Researchers looking for a better way to diagnose drug-induced liver injury (DILI) have found evidence to support the use of the Revised Electronic Causality Assessment Method (RECAM).

The broadly used Roussel Uclaf Causality Assessment Method (RUCAM), introduced in 1993, “has been a valuable clinical framework for DILI diagnosis,” but it has been clouded by subjectivity and poor reliability, wrote the authors, led by Paul H. Hayashi, MD, MPH, with the Food and Drug Administration, in Hepatology. Citing a review from the Journal of Hepatology, Dr. Hayashi and colleagues noted three major problems: “(1) unclear operating instructions and subjectivity leading to poor reliability and usability, (2) unclear validity due to lack of an accepted gold standard and (3) domain criteria that are not evidence-based.”

Comstock Images/Thinkstock

Currently, a diagnosis of DILI is primarily based on clinicians’ judgment and ruling out alternative diagnoses, the authors of this study wrote. The lack of an evidence-based and reliable diagnostic tool is a significant obstacle in clinical care and research .
 

Reaching a new method

The researchers used classification tree analysis to set diagnostic cut-offs for RECAM and then compared RECAM with RUCAM for correlation with expert opinion diagnostic categories in 194 DILI cases (98 from the Drug-Induced Liver Injury Network, 96 from the Spanish DILI Registry).

The area under receiver operator curves for identifying at least probable DILI were the same at 0.89 for both RECAM and RUCAM.

The authors wrote, “However, RECAM diagnostic categories have better observed overall agreement with expert opinion (0.62 vs. 0.56 weighted kappa, P = .14), and had better sensitivity to detect extreme diagnostic categories (73 vs. 54 for highly likely or high probable, P = .02; 65 vs. 48 for unlikely/excluded, P = .08) than RUCAM diagnostic categories.”

They concluded that RECAM “is at least as capable as RUCAM in diagnosing DILI compared to expert opinion but is better than RUCAM at the diagnostic extremes.”

RECAM appears to add objectivity and clarity that can improve precision and reliability when diagnosing DILI and improve diagnostic standardization, according to authors. It has automated scoring, which reduces subjective input and should lead to better reliability among raters, something that has limited RUCAM’s adaptation in clinical practice and research.

RECAM has automatic warnings for data inconsistencies, which DILI and RUCAM do not. In RUCAM, a different diagnosis or other data could rule out DILI, but the case would still gain points in other criteria.

The authors explained, “Even when data clearly diagnose acute viral hepatitis or autoimmune hepatitis by simplified autoimmune hepatitis score, points are still given for latency, dechallenge, or underlying hepatotoxicity risk of the drug. In these situations of highly implausible DILI, RECAM gives warnings to stop with an imputed total score of –6. One can over-ride these warnings, if one believes DILI may be concurrent with the non-DILI diagnosis. However, –6 points are still assessed.”
 

Diagnosis of exclusion

Paul Martin, MD, chief, division of digestive health and liver diseases, Mandel Chair in Gastroenterology and professor of medicine at the University of Miami, said in an interview that he hopes RECAM will become widely used and better address a condition that sometimes doesn’t get enough attention. DILI remains underappreciated, he said, despite it being a major cause of morbidity and mortality in some patients.

“Any algorithm or criteria that can improve diagnostic accuracy is useful because typically it is a diagnosis of exclusion,” Dr. Martin said. “This new system seems to be as good as any other prior algorithms to diagnose drug-induced liver injury.”

He added, “This should help clinicians with individual patients with unexplained liver disease.”

The authors noted some limitations. RECAM was developed in U.S. and Spanish cohorts, so its performance in other regions is unclear. Both registries have minimum enrollment requirements for liver enzyme and bilirubin elevation, so it is not known how effective RECAM is in less severe cases. It also needs to be tested by other clinicians, including nonhepatologists.

The authors also added, “It is currently limited to single-agent medication cases leaving the user to score each medication individually in multidrug cases. However, any competing medication causing loss of points in the RUCAM, probably deserves its own RECAM score.”

The DILIN is structured as a cooperative agreement with funds provided by the National Institute of Diabetes and Digestive and Kidney Diseases.

Dr. Hayashi is employed by the FDA, but the conclusions of this paper do not reflect any opinion of the FDA. One coauthor has advised Pfizer, GSK, and NuCANA through Nottingham University Consultants, and another has received support from Gilead and AbbVie and consulted for Sanofi. The remaining authors have no conflicts. Dr. Martin reports no relevant financial relationships.

Researchers looking for a better way to diagnose drug-induced liver injury (DILI) have found evidence to support the use of the Revised Electronic Causality Assessment Method (RECAM).

The broadly used Roussel Uclaf Causality Assessment Method (RUCAM), introduced in 1993, “has been a valuable clinical framework for DILI diagnosis,” but it has been clouded by subjectivity and poor reliability, wrote the authors, led by Paul H. Hayashi, MD, MPH, with the Food and Drug Administration, in Hepatology. Citing a review from the Journal of Hepatology, Dr. Hayashi and colleagues noted three major problems: “(1) unclear operating instructions and subjectivity leading to poor reliability and usability, (2) unclear validity due to lack of an accepted gold standard and (3) domain criteria that are not evidence-based.”

Comstock Images/Thinkstock

Currently, a diagnosis of DILI is primarily based on clinicians’ judgment and ruling out alternative diagnoses, the authors of this study wrote. The lack of an evidence-based and reliable diagnostic tool is a significant obstacle in clinical care and research .
 

Reaching a new method

The researchers used classification tree analysis to set diagnostic cut-offs for RECAM and then compared RECAM with RUCAM for correlation with expert opinion diagnostic categories in 194 DILI cases (98 from the Drug-Induced Liver Injury Network, 96 from the Spanish DILI Registry).

The area under receiver operator curves for identifying at least probable DILI were the same at 0.89 for both RECAM and RUCAM.

The authors wrote, “However, RECAM diagnostic categories have better observed overall agreement with expert opinion (0.62 vs. 0.56 weighted kappa, P = .14), and had better sensitivity to detect extreme diagnostic categories (73 vs. 54 for highly likely or high probable, P = .02; 65 vs. 48 for unlikely/excluded, P = .08) than RUCAM diagnostic categories.”

They concluded that RECAM “is at least as capable as RUCAM in diagnosing DILI compared to expert opinion but is better than RUCAM at the diagnostic extremes.”

RECAM appears to add objectivity and clarity that can improve precision and reliability when diagnosing DILI and improve diagnostic standardization, according to authors. It has automated scoring, which reduces subjective input and should lead to better reliability among raters, something that has limited RUCAM’s adaptation in clinical practice and research.

RECAM has automatic warnings for data inconsistencies, which DILI and RUCAM do not. In RUCAM, a different diagnosis or other data could rule out DILI, but the case would still gain points in other criteria.

The authors explained, “Even when data clearly diagnose acute viral hepatitis or autoimmune hepatitis by simplified autoimmune hepatitis score, points are still given for latency, dechallenge, or underlying hepatotoxicity risk of the drug. In these situations of highly implausible DILI, RECAM gives warnings to stop with an imputed total score of –6. One can over-ride these warnings, if one believes DILI may be concurrent with the non-DILI diagnosis. However, –6 points are still assessed.”
 

Diagnosis of exclusion

Paul Martin, MD, chief, division of digestive health and liver diseases, Mandel Chair in Gastroenterology and professor of medicine at the University of Miami, said in an interview that he hopes RECAM will become widely used and better address a condition that sometimes doesn’t get enough attention. DILI remains underappreciated, he said, despite it being a major cause of morbidity and mortality in some patients.

“Any algorithm or criteria that can improve diagnostic accuracy is useful because typically it is a diagnosis of exclusion,” Dr. Martin said. “This new system seems to be as good as any other prior algorithms to diagnose drug-induced liver injury.”

He added, “This should help clinicians with individual patients with unexplained liver disease.”

The authors noted some limitations. RECAM was developed in U.S. and Spanish cohorts, so its performance in other regions is unclear. Both registries have minimum enrollment requirements for liver enzyme and bilirubin elevation, so it is not known how effective RECAM is in less severe cases. It also needs to be tested by other clinicians, including nonhepatologists.

The authors also added, “It is currently limited to single-agent medication cases leaving the user to score each medication individually in multidrug cases. However, any competing medication causing loss of points in the RUCAM, probably deserves its own RECAM score.”

The DILIN is structured as a cooperative agreement with funds provided by the National Institute of Diabetes and Digestive and Kidney Diseases.

Dr. Hayashi is employed by the FDA, but the conclusions of this paper do not reflect any opinion of the FDA. One coauthor has advised Pfizer, GSK, and NuCANA through Nottingham University Consultants, and another has received support from Gilead and AbbVie and consulted for Sanofi. The remaining authors have no conflicts. Dr. Martin reports no relevant financial relationships.

Researchers looking for a better way to diagnose drug-induced liver injury (DILI) have found evidence to support the use of the Revised Electronic Causality Assessment Method (RECAM).

The broadly used Roussel Uclaf Causality Assessment Method (RUCAM), introduced in 1993, “has been a valuable clinical framework for DILI diagnosis,” but it has been clouded by subjectivity and poor reliability, wrote the authors, led by Paul H. Hayashi, MD, MPH, with the Food and Drug Administration, in Hepatology. Citing a review from the Journal of Hepatology, Dr. Hayashi and colleagues noted three major problems: “(1) unclear operating instructions and subjectivity leading to poor reliability and usability, (2) unclear validity due to lack of an accepted gold standard and (3) domain criteria that are not evidence-based.”

Comstock Images/Thinkstock

Currently, a diagnosis of DILI is primarily based on clinicians’ judgment and ruling out alternative diagnoses, the authors of this study wrote. The lack of an evidence-based and reliable diagnostic tool is a significant obstacle in clinical care and research .
 

Reaching a new method

The researchers used classification tree analysis to set diagnostic cut-offs for RECAM and then compared RECAM with RUCAM for correlation with expert opinion diagnostic categories in 194 DILI cases (98 from the Drug-Induced Liver Injury Network, 96 from the Spanish DILI Registry).

The area under receiver operator curves for identifying at least probable DILI were the same at 0.89 for both RECAM and RUCAM.

The authors wrote, “However, RECAM diagnostic categories have better observed overall agreement with expert opinion (0.62 vs. 0.56 weighted kappa, P = .14), and had better sensitivity to detect extreme diagnostic categories (73 vs. 54 for highly likely or high probable, P = .02; 65 vs. 48 for unlikely/excluded, P = .08) than RUCAM diagnostic categories.”

They concluded that RECAM “is at least as capable as RUCAM in diagnosing DILI compared to expert opinion but is better than RUCAM at the diagnostic extremes.”

RECAM appears to add objectivity and clarity that can improve precision and reliability when diagnosing DILI and improve diagnostic standardization, according to authors. It has automated scoring, which reduces subjective input and should lead to better reliability among raters, something that has limited RUCAM’s adaptation in clinical practice and research.

RECAM has automatic warnings for data inconsistencies, which DILI and RUCAM do not. In RUCAM, a different diagnosis or other data could rule out DILI, but the case would still gain points in other criteria.

The authors explained, “Even when data clearly diagnose acute viral hepatitis or autoimmune hepatitis by simplified autoimmune hepatitis score, points are still given for latency, dechallenge, or underlying hepatotoxicity risk of the drug. In these situations of highly implausible DILI, RECAM gives warnings to stop with an imputed total score of –6. One can over-ride these warnings, if one believes DILI may be concurrent with the non-DILI diagnosis. However, –6 points are still assessed.”
 

Diagnosis of exclusion

Paul Martin, MD, chief, division of digestive health and liver diseases, Mandel Chair in Gastroenterology and professor of medicine at the University of Miami, said in an interview that he hopes RECAM will become widely used and better address a condition that sometimes doesn’t get enough attention. DILI remains underappreciated, he said, despite it being a major cause of morbidity and mortality in some patients.

“Any algorithm or criteria that can improve diagnostic accuracy is useful because typically it is a diagnosis of exclusion,” Dr. Martin said. “This new system seems to be as good as any other prior algorithms to diagnose drug-induced liver injury.”

He added, “This should help clinicians with individual patients with unexplained liver disease.”

The authors noted some limitations. RECAM was developed in U.S. and Spanish cohorts, so its performance in other regions is unclear. Both registries have minimum enrollment requirements for liver enzyme and bilirubin elevation, so it is not known how effective RECAM is in less severe cases. It also needs to be tested by other clinicians, including nonhepatologists.

The authors also added, “It is currently limited to single-agent medication cases leaving the user to score each medication individually in multidrug cases. However, any competing medication causing loss of points in the RUCAM, probably deserves its own RECAM score.”

The DILIN is structured as a cooperative agreement with funds provided by the National Institute of Diabetes and Digestive and Kidney Diseases.

Dr. Hayashi is employed by the FDA, but the conclusions of this paper do not reflect any opinion of the FDA. One coauthor has advised Pfizer, GSK, and NuCANA through Nottingham University Consultants, and another has received support from Gilead and AbbVie and consulted for Sanofi. The remaining authors have no conflicts. Dr. Martin reports no relevant financial relationships.

The introduction of hemoglobin A1c as an option for diagnosing type 2 diabetes over a decade ago may have resulted in underdiagnosis, new research indicates.

In 2011, the World Health Organization advised that A1c measurement, with a cutoff value of 6.5%, could be used to diagnose diabetes. The American Diabetes Association had issued similar guidance in 2010.

Prior to that time, the less-convenient 2-hour oral glucose tolerance test (OGTT) and fasting blood glucose (FBG) were the only recommended tests. While WHO made no recommendations for interpreting values below 6.5%, the ADA designated 5.7%-6.4% as prediabetes.

The new study, published online in The Lancet Regional Health–Europe, showed that the incidence of type 2 diabetes in Denmark had been increasing prior to the 2012 adoption of A1c as a diagnostic option but declined thereafter. And all-cause mortality among people with type 2 diabetes, which had been dropping, began to increase after that time.  

“Our findings suggest that fewer patients have been diagnosed with [type 2 diabetes] since A1c testing was introduced as a convenient diagnostic option. We may thus be missing a group with borderline increased A1c values that is still at high metabolic and cardiovascular risk,” Jakob S. Knudsen, MD, of the department of clinical epidemiology, Aarhus (Denmark) University Hospital, and colleagues wrote.

Therefore, Dr. Knudsen said in an interview, clinicians should “consider testing with FBG or OGTT when presented with borderline A1c values.”

The reason for the increase in mortality after incident type 2 diabetes diagnosis, he said, “is that the patients who would have reduced the average mortality are no longer diagnosed...This does not reflect that we are treating already diagnosed patients any worse, rather some patients are not diagnosed.”

But M. Sue Kirkman, MD, emeritus professor of medicine at the University of North Carolina at Chapel Hill, who was part of the writing group for the 2010 ADA guidelines, isn’t convinced.

“This is an interesting paper, but it is a bit hard to believe that a change in WHO recommendations would have such a large and almost immediate impact on incidence and mortality. It seems likely that ... factors [other] than just the changes in recommendations for the diagnostic test account for these findings,” she said.

Dr. Kirkman pointed to new data just out from the Centers for Disease Control and Prevention on Jan. 26 that don›t show evidence of a higher proportion of people in the United States who have undiagnosed diabetes, “which would be expected if more cases were being ‘missed’ by A1c.”

She added that the CDC incidence data “show a continuing steady rate of decline in incidence that began in 2008, before any organizations recommended using A1c to screen for or diagnose diabetes.” Moreover, “there is evidence that type 2 diabetes incidence has fallen or plateaued in many countries since 2006, well before the WHO recommendation, with most of the studies from developed countries.”

But Dr. Knudsen also cited other data, including a study that showed a drop or stabilization in diagnosed diabetes incidence in high-income countries since 2010.

“That study concluded that the reasons for the declines in the incidence of diagnosed diabetes warrant further investigation with appropriate data sources, which was a main objective of our study,” wrote Dr. Knudsen and coauthors.

Dr. Knudsen said in an interview: “We are not the first to make the point that this sudden change is related to A1c introduction...but we are the first to have the data to clearly show that is the case.”

Diabetes incidence dropped but mortality rose after 2010

The population-based longitudinal study used four Danish medical databases and included 415,553 patients treated for type 2 diabetes for the first time from 1995-2018 and 2,060,279 matched comparators not treated for diabetes.

From 1995 until the 2012 introduction of A1c as a diagnostic option, the annual standardized incidence rates of type 2 diabetes more than doubled, from 193 per 100,000 population to 396 per 100,000 population, at a rate of 4.1% per year.

But from 2011 to 2018, the annual standardized incidence rate declined by 36%, to 253 per 100,000 population, a 5.7% annualized decrease.

The increase prior to 2011 occurred in both men and women and in all age groups, while the subsequent decline was seen primarily in the older age groups. The all-cause mortality risk within the first year after diabetes diagnosis was higher than subsequent 1-year mortality risks and not different between men and women.

From the periods 1995-1997 to 2010-2012, the adjusted mortality rate among those with type 2 diabetes decreased by 44%, from 72 deaths per 1000 person-years to 40 deaths per 1000 person-years (adjusted mortality rate ratio, 0.55). After that low level in 2010-2012, mortality increased by 27% to 48 per 1000 person-years (adjusted mortality rate ratio 0.69, compared with 1995-1997).  

The reversed mortality trend after 2010-2012 was caused almost entirely by the increase in the first year after diabetes diagnosis, Dr. Knudsen and colleagues noted.

According to Dr. Kirkman, “A1c is strongly predictive of complications and mortality. That plus its ease of use and the fact that more people may be screened mean it’s still a good option. But for any of these tests, people who are slightly below the cut-point should not be considered normal or low risk.”

Indeed, Dr. Knudsen and colleagues said, “these findings may have implications for clinical practice and suggest that a more multifactorial view of metabolic risk is needed.”

Dr. Knudsen and Dr. Kirkman have reported no relevant financial relationships.

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

The introduction of hemoglobin A1c as an option for diagnosing type 2 diabetes over a decade ago may have resulted in underdiagnosis, new research indicates.

