Physician authors of clinical practice guidelines for psoriatic arthritis in the United States and Japan received payments from pharmaceutical companies totaling over $7 million during 2016-2018, according to a retrospective analysis of all authors on the most recent guidelines issued by the American College of Rheumatology (ACR) and the Japanese Dermatological Association (JDA).

In addition to finding that the majority of the authors of psoriatic arthritis (PsA) clinical practice guidelines (CPGs) issued by the JDA and ACR received substantial personal payments from pharmaceutical companies before and during CPG development, researchers led by Hanano Mamada and Anju Murayama of the Medical Governance Research Institute, Tokyo, wrote in Arthritis Care & Research that “several CPG authors self-cited their articles without the disclosure of NFCOI [nonfinancial conflicts of interest], and most of the recommendations were based on low or very low quality of evidence. Although the COI policies used by JDA and ACR are clearly inadequate, no significant revisions have been made for the last 3 years.”

Based on their findings, which were made using payment data from major Japanese pharmaceutical companies and the U.S. Open Payments Database from 2016 to 2018, the researchers suggested that the medical societies should:

• Adopt global standard COI policies from organizations such as the National Academy of Medicine and Guidelines International Network, including a 3-year lookback period for COI declaration.
• Consider a comprehensive definition and rigorous management with full disclosure of NFCOI.
• Publish a list of authors making each recommendation to grasp the implications of COI in clinical practice guidelines.
• Mention the detailed date of the COI disclosure, which should be close to the publication date as much as possible.

Financial conflicts of interest

The researchers used payment data published between 2016 and 2018 for all 83 companies belonging to the Japan Pharmaceutical Manufacturers Association, focusing on personal payments (for lecturing, writing, and consultancy) and excluding research payments, “since in Japan, the name, institution, and position of the author or researcher who received the research payment is not disclosed, which makes assessing research payments difficult.” To evaluate authors’ FCOI in the ACR’s CPG, the researchers analyzed the U.S. Open Payments Database “for all categories of general payments such as speaking, consulting, meals, and travel expenses 3 years from before the guideline’s first online publication on November 30, 2018.”

The 2018 ACR/National Psoriasis Foundation Guideline for the Treatment of Psoriatic Arthritis had 36 authors and the JDA’s Clinical Practice Guideline for the Treatment of Psoriatic Arthritis 2019 had 23. Overall, 61% of JDA authors and half of ACR authors voluntarily declared FCOI with pharmaceutical companies; 25 of the ACR authors were U.S. physicians and could be included in the Open Payments Database search.

A total of 21 (91.3%) JDA authors and 21 (84.0%) ACR authors received at least one payment, with the combined total of $3,335,413 and $4,081,629 payments, respectively, over the 3 years. The average and median personal payments were $145,018 and $123,876 for JDA authors and $162,825 and $58,826 for ACR authors. When the payments to ACR authors were limited to lecturing, writing, and consulting fees that are required under the ACR’s COI policy, the mean was $130,102 and median was $39,375. The corresponding payments for JDA authors were $123,876 and $8,170, respectively,

The researchers found undisclosed payments for more than three-quarters of physician authors of the Japanese guideline, and nearly half of the doctors authoring the American guideline had undisclosed payments. These added up to $474,000 for the JDA, which amounted to 38% of the total for personal payments that must be reported to the JDA based on its COI policy for clinical practice guidelines, and $218,000 for the ACR, amounting to 18% of the total for personal payments that must be reported to the society based on its COI policy.

Of the 11 ACR authors who were not eligible for the U.S. Open Payments Database search, 5 declared FCOI with pharmaceutical companies in the guideline, meaning that 26 (72%) of the 36 authors had FCOI with pharmaceutical companies.

The ACR only required authors to declare FCOI covering 1 year before and during guideline development, and although the JDA required authors to declare their FCOI for the past 3 years of guideline development, the study authors noted that the JDA guideline disclosed them for only 2 years (between Jan. 1, 2017, and Dec. 31, 2018).

“It is true that influential doctors such as clinical practice guideline authors tend to receive various types of payments from pharmaceutical companies and that it is difficult to conduct research without funding from pharmaceutical companies. However, our current research mainly focuses on personal payments from pharmaceutical companies such as lecture fees and consulting fees. These payments are recognized as pocket money and are not used for research. Thus, it is questionable that the observed relationships are something evitable,” the researchers wrote.
 

Nonfinancial conflicts of interest

Many authors of the ACR’s CPG and the JDA’s CPG also had NFCOI, defined objectively in this study as self-citation rate. NFCOI have been more broadly defined by the International Committee of Medical Journal Editors (ICMJE) as “conflicts, such as personal relationships or rivalries, academic competition, and intellectual beliefs”; the ICMJE recommends reporting NFCOI on its COI form.

The JDA guideline included self-citations by 78% of its authors, compared with 32% of the ACR guideline authors, but this weighed differently among the two guidelines in that only 12 of the 354 (3.4%) citations in the JDA guideline were self-cited, compared with 46 of 137 (34%) citations in the ACR guideline.

The researchers noted that while the self-citation rates between JDA and ACR authors “differed remarkably,” the impact of ACR authors on CPG recommendations was much more direct. Three-quarters of JDA authors’ self-cited articles were about observational studies, whereas 52% of the ACR authors’ self-cited articles were clinical trials, most of which were randomized, controlled studies, and these NFCOI were not disclosed in the guideline.

Half of the strong recommendations in the JDA guideline were based on low or very low quality of evidence, whereas the ACR guideline had no strong recommendations based on low or very low quality of evidence.

This study was supported by the nonprofit Medical Governance Research Institute, which receives donations from Ain Pharmacies Inc., other organizations, and private individuals. The study also received support from the Tansa (formerly known as the Waseda Chronicle), an independent nonprofit news organization dedicated to investigative journalism. Three authors reported receiving personal fees from several pharmaceutical companies for work outside of the scope of this study.

Physician authors of clinical practice guidelines for psoriatic arthritis in the United States and Japan received payments from pharmaceutical companies totaling over $7 million during 2016-2018, according to a retrospective analysis of all authors on the most recent guidelines issued by the American College of Rheumatology (ACR) and the Japanese Dermatological Association (JDA).

In addition to finding that the majority of the authors of psoriatic arthritis (PsA) clinical practice guidelines (CPGs) issued by the JDA and ACR received substantial personal payments from pharmaceutical companies before and during CPG development, researchers led by Hanano Mamada and Anju Murayama of the Medical Governance Research Institute, Tokyo, wrote in Arthritis Care & Research that “several CPG authors self-cited their articles without the disclosure of NFCOI [nonfinancial conflicts of interest], and most of the recommendations were based on low or very low quality of evidence. Although the COI policies used by JDA and ACR are clearly inadequate, no significant revisions have been made for the last 3 years.”

Based on their findings, which were made using payment data from major Japanese pharmaceutical companies and the U.S. Open Payments Database from 2016 to 2018, the researchers suggested that the medical societies should:

• Adopt global standard COI policies from organizations such as the National Academy of Medicine and Guidelines International Network, including a 3-year lookback period for COI declaration.
• Consider a comprehensive definition and rigorous management with full disclosure of NFCOI.
• Publish a list of authors making each recommendation to grasp the implications of COI in clinical practice guidelines.
• Mention the detailed date of the COI disclosure, which should be close to the publication date as much as possible.

Financial conflicts of interest

The researchers used payment data published between 2016 and 2018 for all 83 companies belonging to the Japan Pharmaceutical Manufacturers Association, focusing on personal payments (for lecturing, writing, and consultancy) and excluding research payments, “since in Japan, the name, institution, and position of the author or researcher who received the research payment is not disclosed, which makes assessing research payments difficult.” To evaluate authors’ FCOI in the ACR’s CPG, the researchers analyzed the U.S. Open Payments Database “for all categories of general payments such as speaking, consulting, meals, and travel expenses 3 years from before the guideline’s first online publication on November 30, 2018.”

The 2018 ACR/National Psoriasis Foundation Guideline for the Treatment of Psoriatic Arthritis had 36 authors and the JDA’s Clinical Practice Guideline for the Treatment of Psoriatic Arthritis 2019 had 23. Overall, 61% of JDA authors and half of ACR authors voluntarily declared FCOI with pharmaceutical companies; 25 of the ACR authors were U.S. physicians and could be included in the Open Payments Database search.

A total of 21 (91.3%) JDA authors and 21 (84.0%) ACR authors received at least one payment, with the combined total of $3,335,413 and $4,081,629 payments, respectively, over the 3 years. The average and median personal payments were $145,018 and $123,876 for JDA authors and $162,825 and $58,826 for ACR authors. When the payments to ACR authors were limited to lecturing, writing, and consulting fees that are required under the ACR’s COI policy, the mean was $130,102 and median was $39,375. The corresponding payments for JDA authors were $123,876 and $8,170, respectively,

The researchers found undisclosed payments for more than three-quarters of physician authors of the Japanese guideline, and nearly half of the doctors authoring the American guideline had undisclosed payments. These added up to $474,000 for the JDA, which amounted to 38% of the total for personal payments that must be reported to the JDA based on its COI policy for clinical practice guidelines, and $218,000 for the ACR, amounting to 18% of the total for personal payments that must be reported to the society based on its COI policy.

Of the 11 ACR authors who were not eligible for the U.S. Open Payments Database search, 5 declared FCOI with pharmaceutical companies in the guideline, meaning that 26 (72%) of the 36 authors had FCOI with pharmaceutical companies.

The ACR only required authors to declare FCOI covering 1 year before and during guideline development, and although the JDA required authors to declare their FCOI for the past 3 years of guideline development, the study authors noted that the JDA guideline disclosed them for only 2 years (between Jan. 1, 2017, and Dec. 31, 2018).

“It is true that influential doctors such as clinical practice guideline authors tend to receive various types of payments from pharmaceutical companies and that it is difficult to conduct research without funding from pharmaceutical companies. However, our current research mainly focuses on personal payments from pharmaceutical companies such as lecture fees and consulting fees. These payments are recognized as pocket money and are not used for research. Thus, it is questionable that the observed relationships are something evitable,” the researchers wrote.
 

Nonfinancial conflicts of interest

Many authors of the ACR’s CPG and the JDA’s CPG also had NFCOI, defined objectively in this study as self-citation rate. NFCOI have been more broadly defined by the International Committee of Medical Journal Editors (ICMJE) as “conflicts, such as personal relationships or rivalries, academic competition, and intellectual beliefs”; the ICMJE recommends reporting NFCOI on its COI form.

The JDA guideline included self-citations by 78% of its authors, compared with 32% of the ACR guideline authors, but this weighed differently among the two guidelines in that only 12 of the 354 (3.4%) citations in the JDA guideline were self-cited, compared with 46 of 137 (34%) citations in the ACR guideline.

The researchers noted that while the self-citation rates between JDA and ACR authors “differed remarkably,” the impact of ACR authors on CPG recommendations was much more direct. Three-quarters of JDA authors’ self-cited articles were about observational studies, whereas 52% of the ACR authors’ self-cited articles were clinical trials, most of which were randomized, controlled studies, and these NFCOI were not disclosed in the guideline.

Half of the strong recommendations in the JDA guideline were based on low or very low quality of evidence, whereas the ACR guideline had no strong recommendations based on low or very low quality of evidence.

This study was supported by the nonprofit Medical Governance Research Institute, which receives donations from Ain Pharmacies Inc., other organizations, and private individuals. The study also received support from the Tansa (formerly known as the Waseda Chronicle), an independent nonprofit news organization dedicated to investigative journalism. Three authors reported receiving personal fees from several pharmaceutical companies for work outside of the scope of this study.

Physician authors of clinical practice guidelines for psoriatic arthritis in the United States and Japan received payments from pharmaceutical companies totaling over $7 million during 2016-2018, according to a retrospective analysis of all authors on the most recent guidelines issued by the American College of Rheumatology (ACR) and the Japanese Dermatological Association (JDA).

In addition to finding that the majority of the authors of psoriatic arthritis (PsA) clinical practice guidelines (CPGs) issued by the JDA and ACR received substantial personal payments from pharmaceutical companies before and during CPG development, researchers led by Hanano Mamada and Anju Murayama of the Medical Governance Research Institute, Tokyo, wrote in Arthritis Care & Research that “several CPG authors self-cited their articles without the disclosure of NFCOI [nonfinancial conflicts of interest], and most of the recommendations were based on low or very low quality of evidence. Although the COI policies used by JDA and ACR are clearly inadequate, no significant revisions have been made for the last 3 years.”

Based on their findings, which were made using payment data from major Japanese pharmaceutical companies and the U.S. Open Payments Database from 2016 to 2018, the researchers suggested that the medical societies should:

• Adopt global standard COI policies from organizations such as the National Academy of Medicine and Guidelines International Network, including a 3-year lookback period for COI declaration.
• Consider a comprehensive definition and rigorous management with full disclosure of NFCOI.
• Publish a list of authors making each recommendation to grasp the implications of COI in clinical practice guidelines.
• Mention the detailed date of the COI disclosure, which should be close to the publication date as much as possible.

Financial conflicts of interest

The researchers used payment data published between 2016 and 2018 for all 83 companies belonging to the Japan Pharmaceutical Manufacturers Association, focusing on personal payments (for lecturing, writing, and consultancy) and excluding research payments, “since in Japan, the name, institution, and position of the author or researcher who received the research payment is not disclosed, which makes assessing research payments difficult.” To evaluate authors’ FCOI in the ACR’s CPG, the researchers analyzed the U.S. Open Payments Database “for all categories of general payments such as speaking, consulting, meals, and travel expenses 3 years from before the guideline’s first online publication on November 30, 2018.”

The 2018 ACR/National Psoriasis Foundation Guideline for the Treatment of Psoriatic Arthritis had 36 authors and the JDA’s Clinical Practice Guideline for the Treatment of Psoriatic Arthritis 2019 had 23. Overall, 61% of JDA authors and half of ACR authors voluntarily declared FCOI with pharmaceutical companies; 25 of the ACR authors were U.S. physicians and could be included in the Open Payments Database search.

A total of 21 (91.3%) JDA authors and 21 (84.0%) ACR authors received at least one payment, with the combined total of $3,335,413 and $4,081,629 payments, respectively, over the 3 years. The average and median personal payments were $145,018 and $123,876 for JDA authors and $162,825 and $58,826 for ACR authors. When the payments to ACR authors were limited to lecturing, writing, and consulting fees that are required under the ACR’s COI policy, the mean was $130,102 and median was $39,375. The corresponding payments for JDA authors were $123,876 and $8,170, respectively,

The researchers found undisclosed payments for more than three-quarters of physician authors of the Japanese guideline, and nearly half of the doctors authoring the American guideline had undisclosed payments. These added up to $474,000 for the JDA, which amounted to 38% of the total for personal payments that must be reported to the JDA based on its COI policy for clinical practice guidelines, and $218,000 for the ACR, amounting to 18% of the total for personal payments that must be reported to the society based on its COI policy.

Of the 11 ACR authors who were not eligible for the U.S. Open Payments Database search, 5 declared FCOI with pharmaceutical companies in the guideline, meaning that 26 (72%) of the 36 authors had FCOI with pharmaceutical companies.

The ACR only required authors to declare FCOI covering 1 year before and during guideline development, and although the JDA required authors to declare their FCOI for the past 3 years of guideline development, the study authors noted that the JDA guideline disclosed them for only 2 years (between Jan. 1, 2017, and Dec. 31, 2018).

“It is true that influential doctors such as clinical practice guideline authors tend to receive various types of payments from pharmaceutical companies and that it is difficult to conduct research without funding from pharmaceutical companies. However, our current research mainly focuses on personal payments from pharmaceutical companies such as lecture fees and consulting fees. These payments are recognized as pocket money and are not used for research. Thus, it is questionable that the observed relationships are something evitable,” the researchers wrote.
 

Nonfinancial conflicts of interest

Many authors of the ACR’s CPG and the JDA’s CPG also had NFCOI, defined objectively in this study as self-citation rate. NFCOI have been more broadly defined by the International Committee of Medical Journal Editors (ICMJE) as “conflicts, such as personal relationships or rivalries, academic competition, and intellectual beliefs”; the ICMJE recommends reporting NFCOI on its COI form.

The JDA guideline included self-citations by 78% of its authors, compared with 32% of the ACR guideline authors, but this weighed differently among the two guidelines in that only 12 of the 354 (3.4%) citations in the JDA guideline were self-cited, compared with 46 of 137 (34%) citations in the ACR guideline.

The researchers noted that while the self-citation rates between JDA and ACR authors “differed remarkably,” the impact of ACR authors on CPG recommendations was much more direct. Three-quarters of JDA authors’ self-cited articles were about observational studies, whereas 52% of the ACR authors’ self-cited articles were clinical trials, most of which were randomized, controlled studies, and these NFCOI were not disclosed in the guideline.

Half of the strong recommendations in the JDA guideline were based on low or very low quality of evidence, whereas the ACR guideline had no strong recommendations based on low or very low quality of evidence.

This study was supported by the nonprofit Medical Governance Research Institute, which receives donations from Ain Pharmacies Inc., other organizations, and private individuals. The study also received support from the Tansa (formerly known as the Waseda Chronicle), an independent nonprofit news organization dedicated to investigative journalism. Three authors reported receiving personal fees from several pharmaceutical companies for work outside of the scope of this study.

To be cost effective, compared with metformin, for initial therapy for type 2 diabetes, prices for a sodium-glucose cotransporter-2 (SGLT2) inhibitor or a glucagon-like peptide-1 (GLP-1) agonist would have to fall by at least 70% and at least 90%, respectively, according to estimates.

