Rare Diseases

Reduced levels of the cholinergic-system enzyme butyrylcholinesterase (BChE) may provide another piece of the puzzle for sudden infant death syndrome (SIDS), preliminary data from Australian researchers suggested.

A small case-control study led by Carmel T. Harrington, PhD,* a sleep medicine expert and honorary research fellow at the Children’s Hospital at Westmead (Australia), found that measurements in 722 dried blood spots taken during neonatal screening 2 or 3 days after birth were lower in babies who subsequently died of SIDS, compared with those of matched surviving controls and other babies who died of non-SIDS causes.

* This story was corrected on 5/20/2022.

Reduced levels of the cholinergic-system enzyme butyrylcholinesterase (BChE) may provide another piece of the puzzle for sudden infant death syndrome (SIDS), preliminary data from Australian researchers suggested.

A small case-control study led by Carmel T. Harrington, PhD,* a sleep medicine expert and honorary research fellow at the Children’s Hospital at Westmead (Australia), found that measurements in 722 dried blood spots taken during neonatal screening 2 or 3 days after birth were lower in babies who subsequently died of SIDS, compared with those of matched surviving controls and other babies who died of non-SIDS causes.

* This story was corrected on 5/20/2022.

Reduced levels of the cholinergic-system enzyme butyrylcholinesterase (BChE) may provide another piece of the puzzle for sudden infant death syndrome (SIDS), preliminary data from Australian researchers suggested.

A small case-control study led by Carmel T. Harrington, PhD,* a sleep medicine expert and honorary research fellow at the Children’s Hospital at Westmead (Australia), found that measurements in 722 dried blood spots taken during neonatal screening 2 or 3 days after birth were lower in babies who subsequently died of SIDS, compared with those of matched surviving controls and other babies who died of non-SIDS causes.

* This story was corrected on 5/20/2022.

The Food and Drug Administration has approved an orally administered version of edaravone (Radicava ORS, Mitsubishi Tanabe Pharma America) for adults with amyotrophic lateral sclerosis (ALS). Edaravone is a pyrazolone free-radical scavenger thought to lessen the effects of oxidative stress, which is a probable factor in ALS onset and progression. The drug was first approved in 2017 as an intravenous (IV) infusion to treat ALS.

Radicava ORS is self-administered and can be taken at home. After fasting overnight, Radicava ORS should be taken in the morning orally or through a feeding tube. The oral version has the same dosing regimen as the original IV version, with an initial treatment cycle of daily dosing for 14 days, followed by a 14-day drug-free period and subsequent treatment cycles consisting of daily dosing for 10 out of 14-day periods, followed by 14-day drug-free periods.

Compared with the IV formation of Radicava, Radicava ORS has been shown to generate comparable levels of active drug in the bloodstream, the FDA said.

The FDA determined that IV Radicava was effective based on a 6-month clinical trial in Japan involving 137 individuals who were randomly chosen to receive either the drug or a placebo. At 24 weeks, individuals receiving Radicava showed less decline on a clinical assessment of daily functioning, compared with those receiving placebo.

The most common side effects of Radicava are bruising, problems walking, and headache. Fatigue is also a possible side effect from Radicava ORS. Both formulations can have serious side effects associated with allergic reactions, including hives, rash, and shortness of breath.

Full prescribing information, including additional information on risks associated with Radicava ORS, is available online.

The FDA granted Radicava ORS orphan drug status, priority review, and Fast Track designations.

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

The Food and Drug Administration has approved an orally administered version of edaravone (Radicava ORS, Mitsubishi Tanabe Pharma America) for adults with amyotrophic lateral sclerosis (ALS). Edaravone is a pyrazolone free-radical scavenger thought to lessen the effects of oxidative stress, which is a probable factor in ALS onset and progression. The drug was first approved in 2017 as an intravenous (IV) infusion to treat ALS.

Radicava ORS is self-administered and can be taken at home. After fasting overnight, Radicava ORS should be taken in the morning orally or through a feeding tube. The oral version has the same dosing regimen as the original IV version, with an initial treatment cycle of daily dosing for 14 days, followed by a 14-day drug-free period and subsequent treatment cycles consisting of daily dosing for 10 out of 14-day periods, followed by 14-day drug-free periods.

Compared with the IV formation of Radicava, Radicava ORS has been shown to generate comparable levels of active drug in the bloodstream, the FDA said.

The FDA determined that IV Radicava was effective based on a 6-month clinical trial in Japan involving 137 individuals who were randomly chosen to receive either the drug or a placebo. At 24 weeks, individuals receiving Radicava showed less decline on a clinical assessment of daily functioning, compared with those receiving placebo.

The most common side effects of Radicava are bruising, problems walking, and headache. Fatigue is also a possible side effect from Radicava ORS. Both formulations can have serious side effects associated with allergic reactions, including hives, rash, and shortness of breath.

Full prescribing information, including additional information on risks associated with Radicava ORS, is available online.

The FDA granted Radicava ORS orphan drug status, priority review, and Fast Track designations.

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

The Food and Drug Administration has approved an orally administered version of edaravone (Radicava ORS, Mitsubishi Tanabe Pharma America) for adults with amyotrophic lateral sclerosis (ALS). Edaravone is a pyrazolone free-radical scavenger thought to lessen the effects of oxidative stress, which is a probable factor in ALS onset and progression. The drug was first approved in 2017 as an intravenous (IV) infusion to treat ALS.

Radicava ORS is self-administered and can be taken at home. After fasting overnight, Radicava ORS should be taken in the morning orally or through a feeding tube. The oral version has the same dosing regimen as the original IV version, with an initial treatment cycle of daily dosing for 14 days, followed by a 14-day drug-free period and subsequent treatment cycles consisting of daily dosing for 10 out of 14-day periods, followed by 14-day drug-free periods.

Compared with the IV formation of Radicava, Radicava ORS has been shown to generate comparable levels of active drug in the bloodstream, the FDA said.

The FDA determined that IV Radicava was effective based on a 6-month clinical trial in Japan involving 137 individuals who were randomly chosen to receive either the drug or a placebo. At 24 weeks, individuals receiving Radicava showed less decline on a clinical assessment of daily functioning, compared with those receiving placebo.

The most common side effects of Radicava are bruising, problems walking, and headache. Fatigue is also a possible side effect from Radicava ORS. Both formulations can have serious side effects associated with allergic reactions, including hives, rash, and shortness of breath.

Full prescribing information, including additional information on risks associated with Radicava ORS, is available online.

The FDA granted Radicava ORS orphan drug status, priority review, and Fast Track designations.

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

All patients with idiopathic inflammatory myopathies (IIM) should be screened for swallowing difficulties, according to the first evidence-based guideline to be produced.

The guideline, which has been developed by a working group of the British Society for Rheumatology (BSR), also advises that all diagnosed patients should have their myositis antibody levels checked and have their overall well-being assessed. Other recommendations for all patients include the use of glucocorticoids to reduce muscle inflammation and conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) for long-term treatment.

“Finally, now, we’re able to standardize the way we treat adults and children with IIM,” senior guideline author Hector Chinoy, PhD, said at the society’s annual meeting.

It has been a long labor of love, however, taking 4 years to get the guideline published, said Dr. Chinoy, professor of rheumatology and neuromuscular disease at the University of Manchester (England), and a consultant at Salford (England) Royal Hospital.

“We’re not covering diagnosis, classification, or the investigation of suspected IIM,” said Dr. Chinoy. Inclusion body myositis also is not included.

Altogether, there are 13 recommendations that have been developed using a PICO (patient or population, intervention, comparison, outcome) format, graded based on the quality of the available evidence, and then voted on by the working group members to give a score of the strength of agreement. Dr. Chinoy noted that there was a checklist included in the Supplementary Data section of the guideline to help follow the recommendations.

“The target audience for the guideline reflects the variety of clinicians caring for patients with IIM,” Dr. Chinoy said. So that is not just pediatric and adult rheumatologists, but also neurologists, dermatologists, respiratory physicians, oncologists, gastroenterologists, cardiologists, and of course other health care professionals. This includes rheumatology and neurology nurses, psychologists, speech and language therapists, and podiatrists, as well as rheumatology specialist pharmacists, physiotherapists, and occupational therapists.

With reference to the latter, Liza McCann, MBBS, who co-led the development of the guideline, said in a statement released by the BSR that the guideline “highlights the importance of exercise, led and monitored by specialist physiotherapists and occupational therapists.”

Dr. McCann, a consultant pediatric rheumatologist at Alder Hey Hospital, Liverpool, England, and Honorary Clinical Lecturer at the University of Liverpool, added that the guidelines also cover “the need to address psychological wellbeing as an integral part of treatment, in parallel with pharmacological therapies.”

Recommendation highlights

Some of the highlights of the recommendations include the use of high-dose glucocorticoids to manage skeletal muscle inflammation at the time of treatment induction, with specific guidance on the different doses to use in adults and in children. There also is guidance on the use of csDMARDs in both populations and what to use if there is refractory disease – with the strongest evidence supporting the use of intravenous immunoglobulin (IVIG) or cyclophosphamide, and possibly rituximab and abatacept.

“There is insufficient evidence to recommend JAK inhibition,” Dr. Chinoy said. The data search used to develop the guideline had a cutoff of October 2020, but even now there is only anecdotal evidence from case studies, he added.

Importantly, the guidelines recognize that childhood IIM differs from adult disease and call for children to be managed by pediatric specialists.

“Routine assessment of dysphagia should be considered in all patients,” Dr. Chinoy said, “so ask the question.” The recommendation is that a swallowing assessment should involve a speech and language therapist or gastroenterologist, and that IVIG be considered for active disease and dysphagia that is resistant to other treatments.

There also are recommendations to screen adult patients for interstitial lung disease, consider fracture risk, and screen adult patients for cancer if they have specific risk factors that include older age at onset, male gender, dysphagia, and rapid disease onset, among others.
 

Separate cancer screening guidelines on cards

“Around one in four patients with myositis will develop cancer within the 3 years either before or after myositis onset,” Alexander Oldroyd, MBChB, PhD, said in a separate presentation at the BSR annual meeting.

“It’s a hugely increased risk compared to the general population, and a great worry for patients,” he added. Exactly why there is an increased risk is not known, but “there’s a big link between the biological onset of cancer and myositis.”

Dr. Oldroyd, who is an NIHR Academic Clinical Lecturer at the University of Manchester in England and a coauthor of the BSR myositis guideline, is part of a special interest group set up by the International Myositis Assessment and Clinical Studies Group (IMACS) that is in the process of developing separate guidelines for cancer screening in people newly diagnosed with IIM.

The aim was to produce evidence-based recommendations that were both “pragmatic and practical,” that could help clinicians answer patient’s questions on their risk and how best and how often to screen them, Dr. Oldroyd explained. Importantly, IMACS has endeavored to create recommendations that should be applicable across different countries and health care systems.

“We had to acknowledge that there’s not a lot of evidence base there,” Dr. Oldroyd said, noting that he and colleagues conducted a systematic literature review and meta-analysis and used a Delphi process to draft 20 recommendations. These cover identifying risk factors for cancer in people with myositis and categorizing people into low, medium, and high-risk categories. The recommendations also cover what should constitute basic and enhanced screening, and how often someone should be screened.

Moreover, the authors make recommendations on the use of imaging modalities such as PET and CT scans, as well as upper and lower gastrointestinal endoscopy and naso-endoscopy.

“As rheumatologists, we don’t talk about cancer a lot,” Dr. Oldroyd said. “We pick up a lot of incidental cancers, but we don’t usually talk about cancer screening with patients.” That’s something that needs to change, he said.

“It’s important – just get it out in the open, talk to people about it,” Dr. Oldroyd said.

“Tell them what you’re wanting to do, how you’re wanting to investigate for it, clearly communicate their risk,” he said. “But also acknowledge the limited evidence as well, and clearly communicate the results.”

Dr. Chinoy acknowledged he had received fees for presentations (UCB, Biogen), consultancy (Alexion, Novartis, Eli Lilly, Orphazyme, AstraZeneca), or grant support (Eli Lilly, UCB) that had been paid via his institution for the purpose of furthering myositis research. Dr. Oldroyd had no conflicts of interest to disclose.

All patients with idiopathic inflammatory myopathies (IIM) should be screened for swallowing difficulties, according to the first evidence-based guideline to be produced.

The guideline, which has been developed by a working group of the British Society for Rheumatology (BSR), also advises that all diagnosed patients should have their myositis antibody levels checked and have their overall well-being assessed. Other recommendations for all patients include the use of glucocorticoids to reduce muscle inflammation and conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) for long-term treatment.

“Finally, now, we’re able to standardize the way we treat adults and children with IIM,” senior guideline author Hector Chinoy, PhD, said at the society’s annual meeting.

It has been a long labor of love, however, taking 4 years to get the guideline published, said Dr. Chinoy, professor of rheumatology and neuromuscular disease at the University of Manchester (England), and a consultant at Salford (England) Royal Hospital.

“We’re not covering diagnosis, classification, or the investigation of suspected IIM,” said Dr. Chinoy. Inclusion body myositis also is not included.

Altogether, there are 13 recommendations that have been developed using a PICO (patient or population, intervention, comparison, outcome) format, graded based on the quality of the available evidence, and then voted on by the working group members to give a score of the strength of agreement. Dr. Chinoy noted that there was a checklist included in the Supplementary Data section of the guideline to help follow the recommendations.

“The target audience for the guideline reflects the variety of clinicians caring for patients with IIM,” Dr. Chinoy said. So that is not just pediatric and adult rheumatologists, but also neurologists, dermatologists, respiratory physicians, oncologists, gastroenterologists, cardiologists, and of course other health care professionals. This includes rheumatology and neurology nurses, psychologists, speech and language therapists, and podiatrists, as well as rheumatology specialist pharmacists, physiotherapists, and occupational therapists.

With reference to the latter, Liza McCann, MBBS, who co-led the development of the guideline, said in a statement released by the BSR that the guideline “highlights the importance of exercise, led and monitored by specialist physiotherapists and occupational therapists.”

Dr. McCann, a consultant pediatric rheumatologist at Alder Hey Hospital, Liverpool, England, and Honorary Clinical Lecturer at the University of Liverpool, added that the guidelines also cover “the need to address psychological wellbeing as an integral part of treatment, in parallel with pharmacological therapies.”

Recommendation highlights

Some of the highlights of the recommendations include the use of high-dose glucocorticoids to manage skeletal muscle inflammation at the time of treatment induction, with specific guidance on the different doses to use in adults and in children. There also is guidance on the use of csDMARDs in both populations and what to use if there is refractory disease – with the strongest evidence supporting the use of intravenous immunoglobulin (IVIG) or cyclophosphamide, and possibly rituximab and abatacept.

“There is insufficient evidence to recommend JAK inhibition,” Dr. Chinoy said. The data search used to develop the guideline had a cutoff of October 2020, but even now there is only anecdotal evidence from case studies, he added.

Importantly, the guidelines recognize that childhood IIM differs from adult disease and call for children to be managed by pediatric specialists.

“Routine assessment of dysphagia should be considered in all patients,” Dr. Chinoy said, “so ask the question.” The recommendation is that a swallowing assessment should involve a speech and language therapist or gastroenterologist, and that IVIG be considered for active disease and dysphagia that is resistant to other treatments.

There also are recommendations to screen adult patients for interstitial lung disease, consider fracture risk, and screen adult patients for cancer if they have specific risk factors that include older age at onset, male gender, dysphagia, and rapid disease onset, among others.
 

Separate cancer screening guidelines on cards

“Around one in four patients with myositis will develop cancer within the 3 years either before or after myositis onset,” Alexander Oldroyd, MBChB, PhD, said in a separate presentation at the BSR annual meeting.

“It’s a hugely increased risk compared to the general population, and a great worry for patients,” he added. Exactly why there is an increased risk is not known, but “there’s a big link between the biological onset of cancer and myositis.”