In 2011, the World Health Organization advised that A1c measurement, with a cutoff value of 6.5%, could be used to diagnose diabetes. The American Diabetes Association had issued similar guidance in 2010.

Prior to that time, the less-convenient 2-hour oral glucose tolerance test (OGTT) and fasting blood glucose (FBG) were the only recommended tests. While WHO made no recommendations for interpreting values below 6.5%, the ADA designated 5.7%-6.4% as prediabetes.

The new study, published online in The Lancet Regional Health–Europe, showed that the incidence of type 2 diabetes in Denmark had been increasing prior to the 2012 adoption of A1c as a diagnostic option but declined thereafter. And all-cause mortality among people with type 2 diabetes, which had been dropping, began to increase after that time.  

“Our findings suggest that fewer patients have been diagnosed with [type 2 diabetes] since A1c testing was introduced as a convenient diagnostic option. We may thus be missing a group with borderline increased A1c values that is still at high metabolic and cardiovascular risk,” Jakob S. Knudsen, MD, of the department of clinical epidemiology, Aarhus (Denmark) University Hospital, and colleagues wrote.

Therefore, Dr. Knudsen said in an interview, clinicians should “consider testing with FBG or OGTT when presented with borderline A1c values.”

The reason for the increase in mortality after incident type 2 diabetes diagnosis, he said, “is that the patients who would have reduced the average mortality are no longer diagnosed...This does not reflect that we are treating already diagnosed patients any worse, rather some patients are not diagnosed.”

But M. Sue Kirkman, MD, emeritus professor of medicine at the University of North Carolina at Chapel Hill, who was part of the writing group for the 2010 ADA guidelines, isn’t convinced.

“This is an interesting paper, but it is a bit hard to believe that a change in WHO recommendations would have such a large and almost immediate impact on incidence and mortality. It seems likely that ... factors [other] than just the changes in recommendations for the diagnostic test account for these findings,” she said.

Dr. Kirkman pointed to new data just out from the Centers for Disease Control and Prevention on Jan. 26 that don›t show evidence of a higher proportion of people in the United States who have undiagnosed diabetes, “which would be expected if more cases were being ‘missed’ by A1c.”

She added that the CDC incidence data “show a continuing steady rate of decline in incidence that began in 2008, before any organizations recommended using A1c to screen for or diagnose diabetes.” Moreover, “there is evidence that type 2 diabetes incidence has fallen or plateaued in many countries since 2006, well before the WHO recommendation, with most of the studies from developed countries.”

But Dr. Knudsen also cited other data, including a study that showed a drop or stabilization in diagnosed diabetes incidence in high-income countries since 2010.

“That study concluded that the reasons for the declines in the incidence of diagnosed diabetes warrant further investigation with appropriate data sources, which was a main objective of our study,” wrote Dr. Knudsen and coauthors.

Dr. Knudsen said in an interview: “We are not the first to make the point that this sudden change is related to A1c introduction...but we are the first to have the data to clearly show that is the case.”

Diabetes incidence dropped but mortality rose after 2010

The population-based longitudinal study used four Danish medical databases and included 415,553 patients treated for type 2 diabetes for the first time from 1995-2018 and 2,060,279 matched comparators not treated for diabetes.

From 1995 until the 2012 introduction of A1c as a diagnostic option, the annual standardized incidence rates of type 2 diabetes more than doubled, from 193 per 100,000 population to 396 per 100,000 population, at a rate of 4.1% per year.

But from 2011 to 2018, the annual standardized incidence rate declined by 36%, to 253 per 100,000 population, a 5.7% annualized decrease.

The increase prior to 2011 occurred in both men and women and in all age groups, while the subsequent decline was seen primarily in the older age groups. The all-cause mortality risk within the first year after diabetes diagnosis was higher than subsequent 1-year mortality risks and not different between men and women.

From the periods 1995-1997 to 2010-2012, the adjusted mortality rate among those with type 2 diabetes decreased by 44%, from 72 deaths per 1000 person-years to 40 deaths per 1000 person-years (adjusted mortality rate ratio, 0.55). After that low level in 2010-2012, mortality increased by 27% to 48 per 1000 person-years (adjusted mortality rate ratio 0.69, compared with 1995-1997).  

The reversed mortality trend after 2010-2012 was caused almost entirely by the increase in the first year after diabetes diagnosis, Dr. Knudsen and colleagues noted.

According to Dr. Kirkman, “A1c is strongly predictive of complications and mortality. That plus its ease of use and the fact that more people may be screened mean it’s still a good option. But for any of these tests, people who are slightly below the cut-point should not be considered normal or low risk.”

Indeed, Dr. Knudsen and colleagues said, “these findings may have implications for clinical practice and suggest that a more multifactorial view of metabolic risk is needed.”

Dr. Knudsen and Dr. Kirkman have reported no relevant financial relationships.

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

The introduction of hemoglobin A1c as an option for diagnosing type 2 diabetes over a decade ago may have resulted in underdiagnosis, new research indicates.

In 2011, the World Health Organization advised that A1c measurement, with a cutoff value of 6.5%, could be used to diagnose diabetes. The American Diabetes Association had issued similar guidance in 2010.

Prior to that time, the less-convenient 2-hour oral glucose tolerance test (OGTT) and fasting blood glucose (FBG) were the only recommended tests. While WHO made no recommendations for interpreting values below 6.5%, the ADA designated 5.7%-6.4% as prediabetes.

The new study, published online in The Lancet Regional Health–Europe, showed that the incidence of type 2 diabetes in Denmark had been increasing prior to the 2012 adoption of A1c as a diagnostic option but declined thereafter. And all-cause mortality among people with type 2 diabetes, which had been dropping, began to increase after that time.  

“Our findings suggest that fewer patients have been diagnosed with [type 2 diabetes] since A1c testing was introduced as a convenient diagnostic option. We may thus be missing a group with borderline increased A1c values that is still at high metabolic and cardiovascular risk,” Jakob S. Knudsen, MD, of the department of clinical epidemiology, Aarhus (Denmark) University Hospital, and colleagues wrote.

Therefore, Dr. Knudsen said in an interview, clinicians should “consider testing with FBG or OGTT when presented with borderline A1c values.”

The reason for the increase in mortality after incident type 2 diabetes diagnosis, he said, “is that the patients who would have reduced the average mortality are no longer diagnosed...This does not reflect that we are treating already diagnosed patients any worse, rather some patients are not diagnosed.”

But M. Sue Kirkman, MD, emeritus professor of medicine at the University of North Carolina at Chapel Hill, who was part of the writing group for the 2010 ADA guidelines, isn’t convinced.

“This is an interesting paper, but it is a bit hard to believe that a change in WHO recommendations would have such a large and almost immediate impact on incidence and mortality. It seems likely that ... factors [other] than just the changes in recommendations for the diagnostic test account for these findings,” she said.

Dr. Kirkman pointed to new data just out from the Centers for Disease Control and Prevention on Jan. 26 that don›t show evidence of a higher proportion of people in the United States who have undiagnosed diabetes, “which would be expected if more cases were being ‘missed’ by A1c.”

She added that the CDC incidence data “show a continuing steady rate of decline in incidence that began in 2008, before any organizations recommended using A1c to screen for or diagnose diabetes.” Moreover, “there is evidence that type 2 diabetes incidence has fallen or plateaued in many countries since 2006, well before the WHO recommendation, with most of the studies from developed countries.”

But Dr. Knudsen also cited other data, including a study that showed a drop or stabilization in diagnosed diabetes incidence in high-income countries since 2010.

“That study concluded that the reasons for the declines in the incidence of diagnosed diabetes warrant further investigation with appropriate data sources, which was a main objective of our study,” wrote Dr. Knudsen and coauthors.

Dr. Knudsen said in an interview: “We are not the first to make the point that this sudden change is related to A1c introduction...but we are the first to have the data to clearly show that is the case.”

Diabetes incidence dropped but mortality rose after 2010

The population-based longitudinal study used four Danish medical databases and included 415,553 patients treated for type 2 diabetes for the first time from 1995-2018 and 2,060,279 matched comparators not treated for diabetes.

From 1995 until the 2012 introduction of A1c as a diagnostic option, the annual standardized incidence rates of type 2 diabetes more than doubled, from 193 per 100,000 population to 396 per 100,000 population, at a rate of 4.1% per year.

But from 2011 to 2018, the annual standardized incidence rate declined by 36%, to 253 per 100,000 population, a 5.7% annualized decrease.

The increase prior to 2011 occurred in both men and women and in all age groups, while the subsequent decline was seen primarily in the older age groups. The all-cause mortality risk within the first year after diabetes diagnosis was higher than subsequent 1-year mortality risks and not different between men and women.

From the periods 1995-1997 to 2010-2012, the adjusted mortality rate among those with type 2 diabetes decreased by 44%, from 72 deaths per 1000 person-years to 40 deaths per 1000 person-years (adjusted mortality rate ratio, 0.55). After that low level in 2010-2012, mortality increased by 27% to 48 per 1000 person-years (adjusted mortality rate ratio 0.69, compared with 1995-1997).  

The reversed mortality trend after 2010-2012 was caused almost entirely by the increase in the first year after diabetes diagnosis, Dr. Knudsen and colleagues noted.

According to Dr. Kirkman, “A1c is strongly predictive of complications and mortality. That plus its ease of use and the fact that more people may be screened mean it’s still a good option. But for any of these tests, people who are slightly below the cut-point should not be considered normal or low risk.”

Indeed, Dr. Knudsen and colleagues said, “these findings may have implications for clinical practice and suggest that a more multifactorial view of metabolic risk is needed.”

Dr. Knudsen and Dr. Kirkman have reported no relevant financial relationships.

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

Acne vulgaris is an extremely common dermatologic disease affecting 40 to 50 million individuals in the United States each year, with a prevalence of 85% in adolescents and young adults aged 12 to 24 years. For some patients, the disease may persist well into adulthood, affecting 8% of adults aged 25 and 34 years.¹ Acne negatively impacts patients’ quality of life and productivity, with an estimated direct and indirect cost of over $3 billion per year.²

Oral isotretinoin, a vitamin A derivative, is approved by the US Food and Drug Administration for the treatment of severe nodulocystic acne. Isotretinoin reduces the size and secretions of sebaceous glands, inhibits growth and resulting inflammation of Cutibacterium acnes, and normalizes the differentiation of follicular keratinocytes, resulting in permanent changes in the pathogenesis of acne that may lead to remission.³ The use of oral isotretinoin in the active-duty US Military population may cause service members to be nondeployable or limit their ability to function in special roles (eg, pilot, submariner).⁴ Treatment regimens that minimize the course duration of isotretinoin and reduce the risk for relapse that requires a retrial of isotretinoin may, in turn, increase a service member’s readiness, deployment availability, and ability to perform unique occupational roles.

Additionally, teledermatology has been increasingly utilized to maintain treatment continuity for patients on isotretinoin during the COVID-19 pandemic.⁵ Application of this technology in the military also may be used to facilitate timely isotretinoin treatment regimens in active-duty service members to minimize course duration and increase readiness.

In this article, we discuss an accelerated course of oral isotretinoin as a safe and effective option for military service members bound by duty restrictions and operational timelines and explore the role of teledermatology for the treatment of acne in military service members.

Isotretinoin for Acne

Isotretinoin typically is initiated at a dosage of 0.5 mg/kg daily, increasing to 1 mg/kg daily with a goal cumulative dose between 120 and 150 mg/kg. Relapse may occur after completing a treatment course and is associated with cumulative dosing less than 120 mg/kg.⁶ The average duration of acne treatment with oral isotretinoin is approximately 6 months.⁷ At therapeutic doses, nearly all patients experience side effects, most commonly dryness and desquamation of the skin and mucous membranes, as well as possible involvement of the lips, eyes, and nose. Notable extracutaneous side effects include headache, visual disturbances at night, idiopathic intracranial hypertension, and myalgia. Serum cholesterol, triglycerides, and transaminases may be increased in patients taking isotretinoin, which requires routine monitoring using serum lipid profiles and liver function studies. A potential association between isotretinoin and inflammatory bowel disease and changes in mood have been reported, but current data do not suggest an evidence-based link.^6,8 Isotretinoin is a potent teratogen, and in the United States, all patients are required to enroll in iPLEDGE, a US Food and Drug Administration–approved pregnancy prevention program that monitors prescribing and dispensing of the medication. For patients who can become pregnant, iPLEDGE requires use of 2 forms of contraception as well as monthly pregnancy tests prior to dispensing the medication.

Acne in Military Service Members

Acne is exceedingly common in the active-duty military population. In 2018, more than 40% of soldiers, sailors, airmen, and marines were 25 years or younger, and 75% of all US service members were 35 years or younger, corresponding to acne peak incidences.^1,9 Management of acne in this population requires unique treatment considerations due to distinctive occupational requirements of and hazards faced by military personnel. Use of personal protective equipment, including gas masks, safety restraints, parachute rigging, and flak jackets, may be limiting in individuals with moderate to severe acne.¹⁰ For example, severe nodulocystic acne on the chin and jawline can interfere with proper wear of the chin strap on a Kevlar helmet. The severity of acne often necessitates the use of oral isotretinoin therapy, which is considered disqualifying for many special military assignments, including submarine duty, nuclear field duty, and diving duty.¹¹ In military aviation communities, oral isotretinoin requires grounding for the duration of therapy plus 3 months after cessation. Slit-lamp examination, triglycerides, and transaminase levels must be normal prior to returning to unrestricted duty.¹² Furthermore, use of oral isotretinoin may limit overseas assignments or deployment eligibility.⁴

The high prevalence of acne and the operationally limiting consequences of isotretinoin therapy present a unique challenge for dermatologists treating military personnel. The average duration of isotretinoin treatment is approximately 6 months,⁷ which represents a considerable amount of time during an average 4-year enlistment contract. Therapeutic treatment strategies that (1) reduce the duration of oral isotretinoin therapy, (2) reduce the risk for relapse, and (3) increase medication compliance can reduce the operational impact of this acne treatment. Such treatment strategies are discussed below.

An optimal isotretinoin dosing regimen would achieve swift resolution of acne lesions and reduce the overall relapse rate requiring retrial of isotretinoin, thereby minimizing the operational- and duty-limiting impacts of the medication. Cyrulnik et al¹³ studied treatment outcomes of high-dose isotretinoin for acne vulgaris using a mean dosage of 1.6 mg/kg daily with an average cumulative dosage of 290 mg/kg. They demonstrated 100% clearance of lesions over 6 months, with a 12.5% relapse rate at 3 years. Aside from an increased rate of elevated transaminases, incidence of adverse effects and laboratory abnormalities were not significantly increased compared to conventional dosing regimens.¹³ The goal cumulative dosing of 120 to 150 mg/kg can be achieved 1 to 2 months earlier using a dosage of 1.6 mg/kg daily vs a conventional dosage of 1 mg/kg daily.

It has been hypothesized that higher cumulative doses of oral isotretinoin reduce the risk for relapse of acne and retrial of oral isotretinoin.¹⁴ Blasiak et al¹⁵ studied relapse and retrial of oral isotretinoin in acne patients who received cumulative dosing higher or lower than 220 mg/kg. A clinically but not statistically significant reduced relapse rate was observed in the cohort that received cumulative dosing higher than 220 mg/kg. No statistically significant difference in rates of adverse advents was observed aside from an increase in retinoid dermatitis in the cohort that received cumulative dosing higher than 220 mg/kg. Higher but not statistically significant rates of adverse events were seen in the group that received dosing higher than 220 mg/kg.¹⁵ Cumulative doses of oral isotretinoin higher than the 120 to 150 mg/kg range may decrease the risk for acne relapse and the need for an additional course of oral isotretinoin, which would reduce a service member’s total time away from deployment and full duty.

Relapse requiring a retrial of oral isotretinoin not only increases the operational cost of acne treatment but also considerably increases the monetary cost to the health care system. In a cost-analysis model, cumulative doses of oral isotretinoin higher than 230 mg/kg have a decreased overall cost compared to traditional cumulative dosing of less than 150 mg/kg due to the cost of relapse.¹⁶

Limitations of high daily and cumulative dosing regimens of oral isotretinoin are chiefly the dose-dependent rate of adverse effects. Low-dose regimens are associated with a reduced risk of isotretinoin-related side effects.^6,17 Acute acne flares may be seen following initial administration of oral isotretinoin and are aggravated by increases in dosage.¹⁸ Isotretinoin-induced acne fulminans is a rare but devastating complication observed with high initial doses of oral isotretinoin in patients with severe acne.¹⁹ The risks and benefits of high daily and cumulatively dosed isotretinoin must be carefully considered in patients with severe acne.

Teledermatology: A Force for Readiness

The COVID-19 pandemic drastically changed the dermatology practice landscape with recommendations to cancel all elective outpatient visits in favor of teledermatology encounters.²⁰ This decreased access to care, which resulted in an increase in drug interruption for dermatology patients, including patients on oral isotretinoin.²¹ Teledermatology has been increasingly utilized to maintain continuity of care for the management of patients taking isotretinoin.⁵ Routine utilization of teledermatology evaluation in military practices could expedite care, decrease patient travel time, and allow for in-clinic visits to be utilized for higher-acuity concerns.²²

The use of teledermatology for uncomplicated oral isotretinoin management has the potential to increase medication compliance and decrease the amount of travel time for active-duty service members; for example, consider a military dermatology practice based in San Diego, California, that accepts referrals from military bases 3 hours away by car. After an initial consultation for consideration and initiation of oral isotretinoin, teledermatology appointments can save the active-duty service member 3 hours of travel time for each follow-up visit per month. This ultimately increases operational productivity, reduces barriers to accessing care, and improves patient satisfaction.²³

Although military personnel usually are located at duty stations for 2 to 4 years, training exercises and military vocational schools often temporarily take personnel away from their home station. These temporary-duty assignments have the potential to interrupt medical follow-up appointments and may cause delays in treatment for individuals who miss monthly isotretinoin visits. When deemed appropriate by the prescribing dermatologist, teledermatology allows for increased continuity of care for active-duty service members and maintenance of a therapeutic isotretinoin course despite temporary geographic displacement.

