82 vs. 1.23, respectively), a sustained cure was achieved in 97% of the FMT group, compared with 38% in the antibiotics group.

Blood cultures were done if patients developed a temperature above 30° C or showed symptoms that might be attributable to sepsis. Bloodstream infections were diagnosed in 5% (5 patients) of those treated with FMT, and 22% (40 patients) in the antibiotics group.

The patients in the FMT group with bloodstream infections all had bacterial infections – one of which was polymicrobial – and there were no cases of fungal bloodstream infections. In the antibiotics group, 28 patients (15%) had bacterial bloodstream infections – 11 of which were polymicrobial – and 12 (7%) had fungal bloodstream infections.

Bloodstream infections were particularly evident among the 11 patients whose C. difficile infection was treated with fidaxomicin, 4 of whom developed a bloodstream infection.

Overall, 27% of patients died during the 90-day follow-up, with 7% dying because of bloodstream infections, all of whom were in the antibiotic-treated cohort. Three patients in the FMT group died because of overwhelming C. difficile infection, compared with 12 in the antibiotic cohort.

Nearly three-quarters of deaths occurred within 30 days of the end of treatment; 5 of these deaths were in the FMT group, and 53 were in the antibiotics group.

“These findings suggest that the longer 90-day [overall survival] of patients in the FMT group is attributable to cure of [C. difficile infection] leading to an improvement in clinical condition,” wrote Gianluca Ianiro, MD, from the Catholic University of the Sacred Heart in Rome, and coauthors.

The 90-day overall survival rate was 92% in the FMT group and 61% in the antibiotic group. Patients treated with FMT also showed significantly shorter mean duration of hospital stay at 13.3 days, compared with 29.7 days in patients treated with antibiotics.

The authors noted the results should be interpreted with caution because of baseline differences between the two groups that were not entirely accounted for by using propensity matching. However, even in the propensity-matched cohort of 57 patients from each group, there was still a significantly higher overall survival at 90 days among patients treated with FMT.

One author declared grants from the pharmaceutical sector outside the submitted work. No funding or other conflicts of interest were reported.

SOURCE: Ianiro G et al. Ann Intern Med. 2019 Nov 4. doi: 10.7326/M18-3635.

Treating Clostridioides difficile infection with fecal microbiota transplantation is associated with a lower risk of bloodstream infection and recurrence than treatment with antibiotics, new research has found.

A paper published in Annals of Internal Medicine presents outcomes of a prospective cohort study in 290 inpatients with recurrent C. difficile infection, 109 of whom were treated with fecal microbiota transplantation (FMT); the remainder were treated with antibiotics including metronidazole, vancomycin, and fidaxomicin.

While the FMT group had a higher mean number of previous C. difficile infections than the antibiotics group (2.82 vs. 1.23, respectively), a sustained cure was achieved in 97% of the FMT group, compared with 38% in the antibiotics group.

Blood cultures were done if patients developed a temperature above 30° C or showed symptoms that might be attributable to sepsis. Bloodstream infections were diagnosed in 5% (5 patients) of those treated with FMT, and 22% (40 patients) in the antibiotics group.

The patients in the FMT group with bloodstream infections all had bacterial infections – one of which was polymicrobial – and there were no cases of fungal bloodstream infections. In the antibiotics group, 28 patients (15%) had bacterial bloodstream infections – 11 of which were polymicrobial – and 12 (7%) had fungal bloodstream infections.

Bloodstream infections were particularly evident among the 11 patients whose C. difficile infection was treated with fidaxomicin, 4 of whom developed a bloodstream infection.

Overall, 27% of patients died during the 90-day follow-up, with 7% dying because of bloodstream infections, all of whom were in the antibiotic-treated cohort. Three patients in the FMT group died because of overwhelming C. difficile infection, compared with 12 in the antibiotic cohort.

Nearly three-quarters of deaths occurred within 30 days of the end of treatment; 5 of these deaths were in the FMT group, and 53 were in the antibiotics group.

“These findings suggest that the longer 90-day [overall survival] of patients in the FMT group is attributable to cure of [C. difficile infection] leading to an improvement in clinical condition,” wrote Gianluca Ianiro, MD, from the Catholic University of the Sacred Heart in Rome, and coauthors.