Thinkstock Photos

The study, modeled on U.S. patients, by Jin G. Choi, MD, and colleagues, was published online Oct. 3 in the Annals of Internal Medicine.

The researchers simulated the lifetime incidence, prevalence, mortality, and costs associated with three different first-line treatment strategies – metformin, an SGLT2 inhibitor, or a GLP-1 agonist – in U.S. patients with untreated type 2 diabetes.

Compared with patients who received initial treatment with metformin, those who received one of the newer drugs had 4.4% to 5.2% lower lifetime rates of congestive heart failure, ischemic heart disease, myocardial infarction, and stroke.

However, to be cost-effective at under $150,000 per quality-adjusted life-years (QALY), SGLT2 inhibitors would need to cost less than $5 a day ($1,800 a year), and GLP-1 agonists would have to cost less than $6 a day ($2,100 a year), a lot less than now.

Knowing how expensive these drugs are, “I am not surprised” that the model predicts that the price would have to drop so much to make them cost-effective, compared with first-line treatment with metformin, senior author Neda Laiteerapong, MD, said in an interview.

“But I am disappointed,” she said, because these drugs are very effective, and if the prices were lower, more people could benefit.

“In the interest of improving access to high-quality care in the United States, our study results indicate the need to reduce SGLT2 inhibitor and GLP-1 receptor agonist medication costs substantially for patients with type 2 [diabetes] to improve health outcomes and prevent exacerbating diabetes health disparities,” the researchers conclude.

One way that the newer drugs might be more widely affordable is if the government became involved, possibly by passing a law similar to the Affordable Insulin Now Act, speculated Dr. Laiteerapong, who is associate director at the Center for Chronic Disease Research and Policy, University of Chicago.
 

‘Current prices too high to encourage first-line adoption’

Guidelines recommend the use of SGLT2 inhibitors and GLP-1 agonists as second-line therapies for patients with type 2 diabetes, but it has not been clear if clinical benefits would outweigh costs for use as first-line therapies.

“Although clinical trials have demonstrated the clinical effectiveness of these newer drugs, they are hundreds of times more expensive than other ... diabetes drugs,” the researchers note.

On the other hand, costs may fall in the coming years when these new drugs come off-patent.

The current study was designed to help inform future clinical guidelines.

The researchers created a population simulation model based on the United Kingdom Prospective Diabetes Study, Outcomes Model version 2 (UKPDS OM2) for diabetes-related complications and mortality, with added information about hypoglycemic events, quality of life, and U.S. costs. 

The researchers also identified a nationally representative sample of people who would be eligible to start first-line diabetes therapy when their A1c reached 7% for the model. 

Using National Health and Nutrition Examination Survey (NHANES) data (2013-2016), the researchers identified about 7.3 million U.S. adults aged 18 and older with self-reported diabetes or an A1c greater than 6.5% with no reported use of diabetes medications.

Patients were an average age of 55, and 55% were women. They had had diabetes for an average of 4.2 years, and 36% had a history of diabetes complications.

The model projected that patients would have an improved life expectancy of 3.0 and 3.4 months from first-line SGLT2 inhibitors and GLP-1 agonists, respectively, compared with initial therapy with metformin due to reduced rates of macrovascular disease.  

“However, the current drug costs would be too high to encourage their adoption as first-line for usual clinical practice,” the researchers report.
 

‘Disparities could remain for decades’

Generic SGLT2 inhibitors could enter the marketplace shortly, because one of two dapagliflozin patents expired in October 2020 and approval for generic alternatives has been sought from the U.S. Food and Drug Administration, Dr. Choi and colleagues note.

However, it could still take decades for medication prices to drop low enough to become affordable, the group cautions. For example, a generic GLP-1 agonist became available in 2017, but costs remain high.

“Without external incentives,” the group writes, “limited access to these drug classes will likely persist (for example, due to higher copays or requirements for prior authorizations), as will further diabetes disparities – for decades into the future – because of differential access to care due to insurance (for example, private vs. public), which often tracks race and ethnicity.”

The study was supported by the American Diabetes Association. Dr. Choi was supported by a National Institutes of Health, National Institute on Aging grant. Dr. Laiteerapong and other co-authors are members of the National Institute of Diabetes and Digestive and Kidney Diseases Chicago Center for Diabetes Translation Research at the University of Chicago. Dr. Choi and Dr. Laiteerapong have reported no relevant financial relationships.

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

To be cost effective, compared with metformin, for initial therapy for type 2 diabetes, prices for a sodium-glucose cotransporter-2 (SGLT2) inhibitor or a glucagon-like peptide-1 (GLP-1) agonist would have to fall by at least 70% and at least 90%, respectively, according to estimates.

Thinkstock Photos

The study, modeled on U.S. patients, by Jin G. Choi, MD, and colleagues, was published online Oct. 3 in the Annals of Internal Medicine.

The researchers simulated the lifetime incidence, prevalence, mortality, and costs associated with three different first-line treatment strategies – metformin, an SGLT2 inhibitor, or a GLP-1 agonist – in U.S. patients with untreated type 2 diabetes.

Compared with patients who received initial treatment with metformin, those who received one of the newer drugs had 4.4% to 5.2% lower lifetime rates of congestive heart failure, ischemic heart disease, myocardial infarction, and stroke.

However, to be cost-effective at under $150,000 per quality-adjusted life-years (QALY), SGLT2 inhibitors would need to cost less than $5 a day ($1,800 a year), and GLP-1 agonists would have to cost less than $6 a day ($2,100 a year), a lot less than now.

Knowing how expensive these drugs are, “I am not surprised” that the model predicts that the price would have to drop so much to make them cost-effective, compared with first-line treatment with metformin, senior author Neda Laiteerapong, MD, said in an interview.

“But I am disappointed,” she said, because these drugs are very effective, and if the prices were lower, more people could benefit.

“In the interest of improving access to high-quality care in the United States, our study results indicate the need to reduce SGLT2 inhibitor and GLP-1 receptor agonist medication costs substantially for patients with type 2 [diabetes] to improve health outcomes and prevent exacerbating diabetes health disparities,” the researchers conclude.

One way that the newer drugs might be more widely affordable is if the government became involved, possibly by passing a law similar to the Affordable Insulin Now Act, speculated Dr. Laiteerapong, who is associate director at the Center for Chronic Disease Research and Policy, University of Chicago.
 

‘Current prices too high to encourage first-line adoption’

Guidelines recommend the use of SGLT2 inhibitors and GLP-1 agonists as second-line therapies for patients with type 2 diabetes, but it has not been clear if clinical benefits would outweigh costs for use as first-line therapies.

“Although clinical trials have demonstrated the clinical effectiveness of these newer drugs, they are hundreds of times more expensive than other ... diabetes drugs,” the researchers note.

On the other hand, costs may fall in the coming years when these new drugs come off-patent.

The current study was designed to help inform future clinical guidelines.

The researchers created a population simulation model based on the United Kingdom Prospective Diabetes Study, Outcomes Model version 2 (UKPDS OM2) for diabetes-related complications and mortality, with added information about hypoglycemic events, quality of life, and U.S. costs. 

The researchers also identified a nationally representative sample of people who would be eligible to start first-line diabetes therapy when their A1c reached 7% for the model. 

Using National Health and Nutrition Examination Survey (NHANES) data (2013-2016), the researchers identified about 7.3 million U.S. adults aged 18 and older with self-reported diabetes or an A1c greater than 6.5% with no reported use of diabetes medications.

Patients were an average age of 55, and 55% were women. They had had diabetes for an average of 4.2 years, and 36% had a history of diabetes complications.

The model projected that patients would have an improved life expectancy of 3.0 and 3.4 months from first-line SGLT2 inhibitors and GLP-1 agonists, respectively, compared with initial therapy with metformin due to reduced rates of macrovascular disease.  

“However, the current drug costs would be too high to encourage their adoption as first-line for usual clinical practice,” the researchers report.
 

‘Disparities could remain for decades’

Generic SGLT2 inhibitors could enter the marketplace shortly, because one of two dapagliflozin patents expired in October 2020 and approval for generic alternatives has been sought from the U.S. Food and Drug Administration, Dr. Choi and colleagues note.

However, it could still take decades for medication prices to drop low enough to become affordable, the group cautions. For example, a generic GLP-1 agonist became available in 2017, but costs remain high.

“Without external incentives,” the group writes, “limited access to these drug classes will likely persist (for example, due to higher copays or requirements for prior authorizations), as will further diabetes disparities – for decades into the future – because of differential access to care due to insurance (for example, private vs. public), which often tracks race and ethnicity.”

The study was supported by the American Diabetes Association. Dr. Choi was supported by a National Institutes of Health, National Institute on Aging grant. Dr. Laiteerapong and other co-authors are members of the National Institute of Diabetes and Digestive and Kidney Diseases Chicago Center for Diabetes Translation Research at the University of Chicago. Dr. Choi and Dr. Laiteerapong have reported no relevant financial relationships.

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

To be cost effective, compared with metformin, for initial therapy for type 2 diabetes, prices for a sodium-glucose cotransporter-2 (SGLT2) inhibitor or a glucagon-like peptide-1 (GLP-1) agonist would have to fall by at least 70% and at least 90%, respectively, according to estimates.

Thinkstock Photos

The study, modeled on U.S. patients, by Jin G. Choi, MD, and colleagues, was published online Oct. 3 in the Annals of Internal Medicine.

The researchers simulated the lifetime incidence, prevalence, mortality, and costs associated with three different first-line treatment strategies – metformin, an SGLT2 inhibitor, or a GLP-1 agonist – in U.S. patients with untreated type 2 diabetes.

Compared with patients who received initial treatment with metformin, those who received one of the newer drugs had 4.4% to 5.2% lower lifetime rates of congestive heart failure, ischemic heart disease, myocardial infarction, and stroke.

However, to be cost-effective at under $150,000 per quality-adjusted life-years (QALY), SGLT2 inhibitors would need to cost less than $5 a day ($1,800 a year), and GLP-1 agonists would have to cost less than $6 a day ($2,100 a year), a lot less than now.

Knowing how expensive these drugs are, “I am not surprised” that the model predicts that the price would have to drop so much to make them cost-effective, compared with first-line treatment with metformin, senior author Neda Laiteerapong, MD, said in an interview.

“But I am disappointed,” she said, because these drugs are very effective, and if the prices were lower, more people could benefit.

“In the interest of improving access to high-quality care in the United States, our study results indicate the need to reduce SGLT2 inhibitor and GLP-1 receptor agonist medication costs substantially for patients with type 2 [diabetes] to improve health outcomes and prevent exacerbating diabetes health disparities,” the researchers conclude.

One way that the newer drugs might be more widely affordable is if the government became involved, possibly by passing a law similar to the Affordable Insulin Now Act, speculated Dr. Laiteerapong, who is associate director at the Center for Chronic Disease Research and Policy, University of Chicago.
 

‘Current prices too high to encourage first-line adoption’

Guidelines recommend the use of SGLT2 inhibitors and GLP-1 agonists as second-line therapies for patients with type 2 diabetes, but it has not been clear if clinical benefits would outweigh costs for use as first-line therapies.

“Although clinical trials have demonstrated the clinical effectiveness of these newer drugs, they are hundreds of times more expensive than other ... diabetes drugs,” the researchers note.

On the other hand, costs may fall in the coming years when these new drugs come off-patent.

The current study was designed to help inform future clinical guidelines.

The researchers created a population simulation model based on the United Kingdom Prospective Diabetes Study, Outcomes Model version 2 (UKPDS OM2) for diabetes-related complications and mortality, with added information about hypoglycemic events, quality of life, and U.S. costs. 

The researchers also identified a nationally representative sample of people who would be eligible to start first-line diabetes therapy when their A1c reached 7% for the model. 

Using National Health and Nutrition Examination Survey (NHANES) data (2013-2016), the researchers identified about 7.3 million U.S. adults aged 18 and older with self-reported diabetes or an A1c greater than 6.5% with no reported use of diabetes medications.

Patients were an average age of 55, and 55% were women. They had had diabetes for an average of 4.2 years, and 36% had a history of diabetes complications.

The model projected that patients would have an improved life expectancy of 3.0 and 3.4 months from first-line SGLT2 inhibitors and GLP-1 agonists, respectively, compared with initial therapy with metformin due to reduced rates of macrovascular disease.  

“However, the current drug costs would be too high to encourage their adoption as first-line for usual clinical practice,” the researchers report.
 

‘Disparities could remain for decades’

Generic SGLT2 inhibitors could enter the marketplace shortly, because one of two dapagliflozin patents expired in October 2020 and approval for generic alternatives has been sought from the U.S. Food and Drug Administration, Dr. Choi and colleagues note.

However, it could still take decades for medication prices to drop low enough to become affordable, the group cautions. For example, a generic GLP-1 agonist became available in 2017, but costs remain high.

“Without external incentives,” the group writes, “limited access to these drug classes will likely persist (for example, due to higher copays or requirements for prior authorizations), as will further diabetes disparities – for decades into the future – because of differential access to care due to insurance (for example, private vs. public), which often tracks race and ethnicity.”

The study was supported by the American Diabetes Association. Dr. Choi was supported by a National Institutes of Health, National Institute on Aging grant. Dr. Laiteerapong and other co-authors are members of the National Institute of Diabetes and Digestive and Kidney Diseases Chicago Center for Diabetes Translation Research at the University of Chicago. Dr. Choi and Dr. Laiteerapong have reported no relevant financial relationships.

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

Herpes simplex keratitis (HSK) is a common yet potentially blinding condition caused by a primary or reactivated herpetic infection of the cornea.¹ The Herpetic Eye Disease Study established the standard of care in HSK management.² Treatments range from oral antivirals and artificial tears to topical antibiotics, amniotic membranes, and corneal transplantation.³ Patients with immune stromal keratitis (ISK) may experience low-grade chronic keratitis for years.⁴ ISK is classified by a cellular and neovascularization infiltration of the cornea.⁵ We present a case of a patient with recurrent ISK and review its presentation, diagnosis, and management.

Case Presentation

A 52-year-old man presented to the eye clinic with a watery and itchy right eye with mildly blurred vision. His ocular history was unremarkable. His medical history was notable for hepatitis C, hypertension, alcohol and drug dependence, homelessness, and a COVID-19–induced coma. His medications included trazodone, nifedipine, clonidine HCl, and buprenorphine/naloxone.

On clinical examination, the patient’s best-corrected visual acuity was 20/40 in the right eye and 20/20 in the left. Corneal sensitivity was absent in the right eye and intact in the left. Anterior segment findings in the right eye included 360-degree superficial corneal neovascularization, deep neovascularization temporally, scattered patches of corneal haze, epithelial irregularity, and 2+ diffuse bulbar conjunctival injection (Figure 1). The anterior segment of the left eye and the posterior segments of both eyes were unremarkable. The differential diagnosis included HSK, syphilis, Cogan syndrome, varicella-zoster virus keratitis, Epstein-Barr virus keratitis, and Lyme disease. With consultation from a corneal specialist, the patient was given the presumptive diagnosis of ISK in the right eye based on unilateral corneal presentation and lack of corneal sensitivity. He was treated with 1-g oral valacyclovir HCl 3 times daily and 1 drop of prednisolone acetate 1% suspension 3 times daily in the right eye.

The patient followed up 2 weeks later. He reported good adherence to the ISK medication regimen. His symptoms had resolved, and his visual acuity returned to 20/20 in the right eye. Slit-lamp examination showed improvement in injection, and the superficial corneal neovascularization had cleared. A trace ghost vessel was seen temporally at a site of deep neovascularization (Figure 2). He was instructed to continue valacyclovir once daily and prednisolone drops once daily in the right eye and to follow up in 1 month.

At the 1-month follow-up, the patient’s signs and symptoms had reverted to his original presentation. The patient reported poor adherence to the medication regimen, having missed multiple doses of prednisolone drops as well as valacyclovir. The patient was counseled again on the ISK regimen, and the prednisolone drops and 1-g oral valacyclovir were refilled. A follow-up visit was scheduled for 2 weeks. Additional follow-up revealed a resolved corneal appearance and bimonthly follow-ups were scheduled thereafter.

Discussion

HSK is the most common infectious cause of unilateral blindness and vision impairment in the world.² This case highlights the diagnosis and management of a patient with ISK, a type of HSK characterized by decreased corneal sensitivity and unilateral stromal opacification or neovascularization.⁶

ISK is caused by the herpes simplex virus (HSV), a double-stranded enveloped DNA virus that occurs worldwide with little variation, replicates in many types of cells, has rapid growth, and is cytolytic, causing necrosis of nearby cells. Transmission is via direct contact and there is a lifelong latency period in the trigeminal ganglia. Both primary and reactivation infections of HSK can affect a broad array of ocular structures, from the lids to the retina. Infectious epithelial keratitis, also known as dendritic keratitis, is the reactivation of the live virus and is the most common presentation of HSK. ISK is responsible for 20% to 48% of recurrent HSV disease and is the leading cause of vision loss. ISK is the result of an immune-mediated inflammatory response due to a retained viral antigen within the stromal tissue.⁷ Inflammation in the corneal stroma leads to corneal haze and eventually focal or diffuse scarring, reducing the visual potential.⁷ This presentation may occur days to years after the initial epithelial episode and may persist for years. Although this patient did not present with infectious epithelial keratitis, it is possible he had a previous episode not mentioned as a history was difficult to obtain, and it can be subtle or innocuous, like pink eye.

Symptoms of ISK include unilateral redness, photophobia, tearing, eye pain, and blurred vision, as described by this patient. On examination, initial manifestations of ISK include corneal haze, edema, scarring, and neovascularization.⁷ Again, this patient presented with edema and neovascularization. These signs may improve with prompt diagnosis and treatment. More frequent reactivated disease leads to a higher propensity of corneal scarring and irregular astigmatism, reducing the visual outcome.