Dr. Oldroyd, who is an NIHR Academic Clinical Lecturer at the University of Manchester in England and a coauthor of the BSR myositis guideline, is part of a special interest group set up by the International Myositis Assessment and Clinical Studies Group (IMACS) that is in the process of developing separate guidelines for cancer screening in people newly diagnosed with IIM.

The aim was to produce evidence-based recommendations that were both “pragmatic and practical,” that could help clinicians answer patient’s questions on their risk and how best and how often to screen them, Dr. Oldroyd explained. Importantly, IMACS has endeavored to create recommendations that should be applicable across different countries and health care systems.

“We had to acknowledge that there’s not a lot of evidence base there,” Dr. Oldroyd said, noting that he and colleagues conducted a systematic literature review and meta-analysis and used a Delphi process to draft 20 recommendations. These cover identifying risk factors for cancer in people with myositis and categorizing people into low, medium, and high-risk categories. The recommendations also cover what should constitute basic and enhanced screening, and how often someone should be screened.

Moreover, the authors make recommendations on the use of imaging modalities such as PET and CT scans, as well as upper and lower gastrointestinal endoscopy and naso-endoscopy.

“As rheumatologists, we don’t talk about cancer a lot,” Dr. Oldroyd said. “We pick up a lot of incidental cancers, but we don’t usually talk about cancer screening with patients.” That’s something that needs to change, he said.

“It’s important – just get it out in the open, talk to people about it,” Dr. Oldroyd said.

“Tell them what you’re wanting to do, how you’re wanting to investigate for it, clearly communicate their risk,” he said. “But also acknowledge the limited evidence as well, and clearly communicate the results.”

Dr. Chinoy acknowledged he had received fees for presentations (UCB, Biogen), consultancy (Alexion, Novartis, Eli Lilly, Orphazyme, AstraZeneca), or grant support (Eli Lilly, UCB) that had been paid via his institution for the purpose of furthering myositis research. Dr. Oldroyd had no conflicts of interest to disclose.

All patients with idiopathic inflammatory myopathies (IIM) should be screened for swallowing difficulties, according to the first evidence-based guideline to be produced.

The guideline, which has been developed by a working group of the British Society for Rheumatology (BSR), also advises that all diagnosed patients should have their myositis antibody levels checked and have their overall well-being assessed. Other recommendations for all patients include the use of glucocorticoids to reduce muscle inflammation and conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) for long-term treatment.

“Finally, now, we’re able to standardize the way we treat adults and children with IIM,” senior guideline author Hector Chinoy, PhD, said at the society’s annual meeting.

It has been a long labor of love, however, taking 4 years to get the guideline published, said Dr. Chinoy, professor of rheumatology and neuromuscular disease at the University of Manchester (England), and a consultant at Salford (England) Royal Hospital.

“We’re not covering diagnosis, classification, or the investigation of suspected IIM,” said Dr. Chinoy. Inclusion body myositis also is not included.

Altogether, there are 13 recommendations that have been developed using a PICO (patient or population, intervention, comparison, outcome) format, graded based on the quality of the available evidence, and then voted on by the working group members to give a score of the strength of agreement. Dr. Chinoy noted that there was a checklist included in the Supplementary Data section of the guideline to help follow the recommendations.

“The target audience for the guideline reflects the variety of clinicians caring for patients with IIM,” Dr. Chinoy said. So that is not just pediatric and adult rheumatologists, but also neurologists, dermatologists, respiratory physicians, oncologists, gastroenterologists, cardiologists, and of course other health care professionals. This includes rheumatology and neurology nurses, psychologists, speech and language therapists, and podiatrists, as well as rheumatology specialist pharmacists, physiotherapists, and occupational therapists.

With reference to the latter, Liza McCann, MBBS, who co-led the development of the guideline, said in a statement released by the BSR that the guideline “highlights the importance of exercise, led and monitored by specialist physiotherapists and occupational therapists.”

Dr. McCann, a consultant pediatric rheumatologist at Alder Hey Hospital, Liverpool, England, and Honorary Clinical Lecturer at the University of Liverpool, added that the guidelines also cover “the need to address psychological wellbeing as an integral part of treatment, in parallel with pharmacological therapies.”

Recommendation highlights

Some of the highlights of the recommendations include the use of high-dose glucocorticoids to manage skeletal muscle inflammation at the time of treatment induction, with specific guidance on the different doses to use in adults and in children. There also is guidance on the use of csDMARDs in both populations and what to use if there is refractory disease – with the strongest evidence supporting the use of intravenous immunoglobulin (IVIG) or cyclophosphamide, and possibly rituximab and abatacept.

“There is insufficient evidence to recommend JAK inhibition,” Dr. Chinoy said. The data search used to develop the guideline had a cutoff of October 2020, but even now there is only anecdotal evidence from case studies, he added.

Importantly, the guidelines recognize that childhood IIM differs from adult disease and call for children to be managed by pediatric specialists.

“Routine assessment of dysphagia should be considered in all patients,” Dr. Chinoy said, “so ask the question.” The recommendation is that a swallowing assessment should involve a speech and language therapist or gastroenterologist, and that IVIG be considered for active disease and dysphagia that is resistant to other treatments.

There also are recommendations to screen adult patients for interstitial lung disease, consider fracture risk, and screen adult patients for cancer if they have specific risk factors that include older age at onset, male gender, dysphagia, and rapid disease onset, among others.
 

Separate cancer screening guidelines on cards

“Around one in four patients with myositis will develop cancer within the 3 years either before or after myositis onset,” Alexander Oldroyd, MBChB, PhD, said in a separate presentation at the BSR annual meeting.

“It’s a hugely increased risk compared to the general population, and a great worry for patients,” he added. Exactly why there is an increased risk is not known, but “there’s a big link between the biological onset of cancer and myositis.”

Dr. Oldroyd, who is an NIHR Academic Clinical Lecturer at the University of Manchester in England and a coauthor of the BSR myositis guideline, is part of a special interest group set up by the International Myositis Assessment and Clinical Studies Group (IMACS) that is in the process of developing separate guidelines for cancer screening in people newly diagnosed with IIM.

The aim was to produce evidence-based recommendations that were both “pragmatic and practical,” that could help clinicians answer patient’s questions on their risk and how best and how often to screen them, Dr. Oldroyd explained. Importantly, IMACS has endeavored to create recommendations that should be applicable across different countries and health care systems.

“We had to acknowledge that there’s not a lot of evidence base there,” Dr. Oldroyd said, noting that he and colleagues conducted a systematic literature review and meta-analysis and used a Delphi process to draft 20 recommendations. These cover identifying risk factors for cancer in people with myositis and categorizing people into low, medium, and high-risk categories. The recommendations also cover what should constitute basic and enhanced screening, and how often someone should be screened.

Moreover, the authors make recommendations on the use of imaging modalities such as PET and CT scans, as well as upper and lower gastrointestinal endoscopy and naso-endoscopy.

“As rheumatologists, we don’t talk about cancer a lot,” Dr. Oldroyd said. “We pick up a lot of incidental cancers, but we don’t usually talk about cancer screening with patients.” That’s something that needs to change, he said.

“It’s important – just get it out in the open, talk to people about it,” Dr. Oldroyd said.

“Tell them what you’re wanting to do, how you’re wanting to investigate for it, clearly communicate their risk,” he said. “But also acknowledge the limited evidence as well, and clearly communicate the results.”

Dr. Chinoy acknowledged he had received fees for presentations (UCB, Biogen), consultancy (Alexion, Novartis, Eli Lilly, Orphazyme, AstraZeneca), or grant support (Eli Lilly, UCB) that had been paid via his institution for the purpose of furthering myositis research. Dr. Oldroyd had no conflicts of interest to disclose.

Children with juvenile idiopathic arthritis (JIA) who need a tumor necrosis factor (TNF) inhibitor after failing conventional disease-modifying antirheumatic drug (DMARD) treatment often experience insurance delays before beginning the new drug because of prior authorization denials, according to research presented at the 2022 annual meeting of the Childhood Arthritis and Rheumatology Research Alliance (CARRA). The findings were also published  as a research letter in JAMA Network Open.

“Prompt escalation to TNF inhibitors is recommended for children with JIA refractory to DMARDs,” author Jordan Roberts, MD, a clinical fellow of the Harvard Medical School Rheumatology Program, Boston, told CARRA attendees. TNF inhibitors are increasingly used as first-line treatment in JIA since growing evidence suggests better outcomes from early treatment with biologics. “Prior authorization requirements that delay TNF inhibitor initiation among children with JIA are common in clinical practice,” Dr. Roberts said, but little evidence exists to understand the extent of this problem and its causes.

The researchers therefore conducted a retrospective cohort study using a search of electronic health records from January 2018 to December 2019 to find all children at a single center with a new diagnosis of nonsystemic JIA. Then the authors pulled the timing of prior authorization requests, approvals, denials, and first TNF inhibitor dose from the medical notes. They also sought out any children who had been recommended a TNF inhibitor but never started one.

The total population included 54 children with an average age of 10 years, about two-thirds of whom had private insurance (63%). The group was predominantly White (63%), although 13% declined to provide race, and 7% were Hispanic. Most subtypes of disease were represented: oligoarticular persistent (28%), oligoarticular extended (2%), polyarticular rheumatoid factor-negative (15%), polyarticular rheumatoid factor-positive (15%), psoriatic arthritis (26%), enthesitis-related arthritis (12%), and undifferentiated arthritis (2%).

The 44 participants with private insurance had an average of two joints with active disease, while the 10 patients with public insurance had an average of four involved joints. Nearly all the patients (91%) had previously taken or were currently taking DMARDs when the prior authorization was submitted, and 61% had received NSAIDs.

All but one of the patients’ insurance plans required a prior authorization. The first prior authorization was denied for about one-third of the public insurance patients (30%) and a quarter of the private insurance patients. About 1 in 5 patients overall (22%) required a written appeal to override the denial, and 4% required peer-to-peer review. Meanwhile, 7% of patients began another medication because of the denial.

It took a median of 3 days for prior authorizations to be approved and a median of 24 days from the time the TNF inhibitor was recommended to the patient receiving the first dose. However, 22% of patients waited at least 2 weeks before the prior authorization was approved, and more than a quarter of the requests took over 30 days before the patient could begin the medication. In the public insurance group in particular, a quarter of children waited at least 19 days for approval and at least 44 days before starting the medication.

In fact, when the researchers looked at the difference in approval time between those who did and did not receive an initial denial, the difference was stark. Median approval time was 16 days when the prior authorization was denied, compared with a median of 5 days when the first prior authorization was approved. Similarly, time to initiation of the drug after recommendation was a median of 35 days for those whose prior authorization was first denied and 17 days for those with an initial approval.

The most common reason for an initial denial was the insurance company requiring a different TNF inhibitor than the one the rheumatologist wanted to prescribe. “These were all children whose rheumatologist has recommended either infliximab or etanercept that were required to use adalimumab instead,” Dr. Roberts said.

The other reasons for initial denial were similarly familiar ones:

• Required submission to another insurer
• Additional documentation required
• Lack of medical necessity
• Prescription was for an indication not approved by the Food and Drug Administration
• Age of patient
• Nonbiologic DMARD required
• NSAID required for step therapy

Only three children who were advised to begin a TNF inhibitor did not do so, including one who was lost to follow-up, one who had injection-related anxiety, and one who had safety concerns about the medication.

“Several children were required to use alternative TNF inhibitors than the one that was recommended due to restricted formularies, which may reduce shared decisionmaking between physicians and families and may not be the optimal clinical choice for an individual child,” Dr. Roberts said in her conclusion. Most children, however, were able to get approval for the TNF inhibitor originally requested, “suggesting that utilization management strategies present barriers to timely care despite appropriate specialty medication requests,” she said. “Therefore, it’s important for us to advocate for access to medications for children with JIA.”

Findings are not surprising

“I have these same experiences at my institution – often insurance will dictate clinical practice, and step therapy is the only option, causing a delay to initiation of TNFi even if we think, as the pediatric rheumatologist, that a child needs this medicine to be initiated on presentation to our clinic,” Nayimisha Balmuri, MD, assistant professor of pediatrics in the division of allergy, immunology, and rheumatology at the Johns Hopkins School of Medicine, Baltimore, told this news organization.

Dr. Balmuri, who was not involved in the study, noted that in her clinic at Johns Hopkins, it is hit or miss if an appeal to insurance companies or to the state (if it is Medicaid coverage) will be successful. “Unfortunately, [we are] mostly unsuccessful, and we have to try another DMARD for 8 to 12 weeks first before trying to get TNFi,” she said.

Dr. Balmuri called for bringing these issues to the attention of state and federal legislators. “It’s so important for us to continue to advocate for our patients at the state and national level! We are the advocates for our patients, and we are uniquely trained to know the best medications to initiate to help patients maximize their chance to reach remission of arthritis. Insurance companies need to hear our voices!”

Dr. Roberts reported grants from CARRA, the Lupus Foundation of America, and the National Institute of Allergy and Infectious Diseases during the conduct of the study.

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

Children with juvenile idiopathic arthritis (JIA) who need a tumor necrosis factor (TNF) inhibitor after failing conventional disease-modifying antirheumatic drug (DMARD) treatment often experience insurance delays before beginning the new drug because of prior authorization denials, according to research presented at the 2022 annual meeting of the Childhood Arthritis and Rheumatology Research Alliance (CARRA). The findings were also published  as a research letter in JAMA Network Open.

“Prompt escalation to TNF inhibitors is recommended for children with JIA refractory to DMARDs,” author Jordan Roberts, MD, a clinical fellow of the Harvard Medical School Rheumatology Program, Boston, told CARRA attendees. TNF inhibitors are increasingly used as first-line treatment in JIA since growing evidence suggests better outcomes from early treatment with biologics. “Prior authorization requirements that delay TNF inhibitor initiation among children with JIA are common in clinical practice,” Dr. Roberts said, but little evidence exists to understand the extent of this problem and its causes.

The researchers therefore conducted a retrospective cohort study using a search of electronic health records from January 2018 to December 2019 to find all children at a single center with a new diagnosis of nonsystemic JIA. Then the authors pulled the timing of prior authorization requests, approvals, denials, and first TNF inhibitor dose from the medical notes. They also sought out any children who had been recommended a TNF inhibitor but never started one.

The total population included 54 children with an average age of 10 years, about two-thirds of whom had private insurance (63%). The group was predominantly White (63%), although 13% declined to provide race, and 7% were Hispanic. Most subtypes of disease were represented: oligoarticular persistent (28%), oligoarticular extended (2%), polyarticular rheumatoid factor-negative (15%), polyarticular rheumatoid factor-positive (15%), psoriatic arthritis (26%), enthesitis-related arthritis (12%), and undifferentiated arthritis (2%).

The 44 participants with private insurance had an average of two joints with active disease, while the 10 patients with public insurance had an average of four involved joints. Nearly all the patients (91%) had previously taken or were currently taking DMARDs when the prior authorization was submitted, and 61% had received NSAIDs.

All but one of the patients’ insurance plans required a prior authorization. The first prior authorization was denied for about one-third of the public insurance patients (30%) and a quarter of the private insurance patients. About 1 in 5 patients overall (22%) required a written appeal to override the denial, and 4% required peer-to-peer review. Meanwhile, 7% of patients began another medication because of the denial.

It took a median of 3 days for prior authorizations to be approved and a median of 24 days from the time the TNF inhibitor was recommended to the patient receiving the first dose. However, 22% of patients waited at least 2 weeks before the prior authorization was approved, and more than a quarter of the requests took over 30 days before the patient could begin the medication. In the public insurance group in particular, a quarter of children waited at least 19 days for approval and at least 44 days before starting the medication.