The 90-day overall survival rate was 92% in the FMT group and 61% in the antibiotic group. Patients treated with FMT also showed significantly shorter mean duration of hospital stay at 13.3 days, compared with 29.7 days in patients treated with antibiotics.

The authors noted the results should be interpreted with caution because of baseline differences between the two groups that were not entirely accounted for by using propensity matching. However, even in the propensity-matched cohort of 57 patients from each group, there was still a significantly higher overall survival at 90 days among patients treated with FMT.

One author declared grants from the pharmaceutical sector outside the submitted work. No funding or other conflicts of interest were reported.

SOURCE: Ianiro G et al. Ann Intern Med. 2019 Nov 4. doi: 10.7326/M18-3635.

Treating Clostridioides difficile infection with fecal microbiota transplantation is associated with a lower risk of bloodstream infection and recurrence than treatment with antibiotics, new research has found.

A paper published in Annals of Internal Medicine presents outcomes of a prospective cohort study in 290 inpatients with recurrent C. difficile infection, 109 of whom were treated with fecal microbiota transplantation (FMT); the remainder were treated with antibiotics including metronidazole, vancomycin, and fidaxomicin.

While the FMT group had a higher mean number of previous C. difficile infections than the antibiotics group (2.82 vs. 1.23, respectively), a sustained cure was achieved in 97% of the FMT group, compared with 38% in the antibiotics group.

Blood cultures were done if patients developed a temperature above 30° C or showed symptoms that might be attributable to sepsis. Bloodstream infections were diagnosed in 5% (5 patients) of those treated with FMT, and 22% (40 patients) in the antibiotics group.

The patients in the FMT group with bloodstream infections all had bacterial infections – one of which was polymicrobial – and there were no cases of fungal bloodstream infections. In the antibiotics group, 28 patients (15%) had bacterial bloodstream infections – 11 of which were polymicrobial – and 12 (7%) had fungal bloodstream infections.

Bloodstream infections were particularly evident among the 11 patients whose C. difficile infection was treated with fidaxomicin, 4 of whom developed a bloodstream infection.

Overall, 27% of patients died during the 90-day follow-up, with 7% dying because of bloodstream infections, all of whom were in the antibiotic-treated cohort. Three patients in the FMT group died because of overwhelming C. difficile infection, compared with 12 in the antibiotic cohort.

Nearly three-quarters of deaths occurred within 30 days of the end of treatment; 5 of these deaths were in the FMT group, and 53 were in the antibiotics group.

“These findings suggest that the longer 90-day [overall survival] of patients in the FMT group is attributable to cure of [C. difficile infection] leading to an improvement in clinical condition,” wrote Gianluca Ianiro, MD, from the Catholic University of the Sacred Heart in Rome, and coauthors.

The 90-day overall survival rate was 92% in the FMT group and 61% in the antibiotic group. Patients treated with FMT also showed significantly shorter mean duration of hospital stay at 13.3 days, compared with 29.7 days in patients treated with antibiotics.

The authors noted the results should be interpreted with caution because of baseline differences between the two groups that were not entirely accounted for by using propensity matching. However, even in the propensity-matched cohort of 57 patients from each group, there was still a significantly higher overall survival at 90 days among patients treated with FMT.

One author declared grants from the pharmaceutical sector outside the submitted work. No funding or other conflicts of interest were reported.

SOURCE: Ianiro G et al. Ann Intern Med. 2019 Nov 4. doi: 10.7326/M18-3635.

Background: Despite the rise in utilization of PICC lines, few studies have addressed complications experienced by patients following PICC placement, especially subsequent to discharge from the inpatient setting.

Dr. Cooke is a hospitalist at Beth Israel Deaconess Medical Center.

Background: Despite the rise in utilization of PICC lines, few studies have addressed complications experienced by patients following PICC placement, especially subsequent to discharge from the inpatient setting.

Dr. Cooke is a hospitalist at Beth Israel Deaconess Medical Center.

Background: Despite the rise in utilization of PICC lines, few studies have addressed complications experienced by patients following PICC placement, especially subsequent to discharge from the inpatient setting.