The standard of care established by the Herpetic Eye Disease Study recommends that a patient with presumed ISK should be started on oral antiviral therapy and, in the absence of epithelial disease, topical steroids. Oral antivirals, such as acyclovir and valacyclovir, have good ocular penetration, a good safety profile, a low susceptibility of resistance, and are well tolerated with long-term treatment.^2,8 There were no known interactions between any of the patient’s medications and valacyclovir. Oral antivirals should be used in the initial presentation and for maintenance therapy to help reduce the chance of recurrent disease. Initial treatment for ISK is 1-g valacyclovir 3 times daily. When the eye becomes quiet, that dosage can be tapered to 1 g twice daily, to 1 g once daily, and eventually to a maintenance dose of 500 mg daily. Topical steroids block the inflammatory cascade, therefore reducing the corneal inflammation and potential scarring, further reducing the risk of visual impairment.⁹ Initial treatment is 1 drop 3 times daily, then can be tapered at the same schedule as the oral acyclovir to help simplify adherence for the patient. After 1 drop once daily, steroids may be discontinued while the oral antiviral maintenance dosage continues. Follow-ups should be performed on a monthly to bimonthly basis to evaluate intraocular pressure, ensuring there is no steroid response.

As seen in this patient, adherence with a treatment regimen and awareness of factors, such as a complex psychosocial history that may impact this adherence, are of utmost importance.⁷

Conclusions

ISK presents unilaterally with decreased or absent corneal sensitivity and nonspecific symptoms. It should be at the top of the list in the differential diagnosis in any patient with unilateral corneal edema, opacification, or neovascularization, and the patient should be started on oral antiviral therapy.

Herpes simplex keratitis (HSK) is a common yet potentially blinding condition caused by a primary or reactivated herpetic infection of the cornea.¹ The Herpetic Eye Disease Study established the standard of care in HSK management.² Treatments range from oral antivirals and artificial tears to topical antibiotics, amniotic membranes, and corneal transplantation.³ Patients with immune stromal keratitis (ISK) may experience low-grade chronic keratitis for years.⁴ ISK is classified by a cellular and neovascularization infiltration of the cornea.⁵ We present a case of a patient with recurrent ISK and review its presentation, diagnosis, and management.

Case Presentation

A 52-year-old man presented to the eye clinic with a watery and itchy right eye with mildly blurred vision. His ocular history was unremarkable. His medical history was notable for hepatitis C, hypertension, alcohol and drug dependence, homelessness, and a COVID-19–induced coma. His medications included trazodone, nifedipine, clonidine HCl, and buprenorphine/naloxone.

On clinical examination, the patient’s best-corrected visual acuity was 20/40 in the right eye and 20/20 in the left. Corneal sensitivity was absent in the right eye and intact in the left. Anterior segment findings in the right eye included 360-degree superficial corneal neovascularization, deep neovascularization temporally, scattered patches of corneal haze, epithelial irregularity, and 2+ diffuse bulbar conjunctival injection (Figure 1). The anterior segment of the left eye and the posterior segments of both eyes were unremarkable. The differential diagnosis included HSK, syphilis, Cogan syndrome, varicella-zoster virus keratitis, Epstein-Barr virus keratitis, and Lyme disease. With consultation from a corneal specialist, the patient was given the presumptive diagnosis of ISK in the right eye based on unilateral corneal presentation and lack of corneal sensitivity. He was treated with 1-g oral valacyclovir HCl 3 times daily and 1 drop of prednisolone acetate 1% suspension 3 times daily in the right eye.

The patient followed up 2 weeks later. He reported good adherence to the ISK medication regimen. His symptoms had resolved, and his visual acuity returned to 20/20 in the right eye. Slit-lamp examination showed improvement in injection, and the superficial corneal neovascularization had cleared. A trace ghost vessel was seen temporally at a site of deep neovascularization (Figure 2). He was instructed to continue valacyclovir once daily and prednisolone drops once daily in the right eye and to follow up in 1 month.

At the 1-month follow-up, the patient’s signs and symptoms had reverted to his original presentation. The patient reported poor adherence to the medication regimen, having missed multiple doses of prednisolone drops as well as valacyclovir. The patient was counseled again on the ISK regimen, and the prednisolone drops and 1-g oral valacyclovir were refilled. A follow-up visit was scheduled for 2 weeks. Additional follow-up revealed a resolved corneal appearance and bimonthly follow-ups were scheduled thereafter.

Discussion

HSK is the most common infectious cause of unilateral blindness and vision impairment in the world.² This case highlights the diagnosis and management of a patient with ISK, a type of HSK characterized by decreased corneal sensitivity and unilateral stromal opacification or neovascularization.⁶

ISK is caused by the herpes simplex virus (HSV), a double-stranded enveloped DNA virus that occurs worldwide with little variation, replicates in many types of cells, has rapid growth, and is cytolytic, causing necrosis of nearby cells. Transmission is via direct contact and there is a lifelong latency period in the trigeminal ganglia. Both primary and reactivation infections of HSK can affect a broad array of ocular structures, from the lids to the retina. Infectious epithelial keratitis, also known as dendritic keratitis, is the reactivation of the live virus and is the most common presentation of HSK. ISK is responsible for 20% to 48% of recurrent HSV disease and is the leading cause of vision loss. ISK is the result of an immune-mediated inflammatory response due to a retained viral antigen within the stromal tissue.⁷ Inflammation in the corneal stroma leads to corneal haze and eventually focal or diffuse scarring, reducing the visual potential.⁷ This presentation may occur days to years after the initial epithelial episode and may persist for years. Although this patient did not present with infectious epithelial keratitis, it is possible he had a previous episode not mentioned as a history was difficult to obtain, and it can be subtle or innocuous, like pink eye.

Symptoms of ISK include unilateral redness, photophobia, tearing, eye pain, and blurred vision, as described by this patient. On examination, initial manifestations of ISK include corneal haze, edema, scarring, and neovascularization.⁷ Again, this patient presented with edema and neovascularization. These signs may improve with prompt diagnosis and treatment. More frequent reactivated disease leads to a higher propensity of corneal scarring and irregular astigmatism, reducing the visual outcome.

The standard of care established by the Herpetic Eye Disease Study recommends that a patient with presumed ISK should be started on oral antiviral therapy and, in the absence of epithelial disease, topical steroids. Oral antivirals, such as acyclovir and valacyclovir, have good ocular penetration, a good safety profile, a low susceptibility of resistance, and are well tolerated with long-term treatment.^2,8 There were no known interactions between any of the patient’s medications and valacyclovir. Oral antivirals should be used in the initial presentation and for maintenance therapy to help reduce the chance of recurrent disease. Initial treatment for ISK is 1-g valacyclovir 3 times daily. When the eye becomes quiet, that dosage can be tapered to 1 g twice daily, to 1 g once daily, and eventually to a maintenance dose of 500 mg daily. Topical steroids block the inflammatory cascade, therefore reducing the corneal inflammation and potential scarring, further reducing the risk of visual impairment.⁹ Initial treatment is 1 drop 3 times daily, then can be tapered at the same schedule as the oral acyclovir to help simplify adherence for the patient. After 1 drop once daily, steroids may be discontinued while the oral antiviral maintenance dosage continues. Follow-ups should be performed on a monthly to bimonthly basis to evaluate intraocular pressure, ensuring there is no steroid response.

As seen in this patient, adherence with a treatment regimen and awareness of factors, such as a complex psychosocial history that may impact this adherence, are of utmost importance.⁷

Conclusions

ISK presents unilaterally with decreased or absent corneal sensitivity and nonspecific symptoms. It should be at the top of the list in the differential diagnosis in any patient with unilateral corneal edema, opacification, or neovascularization, and the patient should be started on oral antiviral therapy.

Herpes simplex keratitis (HSK) is a common yet potentially blinding condition caused by a primary or reactivated herpetic infection of the cornea.¹ The Herpetic Eye Disease Study established the standard of care in HSK management.² Treatments range from oral antivirals and artificial tears to topical antibiotics, amniotic membranes, and corneal transplantation.³ Patients with immune stromal keratitis (ISK) may experience low-grade chronic keratitis for years.⁴ ISK is classified by a cellular and neovascularization infiltration of the cornea.⁵ We present a case of a patient with recurrent ISK and review its presentation, diagnosis, and management.

Case Presentation

A 52-year-old man presented to the eye clinic with a watery and itchy right eye with mildly blurred vision. His ocular history was unremarkable. His medical history was notable for hepatitis C, hypertension, alcohol and drug dependence, homelessness, and a COVID-19–induced coma. His medications included trazodone, nifedipine, clonidine HCl, and buprenorphine/naloxone.

On clinical examination, the patient’s best-corrected visual acuity was 20/40 in the right eye and 20/20 in the left. Corneal sensitivity was absent in the right eye and intact in the left. Anterior segment findings in the right eye included 360-degree superficial corneal neovascularization, deep neovascularization temporally, scattered patches of corneal haze, epithelial irregularity, and 2+ diffuse bulbar conjunctival injection (Figure 1). The anterior segment of the left eye and the posterior segments of both eyes were unremarkable. The differential diagnosis included HSK, syphilis, Cogan syndrome, varicella-zoster virus keratitis, Epstein-Barr virus keratitis, and Lyme disease. With consultation from a corneal specialist, the patient was given the presumptive diagnosis of ISK in the right eye based on unilateral corneal presentation and lack of corneal sensitivity. He was treated with 1-g oral valacyclovir HCl 3 times daily and 1 drop of prednisolone acetate 1% suspension 3 times daily in the right eye.

The patient followed up 2 weeks later. He reported good adherence to the ISK medication regimen. His symptoms had resolved, and his visual acuity returned to 20/20 in the right eye. Slit-lamp examination showed improvement in injection, and the superficial corneal neovascularization had cleared. A trace ghost vessel was seen temporally at a site of deep neovascularization (Figure 2). He was instructed to continue valacyclovir once daily and prednisolone drops once daily in the right eye and to follow up in 1 month.

At the 1-month follow-up, the patient’s signs and symptoms had reverted to his original presentation. The patient reported poor adherence to the medication regimen, having missed multiple doses of prednisolone drops as well as valacyclovir. The patient was counseled again on the ISK regimen, and the prednisolone drops and 1-g oral valacyclovir were refilled. A follow-up visit was scheduled for 2 weeks. Additional follow-up revealed a resolved corneal appearance and bimonthly follow-ups were scheduled thereafter.

Discussion

HSK is the most common infectious cause of unilateral blindness and vision impairment in the world.² This case highlights the diagnosis and management of a patient with ISK, a type of HSK characterized by decreased corneal sensitivity and unilateral stromal opacification or neovascularization.⁶

ISK is caused by the herpes simplex virus (HSV), a double-stranded enveloped DNA virus that occurs worldwide with little variation, replicates in many types of cells, has rapid growth, and is cytolytic, causing necrosis of nearby cells. Transmission is via direct contact and there is a lifelong latency period in the trigeminal ganglia. Both primary and reactivation infections of HSK can affect a broad array of ocular structures, from the lids to the retina. Infectious epithelial keratitis, also known as dendritic keratitis, is the reactivation of the live virus and is the most common presentation of HSK. ISK is responsible for 20% to 48% of recurrent HSV disease and is the leading cause of vision loss. ISK is the result of an immune-mediated inflammatory response due to a retained viral antigen within the stromal tissue.⁷ Inflammation in the corneal stroma leads to corneal haze and eventually focal or diffuse scarring, reducing the visual potential.⁷ This presentation may occur days to years after the initial epithelial episode and may persist for years. Although this patient did not present with infectious epithelial keratitis, it is possible he had a previous episode not mentioned as a history was difficult to obtain, and it can be subtle or innocuous, like pink eye.

Symptoms of ISK include unilateral redness, photophobia, tearing, eye pain, and blurred vision, as described by this patient. On examination, initial manifestations of ISK include corneal haze, edema, scarring, and neovascularization.⁷ Again, this patient presented with edema and neovascularization. These signs may improve with prompt diagnosis and treatment. More frequent reactivated disease leads to a higher propensity of corneal scarring and irregular astigmatism, reducing the visual outcome.

The standard of care established by the Herpetic Eye Disease Study recommends that a patient with presumed ISK should be started on oral antiviral therapy and, in the absence of epithelial disease, topical steroids. Oral antivirals, such as acyclovir and valacyclovir, have good ocular penetration, a good safety profile, a low susceptibility of resistance, and are well tolerated with long-term treatment.^2,8 There were no known interactions between any of the patient’s medications and valacyclovir. Oral antivirals should be used in the initial presentation and for maintenance therapy to help reduce the chance of recurrent disease. Initial treatment for ISK is 1-g valacyclovir 3 times daily. When the eye becomes quiet, that dosage can be tapered to 1 g twice daily, to 1 g once daily, and eventually to a maintenance dose of 500 mg daily. Topical steroids block the inflammatory cascade, therefore reducing the corneal inflammation and potential scarring, further reducing the risk of visual impairment.⁹ Initial treatment is 1 drop 3 times daily, then can be tapered at the same schedule as the oral acyclovir to help simplify adherence for the patient. After 1 drop once daily, steroids may be discontinued while the oral antiviral maintenance dosage continues. Follow-ups should be performed on a monthly to bimonthly basis to evaluate intraocular pressure, ensuring there is no steroid response.

As seen in this patient, adherence with a treatment regimen and awareness of factors, such as a complex psychosocial history that may impact this adherence, are of utmost importance.⁷

Conclusions

ISK presents unilaterally with decreased or absent corneal sensitivity and nonspecific symptoms. It should be at the top of the list in the differential diagnosis in any patient with unilateral corneal edema, opacification, or neovascularization, and the patient should be started on oral antiviral therapy.

Respiratory-Related Sleep Disorders Section

Sleep health and fatigue mitigation during medical training

Medical trainees may experience acute or chronic sleep deprivation due to extended work hours and shift-work sleep schedules. Extended work hours may lead to serious medical errors, percutaneous injuries, prolonged task completion, and car crashes or near misses while driving (Landrigan, et al. N Engl J Med. 2004;351:1838; Ayas, et al. JAMA. 2006;296[9]:1055; Taffinder, et al. Lancet. 1998;352[9135]:1191; Barger, et al. N Engl J Med. 2005 Jan 13;352[2]:125).

Chronic sleep restriction also results in neurobehavioral and cognitive dysfunction without a proportionate increase in self-perceived sleepiness [Belenky, et al. J Sleep Res. 2003;12[1]:1; Van Dongen, et al. Sleep. 2003;26[2]:117). In 1987, when sleep deprivation was cited as a major cause of 18-year-old Libby Zion’s death, the ACGME restricted residents from working more than 80 hours per week. ACGME mandates that training programs provide yearly fatigue mitigation education.

A “Sleep Alertness and Fatigue Education in Residency” module may be purchased through the American Academy of Sleep Medicine. While one-time education opportunities are available, there remains a need for access to longitudinal, individualized tools during varying rotations and circumstances, as education alone has not been shown to improve sleep quality (Mazar D, et al. J Clin Sleep Med. 2021;17[6]:1211). The American Thoracic Society Early Career Professional Working Group offers individualized lectures to training programs. Wake Up and Learn is a sleep education program for children and teens that is currently being expanded for medical trainees.

Further data are needed to see if longitudinal and individualized support can promote better sleep quality among trainees.

Aesha Jobanputra, MD
Section Member

Sreelatha Naik, MD
Member-at-Large

Respiratory-Related Sleep Disorders Section

Sleep health and fatigue mitigation during medical training

Medical trainees may experience acute or chronic sleep deprivation due to extended work hours and shift-work sleep schedules. Extended work hours may lead to serious medical errors, percutaneous injuries, prolonged task completion, and car crashes or near misses while driving (Landrigan, et al. N Engl J Med. 2004;351:1838; Ayas, et al. JAMA. 2006;296[9]:1055; Taffinder, et al. Lancet. 1998;352[9135]:1191; Barger, et al. N Engl J Med. 2005 Jan 13;352[2]:125).

Chronic sleep restriction also results in neurobehavioral and cognitive dysfunction without a proportionate increase in self-perceived sleepiness [Belenky, et al. J Sleep Res. 2003;12[1]:1; Van Dongen, et al. Sleep. 2003;26[2]:117). In 1987, when sleep deprivation was cited as a major cause of 18-year-old Libby Zion’s death, the ACGME restricted residents from working more than 80 hours per week. ACGME mandates that training programs provide yearly fatigue mitigation education.

A “Sleep Alertness and Fatigue Education in Residency” module may be purchased through the American Academy of Sleep Medicine. While one-time education opportunities are available, there remains a need for access to longitudinal, individualized tools during varying rotations and circumstances, as education alone has not been shown to improve sleep quality (Mazar D, et al. J Clin Sleep Med. 2021;17[6]:1211). The American Thoracic Society Early Career Professional Working Group offers individualized lectures to training programs. Wake Up and Learn is a sleep education program for children and teens that is currently being expanded for medical trainees.

Further data are needed to see if longitudinal and individualized support can promote better sleep quality among trainees.

Aesha Jobanputra, MD
Section Member

Sreelatha Naik, MD
Member-at-Large

Respiratory-Related Sleep Disorders Section

Sleep health and fatigue mitigation during medical training

Medical trainees may experience acute or chronic sleep deprivation due to extended work hours and shift-work sleep schedules. Extended work hours may lead to serious medical errors, percutaneous injuries, prolonged task completion, and car crashes or near misses while driving (Landrigan, et al. N Engl J Med. 2004;351:1838; Ayas, et al. JAMA. 2006;296[9]:1055; Taffinder, et al. Lancet. 1998;352[9135]:1191; Barger, et al. N Engl J Med. 2005 Jan 13;352[2]:125).