By facilitating regular follow-up appointments, teledermatology can minimize the amount of time an active-duty service member is on a course of oral isotretinoin, thereby reducing the operational and duty-limiting implications of the medication.

Final Thoughts

Acne is a common dermatologic concern within the active-duty military population. Oral isotretinoin is indicated for treatment-resistant moderate or severe acne; however, it limits the ability of service members to deploy and is disqualifying for special military assignments. High daily- and cumulative-dose isotretinoin treatment strategies can reduce the duration of therapy and may be associated with a decrease in acne relapse and the need for retrial. Teledermatology can increase access to care and facilitate the completion of oral isotretinoin courses in a timely manner. These treatment strategies may help mitigate the duty-limiting impact of oral isotretinoin therapy in military service members.

Acne vulgaris is an extremely common dermatologic disease affecting 40 to 50 million individuals in the United States each year, with a prevalence of 85% in adolescents and young adults aged 12 to 24 years. For some patients, the disease may persist well into adulthood, affecting 8% of adults aged 25 and 34 years.¹ Acne negatively impacts patients’ quality of life and productivity, with an estimated direct and indirect cost of over $3 billion per year.²

Oral isotretinoin, a vitamin A derivative, is approved by the US Food and Drug Administration for the treatment of severe nodulocystic acne. Isotretinoin reduces the size and secretions of sebaceous glands, inhibits growth and resulting inflammation of Cutibacterium acnes, and normalizes the differentiation of follicular keratinocytes, resulting in permanent changes in the pathogenesis of acne that may lead to remission.³ The use of oral isotretinoin in the active-duty US Military population may cause service members to be nondeployable or limit their ability to function in special roles (eg, pilot, submariner).⁴ Treatment regimens that minimize the course duration of isotretinoin and reduce the risk for relapse that requires a retrial of isotretinoin may, in turn, increase a service member’s readiness, deployment availability, and ability to perform unique occupational roles.

Additionally, teledermatology has been increasingly utilized to maintain treatment continuity for patients on isotretinoin during the COVID-19 pandemic.⁵ Application of this technology in the military also may be used to facilitate timely isotretinoin treatment regimens in active-duty service members to minimize course duration and increase readiness.

In this article, we discuss an accelerated course of oral isotretinoin as a safe and effective option for military service members bound by duty restrictions and operational timelines and explore the role of teledermatology for the treatment of acne in military service members.

Isotretinoin for Acne

Isotretinoin typically is initiated at a dosage of 0.5 mg/kg daily, increasing to 1 mg/kg daily with a goal cumulative dose between 120 and 150 mg/kg. Relapse may occur after completing a treatment course and is associated with cumulative dosing less than 120 mg/kg.⁶ The average duration of acne treatment with oral isotretinoin is approximately 6 months.⁷ At therapeutic doses, nearly all patients experience side effects, most commonly dryness and desquamation of the skin and mucous membranes, as well as possible involvement of the lips, eyes, and nose. Notable extracutaneous side effects include headache, visual disturbances at night, idiopathic intracranial hypertension, and myalgia. Serum cholesterol, triglycerides, and transaminases may be increased in patients taking isotretinoin, which requires routine monitoring using serum lipid profiles and liver function studies. A potential association between isotretinoin and inflammatory bowel disease and changes in mood have been reported, but current data do not suggest an evidence-based link.^6,8 Isotretinoin is a potent teratogen, and in the United States, all patients are required to enroll in iPLEDGE, a US Food and Drug Administration–approved pregnancy prevention program that monitors prescribing and dispensing of the medication. For patients who can become pregnant, iPLEDGE requires use of 2 forms of contraception as well as monthly pregnancy tests prior to dispensing the medication.

Acne in Military Service Members

Acne is exceedingly common in the active-duty military population. In 2018, more than 40% of soldiers, sailors, airmen, and marines were 25 years or younger, and 75% of all US service members were 35 years or younger, corresponding to acne peak incidences.^1,9 Management of acne in this population requires unique treatment considerations due to distinctive occupational requirements of and hazards faced by military personnel. Use of personal protective equipment, including gas masks, safety restraints, parachute rigging, and flak jackets, may be limiting in individuals with moderate to severe acne.¹⁰ For example, severe nodulocystic acne on the chin and jawline can interfere with proper wear of the chin strap on a Kevlar helmet. The severity of acne often necessitates the use of oral isotretinoin therapy, which is considered disqualifying for many special military assignments, including submarine duty, nuclear field duty, and diving duty.¹¹ In military aviation communities, oral isotretinoin requires grounding for the duration of therapy plus 3 months after cessation. Slit-lamp examination, triglycerides, and transaminase levels must be normal prior to returning to unrestricted duty.¹² Furthermore, use of oral isotretinoin may limit overseas assignments or deployment eligibility.⁴

The high prevalence of acne and the operationally limiting consequences of isotretinoin therapy present a unique challenge for dermatologists treating military personnel. The average duration of isotretinoin treatment is approximately 6 months,⁷ which represents a considerable amount of time during an average 4-year enlistment contract. Therapeutic treatment strategies that (1) reduce the duration of oral isotretinoin therapy, (2) reduce the risk for relapse, and (3) increase medication compliance can reduce the operational impact of this acne treatment. Such treatment strategies are discussed below.

An optimal isotretinoin dosing regimen would achieve swift resolution of acne lesions and reduce the overall relapse rate requiring retrial of isotretinoin, thereby minimizing the operational- and duty-limiting impacts of the medication. Cyrulnik et al¹³ studied treatment outcomes of high-dose isotretinoin for acne vulgaris using a mean dosage of 1.6 mg/kg daily with an average cumulative dosage of 290 mg/kg. They demonstrated 100% clearance of lesions over 6 months, with a 12.5% relapse rate at 3 years. Aside from an increased rate of elevated transaminases, incidence of adverse effects and laboratory abnormalities were not significantly increased compared to conventional dosing regimens.¹³ The goal cumulative dosing of 120 to 150 mg/kg can be achieved 1 to 2 months earlier using a dosage of 1.6 mg/kg daily vs a conventional dosage of 1 mg/kg daily.

It has been hypothesized that higher cumulative doses of oral isotretinoin reduce the risk for relapse of acne and retrial of oral isotretinoin.¹⁴ Blasiak et al¹⁵ studied relapse and retrial of oral isotretinoin in acne patients who received cumulative dosing higher or lower than 220 mg/kg. A clinically but not statistically significant reduced relapse rate was observed in the cohort that received cumulative dosing higher than 220 mg/kg. No statistically significant difference in rates of adverse advents was observed aside from an increase in retinoid dermatitis in the cohort that received cumulative dosing higher than 220 mg/kg. Higher but not statistically significant rates of adverse events were seen in the group that received dosing higher than 220 mg/kg.¹⁵ Cumulative doses of oral isotretinoin higher than the 120 to 150 mg/kg range may decrease the risk for acne relapse and the need for an additional course of oral isotretinoin, which would reduce a service member’s total time away from deployment and full duty.

Relapse requiring a retrial of oral isotretinoin not only increases the operational cost of acne treatment but also considerably increases the monetary cost to the health care system. In a cost-analysis model, cumulative doses of oral isotretinoin higher than 230 mg/kg have a decreased overall cost compared to traditional cumulative dosing of less than 150 mg/kg due to the cost of relapse.¹⁶

Limitations of high daily and cumulative dosing regimens of oral isotretinoin are chiefly the dose-dependent rate of adverse effects. Low-dose regimens are associated with a reduced risk of isotretinoin-related side effects.^6,17 Acute acne flares may be seen following initial administration of oral isotretinoin and are aggravated by increases in dosage.¹⁸ Isotretinoin-induced acne fulminans is a rare but devastating complication observed with high initial doses of oral isotretinoin in patients with severe acne.¹⁹ The risks and benefits of high daily and cumulatively dosed isotretinoin must be carefully considered in patients with severe acne.

Teledermatology: A Force for Readiness

The COVID-19 pandemic drastically changed the dermatology practice landscape with recommendations to cancel all elective outpatient visits in favor of teledermatology encounters.²⁰ This decreased access to care, which resulted in an increase in drug interruption for dermatology patients, including patients on oral isotretinoin.²¹ Teledermatology has been increasingly utilized to maintain continuity of care for the management of patients taking isotretinoin.⁵ Routine utilization of teledermatology evaluation in military practices could expedite care, decrease patient travel time, and allow for in-clinic visits to be utilized for higher-acuity concerns.²²

The use of teledermatology for uncomplicated oral isotretinoin management has the potential to increase medication compliance and decrease the amount of travel time for active-duty service members; for example, consider a military dermatology practice based in San Diego, California, that accepts referrals from military bases 3 hours away by car. After an initial consultation for consideration and initiation of oral isotretinoin, teledermatology appointments can save the active-duty service member 3 hours of travel time for each follow-up visit per month. This ultimately increases operational productivity, reduces barriers to accessing care, and improves patient satisfaction.²³

Although military personnel usually are located at duty stations for 2 to 4 years, training exercises and military vocational schools often temporarily take personnel away from their home station. These temporary-duty assignments have the potential to interrupt medical follow-up appointments and may cause delays in treatment for individuals who miss monthly isotretinoin visits. When deemed appropriate by the prescribing dermatologist, teledermatology allows for increased continuity of care for active-duty service members and maintenance of a therapeutic isotretinoin course despite temporary geographic displacement.

By facilitating regular follow-up appointments, teledermatology can minimize the amount of time an active-duty service member is on a course of oral isotretinoin, thereby reducing the operational and duty-limiting implications of the medication.

Final Thoughts

Acne is a common dermatologic concern within the active-duty military population. Oral isotretinoin is indicated for treatment-resistant moderate or severe acne; however, it limits the ability of service members to deploy and is disqualifying for special military assignments. High daily- and cumulative-dose isotretinoin treatment strategies can reduce the duration of therapy and may be associated with a decrease in acne relapse and the need for retrial. Teledermatology can increase access to care and facilitate the completion of oral isotretinoin courses in a timely manner. These treatment strategies may help mitigate the duty-limiting impact of oral isotretinoin therapy in military service members.

Acne vulgaris is an extremely common dermatologic disease affecting 40 to 50 million individuals in the United States each year, with a prevalence of 85% in adolescents and young adults aged 12 to 24 years. For some patients, the disease may persist well into adulthood, affecting 8% of adults aged 25 and 34 years.¹ Acne negatively impacts patients’ quality of life and productivity, with an estimated direct and indirect cost of over $3 billion per year.²

Oral isotretinoin, a vitamin A derivative, is approved by the US Food and Drug Administration for the treatment of severe nodulocystic acne. Isotretinoin reduces the size and secretions of sebaceous glands, inhibits growth and resulting inflammation of Cutibacterium acnes, and normalizes the differentiation of follicular keratinocytes, resulting in permanent changes in the pathogenesis of acne that may lead to remission.³ The use of oral isotretinoin in the active-duty US Military population may cause service members to be nondeployable or limit their ability to function in special roles (eg, pilot, submariner).⁴ Treatment regimens that minimize the course duration of isotretinoin and reduce the risk for relapse that requires a retrial of isotretinoin may, in turn, increase a service member’s readiness, deployment availability, and ability to perform unique occupational roles.

Additionally, teledermatology has been increasingly utilized to maintain treatment continuity for patients on isotretinoin during the COVID-19 pandemic.⁵ Application of this technology in the military also may be used to facilitate timely isotretinoin treatment regimens in active-duty service members to minimize course duration and increase readiness.

In this article, we discuss an accelerated course of oral isotretinoin as a safe and effective option for military service members bound by duty restrictions and operational timelines and explore the role of teledermatology for the treatment of acne in military service members.

Isotretinoin for Acne

Isotretinoin typically is initiated at a dosage of 0.5 mg/kg daily, increasing to 1 mg/kg daily with a goal cumulative dose between 120 and 150 mg/kg. Relapse may occur after completing a treatment course and is associated with cumulative dosing less than 120 mg/kg.⁶ The average duration of acne treatment with oral isotretinoin is approximately 6 months.⁷ At therapeutic doses, nearly all patients experience side effects, most commonly dryness and desquamation of the skin and mucous membranes, as well as possible involvement of the lips, eyes, and nose. Notable extracutaneous side effects include headache, visual disturbances at night, idiopathic intracranial hypertension, and myalgia. Serum cholesterol, triglycerides, and transaminases may be increased in patients taking isotretinoin, which requires routine monitoring using serum lipid profiles and liver function studies. A potential association between isotretinoin and inflammatory bowel disease and changes in mood have been reported, but current data do not suggest an evidence-based link.^6,8 Isotretinoin is a potent teratogen, and in the United States, all patients are required to enroll in iPLEDGE, a US Food and Drug Administration–approved pregnancy prevention program that monitors prescribing and dispensing of the medication. For patients who can become pregnant, iPLEDGE requires use of 2 forms of contraception as well as monthly pregnancy tests prior to dispensing the medication.

Acne in Military Service Members

Acne is exceedingly common in the active-duty military population. In 2018, more than 40% of soldiers, sailors, airmen, and marines were 25 years or younger, and 75% of all US service members were 35 years or younger, corresponding to acne peak incidences.^1,9 Management of acne in this population requires unique treatment considerations due to distinctive occupational requirements of and hazards faced by military personnel. Use of personal protective equipment, including gas masks, safety restraints, parachute rigging, and flak jackets, may be limiting in individuals with moderate to severe acne.¹⁰ For example, severe nodulocystic acne on the chin and jawline can interfere with proper wear of the chin strap on a Kevlar helmet. The severity of acne often necessitates the use of oral isotretinoin therapy, which is considered disqualifying for many special military assignments, including submarine duty, nuclear field duty, and diving duty.¹¹ In military aviation communities, oral isotretinoin requires grounding for the duration of therapy plus 3 months after cessation. Slit-lamp examination, triglycerides, and transaminase levels must be normal prior to returning to unrestricted duty.¹² Furthermore, use of oral isotretinoin may limit overseas assignments or deployment eligibility.⁴

The high prevalence of acne and the operationally limiting consequences of isotretinoin therapy present a unique challenge for dermatologists treating military personnel. The average duration of isotretinoin treatment is approximately 6 months,⁷ which represents a considerable amount of time during an average 4-year enlistment contract. Therapeutic treatment strategies that (1) reduce the duration of oral isotretinoin therapy, (2) reduce the risk for relapse, and (3) increase medication compliance can reduce the operational impact of this acne treatment. Such treatment strategies are discussed below.

An optimal isotretinoin dosing regimen would achieve swift resolution of acne lesions and reduce the overall relapse rate requiring retrial of isotretinoin, thereby minimizing the operational- and duty-limiting impacts of the medication. Cyrulnik et al¹³ studied treatment outcomes of high-dose isotretinoin for acne vulgaris using a mean dosage of 1.6 mg/kg daily with an average cumulative dosage of 290 mg/kg. They demonstrated 100% clearance of lesions over 6 months, with a 12.5% relapse rate at 3 years. Aside from an increased rate of elevated transaminases, incidence of adverse effects and laboratory abnormalities were not significantly increased compared to conventional dosing regimens.¹³ The goal cumulative dosing of 120 to 150 mg/kg can be achieved 1 to 2 months earlier using a dosage of 1.6 mg/kg daily vs a conventional dosage of 1 mg/kg daily.

It has been hypothesized that higher cumulative doses of oral isotretinoin reduce the risk for relapse of acne and retrial of oral isotretinoin.¹⁴ Blasiak et al¹⁵ studied relapse and retrial of oral isotretinoin in acne patients who received cumulative dosing higher or lower than 220 mg/kg. A clinically but not statistically significant reduced relapse rate was observed in the cohort that received cumulative dosing higher than 220 mg/kg. No statistically significant difference in rates of adverse advents was observed aside from an increase in retinoid dermatitis in the cohort that received cumulative dosing higher than 220 mg/kg. Higher but not statistically significant rates of adverse events were seen in the group that received dosing higher than 220 mg/kg.¹⁵ Cumulative doses of oral isotretinoin higher than the 120 to 150 mg/kg range may decrease the risk for acne relapse and the need for an additional course of oral isotretinoin, which would reduce a service member’s total time away from deployment and full duty.

Relapse requiring a retrial of oral isotretinoin not only increases the operational cost of acne treatment but also considerably increases the monetary cost to the health care system. In a cost-analysis model, cumulative doses of oral isotretinoin higher than 230 mg/kg have a decreased overall cost compared to traditional cumulative dosing of less than 150 mg/kg due to the cost of relapse.¹⁶

Limitations of high daily and cumulative dosing regimens of oral isotretinoin are chiefly the dose-dependent rate of adverse effects. Low-dose regimens are associated with a reduced risk of isotretinoin-related side effects.^6,17 Acute acne flares may be seen following initial administration of oral isotretinoin and are aggravated by increases in dosage.¹⁸ Isotretinoin-induced acne fulminans is a rare but devastating complication observed with high initial doses of oral isotretinoin in patients with severe acne.¹⁹ The risks and benefits of high daily and cumulatively dosed isotretinoin must be carefully considered in patients with severe acne.

Teledermatology: A Force for Readiness

The COVID-19 pandemic drastically changed the dermatology practice landscape with recommendations to cancel all elective outpatient visits in favor of teledermatology encounters.²⁰ This decreased access to care, which resulted in an increase in drug interruption for dermatology patients, including patients on oral isotretinoin.²¹ Teledermatology has been increasingly utilized to maintain continuity of care for the management of patients taking isotretinoin.⁵ Routine utilization of teledermatology evaluation in military practices could expedite care, decrease patient travel time, and allow for in-clinic visits to be utilized for higher-acuity concerns.²²

The use of teledermatology for uncomplicated oral isotretinoin management has the potential to increase medication compliance and decrease the amount of travel time for active-duty service members; for example, consider a military dermatology practice based in San Diego, California, that accepts referrals from military bases 3 hours away by car. After an initial consultation for consideration and initiation of oral isotretinoin, teledermatology appointments can save the active-duty service member 3 hours of travel time for each follow-up visit per month. This ultimately increases operational productivity, reduces barriers to accessing care, and improves patient satisfaction.²³

Although military personnel usually are located at duty stations for 2 to 4 years, training exercises and military vocational schools often temporarily take personnel away from their home station. These temporary-duty assignments have the potential to interrupt medical follow-up appointments and may cause delays in treatment for individuals who miss monthly isotretinoin visits. When deemed appropriate by the prescribing dermatologist, teledermatology allows for increased continuity of care for active-duty service members and maintenance of a therapeutic isotretinoin course despite temporary geographic displacement.