In fact, when the researchers looked at the difference in approval time between those who did and did not receive an initial denial, the difference was stark. Median approval time was 16 days when the prior authorization was denied, compared with a median of 5 days when the first prior authorization was approved. Similarly, time to initiation of the drug after recommendation was a median of 35 days for those whose prior authorization was first denied and 17 days for those with an initial approval.

The most common reason for an initial denial was the insurance company requiring a different TNF inhibitor than the one the rheumatologist wanted to prescribe. “These were all children whose rheumatologist has recommended either infliximab or etanercept that were required to use adalimumab instead,” Dr. Roberts said.

The other reasons for initial denial were similarly familiar ones:

• Required submission to another insurer
• Additional documentation required
• Lack of medical necessity
• Prescription was for an indication not approved by the Food and Drug Administration
• Age of patient
• Nonbiologic DMARD required
• NSAID required for step therapy

Only three children who were advised to begin a TNF inhibitor did not do so, including one who was lost to follow-up, one who had injection-related anxiety, and one who had safety concerns about the medication.

“Several children were required to use alternative TNF inhibitors than the one that was recommended due to restricted formularies, which may reduce shared decisionmaking between physicians and families and may not be the optimal clinical choice for an individual child,” Dr. Roberts said in her conclusion. Most children, however, were able to get approval for the TNF inhibitor originally requested, “suggesting that utilization management strategies present barriers to timely care despite appropriate specialty medication requests,” she said. “Therefore, it’s important for us to advocate for access to medications for children with JIA.”

Findings are not surprising

“I have these same experiences at my institution – often insurance will dictate clinical practice, and step therapy is the only option, causing a delay to initiation of TNFi even if we think, as the pediatric rheumatologist, that a child needs this medicine to be initiated on presentation to our clinic,” Nayimisha Balmuri, MD, assistant professor of pediatrics in the division of allergy, immunology, and rheumatology at the Johns Hopkins School of Medicine, Baltimore, told this news organization.

Dr. Balmuri, who was not involved in the study, noted that in her clinic at Johns Hopkins, it is hit or miss if an appeal to insurance companies or to the state (if it is Medicaid coverage) will be successful. “Unfortunately, [we are] mostly unsuccessful, and we have to try another DMARD for 8 to 12 weeks first before trying to get TNFi,” she said.

Dr. Balmuri called for bringing these issues to the attention of state and federal legislators. “It’s so important for us to continue to advocate for our patients at the state and national level! We are the advocates for our patients, and we are uniquely trained to know the best medications to initiate to help patients maximize their chance to reach remission of arthritis. Insurance companies need to hear our voices!”

Dr. Roberts reported grants from CARRA, the Lupus Foundation of America, and the National Institute of Allergy and Infectious Diseases during the conduct of the study.

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

Children with juvenile idiopathic arthritis (JIA) who need a tumor necrosis factor (TNF) inhibitor after failing conventional disease-modifying antirheumatic drug (DMARD) treatment often experience insurance delays before beginning the new drug because of prior authorization denials, according to research presented at the 2022 annual meeting of the Childhood Arthritis and Rheumatology Research Alliance (CARRA). The findings were also published  as a research letter in JAMA Network Open.

“Prompt escalation to TNF inhibitors is recommended for children with JIA refractory to DMARDs,” author Jordan Roberts, MD, a clinical fellow of the Harvard Medical School Rheumatology Program, Boston, told CARRA attendees. TNF inhibitors are increasingly used as first-line treatment in JIA since growing evidence suggests better outcomes from early treatment with biologics. “Prior authorization requirements that delay TNF inhibitor initiation among children with JIA are common in clinical practice,” Dr. Roberts said, but little evidence exists to understand the extent of this problem and its causes.

The researchers therefore conducted a retrospective cohort study using a search of electronic health records from January 2018 to December 2019 to find all children at a single center with a new diagnosis of nonsystemic JIA. Then the authors pulled the timing of prior authorization requests, approvals, denials, and first TNF inhibitor dose from the medical notes. They also sought out any children who had been recommended a TNF inhibitor but never started one.

The total population included 54 children with an average age of 10 years, about two-thirds of whom had private insurance (63%). The group was predominantly White (63%), although 13% declined to provide race, and 7% were Hispanic. Most subtypes of disease were represented: oligoarticular persistent (28%), oligoarticular extended (2%), polyarticular rheumatoid factor-negative (15%), polyarticular rheumatoid factor-positive (15%), psoriatic arthritis (26%), enthesitis-related arthritis (12%), and undifferentiated arthritis (2%).

The 44 participants with private insurance had an average of two joints with active disease, while the 10 patients with public insurance had an average of four involved joints. Nearly all the patients (91%) had previously taken or were currently taking DMARDs when the prior authorization was submitted, and 61% had received NSAIDs.

All but one of the patients’ insurance plans required a prior authorization. The first prior authorization was denied for about one-third of the public insurance patients (30%) and a quarter of the private insurance patients. About 1 in 5 patients overall (22%) required a written appeal to override the denial, and 4% required peer-to-peer review. Meanwhile, 7% of patients began another medication because of the denial.

It took a median of 3 days for prior authorizations to be approved and a median of 24 days from the time the TNF inhibitor was recommended to the patient receiving the first dose. However, 22% of patients waited at least 2 weeks before the prior authorization was approved, and more than a quarter of the requests took over 30 days before the patient could begin the medication. In the public insurance group in particular, a quarter of children waited at least 19 days for approval and at least 44 days before starting the medication.

In fact, when the researchers looked at the difference in approval time between those who did and did not receive an initial denial, the difference was stark. Median approval time was 16 days when the prior authorization was denied, compared with a median of 5 days when the first prior authorization was approved. Similarly, time to initiation of the drug after recommendation was a median of 35 days for those whose prior authorization was first denied and 17 days for those with an initial approval.

The most common reason for an initial denial was the insurance company requiring a different TNF inhibitor than the one the rheumatologist wanted to prescribe. “These were all children whose rheumatologist has recommended either infliximab or etanercept that were required to use adalimumab instead,” Dr. Roberts said.

The other reasons for initial denial were similarly familiar ones:

• Required submission to another insurer
• Additional documentation required
• Lack of medical necessity
• Prescription was for an indication not approved by the Food and Drug Administration
• Age of patient
• Nonbiologic DMARD required
• NSAID required for step therapy

Only three children who were advised to begin a TNF inhibitor did not do so, including one who was lost to follow-up, one who had injection-related anxiety, and one who had safety concerns about the medication.

“Several children were required to use alternative TNF inhibitors than the one that was recommended due to restricted formularies, which may reduce shared decisionmaking between physicians and families and may not be the optimal clinical choice for an individual child,” Dr. Roberts said in her conclusion. Most children, however, were able to get approval for the TNF inhibitor originally requested, “suggesting that utilization management strategies present barriers to timely care despite appropriate specialty medication requests,” she said. “Therefore, it’s important for us to advocate for access to medications for children with JIA.”

Findings are not surprising

“I have these same experiences at my institution – often insurance will dictate clinical practice, and step therapy is the only option, causing a delay to initiation of TNFi even if we think, as the pediatric rheumatologist, that a child needs this medicine to be initiated on presentation to our clinic,” Nayimisha Balmuri, MD, assistant professor of pediatrics in the division of allergy, immunology, and rheumatology at the Johns Hopkins School of Medicine, Baltimore, told this news organization.

Dr. Balmuri, who was not involved in the study, noted that in her clinic at Johns Hopkins, it is hit or miss if an appeal to insurance companies or to the state (if it is Medicaid coverage) will be successful. “Unfortunately, [we are] mostly unsuccessful, and we have to try another DMARD for 8 to 12 weeks first before trying to get TNFi,” she said.

Dr. Balmuri called for bringing these issues to the attention of state and federal legislators. “It’s so important for us to continue to advocate for our patients at the state and national level! We are the advocates for our patients, and we are uniquely trained to know the best medications to initiate to help patients maximize their chance to reach remission of arthritis. Insurance companies need to hear our voices!”

Dr. Roberts reported grants from CARRA, the Lupus Foundation of America, and the National Institute of Allergy and Infectious Diseases during the conduct of the study.

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

This spring, global health advisories have been issued regarding an alarming – and as-yet unexplained – uptick of hepatitis in children. Currently, over 200 cases have been reported worldwide, a relatively small amount that nonetheless belies a considerable toll, including several deaths and the need for liver transplantation in a number of patients. The long-term implications are not yet known. Global health officials are working hard to determine a cause, with many focusing on the underlying cases of adenovirus that several patients have presented with.

To understand more, this news organization reached out to frequent contributor William F. Balistreri, MD, a specialist in pediatric gastroenterology and hepatology at Cincinnati Children’s Hospital Medical Center, where to date they have treated at least six cases of hepatitis in otherwise healthy young children, with one requiring a liver transplant. Dr. Balistreri discussed how the outbreak has developed to date, his advice to hepatologists and pediatricians, and where we stand now in this fast-evolving crisis.
 

Tracing the outbreak in the United States

How has this outbreak played out thus far in the United States, and what have we learned from that?

Sporadic reports of cases in multiple states are appearing. On April 21, 2022, a health alert was issued by the Centers for Disease Control and Prevention, recommending testing for adenovirus in children with acute hepatitis of an unknown etiology.

Baker and colleagues recently described five children with severe hepatitis and adenovirus viremia who were admitted to a children’s hospital in Birmingham, Ala., between October and November 2021. In collaboration with local and state officials, the CDC reviewed clinical records in order to identify patients with hepatitis and concomitant adenovirus infection, confirmed by polymerase chain reaction (PCR).

By February 2022, a total of nine children were identified. There was no epidemiologic linkage among these nine patients; all were well and immunocompetent. The prodromal features were somewhat similar: upper respiratory infection, vomiting, diarrhea, and jaundice. All children had markedly elevated aminotransferase levels and variably elevated total bilirubin levels. Extensive workup for other causes of acute liver injury (for example, other viruses, toxins/drugs, metabolic and autoimmune diseases) was unrevealing.

Specifically, none had documented SARS-CoV-2 infection. However, in all nine children, adenovirus was detected in whole blood samples. In the six children who underwent liver biopsy, there was nonspecific hepatitis, without inclusions or immunohistochemical detection of viral agents, including adenovirus. In three patients, the liver injury progressed, and despite the administration of antiviral agents, two underwent liver transplantation.

Baker and colleagues also suggested that measurement of adenovirus titers in whole blood (rather than plasma) may be more sensitive.

The CDC has recommended monitoring and surveillance in order to more fully understand the nature of the illness.
 

European and global cases

What has been the experience with this in Europe and elsewhere globally?

In mid-to-late 2021, several cases of acute hepatitis of unknown nature in children were identified in Europe. Public health officials in the United Kingdom investigated the high number of cases seen in children from England, Scotland, and Wales. They noted approximately 60 cases in England, mostly in children aged 2-5 years.

Marsh and colleagues reported a cluster of cases of severe hepatitis of unknown origin in Scotland affecting children aged 3-5 years. In Scotland, admitted cases were routinely tested for SARS-CoV-2. Of the 13 cases, five had a recent positive test. They discussed the possibility of increased severity of disease following infection with Omicron BA.2 (the dominant SARS-CoV-2 virus circulating in Scotland at that time) or infection by an uncharacterized SARS-CoV-2 variant. None of the children had been vaccinated for SARS-CoV-2.

On April 15, 2022, the World Health Organization Disease Outbreak News published a report of acute hepatitis of unknown etiology occurring in Great Britain and Northern Ireland. By April 21, 2022, 169 cases of acute hepatitis of unknown origin in children younger than 16 years had been reported from 11 countries in the WHO European region and 1 country in the WHO region of the Americas. Approximately 10% required a liver transplantation and at least one death was reported.

What has been established about the possible connection to the SARS-CoV-2 virus, particularly as it relates to coinfection with adenovirus?

In that WHO report of 169 cases, adenovirus was detected in 74 and SARS-CoV-2 in 20. Of note, 19 cases had a SARS-CoV-2 and adenovirus coinfection.

The report’s authors emphasized that, “while adenovirus is a possible hypothesis, investigations are ongoing for the causative agent.” The authors questioned whether this represents a continuing increase in cases of hepatitis or reflects an increased awareness.

The stated priority of the WHO is to determine the cause and to further refine control and prevention actions.

Given the worldwide nature of this outbreak, have connections between any of the cases been made yet?

Not to my knowledge.
 

What clinicians need to know

What makes this outbreak of hepatitis cases particularly concerning to the health care community, in comparison to other childhood diseases that occur globally? Is it because the cause is unknown or is it for other reasons?

It may be a collective heightened concern following the emergence of COVID.

Whether it represents a new form of acute hepatitis, a continuing increase in cases of hepatitis, or an increased awareness because of the well-publicized alerts remains to be determined. We certainly saw “viral-induced hepatitis” in the past.

Young patients may first be brought to pediatricians. What, if anything, should pediatricians be on the lookout for? Do they need a heightened index of suspicion or are the cases too rare at this point?

An awareness of the “outbreak” may allow the clinician to extend the typical workup of a child presenting with an undefined, presumably viral illness.

In the cases reported, the prodromal and/or presenting symptoms were respiratory and gastrointestinal in nature. They include nausea, vomiting, diarrhea, and abdominal pain.

Specifically, if jaundice and/or scleral icterus is noted, then hepatitis should be suspected.

Should pediatricians consider early referral to a pediatric gastroenterologist or hepatologist?

Yes, because there is the potential for finding a treatable cause (for example, autoimmune hepatitis or a specific metabolic disease) in a patient presenting in this fashion.

In addition, the potential for progression to acute liver failure (with coagulopathy and encephalopathy), albeit rare, exists.

What do hepatologists need to be doing when presented with suspected cases?

The typical clinical picture holds and the workup is standard. The one new key, given the recent data, is to test for adenovirus, using whole blood versus plasma, as the former may be more sensitive.

In addition, it is prudent to check for SARS-CoV-2 by PCR.

What are the major questions that remain and that you’d like to see elucidated going forward?

There are many. Is this a new disease? A new variant of adenovirus? A synergy or susceptibility related to SARS-CoV-2? Is it related to a variant of SARS-CoV-2? Is it triggering an adverse immune response? Are there other epigenetic factors involved? And finally, is this an increase, or is it related to a collective heightened concern following the pandemic?

Dr. Balistreri is the Dorothy M.M. Kersten Professor of Pediatrics, director emeritus of the Pediatric Liver Care Center, medical director emeritus of liver transplantation, and professor at the University of Cincinnati; he is also with the department of pediatrics at Cincinnati Children’s Hospital Medical Center.

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

This spring, global health advisories have been issued regarding an alarming – and as-yet unexplained – uptick of hepatitis in children. Currently, over 200 cases have been reported worldwide, a relatively small amount that nonetheless belies a considerable toll, including several deaths and the need for liver transplantation in a number of patients. The long-term implications are not yet known. Global health officials are working hard to determine a cause, with many focusing on the underlying cases of adenovirus that several patients have presented with.

To understand more, this news organization reached out to frequent contributor William F. Balistreri, MD, a specialist in pediatric gastroenterology and hepatology at Cincinnati Children’s Hospital Medical Center, where to date they have treated at least six cases of hepatitis in otherwise healthy young children, with one requiring a liver transplant. Dr. Balistreri discussed how the outbreak has developed to date, his advice to hepatologists and pediatricians, and where we stand now in this fast-evolving crisis.
 

Tracing the outbreak in the United States

How has this outbreak played out thus far in the United States, and what have we learned from that?

Sporadic reports of cases in multiple states are appearing. On April 21, 2022, a health alert was issued by the Centers for Disease Control and Prevention, recommending testing for adenovirus in children with acute hepatitis of an unknown etiology.

Baker and colleagues recently described five children with severe hepatitis and adenovirus viremia who were admitted to a children’s hospital in Birmingham, Ala., between October and November 2021. In collaboration with local and state officials, the CDC reviewed clinical records in order to identify patients with hepatitis and concomitant adenovirus infection, confirmed by polymerase chain reaction (PCR).