Chronic sleep restriction also results in neurobehavioral and cognitive dysfunction without a proportionate increase in self-perceived sleepiness [Belenky, et al. J Sleep Res. 2003;12[1]:1; Van Dongen, et al. Sleep. 2003;26[2]:117). In 1987, when sleep deprivation was cited as a major cause of 18-year-old Libby Zion’s death, the ACGME restricted residents from working more than 80 hours per week. ACGME mandates that training programs provide yearly fatigue mitigation education.

A “Sleep Alertness and Fatigue Education in Residency” module may be purchased through the American Academy of Sleep Medicine. While one-time education opportunities are available, there remains a need for access to longitudinal, individualized tools during varying rotations and circumstances, as education alone has not been shown to improve sleep quality (Mazar D, et al. J Clin Sleep Med. 2021;17[6]:1211). The American Thoracic Society Early Career Professional Working Group offers individualized lectures to training programs. Wake Up and Learn is a sleep education program for children and teens that is currently being expanded for medical trainees.

Further data are needed to see if longitudinal and individualized support can promote better sleep quality among trainees.

Aesha Jobanputra, MD
Section Member

Sreelatha Naik, MD
Member-at-Large

Brent called his dad, Jeb Teichman, MD, in November 2019 saying he had felt sick for the past 3 days. The otherwise-healthy 29-year-old had a cough, sore throat, and was running a fever.

“It was what the CDC [Centers for Disease Control and Prevention] would call classic influenza-like illness,” Dr. Teichman said. “It was too late to start antivirals, so I gave him advice on symptomatic treatment. We texted the next day, and I was glad to hear that his fever was trending down and that he was feeling a little bit better.”

Two days later, his son called again. 

“He said he was having trouble breathing, and over the phone I could hear him hyperventilating.” The retired pediatrician and health care executive told his son to seek medical care. 

“Then I got the call that no parent wants to get.” 

Brent’s cousin Jake called saying he couldn’t wake Brent up.

“I called Jake back a few minutes later and asked him to hold up the phone,” Dr. Teichman said. “I listened to EMS working on my son, calling for round after round of many medications. He was in arrest and they couldn’t revive him.”

“To this day when I close my eyes at night, I still hear the beeping of those monitors.”

Brent had no health conditions to put him at higher risk for complications of the flu. “Brent was a wonderful son, brother, uncle, and friend. He had a passion for everything he did, and that included his chosen calling of the culinary arts but also included University of Kentucky sports,” Dr. Teichman said.

Brent planned to get a flu vaccine but had not done it yet. “In his obituary, we requested that, in lieu of flowers or donations, people go get their flu shot,” Dr. Teichman said.

“I’m here today to put a face on influenza,” Dr. Teichman said at a news briefing Oct. 4 on preventing the flu and pneumococcal disease, sponsored by the National Foundation for Infectious Diseases.
 

New survey numbers ‘alarming’

The NFID commissioned a national survey of more than 1,000 U.S. adults to better understand their knowledge and attitudes about the flu, pneumococcal disease, vaccines, and the impact of COVID-19.

“We were alarmed to learn that only 49% of U.S. adults plan to get their flu vaccine this season,” said Patricia A. “Patsy” Stinchfield, a registered nurse, NFID president, and moderator of the news briefing. “That is not good enough.”

In addition, 22% of people at higher risk for flu-related complications do not plan to get vaccinated this season. “That’s a dangerous risk to take,” Ms. Stinchfield said. 

An encouraging finding, she said, is that 69% of adults surveyed recognize that an annual flu vaccination is the best way to prevent flu-related hospitalizations and death. 

“So, most people know what to do. We just need to do it,” she said.

The top reason for not getting a flu shot in 2022 mentioned by 41% of people surveyed, is they do not think vaccines work very well. Another 39% are concerned about vaccine side effects, and 28% skip the vaccine because they “never get the flu.” 

The experts on the panel emphasized the recommendation that all Americans 6 months or older get the flu vaccine, preferably by the end of October. Vaccination is especially important for those at higher risk of complications from the flu, including children under 5, pregnant women, people with one or more health conditions, the immunocompromised, and Americans 65 years and older. 

Ms. Stinchfield acknowledged that the effectiveness of the flu vaccine varies season to season, but even if the vaccine does not completely match the circulating viruses, it can help prevent serious outcomes like hospitalization and death. One of the serious potential complications is pneumonia or “pneumococcal disease.” 

“Our survey shows that only 29% of those at risk have been advised to receive a pneumococcal vaccine,” Ms. Stinchfield said. “The good news is that, among those who were advised to get the vaccine, 74% did receive their pneumococcal vaccine,” she said. “This underscores a key point to you, my fellow clinicians: As health professionals, our recommendations matter.”
 

Higher doses for 65+ Americans

The CDC updated recommendations this flu season for adults 65 and older to receive one of three preferentially recommended flu vaccines, said CDC Director Rochelle Walensky, MD. The CDC is recommending higher-dose, stronger vaccines for older Americans “based on a review of the available studies, which suggested that in this age group, these vaccines are potentially more effective than standard-dose ... vaccines.”

During most seasons, people 65 and older bear the greatest burden of severe flu disease, accounting for most flu-related hospitalizations and deaths. 

“They are the largest vulnerable segment of our society,” Dr. Walensky said. 
 

What will this flu season be like?

Health officials in the flu vaccine business also tend to be in the flu season prediction business. That includes Dr. Walensky.

“While we will never exactly know what each flu season will hold, we do know that every year, the best way you can protect yourself and those around you is to get your annual flu vaccine,” she said while taking part remotely in the briefing. 

How severe will the flu season be in 2022-23? William Schaffner, MD, said he gets that question a lot. “Don’t think about that. Just focus on the fact that flu will be with us each year.

“We were a little bit spoiled. We’ve had two mild influenza seasons,” said Dr. Schaffner, medical director of NFID and a professor of infectious diseases and preventive medicine at Vanderbilt University, Nashville, Tenn. “I think with all the interest in COVID, people have rather forgotten about influenza. I’ve had to remind them that this is yet another serious winter respiratory virus. 

“As I like to say, flu is fickle. It’s difficult to predict how serious this next outbreak of influenza this season is going to be. We could look at what happened in the Southern Hemisphere,” he said. 

For example, Australia had the worst influenza season in the past 5 years, Schaffner said. “If you want a hint of what might happen here and you want yet another reason to be vaccinated, there it is.”

What we do know, Dr. Walensky said, is that the timing and severity of the past two flu seasons in the U.S. have been different than typical flu seasons. “And this is likely due to the COVID mitigation measures and other changes in circulating respiratory viruses.” Also, although last flu season was “relatively mild,” there was more flu activity than in the prior, 2020-21 season. 

Also, Dr. Walensky said, last season’s flu cases began to increase in November and remained elevated until mid-June, “making it the latest season on record.”

The official cause of Brent Teichman’s death was multilobar pneumonia, cause undetermined. “But after 30-plus years as a pediatrician ... I know influenza when I see it,” Dr. Teichman said.

“There’s a hole in our hearts that will never heal. Loss of a child is devastating,” he said. The flu “can take the life of a healthy young person, as it did to my son.

“And for all those listening to my story who are vaccine hesitant, do it for those who love you. So that they won’t walk the path that we and many other families in this country have walked.”

To prove their point, Dr. Teichman and Ms. Stinchfield raised their sleeves and received flu shots during the news briefing. 

“This one is for Brent,” Dr. Teichman said.

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

Brent called his dad, Jeb Teichman, MD, in November 2019 saying he had felt sick for the past 3 days. The otherwise-healthy 29-year-old had a cough, sore throat, and was running a fever.

“It was what the CDC [Centers for Disease Control and Prevention] would call classic influenza-like illness,” Dr. Teichman said. “It was too late to start antivirals, so I gave him advice on symptomatic treatment. We texted the next day, and I was glad to hear that his fever was trending down and that he was feeling a little bit better.”

Two days later, his son called again. 

“He said he was having trouble breathing, and over the phone I could hear him hyperventilating.” The retired pediatrician and health care executive told his son to seek medical care. 

“Then I got the call that no parent wants to get.” 

Brent’s cousin Jake called saying he couldn’t wake Brent up.

“I called Jake back a few minutes later and asked him to hold up the phone,” Dr. Teichman said. “I listened to EMS working on my son, calling for round after round of many medications. He was in arrest and they couldn’t revive him.”

“To this day when I close my eyes at night, I still hear the beeping of those monitors.”

Brent had no health conditions to put him at higher risk for complications of the flu. “Brent was a wonderful son, brother, uncle, and friend. He had a passion for everything he did, and that included his chosen calling of the culinary arts but also included University of Kentucky sports,” Dr. Teichman said.

Brent planned to get a flu vaccine but had not done it yet. “In his obituary, we requested that, in lieu of flowers or donations, people go get their flu shot,” Dr. Teichman said.

“I’m here today to put a face on influenza,” Dr. Teichman said at a news briefing Oct. 4 on preventing the flu and pneumococcal disease, sponsored by the National Foundation for Infectious Diseases.
 

New survey numbers ‘alarming’

The NFID commissioned a national survey of more than 1,000 U.S. adults to better understand their knowledge and attitudes about the flu, pneumococcal disease, vaccines, and the impact of COVID-19.

“We were alarmed to learn that only 49% of U.S. adults plan to get their flu vaccine this season,” said Patricia A. “Patsy” Stinchfield, a registered nurse, NFID president, and moderator of the news briefing. “That is not good enough.”

In addition, 22% of people at higher risk for flu-related complications do not plan to get vaccinated this season. “That’s a dangerous risk to take,” Ms. Stinchfield said. 

An encouraging finding, she said, is that 69% of adults surveyed recognize that an annual flu vaccination is the best way to prevent flu-related hospitalizations and death. 

“So, most people know what to do. We just need to do it,” she said.

The top reason for not getting a flu shot in 2022 mentioned by 41% of people surveyed, is they do not think vaccines work very well. Another 39% are concerned about vaccine side effects, and 28% skip the vaccine because they “never get the flu.” 

The experts on the panel emphasized the recommendation that all Americans 6 months or older get the flu vaccine, preferably by the end of October. Vaccination is especially important for those at higher risk of complications from the flu, including children under 5, pregnant women, people with one or more health conditions, the immunocompromised, and Americans 65 years and older. 

Ms. Stinchfield acknowledged that the effectiveness of the flu vaccine varies season to season, but even if the vaccine does not completely match the circulating viruses, it can help prevent serious outcomes like hospitalization and death. One of the serious potential complications is pneumonia or “pneumococcal disease.” 

“Our survey shows that only 29% of those at risk have been advised to receive a pneumococcal vaccine,” Ms. Stinchfield said. “The good news is that, among those who were advised to get the vaccine, 74% did receive their pneumococcal vaccine,” she said. “This underscores a key point to you, my fellow clinicians: As health professionals, our recommendations matter.”
 

Higher doses for 65+ Americans

The CDC updated recommendations this flu season for adults 65 and older to receive one of three preferentially recommended flu vaccines, said CDC Director Rochelle Walensky, MD. The CDC is recommending higher-dose, stronger vaccines for older Americans “based on a review of the available studies, which suggested that in this age group, these vaccines are potentially more effective than standard-dose ... vaccines.”

During most seasons, people 65 and older bear the greatest burden of severe flu disease, accounting for most flu-related hospitalizations and deaths. 

“They are the largest vulnerable segment of our society,” Dr. Walensky said. 
 

What will this flu season be like?

Health officials in the flu vaccine business also tend to be in the flu season prediction business. That includes Dr. Walensky.

“While we will never exactly know what each flu season will hold, we do know that every year, the best way you can protect yourself and those around you is to get your annual flu vaccine,” she said while taking part remotely in the briefing. 

How severe will the flu season be in 2022-23? William Schaffner, MD, said he gets that question a lot. “Don’t think about that. Just focus on the fact that flu will be with us each year.

“We were a little bit spoiled. We’ve had two mild influenza seasons,” said Dr. Schaffner, medical director of NFID and a professor of infectious diseases and preventive medicine at Vanderbilt University, Nashville, Tenn. “I think with all the interest in COVID, people have rather forgotten about influenza. I’ve had to remind them that this is yet another serious winter respiratory virus. 

“As I like to say, flu is fickle. It’s difficult to predict how serious this next outbreak of influenza this season is going to be. We could look at what happened in the Southern Hemisphere,” he said. 

For example, Australia had the worst influenza season in the past 5 years, Schaffner said. “If you want a hint of what might happen here and you want yet another reason to be vaccinated, there it is.”

What we do know, Dr. Walensky said, is that the timing and severity of the past two flu seasons in the U.S. have been different than typical flu seasons. “And this is likely due to the COVID mitigation measures and other changes in circulating respiratory viruses.” Also, although last flu season was “relatively mild,” there was more flu activity than in the prior, 2020-21 season. 

Also, Dr. Walensky said, last season’s flu cases began to increase in November and remained elevated until mid-June, “making it the latest season on record.”

The official cause of Brent Teichman’s death was multilobar pneumonia, cause undetermined. “But after 30-plus years as a pediatrician ... I know influenza when I see it,” Dr. Teichman said.

“There’s a hole in our hearts that will never heal. Loss of a child is devastating,” he said. The flu “can take the life of a healthy young person, as it did to my son.

“And for all those listening to my story who are vaccine hesitant, do it for those who love you. So that they won’t walk the path that we and many other families in this country have walked.”

To prove their point, Dr. Teichman and Ms. Stinchfield raised their sleeves and received flu shots during the news briefing. 

“This one is for Brent,” Dr. Teichman said.

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

Brent called his dad, Jeb Teichman, MD, in November 2019 saying he had felt sick for the past 3 days. The otherwise-healthy 29-year-old had a cough, sore throat, and was running a fever.

“It was what the CDC [Centers for Disease Control and Prevention] would call classic influenza-like illness,” Dr. Teichman said. “It was too late to start antivirals, so I gave him advice on symptomatic treatment. We texted the next day, and I was glad to hear that his fever was trending down and that he was feeling a little bit better.”

Two days later, his son called again. 

“He said he was having trouble breathing, and over the phone I could hear him hyperventilating.” The retired pediatrician and health care executive told his son to seek medical care. 

“Then I got the call that no parent wants to get.” 

Brent’s cousin Jake called saying he couldn’t wake Brent up.

“I called Jake back a few minutes later and asked him to hold up the phone,” Dr. Teichman said. “I listened to EMS working on my son, calling for round after round of many medications. He was in arrest and they couldn’t revive him.”

“To this day when I close my eyes at night, I still hear the beeping of those monitors.”

Brent had no health conditions to put him at higher risk for complications of the flu. “Brent was a wonderful son, brother, uncle, and friend. He had a passion for everything he did, and that included his chosen calling of the culinary arts but also included University of Kentucky sports,” Dr. Teichman said.

Brent planned to get a flu vaccine but had not done it yet. “In his obituary, we requested that, in lieu of flowers or donations, people go get their flu shot,” Dr. Teichman said.

“I’m here today to put a face on influenza,” Dr. Teichman said at a news briefing Oct. 4 on preventing the flu and pneumococcal disease, sponsored by the National Foundation for Infectious Diseases.
 

New survey numbers ‘alarming’

The NFID commissioned a national survey of more than 1,000 U.S. adults to better understand their knowledge and attitudes about the flu, pneumococcal disease, vaccines, and the impact of COVID-19.

“We were alarmed to learn that only 49% of U.S. adults plan to get their flu vaccine this season,” said Patricia A. “Patsy” Stinchfield, a registered nurse, NFID president, and moderator of the news briefing. “That is not good enough.”

In addition, 22% of people at higher risk for flu-related complications do not plan to get vaccinated this season. “That’s a dangerous risk to take,” Ms. Stinchfield said. 

An encouraging finding, she said, is that 69% of adults surveyed recognize that an annual flu vaccination is the best way to prevent flu-related hospitalizations and death. 

“So, most people know what to do. We just need to do it,” she said.

The top reason for not getting a flu shot in 2022 mentioned by 41% of people surveyed, is they do not think vaccines work very well. Another 39% are concerned about vaccine side effects, and 28% skip the vaccine because they “never get the flu.” 

The experts on the panel emphasized the recommendation that all Americans 6 months or older get the flu vaccine, preferably by the end of October. Vaccination is especially important for those at higher risk of complications from the flu, including children under 5, pregnant women, people with one or more health conditions, the immunocompromised, and Americans 65 years and older. 

Ms. Stinchfield acknowledged that the effectiveness of the flu vaccine varies season to season, but even if the vaccine does not completely match the circulating viruses, it can help prevent serious outcomes like hospitalization and death. One of the serious potential complications is pneumonia or “pneumococcal disease.” 

“Our survey shows that only 29% of those at risk have been advised to receive a pneumococcal vaccine,” Ms. Stinchfield said. “The good news is that, among those who were advised to get the vaccine, 74% did receive their pneumococcal vaccine,” she said. “This underscores a key point to you, my fellow clinicians: As health professionals, our recommendations matter.”
 

Higher doses for 65+ Americans

The CDC updated recommendations this flu season for adults 65 and older to receive one of three preferentially recommended flu vaccines, said CDC Director Rochelle Walensky, MD. The CDC is recommending higher-dose, stronger vaccines for older Americans “based on a review of the available studies, which suggested that in this age group, these vaccines are potentially more effective than standard-dose ... vaccines.”

During most seasons, people 65 and older bear the greatest burden of severe flu disease, accounting for most flu-related hospitalizations and deaths. 