By facilitating regular follow-up appointments, teledermatology can minimize the amount of time an active-duty service member is on a course of oral isotretinoin, thereby reducing the operational and duty-limiting implications of the medication.

Final Thoughts

Acne is a common dermatologic concern within the active-duty military population. Oral isotretinoin is indicated for treatment-resistant moderate or severe acne; however, it limits the ability of service members to deploy and is disqualifying for special military assignments. High daily- and cumulative-dose isotretinoin treatment strategies can reduce the duration of therapy and may be associated with a decrease in acne relapse and the need for retrial. Teledermatology can increase access to care and facilitate the completion of oral isotretinoin courses in a timely manner. These treatment strategies may help mitigate the duty-limiting impact of oral isotretinoin therapy in military service members.

The potential effectiveness of using vaginal progesterone to prevent preterm birth in two different populations was the focus of a pair of studies with mixed results at the annual meeting sponsored by the Society for Maternal-Fetal Medicine on Feb. 3. One study found no benefit from vaginal progesterone in those with first trimester bleeding, while the other, in a head-to-head comparison with 17-alpha-hydroxyprogesterone caproate (17-OHPC), found vaginal progesterone performs similarly to 17-OHPC in singleton pregnancies with a history of preterm birth.

While the first study does not suggest any changes in clinical practice, the second one suggests that vaginal progesterone is an alternative to 17-OHPC, as the American College of Obstetricians and Gynecologists currently recommends. SMFM currently only includes 17-OHPC in its guidelines.

“In otherwise low-risk pregnancies with first trimester bleeding, progesterone should not be prescribed for the prevention of miscarriage or prematurity,” Haim A. Abenhaim, MD, MPH, of the Jewish General Hospital at McGill University, Montreal, told attendees in his presentation.

”Publishing the negative result is so important because this helps the overall body of literature reduce the amount of publication bias that exists in the literature,” Michael Richley, MD, an ob.gyn. and maternal-fetal medicine fellow at the University of California, Los Angeles, said in an interview. Dr. Richley was not involved in the research but attended the presentation.
 

Vaginal progesterone for first trimester bleeding

Most preterm birth occurs in pregnancies with no identifiable risk factors, but first-trimester bleeding may indicate subchorionic hemorrhage from placental detachment, which can increase the risk of preterm birth. Other risk factors where progesterone has previously shown effectiveness in reducing preterm birth risk include short cervix and a history of prior preterm birth.

The first study (PREEMPT) was a double-blind, randomized controlled trial conducted at six Canadian hospitals with 533 women. The participants all experienced bleeding within the first 14 weeks of pregnancy and a documented subchorionic hemorrhage. The trial excluded those who already required progesterone, had contraindications to progesterone or had an alternate cause of bleeding.

The intervention group included 264 women randomly assigned to use 200 mg of micronized progesterone administered with a vaginal suppository at bedtime, while the placebo group included 269 women who used a vaginal suppository with no medication, both administered until 34 weeks of pregnancy. The groups were not significantly different in age, race, or former pregnancies, live births, and miscarriages. They were also similar in clinical characteristics of bleeding and subchorionic hemorrhage.

The proportion of term births was similar between the progesterone (74.6%) and placebo (70.6%) groups (P =.3), as was the proportion of preterm births (10.2% progesterone vs. 12.3% placebo, P =.46). There were also no significant differences in the secondary outcomes of cramping, hospital admission, bed rest, or preventive measures, including pessary, cerclage, antibiotics, magnesium, and nifedipine. Newborns across both groups were statistically similar in average birth weight and distribution of birth weights and in incidence of neonatal ICU admission or respiratory distress syndrome. Adverse events were similar across both groups.

”The results are not surprising as several studies in the past have shown similar lack of efficacy,” Dr. said. “The pathophysiology of subchorionic hematoma is different from the multifactorial etiologies of spontaneous preterm birth, and given our lack of clear understanding of the actions of progesterone, the lack of efficacy in this subgroup with subchorionic hematoma is not surprising.”

Dr. Richley did note that having a low-risk population to start with may have affected the findings, which might be different in a high-risk population.

“I don’t believe this will change anything within clinical practice. At this time, progesterone is not used in any form in the setting of first trimester threatened abortion by maternal-fetal medicine specialists,” Dr. Richley said. “There may be other subgroups of clinicians who do prescribe progesterone in this setting, and these data should further encourage them to move away from this practice.”

Dr. Abenhaim noted a couple unexpected issues that occurred during the course of the study, such as underreporting of subchorionic hemorrhage with radiologic confirmation that resulted in a smaller population and a change in protocol to include patients with no identifiable secondary source of bleeding. The pandemic also halted enrollment, and the investigators halted the trial when recruitment could have continued since interim analysis showed no likely benefit.

Though first trimester bleeding is associated with a 25%-30% increased risk of miscarriage or preterm birth, the findings showed that progesterone did not prevent miscarriage or prematurity, or increase the live birth rate, in low-risk patients with first trimester bleeding.
 

Vaginal progesterone vs. 17-OHPC

Although a 2017 meta-analysis had found vaginal progesterone to be superior to 17-OHPC in preventing preterm birth, few studies were available, and they had wide confidence intervals. This open-label randomized controlled trial took place at five U.S. sites and included participants who had a singleton pregnancy less than 24 weeks along and a history of singleton preterm birth between 16 and 37 weeks. The trials excluded those with placenta previa or accreta, preterm labor, preterm premature rupture of the membranes, clinical chorioamnionitis, or a major fetal anomaly or chromosomal disorder.

Among 205 women initially randomized, 94 in each group completed the trial, either inserting 200 mg of micronized progesterone daily with a vaginal suppository or receiving 250 mg of weekly intramuscular injections of 17-OHPC from 16 to 36 weeks’ gestation. The only significant difference between the groups in demographics or clinical features was that the vaginal progesterone group had a higher proportion of multiple past preterm births (33%) compared with the 17-OHPC group (17%). Cervical length and use of cerclage were also similar between the groups.

Though 30.9% of the vaginal progesterone group delivered preterm before 37 weeks, compared with 38.3% in the 17-OHPC group, the difference was not significant (P =.28). There was a borderline statistical difference between gestational age at delivery: 37.4 weeks in the vaginal progesterone group versus 36.3 weeks in the 17-OHPC group (P =.047). Neonatal outcomes were clinically similar between the two groups. Therapy initiation did slightly differ between the groups, with an average start 1 gestational week earlier in the vaginal progesterone group (16.9 vs. 17.8, P =.001) and a higher proportion of patients in the 17-OHPC group initiating therapy after 20 weeks (16.5% vs. 2.2%, P =.001). Adherence was otherwise similar between the groups, and the groups reported similar rates and types of side effects.

The trial did not meet the primary endpoint of vaginal progesterone reducing risk of recurrent preterm birth by 50%, compared with 17-OHPC, but it may increase latency to delivery, Rupsa C. Boelig, MD, of Thomas Jefferson University, Philadelphia, told attendees. Though this was the largest trial to compare vaginal progesterone with 17-OHPC for preventing preterm birth, it was underpowered to detect a difference in efficacy, to conduct subgroup analyses, and to assess secondary outcomes, Dr. Boelig noted. “Baseline difference in preterm birth risk may affect apparent relative efficacy of vaginal progesterone.”

Nevertheless, the “totality of evidence appears to be greater for vaginal progesterone,” Dr. Boelig said, making vaginal progesterone an acceptable alternative to 17-OHPC. ACOG recommendations currently include offering either, but SMFM recommendations only mention 17-OHPC.

It’s worth noting, however, that the future of 17-OHPC, a synthetic compound, compared with naturally occurring micronized progesterone, continues to be uncertain following a 2020 study that found no evidence of its efficacy, leading the Food and Drug Administration to withdraw its approval for prevention of preterm birth. ”These findings are important especially in light of the controversy surrounding 17-OHP,” Jenny Mei, MD, a maternal-fetal medicine fellow at UCLA, said in an interview after attending the presentation. “It is also sometimes difficult for patients to commit to weekly 17-OHPC injections, which requires time and many doctors visits, as compared to vaginal progesterone, which patients can administer at home.” Since this study does not have a placebo group, “it does not address the question of the overall efficacy of either medication compared to a control,” Dr. Mei said. ”It is also a somewhat small patient population so the results may change with a larger population. The authors conclude it is worth readdressing the use of vaginal progesterone for these patients.”

Herman L. Hedriana, MD, professor and director of the division of maternal-fetal medicine and the maternal-fetal medicine fellowship program at the University of California, Davis, also pointed out notable differences between the two compounds.

“One has to remember that the formulation and mechanism of action are very different between 17-OHPC and the vaginal application of micronized progesterone. We do not have enough data to say one is superior versus the other,” said Dr. Hedriana, who was not involved in the research. “With 17-OHPC, the mechanism of action appears to be influenced by how the drug is metabolized based on race and ethnicity makeup, and may be influence by epigenetics,” while the mechanism for vaginal progesterone is probably local “given it is applied directly next to the cervix; hence, the results are it is effective in short cervices.” But those differing mechanisms don’t change the clinical significance of the findings. “One can use vaginal progesterone or 17-OHPC based on patient preference and availability,” Dr. Hedriana said.

The researchers of both studies reported no personal financial or industry disclosures, though Dr. Boelig disclosed that she had taken 17-OHPC and had cerclages during both her pregnancies, which resulted in healthy children today. The PREEMPT trial was funded by the Canadian Institutes of Health Research. The head-to-head trial was funded by the National Institute of Child Health and Development, the March of Dimes, the EW Thrasher Foundation, the PhRMA Foundation, and Covis Pharma, who manufactures the 17-OHPC drug Makena.

This story was updated on 2/8/2022.

The potential effectiveness of using vaginal progesterone to prevent preterm birth in two different populations was the focus of a pair of studies with mixed results at the annual meeting sponsored by the Society for Maternal-Fetal Medicine on Feb. 3. One study found no benefit from vaginal progesterone in those with first trimester bleeding, while the other, in a head-to-head comparison with 17-alpha-hydroxyprogesterone caproate (17-OHPC), found vaginal progesterone performs similarly to 17-OHPC in singleton pregnancies with a history of preterm birth.

While the first study does not suggest any changes in clinical practice, the second one suggests that vaginal progesterone is an alternative to 17-OHPC, as the American College of Obstetricians and Gynecologists currently recommends. SMFM currently only includes 17-OHPC in its guidelines.

“In otherwise low-risk pregnancies with first trimester bleeding, progesterone should not be prescribed for the prevention of miscarriage or prematurity,” Haim A. Abenhaim, MD, MPH, of the Jewish General Hospital at McGill University, Montreal, told attendees in his presentation.

”Publishing the negative result is so important because this helps the overall body of literature reduce the amount of publication bias that exists in the literature,” Michael Richley, MD, an ob.gyn. and maternal-fetal medicine fellow at the University of California, Los Angeles, said in an interview. Dr. Richley was not involved in the research but attended the presentation.
 

Vaginal progesterone for first trimester bleeding

Most preterm birth occurs in pregnancies with no identifiable risk factors, but first-trimester bleeding may indicate subchorionic hemorrhage from placental detachment, which can increase the risk of preterm birth. Other risk factors where progesterone has previously shown effectiveness in reducing preterm birth risk include short cervix and a history of prior preterm birth.

The first study (PREEMPT) was a double-blind, randomized controlled trial conducted at six Canadian hospitals with 533 women. The participants all experienced bleeding within the first 14 weeks of pregnancy and a documented subchorionic hemorrhage. The trial excluded those who already required progesterone, had contraindications to progesterone or had an alternate cause of bleeding.

The intervention group included 264 women randomly assigned to use 200 mg of micronized progesterone administered with a vaginal suppository at bedtime, while the placebo group included 269 women who used a vaginal suppository with no medication, both administered until 34 weeks of pregnancy. The groups were not significantly different in age, race, or former pregnancies, live births, and miscarriages. They were also similar in clinical characteristics of bleeding and subchorionic hemorrhage.

The proportion of term births was similar between the progesterone (74.6%) and placebo (70.6%) groups (P =.3), as was the proportion of preterm births (10.2% progesterone vs. 12.3% placebo, P =.46). There were also no significant differences in the secondary outcomes of cramping, hospital admission, bed rest, or preventive measures, including pessary, cerclage, antibiotics, magnesium, and nifedipine. Newborns across both groups were statistically similar in average birth weight and distribution of birth weights and in incidence of neonatal ICU admission or respiratory distress syndrome. Adverse events were similar across both groups.

”The results are not surprising as several studies in the past have shown similar lack of efficacy,” Dr. said. “The pathophysiology of subchorionic hematoma is different from the multifactorial etiologies of spontaneous preterm birth, and given our lack of clear understanding of the actions of progesterone, the lack of efficacy in this subgroup with subchorionic hematoma is not surprising.”

Dr. Richley did note that having a low-risk population to start with may have affected the findings, which might be different in a high-risk population.

“I don’t believe this will change anything within clinical practice. At this time, progesterone is not used in any form in the setting of first trimester threatened abortion by maternal-fetal medicine specialists,” Dr. Richley said. “There may be other subgroups of clinicians who do prescribe progesterone in this setting, and these data should further encourage them to move away from this practice.”

Dr. Abenhaim noted a couple unexpected issues that occurred during the course of the study, such as underreporting of subchorionic hemorrhage with radiologic confirmation that resulted in a smaller population and a change in protocol to include patients with no identifiable secondary source of bleeding. The pandemic also halted enrollment, and the investigators halted the trial when recruitment could have continued since interim analysis showed no likely benefit.

Though first trimester bleeding is associated with a 25%-30% increased risk of miscarriage or preterm birth, the findings showed that progesterone did not prevent miscarriage or prematurity, or increase the live birth rate, in low-risk patients with first trimester bleeding.
 

Vaginal progesterone vs. 17-OHPC

Although a 2017 meta-analysis had found vaginal progesterone to be superior to 17-OHPC in preventing preterm birth, few studies were available, and they had wide confidence intervals. This open-label randomized controlled trial took place at five U.S. sites and included participants who had a singleton pregnancy less than 24 weeks along and a history of singleton preterm birth between 16 and 37 weeks. The trials excluded those with placenta previa or accreta, preterm labor, preterm premature rupture of the membranes, clinical chorioamnionitis, or a major fetal anomaly or chromosomal disorder.

Among 205 women initially randomized, 94 in each group completed the trial, either inserting 200 mg of micronized progesterone daily with a vaginal suppository or receiving 250 mg of weekly intramuscular injections of 17-OHPC from 16 to 36 weeks’ gestation. The only significant difference between the groups in demographics or clinical features was that the vaginal progesterone group had a higher proportion of multiple past preterm births (33%) compared with the 17-OHPC group (17%). Cervical length and use of cerclage were also similar between the groups.

Though 30.9% of the vaginal progesterone group delivered preterm before 37 weeks, compared with 38.3% in the 17-OHPC group, the difference was not significant (P =.28). There was a borderline statistical difference between gestational age at delivery: 37.4 weeks in the vaginal progesterone group versus 36.3 weeks in the 17-OHPC group (P =.047). Neonatal outcomes were clinically similar between the two groups. Therapy initiation did slightly differ between the groups, with an average start 1 gestational week earlier in the vaginal progesterone group (16.9 vs. 17.8, P =.001) and a higher proportion of patients in the 17-OHPC group initiating therapy after 20 weeks (16.5% vs. 2.2%, P =.001). Adherence was otherwise similar between the groups, and the groups reported similar rates and types of side effects.

The trial did not meet the primary endpoint of vaginal progesterone reducing risk of recurrent preterm birth by 50%, compared with 17-OHPC, but it may increase latency to delivery, Rupsa C. Boelig, MD, of Thomas Jefferson University, Philadelphia, told attendees. Though this was the largest trial to compare vaginal progesterone with 17-OHPC for preventing preterm birth, it was underpowered to detect a difference in efficacy, to conduct subgroup analyses, and to assess secondary outcomes, Dr. Boelig noted. “Baseline difference in preterm birth risk may affect apparent relative efficacy of vaginal progesterone.”

Nevertheless, the “totality of evidence appears to be greater for vaginal progesterone,” Dr. Boelig said, making vaginal progesterone an acceptable alternative to 17-OHPC. ACOG recommendations currently include offering either, but SMFM recommendations only mention 17-OHPC.

It’s worth noting, however, that the future of 17-OHPC, a synthetic compound, compared with naturally occurring micronized progesterone, continues to be uncertain following a 2020 study that found no evidence of its efficacy, leading the Food and Drug Administration to withdraw its approval for prevention of preterm birth. ”These findings are important especially in light of the controversy surrounding 17-OHP,” Jenny Mei, MD, a maternal-fetal medicine fellow at UCLA, said in an interview after attending the presentation. “It is also sometimes difficult for patients to commit to weekly 17-OHPC injections, which requires time and many doctors visits, as compared to vaginal progesterone, which patients can administer at home.” Since this study does not have a placebo group, “it does not address the question of the overall efficacy of either medication compared to a control,” Dr. Mei said. ”It is also a somewhat small patient population so the results may change with a larger population. The authors conclude it is worth readdressing the use of vaginal progesterone for these patients.”

Herman L. Hedriana, MD, professor and director of the division of maternal-fetal medicine and the maternal-fetal medicine fellowship program at the University of California, Davis, also pointed out notable differences between the two compounds.