By February 2022, a total of nine children were identified. There was no epidemiologic linkage among these nine patients; all were well and immunocompetent. The prodromal features were somewhat similar: upper respiratory infection, vomiting, diarrhea, and jaundice. All children had markedly elevated aminotransferase levels and variably elevated total bilirubin levels. Extensive workup for other causes of acute liver injury (for example, other viruses, toxins/drugs, metabolic and autoimmune diseases) was unrevealing.

Specifically, none had documented SARS-CoV-2 infection. However, in all nine children, adenovirus was detected in whole blood samples. In the six children who underwent liver biopsy, there was nonspecific hepatitis, without inclusions or immunohistochemical detection of viral agents, including adenovirus. In three patients, the liver injury progressed, and despite the administration of antiviral agents, two underwent liver transplantation.

Baker and colleagues also suggested that measurement of adenovirus titers in whole blood (rather than plasma) may be more sensitive.

The CDC has recommended monitoring and surveillance in order to more fully understand the nature of the illness.
 

European and global cases

What has been the experience with this in Europe and elsewhere globally?

In mid-to-late 2021, several cases of acute hepatitis of unknown nature in children were identified in Europe. Public health officials in the United Kingdom investigated the high number of cases seen in children from England, Scotland, and Wales. They noted approximately 60 cases in England, mostly in children aged 2-5 years.

Marsh and colleagues reported a cluster of cases of severe hepatitis of unknown origin in Scotland affecting children aged 3-5 years. In Scotland, admitted cases were routinely tested for SARS-CoV-2. Of the 13 cases, five had a recent positive test. They discussed the possibility of increased severity of disease following infection with Omicron BA.2 (the dominant SARS-CoV-2 virus circulating in Scotland at that time) or infection by an uncharacterized SARS-CoV-2 variant. None of the children had been vaccinated for SARS-CoV-2.

On April 15, 2022, the World Health Organization Disease Outbreak News published a report of acute hepatitis of unknown etiology occurring in Great Britain and Northern Ireland. By April 21, 2022, 169 cases of acute hepatitis of unknown origin in children younger than 16 years had been reported from 11 countries in the WHO European region and 1 country in the WHO region of the Americas. Approximately 10% required a liver transplantation and at least one death was reported.

What has been established about the possible connection to the SARS-CoV-2 virus, particularly as it relates to coinfection with adenovirus?

In that WHO report of 169 cases, adenovirus was detected in 74 and SARS-CoV-2 in 20. Of note, 19 cases had a SARS-CoV-2 and adenovirus coinfection.

The report’s authors emphasized that, “while adenovirus is a possible hypothesis, investigations are ongoing for the causative agent.” The authors questioned whether this represents a continuing increase in cases of hepatitis or reflects an increased awareness.

The stated priority of the WHO is to determine the cause and to further refine control and prevention actions.

Given the worldwide nature of this outbreak, have connections between any of the cases been made yet?

Not to my knowledge.
 

What clinicians need to know

What makes this outbreak of hepatitis cases particularly concerning to the health care community, in comparison to other childhood diseases that occur globally? Is it because the cause is unknown or is it for other reasons?

It may be a collective heightened concern following the emergence of COVID.

Whether it represents a new form of acute hepatitis, a continuing increase in cases of hepatitis, or an increased awareness because of the well-publicized alerts remains to be determined. We certainly saw “viral-induced hepatitis” in the past.

Young patients may first be brought to pediatricians. What, if anything, should pediatricians be on the lookout for? Do they need a heightened index of suspicion or are the cases too rare at this point?

An awareness of the “outbreak” may allow the clinician to extend the typical workup of a child presenting with an undefined, presumably viral illness.

In the cases reported, the prodromal and/or presenting symptoms were respiratory and gastrointestinal in nature. They include nausea, vomiting, diarrhea, and abdominal pain.

Specifically, if jaundice and/or scleral icterus is noted, then hepatitis should be suspected.

Should pediatricians consider early referral to a pediatric gastroenterologist or hepatologist?

Yes, because there is the potential for finding a treatable cause (for example, autoimmune hepatitis or a specific metabolic disease) in a patient presenting in this fashion.

In addition, the potential for progression to acute liver failure (with coagulopathy and encephalopathy), albeit rare, exists.

What do hepatologists need to be doing when presented with suspected cases?

The typical clinical picture holds and the workup is standard. The one new key, given the recent data, is to test for adenovirus, using whole blood versus plasma, as the former may be more sensitive.

In addition, it is prudent to check for SARS-CoV-2 by PCR.

What are the major questions that remain and that you’d like to see elucidated going forward?

There are many. Is this a new disease? A new variant of adenovirus? A synergy or susceptibility related to SARS-CoV-2? Is it related to a variant of SARS-CoV-2? Is it triggering an adverse immune response? Are there other epigenetic factors involved? And finally, is this an increase, or is it related to a collective heightened concern following the pandemic?

Dr. Balistreri is the Dorothy M.M. Kersten Professor of Pediatrics, director emeritus of the Pediatric Liver Care Center, medical director emeritus of liver transplantation, and professor at the University of Cincinnati; he is also with the department of pediatrics at Cincinnati Children’s Hospital Medical Center.

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

This spring, global health advisories have been issued regarding an alarming – and as-yet unexplained – uptick of hepatitis in children. Currently, over 200 cases have been reported worldwide, a relatively small amount that nonetheless belies a considerable toll, including several deaths and the need for liver transplantation in a number of patients. The long-term implications are not yet known. Global health officials are working hard to determine a cause, with many focusing on the underlying cases of adenovirus that several patients have presented with.

To understand more, this news organization reached out to frequent contributor William F. Balistreri, MD, a specialist in pediatric gastroenterology and hepatology at Cincinnati Children’s Hospital Medical Center, where to date they have treated at least six cases of hepatitis in otherwise healthy young children, with one requiring a liver transplant. Dr. Balistreri discussed how the outbreak has developed to date, his advice to hepatologists and pediatricians, and where we stand now in this fast-evolving crisis.
 

Tracing the outbreak in the United States

How has this outbreak played out thus far in the United States, and what have we learned from that?

Sporadic reports of cases in multiple states are appearing. On April 21, 2022, a health alert was issued by the Centers for Disease Control and Prevention, recommending testing for adenovirus in children with acute hepatitis of an unknown etiology.

Baker and colleagues recently described five children with severe hepatitis and adenovirus viremia who were admitted to a children’s hospital in Birmingham, Ala., between October and November 2021. In collaboration with local and state officials, the CDC reviewed clinical records in order to identify patients with hepatitis and concomitant adenovirus infection, confirmed by polymerase chain reaction (PCR).

By February 2022, a total of nine children were identified. There was no epidemiologic linkage among these nine patients; all were well and immunocompetent. The prodromal features were somewhat similar: upper respiratory infection, vomiting, diarrhea, and jaundice. All children had markedly elevated aminotransferase levels and variably elevated total bilirubin levels. Extensive workup for other causes of acute liver injury (for example, other viruses, toxins/drugs, metabolic and autoimmune diseases) was unrevealing.

Specifically, none had documented SARS-CoV-2 infection. However, in all nine children, adenovirus was detected in whole blood samples. In the six children who underwent liver biopsy, there was nonspecific hepatitis, without inclusions or immunohistochemical detection of viral agents, including adenovirus. In three patients, the liver injury progressed, and despite the administration of antiviral agents, two underwent liver transplantation.

Baker and colleagues also suggested that measurement of adenovirus titers in whole blood (rather than plasma) may be more sensitive.

The CDC has recommended monitoring and surveillance in order to more fully understand the nature of the illness.
 

European and global cases

What has been the experience with this in Europe and elsewhere globally?

In mid-to-late 2021, several cases of acute hepatitis of unknown nature in children were identified in Europe. Public health officials in the United Kingdom investigated the high number of cases seen in children from England, Scotland, and Wales. They noted approximately 60 cases in England, mostly in children aged 2-5 years.

Marsh and colleagues reported a cluster of cases of severe hepatitis of unknown origin in Scotland affecting children aged 3-5 years. In Scotland, admitted cases were routinely tested for SARS-CoV-2. Of the 13 cases, five had a recent positive test. They discussed the possibility of increased severity of disease following infection with Omicron BA.2 (the dominant SARS-CoV-2 virus circulating in Scotland at that time) or infection by an uncharacterized SARS-CoV-2 variant. None of the children had been vaccinated for SARS-CoV-2.

On April 15, 2022, the World Health Organization Disease Outbreak News published a report of acute hepatitis of unknown etiology occurring in Great Britain and Northern Ireland. By April 21, 2022, 169 cases of acute hepatitis of unknown origin in children younger than 16 years had been reported from 11 countries in the WHO European region and 1 country in the WHO region of the Americas. Approximately 10% required a liver transplantation and at least one death was reported.

What has been established about the possible connection to the SARS-CoV-2 virus, particularly as it relates to coinfection with adenovirus?

In that WHO report of 169 cases, adenovirus was detected in 74 and SARS-CoV-2 in 20. Of note, 19 cases had a SARS-CoV-2 and adenovirus coinfection.

The report’s authors emphasized that, “while adenovirus is a possible hypothesis, investigations are ongoing for the causative agent.” The authors questioned whether this represents a continuing increase in cases of hepatitis or reflects an increased awareness.

The stated priority of the WHO is to determine the cause and to further refine control and prevention actions.

Given the worldwide nature of this outbreak, have connections between any of the cases been made yet?

Not to my knowledge.
 

What clinicians need to know

What makes this outbreak of hepatitis cases particularly concerning to the health care community, in comparison to other childhood diseases that occur globally? Is it because the cause is unknown or is it for other reasons?

It may be a collective heightened concern following the emergence of COVID.

Whether it represents a new form of acute hepatitis, a continuing increase in cases of hepatitis, or an increased awareness because of the well-publicized alerts remains to be determined. We certainly saw “viral-induced hepatitis” in the past.

Young patients may first be brought to pediatricians. What, if anything, should pediatricians be on the lookout for? Do they need a heightened index of suspicion or are the cases too rare at this point?

An awareness of the “outbreak” may allow the clinician to extend the typical workup of a child presenting with an undefined, presumably viral illness.

In the cases reported, the prodromal and/or presenting symptoms were respiratory and gastrointestinal in nature. They include nausea, vomiting, diarrhea, and abdominal pain.

Specifically, if jaundice and/or scleral icterus is noted, then hepatitis should be suspected.

Should pediatricians consider early referral to a pediatric gastroenterologist or hepatologist?

Yes, because there is the potential for finding a treatable cause (for example, autoimmune hepatitis or a specific metabolic disease) in a patient presenting in this fashion.

In addition, the potential for progression to acute liver failure (with coagulopathy and encephalopathy), albeit rare, exists.

What do hepatologists need to be doing when presented with suspected cases?

The typical clinical picture holds and the workup is standard. The one new key, given the recent data, is to test for adenovirus, using whole blood versus plasma, as the former may be more sensitive.

In addition, it is prudent to check for SARS-CoV-2 by PCR.

What are the major questions that remain and that you’d like to see elucidated going forward?

There are many. Is this a new disease? A new variant of adenovirus? A synergy or susceptibility related to SARS-CoV-2? Is it related to a variant of SARS-CoV-2? Is it triggering an adverse immune response? Are there other epigenetic factors involved? And finally, is this an increase, or is it related to a collective heightened concern following the pandemic?

Dr. Balistreri is the Dorothy M.M. Kersten Professor of Pediatrics, director emeritus of the Pediatric Liver Care Center, medical director emeritus of liver transplantation, and professor at the University of Cincinnati; he is also with the department of pediatrics at Cincinnati Children’s Hospital Medical Center.

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

I’m often in the position of caring for patients after they’ve stopped active cancer treatments, but before they’ve made the decision to enroll in hospice. They remain under my care until they feel emotionally ready, or until their care needs have escalated to the point in which hospice is unavoidable.

Jenny, a mom in her 50s with metastatic pancreatic cancer, stopped coming to the clinic. She lived about 40 minutes away from the clinic and was no longer receiving treatment. The car rides were painful and difficult for her. I held weekly video visits with her for 2 months before she eventually went to hospice and passed away. Before she died, she shared with me her sadness that her oncologist – who had taken care of her for 3 years – had “washed his hands of [me].” She rarely heard from him after their final conversation in the clinic when he informed her that she was no longer a candidate for further therapy. The sense of abandonment Jenny described was visceral and devastating. With her permission, I let her oncology team know how she felt and they reached out to her just 1 week before her death. After she died, her husband told me how meaningful it had been for the whole family to hear from Jenny’s oncologist who told them that she had done everything possible to fight her cancer and that “no stone was left unturned.” Her husband felt this final conversation provided Jenny with the closure she needed to pass away peacefully.

Transitioning from active therapy to symptom management

Switching gears from an all-out pursuit of active therapy to focusing on cancer symptoms is often a scary transition for patients and their families. The transition is often viewed as a movement away from hope and optimism to “giving up the fight.” Whether you agree with the warrior language or not, many patients still describe their journey in these terms and thus, experience enrollment in hospice as a sense of having failed.

The sense of failure can be compounded by feelings of abandonment by oncology providers when they are referred without much guidance or continuity through the hospice enrollment process. Unfortunately, the consequences of suboptimal hospice transitions can be damaging, especially for the mental health and well-being of the patient and their surviving loved ones. Hospice transitions seem to reside in an area of clinical practice that is overlooked or, in my experience they are considered an afterthought by many oncologists.

When managed poorly, hospice transitions can easily lead to patient and family harm, which is a claim supported by research. A qualitative study published in 2019 included 92 caregivers of patients with terminal cancer. The authors found three common pathways for end-of-life transitions – a frictionless transition in which the patient and family are well prepared in advance by their oncologist; a more turbulent transition in which patient and family had direct conversations with their oncologist about the incurability of the disease and the lack of efficacy of further treatments, but were given no guidance on prognosis; and a third type of transition marked by abrupt shifts toward end-of-life care occurring in extremis and typically in the hospital.

In the latter two groups, caregivers felt their loved ones died very quickly after stopping treatment, taking them by surprise and leaving them rushing to put end-of-life care plans in place without much support from their oncologists. In the last group, caregivers shared they received their first prognostic information from the hospital or ICU doctor caring for their actively dying loved one, leaving them with a sense of anger and betrayal toward their oncologist for allowing them to be so ill-prepared.

A Japanese survey published in 2018 in The Oncologist of families of cancer patients who had passed away under hospice care over a 2-year period (2012-2014), found that about one-quarter felt abandoned by oncologists. Several factors that were associated with feeling either more or less abandonment. Spouses of patients, patients aged less than 60 years, and patients whose oncologists informed them that there was “nothing more to do” felt more abandoned by oncologists; whereas families for whom the oncologist provided reassurance about the trajectory of care, recommended hospice, and engaged with a palliative care team felt less abandoned by oncologists. Families who felt more abandoned had higher levels of depression and grief when measured with standardized instruments.
 

‘Don’t just put in the hospice order and walk away’

Fortunately, there are a few low-resource interventions that can improve the quality of care-to-hospice transitions and prevent the sense of abandonment felt by many patients and families.

First, don’t just put in the hospice order and walk away. Designate a staffer in your office to contact hospice directly, ensure all medical records are faxed and received, and update the patient and family on this progress throughout the transition. Taking care of details like these ensures the patient enrolls in hospice in a timely manner and reduces the chance the patient, who is likely to be quite sick at this point, will end up in the hospital despite your best efforts to get hospice involved.

Make sure the patient and family understand that you are still their oncologist and still available to them. If they want to continue care with you, have them name you as the “non–hospice-attending physician” so that you can continue to bill for telemedicine and office visits using the terminal diagnosis (with a billing modifier). This does not mean that you will be expected to manage the patient’s hospice problem list or respond to hospice nurse calls at 2 a.m. – the hospice doctor will still do this. It just ensures that patients do not receive a bill if you continue to see them.