Dr. Cooke is a hospitalist at Beth Israel Deaconess Medical Center.

A new study has uncovered how the measles virus (MeV) can induce immunosuppression by delaying the reconstitution of B cells.

CDC/ Cynthia S. Goldsmith; William Bellini, Ph.D.

“Our findings provide a biological explanation for the observed increase in childhood mortality and secondary infections several years after an episode of measles,” said Velislava N. Petrova, PhD, of the Wellcome Sanger Institute in Cambridge, England, and coauthors. The study was published in Science Immunology.

To determine if B-cell impairment can lead to measles-associated immunosuppression, the researchers investigated genetic changes in 26 unvaccinated children from the Netherlands who previously had measles. Their antibody genes were sequenced before any symptoms of measles developed and roughly 40 days after rash. Two control groups also were sequenced accordingly: vaccinated adults and three unvaccinated children from the same community who were not infected with measles.

Naive B cells from individuals in the vaccinated and uninfected control groups showed high correlation of immunoglobulin heavy chain (IGHV-J) gene frequencies across time periods (R² = 0.96 and 0.92, respectively) but no significant differences in gene expression (P greater than .05). At the same time, although B cell frequencies in measles patients recovered to levels before infection, they had significant changes in IGHV-J gene frequencies (P = .01) and decreased correlation in gene expression (R² = 0.78).

In addition, individuals in the control groups had “a stable genetic composition of B memory cells” but no significant changes in the third complementarity-determining region (CDR3) lengths or mutational frequency of IGHV genes (P greater than .05). B memory cells in measles patients, however, showed increases in mutational frequency (P = .0008) and a reduction in CDR3 length (P = .017) of IGHV genes, Dr. Petrova and associates said.

Finally, the researchers confirmed a hypothesis about the depletion of B memory cell clones during measles and a repopulation of new cells with less clonal expansion. The frequency of individual IGHV-J gene combinations before infection was correlated with a reduction after infection, “with the most frequent combinations undergoing the most marked depletion” and the result being an increase in genetic diversity.

To further test their findings, the researchers vaccinated two groups of four ferrets with live-attenuated influenza vaccine (LAIV) and at 4 weeks infected one of the groups with canine distemper virus (CDV), a surrogate for MeV. At 14 weeks after vaccination, the uninfected group maintained high levels of influenza-specific neutralizing antibodies while the infected group saw impaired B cells and a subsequent reduction in neutralizing antibodies.
 

Understanding the impact of measles on the immune system

“How measles infection has such a long-lasting deleterious effect on the immune system while allowing robust immunity against itself has been a burning immunological question,” Duane R. Wesemann, MD, PhD, of Brigham and Women’s Hospital in Boston, said in an accompanying editorial. The research from Petrova et al. begins to answer that question.

Among the observations he found most interesting was how “post-measles memory cells were more diverse than the pre-measles memory pool,” despite expectations that measles immunity would be dominant. He speculated that the void in memory cells is filled by a set of clones binding to unidentified or nonnative antigens, which may bring polyclonal diversity into B memory cells.

More research is needed to determine just what these findings mean, including looking beyond memory cell depletion and focusing on the impact of immature immunoglobulin repertoires in naive cells. But his broad takeaway is that measles remains both a public health concern and an opportunity to understand how the human body counters disease.

“The unique relationship measles has with the human immune system,” he said, “can illuminate aspects of its inner workings.”

The study was funded by grants to the investigators the Indonesian Endowment Fund for Education, the Wellcome Trust, the German Centre for Infection Research, the Collaborative Research Centre of the German Research Foundation, the German Ministry of Health, and the Royal Society. The authors declared no conflicts of interest. Dr. Wesemann reported receiving support from National Institutes of Health grants and an award from the Burroughs Wellcome Fund; he also reports being a consultant for OpenBiome.

SOURCE: Petrova VN et al. Sci Immunol. 2019 Nov 1. doi: 10.1126/sciimmunol.aay6125; Wesemann DR. Sci Immunol. 2019 Nov 1. doi: 10.1126/sciimmunol.aaz4195.