“One has to remember that the formulation and mechanism of action are very different between 17-OHPC and the vaginal application of micronized progesterone. We do not have enough data to say one is superior versus the other,” said Dr. Hedriana, who was not involved in the research. “With 17-OHPC, the mechanism of action appears to be influenced by how the drug is metabolized based on race and ethnicity makeup, and may be influence by epigenetics,” while the mechanism for vaginal progesterone is probably local “given it is applied directly next to the cervix; hence, the results are it is effective in short cervices.” But those differing mechanisms don’t change the clinical significance of the findings. “One can use vaginal progesterone or 17-OHPC based on patient preference and availability,” Dr. Hedriana said.

The researchers of both studies reported no personal financial or industry disclosures, though Dr. Boelig disclosed that she had taken 17-OHPC and had cerclages during both her pregnancies, which resulted in healthy children today. The PREEMPT trial was funded by the Canadian Institutes of Health Research. The head-to-head trial was funded by the National Institute of Child Health and Development, the March of Dimes, the EW Thrasher Foundation, the PhRMA Foundation, and Covis Pharma, who manufactures the 17-OHPC drug Makena.

This story was updated on 2/8/2022.

The potential effectiveness of using vaginal progesterone to prevent preterm birth in two different populations was the focus of a pair of studies with mixed results at the annual meeting sponsored by the Society for Maternal-Fetal Medicine on Feb. 3. One study found no benefit from vaginal progesterone in those with first trimester bleeding, while the other, in a head-to-head comparison with 17-alpha-hydroxyprogesterone caproate (17-OHPC), found vaginal progesterone performs similarly to 17-OHPC in singleton pregnancies with a history of preterm birth.

While the first study does not suggest any changes in clinical practice, the second one suggests that vaginal progesterone is an alternative to 17-OHPC, as the American College of Obstetricians and Gynecologists currently recommends. SMFM currently only includes 17-OHPC in its guidelines.

“In otherwise low-risk pregnancies with first trimester bleeding, progesterone should not be prescribed for the prevention of miscarriage or prematurity,” Haim A. Abenhaim, MD, MPH, of the Jewish General Hospital at McGill University, Montreal, told attendees in his presentation.

”Publishing the negative result is so important because this helps the overall body of literature reduce the amount of publication bias that exists in the literature,” Michael Richley, MD, an ob.gyn. and maternal-fetal medicine fellow at the University of California, Los Angeles, said in an interview. Dr. Richley was not involved in the research but attended the presentation.
 

Vaginal progesterone for first trimester bleeding

Most preterm birth occurs in pregnancies with no identifiable risk factors, but first-trimester bleeding may indicate subchorionic hemorrhage from placental detachment, which can increase the risk of preterm birth. Other risk factors where progesterone has previously shown effectiveness in reducing preterm birth risk include short cervix and a history of prior preterm birth.

The first study (PREEMPT) was a double-blind, randomized controlled trial conducted at six Canadian hospitals with 533 women. The participants all experienced bleeding within the first 14 weeks of pregnancy and a documented subchorionic hemorrhage. The trial excluded those who already required progesterone, had contraindications to progesterone or had an alternate cause of bleeding.

The intervention group included 264 women randomly assigned to use 200 mg of micronized progesterone administered with a vaginal suppository at bedtime, while the placebo group included 269 women who used a vaginal suppository with no medication, both administered until 34 weeks of pregnancy. The groups were not significantly different in age, race, or former pregnancies, live births, and miscarriages. They were also similar in clinical characteristics of bleeding and subchorionic hemorrhage.

The proportion of term births was similar between the progesterone (74.6%) and placebo (70.6%) groups (P =.3), as was the proportion of preterm births (10.2% progesterone vs. 12.3% placebo, P =.46). There were also no significant differences in the secondary outcomes of cramping, hospital admission, bed rest, or preventive measures, including pessary, cerclage, antibiotics, magnesium, and nifedipine. Newborns across both groups were statistically similar in average birth weight and distribution of birth weights and in incidence of neonatal ICU admission or respiratory distress syndrome. Adverse events were similar across both groups.

”The results are not surprising as several studies in the past have shown similar lack of efficacy,” Dr. said. “The pathophysiology of subchorionic hematoma is different from the multifactorial etiologies of spontaneous preterm birth, and given our lack of clear understanding of the actions of progesterone, the lack of efficacy in this subgroup with subchorionic hematoma is not surprising.”

Dr. Richley did note that having a low-risk population to start with may have affected the findings, which might be different in a high-risk population.

“I don’t believe this will change anything within clinical practice. At this time, progesterone is not used in any form in the setting of first trimester threatened abortion by maternal-fetal medicine specialists,” Dr. Richley said. “There may be other subgroups of clinicians who do prescribe progesterone in this setting, and these data should further encourage them to move away from this practice.”

Dr. Abenhaim noted a couple unexpected issues that occurred during the course of the study, such as underreporting of subchorionic hemorrhage with radiologic confirmation that resulted in a smaller population and a change in protocol to include patients with no identifiable secondary source of bleeding. The pandemic also halted enrollment, and the investigators halted the trial when recruitment could have continued since interim analysis showed no likely benefit.

Though first trimester bleeding is associated with a 25%-30% increased risk of miscarriage or preterm birth, the findings showed that progesterone did not prevent miscarriage or prematurity, or increase the live birth rate, in low-risk patients with first trimester bleeding.
 

Vaginal progesterone vs. 17-OHPC

Although a 2017 meta-analysis had found vaginal progesterone to be superior to 17-OHPC in preventing preterm birth, few studies were available, and they had wide confidence intervals. This open-label randomized controlled trial took place at five U.S. sites and included participants who had a singleton pregnancy less than 24 weeks along and a history of singleton preterm birth between 16 and 37 weeks. The trials excluded those with placenta previa or accreta, preterm labor, preterm premature rupture of the membranes, clinical chorioamnionitis, or a major fetal anomaly or chromosomal disorder.

Among 205 women initially randomized, 94 in each group completed the trial, either inserting 200 mg of micronized progesterone daily with a vaginal suppository or receiving 250 mg of weekly intramuscular injections of 17-OHPC from 16 to 36 weeks’ gestation. The only significant difference between the groups in demographics or clinical features was that the vaginal progesterone group had a higher proportion of multiple past preterm births (33%) compared with the 17-OHPC group (17%). Cervical length and use of cerclage were also similar between the groups.

Though 30.9% of the vaginal progesterone group delivered preterm before 37 weeks, compared with 38.3% in the 17-OHPC group, the difference was not significant (P =.28). There was a borderline statistical difference between gestational age at delivery: 37.4 weeks in the vaginal progesterone group versus 36.3 weeks in the 17-OHPC group (P =.047). Neonatal outcomes were clinically similar between the two groups. Therapy initiation did slightly differ between the groups, with an average start 1 gestational week earlier in the vaginal progesterone group (16.9 vs. 17.8, P =.001) and a higher proportion of patients in the 17-OHPC group initiating therapy after 20 weeks (16.5% vs. 2.2%, P =.001). Adherence was otherwise similar between the groups, and the groups reported similar rates and types of side effects.

The trial did not meet the primary endpoint of vaginal progesterone reducing risk of recurrent preterm birth by 50%, compared with 17-OHPC, but it may increase latency to delivery, Rupsa C. Boelig, MD, of Thomas Jefferson University, Philadelphia, told attendees. Though this was the largest trial to compare vaginal progesterone with 17-OHPC for preventing preterm birth, it was underpowered to detect a difference in efficacy, to conduct subgroup analyses, and to assess secondary outcomes, Dr. Boelig noted. “Baseline difference in preterm birth risk may affect apparent relative efficacy of vaginal progesterone.”

Nevertheless, the “totality of evidence appears to be greater for vaginal progesterone,” Dr. Boelig said, making vaginal progesterone an acceptable alternative to 17-OHPC. ACOG recommendations currently include offering either, but SMFM recommendations only mention 17-OHPC.

It’s worth noting, however, that the future of 17-OHPC, a synthetic compound, compared with naturally occurring micronized progesterone, continues to be uncertain following a 2020 study that found no evidence of its efficacy, leading the Food and Drug Administration to withdraw its approval for prevention of preterm birth. ”These findings are important especially in light of the controversy surrounding 17-OHP,” Jenny Mei, MD, a maternal-fetal medicine fellow at UCLA, said in an interview after attending the presentation. “It is also sometimes difficult for patients to commit to weekly 17-OHPC injections, which requires time and many doctors visits, as compared to vaginal progesterone, which patients can administer at home.” Since this study does not have a placebo group, “it does not address the question of the overall efficacy of either medication compared to a control,” Dr. Mei said. ”It is also a somewhat small patient population so the results may change with a larger population. The authors conclude it is worth readdressing the use of vaginal progesterone for these patients.”

Herman L. Hedriana, MD, professor and director of the division of maternal-fetal medicine and the maternal-fetal medicine fellowship program at the University of California, Davis, also pointed out notable differences between the two compounds.

“One has to remember that the formulation and mechanism of action are very different between 17-OHPC and the vaginal application of micronized progesterone. We do not have enough data to say one is superior versus the other,” said Dr. Hedriana, who was not involved in the research. “With 17-OHPC, the mechanism of action appears to be influenced by how the drug is metabolized based on race and ethnicity makeup, and may be influence by epigenetics,” while the mechanism for vaginal progesterone is probably local “given it is applied directly next to the cervix; hence, the results are it is effective in short cervices.” But those differing mechanisms don’t change the clinical significance of the findings. “One can use vaginal progesterone or 17-OHPC based on patient preference and availability,” Dr. Hedriana said.

The researchers of both studies reported no personal financial or industry disclosures, though Dr. Boelig disclosed that she had taken 17-OHPC and had cerclages during both her pregnancies, which resulted in healthy children today. The PREEMPT trial was funded by the Canadian Institutes of Health Research. The head-to-head trial was funded by the National Institute of Child Health and Development, the March of Dimes, the EW Thrasher Foundation, the PhRMA Foundation, and Covis Pharma, who manufactures the 17-OHPC drug Makena.

This story was updated on 2/8/2022.

Low-dose aspirin may increase risk of postpartum bleeding if patients don’t discontinue its use at least 7 days before delivery, but it’s otherwise unclear whether its use increases bleeding risk, according to research presented Feb. 5 at the meeting sponsored by the Society for Maternal-Fetal Medicine.

“These findings were a little surprising to me because we have generally been taught that aspirin is safe to continue up until delivery with minimal risk,” Jenny Mei, MD, a maternal-fetal medicine fellow at the University of California, Los Angeles, said in an interview after attending the presentation. “Theoretically it makes sense that it may increase bleeding risk, but multiple studies in the past analyzing its use with gynecological surgery show minimal risk, which was conferred to the obstetrical population as well.”

She noted, however, that patients prescribed low-dose aspirin already have risk factors that may increase their risk of postpartum bleeding, and the study’s finding of possible increased risk was not statistically significant after accounting for those confounders. “I wouldn’t change my practice management over it, but it does raise awareness that all interventions likely come with some risk,” Dr. Mei said.

Hypertensive disorders of pregnancy are responsible for 6.6% of U.S. pregnancy-related deaths. The SMFM currently recommends low-dose aspirin starting at 12 weeks’ gestation in patients at high risk for preeclampsia, which includes people with multifetal gestation, chronic hypertension, pregestational diabetes, renal disease, autoimmune disease, or a history of preeclampsia. However, previous research has shown mixed results on the safety of low-dose aspirin in terms of bleeding risk, Kelsey White, MD, a second-year maternal-fetal medicine fellow of the Yale University, New Haven, Conn., told attendees.

This retrospective study compared a bleeding composite endpoint among those who did and did not take low-dose aspirin between January 2018 and April 2021. The composite included an estimated blood loss of greater than 1,000 mL, postpartum hemorrhage based on ICD-9/10 code diagnosis, and red blood cell transfusion. The researchers also compared bleeding risk within the aspirin group based on discontinuation at greater or less than 7 days before delivery.

Among 16,980 patients, 11.3% were prescribed low-dose aspirin. The patients prescribed low-dose aspirin significantly differed from those not prescribed it in all demographic and clinical characteristics except placenta accreta spectrum. The average age of the aspirin group was 39 years, compared with 24 years in the nonaspirin group (P < .01). More of the aspirin group patients were Hispanic and Black, and 52.3% of patients taking aspirin had a body mass index greater than 30 kg/m², compared with 22.9% of the nonaspirin group. Rates of diabetes, lupus, fibroids, nonaspirin anticoagulation use, cesarean delivery, and preterm delivery were all greater in the aspirin group.

In addition, 43.9% of the patients in the aspirin group had a hypertensive disorder, including 20.2% with preeclampsia, compared with 17.1% with hypertensive disorders, including 6.2% with preeclampsia, in the group not taking aspirin (P < .0001). “This shows that a high-risk population was prescribed aspirin, which correlates to the recommended prescription guidelines,” Dr. White said.

The postpartum bleeding composite outcome occurred in 14.7% of patients in the low-dose aspirin group, compared with 9.2% of patients in the nonaspirin group, for an unadjusted 1.7 times greater risk of bleeding (95% confidence interval, 1.49-1.96). After adjustment for confounders, the risk declined and was no longer statistically significant (aOR = 1.15; 95% CI, 0.98-1.34).

Meanwhile, 15% of those who discontinued aspirin within 7 days of delivery had postpartum bleeding, compared with 9% of those who discontinued aspirin at 7 or more days before delivery (P = .03).

Therefore, while the study found only a possible, nonsignificant association between low-dose aspirin and postpartum bleeding, risk of bleeding was significantly greater among those who discontinued aspirin only in the last week before delivery.

”Our study is timely and supports a recent Swedish study [that] found an increased risk of intrapartum bleeding, postpartum hemorrhage, and postpartum hematoma,” Dr. White said. She also noted that the United States Preventive Services Task Force changed their recommendation in 2021 for low-dose aspirin prophylaxis for cardiovascular disease.

“They now recommend against the use of low-dose aspirin for prevention in adults without a history of cardiovascular disease,” Dr. White said. “The change in recommendations came after recent randomized control trials showed that low-dose aspirin had very little benefit and may increase the risk of bleeding.”

However, Dr. White added that they “do not believe this study should be used to make any clinical decisions.” While the study had a large sample size, it was limited by its retrospective reliance on EMR data, including the EMR medication list, and the researchers couldn’t assess patient compliance or patient use of over-the-counter aspirin not recorded in the EMR.

Deirdre Lyell, MD, a professor of maternal-fetal medicine at Stanford (Calif.) University, agreed that the findings should not impact clinical practice given its limitations.

“The investigators could not entirely identify who stopped low-dose aspirin and when. When they estimated timing of stoppage of low-dose aspirin, their data suggested a small benefit among those who discontinued it at least 7 days before delivery, though this should be interpreted with caution, given the potential inaccuracy in these data,” Dr. Lyell, who was not involved in the study, said in an interview. “Their study did not examine factors that should be used to confirm if there are real differences in blood loss, such as changes in blood counts before and after delivery, or more use of medications that we use to stop heavy bleeding.”

In fact, Dr. Lyell noted, other research at the SMFM meeting found ”that low-dose aspirin is not used frequently enough in patients who might benefit, such as those at high risk for preeclampsia,” she said. ”Low-dose aspirin among those at increased risk has been shown to reduce rates of preeclampsia, reducing the likelihood of risky situations for moms and babies.”

The authors had no disclosures. Dr. Lyell has consulted for Bloomlife, a uterine contraction and fetal monitor. Dr. White and Dr. Mei had no disclosures.
 

Low-dose aspirin may increase risk of postpartum bleeding if patients don’t discontinue its use at least 7 days before delivery, but it’s otherwise unclear whether its use increases bleeding risk, according to research presented Feb. 5 at the meeting sponsored by the Society for Maternal-Fetal Medicine.

“These findings were a little surprising to me because we have generally been taught that aspirin is safe to continue up until delivery with minimal risk,” Jenny Mei, MD, a maternal-fetal medicine fellow at the University of California, Los Angeles, said in an interview after attending the presentation. “Theoretically it makes sense that it may increase bleeding risk, but multiple studies in the past analyzing its use with gynecological surgery show minimal risk, which was conferred to the obstetrical population as well.”

She noted, however, that patients prescribed low-dose aspirin already have risk factors that may increase their risk of postpartum bleeding, and the study’s finding of possible increased risk was not statistically significant after accounting for those confounders. “I wouldn’t change my practice management over it, but it does raise awareness that all interventions likely come with some risk,” Dr. Mei said.

Hypertensive disorders of pregnancy are responsible for 6.6% of U.S. pregnancy-related deaths. The SMFM currently recommends low-dose aspirin starting at 12 weeks’ gestation in patients at high risk for preeclampsia, which includes people with multifetal gestation, chronic hypertension, pregestational diabetes, renal disease, autoimmune disease, or a history of preeclampsia. However, previous research has shown mixed results on the safety of low-dose aspirin in terms of bleeding risk, Kelsey White, MD, a second-year maternal-fetal medicine fellow of the Yale University, New Haven, Conn., told attendees.

This retrospective study compared a bleeding composite endpoint among those who did and did not take low-dose aspirin between January 2018 and April 2021. The composite included an estimated blood loss of greater than 1,000 mL, postpartum hemorrhage based on ICD-9/10 code diagnosis, and red blood cell transfusion. The researchers also compared bleeding risk within the aspirin group based on discontinuation at greater or less than 7 days before delivery.

Among 16,980 patients, 11.3% were prescribed low-dose aspirin. The patients prescribed low-dose aspirin significantly differed from those not prescribed it in all demographic and clinical characteristics except placenta accreta spectrum. The average age of the aspirin group was 39 years, compared with 24 years in the nonaspirin group (P < .01). More of the aspirin group patients were Hispanic and Black, and 52.3% of patients taking aspirin had a body mass index greater than 30 kg/m², compared with 22.9% of the nonaspirin group. Rates of diabetes, lupus, fibroids, nonaspirin anticoagulation use, cesarean delivery, and preterm delivery were all greater in the aspirin group.