If ongoing office or video visits are too much for the patient and family, consider assigning a member of your team to call the patient and family on a weekly basis to check in and offer support. A small 2018 pilot study aimed at improving communication found that when caregivers of advanced cancer patients transitioning to hospice received weekly supportive phone calls by a member of their oncology team (typically a nurse or nurse practitioner), they felt emotionally supported, had good continuity of care throughout the hospice enrollment, and appreciated the ability to have closure with their oncology team. In other words, a sense of abandonment was prevented and the patient-provider relationship was actually deepened through the transition.

These suggestions are not rocket science – they are simple, obvious ways to try to restore patient-centeredness to a transition that for providers can seem routine, but for patients and families is often the first time they have confronted the reality that death is approaching. That reality is terrifying and overwhelming. Patients and caregivers need our support more during hospice transitions than at any other point during their cancer journey – except perhaps at diagnosis.

As with Jenny, my patient who felt abandoned, all it took was a single call by her oncology team to restore the trust and heal the sense of feeling forsaken by the people who cared for her for years. Sometimes, even just one more phone call can feel like a lot to a chronically overburdened provider – but what a difference a simple call can make.

Ms. D’Ambruoso is a hospice and palliative care nurse practitioner for UCLA Health Cancer Care, Santa Monica, Calif.

I’m often in the position of caring for patients after they’ve stopped active cancer treatments, but before they’ve made the decision to enroll in hospice. They remain under my care until they feel emotionally ready, or until their care needs have escalated to the point in which hospice is unavoidable.

Jenny, a mom in her 50s with metastatic pancreatic cancer, stopped coming to the clinic. She lived about 40 minutes away from the clinic and was no longer receiving treatment. The car rides were painful and difficult for her. I held weekly video visits with her for 2 months before she eventually went to hospice and passed away. Before she died, she shared with me her sadness that her oncologist – who had taken care of her for 3 years – had “washed his hands of [me].” She rarely heard from him after their final conversation in the clinic when he informed her that she was no longer a candidate for further therapy. The sense of abandonment Jenny described was visceral and devastating. With her permission, I let her oncology team know how she felt and they reached out to her just 1 week before her death. After she died, her husband told me how meaningful it had been for the whole family to hear from Jenny’s oncologist who told them that she had done everything possible to fight her cancer and that “no stone was left unturned.” Her husband felt this final conversation provided Jenny with the closure she needed to pass away peacefully.

Transitioning from active therapy to symptom management

Switching gears from an all-out pursuit of active therapy to focusing on cancer symptoms is often a scary transition for patients and their families. The transition is often viewed as a movement away from hope and optimism to “giving up the fight.” Whether you agree with the warrior language or not, many patients still describe their journey in these terms and thus, experience enrollment in hospice as a sense of having failed.

The sense of failure can be compounded by feelings of abandonment by oncology providers when they are referred without much guidance or continuity through the hospice enrollment process. Unfortunately, the consequences of suboptimal hospice transitions can be damaging, especially for the mental health and well-being of the patient and their surviving loved ones. Hospice transitions seem to reside in an area of clinical practice that is overlooked or, in my experience they are considered an afterthought by many oncologists.

When managed poorly, hospice transitions can easily lead to patient and family harm, which is a claim supported by research. A qualitative study published in 2019 included 92 caregivers of patients with terminal cancer. The authors found three common pathways for end-of-life transitions – a frictionless transition in which the patient and family are well prepared in advance by their oncologist; a more turbulent transition in which patient and family had direct conversations with their oncologist about the incurability of the disease and the lack of efficacy of further treatments, but were given no guidance on prognosis; and a third type of transition marked by abrupt shifts toward end-of-life care occurring in extremis and typically in the hospital.

In the latter two groups, caregivers felt their loved ones died very quickly after stopping treatment, taking them by surprise and leaving them rushing to put end-of-life care plans in place without much support from their oncologists. In the last group, caregivers shared they received their first prognostic information from the hospital or ICU doctor caring for their actively dying loved one, leaving them with a sense of anger and betrayal toward their oncologist for allowing them to be so ill-prepared.

A Japanese survey published in 2018 in The Oncologist of families of cancer patients who had passed away under hospice care over a 2-year period (2012-2014), found that about one-quarter felt abandoned by oncologists. Several factors that were associated with feeling either more or less abandonment. Spouses of patients, patients aged less than 60 years, and patients whose oncologists informed them that there was “nothing more to do” felt more abandoned by oncologists; whereas families for whom the oncologist provided reassurance about the trajectory of care, recommended hospice, and engaged with a palliative care team felt less abandoned by oncologists. Families who felt more abandoned had higher levels of depression and grief when measured with standardized instruments.
 

‘Don’t just put in the hospice order and walk away’

Fortunately, there are a few low-resource interventions that can improve the quality of care-to-hospice transitions and prevent the sense of abandonment felt by many patients and families.

First, don’t just put in the hospice order and walk away. Designate a staffer in your office to contact hospice directly, ensure all medical records are faxed and received, and update the patient and family on this progress throughout the transition. Taking care of details like these ensures the patient enrolls in hospice in a timely manner and reduces the chance the patient, who is likely to be quite sick at this point, will end up in the hospital despite your best efforts to get hospice involved.

Make sure the patient and family understand that you are still their oncologist and still available to them. If they want to continue care with you, have them name you as the “non–hospice-attending physician” so that you can continue to bill for telemedicine and office visits using the terminal diagnosis (with a billing modifier). This does not mean that you will be expected to manage the patient’s hospice problem list or respond to hospice nurse calls at 2 a.m. – the hospice doctor will still do this. It just ensures that patients do not receive a bill if you continue to see them.

If ongoing office or video visits are too much for the patient and family, consider assigning a member of your team to call the patient and family on a weekly basis to check in and offer support. A small 2018 pilot study aimed at improving communication found that when caregivers of advanced cancer patients transitioning to hospice received weekly supportive phone calls by a member of their oncology team (typically a nurse or nurse practitioner), they felt emotionally supported, had good continuity of care throughout the hospice enrollment, and appreciated the ability to have closure with their oncology team. In other words, a sense of abandonment was prevented and the patient-provider relationship was actually deepened through the transition.

These suggestions are not rocket science – they are simple, obvious ways to try to restore patient-centeredness to a transition that for providers can seem routine, but for patients and families is often the first time they have confronted the reality that death is approaching. That reality is terrifying and overwhelming. Patients and caregivers need our support more during hospice transitions than at any other point during their cancer journey – except perhaps at diagnosis.

As with Jenny, my patient who felt abandoned, all it took was a single call by her oncology team to restore the trust and heal the sense of feeling forsaken by the people who cared for her for years. Sometimes, even just one more phone call can feel like a lot to a chronically overburdened provider – but what a difference a simple call can make.

Ms. D’Ambruoso is a hospice and palliative care nurse practitioner for UCLA Health Cancer Care, Santa Monica, Calif.

I’m often in the position of caring for patients after they’ve stopped active cancer treatments, but before they’ve made the decision to enroll in hospice. They remain under my care until they feel emotionally ready, or until their care needs have escalated to the point in which hospice is unavoidable.

Jenny, a mom in her 50s with metastatic pancreatic cancer, stopped coming to the clinic. She lived about 40 minutes away from the clinic and was no longer receiving treatment. The car rides were painful and difficult for her. I held weekly video visits with her for 2 months before she eventually went to hospice and passed away. Before she died, she shared with me her sadness that her oncologist – who had taken care of her for 3 years – had “washed his hands of [me].” She rarely heard from him after their final conversation in the clinic when he informed her that she was no longer a candidate for further therapy. The sense of abandonment Jenny described was visceral and devastating. With her permission, I let her oncology team know how she felt and they reached out to her just 1 week before her death. After she died, her husband told me how meaningful it had been for the whole family to hear from Jenny’s oncologist who told them that she had done everything possible to fight her cancer and that “no stone was left unturned.” Her husband felt this final conversation provided Jenny with the closure she needed to pass away peacefully.

Transitioning from active therapy to symptom management

Switching gears from an all-out pursuit of active therapy to focusing on cancer symptoms is often a scary transition for patients and their families. The transition is often viewed as a movement away from hope and optimism to “giving up the fight.” Whether you agree with the warrior language or not, many patients still describe their journey in these terms and thus, experience enrollment in hospice as a sense of having failed.

The sense of failure can be compounded by feelings of abandonment by oncology providers when they are referred without much guidance or continuity through the hospice enrollment process. Unfortunately, the consequences of suboptimal hospice transitions can be damaging, especially for the mental health and well-being of the patient and their surviving loved ones. Hospice transitions seem to reside in an area of clinical practice that is overlooked or, in my experience they are considered an afterthought by many oncologists.

When managed poorly, hospice transitions can easily lead to patient and family harm, which is a claim supported by research. A qualitative study published in 2019 included 92 caregivers of patients with terminal cancer. The authors found three common pathways for end-of-life transitions – a frictionless transition in which the patient and family are well prepared in advance by their oncologist; a more turbulent transition in which patient and family had direct conversations with their oncologist about the incurability of the disease and the lack of efficacy of further treatments, but were given no guidance on prognosis; and a third type of transition marked by abrupt shifts toward end-of-life care occurring in extremis and typically in the hospital.

In the latter two groups, caregivers felt their loved ones died very quickly after stopping treatment, taking them by surprise and leaving them rushing to put end-of-life care plans in place without much support from their oncologists. In the last group, caregivers shared they received their first prognostic information from the hospital or ICU doctor caring for their actively dying loved one, leaving them with a sense of anger and betrayal toward their oncologist for allowing them to be so ill-prepared.

A Japanese survey published in 2018 in The Oncologist of families of cancer patients who had passed away under hospice care over a 2-year period (2012-2014), found that about one-quarter felt abandoned by oncologists. Several factors that were associated with feeling either more or less abandonment. Spouses of patients, patients aged less than 60 years, and patients whose oncologists informed them that there was “nothing more to do” felt more abandoned by oncologists; whereas families for whom the oncologist provided reassurance about the trajectory of care, recommended hospice, and engaged with a palliative care team felt less abandoned by oncologists. Families who felt more abandoned had higher levels of depression and grief when measured with standardized instruments.
 

‘Don’t just put in the hospice order and walk away’

Fortunately, there are a few low-resource interventions that can improve the quality of care-to-hospice transitions and prevent the sense of abandonment felt by many patients and families.

First, don’t just put in the hospice order and walk away. Designate a staffer in your office to contact hospice directly, ensure all medical records are faxed and received, and update the patient and family on this progress throughout the transition. Taking care of details like these ensures the patient enrolls in hospice in a timely manner and reduces the chance the patient, who is likely to be quite sick at this point, will end up in the hospital despite your best efforts to get hospice involved.

Make sure the patient and family understand that you are still their oncologist and still available to them. If they want to continue care with you, have them name you as the “non–hospice-attending physician” so that you can continue to bill for telemedicine and office visits using the terminal diagnosis (with a billing modifier). This does not mean that you will be expected to manage the patient’s hospice problem list or respond to hospice nurse calls at 2 a.m. – the hospice doctor will still do this. It just ensures that patients do not receive a bill if you continue to see them.

If ongoing office or video visits are too much for the patient and family, consider assigning a member of your team to call the patient and family on a weekly basis to check in and offer support. A small 2018 pilot study aimed at improving communication found that when caregivers of advanced cancer patients transitioning to hospice received weekly supportive phone calls by a member of their oncology team (typically a nurse or nurse practitioner), they felt emotionally supported, had good continuity of care throughout the hospice enrollment, and appreciated the ability to have closure with their oncology team. In other words, a sense of abandonment was prevented and the patient-provider relationship was actually deepened through the transition.

These suggestions are not rocket science – they are simple, obvious ways to try to restore patient-centeredness to a transition that for providers can seem routine, but for patients and families is often the first time they have confronted the reality that death is approaching. That reality is terrifying and overwhelming. Patients and caregivers need our support more during hospice transitions than at any other point during their cancer journey – except perhaps at diagnosis.

As with Jenny, my patient who felt abandoned, all it took was a single call by her oncology team to restore the trust and heal the sense of feeling forsaken by the people who cared for her for years. Sometimes, even just one more phone call can feel like a lot to a chronically overburdened provider – but what a difference a simple call can make.

Ms. D’Ambruoso is a hospice and palliative care nurse practitioner for UCLA Health Cancer Care, Santa Monica, Calif.

This is a transcript of a video that first appeared on Medscape.com. It has been edited for clarity.

On April 21, 2022, the Centers for Disease Control and Prevention released a Health Alert Network advisory regarding a cluster of nine cases of acute hepatitis in children in Alabama over a 5-month period from October 2021 to February 2022 – a rate substantially higher than what would be expected, given the relative rarity of hepatitis in children.

Standard workup was negative for the common causative agents – hepatitis A, B, and C – and no toxic exposures were identified. But there was one common thread among all these kids: They all tested positive for adenovirus.

And that is really strange.

There are about 100 circulating adenoviruses in the world that we know of, and around 50 of them infect humans. If you are an adult, it’s a virtual certainty that you have been infected with an adenovirus in the past. Most strains cause symptoms we would describe as the common cold: runny nose, sore throat. Some strains cause conjunctivitis (pink eye). Some cause gastrointestinal illness – the stomach bugs that kids get.

It’s the banality of adenovirus that makes this hepatitis finding so surprising.

The United States is not alone in reporting this new hepatitis syndrome. As of April 21, 169 cases have been reported across the world, including 114 in the United Kingdom.

Of the 169 cases reported worldwide, 74 had evidence of adenovirus infection. On molecular testing, 18 of those were adenovirus 41.

What I wanted to do today was go through the various hypotheses for what could be going on with these hepatitis cases, one by one, and highlight the evidence supporting them. We won’t reach a conclusion, but hopefully by the end, the path forward will be more clear. OK, let’s get started.

Hypothesis 1: Nothing is happening.

It’s worth noting that “clusters” of disease occur all the time, even when no relevant epidemiologic process has occurred. If there is some baseline rate of hepatitis, every once in a while, through bad luck alone, you’d see a group of cases all at once. This is known as the clustering illusion. And I’m quite confident in saying that this is not the case here.

For one, this phenomenon is worldwide, as we know from the World Health Organization report. In fact, the CDC didn’t provide the most detailed data about the nine (now 12) cases in the United States. This study from Scotland is the first to give a detailed accounting of cases, reporting on 13 cases of acute hepatitis of unknown cause in kids at a single hospital from January to April. Typically, the hospital sees fewer than four cases of hepatitis per year. Five of these 13 kids tested positive for adenovirus. So let’s take the clustering illusion off the list.

Hypothesis 2: It’s adenovirus.

The major evidence supporting adenovirus as the causative agent here is that a lot of these kids had adenovirus, and adenovirus 41 – a gut-tropic strain – in particular. This is important, because stool testing might be necessary for diagnosis and lots of kids with this condition didn’t get that. In other words, we have hard evidence of adenovirus infection in about 40% of the cases so far, but the true number might be substantially higher.

That said, adenovirus is seasonal, and we are in adenovirus season. Granted, 40% seems quite a bit higher than the background infection rate, but we have to be careful not to assume that correlation means causation.

The evidence against adenovirus, even adenovirus 41, is that this acute hepatitis syndrome is new, and adenovirus 41 is not. To be fair, we know adenoviruses can cause acute hepatitis, but the vast majority of reports are in immunocompromised individuals – organ transplant recipients and those with HIV. I was able to find just a handful of cases of immunocompetent kids developing hepatitis from adenovirus prior to this current outbreak.

The current outbreak would exceed the published literature by nearly two orders of magnitude. It feels like something else has to be going on.

Hypothesis 3: It’s coronavirus.