A new study has uncovered how the measles virus (MeV) can induce immunosuppression by delaying the reconstitution of B cells.

CDC/ Cynthia S. Goldsmith; William Bellini, Ph.D.

“Our findings provide a biological explanation for the observed increase in childhood mortality and secondary infections several years after an episode of measles,” said Velislava N. Petrova, PhD, of the Wellcome Sanger Institute in Cambridge, England, and coauthors. The study was published in Science Immunology.

To determine if B-cell impairment can lead to measles-associated immunosuppression, the researchers investigated genetic changes in 26 unvaccinated children from the Netherlands who previously had measles. Their antibody genes were sequenced before any symptoms of measles developed and roughly 40 days after rash. Two control groups also were sequenced accordingly: vaccinated adults and three unvaccinated children from the same community who were not infected with measles.

Naive B cells from individuals in the vaccinated and uninfected control groups showed high correlation of immunoglobulin heavy chain (IGHV-J) gene frequencies across time periods (R² = 0.96 and 0.92, respectively) but no significant differences in gene expression (P greater than .05). At the same time, although B cell frequencies in measles patients recovered to levels before infection, they had significant changes in IGHV-J gene frequencies (P = .01) and decreased correlation in gene expression (R² = 0.78).

In addition, individuals in the control groups had “a stable genetic composition of B memory cells” but no significant changes in the third complementarity-determining region (CDR3) lengths or mutational frequency of IGHV genes (P greater than .05). B memory cells in measles patients, however, showed increases in mutational frequency (P = .0008) and a reduction in CDR3 length (P = .017) of IGHV genes, Dr. Petrova and associates said.

Finally, the researchers confirmed a hypothesis about the depletion of B memory cell clones during measles and a repopulation of new cells with less clonal expansion. The frequency of individual IGHV-J gene combinations before infection was correlated with a reduction after infection, “with the most frequent combinations undergoing the most marked depletion” and the result being an increase in genetic diversity.

To further test their findings, the researchers vaccinated two groups of four ferrets with live-attenuated influenza vaccine (LAIV) and at 4 weeks infected one of the groups with canine distemper virus (CDV), a surrogate for MeV. At 14 weeks after vaccination, the uninfected group maintained high levels of influenza-specific neutralizing antibodies while the infected group saw impaired B cells and a subsequent reduction in neutralizing antibodies.
 

Understanding the impact of measles on the immune system

“How measles infection has such a long-lasting deleterious effect on the immune system while allowing robust immunity against itself has been a burning immunological question,” Duane R. Wesemann, MD, PhD, of Brigham and Women’s Hospital in Boston, said in an accompanying editorial. The research from Petrova et al. begins to answer that question.

Among the observations he found most interesting was how “post-measles memory cells were more diverse than the pre-measles memory pool,” despite expectations that measles immunity would be dominant. He speculated that the void in memory cells is filled by a set of clones binding to unidentified or nonnative antigens, which may bring polyclonal diversity into B memory cells.

More research is needed to determine just what these findings mean, including looking beyond memory cell depletion and focusing on the impact of immature immunoglobulin repertoires in naive cells. But his broad takeaway is that measles remains both a public health concern and an opportunity to understand how the human body counters disease.

“The unique relationship measles has with the human immune system,” he said, “can illuminate aspects of its inner workings.”

The study was funded by grants to the investigators the Indonesian Endowment Fund for Education, the Wellcome Trust, the German Centre for Infection Research, the Collaborative Research Centre of the German Research Foundation, the German Ministry of Health, and the Royal Society. The authors declared no conflicts of interest. Dr. Wesemann reported receiving support from National Institutes of Health grants and an award from the Burroughs Wellcome Fund; he also reports being a consultant for OpenBiome.

SOURCE: Petrova VN et al. Sci Immunol. 2019 Nov 1. doi: 10.1126/sciimmunol.aay6125; Wesemann DR. Sci Immunol. 2019 Nov 1. doi: 10.1126/sciimmunol.aaz4195.

A new study has uncovered how the measles virus (MeV) can induce immunosuppression by delaying the reconstitution of B cells.