In addition, 43.9% of the patients in the aspirin group had a hypertensive disorder, including 20.2% with preeclampsia, compared with 17.1% with hypertensive disorders, including 6.2% with preeclampsia, in the group not taking aspirin (P < .0001). “This shows that a high-risk population was prescribed aspirin, which correlates to the recommended prescription guidelines,” Dr. White said.

The postpartum bleeding composite outcome occurred in 14.7% of patients in the low-dose aspirin group, compared with 9.2% of patients in the nonaspirin group, for an unadjusted 1.7 times greater risk of bleeding (95% confidence interval, 1.49-1.96). After adjustment for confounders, the risk declined and was no longer statistically significant (aOR = 1.15; 95% CI, 0.98-1.34).

Meanwhile, 15% of those who discontinued aspirin within 7 days of delivery had postpartum bleeding, compared with 9% of those who discontinued aspirin at 7 or more days before delivery (P = .03).

Therefore, while the study found only a possible, nonsignificant association between low-dose aspirin and postpartum bleeding, risk of bleeding was significantly greater among those who discontinued aspirin only in the last week before delivery.

”Our study is timely and supports a recent Swedish study [that] found an increased risk of intrapartum bleeding, postpartum hemorrhage, and postpartum hematoma,” Dr. White said. She also noted that the United States Preventive Services Task Force changed their recommendation in 2021 for low-dose aspirin prophylaxis for cardiovascular disease.

“They now recommend against the use of low-dose aspirin for prevention in adults without a history of cardiovascular disease,” Dr. White said. “The change in recommendations came after recent randomized control trials showed that low-dose aspirin had very little benefit and may increase the risk of bleeding.”

However, Dr. White added that they “do not believe this study should be used to make any clinical decisions.” While the study had a large sample size, it was limited by its retrospective reliance on EMR data, including the EMR medication list, and the researchers couldn’t assess patient compliance or patient use of over-the-counter aspirin not recorded in the EMR.

Deirdre Lyell, MD, a professor of maternal-fetal medicine at Stanford (Calif.) University, agreed that the findings should not impact clinical practice given its limitations.

“The investigators could not entirely identify who stopped low-dose aspirin and when. When they estimated timing of stoppage of low-dose aspirin, their data suggested a small benefit among those who discontinued it at least 7 days before delivery, though this should be interpreted with caution, given the potential inaccuracy in these data,” Dr. Lyell, who was not involved in the study, said in an interview. “Their study did not examine factors that should be used to confirm if there are real differences in blood loss, such as changes in blood counts before and after delivery, or more use of medications that we use to stop heavy bleeding.”

In fact, Dr. Lyell noted, other research at the SMFM meeting found ”that low-dose aspirin is not used frequently enough in patients who might benefit, such as those at high risk for preeclampsia,” she said. ”Low-dose aspirin among those at increased risk has been shown to reduce rates of preeclampsia, reducing the likelihood of risky situations for moms and babies.”

The authors had no disclosures. Dr. Lyell has consulted for Bloomlife, a uterine contraction and fetal monitor. Dr. White and Dr. Mei had no disclosures.
 

Low-dose aspirin may increase risk of postpartum bleeding if patients don’t discontinue its use at least 7 days before delivery, but it’s otherwise unclear whether its use increases bleeding risk, according to research presented Feb. 5 at the meeting sponsored by the Society for Maternal-Fetal Medicine.

“These findings were a little surprising to me because we have generally been taught that aspirin is safe to continue up until delivery with minimal risk,” Jenny Mei, MD, a maternal-fetal medicine fellow at the University of California, Los Angeles, said in an interview after attending the presentation. “Theoretically it makes sense that it may increase bleeding risk, but multiple studies in the past analyzing its use with gynecological surgery show minimal risk, which was conferred to the obstetrical population as well.”

She noted, however, that patients prescribed low-dose aspirin already have risk factors that may increase their risk of postpartum bleeding, and the study’s finding of possible increased risk was not statistically significant after accounting for those confounders. “I wouldn’t change my practice management over it, but it does raise awareness that all interventions likely come with some risk,” Dr. Mei said.

Hypertensive disorders of pregnancy are responsible for 6.6% of U.S. pregnancy-related deaths. The SMFM currently recommends low-dose aspirin starting at 12 weeks’ gestation in patients at high risk for preeclampsia, which includes people with multifetal gestation, chronic hypertension, pregestational diabetes, renal disease, autoimmune disease, or a history of preeclampsia. However, previous research has shown mixed results on the safety of low-dose aspirin in terms of bleeding risk, Kelsey White, MD, a second-year maternal-fetal medicine fellow of the Yale University, New Haven, Conn., told attendees.

This retrospective study compared a bleeding composite endpoint among those who did and did not take low-dose aspirin between January 2018 and April 2021. The composite included an estimated blood loss of greater than 1,000 mL, postpartum hemorrhage based on ICD-9/10 code diagnosis, and red blood cell transfusion. The researchers also compared bleeding risk within the aspirin group based on discontinuation at greater or less than 7 days before delivery.

Among 16,980 patients, 11.3% were prescribed low-dose aspirin. The patients prescribed low-dose aspirin significantly differed from those not prescribed it in all demographic and clinical characteristics except placenta accreta spectrum. The average age of the aspirin group was 39 years, compared with 24 years in the nonaspirin group (P < .01). More of the aspirin group patients were Hispanic and Black, and 52.3% of patients taking aspirin had a body mass index greater than 30 kg/m², compared with 22.9% of the nonaspirin group. Rates of diabetes, lupus, fibroids, nonaspirin anticoagulation use, cesarean delivery, and preterm delivery were all greater in the aspirin group.

In addition, 43.9% of the patients in the aspirin group had a hypertensive disorder, including 20.2% with preeclampsia, compared with 17.1% with hypertensive disorders, including 6.2% with preeclampsia, in the group not taking aspirin (P < .0001). “This shows that a high-risk population was prescribed aspirin, which correlates to the recommended prescription guidelines,” Dr. White said.

The postpartum bleeding composite outcome occurred in 14.7% of patients in the low-dose aspirin group, compared with 9.2% of patients in the nonaspirin group, for an unadjusted 1.7 times greater risk of bleeding (95% confidence interval, 1.49-1.96). After adjustment for confounders, the risk declined and was no longer statistically significant (aOR = 1.15; 95% CI, 0.98-1.34).

Meanwhile, 15% of those who discontinued aspirin within 7 days of delivery had postpartum bleeding, compared with 9% of those who discontinued aspirin at 7 or more days before delivery (P = .03).

Therefore, while the study found only a possible, nonsignificant association between low-dose aspirin and postpartum bleeding, risk of bleeding was significantly greater among those who discontinued aspirin only in the last week before delivery.

”Our study is timely and supports a recent Swedish study [that] found an increased risk of intrapartum bleeding, postpartum hemorrhage, and postpartum hematoma,” Dr. White said. She also noted that the United States Preventive Services Task Force changed their recommendation in 2021 for low-dose aspirin prophylaxis for cardiovascular disease.

“They now recommend against the use of low-dose aspirin for prevention in adults without a history of cardiovascular disease,” Dr. White said. “The change in recommendations came after recent randomized control trials showed that low-dose aspirin had very little benefit and may increase the risk of bleeding.”

However, Dr. White added that they “do not believe this study should be used to make any clinical decisions.” While the study had a large sample size, it was limited by its retrospective reliance on EMR data, including the EMR medication list, and the researchers couldn’t assess patient compliance or patient use of over-the-counter aspirin not recorded in the EMR.

Deirdre Lyell, MD, a professor of maternal-fetal medicine at Stanford (Calif.) University, agreed that the findings should not impact clinical practice given its limitations.

“The investigators could not entirely identify who stopped low-dose aspirin and when. When they estimated timing of stoppage of low-dose aspirin, their data suggested a small benefit among those who discontinued it at least 7 days before delivery, though this should be interpreted with caution, given the potential inaccuracy in these data,” Dr. Lyell, who was not involved in the study, said in an interview. “Their study did not examine factors that should be used to confirm if there are real differences in blood loss, such as changes in blood counts before and after delivery, or more use of medications that we use to stop heavy bleeding.”

In fact, Dr. Lyell noted, other research at the SMFM meeting found ”that low-dose aspirin is not used frequently enough in patients who might benefit, such as those at high risk for preeclampsia,” she said. ”Low-dose aspirin among those at increased risk has been shown to reduce rates of preeclampsia, reducing the likelihood of risky situations for moms and babies.”

The authors had no disclosures. Dr. Lyell has consulted for Bloomlife, a uterine contraction and fetal monitor. Dr. White and Dr. Mei had no disclosures.
 

A new, highly-virulent form of the HIV-1 virus has been discovered in the Netherlands by an international collaboration led by researchers at the University of Oxford’s Big Data Institute.

In a study published in the journal Science, researchers identified a VB variant (virulent subtype B) of HIV-1 linked to higher viral loads, increased transmissibility, and a faster decline in CD4 cell levels, leading to increased immune deficiency.

In light of the ongoing pandemic and current focus on SARS-CoV-19 virus variants such as Delta or Omicron, the discovery provides a salutary reminder that other viral pathogens, including those responsible for many long-standing endemic diseases, undergo a similar process of mutation.

Lead author Dr. Chris Wymant said: “Before this study, the genetics of the HIV virus were known to be relevant for virulence, implying that the evolution of a new variant could change its impact on health. Discovery of the VB variant demonstrated this, providing a rare example of the risk posed by viral virulence evolution.”
 

Global disease, local variants

Human immunodeficiency virus (HIV) infections affect around 38 million people worldwide, with more than half a million  people dying from AIDS-related illnesses each year. The disease-causing retroviruses, of which the HIV-1 virus is most common, destroy CD4+ T cells, causing immune deficiency and leading eventually to AIDS.

RNA viruses such as HIV-1 have long been a particular concern to scientists because their error-prone replication, lacking the error-correcting mechanisms of DNA, results in more spontaneous mutations and so a higher potential for acquiring new characteristics.

The VB variant of HIV-1 was first detected in samples from 2,461 HIV-positive people whose viral genomes were sequenced as part of the ongoing BEEHIVE project. Within this cohort, researchers identified 17 people with very highly elevated viral loads.

As 15 of these individuals came from the Netherlands, the researchers next examined virus gene data from 6,706 HIV-positive patients in a Dutch HIV cohort study (ATHENA), identifying a further 92 people carrying the same VB variant.

By analysing patterns of genetic variation in the samples, researchers estimated that the VB variant first emerged in the Netherlands in the late 1990s, occurring through de novo mutations rather than recombination. It spread more quickly than other HIV variants initially, but cases have been declining since around 2010, most likely due to the availability of more effective combination anti-retroviral treatments.
 

Increased virulence

The researchers found a number of differences in people infected with the VB variant compared with those infected by other HIV variants. Prior to starting anti-retroviral treatment, individuals with the VB variant were found to have:

Around a 3.5- to 5.5-fold increase in viral load (a marker for viral virulence)

Double the rate of CD4 cell decline compared with individuals with other subtype-B strains, even after adjusting for viral load

Increased risk of transmitting the virus (the study used the virus ‘local branching index’ as a proxy for transmissibility).

Reassuringly, after starting anti-retroviral treatment, individuals with the VB variant showed similar CD4 cell recovery and survival to individuals with other HIV variants. However, the authors emphasise that due of the more rapid decline in immune function with the VB variant, it is critical to identify VB-positive individuals early and start treatment promptly.

Senior author Professor Christophe Fraser explained: “Our findings emphasise the importance of World Health Organization guidance that individuals at risk of acquiring HIV have access to regular testing to allow early diagnosis, followed by immediate treatment.

“This limits the amount of time HIV can damage an individual’s immune system and jeopardise their health. It also ensures that HIV is suppressed as quickly as possible, which prevents transmission to other individuals.”

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

A new, highly-virulent form of the HIV-1 virus has been discovered in the Netherlands by an international collaboration led by researchers at the University of Oxford’s Big Data Institute.

In a study published in the journal Science, researchers identified a VB variant (virulent subtype B) of HIV-1 linked to higher viral loads, increased transmissibility, and a faster decline in CD4 cell levels, leading to increased immune deficiency.

In light of the ongoing pandemic and current focus on SARS-CoV-19 virus variants such as Delta or Omicron, the discovery provides a salutary reminder that other viral pathogens, including those responsible for many long-standing endemic diseases, undergo a similar process of mutation.

Lead author Dr. Chris Wymant said: “Before this study, the genetics of the HIV virus were known to be relevant for virulence, implying that the evolution of a new variant could change its impact on health. Discovery of the VB variant demonstrated this, providing a rare example of the risk posed by viral virulence evolution.”
 

Global disease, local variants

Human immunodeficiency virus (HIV) infections affect around 38 million people worldwide, with more than half a million  people dying from AIDS-related illnesses each year. The disease-causing retroviruses, of which the HIV-1 virus is most common, destroy CD4+ T cells, causing immune deficiency and leading eventually to AIDS.

RNA viruses such as HIV-1 have long been a particular concern to scientists because their error-prone replication, lacking the error-correcting mechanisms of DNA, results in more spontaneous mutations and so a higher potential for acquiring new characteristics.

The VB variant of HIV-1 was first detected in samples from 2,461 HIV-positive people whose viral genomes were sequenced as part of the ongoing BEEHIVE project. Within this cohort, researchers identified 17 people with very highly elevated viral loads.

As 15 of these individuals came from the Netherlands, the researchers next examined virus gene data from 6,706 HIV-positive patients in a Dutch HIV cohort study (ATHENA), identifying a further 92 people carrying the same VB variant.

By analysing patterns of genetic variation in the samples, researchers estimated that the VB variant first emerged in the Netherlands in the late 1990s, occurring through de novo mutations rather than recombination. It spread more quickly than other HIV variants initially, but cases have been declining since around 2010, most likely due to the availability of more effective combination anti-retroviral treatments.
 

Increased virulence

The researchers found a number of differences in people infected with the VB variant compared with those infected by other HIV variants. Prior to starting anti-retroviral treatment, individuals with the VB variant were found to have:

Around a 3.5- to 5.5-fold increase in viral load (a marker for viral virulence)

Double the rate of CD4 cell decline compared with individuals with other subtype-B strains, even after adjusting for viral load

Increased risk of transmitting the virus (the study used the virus ‘local branching index’ as a proxy for transmissibility).

Reassuringly, after starting anti-retroviral treatment, individuals with the VB variant showed similar CD4 cell recovery and survival to individuals with other HIV variants. However, the authors emphasise that due of the more rapid decline in immune function with the VB variant, it is critical to identify VB-positive individuals early and start treatment promptly.

Senior author Professor Christophe Fraser explained: “Our findings emphasise the importance of World Health Organization guidance that individuals at risk of acquiring HIV have access to regular testing to allow early diagnosis, followed by immediate treatment.

“This limits the amount of time HIV can damage an individual’s immune system and jeopardise their health. It also ensures that HIV is suppressed as quickly as possible, which prevents transmission to other individuals.”

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

A new, highly-virulent form of the HIV-1 virus has been discovered in the Netherlands by an international collaboration led by researchers at the University of Oxford’s Big Data Institute.

In a study published in the journal Science, researchers identified a VB variant (virulent subtype B) of HIV-1 linked to higher viral loads, increased transmissibility, and a faster decline in CD4 cell levels, leading to increased immune deficiency.

In light of the ongoing pandemic and current focus on SARS-CoV-19 virus variants such as Delta or Omicron, the discovery provides a salutary reminder that other viral pathogens, including those responsible for many long-standing endemic diseases, undergo a similar process of mutation.

Lead author Dr. Chris Wymant said: “Before this study, the genetics of the HIV virus were known to be relevant for virulence, implying that the evolution of a new variant could change its impact on health. Discovery of the VB variant demonstrated this, providing a rare example of the risk posed by viral virulence evolution.”
 

Global disease, local variants

Human immunodeficiency virus (HIV) infections affect around 38 million people worldwide, with more than half a million  people dying from AIDS-related illnesses each year. The disease-causing retroviruses, of which the HIV-1 virus is most common, destroy CD4+ T cells, causing immune deficiency and leading eventually to AIDS.

RNA viruses such as HIV-1 have long been a particular concern to scientists because their error-prone replication, lacking the error-correcting mechanisms of DNA, results in more spontaneous mutations and so a higher potential for acquiring new characteristics.

The VB variant of HIV-1 was first detected in samples from 2,461 HIV-positive people whose viral genomes were sequenced as part of the ongoing BEEHIVE project. Within this cohort, researchers identified 17 people with very highly elevated viral loads.

As 15 of these individuals came from the Netherlands, the researchers next examined virus gene data from 6,706 HIV-positive patients in a Dutch HIV cohort study (ATHENA), identifying a further 92 people carrying the same VB variant.

By analysing patterns of genetic variation in the samples, researchers estimated that the VB variant first emerged in the Netherlands in the late 1990s, occurring through de novo mutations rather than recombination. It spread more quickly than other HIV variants initially, but cases have been declining since around 2010, most likely due to the availability of more effective combination anti-retroviral treatments.
 

Increased virulence

The researchers found a number of differences in people infected with the VB variant compared with those infected by other HIV variants. Prior to starting anti-retroviral treatment, individuals with the VB variant were found to have:

Around a 3.5- to 5.5-fold increase in viral load (a marker for viral virulence)

Double the rate of CD4 cell decline compared with individuals with other subtype-B strains, even after adjusting for viral load

Increased risk of transmitting the virus (the study used the virus ‘local branching index’ as a proxy for transmissibility).

Reassuringly, after starting anti-retroviral treatment, individuals with the VB variant showed similar CD4 cell recovery and survival to individuals with other HIV variants. However, the authors emphasise that due of the more rapid decline in immune function with the VB variant, it is critical to identify VB-positive individuals early and start treatment promptly.

Senior author Professor Christophe Fraser explained: “Our findings emphasise the importance of World Health Organization guidance that individuals at risk of acquiring HIV have access to regular testing to allow early diagnosis, followed by immediate treatment.