SARS-CoV-2 is a strange virus, both in its acute presentation and its long-term outcomes. It was clear early in the pandemic that some children infected by the coronavirus would develop MIS-C – multisystem inflammatory syndrome in children. MIS-C is associated with hepatitis in about 10% of children, according to this New England Journal of Medicine

But the presentation of these kids is quite different from MIS-C; fever is rare, for example. The WHO reports that of the 169 identified cases so far, 20 had active COVID infection. The Scotland cohort suggests that a similar proportion had past COVID infections. In other times, we might consider this a smoking gun, but at this point a history of COVID is not remarkable – after the Omicron wave, it’s about as common to have a history of COVID as it is not to have a history of COVID.

A brief aside here. This is not because of coronavirus vaccination. Of the more than 100 cases reported in the United Kingdom, none of these kids were vaccinated. So let’s put aside the possibility that this is a vaccine effect – there’s no real evidence to support that.

Which brings us to …

Hypothesis 4: It’s coronavirus and adenovirus.

This is sort of intriguing and can work a few different ways, via a direct and indirect path.

In the direct path, we posit that COVID infection does something to kids’ immune systems – something we don’t yet understand that limits their ability to fight off adenovirus. There is some support for this idea. This study in Immunity found that COVID infection can functionally impair dendritic cells and T-cells, including natural killer cells. These cells are important components of our innate antiviral immunity.

There’s an indirect path as well. COVID has led to lockdowns, distancing, masking – stuff that prevents kids from being exposed to germs from other kids. Could a lack of exposure to adenovirus or other viruses because of distancing increase the risk for severe disease when restrictions are lifted? Also possible – the severity of respiratory syncytial virus (RSV) infections this year is substantially higher than what we’ve seen in the past, for example.

And finally, hypothesis 5: This is something new.

We can’t ignore the possibility that this is simply a new disease-causing agent. Toxicology studies so far have been negative, and we wouldn’t expect hepatitis from a chemical toxin to appear in multiple countries around the world; this is almost certainly a biological phenomenon. It is possible that this is a new strain of adenovirus 41, or that adenovirus is a red herring altogether. Remember, we knew about “non-A/non-B viral hepatitis” for more than 2 decades before hepatitis C was discovered.

The pace of science is faster now, fortunately, and information is coming out quickly. As we learn more, we’ll share it with you.

Dr. Wilson, MD, MSCE, is an associate professor of medicine at Yale University, New Haven, Conn., and director of Yale’s Clinical and Translational Research Accelerator. His science communication work can be found in the Huffington Post, on NPR, and on Medscape. He tweets @fperrywilson and hosts a repository of his communication work at www.methodsman.com. Dr. Wilson has disclosed no relevant financial relationships.

 

This is a transcript of a video that first appeared on Medscape.com. It has been edited for clarity.

On April 21, 2022, the Centers for Disease Control and Prevention released a Health Alert Network advisory regarding a cluster of nine cases of acute hepatitis in children in Alabama over a 5-month period from October 2021 to February 2022 – a rate substantially higher than what would be expected, given the relative rarity of hepatitis in children.

Standard workup was negative for the common causative agents – hepatitis A, B, and C – and no toxic exposures were identified. But there was one common thread among all these kids: They all tested positive for adenovirus.

And that is really strange.

There are about 100 circulating adenoviruses in the world that we know of, and around 50 of them infect humans. If you are an adult, it’s a virtual certainty that you have been infected with an adenovirus in the past. Most strains cause symptoms we would describe as the common cold: runny nose, sore throat. Some strains cause conjunctivitis (pink eye). Some cause gastrointestinal illness – the stomach bugs that kids get.

It’s the banality of adenovirus that makes this hepatitis finding so surprising.

The United States is not alone in reporting this new hepatitis syndrome. As of April 21, 169 cases have been reported across the world, including 114 in the United Kingdom.

Of the 169 cases reported worldwide, 74 had evidence of adenovirus infection. On molecular testing, 18 of those were adenovirus 41.

What I wanted to do today was go through the various hypotheses for what could be going on with these hepatitis cases, one by one, and highlight the evidence supporting them. We won’t reach a conclusion, but hopefully by the end, the path forward will be more clear. OK, let’s get started.

Hypothesis 1: Nothing is happening.

It’s worth noting that “clusters” of disease occur all the time, even when no relevant epidemiologic process has occurred. If there is some baseline rate of hepatitis, every once in a while, through bad luck alone, you’d see a group of cases all at once. This is known as the clustering illusion. And I’m quite confident in saying that this is not the case here.

For one, this phenomenon is worldwide, as we know from the World Health Organization report. In fact, the CDC didn’t provide the most detailed data about the nine (now 12) cases in the United States. This study from Scotland is the first to give a detailed accounting of cases, reporting on 13 cases of acute hepatitis of unknown cause in kids at a single hospital from January to April. Typically, the hospital sees fewer than four cases of hepatitis per year. Five of these 13 kids tested positive for adenovirus. So let’s take the clustering illusion off the list.

Hypothesis 2: It’s adenovirus.

The major evidence supporting adenovirus as the causative agent here is that a lot of these kids had adenovirus, and adenovirus 41 – a gut-tropic strain – in particular. This is important, because stool testing might be necessary for diagnosis and lots of kids with this condition didn’t get that. In other words, we have hard evidence of adenovirus infection in about 40% of the cases so far, but the true number might be substantially higher.

That said, adenovirus is seasonal, and we are in adenovirus season. Granted, 40% seems quite a bit higher than the background infection rate, but we have to be careful not to assume that correlation means causation.

The evidence against adenovirus, even adenovirus 41, is that this acute hepatitis syndrome is new, and adenovirus 41 is not. To be fair, we know adenoviruses can cause acute hepatitis, but the vast majority of reports are in immunocompromised individuals – organ transplant recipients and those with HIV. I was able to find just a handful of cases of immunocompetent kids developing hepatitis from adenovirus prior to this current outbreak.

The current outbreak would exceed the published literature by nearly two orders of magnitude. It feels like something else has to be going on.

Hypothesis 3: It’s coronavirus.

SARS-CoV-2 is a strange virus, both in its acute presentation and its long-term outcomes. It was clear early in the pandemic that some children infected by the coronavirus would develop MIS-C – multisystem inflammatory syndrome in children. MIS-C is associated with hepatitis in about 10% of children, according to this New England Journal of Medicine

But the presentation of these kids is quite different from MIS-C; fever is rare, for example. The WHO reports that of the 169 identified cases so far, 20 had active COVID infection. The Scotland cohort suggests that a similar proportion had past COVID infections. In other times, we might consider this a smoking gun, but at this point a history of COVID is not remarkable – after the Omicron wave, it’s about as common to have a history of COVID as it is not to have a history of COVID.

A brief aside here. This is not because of coronavirus vaccination. Of the more than 100 cases reported in the United Kingdom, none of these kids were vaccinated. So let’s put aside the possibility that this is a vaccine effect – there’s no real evidence to support that.

Which brings us to …

Hypothesis 4: It’s coronavirus and adenovirus.

This is sort of intriguing and can work a few different ways, via a direct and indirect path.

In the direct path, we posit that COVID infection does something to kids’ immune systems – something we don’t yet understand that limits their ability to fight off adenovirus. There is some support for this idea. This study in Immunity found that COVID infection can functionally impair dendritic cells and T-cells, including natural killer cells. These cells are important components of our innate antiviral immunity.

There’s an indirect path as well. COVID has led to lockdowns, distancing, masking – stuff that prevents kids from being exposed to germs from other kids. Could a lack of exposure to adenovirus or other viruses because of distancing increase the risk for severe disease when restrictions are lifted? Also possible – the severity of respiratory syncytial virus (RSV) infections this year is substantially higher than what we’ve seen in the past, for example.

And finally, hypothesis 5: This is something new.

We can’t ignore the possibility that this is simply a new disease-causing agent. Toxicology studies so far have been negative, and we wouldn’t expect hepatitis from a chemical toxin to appear in multiple countries around the world; this is almost certainly a biological phenomenon. It is possible that this is a new strain of adenovirus 41, or that adenovirus is a red herring altogether. Remember, we knew about “non-A/non-B viral hepatitis” for more than 2 decades before hepatitis C was discovered.

The pace of science is faster now, fortunately, and information is coming out quickly. As we learn more, we’ll share it with you.

Dr. Wilson, MD, MSCE, is an associate professor of medicine at Yale University, New Haven, Conn., and director of Yale’s Clinical and Translational Research Accelerator. His science communication work can be found in the Huffington Post, on NPR, and on Medscape. He tweets @fperrywilson and hosts a repository of his communication work at www.methodsman.com. Dr. Wilson has disclosed no relevant financial relationships.

 

This is a transcript of a video that first appeared on Medscape.com. It has been edited for clarity.

On April 21, 2022, the Centers for Disease Control and Prevention released a Health Alert Network advisory regarding a cluster of nine cases of acute hepatitis in children in Alabama over a 5-month period from October 2021 to February 2022 – a rate substantially higher than what would be expected, given the relative rarity of hepatitis in children.

Standard workup was negative for the common causative agents – hepatitis A, B, and C – and no toxic exposures were identified. But there was one common thread among all these kids: They all tested positive for adenovirus.

And that is really strange.

There are about 100 circulating adenoviruses in the world that we know of, and around 50 of them infect humans. If you are an adult, it’s a virtual certainty that you have been infected with an adenovirus in the past. Most strains cause symptoms we would describe as the common cold: runny nose, sore throat. Some strains cause conjunctivitis (pink eye). Some cause gastrointestinal illness – the stomach bugs that kids get.

It’s the banality of adenovirus that makes this hepatitis finding so surprising.

The United States is not alone in reporting this new hepatitis syndrome. As of April 21, 169 cases have been reported across the world, including 114 in the United Kingdom.

Of the 169 cases reported worldwide, 74 had evidence of adenovirus infection. On molecular testing, 18 of those were adenovirus 41.

What I wanted to do today was go through the various hypotheses for what could be going on with these hepatitis cases, one by one, and highlight the evidence supporting them. We won’t reach a conclusion, but hopefully by the end, the path forward will be more clear. OK, let’s get started.

Hypothesis 1: Nothing is happening.

It’s worth noting that “clusters” of disease occur all the time, even when no relevant epidemiologic process has occurred. If there is some baseline rate of hepatitis, every once in a while, through bad luck alone, you’d see a group of cases all at once. This is known as the clustering illusion. And I’m quite confident in saying that this is not the case here.

For one, this phenomenon is worldwide, as we know from the World Health Organization report. In fact, the CDC didn’t provide the most detailed data about the nine (now 12) cases in the United States. This study from Scotland is the first to give a detailed accounting of cases, reporting on 13 cases of acute hepatitis of unknown cause in kids at a single hospital from January to April. Typically, the hospital sees fewer than four cases of hepatitis per year. Five of these 13 kids tested positive for adenovirus. So let’s take the clustering illusion off the list.

Hypothesis 2: It’s adenovirus.

The major evidence supporting adenovirus as the causative agent here is that a lot of these kids had adenovirus, and adenovirus 41 – a gut-tropic strain – in particular. This is important, because stool testing might be necessary for diagnosis and lots of kids with this condition didn’t get that. In other words, we have hard evidence of adenovirus infection in about 40% of the cases so far, but the true number might be substantially higher.

That said, adenovirus is seasonal, and we are in adenovirus season. Granted, 40% seems quite a bit higher than the background infection rate, but we have to be careful not to assume that correlation means causation.

The evidence against adenovirus, even adenovirus 41, is that this acute hepatitis syndrome is new, and adenovirus 41 is not. To be fair, we know adenoviruses can cause acute hepatitis, but the vast majority of reports are in immunocompromised individuals – organ transplant recipients and those with HIV. I was able to find just a handful of cases of immunocompetent kids developing hepatitis from adenovirus prior to this current outbreak.

The current outbreak would exceed the published literature by nearly two orders of magnitude. It feels like something else has to be going on.

Hypothesis 3: It’s coronavirus.

SARS-CoV-2 is a strange virus, both in its acute presentation and its long-term outcomes. It was clear early in the pandemic that some children infected by the coronavirus would develop MIS-C – multisystem inflammatory syndrome in children. MIS-C is associated with hepatitis in about 10% of children, according to this New England Journal of Medicine

But the presentation of these kids is quite different from MIS-C; fever is rare, for example. The WHO reports that of the 169 identified cases so far, 20 had active COVID infection. The Scotland cohort suggests that a similar proportion had past COVID infections. In other times, we might consider this a smoking gun, but at this point a history of COVID is not remarkable – after the Omicron wave, it’s about as common to have a history of COVID as it is not to have a history of COVID.

A brief aside here. This is not because of coronavirus vaccination. Of the more than 100 cases reported in the United Kingdom, none of these kids were vaccinated. So let’s put aside the possibility that this is a vaccine effect – there’s no real evidence to support that.

Which brings us to …

Hypothesis 4: It’s coronavirus and adenovirus.

This is sort of intriguing and can work a few different ways, via a direct and indirect path.

In the direct path, we posit that COVID infection does something to kids’ immune systems – something we don’t yet understand that limits their ability to fight off adenovirus. There is some support for this idea. This study in Immunity found that COVID infection can functionally impair dendritic cells and T-cells, including natural killer cells. These cells are important components of our innate antiviral immunity.

There’s an indirect path as well. COVID has led to lockdowns, distancing, masking – stuff that prevents kids from being exposed to germs from other kids. Could a lack of exposure to adenovirus or other viruses because of distancing increase the risk for severe disease when restrictions are lifted? Also possible – the severity of respiratory syncytial virus (RSV) infections this year is substantially higher than what we’ve seen in the past, for example.

And finally, hypothesis 5: This is something new.

We can’t ignore the possibility that this is simply a new disease-causing agent. Toxicology studies so far have been negative, and we wouldn’t expect hepatitis from a chemical toxin to appear in multiple countries around the world; this is almost certainly a biological phenomenon. It is possible that this is a new strain of adenovirus 41, or that adenovirus is a red herring altogether. Remember, we knew about “non-A/non-B viral hepatitis” for more than 2 decades before hepatitis C was discovered.

The pace of science is faster now, fortunately, and information is coming out quickly. As we learn more, we’ll share it with you.

Dr. Wilson, MD, MSCE, is an associate professor of medicine at Yale University, New Haven, Conn., and director of Yale’s Clinical and Translational Research Accelerator. His science communication work can be found in the Huffington Post, on NPR, and on Medscape. He tweets @fperrywilson and hosts a repository of his communication work at www.methodsman.com. Dr. Wilson has disclosed no relevant financial relationships.

 

New surveillance data from the Vaccine Adverse Event Reporting System (VAERS) confirm a small but statistically significant increased risk for Guillain-Barré syndrome (GBS) in the 3 weeks after receipt of the Janssen/Johnson & Johnson COVID-19 vaccine.

The Janssen vaccine (Ad26.COV2.S) is a replication-incompetent adenoviral vector vaccine.

The data show no increased risk of GBS with the Pfizer (BNT162b2) or Moderna (mRNA-1273) shots – both mRNA vaccines.

“Our findings support the current guidance from U.S. health officials that preferentially recommend use of mRNA COVID-19 vaccines for primary and booster doses,” Nicola Klein, MD, PhD, with Kaiser Permanente Vaccine Study Center, Oakland, Calif., told this news organization.

“Individuals who choose to receive Janssen/J&J COVID-19 vaccine should be informed of the potential safety risks, including GBS,” Dr. Klein said.

The study was published online in JAMA Network Open.
 

Eleven cases

Between mid-December 2020 and mid-November 2021, roughly 15.1 million doses of COVID-19 vaccine were administered to nearly 7.9 million adults in the United States.

This includes roughly 483,000 doses of the Janssen vaccine, 8.8 million doses of the Pfizer vaccine, and 5.8 million doses of the Moderna vaccine.