CDC/ Cynthia S. Goldsmith; William Bellini, Ph.D.

“Our findings provide a biological explanation for the observed increase in childhood mortality and secondary infections several years after an episode of measles,” said Velislava N. Petrova, PhD, of the Wellcome Sanger Institute in Cambridge, England, and coauthors. The study was published in Science Immunology.

To determine if B-cell impairment can lead to measles-associated immunosuppression, the researchers investigated genetic changes in 26 unvaccinated children from the Netherlands who previously had measles. Their antibody genes were sequenced before any symptoms of measles developed and roughly 40 days after rash. Two control groups also were sequenced accordingly: vaccinated adults and three unvaccinated children from the same community who were not infected with measles.

Naive B cells from individuals in the vaccinated and uninfected control groups showed high correlation of immunoglobulin heavy chain (IGHV-J) gene frequencies across time periods (R² = 0.96 and 0.92, respectively) but no significant differences in gene expression (P greater than .05). At the same time, although B cell frequencies in measles patients recovered to levels before infection, they had significant changes in IGHV-J gene frequencies (P = .01) and decreased correlation in gene expression (R² = 0.78).

In addition, individuals in the control groups had “a stable genetic composition of B memory cells” but no significant changes in the third complementarity-determining region (CDR3) lengths or mutational frequency of IGHV genes (P greater than .05). B memory cells in measles patients, however, showed increases in mutational frequency (P = .0008) and a reduction in CDR3 length (P = .017) of IGHV genes, Dr. Petrova and associates said.

Finally, the researchers confirmed a hypothesis about the depletion of B memory cell clones during measles and a repopulation of new cells with less clonal expansion. The frequency of individual IGHV-J gene combinations before infection was correlated with a reduction after infection, “with the most frequent combinations undergoing the most marked depletion” and the result being an increase in genetic diversity.

To further test their findings, the researchers vaccinated two groups of four ferrets with live-attenuated influenza vaccine (LAIV) and at 4 weeks infected one of the groups with canine distemper virus (CDV), a surrogate for MeV. At 14 weeks after vaccination, the uninfected group maintained high levels of influenza-specific neutralizing antibodies while the infected group saw impaired B cells and a subsequent reduction in neutralizing antibodies.
 

Understanding the impact of measles on the immune system

“How measles infection has such a long-lasting deleterious effect on the immune system while allowing robust immunity against itself has been a burning immunological question,” Duane R. Wesemann, MD, PhD, of Brigham and Women’s Hospital in Boston, said in an accompanying editorial. The research from Petrova et al. begins to answer that question.

Among the observations he found most interesting was how “post-measles memory cells were more diverse than the pre-measles memory pool,” despite expectations that measles immunity would be dominant. He speculated that the void in memory cells is filled by a set of clones binding to unidentified or nonnative antigens, which may bring polyclonal diversity into B memory cells.

More research is needed to determine just what these findings mean, including looking beyond memory cell depletion and focusing on the impact of immature immunoglobulin repertoires in naive cells. But his broad takeaway is that measles remains both a public health concern and an opportunity to understand how the human body counters disease.

“The unique relationship measles has with the human immune system,” he said, “can illuminate aspects of its inner workings.”

The study was funded by grants to the investigators the Indonesian Endowment Fund for Education, the Wellcome Trust, the German Centre for Infection Research, the Collaborative Research Centre of the German Research Foundation, the German Ministry of Health, and the Royal Society. The authors declared no conflicts of interest. Dr. Wesemann reported receiving support from National Institutes of Health grants and an award from the Burroughs Wellcome Fund; he also reports being a consultant for OpenBiome.

SOURCE: Petrova VN et al. Sci Immunol. 2019 Nov 1. doi: 10.1126/sciimmunol.aay6125; Wesemann DR. Sci Immunol. 2019 Nov 1. doi: 10.1126/sciimmunol.aaz4195.

Religious exemptions for vaccination in kindergartners are lower in states with personal belief exemptions, and they appear to go up when personal belief exemptions go away, which might be caused by a replacement effect, researchers hypothesized in Pediatrics.