“This limits the amount of time HIV can damage an individual’s immune system and jeopardise their health. It also ensures that HIV is suppressed as quickly as possible, which prevents transmission to other individuals.”

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

Samples from patients in the United States and Kenya show an increasing emergence of previously undetected vancomycin-resistant strains of Clostridioides difficile, sparking concern as recurrences in the treatment of C. difficile infection (CDI) continue to rise.

“Our results may help explain a decreasing effectiveness of antibiotic-based therapy in C. difficile infection, since a significant proportion of patients harboring strains with reduced susceptibility to vancomycin may not respond to treatment,” reported the authors in research published recently in Clinical Infectious Diseases.

The spread of the resistant strains “has serious public health implications, underscoring an urgent need for a comprehensive analysis of the circulating strains to help inform clinical decisions,” they added.

Commenting on the findings, Cornelius J. Clancy, MD, professor of medicine at the University of Pittsburgh, and chief of infectious diseases at the Veterans Affairs Pittsburgh Healthcare System, echoed the concern.

“The casual belief has been that [C. difficile] strains at most centers can be assumed to be vancomycin susceptible,” he told this news organization. “This study shows that this assumption can no longer be taken as a given.”

Dr. Clancy, who was not involved with this research, noted that “based on this study, there might be need for the Infectious Diseases Society of America and other organizations to offer guidance on generating good, quality surveillance data for C. difficile resistance.”

With C. difficile showing the ability to resist multiple antibiotics, drugs in the armamentarium to treat the infection have declined in recent years, and recurrences with the infection are reported in up to 25% of cases.

Oral vancomycin is recommended as the antibiotic of choice by the IDSA and the Society for Healthcare Epidemiology of America for severe as well as nonsevere cases of CDI, and although there are reports of nine vancomycin-resistant gene clusters, most involve Enterococcus.

To take a closer look at the prevalence of vancomycin-resistant C. difficile strains, first author Charles Darkoh, PhD, with the Center for Infectious Diseases at the University of Texas Health Science Center, Houston, and colleagues analyzed stool samples from patients with CDI, including 438 patients in Houston, taken between 2012 and 2017, and 98 in Nairobi, Kenya, taken in 2017.

They found that, among samples from patients in Houston, over the time period, 26% showed vancomycin nonsusceptible C. difficile isolates and 29% had isolates that were metronidazole resistant.

And among samples from the Nairobi patients, 67% harbored vancomycin-resistant isolates and 85% had isolates resistant to metronidazole.

Of note, the proportion of samples containing vancomycin-resistant C. difficile in the Houston patients showed a marked increase over time, from «complete absence» in 2012 to approximately 35% in 2017, the authors reported.

“These nonsusceptibility rates significantly exceeded prior reports from other studies conducted in the United States and Europe from 2011 to 2014, suggesting a lower percentage of resistance to both metronidazole and vancomycin,” the authors wrote.

Further experiments on mouse models infected with one of the vancomycin-resistant isolates showed that treatment with vancomycin failed to eradicate the infection, and 5-day survival was significantly lower after vancomycin treatment in those mice (25%) versus those infected with strains known to be vancomycin sensitive (50%).
 

Unrecognized genetic strains

Whole-genome sequencing of 10 of the resistant isolates showed no matches with gene clusters that have been previously recognized as being vancomycin resistant, suggesting the emergence of new clusters.

“Together, these results suggest unknown genetic elements associated with vancomycin nonsusceptibility in isolates circulating in the patient population,” the authors wrote.

Dr. Darkoh told this news organization that the research team is currently working to further investigate the patterns and mechanisms.

“We are currently working on a follow-up study for the next 5 years to find out how widespread this is,” he said. “We want to make sure it’s not necessarily just occurring in the settings we studied, and we also need to establish the mechanism of resistance.”

Further commenting on the results, Dr. Clancy noted that “the extent of resistance caught many in the field a bit off guard, as they are higher than previously reported.”

“The data are also concerning because most centers do not routinely test C. difficile for drug susceptibility.”

Dr. Clancy noted that “another immediately pressing need is to understand mechanisms of resistance. It was quite striking that vancomycin-resistant strains in this study did not carry vanA genes, pointing to previously unrecognized mechanisms of resistance.”

“As is often the case, antibiotic overuse was likely a factor in the resistances, with overtesting often leading to overtreatment of C. difficile,” Dr. Clancy said. “The situation may have been compounded by failure to appreciate how entrenched C. difficile resistance may be at certain hospitals, since widespread susceptibility testing is generally not routinely performed.”

As alternative treatments, Dr. Clancy pointed to the recent IDSA update, which included a stronger endorsement of fidaxomicin.

“Of course, there is also the need to assure that data on resistance to agents like fidaxomicin are generated going forward,” he noted.

The study was supported by was supported by National Institutes of Health, the National Institute of Allergy and Infectious Diseases, the Texas Medical Center Digestive Diseases Center, and the University of Texas Health Science Center. Dr. Darkoh has disclosed no relevant financial relationships. One coauthor received grant support from Merck, Entasis Pharmaceuticals, and MeMed Diagnostics. Dr. Clancy disclosed advisory board, consulting and/or research relationships with Merck, Qpex Biopharma, Shionogi, Astellas, Cidara, Scynexis, and Needham & Associates.

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

Samples from patients in the United States and Kenya show an increasing emergence of previously undetected vancomycin-resistant strains of Clostridioides difficile, sparking concern as recurrences in the treatment of C. difficile infection (CDI) continue to rise.

“Our results may help explain a decreasing effectiveness of antibiotic-based therapy in C. difficile infection, since a significant proportion of patients harboring strains with reduced susceptibility to vancomycin may not respond to treatment,” reported the authors in research published recently in Clinical Infectious Diseases.

The spread of the resistant strains “has serious public health implications, underscoring an urgent need for a comprehensive analysis of the circulating strains to help inform clinical decisions,” they added.

Commenting on the findings, Cornelius J. Clancy, MD, professor of medicine at the University of Pittsburgh, and chief of infectious diseases at the Veterans Affairs Pittsburgh Healthcare System, echoed the concern.

“The casual belief has been that [C. difficile] strains at most centers can be assumed to be vancomycin susceptible,” he told this news organization. “This study shows that this assumption can no longer be taken as a given.”

Dr. Clancy, who was not involved with this research, noted that “based on this study, there might be need for the Infectious Diseases Society of America and other organizations to offer guidance on generating good, quality surveillance data for C. difficile resistance.”

With C. difficile showing the ability to resist multiple antibiotics, drugs in the armamentarium to treat the infection have declined in recent years, and recurrences with the infection are reported in up to 25% of cases.

Oral vancomycin is recommended as the antibiotic of choice by the IDSA and the Society for Healthcare Epidemiology of America for severe as well as nonsevere cases of CDI, and although there are reports of nine vancomycin-resistant gene clusters, most involve Enterococcus.

To take a closer look at the prevalence of vancomycin-resistant C. difficile strains, first author Charles Darkoh, PhD, with the Center for Infectious Diseases at the University of Texas Health Science Center, Houston, and colleagues analyzed stool samples from patients with CDI, including 438 patients in Houston, taken between 2012 and 2017, and 98 in Nairobi, Kenya, taken in 2017.

They found that, among samples from patients in Houston, over the time period, 26% showed vancomycin nonsusceptible C. difficile isolates and 29% had isolates that were metronidazole resistant.

And among samples from the Nairobi patients, 67% harbored vancomycin-resistant isolates and 85% had isolates resistant to metronidazole.

Of note, the proportion of samples containing vancomycin-resistant C. difficile in the Houston patients showed a marked increase over time, from «complete absence» in 2012 to approximately 35% in 2017, the authors reported.

“These nonsusceptibility rates significantly exceeded prior reports from other studies conducted in the United States and Europe from 2011 to 2014, suggesting a lower percentage of resistance to both metronidazole and vancomycin,” the authors wrote.

Further experiments on mouse models infected with one of the vancomycin-resistant isolates showed that treatment with vancomycin failed to eradicate the infection, and 5-day survival was significantly lower after vancomycin treatment in those mice (25%) versus those infected with strains known to be vancomycin sensitive (50%).
 

Unrecognized genetic strains

Whole-genome sequencing of 10 of the resistant isolates showed no matches with gene clusters that have been previously recognized as being vancomycin resistant, suggesting the emergence of new clusters.

“Together, these results suggest unknown genetic elements associated with vancomycin nonsusceptibility in isolates circulating in the patient population,” the authors wrote.

Dr. Darkoh told this news organization that the research team is currently working to further investigate the patterns and mechanisms.

“We are currently working on a follow-up study for the next 5 years to find out how widespread this is,” he said. “We want to make sure it’s not necessarily just occurring in the settings we studied, and we also need to establish the mechanism of resistance.”

Further commenting on the results, Dr. Clancy noted that “the extent of resistance caught many in the field a bit off guard, as they are higher than previously reported.”

“The data are also concerning because most centers do not routinely test C. difficile for drug susceptibility.”

Dr. Clancy noted that “another immediately pressing need is to understand mechanisms of resistance. It was quite striking that vancomycin-resistant strains in this study did not carry vanA genes, pointing to previously unrecognized mechanisms of resistance.”

“As is often the case, antibiotic overuse was likely a factor in the resistances, with overtesting often leading to overtreatment of C. difficile,” Dr. Clancy said. “The situation may have been compounded by failure to appreciate how entrenched C. difficile resistance may be at certain hospitals, since widespread susceptibility testing is generally not routinely performed.”

As alternative treatments, Dr. Clancy pointed to the recent IDSA update, which included a stronger endorsement of fidaxomicin.

“Of course, there is also the need to assure that data on resistance to agents like fidaxomicin are generated going forward,” he noted.

The study was supported by was supported by National Institutes of Health, the National Institute of Allergy and Infectious Diseases, the Texas Medical Center Digestive Diseases Center, and the University of Texas Health Science Center. Dr. Darkoh has disclosed no relevant financial relationships. One coauthor received grant support from Merck, Entasis Pharmaceuticals, and MeMed Diagnostics. Dr. Clancy disclosed advisory board, consulting and/or research relationships with Merck, Qpex Biopharma, Shionogi, Astellas, Cidara, Scynexis, and Needham & Associates.

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

Samples from patients in the United States and Kenya show an increasing emergence of previously undetected vancomycin-resistant strains of Clostridioides difficile, sparking concern as recurrences in the treatment of C. difficile infection (CDI) continue to rise.

“Our results may help explain a decreasing effectiveness of antibiotic-based therapy in C. difficile infection, since a significant proportion of patients harboring strains with reduced susceptibility to vancomycin may not respond to treatment,” reported the authors in research published recently in Clinical Infectious Diseases.

The spread of the resistant strains “has serious public health implications, underscoring an urgent need for a comprehensive analysis of the circulating strains to help inform clinical decisions,” they added.

Commenting on the findings, Cornelius J. Clancy, MD, professor of medicine at the University of Pittsburgh, and chief of infectious diseases at the Veterans Affairs Pittsburgh Healthcare System, echoed the concern.

“The casual belief has been that [C. difficile] strains at most centers can be assumed to be vancomycin susceptible,” he told this news organization. “This study shows that this assumption can no longer be taken as a given.”

Dr. Clancy, who was not involved with this research, noted that “based on this study, there might be need for the Infectious Diseases Society of America and other organizations to offer guidance on generating good, quality surveillance data for C. difficile resistance.”

With C. difficile showing the ability to resist multiple antibiotics, drugs in the armamentarium to treat the infection have declined in recent years, and recurrences with the infection are reported in up to 25% of cases.

Oral vancomycin is recommended as the antibiotic of choice by the IDSA and the Society for Healthcare Epidemiology of America for severe as well as nonsevere cases of CDI, and although there are reports of nine vancomycin-resistant gene clusters, most involve Enterococcus.

To take a closer look at the prevalence of vancomycin-resistant C. difficile strains, first author Charles Darkoh, PhD, with the Center for Infectious Diseases at the University of Texas Health Science Center, Houston, and colleagues analyzed stool samples from patients with CDI, including 438 patients in Houston, taken between 2012 and 2017, and 98 in Nairobi, Kenya, taken in 2017.

They found that, among samples from patients in Houston, over the time period, 26% showed vancomycin nonsusceptible C. difficile isolates and 29% had isolates that were metronidazole resistant.

And among samples from the Nairobi patients, 67% harbored vancomycin-resistant isolates and 85% had isolates resistant to metronidazole.

Of note, the proportion of samples containing vancomycin-resistant C. difficile in the Houston patients showed a marked increase over time, from «complete absence» in 2012 to approximately 35% in 2017, the authors reported.

“These nonsusceptibility rates significantly exceeded prior reports from other studies conducted in the United States and Europe from 2011 to 2014, suggesting a lower percentage of resistance to both metronidazole and vancomycin,” the authors wrote.

Further experiments on mouse models infected with one of the vancomycin-resistant isolates showed that treatment with vancomycin failed to eradicate the infection, and 5-day survival was significantly lower after vancomycin treatment in those mice (25%) versus those infected with strains known to be vancomycin sensitive (50%).
 

Unrecognized genetic strains

Whole-genome sequencing of 10 of the resistant isolates showed no matches with gene clusters that have been previously recognized as being vancomycin resistant, suggesting the emergence of new clusters.

“Together, these results suggest unknown genetic elements associated with vancomycin nonsusceptibility in isolates circulating in the patient population,” the authors wrote.

Dr. Darkoh told this news organization that the research team is currently working to further investigate the patterns and mechanisms.

“We are currently working on a follow-up study for the next 5 years to find out how widespread this is,” he said. “We want to make sure it’s not necessarily just occurring in the settings we studied, and we also need to establish the mechanism of resistance.”

Further commenting on the results, Dr. Clancy noted that “the extent of resistance caught many in the field a bit off guard, as they are higher than previously reported.”

“The data are also concerning because most centers do not routinely test C. difficile for drug susceptibility.”

Dr. Clancy noted that “another immediately pressing need is to understand mechanisms of resistance. It was quite striking that vancomycin-resistant strains in this study did not carry vanA genes, pointing to previously unrecognized mechanisms of resistance.”

“As is often the case, antibiotic overuse was likely a factor in the resistances, with overtesting often leading to overtreatment of C. difficile,” Dr. Clancy said. “The situation may have been compounded by failure to appreciate how entrenched C. difficile resistance may be at certain hospitals, since widespread susceptibility testing is generally not routinely performed.”

As alternative treatments, Dr. Clancy pointed to the recent IDSA update, which included a stronger endorsement of fidaxomicin.

“Of course, there is also the need to assure that data on resistance to agents like fidaxomicin are generated going forward,” he noted.

The study was supported by was supported by National Institutes of Health, the National Institute of Allergy and Infectious Diseases, the Texas Medical Center Digestive Diseases Center, and the University of Texas Health Science Center. Dr. Darkoh has disclosed no relevant financial relationships. One coauthor received grant support from Merck, Entasis Pharmaceuticals, and MeMed Diagnostics. Dr. Clancy disclosed advisory board, consulting and/or research relationships with Merck, Qpex Biopharma, Shionogi, Astellas, Cidara, Scynexis, and Needham & Associates.

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

A new drug has become the first and only treatment for people with cold agglutinin disease (CAD) that is approved by the U.S. Food and Drug Administration.

CAD is a rare autoimmune hemolytic anemia, affecting about 5,000 people in the United States. It is caused by antibodies binding to the surface of red blood cells, which starts a process that causes the body’s immune system to mistakenly attack healthy red blood cells and cause their rupture (hemolysis). This can lead to severe anemia, which is often treated by blood transfusions.

The new product is sutimlimab-jome (Enjaymo), and it works by inhibiting the destruction of red blood cells and so decreases the need for blood transfusions.

“For people living with cold agglutinin disease, it is as if their body’s immune system is waging a war on itself. The relentless destruction of healthy red blood cells is a daily, silent reality for people with CAD. For the first time, we have a treatment that targets complement-mediated hemolysis, which is the underlying cause of the red blood cell destruction in many CAD patients,” commented Catherine Broome, MD, associate professor of medicine at Georgetown University Lombardi Comprehensive Cancer Center, in a company press release.

Dr. Broome was the principal investigator in the CARDINAL study, which was the basis for the new approval. In this pivotal study, patients treated with sutimlimab had an improvement in anemia as measured by hemoglobin (Hgb) and bilirubin levels, she commented in the company statement.

The CARDINAL study was a 26-week open-label, single-arm phase 3 study conducted in 24 patients with CAD who had recent history of blood transfusion.

The primary efficacy endpoint was a composite defined as the proportion of patients who achieved normalization of Hgb level greater than or equal to 12 g/dL or demonstrated an increase from baseline in Hgb level greater than or equal to 2 g/dL at the treatment assessment time point (mean value from weeks 23, 25, and 26) and no blood transfusion from weeks 5 through 26.

More than half of the patients (13 of 24, 54%) met the composite primary endpoint criteria, with 17 of 24 (71%) patients remaining transfusion-free after week 5. Most patients (22 of 24, 92%) did not use other CAD-related treatments.

For the secondary measures on disease process, patients enrolled in the trial experienced a mean increase in Hgb level of 2.29 g/dL at week 3 and 3.18 g/dL at the 26-week treatment assessment time points (increasing from the mean baseline level of 8.6 g/dL). In addition, there was a mean reduction in bilirubin levels (n = 14) of -2.23 mg/dL from a mean baseline level of 3.23 mg/dL.

The most common adverse reactions occurring in 10% or more of patients were respiratory tract infection, viral infection, diarrhea, dyspepsia, cough, arthralgia, arthritis, and peripheral edema. Serious adverse reactions were reported in 3 of 24 (13%) patients, and these included streptococcal sepsis and staphylococcal wound infection (n = 1), arthralgia (n = 1), and respiratory tract infection (n = 1).

None of the adverse reactions led to discontinuation of the drug, the company noted. Dosage interruptions due to an adverse reaction occurred in 4 of 24 (17%) patients who received the drug.