The researchers confirmed 11 cases of GBS after the Janssen vaccine.

The unadjusted incidence of GBS (per 100,000 person-years) was 32.4 in the first 21 days after the Janssen vaccine – substantially higher than the expected background rate of 1 to 2 cases per 100,000 person-years.

There were 36 confirmed cases of GBS after mRNA vaccines. The unadjusted incidence in the first 21 days after mRNA vaccination was 1.3 per 100,000 person-years, similar to the overall expected background rate.

In an adjusted head-to-head comparison, GBS incidence during the 21 days after receipt of the Janssen vaccine was 20.6 times higher than the GBS incidence during the 21 days after the Pfizer or Moderna mRNA vaccines, amounting to 15.5 excess cases per million Janssen vaccine recipients.

Most cases of GBS after the Janssen vaccine occurred during the 1- to 21-day risk interval, with the period of greatest risk in the 1-14 days after vaccination.

The findings of this analysis of surveillance data of COVID-19 vaccines are “consistent with an elevated risk of GBS after primary Ad26.COV2.S vaccination,” the authors wrote.
 

Novel presentation?

The researchers note that nearly all individuals who developed GBS after the Janssen vaccine had facial weakness or paralysis, in addition to weakness and decreased reflexes in the limbs, suggesting that the presentation of GBS after COVID-19 adenoviral vector vaccine may be novel.

“More research is needed to determine if the presentation of GBS after adenoviral vector vaccine differs from GBS after other exposures such as Campylobacter jejuni, and to investigate the mechanism for how adenoviral vector vaccines may cause GBS,” Dr. Klein and colleagues said.

“The Vaccine Safety Datalink continues to conduct safety surveillance for all COVID-19 vaccines, including monitoring for GBS and other serious health outcomes after vaccination,” Dr. Klein said in an interview.

This study was supported by the Centers for Disease Control and Prevention. Dr. Klein reported receiving grants from Pfizer research support for a COVID vaccine clinical trial as well as other unrelated studies, grants from Merck, grants from GlaxoSmithKline, grants from Sanofi Pasteur, and grants from Protein Science (now Sanofi Pasteur) outside the submitted work.

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

New surveillance data from the Vaccine Adverse Event Reporting System (VAERS) confirm a small but statistically significant increased risk for Guillain-Barré syndrome (GBS) in the 3 weeks after receipt of the Janssen/Johnson & Johnson COVID-19 vaccine.

The Janssen vaccine (Ad26.COV2.S) is a replication-incompetent adenoviral vector vaccine.

The data show no increased risk of GBS with the Pfizer (BNT162b2) or Moderna (mRNA-1273) shots – both mRNA vaccines.

“Our findings support the current guidance from U.S. health officials that preferentially recommend use of mRNA COVID-19 vaccines for primary and booster doses,” Nicola Klein, MD, PhD, with Kaiser Permanente Vaccine Study Center, Oakland, Calif., told this news organization.

“Individuals who choose to receive Janssen/J&J COVID-19 vaccine should be informed of the potential safety risks, including GBS,” Dr. Klein said.

The study was published online in JAMA Network Open.
 

Eleven cases

Between mid-December 2020 and mid-November 2021, roughly 15.1 million doses of COVID-19 vaccine were administered to nearly 7.9 million adults in the United States.

This includes roughly 483,000 doses of the Janssen vaccine, 8.8 million doses of the Pfizer vaccine, and 5.8 million doses of the Moderna vaccine.

The researchers confirmed 11 cases of GBS after the Janssen vaccine.

The unadjusted incidence of GBS (per 100,000 person-years) was 32.4 in the first 21 days after the Janssen vaccine – substantially higher than the expected background rate of 1 to 2 cases per 100,000 person-years.

There were 36 confirmed cases of GBS after mRNA vaccines. The unadjusted incidence in the first 21 days after mRNA vaccination was 1.3 per 100,000 person-years, similar to the overall expected background rate.

In an adjusted head-to-head comparison, GBS incidence during the 21 days after receipt of the Janssen vaccine was 20.6 times higher than the GBS incidence during the 21 days after the Pfizer or Moderna mRNA vaccines, amounting to 15.5 excess cases per million Janssen vaccine recipients.

Most cases of GBS after the Janssen vaccine occurred during the 1- to 21-day risk interval, with the period of greatest risk in the 1-14 days after vaccination.

The findings of this analysis of surveillance data of COVID-19 vaccines are “consistent with an elevated risk of GBS after primary Ad26.COV2.S vaccination,” the authors wrote.
 

Novel presentation?

The researchers note that nearly all individuals who developed GBS after the Janssen vaccine had facial weakness or paralysis, in addition to weakness and decreased reflexes in the limbs, suggesting that the presentation of GBS after COVID-19 adenoviral vector vaccine may be novel.

“More research is needed to determine if the presentation of GBS after adenoviral vector vaccine differs from GBS after other exposures such as Campylobacter jejuni, and to investigate the mechanism for how adenoviral vector vaccines may cause GBS,” Dr. Klein and colleagues said.

“The Vaccine Safety Datalink continues to conduct safety surveillance for all COVID-19 vaccines, including monitoring for GBS and other serious health outcomes after vaccination,” Dr. Klein said in an interview.

This study was supported by the Centers for Disease Control and Prevention. Dr. Klein reported receiving grants from Pfizer research support for a COVID vaccine clinical trial as well as other unrelated studies, grants from Merck, grants from GlaxoSmithKline, grants from Sanofi Pasteur, and grants from Protein Science (now Sanofi Pasteur) outside the submitted work.

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

New surveillance data from the Vaccine Adverse Event Reporting System (VAERS) confirm a small but statistically significant increased risk for Guillain-Barré syndrome (GBS) in the 3 weeks after receipt of the Janssen/Johnson & Johnson COVID-19 vaccine.

The Janssen vaccine (Ad26.COV2.S) is a replication-incompetent adenoviral vector vaccine.

The data show no increased risk of GBS with the Pfizer (BNT162b2) or Moderna (mRNA-1273) shots – both mRNA vaccines.

“Our findings support the current guidance from U.S. health officials that preferentially recommend use of mRNA COVID-19 vaccines for primary and booster doses,” Nicola Klein, MD, PhD, with Kaiser Permanente Vaccine Study Center, Oakland, Calif., told this news organization.

“Individuals who choose to receive Janssen/J&J COVID-19 vaccine should be informed of the potential safety risks, including GBS,” Dr. Klein said.

The study was published online in JAMA Network Open.
 

Eleven cases

Between mid-December 2020 and mid-November 2021, roughly 15.1 million doses of COVID-19 vaccine were administered to nearly 7.9 million adults in the United States.

This includes roughly 483,000 doses of the Janssen vaccine, 8.8 million doses of the Pfizer vaccine, and 5.8 million doses of the Moderna vaccine.

The researchers confirmed 11 cases of GBS after the Janssen vaccine.

The unadjusted incidence of GBS (per 100,000 person-years) was 32.4 in the first 21 days after the Janssen vaccine – substantially higher than the expected background rate of 1 to 2 cases per 100,000 person-years.

There were 36 confirmed cases of GBS after mRNA vaccines. The unadjusted incidence in the first 21 days after mRNA vaccination was 1.3 per 100,000 person-years, similar to the overall expected background rate.

In an adjusted head-to-head comparison, GBS incidence during the 21 days after receipt of the Janssen vaccine was 20.6 times higher than the GBS incidence during the 21 days after the Pfizer or Moderna mRNA vaccines, amounting to 15.5 excess cases per million Janssen vaccine recipients.

Most cases of GBS after the Janssen vaccine occurred during the 1- to 21-day risk interval, with the period of greatest risk in the 1-14 days after vaccination.

The findings of this analysis of surveillance data of COVID-19 vaccines are “consistent with an elevated risk of GBS after primary Ad26.COV2.S vaccination,” the authors wrote.
 

Novel presentation?

The researchers note that nearly all individuals who developed GBS after the Janssen vaccine had facial weakness or paralysis, in addition to weakness and decreased reflexes in the limbs, suggesting that the presentation of GBS after COVID-19 adenoviral vector vaccine may be novel.

“More research is needed to determine if the presentation of GBS after adenoviral vector vaccine differs from GBS after other exposures such as Campylobacter jejuni, and to investigate the mechanism for how adenoviral vector vaccines may cause GBS,” Dr. Klein and colleagues said.

“The Vaccine Safety Datalink continues to conduct safety surveillance for all COVID-19 vaccines, including monitoring for GBS and other serious health outcomes after vaccination,” Dr. Klein said in an interview.

This study was supported by the Centers for Disease Control and Prevention. Dr. Klein reported receiving grants from Pfizer research support for a COVID vaccine clinical trial as well as other unrelated studies, grants from Merck, grants from GlaxoSmithKline, grants from Sanofi Pasteur, and grants from Protein Science (now Sanofi Pasteur) outside the submitted work.

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

A clinical practice guideline for the diagnosis and management of gastrointestinal hamartomatous polyposis syndromes has just been published by the U.S. Multi-Society Task Force on Colorectal Cancer, which is comprised of experts representing the American College of Gastroenterology, the American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy.

Gastrointestinal hamartomatous polyposis syndromes are rare, autosomal dominant disorders associated with intestinal and extraintestinal tumors. Expert consensus statements have previously offered some recommendations for managing these syndromes, but clinical data are scarce, so the present review “is intended to establish a starting point for future research,” lead author C. Richard Boland, MD, of the University of California, San Diego, and colleagues reported.

According to the investigators, “there are essentially no long-term prospective controlled studies of comparative effectiveness of management strategies for these syndromes.” As a result, their recommendations are based on “low-quality” evidence according to GRADE criteria.

Still, Dr. Boland and colleagues highlighted that “there has been tremendous progress in recent years, both in understanding the underlying genetics that underpin these disorders and in elucidating the biology of associated premalignant and malignant conditions.”

The guideline was published online in Gastroenterology .
 

Four syndromes reviewed

The investigators gathered these data to provide an overview of genetic and clinical features for each syndrome, as well as management strategies. Four disorders are included: juvenile polyposis syndrome; Peutz-Jeghers syndrome; hereditary mixed polyposis syndrome; and PTEN-hamartoma tumor syndrome, encompassing Bannayan-Riley-Ruvalcaba syndrome and Cowden’s syndrome.

Although all gastrointestinal hamartomatous polyposis syndromes are caused by germline alterations, Dr. Boland and colleagues pointed out that diagnoses are typically made based on clinical criteria, with germline results serving as confirmatory evidence.

The guideline recommends that any patient with a family history of hamartomatous polyps, or with a history of at least two hamartomatous polyps, should undergo genetic testing. The guideline also provides more nuanced genetic testing algorithms for each syndrome.

Among all the hamartomatous polyp disorders, Peutz-Jeghers syndrome is most understood, according to the investigators. It is caused by aberrations in the STK11 gene, and is characterized by polyps with “branching bands of smooth muscle covered by hyperplastic glandular mucosa” that may occur in the stomach, small intestine, and colon. Patients are also at risk of extraintestinal neoplasia.

For management of Peutz-Jeghers syndrome, the guideline advises frequent endoscopic surveillance to prevent mechanical obstruction and bleeding, as well as multidisciplinary surveillance of the breasts, pancreas, ovaries, testes, and lungs.

Juvenile polyposis syndrome is most often characterized by solitary, sporadic polyps in the colorectum (98% of patients affected), followed distantly by polyps in the stomach (14%), ileum (7%), jejunum (7%), and duodenum (7%). The condition is linked with abnormalities in BMPR1A or SMAD4 genes, with SMAD4 germline abnormalities more often leading to “massive” gastric polyps, gastrointestinal bleeding, protein-losing enteropathy, and a higher incidence of gastric cancer in adulthood. Most patients with SMAD4 mutations also have hereditary hemorrhagic telangiectasia, characterized by gastrointestinal bleeding from mucocutaneous telangiectasias, arteriovenous malformations, and epistaxis.

Management of juvenile polyposis syndrome depends on frequent colonoscopies with polypectomies beginning at 12-15 years.

“The goal of surveillance in juvenile polyposis syndrome is to mitigate symptoms related to the disorder and decrease the risk of complications from the manifestations, including cancer,” Dr. Boland and colleagues wrote.

PTEN-hamartoma tumor syndrome, which includes both Bannayan-Riley-Ruvalcaba syndrome and Cowden’s syndrome, is caused by abnormalities in the eponymous PTEN gene. Patients with the condition have an increased risk of colon cancer and polyposis, as well as extraintestinal cancers.

Diagnosis of PTEN-hamartoma tumor syndrome may be complex, involving “clinical examination, mammography and breast MRI, thyroid ultrasound, transvaginal ultrasound, upper gastrointestinal endoscopy, colonoscopy, and renal ultrasound,” according to the guideline.

After diagnosis, frequent colonoscopies are recommended, typically starting at age 35 years, as well as continued surveillance of other organs.

Hereditary mixed polyposis syndrome, which involves attenuated colonic polyposis, is the rarest of the four disorders, having been reported in only “a few families,” according to the guideline. The condition has been linked with “large duplications of the promoter region or entire GREM1 gene.”

Onset is typically in the late 20s, “which is when colonoscopic surveillance should begin,” the investigators wrote. More data are needed to determine appropriate surveillance intervals and if the condition is associated with increased risk of extraintestinal neoplasia.

This call for more research into gastrointestinal hamartomatous polyposis syndromes carried through to the conclusion of the guideline.

“Long-term prospective studies of mutation carriers are still needed to further clarify the risk of cancer and the role of surveillance in these syndromes,” Dr. Boland and colleagues wrote. “With increases in genetic testing and evaluation, future studies will be conducted with more robust cohorts of genetically characterized, less heterogeneous populations. However, there is also a need to study patients and families with unusual phenotypes where no genotype can be found.”

The investigators disclosed no conflicts of interest with the current guideline; however, they provided a list of industry relationships, including Salix Pharmaceuticals, Ferring Pharmaceuticals, and Pfizer, among others.

A clinical practice guideline for the diagnosis and management of gastrointestinal hamartomatous polyposis syndromes has just been published by the U.S. Multi-Society Task Force on Colorectal Cancer, which is comprised of experts representing the American College of Gastroenterology, the American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy.

Gastrointestinal hamartomatous polyposis syndromes are rare, autosomal dominant disorders associated with intestinal and extraintestinal tumors. Expert consensus statements have previously offered some recommendations for managing these syndromes, but clinical data are scarce, so the present review “is intended to establish a starting point for future research,” lead author C. Richard Boland, MD, of the University of California, San Diego, and colleagues reported.

According to the investigators, “there are essentially no long-term prospective controlled studies of comparative effectiveness of management strategies for these syndromes.” As a result, their recommendations are based on “low-quality” evidence according to GRADE criteria.

Still, Dr. Boland and colleagues highlighted that “there has been tremendous progress in recent years, both in understanding the underlying genetics that underpin these disorders and in elucidating the biology of associated premalignant and malignant conditions.”

The guideline was published online in Gastroenterology .
 

Four syndromes reviewed

The investigators gathered these data to provide an overview of genetic and clinical features for each syndrome, as well as management strategies. Four disorders are included: juvenile polyposis syndrome; Peutz-Jeghers syndrome; hereditary mixed polyposis syndrome; and PTEN-hamartoma tumor syndrome, encompassing Bannayan-Riley-Ruvalcaba syndrome and Cowden’s syndrome.

Although all gastrointestinal hamartomatous polyposis syndromes are caused by germline alterations, Dr. Boland and colleagues pointed out that diagnoses are typically made based on clinical criteria, with germline results serving as confirmatory evidence.

The guideline recommends that any patient with a family history of hamartomatous polyps, or with a history of at least two hamartomatous polyps, should undergo genetic testing. The guideline also provides more nuanced genetic testing algorithms for each syndrome.