SDI Productions/Getty Images

“Put differently, state-level religious exemption rates appear to be a function of personal belief exemption availability, decreasing significantly when states offer a personal belief exemption alternative,” the researchers explained.

Led by Joshua T.B. Williams, MD, of the department of pediatrics at the Denver Health Medical Center, the researchers sought to update state-level analyses of vaccination exemption rates by performing a cross-sectional, retrospective investigation of publicly available aggregated yearly vaccine reports for kindergartners from the Centers for Disease Control and Prevention. They were specifically interested in the school years of 2011-2012 through 2017-2018 “to extend and provide meaningful comparisons to a previous study of exemption data” that had ended its study period in 2015-2016 (Open Forum Infect Dis. 2017 Nov 15. doi: 10.1093/ofid/ofx244). The researchers adjusted for heterogeneous exemption processes by coding for “difficulty” of obtaining such exemptions in accordance with that previous study’s methods because studies have suggested that nonmedical exemption rates are lower in states with more difficult exemption policies. They also looked at how rates of religious exemptions changed in Vermont after the state eliminated personal, or philosophical, exemptions in 2016. The final analysis included 295 state-years from among the 45 states and the District of Columbia that all allow religious exemptions and the 15 states that permit personal belief exemptions.

The unadjusted analysis showed that the mean proportion of kindergartners with religious exemptions was lower where personal belief exemptions were available (0.41%; 95% confidence interval, 0.28%-0.53%) than they were where only religious exemptions were an option (1.63%; 95% CI, 1.30%-1.97%). In the adjusted analysis, states with both religious and personal belief exemptions were only a quarter as likely to have kindergartners with religious exemptions than those without personal belief exemptions (adjusted risk ratio, 0.25; 95% CI, 0.16-0.38). Furthermore, the proportion of kindergartners in Vermont with religious exemptions went from 0.5% in the years 2011-2012 through 2015-2016 when personal belief exemptions were still an option, to 3.7% in 2016-2017 through 2017-2018, after they went away.

One of the study’s limitations is that not all states used the same methods of data collection; however, the authors felt that, given about three-quarters of states included performed censuses with at least 80% of children counted, the effects on the study’s results should be minimal.

After discussing the role of religious exemptions and some of their history, as well as citing the seemingly paradoxical reported decline in religiosity and rise in religious exemptions, the researchers wrote in their conclusion that these “may be an increasingly problematic or outdated exemption category, and researchers and policy makers must work together to determine how best to balance a respect for religious liberty and the need to protect public health.”

[email protected]

SOURCE: Williams JTB et al. Pediatrics. 2019 Nov. doi: 10.1542/peds.2019-2710.

Religious exemptions for vaccination in kindergartners are lower in states with personal belief exemptions, and they appear to go up when personal belief exemptions go away, which might be caused by a replacement effect, researchers hypothesized in Pediatrics.

SDI Productions/Getty Images

“Put differently, state-level religious exemption rates appear to be a function of personal belief exemption availability, decreasing significantly when states offer a personal belief exemption alternative,” the researchers explained.

Led by Joshua T.B. Williams, MD, of the department of pediatrics at the Denver Health Medical Center, the researchers sought to update state-level analyses of vaccination exemption rates by performing a cross-sectional, retrospective investigation of publicly available aggregated yearly vaccine reports for kindergartners from the Centers for Disease Control and Prevention. They were specifically interested in the school years of 2011-2012 through 2017-2018 “to extend and provide meaningful comparisons to a previous study of exemption data” that had ended its study period in 2015-2016 (Open Forum Infect Dis. 2017 Nov 15. doi: 10.1093/ofid/ofx244). The researchers adjusted for heterogeneous exemption processes by coding for “difficulty” of obtaining such exemptions in accordance with that previous study’s methods because studies have suggested that nonmedical exemption rates are lower in states with more difficult exemption policies. They also looked at how rates of religious exemptions changed in Vermont after the state eliminated personal, or philosophical, exemptions in 2016. The final analysis included 295 state-years from among the 45 states and the District of Columbia that all allow religious exemptions and the 15 states that permit personal belief exemptions.