“They are the largest vulnerable segment of our society,” Dr. Walensky said. 
 

What will this flu season be like?

Health officials in the flu vaccine business also tend to be in the flu season prediction business. That includes Dr. Walensky.

“While we will never exactly know what each flu season will hold, we do know that every year, the best way you can protect yourself and those around you is to get your annual flu vaccine,” she said while taking part remotely in the briefing. 

How severe will the flu season be in 2022-23? William Schaffner, MD, said he gets that question a lot. “Don’t think about that. Just focus on the fact that flu will be with us each year.

“We were a little bit spoiled. We’ve had two mild influenza seasons,” said Dr. Schaffner, medical director of NFID and a professor of infectious diseases and preventive medicine at Vanderbilt University, Nashville, Tenn. “I think with all the interest in COVID, people have rather forgotten about influenza. I’ve had to remind them that this is yet another serious winter respiratory virus. 

“As I like to say, flu is fickle. It’s difficult to predict how serious this next outbreak of influenza this season is going to be. We could look at what happened in the Southern Hemisphere,” he said. 

For example, Australia had the worst influenza season in the past 5 years, Schaffner said. “If you want a hint of what might happen here and you want yet another reason to be vaccinated, there it is.”

What we do know, Dr. Walensky said, is that the timing and severity of the past two flu seasons in the U.S. have been different than typical flu seasons. “And this is likely due to the COVID mitigation measures and other changes in circulating respiratory viruses.” Also, although last flu season was “relatively mild,” there was more flu activity than in the prior, 2020-21 season. 

Also, Dr. Walensky said, last season’s flu cases began to increase in November and remained elevated until mid-June, “making it the latest season on record.”

The official cause of Brent Teichman’s death was multilobar pneumonia, cause undetermined. “But after 30-plus years as a pediatrician ... I know influenza when I see it,” Dr. Teichman said.

“There’s a hole in our hearts that will never heal. Loss of a child is devastating,” he said. The flu “can take the life of a healthy young person, as it did to my son.

“And for all those listening to my story who are vaccine hesitant, do it for those who love you. So that they won’t walk the path that we and many other families in this country have walked.”

To prove their point, Dr. Teichman and Ms. Stinchfield raised their sleeves and received flu shots during the news briefing. 

“This one is for Brent,” Dr. Teichman said.

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

Pleural Disease Section

Aspirate or wait: changing the paradigm for PSP care

There is considerable heterogeneity in the management of primary spontaneous pneumothorax (PSP). Although observation for small asymptomatic PSP is supported by current guidelines, management recommendations for larger PSP remains unclear (MacDuff, et al. Thorax. 2010;65[Suppl 2]:ii18-ii31; Tschopp JM, et al. Eur Respir J. 2015;46[2]:321). Two recent RCTs explore conservative vs intervention-based management in those with larger or symptomatic PSP. In the PSP trial, Brown and colleagues prospectively randomized 316 patients with moderate to large PSP to either conservative management (≥ 4 hour observation) or small-bore chest tube without suction (Brown, et al. N Engl J Med. 2020;382[5]:405). Although noninferiority criteria were met, the primary outcome of radiographic resolution of pneumothorax within 8 weeks of randomization was not statistically robust to conservative assumptions about missing data. They concluded that conservative management was noninferior to intervention, and it resulted in a lower risk of serious adverse events or PSP recurrence than interventional management. The multicenter randomized Ambulatory Management of Primary Pneumothorax (RAMPP) trial compared ambulatory management of PSP using an 8F drainage device to a guideline-driven approach (drainage, aspiration, or both) amongst 236 patients with symptomatic PSP. Intervention shortened length of hospital stay (median 0 vs 4 days, P<.0001), but the intervention arm experienced more adverse events (including enlargement of pneumothorax, as well as device malfunction) (Hallifax RJ, et al. Lancet. 2020;396[10243]:39). These two trials challenge the current guidelines for management for patients with PSP, but both had limitations. Though more data are needed to establish a clear consensus, these studies suggest that a conservative pathway for PSP warrants further consideration.

Tejaswi R. Nadig, MBBS
Member-at-Large

Yaron Gesthalter, MD
Member-at-Large

Priya P. Nath, MD
Member-at-Large

Pleural Disease Section

Aspirate or wait: changing the paradigm for PSP care

There is considerable heterogeneity in the management of primary spontaneous pneumothorax (PSP). Although observation for small asymptomatic PSP is supported by current guidelines, management recommendations for larger PSP remains unclear (MacDuff, et al. Thorax. 2010;65[Suppl 2]:ii18-ii31; Tschopp JM, et al. Eur Respir J. 2015;46[2]:321). Two recent RCTs explore conservative vs intervention-based management in those with larger or symptomatic PSP. In the PSP trial, Brown and colleagues prospectively randomized 316 patients with moderate to large PSP to either conservative management (≥ 4 hour observation) or small-bore chest tube without suction (Brown, et al. N Engl J Med. 2020;382[5]:405). Although noninferiority criteria were met, the primary outcome of radiographic resolution of pneumothorax within 8 weeks of randomization was not statistically robust to conservative assumptions about missing data. They concluded that conservative management was noninferior to intervention, and it resulted in a lower risk of serious adverse events or PSP recurrence than interventional management. The multicenter randomized Ambulatory Management of Primary Pneumothorax (RAMPP) trial compared ambulatory management of PSP using an 8F drainage device to a guideline-driven approach (drainage, aspiration, or both) amongst 236 patients with symptomatic PSP. Intervention shortened length of hospital stay (median 0 vs 4 days, P<.0001), but the intervention arm experienced more adverse events (including enlargement of pneumothorax, as well as device malfunction) (Hallifax RJ, et al. Lancet. 2020;396[10243]:39). These two trials challenge the current guidelines for management for patients with PSP, but both had limitations. Though more data are needed to establish a clear consensus, these studies suggest that a conservative pathway for PSP warrants further consideration.

Tejaswi R. Nadig, MBBS
Member-at-Large

Yaron Gesthalter, MD
Member-at-Large

Priya P. Nath, MD
Member-at-Large

Pleural Disease Section

Aspirate or wait: changing the paradigm for PSP care

There is considerable heterogeneity in the management of primary spontaneous pneumothorax (PSP). Although observation for small asymptomatic PSP is supported by current guidelines, management recommendations for larger PSP remains unclear (MacDuff, et al. Thorax. 2010;65[Suppl 2]:ii18-ii31; Tschopp JM, et al. Eur Respir J. 2015;46[2]:321). Two recent RCTs explore conservative vs intervention-based management in those with larger or symptomatic PSP. In the PSP trial, Brown and colleagues prospectively randomized 316 patients with moderate to large PSP to either conservative management (≥ 4 hour observation) or small-bore chest tube without suction (Brown, et al. N Engl J Med. 2020;382[5]:405). Although noninferiority criteria were met, the primary outcome of radiographic resolution of pneumothorax within 8 weeks of randomization was not statistically robust to conservative assumptions about missing data. They concluded that conservative management was noninferior to intervention, and it resulted in a lower risk of serious adverse events or PSP recurrence than interventional management. The multicenter randomized Ambulatory Management of Primary Pneumothorax (RAMPP) trial compared ambulatory management of PSP using an 8F drainage device to a guideline-driven approach (drainage, aspiration, or both) amongst 236 patients with symptomatic PSP. Intervention shortened length of hospital stay (median 0 vs 4 days, P<.0001), but the intervention arm experienced more adverse events (including enlargement of pneumothorax, as well as device malfunction) (Hallifax RJ, et al. Lancet. 2020;396[10243]:39). These two trials challenge the current guidelines for management for patients with PSP, but both had limitations. Though more data are needed to establish a clear consensus, these studies suggest that a conservative pathway for PSP warrants further consideration.

Tejaswi R. Nadig, MBBS
Member-at-Large

Yaron Gesthalter, MD
Member-at-Large

Priya P. Nath, MD
Member-at-Large

The proper management of subepithelial lesions (SELs) depends on the size, histopathology, malignant potential, and presence of symptoms, according to a new American Gastroenterological Association clinical practice update published in Clinical Gastroenterology and Hepatology.

“SELs are found in 1 in every 300 endoscopies, and two-thirds of these lesions are located in the stomach,” explained Kaveh Sharzehi, MD, an associate professor of medicine in the division of gastroenterology and hepatology at Oregon Health & Science University, Portland, and colleagues. “They represent a heterogeneous group of lesions including nonneoplastic lesions such as ectopic pancreatic tissue and neoplastic lesions. The neoplastic SELs can vary from lesions with no malignant potential such as lipomas to those with malignant potential such as gastrointestinal stromal tumors (GISTs). The majority of SELs are small and found incidentally.”

The authors developed 10 clinical practice advice statements on the diagnosis and management of subepithelial lesions based on a review of the published literature and expert opinion.

First, standard mucosal biopsies often don’t reach deep enough to obtain a pathologic diagnosis for SELs because the lesions have normal overlying mucosa. Forceps bite-on-bite/deep-well biopsies or tunnel biopsies may help to establish a pathologic diagnosis.

Used as an adjunct to standard endoscopy, endoscopic ultrasound (EUS) has become the primary method for determining diagnostic and prognostic characteristics of SELs – such as the layer of origin, echogenicity, and presence of blood vessels within the lesion. It can also help with tissue acquisition.

For SELs arising from the submucosa, EUS-guided fine-needle aspiration and fine-needle biopsy have evolved as widely used methods for obtaining tissue. For SELs arising from muscularis propria, fine-needle aspiration and fine-needle biopsy should be used to determine whether the lesion is a GIST or leiomyoma. Using structural assessment and staining will allow for the differentiation of mesenchymal tumors and assessment of their malignant potential.

To remove SELs, multiple endoscopic resection techniques may be appropriate, depending on the layer of origin, size, and location, with the goal of complete, en bloc resection with no disruption to the wall or capsule of the lesion. These techniques should be limited to endoscopists skilled in advanced tissue resection.

SELs without malignant potential, such as lipoma or pancreatic rest, don’t need further evaluation or surveillance.

SELs that are ulcerated, bleeding, or causing symptoms should be considered for resection.

Other lesions are managed with resection or surveillance based on pathology. For example, leiomyomas, which are benign and most often found in the esophagus, generally don’t require surveillance or resection. On the other hand, all GISTs have some malignant potential, and management varies by size, location, and presence of symptoms. GISTs larger than 2 cm, should be considered for resection. Some GISTs between 2 cm and 4 cm without high-risk features can be removed by using advanced endoscopic resection techniques.

The determination for resection in all cases should include a multidisciplinary approach, with confirmation of a low mitotic index and lack of metastatic disease on cross-sectional imaging.

“The ultimate goal of endoscopic resection is to have a complete resection,” the authors wrote. “Determining the layer of involvement by EUS is critical in planning resection techniques.”

The authors reported no grant support or funding sources for this report. One author serves as a consultant for Boston Scientific, Fujifilm, Intuitive Surgical, Medtronic, and Olympus. The remaining authors disclosed no conflicts.

The proper management of subepithelial lesions (SELs) depends on the size, histopathology, malignant potential, and presence of symptoms, according to a new American Gastroenterological Association clinical practice update published in Clinical Gastroenterology and Hepatology.

“SELs are found in 1 in every 300 endoscopies, and two-thirds of these lesions are located in the stomach,” explained Kaveh Sharzehi, MD, an associate professor of medicine in the division of gastroenterology and hepatology at Oregon Health & Science University, Portland, and colleagues. “They represent a heterogeneous group of lesions including nonneoplastic lesions such as ectopic pancreatic tissue and neoplastic lesions. The neoplastic SELs can vary from lesions with no malignant potential such as lipomas to those with malignant potential such as gastrointestinal stromal tumors (GISTs). The majority of SELs are small and found incidentally.”

The authors developed 10 clinical practice advice statements on the diagnosis and management of subepithelial lesions based on a review of the published literature and expert opinion.

First, standard mucosal biopsies often don’t reach deep enough to obtain a pathologic diagnosis for SELs because the lesions have normal overlying mucosa. Forceps bite-on-bite/deep-well biopsies or tunnel biopsies may help to establish a pathologic diagnosis.

Used as an adjunct to standard endoscopy, endoscopic ultrasound (EUS) has become the primary method for determining diagnostic and prognostic characteristics of SELs – such as the layer of origin, echogenicity, and presence of blood vessels within the lesion. It can also help with tissue acquisition.

For SELs arising from the submucosa, EUS-guided fine-needle aspiration and fine-needle biopsy have evolved as widely used methods for obtaining tissue. For SELs arising from muscularis propria, fine-needle aspiration and fine-needle biopsy should be used to determine whether the lesion is a GIST or leiomyoma. Using structural assessment and staining will allow for the differentiation of mesenchymal tumors and assessment of their malignant potential.

To remove SELs, multiple endoscopic resection techniques may be appropriate, depending on the layer of origin, size, and location, with the goal of complete, en bloc resection with no disruption to the wall or capsule of the lesion. These techniques should be limited to endoscopists skilled in advanced tissue resection.

SELs without malignant potential, such as lipoma or pancreatic rest, don’t need further evaluation or surveillance.

SELs that are ulcerated, bleeding, or causing symptoms should be considered for resection.

Other lesions are managed with resection or surveillance based on pathology. For example, leiomyomas, which are benign and most often found in the esophagus, generally don’t require surveillance or resection. On the other hand, all GISTs have some malignant potential, and management varies by size, location, and presence of symptoms. GISTs larger than 2 cm, should be considered for resection. Some GISTs between 2 cm and 4 cm without high-risk features can be removed by using advanced endoscopic resection techniques.

The determination for resection in all cases should include a multidisciplinary approach, with confirmation of a low mitotic index and lack of metastatic disease on cross-sectional imaging.

“The ultimate goal of endoscopic resection is to have a complete resection,” the authors wrote. “Determining the layer of involvement by EUS is critical in planning resection techniques.”

The authors reported no grant support or funding sources for this report. One author serves as a consultant for Boston Scientific, Fujifilm, Intuitive Surgical, Medtronic, and Olympus. The remaining authors disclosed no conflicts.

The proper management of subepithelial lesions (SELs) depends on the size, histopathology, malignant potential, and presence of symptoms, according to a new American Gastroenterological Association clinical practice update published in Clinical Gastroenterology and Hepatology.

“SELs are found in 1 in every 300 endoscopies, and two-thirds of these lesions are located in the stomach,” explained Kaveh Sharzehi, MD, an associate professor of medicine in the division of gastroenterology and hepatology at Oregon Health & Science University, Portland, and colleagues. “They represent a heterogeneous group of lesions including nonneoplastic lesions such as ectopic pancreatic tissue and neoplastic lesions. The neoplastic SELs can vary from lesions with no malignant potential such as lipomas to those with malignant potential such as gastrointestinal stromal tumors (GISTs). The majority of SELs are small and found incidentally.”

The authors developed 10 clinical practice advice statements on the diagnosis and management of subepithelial lesions based on a review of the published literature and expert opinion.

First, standard mucosal biopsies often don’t reach deep enough to obtain a pathologic diagnosis for SELs because the lesions have normal overlying mucosa. Forceps bite-on-bite/deep-well biopsies or tunnel biopsies may help to establish a pathologic diagnosis.

Used as an adjunct to standard endoscopy, endoscopic ultrasound (EUS) has become the primary method for determining diagnostic and prognostic characteristics of SELs – such as the layer of origin, echogenicity, and presence of blood vessels within the lesion. It can also help with tissue acquisition.

For SELs arising from the submucosa, EUS-guided fine-needle aspiration and fine-needle biopsy have evolved as widely used methods for obtaining tissue. For SELs arising from muscularis propria, fine-needle aspiration and fine-needle biopsy should be used to determine whether the lesion is a GIST or leiomyoma. Using structural assessment and staining will allow for the differentiation of mesenchymal tumors and assessment of their malignant potential.

To remove SELs, multiple endoscopic resection techniques may be appropriate, depending on the layer of origin, size, and location, with the goal of complete, en bloc resection with no disruption to the wall or capsule of the lesion. These techniques should be limited to endoscopists skilled in advanced tissue resection.

SELs without malignant potential, such as lipoma or pancreatic rest, don’t need further evaluation or surveillance.

SELs that are ulcerated, bleeding, or causing symptoms should be considered for resection.

Other lesions are managed with resection or surveillance based on pathology. For example, leiomyomas, which are benign and most often found in the esophagus, generally don’t require surveillance or resection. On the other hand, all GISTs have some malignant potential, and management varies by size, location, and presence of symptoms. GISTs larger than 2 cm, should be considered for resection. Some GISTs between 2 cm and 4 cm without high-risk features can be removed by using advanced endoscopic resection techniques.

The determination for resection in all cases should include a multidisciplinary approach, with confirmation of a low mitotic index and lack of metastatic disease on cross-sectional imaging.

“The ultimate goal of endoscopic resection is to have a complete resection,” the authors wrote. “Determining the layer of involvement by EUS is critical in planning resection techniques.”

The authors reported no grant support or funding sources for this report. One author serves as a consultant for Boston Scientific, Fujifilm, Intuitive Surgical, Medtronic, and Olympus. The remaining authors disclosed no conflicts.

To the Editor:

Segmental neurofibromatosis, or neurofibromatosis type 5 (NF5), is a rare subtype of neurofibromatosis type 1 (NF1)(also known as von Recklinghausen disease). Phenotypic manifestations of NF5 include café-au-lait macules, neurofibromas, or both in 1 or more adjacent dermatomes. In contrast to the systemic features of NF1, the dermatomal distribution of NF5 demonstrates mosaicism due to a spontaneous postzygotic mutation in the neurofibromin 1 gene, NF1. We describe an atypical presentation of NF5 with bilateral features on the upper extremities.