Among all the hamartomatous polyp disorders, Peutz-Jeghers syndrome is most understood, according to the investigators. It is caused by aberrations in the STK11 gene, and is characterized by polyps with “branching bands of smooth muscle covered by hyperplastic glandular mucosa” that may occur in the stomach, small intestine, and colon. Patients are also at risk of extraintestinal neoplasia.

For management of Peutz-Jeghers syndrome, the guideline advises frequent endoscopic surveillance to prevent mechanical obstruction and bleeding, as well as multidisciplinary surveillance of the breasts, pancreas, ovaries, testes, and lungs.

Juvenile polyposis syndrome is most often characterized by solitary, sporadic polyps in the colorectum (98% of patients affected), followed distantly by polyps in the stomach (14%), ileum (7%), jejunum (7%), and duodenum (7%). The condition is linked with abnormalities in BMPR1A or SMAD4 genes, with SMAD4 germline abnormalities more often leading to “massive” gastric polyps, gastrointestinal bleeding, protein-losing enteropathy, and a higher incidence of gastric cancer in adulthood. Most patients with SMAD4 mutations also have hereditary hemorrhagic telangiectasia, characterized by gastrointestinal bleeding from mucocutaneous telangiectasias, arteriovenous malformations, and epistaxis.

Management of juvenile polyposis syndrome depends on frequent colonoscopies with polypectomies beginning at 12-15 years.

“The goal of surveillance in juvenile polyposis syndrome is to mitigate symptoms related to the disorder and decrease the risk of complications from the manifestations, including cancer,” Dr. Boland and colleagues wrote.

PTEN-hamartoma tumor syndrome, which includes both Bannayan-Riley-Ruvalcaba syndrome and Cowden’s syndrome, is caused by abnormalities in the eponymous PTEN gene. Patients with the condition have an increased risk of colon cancer and polyposis, as well as extraintestinal cancers.

Diagnosis of PTEN-hamartoma tumor syndrome may be complex, involving “clinical examination, mammography and breast MRI, thyroid ultrasound, transvaginal ultrasound, upper gastrointestinal endoscopy, colonoscopy, and renal ultrasound,” according to the guideline.

After diagnosis, frequent colonoscopies are recommended, typically starting at age 35 years, as well as continued surveillance of other organs.

Hereditary mixed polyposis syndrome, which involves attenuated colonic polyposis, is the rarest of the four disorders, having been reported in only “a few families,” according to the guideline. The condition has been linked with “large duplications of the promoter region or entire GREM1 gene.”

Onset is typically in the late 20s, “which is when colonoscopic surveillance should begin,” the investigators wrote. More data are needed to determine appropriate surveillance intervals and if the condition is associated with increased risk of extraintestinal neoplasia.

This call for more research into gastrointestinal hamartomatous polyposis syndromes carried through to the conclusion of the guideline.

“Long-term prospective studies of mutation carriers are still needed to further clarify the risk of cancer and the role of surveillance in these syndromes,” Dr. Boland and colleagues wrote. “With increases in genetic testing and evaluation, future studies will be conducted with more robust cohorts of genetically characterized, less heterogeneous populations. However, there is also a need to study patients and families with unusual phenotypes where no genotype can be found.”

The investigators disclosed no conflicts of interest with the current guideline; however, they provided a list of industry relationships, including Salix Pharmaceuticals, Ferring Pharmaceuticals, and Pfizer, among others.

A clinical practice guideline for the diagnosis and management of gastrointestinal hamartomatous polyposis syndromes has just been published by the U.S. Multi-Society Task Force on Colorectal Cancer, which is comprised of experts representing the American College of Gastroenterology, the American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy.

Gastrointestinal hamartomatous polyposis syndromes are rare, autosomal dominant disorders associated with intestinal and extraintestinal tumors. Expert consensus statements have previously offered some recommendations for managing these syndromes, but clinical data are scarce, so the present review “is intended to establish a starting point for future research,” lead author C. Richard Boland, MD, of the University of California, San Diego, and colleagues reported.

According to the investigators, “there are essentially no long-term prospective controlled studies of comparative effectiveness of management strategies for these syndromes.” As a result, their recommendations are based on “low-quality” evidence according to GRADE criteria.

Still, Dr. Boland and colleagues highlighted that “there has been tremendous progress in recent years, both in understanding the underlying genetics that underpin these disorders and in elucidating the biology of associated premalignant and malignant conditions.”

The guideline was published online in Gastroenterology .
 

Four syndromes reviewed

The investigators gathered these data to provide an overview of genetic and clinical features for each syndrome, as well as management strategies. Four disorders are included: juvenile polyposis syndrome; Peutz-Jeghers syndrome; hereditary mixed polyposis syndrome; and PTEN-hamartoma tumor syndrome, encompassing Bannayan-Riley-Ruvalcaba syndrome and Cowden’s syndrome.

Although all gastrointestinal hamartomatous polyposis syndromes are caused by germline alterations, Dr. Boland and colleagues pointed out that diagnoses are typically made based on clinical criteria, with germline results serving as confirmatory evidence.

The guideline recommends that any patient with a family history of hamartomatous polyps, or with a history of at least two hamartomatous polyps, should undergo genetic testing. The guideline also provides more nuanced genetic testing algorithms for each syndrome.

Among all the hamartomatous polyp disorders, Peutz-Jeghers syndrome is most understood, according to the investigators. It is caused by aberrations in the STK11 gene, and is characterized by polyps with “branching bands of smooth muscle covered by hyperplastic glandular mucosa” that may occur in the stomach, small intestine, and colon. Patients are also at risk of extraintestinal neoplasia.

For management of Peutz-Jeghers syndrome, the guideline advises frequent endoscopic surveillance to prevent mechanical obstruction and bleeding, as well as multidisciplinary surveillance of the breasts, pancreas, ovaries, testes, and lungs.

Juvenile polyposis syndrome is most often characterized by solitary, sporadic polyps in the colorectum (98% of patients affected), followed distantly by polyps in the stomach (14%), ileum (7%), jejunum (7%), and duodenum (7%). The condition is linked with abnormalities in BMPR1A or SMAD4 genes, with SMAD4 germline abnormalities more often leading to “massive” gastric polyps, gastrointestinal bleeding, protein-losing enteropathy, and a higher incidence of gastric cancer in adulthood. Most patients with SMAD4 mutations also have hereditary hemorrhagic telangiectasia, characterized by gastrointestinal bleeding from mucocutaneous telangiectasias, arteriovenous malformations, and epistaxis.

Management of juvenile polyposis syndrome depends on frequent colonoscopies with polypectomies beginning at 12-15 years.

“The goal of surveillance in juvenile polyposis syndrome is to mitigate symptoms related to the disorder and decrease the risk of complications from the manifestations, including cancer,” Dr. Boland and colleagues wrote.

PTEN-hamartoma tumor syndrome, which includes both Bannayan-Riley-Ruvalcaba syndrome and Cowden’s syndrome, is caused by abnormalities in the eponymous PTEN gene. Patients with the condition have an increased risk of colon cancer and polyposis, as well as extraintestinal cancers.

Diagnosis of PTEN-hamartoma tumor syndrome may be complex, involving “clinical examination, mammography and breast MRI, thyroid ultrasound, transvaginal ultrasound, upper gastrointestinal endoscopy, colonoscopy, and renal ultrasound,” according to the guideline.

After diagnosis, frequent colonoscopies are recommended, typically starting at age 35 years, as well as continued surveillance of other organs.

Hereditary mixed polyposis syndrome, which involves attenuated colonic polyposis, is the rarest of the four disorders, having been reported in only “a few families,” according to the guideline. The condition has been linked with “large duplications of the promoter region or entire GREM1 gene.”

Onset is typically in the late 20s, “which is when colonoscopic surveillance should begin,” the investigators wrote. More data are needed to determine appropriate surveillance intervals and if the condition is associated with increased risk of extraintestinal neoplasia.

This call for more research into gastrointestinal hamartomatous polyposis syndromes carried through to the conclusion of the guideline.

“Long-term prospective studies of mutation carriers are still needed to further clarify the risk of cancer and the role of surveillance in these syndromes,” Dr. Boland and colleagues wrote. “With increases in genetic testing and evaluation, future studies will be conducted with more robust cohorts of genetically characterized, less heterogeneous populations. However, there is also a need to study patients and families with unusual phenotypes where no genotype can be found.”

The investigators disclosed no conflicts of interest with the current guideline; however, they provided a list of industry relationships, including Salix Pharmaceuticals, Ferring Pharmaceuticals, and Pfizer, among others.

A topical gel that contains birch bark extract as the active ingredient – Filsuvez (Oleogel-S10) – has been recommended for approval for the treatment of skin wounds in patients with epidermolysis bullosa (EB) by the European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use.

“The benefit of Filsuvez is its ability to promote healing of EB partial thickness wounds,” the EMA said in an announcement on April 22. “It is thought to work by modulating inflammatory mediators and stimulating keratinocyte differentiation and migration, thereby promoting wound health and closure,” the statement adds.

The recommended indication for the product – developed by Amryt Pharmaceuticals DAC and currently designated as an orphan drug – is for the treatment of partial-thickness wounds associated with dystrophic and junctional EB in patients aged 6 months and older. The recommendation for approval came after the EMA sought and received external advice from independent physicians treating EB and from patients with the rare disease.

The most common side effects, according to the EMA announcement, are wound complications, application site reactions, wound infections, pruritus, and hypersensitivity reactions.

In February 2022, the Food and Drug Administration declined to approve the company’s new drug application as it was presented and asked the company to submit additional evidence of effectiveness for Oleogel-S10 in EB, the company announced at that time. The statement noted that the company was committed to working with the FDA to identify "the most expeditious pathway towards a potential approval.” 

The company’s pivotal phase 3 trial enrolled 223 patients with EB, including 156 pediatric patients. The patients variously had three types of EB. The trial has two components: A 3-month, double-blind, randomized controlled phase, which has been completed, and an ongoing 24-month open-label, single-arm phase. The trial is being performed at 58 sites in 28 countries.

Results from the randomized controlled phase, reported in 2020, include a statistically significant increase in the proportion of patients achieving complete closure of an EB target wound within 45 days: 41.3% in the Oleogel-S10 group and 28.9% in the control group (P = .013). (Target wounds measured 10 cm² to 50 cm² and were present for at least 21 days but less than 9 months.) The safety profile of the treatment gel was acceptable and was well tolerated, compared with the control gel, according to Amryt’s press release. The results were presented at the European Academy of Dermatology and Venereology Congress in October 2020.

Data from a 12-month interim analysis of the follow-up phase were presented at the annual meeting of the American Academy of Dermatology in March 2022. Results showed further reductions in total body surface area percentage wounding to 5.4% among (from 7.4% at the end of the double-blind period and 12.1% at the beginning of the study) among the patients who continued treatment and who underwent assessment, according to a company press release. Treatment was well tolerated, and no new safety signals were identified, the release said.

A decision by the European Commission is expected within the next 2 months.

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

A topical gel that contains birch bark extract as the active ingredient – Filsuvez (Oleogel-S10) – has been recommended for approval for the treatment of skin wounds in patients with epidermolysis bullosa (EB) by the European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use.

“The benefit of Filsuvez is its ability to promote healing of EB partial thickness wounds,” the EMA said in an announcement on April 22. “It is thought to work by modulating inflammatory mediators and stimulating keratinocyte differentiation and migration, thereby promoting wound health and closure,” the statement adds.

The recommended indication for the product – developed by Amryt Pharmaceuticals DAC and currently designated as an orphan drug – is for the treatment of partial-thickness wounds associated with dystrophic and junctional EB in patients aged 6 months and older. The recommendation for approval came after the EMA sought and received external advice from independent physicians treating EB and from patients with the rare disease.

The most common side effects, according to the EMA announcement, are wound complications, application site reactions, wound infections, pruritus, and hypersensitivity reactions.

In February 2022, the Food and Drug Administration declined to approve the company’s new drug application as it was presented and asked the company to submit additional evidence of effectiveness for Oleogel-S10 in EB, the company announced at that time. The statement noted that the company was committed to working with the FDA to identify "the most expeditious pathway towards a potential approval.” 

The company’s pivotal phase 3 trial enrolled 223 patients with EB, including 156 pediatric patients. The patients variously had three types of EB. The trial has two components: A 3-month, double-blind, randomized controlled phase, which has been completed, and an ongoing 24-month open-label, single-arm phase. The trial is being performed at 58 sites in 28 countries.

Results from the randomized controlled phase, reported in 2020, include a statistically significant increase in the proportion of patients achieving complete closure of an EB target wound within 45 days: 41.3% in the Oleogel-S10 group and 28.9% in the control group (P = .013). (Target wounds measured 10 cm² to 50 cm² and were present for at least 21 days but less than 9 months.) The safety profile of the treatment gel was acceptable and was well tolerated, compared with the control gel, according to Amryt’s press release. The results were presented at the European Academy of Dermatology and Venereology Congress in October 2020.

Data from a 12-month interim analysis of the follow-up phase were presented at the annual meeting of the American Academy of Dermatology in March 2022. Results showed further reductions in total body surface area percentage wounding to 5.4% among (from 7.4% at the end of the double-blind period and 12.1% at the beginning of the study) among the patients who continued treatment and who underwent assessment, according to a company press release. Treatment was well tolerated, and no new safety signals were identified, the release said.

A decision by the European Commission is expected within the next 2 months.

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

A topical gel that contains birch bark extract as the active ingredient – Filsuvez (Oleogel-S10) – has been recommended for approval for the treatment of skin wounds in patients with epidermolysis bullosa (EB) by the European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use.

“The benefit of Filsuvez is its ability to promote healing of EB partial thickness wounds,” the EMA said in an announcement on April 22. “It is thought to work by modulating inflammatory mediators and stimulating keratinocyte differentiation and migration, thereby promoting wound health and closure,” the statement adds.

The recommended indication for the product – developed by Amryt Pharmaceuticals DAC and currently designated as an orphan drug – is for the treatment of partial-thickness wounds associated with dystrophic and junctional EB in patients aged 6 months and older. The recommendation for approval came after the EMA sought and received external advice from independent physicians treating EB and from patients with the rare disease.

The most common side effects, according to the EMA announcement, are wound complications, application site reactions, wound infections, pruritus, and hypersensitivity reactions.

In February 2022, the Food and Drug Administration declined to approve the company’s new drug application as it was presented and asked the company to submit additional evidence of effectiveness for Oleogel-S10 in EB, the company announced at that time. The statement noted that the company was committed to working with the FDA to identify "the most expeditious pathway towards a potential approval.” 

The company’s pivotal phase 3 trial enrolled 223 patients with EB, including 156 pediatric patients. The patients variously had three types of EB. The trial has two components: A 3-month, double-blind, randomized controlled phase, which has been completed, and an ongoing 24-month open-label, single-arm phase. The trial is being performed at 58 sites in 28 countries.

Results from the randomized controlled phase, reported in 2020, include a statistically significant increase in the proportion of patients achieving complete closure of an EB target wound within 45 days: 41.3% in the Oleogel-S10 group and 28.9% in the control group (P = .013). (Target wounds measured 10 cm² to 50 cm² and were present for at least 21 days but less than 9 months.) The safety profile of the treatment gel was acceptable and was well tolerated, compared with the control gel, according to Amryt’s press release. The results were presented at the European Academy of Dermatology and Venereology Congress in October 2020.

Data from a 12-month interim analysis of the follow-up phase were presented at the annual meeting of the American Academy of Dermatology in March 2022. Results showed further reductions in total body surface area percentage wounding to 5.4% among (from 7.4% at the end of the double-blind period and 12.1% at the beginning of the study) among the patients who continued treatment and who underwent assessment, according to a company press release. Treatment was well tolerated, and no new safety signals were identified, the release said.

A decision by the European Commission is expected within the next 2 months.

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