The unadjusted analysis showed that the mean proportion of kindergartners with religious exemptions was lower where personal belief exemptions were available (0.41%; 95% confidence interval, 0.28%-0.53%) than they were where only religious exemptions were an option (1.63%; 95% CI, 1.30%-1.97%). In the adjusted analysis, states with both religious and personal belief exemptions were only a quarter as likely to have kindergartners with religious exemptions than those without personal belief exemptions (adjusted risk ratio, 0.25; 95% CI, 0.16-0.38). Furthermore, the proportion of kindergartners in Vermont with religious exemptions went from 0.5% in the years 2011-2012 through 2015-2016 when personal belief exemptions were still an option, to 3.7% in 2016-2017 through 2017-2018, after they went away.

One of the study’s limitations is that not all states used the same methods of data collection; however, the authors felt that, given about three-quarters of states included performed censuses with at least 80% of children counted, the effects on the study’s results should be minimal.

After discussing the role of religious exemptions and some of their history, as well as citing the seemingly paradoxical reported decline in religiosity and rise in religious exemptions, the researchers wrote in their conclusion that these “may be an increasingly problematic or outdated exemption category, and researchers and policy makers must work together to determine how best to balance a respect for religious liberty and the need to protect public health.”

[email protected]

SOURCE: Williams JTB et al. Pediatrics. 2019 Nov. doi: 10.1542/peds.2019-2710.

Religious exemptions for vaccination in kindergartners are lower in states with personal belief exemptions, and they appear to go up when personal belief exemptions go away, which might be caused by a replacement effect, researchers hypothesized in Pediatrics.

SDI Productions/Getty Images

“Put differently, state-level religious exemption rates appear to be a function of personal belief exemption availability, decreasing significantly when states offer a personal belief exemption alternative,” the researchers explained.

Led by Joshua T.B. Williams, MD, of the department of pediatrics at the Denver Health Medical Center, the researchers sought to update state-level analyses of vaccination exemption rates by performing a cross-sectional, retrospective investigation of publicly available aggregated yearly vaccine reports for kindergartners from the Centers for Disease Control and Prevention. They were specifically interested in the school years of 2011-2012 through 2017-2018 “to extend and provide meaningful comparisons to a previous study of exemption data” that had ended its study period in 2015-2016 (Open Forum Infect Dis. 2017 Nov 15. doi: 10.1093/ofid/ofx244). The researchers adjusted for heterogeneous exemption processes by coding for “difficulty” of obtaining such exemptions in accordance with that previous study’s methods because studies have suggested that nonmedical exemption rates are lower in states with more difficult exemption policies. They also looked at how rates of religious exemptions changed in Vermont after the state eliminated personal, or philosophical, exemptions in 2016. The final analysis included 295 state-years from among the 45 states and the District of Columbia that all allow religious exemptions and the 15 states that permit personal belief exemptions.

The unadjusted analysis showed that the mean proportion of kindergartners with religious exemptions was lower where personal belief exemptions were available (0.41%; 95% confidence interval, 0.28%-0.53%) than they were where only religious exemptions were an option (1.63%; 95% CI, 1.30%-1.97%). In the adjusted analysis, states with both religious and personal belief exemptions were only a quarter as likely to have kindergartners with religious exemptions than those without personal belief exemptions (adjusted risk ratio, 0.25; 95% CI, 0.16-0.38). Furthermore, the proportion of kindergartners in Vermont with religious exemptions went from 0.5% in the years 2011-2012 through 2015-2016 when personal belief exemptions were still an option, to 3.7% in 2016-2017 through 2017-2018, after they went away.

One of the study’s limitations is that not all states used the same methods of data collection; however, the authors felt that, given about three-quarters of states included performed censuses with at least 80% of children counted, the effects on the study’s results should be minimal.

After discussing the role of religious exemptions and some of their history, as well as citing the seemingly paradoxical reported decline in religiosity and rise in religious exemptions, the researchers wrote in their conclusion that these “may be an increasingly problematic or outdated exemption category, and researchers and policy makers must work together to determine how best to balance a respect for religious liberty and the need to protect public health.”

[email protected]

SOURCE: Williams JTB et al. Pediatrics. 2019 Nov. doi: 10.1542/peds.2019-2710.