A 74-year-old woman presented with soft pink- to flesh-colored growths on the left dorsal forearm and hand that were observed incidentally during a Mohs procedure for treatment of a basal cell carcinoma on the upper cutaneous lip. The patient reported that the lesions initially appeared on the left dorsal hand at approximately 16 years of age and had since spread proximally up to the mid dorsal forearm over the course of her lifetime. She denied any pain but claimed the affected area could be itchy. The lesions did not interfere with her daily activities, but they negatively impacted her social life due to their cosmetic appearance as well as her fear that they could be contagious. She denied any family history of NF1.

Physical examination revealed innumerable soft, pink- to flesh-colored cutaneous nodules ranging from 3 to 9 mm in diameter clustered uniformly on the left dorsal hand and lower forearm within the C6, C7, and C8 dermatomal regions (Figure, A). A singular brown patch measuring 20 mm in diameter also was observed on the right dorsal hand within the C6 dermatome, which the patient reported had been present since birth (Figure, B). The nodules and pigmented patch were clinically diagnosed as cutaneous neurofibromas on the left arm and a café-au-lait macule on the right arm, each manifesting within the C6 dermatome on separate upper extremities. Lisch nodules, axillary freckling, and acoustic schwannomas were not observed. Because of the dermatomal distribution of the lesions and lack of family history of NF1, a diagnosis of bilateral NF5 was made. The patient stated she had declined treatment of the neurofibromas from her referring general dermatologist due to possible risk for recurrence.

Segmental neurofibromatosis was first described in 1931 by Gammel,¹ and in 1982, segmental neurofibromatosis was classified as NF5 by Riccardi.² After Tinschert et al³ later demonstrated NF5 to be a somatic mutation of NF1,³ Ruggieri and Huson⁴ proposed the term mosaic neurofibromatosis 1 in 2001.

While the prevalence of NF1 is 1 in 3000 individuals,⁵ NF5 is rare with an occurrence of 1 in 40,000.⁶ In NF5, a spontaneous NF1 gene mutation occurs on chromosome 17 in a dividing cell after conception.⁷ Individuals with NF5 are born mosaic with 2 genotypes—one normal and one abnormal—for the NF1 gene.⁸ This contrasts with the autosomal-dominant and systemic characteristics of NF1, which has the NF1 gene mutation in all cells. Patients with NF5 generally are not expected to have affected offspring because the spontaneous mutation usually arises in somatic cells; however, a postzygotic mutation in the gonadal region could potentially affect germline cells, resulting in vertical transmission, with documented cases of offspring with systemic NF1.⁴ Because of the risk for malignancy with systemic neurofibromatosis, early diagnosis with genetic counseling is imperative in patients with both NF1 and NF5.

Neurofibromatosis type 5 is a clinical diagnosis based on the presence of neurofibromas and/or café-au-lait macules in a dermatomal distribution. The clinical presentation depends on when and where the NF1 gene mutation occurs in utero as cells multiply, differentiate, and migrate.⁸ Earlier mutations result in a broader manifestation of NF5 in comparison to late mutations, which have more localized features. An NF1 gene mutation causes a loss of function of neurofibromin, a tumor suppressor protein, in Schwann cells and fibroblasts.⁸ This produces neurofibromas and café-au-lait macules, respectively.⁸

A large literature review on segmental neurofibromatosis by Garcia-Romero et al⁶ identified 320 individuals who did not meet full inclusion criteria for NF1 between 1977 and 2012. Overall, 76% of cases were unilaterally distributed. The investigators identified 157 individual case reports in which the most to least common presentation was pigmentary changes only, neurofibromas only, mixed pigmentary changes with neurofibromas, and plexiform neurofibromas only; however, many of these cases were children who may have later developed both neurofibromas and pigmentary changes during puberty.⁶ Additional features of NF5 may include freckling, Lisch nodules, optic gliomas, malignant peripheral nerve sheath tumors, skeletal abnormalities, precocious puberty, vascular malformations, hypertension, seizures, and/or learning difficulties based on the affected anatomy.

Segmental neurofibromatosis, or NF5, is a rare subtype of NF1. Our case demonstrates an unusual bilateral distribution of NF5 with cutaneous neurofibromas and a café-au-lait macule on the upper extremities. Awareness of variations of neurofibromatosis and their genetic implications is essential in establishing earlier clinical diagnoses in cases with subtle manifestations.

To the Editor:

Segmental neurofibromatosis, or neurofibromatosis type 5 (NF5), is a rare subtype of neurofibromatosis type 1 (NF1)(also known as von Recklinghausen disease). Phenotypic manifestations of NF5 include café-au-lait macules, neurofibromas, or both in 1 or more adjacent dermatomes. In contrast to the systemic features of NF1, the dermatomal distribution of NF5 demonstrates mosaicism due to a spontaneous postzygotic mutation in the neurofibromin 1 gene, NF1. We describe an atypical presentation of NF5 with bilateral features on the upper extremities.

A 74-year-old woman presented with soft pink- to flesh-colored growths on the left dorsal forearm and hand that were observed incidentally during a Mohs procedure for treatment of a basal cell carcinoma on the upper cutaneous lip. The patient reported that the lesions initially appeared on the left dorsal hand at approximately 16 years of age and had since spread proximally up to the mid dorsal forearm over the course of her lifetime. She denied any pain but claimed the affected area could be itchy. The lesions did not interfere with her daily activities, but they negatively impacted her social life due to their cosmetic appearance as well as her fear that they could be contagious. She denied any family history of NF1.

Physical examination revealed innumerable soft, pink- to flesh-colored cutaneous nodules ranging from 3 to 9 mm in diameter clustered uniformly on the left dorsal hand and lower forearm within the C6, C7, and C8 dermatomal regions (Figure, A). A singular brown patch measuring 20 mm in diameter also was observed on the right dorsal hand within the C6 dermatome, which the patient reported had been present since birth (Figure, B). The nodules and pigmented patch were clinically diagnosed as cutaneous neurofibromas on the left arm and a café-au-lait macule on the right arm, each manifesting within the C6 dermatome on separate upper extremities. Lisch nodules, axillary freckling, and acoustic schwannomas were not observed. Because of the dermatomal distribution of the lesions and lack of family history of NF1, a diagnosis of bilateral NF5 was made. The patient stated she had declined treatment of the neurofibromas from her referring general dermatologist due to possible risk for recurrence.

Segmental neurofibromatosis was first described in 1931 by Gammel,¹ and in 1982, segmental neurofibromatosis was classified as NF5 by Riccardi.² After Tinschert et al³ later demonstrated NF5 to be a somatic mutation of NF1,³ Ruggieri and Huson⁴ proposed the term mosaic neurofibromatosis 1 in 2001.

While the prevalence of NF1 is 1 in 3000 individuals,⁵ NF5 is rare with an occurrence of 1 in 40,000.⁶ In NF5, a spontaneous NF1 gene mutation occurs on chromosome 17 in a dividing cell after conception.⁷ Individuals with NF5 are born mosaic with 2 genotypes—one normal and one abnormal—for the NF1 gene.⁸ This contrasts with the autosomal-dominant and systemic characteristics of NF1, which has the NF1 gene mutation in all cells. Patients with NF5 generally are not expected to have affected offspring because the spontaneous mutation usually arises in somatic cells; however, a postzygotic mutation in the gonadal region could potentially affect germline cells, resulting in vertical transmission, with documented cases of offspring with systemic NF1.⁴ Because of the risk for malignancy with systemic neurofibromatosis, early diagnosis with genetic counseling is imperative in patients with both NF1 and NF5.

Neurofibromatosis type 5 is a clinical diagnosis based on the presence of neurofibromas and/or café-au-lait macules in a dermatomal distribution. The clinical presentation depends on when and where the NF1 gene mutation occurs in utero as cells multiply, differentiate, and migrate.⁸ Earlier mutations result in a broader manifestation of NF5 in comparison to late mutations, which have more localized features. An NF1 gene mutation causes a loss of function of neurofibromin, a tumor suppressor protein, in Schwann cells and fibroblasts.⁸ This produces neurofibromas and café-au-lait macules, respectively.⁸

A large literature review on segmental neurofibromatosis by Garcia-Romero et al⁶ identified 320 individuals who did not meet full inclusion criteria for NF1 between 1977 and 2012. Overall, 76% of cases were unilaterally distributed. The investigators identified 157 individual case reports in which the most to least common presentation was pigmentary changes only, neurofibromas only, mixed pigmentary changes with neurofibromas, and plexiform neurofibromas only; however, many of these cases were children who may have later developed both neurofibromas and pigmentary changes during puberty.⁶ Additional features of NF5 may include freckling, Lisch nodules, optic gliomas, malignant peripheral nerve sheath tumors, skeletal abnormalities, precocious puberty, vascular malformations, hypertension, seizures, and/or learning difficulties based on the affected anatomy.

Segmental neurofibromatosis, or NF5, is a rare subtype of NF1. Our case demonstrates an unusual bilateral distribution of NF5 with cutaneous neurofibromas and a café-au-lait macule on the upper extremities. Awareness of variations of neurofibromatosis and their genetic implications is essential in establishing earlier clinical diagnoses in cases with subtle manifestations.

To the Editor:

Segmental neurofibromatosis, or neurofibromatosis type 5 (NF5), is a rare subtype of neurofibromatosis type 1 (NF1)(also known as von Recklinghausen disease). Phenotypic manifestations of NF5 include café-au-lait macules, neurofibromas, or both in 1 or more adjacent dermatomes. In contrast to the systemic features of NF1, the dermatomal distribution of NF5 demonstrates mosaicism due to a spontaneous postzygotic mutation in the neurofibromin 1 gene, NF1. We describe an atypical presentation of NF5 with bilateral features on the upper extremities.

A 74-year-old woman presented with soft pink- to flesh-colored growths on the left dorsal forearm and hand that were observed incidentally during a Mohs procedure for treatment of a basal cell carcinoma on the upper cutaneous lip. The patient reported that the lesions initially appeared on the left dorsal hand at approximately 16 years of age and had since spread proximally up to the mid dorsal forearm over the course of her lifetime. She denied any pain but claimed the affected area could be itchy. The lesions did not interfere with her daily activities, but they negatively impacted her social life due to their cosmetic appearance as well as her fear that they could be contagious. She denied any family history of NF1.

Physical examination revealed innumerable soft, pink- to flesh-colored cutaneous nodules ranging from 3 to 9 mm in diameter clustered uniformly on the left dorsal hand and lower forearm within the C6, C7, and C8 dermatomal regions (Figure, A). A singular brown patch measuring 20 mm in diameter also was observed on the right dorsal hand within the C6 dermatome, which the patient reported had been present since birth (Figure, B). The nodules and pigmented patch were clinically diagnosed as cutaneous neurofibromas on the left arm and a café-au-lait macule on the right arm, each manifesting within the C6 dermatome on separate upper extremities. Lisch nodules, axillary freckling, and acoustic schwannomas were not observed. Because of the dermatomal distribution of the lesions and lack of family history of NF1, a diagnosis of bilateral NF5 was made. The patient stated she had declined treatment of the neurofibromas from her referring general dermatologist due to possible risk for recurrence.

Segmental neurofibromatosis was first described in 1931 by Gammel,¹ and in 1982, segmental neurofibromatosis was classified as NF5 by Riccardi.² After Tinschert et al³ later demonstrated NF5 to be a somatic mutation of NF1,³ Ruggieri and Huson⁴ proposed the term mosaic neurofibromatosis 1 in 2001.

While the prevalence of NF1 is 1 in 3000 individuals,⁵ NF5 is rare with an occurrence of 1 in 40,000.⁶ In NF5, a spontaneous NF1 gene mutation occurs on chromosome 17 in a dividing cell after conception.⁷ Individuals with NF5 are born mosaic with 2 genotypes—one normal and one abnormal—for the NF1 gene.⁸ This contrasts with the autosomal-dominant and systemic characteristics of NF1, which has the NF1 gene mutation in all cells. Patients with NF5 generally are not expected to have affected offspring because the spontaneous mutation usually arises in somatic cells; however, a postzygotic mutation in the gonadal region could potentially affect germline cells, resulting in vertical transmission, with documented cases of offspring with systemic NF1.⁴ Because of the risk for malignancy with systemic neurofibromatosis, early diagnosis with genetic counseling is imperative in patients with both NF1 and NF5.

Neurofibromatosis type 5 is a clinical diagnosis based on the presence of neurofibromas and/or café-au-lait macules in a dermatomal distribution. The clinical presentation depends on when and where the NF1 gene mutation occurs in utero as cells multiply, differentiate, and migrate.⁸ Earlier mutations result in a broader manifestation of NF5 in comparison to late mutations, which have more localized features. An NF1 gene mutation causes a loss of function of neurofibromin, a tumor suppressor protein, in Schwann cells and fibroblasts.⁸ This produces neurofibromas and café-au-lait macules, respectively.⁸

A large literature review on segmental neurofibromatosis by Garcia-Romero et al⁶ identified 320 individuals who did not meet full inclusion criteria for NF1 between 1977 and 2012. Overall, 76% of cases were unilaterally distributed. The investigators identified 157 individual case reports in which the most to least common presentation was pigmentary changes only, neurofibromas only, mixed pigmentary changes with neurofibromas, and plexiform neurofibromas only; however, many of these cases were children who may have later developed both neurofibromas and pigmentary changes during puberty.⁶ Additional features of NF5 may include freckling, Lisch nodules, optic gliomas, malignant peripheral nerve sheath tumors, skeletal abnormalities, precocious puberty, vascular malformations, hypertension, seizures, and/or learning difficulties based on the affected anatomy.

Segmental neurofibromatosis, or NF5, is a rare subtype of NF1. Our case demonstrates an unusual bilateral distribution of NF5 with cutaneous neurofibromas and a café-au-lait macule on the upper extremities. Awareness of variations of neurofibromatosis and their genetic implications is essential in establishing earlier clinical diagnoses in cases with subtle manifestations.

Until the second half of the 20th century, it was believed that the uterine cavity was sterile. Since then, technological advances have provided insight into the nature of the microbiome throughout the female reproductive tract. The role of these microorganisms on the fertility of women of reproductive age has been the subject of research. Is there an “optimal microbiome” for fertility? Can changing the microbiome of the uterine cavity affect fertility? There is still no definitive scientific response to these questions.

Several studies describe the healthy state of the uterine microbiota in women of reproductive age, with most of these studies reporting dominance of Lactobacillus species. However, by contrast, some studies did not observe Lactobacillus predominance inside the uterine cavity in cases of healthy uterine microbiomes. The presence of other microorganisms, such as Gardnerella vaginalis, was associated with reduced success in patients attempting in vitro fertilization (IVF) treatment, such as, for example, embryo implantation failure and miscarriage.

It is also possible that a physiologic endometrial microbiome could be considered healthy despite a minor presence of pathogenic bacteria. Importantly, responses from the host also modulate many aspects of human conception. These shifts correlate with parameters such as age, hormonal changes, ethnicity, sexual activity, and intrauterine devices.

Carlos Simón, MD, PhD, is a gynecologist and obstetrician and professor at the University of Valencia in Valencia, Spain; Harvard University, Cambridge, Mass.; and Baylor College of Medicine, Houston. He was in São Paulo at the time of the XXVI Brazilian Congress of Assisted Reproduction and agreed to be interviewed by Medscape Portuguese Edition. Dr. Simón, who is Spanish and is an international reference in uterine microbiome studies, created an endometrial receptivity analysis (ERA).

“What we know is that the human uterus has its own microbiome. Thanks to next-generation sequencing (NGS), we can detect microbial DNA. We’re talking about a microbiome that, if changed, affects [embryo] implantation. We have identified that Lactobacilli are the good [microorganisms], but if there are Streptococci, Gardnerella, or other bacteria, the implantation [of the embryo] is affected.”

In 2018, Dr. Simón’s team published a pilot study assessing the microbiome of 30 patients during fertilization treatment. It was observed that, when there is a change in the microbiome, the implantation rate drops to half and the miscarriage rate doubles.

Following this study, also in 2018, the team published a multicenter, prospective, observational study. A 16S ribosomal RNA (16S rRNA) gene sequencing technique was used to analyze endometrial fluid and biopsy samples before embryo transfer in a cohort of 342 infertile patients asymptomatic for infection. Participants underwent fertilization procedures in 13 centers on three continents.

A dysbiotic endometrial microbiota profile composed of Atopobium, Bifidobacterium, Chryseobacterium, Gardnerella, Haemophilus, Klebsiella, Neisseria, Staphylococcus, and Streptococcus was associated with unsuccessful outcomes. In contrast, Lactobacillus was consistently enriched in patients with live birth outcomes. The authors concluded that endometrial microbiota composition before embryo transfer is a useful biomarker to predict reproductive outcome.

“You see a microbial signature in patients who become pregnant, another in those who do not become pregnant, and yet another in those who miscarry,” Dr. Simón summarized. “By knowing this signature, the microbiome can be analyzed and treated so that it is stabilized before the embryo is transferred.”
 

What should be done?

Endometrial microbiome profiles do not use microbial cultures. They are obtained by NGS of the endometrial sample. This is because the 16S rRNA gene, which can be found in bacteria, presents hypervariable regions that serve as markers to identify the bacteria present.

If a microbiome is found to be somewhat unhealthy, it is theoretically possible to change its composition, increasing the chances of successful assisted reproduction. The administration of antibiotics and vaginal probiotics are two treatment approaches.

According to Dr. Simón, treatment is specific to the bacterium (metronidazole, and, if that fails, rifampicin for Gardnerella, amoxicillin and clavulanic acid for Streptococci). Once the pathogenic bacterium has been treated, the probiotics can be administered. “If all is well, we can then go ahead with the procedure,” he explained.

Dr. Simón pointed out that, with respect to treatment, knowledge is still limited and primarily based on case reports. “You look for issues in the microbiome when the patient experiences reproductive failure and there are no other causes,” he emphasized. “Microbiology plays a role in reproduction, affecting the human uterus. It’s good to know about it to improve reproductive outcomes. When there are repeated [embryo] implantation failures, we suggest an endometrial biopsy to identify the implantation window and determine whether the uterine microbiome is healthy or not. And if there are any abnormalities in the microbiome, they can be treated.”

There are still many open questions, such as how long the “good microbiome” lasts after antibiotic therapy. “We suggest checking the microbiome after [antibiotic] treatment and before implanting the embryo,” said Dr. Simón.

Although there is no consensus on how the endometrial microbiota relate to reproductive outcomes, the analysis and change in microbiome are already being offered in clinical practice as a way to increase the chances of conception. Márcia Riboldi, PhD, a genetics specialist serving as Country Manager for Igenomix Brasil and Argentina, the company that offers the analyses, provides an idea of the market for such analyses in Brazil. “We perform approximately 500 analyses per month,” she said, adding that most patients have a history of [embryo] implantation failure or miscarriage.

Matheus Roque, MD, PhD, an IVF specialist, shared two IVF case reports from the Mater Prime Human Reproduction Clinic in the southern region of the city of São Paulo. He emphasized that the decision to perform a microbiome analysis was made only after repeated implantation failure.

“With the outcomes the doctors started to see, the paradigm started to shift,” said Dr. Riboldi. “Why wait for the patient to have [an embryo] transfer failure? Let’s study the endometrium, check the ideal moment for the transfer, see whether it’s receptive or not, if there’s any disease and if there are Lactobacilli,” she proposed. “We need medical training and awareness, and we need to use them appropriately. We have the tests. Doctors need to learn about them and know when and how to use them.” The microbiome analysis costs approximately BRL 2,000, plus expenses for the medical procedure.
 

Is it too early?

Caio Parente Barbosa, MD, PhD, is an obstetrician/gynecologist specializing in human reproduction, as well as the director general and founder of the Fertile Idea Institute for Reproductive Health. He shared a few of his experiences in an interview with this news organization. “I would say it is still too early to confirm that [the microbiome analysis] produces effective outcomes.”

Dr. Barbosa, who is also provost of graduate studies, research, and innovation of the ABC School of Medicine, Santo André, Brazil, emphasized there is still little global experience with these analyses. “There are doubts worldwide regarding whether these analyses produce effective outcomes. Scientific studies are entirely controversial.”

He stated that some professionals recommend the microbiome analysis for “patients who don’t know what else to do,” but also recognized that there is already a demand for patients who don’t fit this category, who research the analyses on social networks and YouTube. “But it is the smallest of demands. Patients are not as worried about this yet.”

Dr. Barbosa recognized that the idea of an increasingly tailored treatment plan is inevitable. He believes that the study and treatment of the microbiome will become more critical in the future, but he thinks it still “does not offer any value.”

Dr. Barbosa emphasized that the financial side of things must also be considered. “If we add all these tests when investigating a patient’s issues, the treatment becomes ridiculously expensive.” He pointed out that health care professionals need to be careful to perform minimal testing. “We have already added some tests, such as the karyotype test, to the minimal testing for all patients.”

Dr. Simón responded to this criticism, stating: “The cost of repeating cycles is always greater than that of being thorough and knowing what’s going on. Nothing is certain, but if my daughter or wife needed it, I would like to have as much information as possible to make this decision.”

Dr. Barbosa and Dr. Simón reported no relevant financial relationships. Dr. Riboldi is Country Manager for Igenomix Brasil and Argentina, the company that offers the analyses.

This article was translated from the Medscape Portuguese edition and appeared on Medscape.com.

Until the second half of the 20th century, it was believed that the uterine cavity was sterile. Since then, technological advances have provided insight into the nature of the microbiome throughout the female reproductive tract. The role of these microorganisms on the fertility of women of reproductive age has been the subject of research. Is there an “optimal microbiome” for fertility? Can changing the microbiome of the uterine cavity affect fertility? There is still no definitive scientific response to these questions.

Several studies describe the healthy state of the uterine microbiota in women of reproductive age, with most of these studies reporting dominance of Lactobacillus species. However, by contrast, some studies did not observe Lactobacillus predominance inside the uterine cavity in cases of healthy uterine microbiomes. The presence of other microorganisms, such as Gardnerella vaginalis, was associated with reduced success in patients attempting in vitro fertilization (IVF) treatment, such as, for example, embryo implantation failure and miscarriage.

It is also possible that a physiologic endometrial microbiome could be considered healthy despite a minor presence of pathogenic bacteria. Importantly, responses from the host also modulate many aspects of human conception. These shifts correlate with parameters such as age, hormonal changes, ethnicity, sexual activity, and intrauterine devices.

Carlos Simón, MD, PhD, is a gynecologist and obstetrician and professor at the University of Valencia in Valencia, Spain; Harvard University, Cambridge, Mass.; and Baylor College of Medicine, Houston. He was in São Paulo at the time of the XXVI Brazilian Congress of Assisted Reproduction and agreed to be interviewed by Medscape Portuguese Edition. Dr. Simón, who is Spanish and is an international reference in uterine microbiome studies, created an endometrial receptivity analysis (ERA).

“What we know is that the human uterus has its own microbiome. Thanks to next-generation sequencing (NGS), we can detect microbial DNA. We’re talking about a microbiome that, if changed, affects [embryo] implantation. We have identified that Lactobacilli are the good [microorganisms], but if there are Streptococci, Gardnerella, or other bacteria, the implantation [of the embryo] is affected.”

In 2018, Dr. Simón’s team published a pilot study assessing the microbiome of 30 patients during fertilization treatment. It was observed that, when there is a change in the microbiome, the implantation rate drops to half and the miscarriage rate doubles.

Following this study, also in 2018, the team published a multicenter, prospective, observational study. A 16S ribosomal RNA (16S rRNA) gene sequencing technique was used to analyze endometrial fluid and biopsy samples before embryo transfer in a cohort of 342 infertile patients asymptomatic for infection. Participants underwent fertilization procedures in 13 centers on three continents.

A dysbiotic endometrial microbiota profile composed of Atopobium, Bifidobacterium, Chryseobacterium, Gardnerella, Haemophilus, Klebsiella, Neisseria, Staphylococcus, and Streptococcus was associated with unsuccessful outcomes. In contrast, Lactobacillus was consistently enriched in patients with live birth outcomes. The authors concluded that endometrial microbiota composition before embryo transfer is a useful biomarker to predict reproductive outcome.

“You see a microbial signature in patients who become pregnant, another in those who do not become pregnant, and yet another in those who miscarry,” Dr. Simón summarized. “By knowing this signature, the microbiome can be analyzed and treated so that it is stabilized before the embryo is transferred.”
 

What should be done?

Endometrial microbiome profiles do not use microbial cultures. They are obtained by NGS of the endometrial sample. This is because the 16S rRNA gene, which can be found in bacteria, presents hypervariable regions that serve as markers to identify the bacteria present.

If a microbiome is found to be somewhat unhealthy, it is theoretically possible to change its composition, increasing the chances of successful assisted reproduction. The administration of antibiotics and vaginal probiotics are two treatment approaches.

According to Dr. Simón, treatment is specific to the bacterium (metronidazole, and, if that fails, rifampicin for Gardnerella, amoxicillin and clavulanic acid for Streptococci). Once the pathogenic bacterium has been treated, the probiotics can be administered. “If all is well, we can then go ahead with the procedure,” he explained.

Dr. Simón pointed out that, with respect to treatment, knowledge is still limited and primarily based on case reports. “You look for issues in the microbiome when the patient experiences reproductive failure and there are no other causes,” he emphasized. “Microbiology plays a role in reproduction, affecting the human uterus. It’s good to know about it to improve reproductive outcomes. When there are repeated [embryo] implantation failures, we suggest an endometrial biopsy to identify the implantation window and determine whether the uterine microbiome is healthy or not. And if there are any abnormalities in the microbiome, they can be treated.”

There are still many open questions, such as how long the “good microbiome” lasts after antibiotic therapy. “We suggest checking the microbiome after [antibiotic] treatment and before implanting the embryo,” said Dr. Simón.

Although there is no consensus on how the endometrial microbiota relate to reproductive outcomes, the analysis and change in microbiome are already being offered in clinical practice as a way to increase the chances of conception. Márcia Riboldi, PhD, a genetics specialist serving as Country Manager for Igenomix Brasil and Argentina, the company that offers the analyses, provides an idea of the market for such analyses in Brazil. “We perform approximately 500 analyses per month,” she said, adding that most patients have a history of [embryo] implantation failure or miscarriage.

Matheus Roque, MD, PhD, an IVF specialist, shared two IVF case reports from the Mater Prime Human Reproduction Clinic in the southern region of the city of São Paulo. He emphasized that the decision to perform a microbiome analysis was made only after repeated implantation failure.

“With the outcomes the doctors started to see, the paradigm started to shift,” said Dr. Riboldi. “Why wait for the patient to have [an embryo] transfer failure? Let’s study the endometrium, check the ideal moment for the transfer, see whether it’s receptive or not, if there’s any disease and if there are Lactobacilli,” she proposed. “We need medical training and awareness, and we need to use them appropriately. We have the tests. Doctors need to learn about them and know when and how to use them.” The microbiome analysis costs approximately BRL 2,000, plus expenses for the medical procedure.
 

Is it too early?

Caio Parente Barbosa, MD, PhD, is an obstetrician/gynecologist specializing in human reproduction, as well as the director general and founder of the Fertile Idea Institute for Reproductive Health. He shared a few of his experiences in an interview with this news organization. “I would say it is still too early to confirm that [the microbiome analysis] produces effective outcomes.”

Dr. Barbosa, who is also provost of graduate studies, research, and innovation of the ABC School of Medicine, Santo André, Brazil, emphasized there is still little global experience with these analyses. “There are doubts worldwide regarding whether these analyses produce effective outcomes. Scientific studies are entirely controversial.”

He stated that some professionals recommend the microbiome analysis for “patients who don’t know what else to do,” but also recognized that there is already a demand for patients who don’t fit this category, who research the analyses on social networks and YouTube. “But it is the smallest of demands. Patients are not as worried about this yet.”

Dr. Barbosa recognized that the idea of an increasingly tailored treatment plan is inevitable. He believes that the study and treatment of the microbiome will become more critical in the future, but he thinks it still “does not offer any value.”

Dr. Barbosa emphasized that the financial side of things must also be considered. “If we add all these tests when investigating a patient’s issues, the treatment becomes ridiculously expensive.” He pointed out that health care professionals need to be careful to perform minimal testing. “We have already added some tests, such as the karyotype test, to the minimal testing for all patients.”

Dr. Simón responded to this criticism, stating: “The cost of repeating cycles is always greater than that of being thorough and knowing what’s going on. Nothing is certain, but if my daughter or wife needed it, I would like to have as much information as possible to make this decision.”

Dr. Barbosa and Dr. Simón reported no relevant financial relationships. Dr. Riboldi is Country Manager for Igenomix Brasil and Argentina, the company that offers the analyses.

This article was translated from the Medscape Portuguese edition and appeared on Medscape.com.

Until the second half of the 20th century, it was believed that the uterine cavity was sterile. Since then, technological advances have provided insight into the nature of the microbiome throughout the female reproductive tract. The role of these microorganisms on the fertility of women of reproductive age has been the subject of research. Is there an “optimal microbiome” for fertility? Can changing the microbiome of the uterine cavity affect fertility? There is still no definitive scientific response to these questions.

Several studies describe the healthy state of the uterine microbiota in women of reproductive age, with most of these studies reporting dominance of Lactobacillus species. However, by contrast, some studies did not observe Lactobacillus predominance inside the uterine cavity in cases of healthy uterine microbiomes. The presence of other microorganisms, such as Gardnerella vaginalis, was associated with reduced success in patients attempting in vitro fertilization (IVF) treatment, such as, for example, embryo implantation failure and miscarriage.

It is also possible that a physiologic endometrial microbiome could be considered healthy despite a minor presence of pathogenic bacteria. Importantly, responses from the host also modulate many aspects of human conception. These shifts correlate with parameters such as age, hormonal changes, ethnicity, sexual activity, and intrauterine devices.

Carlos Simón, MD, PhD, is a gynecologist and obstetrician and professor at the University of Valencia in Valencia, Spain; Harvard University, Cambridge, Mass.; and Baylor College of Medicine, Houston. He was in São Paulo at the time of the XXVI Brazilian Congress of Assisted Reproduction and agreed to be interviewed by Medscape Portuguese Edition. Dr. Simón, who is Spanish and is an international reference in uterine microbiome studies, created an endometrial receptivity analysis (ERA).

“What we know is that the human uterus has its own microbiome. Thanks to next-generation sequencing (NGS), we can detect microbial DNA. We’re talking about a microbiome that, if changed, affects [embryo] implantation. We have identified that Lactobacilli are the good [microorganisms], but if there are Streptococci, Gardnerella, or other bacteria, the implantation [of the embryo] is affected.”

In 2018, Dr. Simón’s team published a pilot study assessing the microbiome of 30 patients during fertilization treatment. It was observed that, when there is a change in the microbiome, the implantation rate drops to half and the miscarriage rate doubles.

Following this study, also in 2018, the team published a multicenter, prospective, observational study. A 16S ribosomal RNA (16S rRNA) gene sequencing technique was used to analyze endometrial fluid and biopsy samples before embryo transfer in a cohort of 342 infertile patients asymptomatic for infection. Participants underwent fertilization procedures in 13 centers on three continents.

A dysbiotic endometrial microbiota profile composed of Atopobium, Bifidobacterium, Chryseobacterium, Gardnerella, Haemophilus, Klebsiella, Neisseria, Staphylococcus, and Streptococcus was associated with unsuccessful outcomes. In contrast, Lactobacillus was consistently enriched in patients with live birth outcomes. The authors concluded that endometrial microbiota composition before embryo transfer is a useful biomarker to predict reproductive outcome.

“You see a microbial signature in patients who become pregnant, another in those who do not become pregnant, and yet another in those who miscarry,” Dr. Simón summarized. “By knowing this signature, the microbiome can be analyzed and treated so that it is stabilized before the embryo is transferred.”
 

What should be done?

Endometrial microbiome profiles do not use microbial cultures. They are obtained by NGS of the endometrial sample. This is because the 16S rRNA gene, which can be found in bacteria, presents hypervariable regions that serve as markers to identify the bacteria present.

If a microbiome is found to be somewhat unhealthy, it is theoretically possible to change its composition, increasing the chances of successful assisted reproduction. The administration of antibiotics and vaginal probiotics are two treatment approaches.

According to Dr. Simón, treatment is specific to the bacterium (metronidazole, and, if that fails, rifampicin for Gardnerella, amoxicillin and clavulanic acid for Streptococci). Once the pathogenic bacterium has been treated, the probiotics can be administered. “If all is well, we can then go ahead with the procedure,” he explained.

Dr. Simón pointed out that, with respect to treatment, knowledge is still limited and primarily based on case reports. “You look for issues in the microbiome when the patient experiences reproductive failure and there are no other causes,” he emphasized. “Microbiology plays a role in reproduction, affecting the human uterus. It’s good to know about it to improve reproductive outcomes. When there are repeated [embryo] implantation failures, we suggest an endometrial biopsy to identify the implantation window and determine whether the uterine microbiome is healthy or not. And if there are any abnormalities in the microbiome, they can be treated.”

There are still many open questions, such as how long the “good microbiome” lasts after antibiotic therapy. “We suggest checking the microbiome after [antibiotic] treatment and before implanting the embryo,” said Dr. Simón.

Although there is no consensus on how the endometrial microbiota relate to reproductive outcomes, the analysis and change in microbiome are already being offered in clinical practice as a way to increase the chances of conception. Márcia Riboldi, PhD, a genetics specialist serving as Country Manager for Igenomix Brasil and Argentina, the company that offers the analyses, provides an idea of the market for such analyses in Brazil. “We perform approximately 500 analyses per month,” she said, adding that most patients have a history of [embryo] implantation failure or miscarriage.

Matheus Roque, MD, PhD, an IVF specialist, shared two IVF case reports from the Mater Prime Human Reproduction Clinic in the southern region of the city of São Paulo. He emphasized that the decision to perform a microbiome analysis was made only after repeated implantation failure.

“With the outcomes the doctors started to see, the paradigm started to shift,” said Dr. Riboldi. “Why wait for the patient to have [an embryo] transfer failure? Let’s study the endometrium, check the ideal moment for the transfer, see whether it’s receptive or not, if there’s any disease and if there are Lactobacilli,” she proposed. “We need medical training and awareness, and we need to use them appropriately. We have the tests. Doctors need to learn about them and know when and how to use them.” The microbiome analysis costs approximately BRL 2,000, plus expenses for the medical procedure.
 

Is it too early?

Caio Parente Barbosa, MD, PhD, is an obstetrician/gynecologist specializing in human reproduction, as well as the director general and founder of the Fertile Idea Institute for Reproductive Health. He shared a few of his experiences in an interview with this news organization. “I would say it is still too early to confirm that [the microbiome analysis] produces effective outcomes.”

Dr. Barbosa, who is also provost of graduate studies, research, and innovation of the ABC School of Medicine, Santo André, Brazil, emphasized there is still little global experience with these analyses. “There are doubts worldwide regarding whether these analyses produce effective outcomes. Scientific studies are entirely controversial.”

He stated that some professionals recommend the microbiome analysis for “patients who don’t know what else to do,” but also recognized that there is already a demand for patients who don’t fit this category, who research the analyses on social networks and YouTube. “But it is the smallest of demands. Patients are not as worried about this yet.”

Dr. Barbosa recognized that the idea of an increasingly tailored treatment plan is inevitable. He believes that the study and treatment of the microbiome will become more critical in the future, but he thinks it still “does not offer any value.”

Dr. Barbosa emphasized that the financial side of things must also be considered. “If we add all these tests when investigating a patient’s issues, the treatment becomes ridiculously expensive.” He pointed out that health care professionals need to be careful to perform minimal testing. “We have already added some tests, such as the karyotype test, to the minimal testing for all patients.”

Dr. Simón responded to this criticism, stating: “The cost of repeating cycles is always greater than that of being thorough and knowing what’s going on. Nothing is certain, but if my daughter or wife needed it, I would like to have as much information as possible to make this decision.”

Dr. Barbosa and Dr. Simón reported no relevant financial relationships. Dr. Riboldi is Country Manager for Igenomix Brasil and Argentina, the company that offers the analyses.

This article was translated from the Medscape Portuguese edition and appeared on Medscape.com.

Fecal microbiota transplantation (FMT) is safe and highly effective as first-line therapy for patients with first or second Clostridioides difficile infection, according to the first randomized, double-blind, placebo-controlled trial of its kind.

Study enrollment was halted after an interim analysis revealed significantly better outcomes among patients who received vancomycin plus FMT versus vancomycin alone, reported lead author Simon Mark Dahl Baunwall, MD, of Aarhus (Denmark) University Hospital and colleagues in The Lancet Gastroenterology & Hepatology.

gaetan stoffel/gettyimages

The investigators noted that the participants represented a real-world patient population, so the data support FMT “as a necessary, effective first-line option” in routine management of C. difficile infection.

“Previous studies have demonstrated clinical cure rates [with FMT] of up to 92%,” Dr. Baunwall and colleagues wrote. “Early use of FMT for first or second C. difficile infection has therapeutic potential, but no formal randomized trials to support use of the approach as a first-line therapy have been done.”

The present trial, conducted at a university hospital in Denmark, involved 42 adult patients with first or second C. difficile infection. Patients were randomized in a 1:1 ratio to receive either vancomycin alone or vancomycin plus FMT. All patients received 125 mg oral vancomycin four times daily for a minimum of 10 days after diagnosis. On day 1 after completion of vancomycin therapy and again between day 3 and 7, patients received either oral FMT or matching placebo, depending on their group. After completing the protocol, patients were followed for 8 weeks or C. difficile recurrence to evaluate resolution of C. difficile–associated diarrhea.

“In this trial, patients were treated with two sequential FMT procedures on separate days,” the investigators noted. “This practice might have overtreated some patients and differs from previous trials. It remains unknown whether optimal effect is achieved by one or two treatments.”

The trial design called for 84 patients, but enrollment was halted after an interim analysis of the above cohort of 42 patients because of significantly lower rate resolution in the placebo group. At the 2-month mark, 90% (95% confidence interval, 70%-99%) of patients in the FMT group had resolution, compared with only 33% (95% CI, 15%-57%) of patients in the placebo group (P = .0003), constituting a 57% (95% CI, 33%-81%) absolute risk reduction.

Most patients experienced adverse events, including 20 in the FMT group and all 21 in the placebo group, although most were transient and nonserious. The most common adverse events were diarrhea, which occurred more frequently in the FMT group (23 vs. 14 events), followed by abdominal pain(14 vs. 11 events) and nausea (12 vs. 5 events).

One limitation of the study was its single-center design with regional uptake; the authors noted that, despite having high statistical power for the clinical effect, the study’s premature termination and low patient number prevent inferences regarding mortality, time to effect, and cost.

“The results of this trial highlight how the use of fecal microbiota transplantation as a first-line treatment can effectively prevent C. difficile recurrence and suggests that microbiota restoration might be necessary to obtain sustained resolution,” the investigators wrote. “At present, only 10% of patients with multiple, recurrent C. difficile infection and indication for FMT receive it. International initiatives address the unmet need, but logistic and regulatory obstacles remain unsolved.”
 

Encouraging findings, lingering concerns

Nicholas Turner, MD, assistant professor in the division of infectious diseases at Duke University, Durham, N.C., praised the study for “pushing the boundaries for FMT,” and noted that the methodology appeared sound. Results in the placebo group, however, cast doubt on the generalizability of the findings, he said.

“If you look at the group that received vancomycin plus placebo, their failure rate was really astoundingly high,” Dr. Turner said in an interview, referring to the 67% failure rate in the control group; he noted previous studies had reported failure rates closer to 10%. “I think that just calls into question just a little bit what happened with that control group.”

Dr. Turner said his confidence would go “way, way up” if the findings were reproduced in a larger study. Ideally, these future trials would use fidaxomicin, he added, which is becoming the preferred option over vancomycin for treating C. difficile.

John Y. Kao, MD, professor of medicine and codirector of the FMT program at University of Michigan Medicine, Ann Arbor, offered a different perspective, suggesting that the control group findings shouldn’t overshadow the efficacy of FMT.

“I agree that historical data would tell us that the placebo population should see a much higher response,” Dr. Kao said in an interview. “In my mind though, the success rate of FMT over placebo is what I would expect. The message of the study should be upheld: that FMT is an effective therapy whether it’s given early or, as the way we give it now, as a sort of rescue therapy.”

Despite this confidence in FMT as an efficacious first-line option, Dr. Kao said it is unlikely to be routinely used in this way anytime soon, even if a larger trial echoes the present results.

“We don’t know the long-term risks of FMT therapy, although we’ve been doing this now probably close to 20 years,” Dr. Kao said.

Specifically, Dr. Kao was most concerned about the long-term risk of colon cancer, as mouse models suggest that microbiome characteristics may affect risk level, and risk may vary based on host-microbiome relationships. In other words, an organism may pose no risk in the gut of the donor, but the same may not be true for the recipient.

While increased rates of colon cancer or other serious illnesses have not been detected in humans who have undergone FMT over the past 2 decades, Dr. Kao said that these findings cannot be extrapolated over a patient’s entire lifetime, especially for younger individuals.

“In a patient that’s 80, you would say, yeah, let’s go ahead and treat you [with FMT] as first-line therapy, whereas someone who’s 20, and has maybe another 50 or 60 years longevity, you may not want to give FMT as first-line therapy,” Dr. Kao said.

This study was supported by Innovation Fund Denmark. The investigators disclosed no competing interests. Dr. Turner previously performed statistical analyses for a Merck study comparing vancomycin, fidaxomicin, and metronidazole for C. difficile infection. Dr. Kao disclosed no relevant conflicts of interest.

Fecal microbiota transplantation (FMT) is safe and highly effective as first-line therapy for patients with first or second Clostridioides difficile infection, according to the first randomized, double-blind, placebo-controlled trial of its kind.

Study enrollment was halted after an interim analysis revealed significantly better outcomes among patients who received vancomycin plus FMT versus vancomycin alone, reported lead author Simon Mark Dahl Baunwall, MD, of Aarhus (Denmark) University Hospital and colleagues in The Lancet Gastroenterology & Hepatology.

gaetan stoffel/gettyimages

The investigators noted that the participants represented a real-world patient population, so the data support FMT “as a necessary, effective first-line option” in routine management of C. difficile infection.

“Previous studies have demonstrated clinical cure rates [with FMT] of up to 92%,” Dr. Baunwall and colleagues wrote. “Early use of FMT for first or second C. difficile infection has therapeutic potential, but no formal randomized trials to support use of the approach as a first-line therapy have been done.”

The present trial, conducted at a university hospital in Denmark, involved 42 adult patients with first or second C. difficile infection. Patients were randomized in a 1:1 ratio to receive either vancomycin alone or vancomycin plus FMT. All patients received 125 mg oral vancomycin four times daily for a minimum of 10 days after diagnosis. On day 1 after completion of vancomycin therapy and again between day 3 and 7, patients received either oral FMT or matching placebo, depending on their group. After completing the protocol, patients were followed for 8 weeks or C. difficile recurrence to evaluate resolution of C. difficile–associated diarrhea.

“In this trial, patients were treated with two sequential FMT procedures on separate days,” the investigators noted. “This practice might have overtreated some patients and differs from previous trials. It remains unknown whether optimal effect is achieved by one or two treatments.”

The trial design called for 84 patients, but enrollment was halted after an interim analysis of the above cohort of 42 patients because of significantly lower rate resolution in the placebo group. At the 2-month mark, 90% (95% confidence interval, 70%-99%) of patients in the FMT group had resolution, compared with only 33% (95% CI, 15%-57%) of patients in the placebo group (P = .0003), constituting a 57% (95% CI, 33%-81%) absolute risk reduction.

Most patients experienced adverse events, including 20 in the FMT group and all 21 in the placebo group, although most were transient and nonserious. The most common adverse events were diarrhea, which occurred more frequently in the FMT group (23 vs. 14 events), followed by abdominal pain(14 vs. 11 events) and nausea (12 vs. 5 events).

One limitation of the study was its single-center design with regional uptake; the authors noted that, despite having high statistical power for the clinical effect, the study’s premature termination and low patient number prevent inferences regarding mortality, time to effect, and cost.

“The results of this trial highlight how the use of fecal microbiota transplantation as a first-line treatment can effectively prevent C. difficile recurrence and suggests that microbiota restoration might be necessary to obtain sustained resolution,” the investigators wrote. “At present, only 10% of patients with multiple, recurrent C. difficile infection and indication for FMT receive it. International initiatives address the unmet need, but logistic and regulatory obstacles remain unsolved.”
 

Encouraging findings, lingering concerns

Nicholas Turner, MD, assistant professor in the division of infectious diseases at Duke University, Durham, N.C., praised the study for “pushing the boundaries for FMT,” and noted that the methodology appeared sound. Results in the placebo group, however, cast doubt on the generalizability of the findings, he said.

“If you look at the group that received vancomycin plus placebo, their failure rate was really astoundingly high,” Dr. Turner said in an interview, referring to the 67% failure rate in the control group; he noted previous studies had reported failure rates closer to 10%. “I think that just calls into question just a little bit what happened with that control group.”

Dr. Turner said his confidence would go “way, way up” if the findings were reproduced in a larger study. Ideally, these future trials would use fidaxomicin, he added, which is becoming the preferred option over vancomycin for treating C. difficile.

John Y. Kao, MD, professor of medicine and codirector of the FMT program at University of Michigan Medicine, Ann Arbor, offered a different perspective, suggesting that the control group findings shouldn’t overshadow the efficacy of FMT.

“I agree that historical data would tell us that the placebo population should see a much higher response,” Dr. Kao said in an interview. “In my mind though, the success rate of FMT over placebo is what I would expect. The message of the study should be upheld: that FMT is an effective therapy whether it’s given early or, as the way we give it now, as a sort of rescue therapy.”

Despite this confidence in FMT as an efficacious first-line option, Dr. Kao said it is unlikely to be routinely used in this way anytime soon, even if a larger trial echoes the present results.

“We don’t know the long-term risks of FMT therapy, although we’ve been doing this now probably close to 20 years,” Dr. Kao said.

Specifically, Dr. Kao was most concerned about the long-term risk of colon cancer, as mouse models suggest that microbiome characteristics may affect risk level, and risk may vary based on host-microbiome relationships. In other words, an organism may pose no risk in the gut of the donor, but the same may not be true for the recipient.

While increased rates of colon cancer or other serious illnesses have not been detected in humans who have undergone FMT over the past 2 decades, Dr. Kao said that these findings cannot be extrapolated over a patient’s entire lifetime, especially for younger individuals.

“In a patient that’s 80, you would say, yeah, let’s go ahead and treat you [with FMT] as first-line therapy, whereas someone who’s 20, and has maybe another 50 or 60 years longevity, you may not want to give FMT as first-line therapy,” Dr. Kao said.

This study was supported by Innovation Fund Denmark. The investigators disclosed no competing interests. Dr. Turner previously performed statistical analyses for a Merck study comparing vancomycin, fidaxomicin, and metronidazole for C. difficile infection. Dr. Kao disclosed no relevant conflicts of interest.

Fecal microbiota transplantation (FMT) is safe and highly effective as first-line therapy for patients with first or second Clostridioides difficile infection, according to the first randomized, double-blind, placebo-controlled trial of its kind.

Study enrollment was halted after an interim analysis revealed significantly better outcomes among patients who received vancomycin plus FMT versus vancomycin alone, reported lead author Simon Mark Dahl Baunwall, MD, of Aarhus (Denmark) University Hospital and colleagues in The Lancet Gastroenterology & Hepatology.

gaetan stoffel/gettyimages

The investigators noted that the participants represented a real-world patient population, so the data support FMT “as a necessary, effective first-line option” in routine management of C. difficile infection.

“Previous studies have demonstrated clinical cure rates [with FMT] of up to 92%,” Dr. Baunwall and colleagues wrote. “Early use of FMT for first or second C. difficile infection has therapeutic potential, but no formal randomized trials to support use of the approach as a first-line therapy have been done.”

The present trial, conducted at a university hospital in Denmark, involved 42 adult patients with first or second C. difficile infection. Patients were randomized in a 1:1 ratio to receive either vancomycin alone or vancomycin plus FMT. All patients received 125 mg oral vancomycin four times daily for a minimum of 10 days after diagnosis. On day 1 after completion of vancomycin therapy and again between day 3 and 7, patients received either oral FMT or matching placebo, depending on their group. After completing the protocol, patients were followed for 8 weeks or C. difficile recurrence to evaluate resolution of C. difficile–associated diarrhea.

“In this trial, patients were treated with two sequential FMT procedures on separate days,” the investigators noted. “This practice might have overtreated some patients and differs from previous trials. It remains unknown whether optimal effect is achieved by one or two treatments.”

The trial design called for 84 patients, but enrollment was halted after an interim analysis of the above cohort of 42 patients because of significantly lower rate resolution in the placebo group. At the 2-month mark, 90% (95% confidence interval, 70%-99%) of patients in the FMT group had resolution, compared with only 33% (95% CI, 15%-57%) of patients in the placebo group (P = .0003), constituting a 57% (95% CI, 33%-81%) absolute risk reduction.

Most patients experienced adverse events, including 20 in the FMT group and all 21 in the placebo group, although most were transient and nonserious. The most common adverse events were diarrhea, which occurred more frequently in the FMT group (23 vs. 14 events), followed by abdominal pain(14 vs. 11 events) and nausea (12 vs. 5 events).

One limitation of the study was its single-center design with regional uptake; the authors noted that, despite having high statistical power for the clinical effect, the study’s premature termination and low patient number prevent inferences regarding mortality, time to effect, and cost.

“The results of this trial highlight how the use of fecal microbiota transplantation as a first-line treatment can effectively prevent C. difficile recurrence and suggests that microbiota restoration might be necessary to obtain sustained resolution,” the investigators wrote. “At present, only 10% of patients with multiple, recurrent C. difficile infection and indication for FMT receive it. International initiatives address the unmet need, but logistic and regulatory obstacles remain unsolved.”
 

Encouraging findings, lingering concerns

Nicholas Turner, MD, assistant professor in the division of infectious diseases at Duke University, Durham, N.C., praised the study for “pushing the boundaries for FMT,” and noted that the methodology appeared sound. Results in the placebo group, however, cast doubt on the generalizability of the findings, he said.

“If you look at the group that received vancomycin plus placebo, their failure rate was really astoundingly high,” Dr. Turner said in an interview, referring to the 67% failure rate in the control group; he noted previous studies had reported failure rates closer to 10%. “I think that just calls into question just a little bit what happened with that control group.”

Dr. Turner said his confidence would go “way, way up” if the findings were reproduced in a larger study. Ideally, these future trials would use fidaxomicin, he added, which is becoming the preferred option over vancomycin for treating C. difficile.

John Y. Kao, MD, professor of medicine and codirector of the FMT program at University of Michigan Medicine, Ann Arbor, offered a different perspective, suggesting that the control group findings shouldn’t overshadow the efficacy of FMT.

“I agree that historical data would tell us that the placebo population should see a much higher response,” Dr. Kao said in an interview. “In my mind though, the success rate of FMT over placebo is what I would expect. The message of the study should be upheld: that FMT is an effective therapy whether it’s given early or, as the way we give it now, as a sort of rescue therapy.”

Despite this confidence in FMT as an efficacious first-line option, Dr. Kao said it is unlikely to be routinely used in this way anytime soon, even if a larger trial echoes the present results.

“We don’t know the long-term risks of FMT therapy, although we’ve been doing this now probably close to 20 years,” Dr. Kao said.

Specifically, Dr. Kao was most concerned about the long-term risk of colon cancer, as mouse models suggest that microbiome characteristics may affect risk level, and risk may vary based on host-microbiome relationships. In other words, an organism may pose no risk in the gut of the donor, but the same may not be true for the recipient.

While increased rates of colon cancer or other serious illnesses have not been detected in humans who have undergone FMT over the past 2 decades, Dr. Kao said that these findings cannot be extrapolated over a patient’s entire lifetime, especially for younger individuals.

“In a patient that’s 80, you would say, yeah, let’s go ahead and treat you [with FMT] as first-line therapy, whereas someone who’s 20, and has maybe another 50 or 60 years longevity, you may not want to give FMT as first-line therapy,” Dr. Kao said.

This study was supported by Innovation Fund Denmark. The investigators disclosed no competing interests. Dr. Turner previously performed statistical analyses for a Merck study comparing vancomycin, fidaxomicin, and metronidazole for C. difficile infection. Dr. Kao disclosed no relevant conflicts of interest.