The recommended dose is based on body weight (6,500 mg for people 39-75 kg and 7,500 mg for people greater than 75 kg). The drug is administered intravenously weekly for the first 2 weeks with administration every 2 weeks thereafter.

Full prescribing information is available here.

The product is a humanized monoclonal antibody that is designed to selectively target and inhibit C1s in the classical complement pathway, which is part of the innate immune system. By blocking C1s, Enjaymo inhibits the activation of the complement cascade in the immune system and inhibits C1-activated hemolysis in CAD to prevent the abnormal destruction of healthy red blood cells. Enjaymo does not inhibit the lectin and alternative pathways, the company noted.

In the U.S., Enjaymo received FDA breakthrough therapy and orphan drug designation, as well as priority review. The product is awaiting approval in Europe and Japan.

Sanofi says the product is expected to be available in the United States in the coming weeks, with a list price, or wholesale acquisition cost, of $1,800 per vial. Actual costs to patients are generally anticipated to be lower, as the list price does not reflect insurance coverage, copay support, or financial assistance from patient support programs. The company offers support for eligible patients on 1-833-223-2428.

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

A new drug has become the first and only treatment for people with cold agglutinin disease (CAD) that is approved by the U.S. Food and Drug Administration.

CAD is a rare autoimmune hemolytic anemia, affecting about 5,000 people in the United States. It is caused by antibodies binding to the surface of red blood cells, which starts a process that causes the body’s immune system to mistakenly attack healthy red blood cells and cause their rupture (hemolysis). This can lead to severe anemia, which is often treated by blood transfusions.

The new product is sutimlimab-jome (Enjaymo), and it works by inhibiting the destruction of red blood cells and so decreases the need for blood transfusions.

“For people living with cold agglutinin disease, it is as if their body’s immune system is waging a war on itself. The relentless destruction of healthy red blood cells is a daily, silent reality for people with CAD. For the first time, we have a treatment that targets complement-mediated hemolysis, which is the underlying cause of the red blood cell destruction in many CAD patients,” commented Catherine Broome, MD, associate professor of medicine at Georgetown University Lombardi Comprehensive Cancer Center, in a company press release.

Dr. Broome was the principal investigator in the CARDINAL study, which was the basis for the new approval. In this pivotal study, patients treated with sutimlimab had an improvement in anemia as measured by hemoglobin (Hgb) and bilirubin levels, she commented in the company statement.

The CARDINAL study was a 26-week open-label, single-arm phase 3 study conducted in 24 patients with CAD who had recent history of blood transfusion.

The primary efficacy endpoint was a composite defined as the proportion of patients who achieved normalization of Hgb level greater than or equal to 12 g/dL or demonstrated an increase from baseline in Hgb level greater than or equal to 2 g/dL at the treatment assessment time point (mean value from weeks 23, 25, and 26) and no blood transfusion from weeks 5 through 26.

More than half of the patients (13 of 24, 54%) met the composite primary endpoint criteria, with 17 of 24 (71%) patients remaining transfusion-free after week 5. Most patients (22 of 24, 92%) did not use other CAD-related treatments.

For the secondary measures on disease process, patients enrolled in the trial experienced a mean increase in Hgb level of 2.29 g/dL at week 3 and 3.18 g/dL at the 26-week treatment assessment time points (increasing from the mean baseline level of 8.6 g/dL). In addition, there was a mean reduction in bilirubin levels (n = 14) of -2.23 mg/dL from a mean baseline level of 3.23 mg/dL.

The most common adverse reactions occurring in 10% or more of patients were respiratory tract infection, viral infection, diarrhea, dyspepsia, cough, arthralgia, arthritis, and peripheral edema. Serious adverse reactions were reported in 3 of 24 (13%) patients, and these included streptococcal sepsis and staphylococcal wound infection (n = 1), arthralgia (n = 1), and respiratory tract infection (n = 1).

None of the adverse reactions led to discontinuation of the drug, the company noted. Dosage interruptions due to an adverse reaction occurred in 4 of 24 (17%) patients who received the drug.

The recommended dose is based on body weight (6,500 mg for people 39-75 kg and 7,500 mg for people greater than 75 kg). The drug is administered intravenously weekly for the first 2 weeks with administration every 2 weeks thereafter.

Full prescribing information is available here.

The product is a humanized monoclonal antibody that is designed to selectively target and inhibit C1s in the classical complement pathway, which is part of the innate immune system. By blocking C1s, Enjaymo inhibits the activation of the complement cascade in the immune system and inhibits C1-activated hemolysis in CAD to prevent the abnormal destruction of healthy red blood cells. Enjaymo does not inhibit the lectin and alternative pathways, the company noted.

In the U.S., Enjaymo received FDA breakthrough therapy and orphan drug designation, as well as priority review. The product is awaiting approval in Europe and Japan.

Sanofi says the product is expected to be available in the United States in the coming weeks, with a list price, or wholesale acquisition cost, of $1,800 per vial. Actual costs to patients are generally anticipated to be lower, as the list price does not reflect insurance coverage, copay support, or financial assistance from patient support programs. The company offers support for eligible patients on 1-833-223-2428.

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

A new drug has become the first and only treatment for people with cold agglutinin disease (CAD) that is approved by the U.S. Food and Drug Administration.

CAD is a rare autoimmune hemolytic anemia, affecting about 5,000 people in the United States. It is caused by antibodies binding to the surface of red blood cells, which starts a process that causes the body’s immune system to mistakenly attack healthy red blood cells and cause their rupture (hemolysis). This can lead to severe anemia, which is often treated by blood transfusions.

The new product is sutimlimab-jome (Enjaymo), and it works by inhibiting the destruction of red blood cells and so decreases the need for blood transfusions.

“For people living with cold agglutinin disease, it is as if their body’s immune system is waging a war on itself. The relentless destruction of healthy red blood cells is a daily, silent reality for people with CAD. For the first time, we have a treatment that targets complement-mediated hemolysis, which is the underlying cause of the red blood cell destruction in many CAD patients,” commented Catherine Broome, MD, associate professor of medicine at Georgetown University Lombardi Comprehensive Cancer Center, in a company press release.

Dr. Broome was the principal investigator in the CARDINAL study, which was the basis for the new approval. In this pivotal study, patients treated with sutimlimab had an improvement in anemia as measured by hemoglobin (Hgb) and bilirubin levels, she commented in the company statement.

The CARDINAL study was a 26-week open-label, single-arm phase 3 study conducted in 24 patients with CAD who had recent history of blood transfusion.

The primary efficacy endpoint was a composite defined as the proportion of patients who achieved normalization of Hgb level greater than or equal to 12 g/dL or demonstrated an increase from baseline in Hgb level greater than or equal to 2 g/dL at the treatment assessment time point (mean value from weeks 23, 25, and 26) and no blood transfusion from weeks 5 through 26.

More than half of the patients (13 of 24, 54%) met the composite primary endpoint criteria, with 17 of 24 (71%) patients remaining transfusion-free after week 5. Most patients (22 of 24, 92%) did not use other CAD-related treatments.

For the secondary measures on disease process, patients enrolled in the trial experienced a mean increase in Hgb level of 2.29 g/dL at week 3 and 3.18 g/dL at the 26-week treatment assessment time points (increasing from the mean baseline level of 8.6 g/dL). In addition, there was a mean reduction in bilirubin levels (n = 14) of -2.23 mg/dL from a mean baseline level of 3.23 mg/dL.

The most common adverse reactions occurring in 10% or more of patients were respiratory tract infection, viral infection, diarrhea, dyspepsia, cough, arthralgia, arthritis, and peripheral edema. Serious adverse reactions were reported in 3 of 24 (13%) patients, and these included streptococcal sepsis and staphylococcal wound infection (n = 1), arthralgia (n = 1), and respiratory tract infection (n = 1).

None of the adverse reactions led to discontinuation of the drug, the company noted. Dosage interruptions due to an adverse reaction occurred in 4 of 24 (17%) patients who received the drug.

The recommended dose is based on body weight (6,500 mg for people 39-75 kg and 7,500 mg for people greater than 75 kg). The drug is administered intravenously weekly for the first 2 weeks with administration every 2 weeks thereafter.

Full prescribing information is available here.

The product is a humanized monoclonal antibody that is designed to selectively target and inhibit C1s in the classical complement pathway, which is part of the innate immune system. By blocking C1s, Enjaymo inhibits the activation of the complement cascade in the immune system and inhibits C1-activated hemolysis in CAD to prevent the abnormal destruction of healthy red blood cells. Enjaymo does not inhibit the lectin and alternative pathways, the company noted.

In the U.S., Enjaymo received FDA breakthrough therapy and orphan drug designation, as well as priority review. The product is awaiting approval in Europe and Japan.

Sanofi says the product is expected to be available in the United States in the coming weeks, with a list price, or wholesale acquisition cost, of $1,800 per vial. Actual costs to patients are generally anticipated to be lower, as the list price does not reflect insurance coverage, copay support, or financial assistance from patient support programs. The company offers support for eligible patients on 1-833-223-2428.

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

Bronchiolitis is the leading cause of infant hospitalizations in the United States and Europe, and almost one-third of these patients go on to develop asthma later in childhood.

But a multinational team of researchers has presented evidence that could avoid that outcome. They identified four different subtypes of bronchiolitis along with a decision tree that can determine which infants are most likely to develop asthma as they get older.

Reporting in the journal eClinical Medicine, Michimasa Fujiogi, MD, of Massachusetts General Hospital and Harvard University, Boston, and colleagues analyzed three multicenter prospective cohort studies that included a combined 3,081 infants hospitalized with severe bronchiolitis.

“This study added a base for the early identification of high-risk patients during early infancy,” Dr. Fujiogi said in an interview. “Using the prediction rule of this study, it is possible to identify groups at high risk of asthma during a critical period of airway development – early infancy.”

The researchers identified four clinically distinct and reproducible profiles of infants hospitalized for bronchiolitis:

• A: characterized by a history of breathing problems and eczema, rhinovirus infection, and low prevalence of respiratory syncytial virus (RSV) infection.
• B: characterized by the classic symptoms of wheezing and cough at presentation, a low prevalence of previous breathing problems and rhinovirus infection, and a high likelihood of RSV infection.
• C: the most severe group, characterized by inadequate oral intake, severe retraction at presentation, and longer hospital stays.
• D: the least ill group, with little history of breathing problems but inadequate oral intake with no or mild retraction.

Infants with profile A had the highest risk for developing asthma – more than 250% greater than with typical bronchiolitis. They were also older and were more likely to have parents who had asthma – and none had solo-RSV infection. In the overall analysis, the risk for developing asthma by age 6 or 7 was 23%.

The researchers stated that the decision tree accurately predicts the high-risk profile with high degrees of sensitivity and specificity. The decision tree used four predictors that together defined infants with profile A: RSV infection status, previous breathing problems, eczema, and parental asthma.

“Our data would facilitate the development of profile-specific prevention strategies for asthma – for example, modification of host response, prophylaxis for severe viral infection – by identifying asthma risk groups early in infancy,” Dr. Fujiogi said.

The study received funding from the National Institutes of Health. Dr. Fujiogi and coauthors have disclosed no relevant financial relationships.

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

Bronchiolitis is the leading cause of infant hospitalizations in the United States and Europe, and almost one-third of these patients go on to develop asthma later in childhood.

But a multinational team of researchers has presented evidence that could avoid that outcome. They identified four different subtypes of bronchiolitis along with a decision tree that can determine which infants are most likely to develop asthma as they get older.

Reporting in the journal eClinical Medicine, Michimasa Fujiogi, MD, of Massachusetts General Hospital and Harvard University, Boston, and colleagues analyzed three multicenter prospective cohort studies that included a combined 3,081 infants hospitalized with severe bronchiolitis.

“This study added a base for the early identification of high-risk patients during early infancy,” Dr. Fujiogi said in an interview. “Using the prediction rule of this study, it is possible to identify groups at high risk of asthma during a critical period of airway development – early infancy.”

The researchers identified four clinically distinct and reproducible profiles of infants hospitalized for bronchiolitis:

• A: characterized by a history of breathing problems and eczema, rhinovirus infection, and low prevalence of respiratory syncytial virus (RSV) infection.
• B: characterized by the classic symptoms of wheezing and cough at presentation, a low prevalence of previous breathing problems and rhinovirus infection, and a high likelihood of RSV infection.
• C: the most severe group, characterized by inadequate oral intake, severe retraction at presentation, and longer hospital stays.
• D: the least ill group, with little history of breathing problems but inadequate oral intake with no or mild retraction.

Infants with profile A had the highest risk for developing asthma – more than 250% greater than with typical bronchiolitis. They were also older and were more likely to have parents who had asthma – and none had solo-RSV infection. In the overall analysis, the risk for developing asthma by age 6 or 7 was 23%.

The researchers stated that the decision tree accurately predicts the high-risk profile with high degrees of sensitivity and specificity. The decision tree used four predictors that together defined infants with profile A: RSV infection status, previous breathing problems, eczema, and parental asthma.

“Our data would facilitate the development of profile-specific prevention strategies for asthma – for example, modification of host response, prophylaxis for severe viral infection – by identifying asthma risk groups early in infancy,” Dr. Fujiogi said.

The study received funding from the National Institutes of Health. Dr. Fujiogi and coauthors have disclosed no relevant financial relationships.

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

Bronchiolitis is the leading cause of infant hospitalizations in the United States and Europe, and almost one-third of these patients go on to develop asthma later in childhood.

But a multinational team of researchers has presented evidence that could avoid that outcome. They identified four different subtypes of bronchiolitis along with a decision tree that can determine which infants are most likely to develop asthma as they get older.

Reporting in the journal eClinical Medicine, Michimasa Fujiogi, MD, of Massachusetts General Hospital and Harvard University, Boston, and colleagues analyzed three multicenter prospective cohort studies that included a combined 3,081 infants hospitalized with severe bronchiolitis.

“This study added a base for the early identification of high-risk patients during early infancy,” Dr. Fujiogi said in an interview. “Using the prediction rule of this study, it is possible to identify groups at high risk of asthma during a critical period of airway development – early infancy.”

The researchers identified four clinically distinct and reproducible profiles of infants hospitalized for bronchiolitis:

• A: characterized by a history of breathing problems and eczema, rhinovirus infection, and low prevalence of respiratory syncytial virus (RSV) infection.
• B: characterized by the classic symptoms of wheezing and cough at presentation, a low prevalence of previous breathing problems and rhinovirus infection, and a high likelihood of RSV infection.
• C: the most severe group, characterized by inadequate oral intake, severe retraction at presentation, and longer hospital stays.
• D: the least ill group, with little history of breathing problems but inadequate oral intake with no or mild retraction.

Infants with profile A had the highest risk for developing asthma – more than 250% greater than with typical bronchiolitis. They were also older and were more likely to have parents who had asthma – and none had solo-RSV infection. In the overall analysis, the risk for developing asthma by age 6 or 7 was 23%.

The researchers stated that the decision tree accurately predicts the high-risk profile with high degrees of sensitivity and specificity. The decision tree used four predictors that together defined infants with profile A: RSV infection status, previous breathing problems, eczema, and parental asthma.

“Our data would facilitate the development of profile-specific prevention strategies for asthma – for example, modification of host response, prophylaxis for severe viral infection – by identifying asthma risk groups early in infancy,” Dr. Fujiogi said.

The study received funding from the National Institutes of Health. Dr. Fujiogi and coauthors have disclosed no relevant financial relationships.

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

Right now, more than 106,600 people in the United States are on the national transplant waiting list, each hoping to hear soon that a lung, kidney, heart, or other vital organ has been found for them. It’s the promise not just of a new organ, but a new life.

Well before they are placed on that list, transplant candidates, as they’re known, are evaluated with a battery of tests and exams to be sure they are infection free, their other organs are healthy, and that all their vaccinations are up to date.

Now, COVID vaccinations – and some people’s resistance to them – have turned what used to be routine preparation controversial.

In January, a 31-year-old Boston father of two declined to get the COVID-19 vaccine, and Brigham and Women’s Hospital officials removed him from the heart transplant waiting list. And in North Carolina, a 38-year-old man in need of a kidney transplant said he, too, was denied the organ when he declined to get the vaccination.

Those are just two of the most recent cases. The decisions by the transplant centers to remove the candidates from the waiting list have set off a national debate among ethicists, family members, doctors, patients, and others.

On social media and in conversation, the question persists: Is removing them from the list unfair and cruel, or simply business as usual to keep the patient as healthy as possible and the transplant as successful as possible?

Two recent tweets sum up the debate.

“The people responsible for this should be charged with attempted homicide,” one Twitter user said, while another suggested that the more accurate way to headline the news about a transplant candidate refusing the COVID-19 vaccine would be: “Patient voluntarily forfeits donor organ.”

Doctors and ethics experts, as well as other patients on the waiting list, say it’s simply good medicine to require the COVID vaccine, along with a host of other pretransplant requirements.
 

Transplant protocols

“Transplant medicine has always been a strong promoter of vaccination,” said Silas Prescod Norman, MD, a clinical associate professor of nephrology and internal medicine at the University of Michigan, Ann Arbor. He is a kidney specialist who works in the university’s transplant clinic.

Requiring the COVID vaccine is in line with requirements to get numerous other vaccines, he said.“Promoting the COVID vaccine among our transplant candidates and recipients is just an extension of our usual practice.

“In transplantation, first and foremost is patient safety,” Dr. Norman said. “And we know that solid organ transplant patients are at substantially higher risk of contracting COVID than nontransplant patients.”

After the transplant, they are placed on immunosuppressant drugs, that weaken the immune system while also decreasing the body’s ability to reject the new organ.

“We know now, because there is good data about the vaccine to show that people who are on transplant medications are less likely to make detectable antibodies after vaccination,” said Dr. Norman, who’s also a medical adviser for the American Kidney Fund, a nonprofit that provides kidney health information and financial assistance for dialysis.

And this is not a surprise because of the immunosuppressive effects, he said. “So it only makes sense to get people vaccinated before transplantation.”

Researchers compared the cases of more than 17,000 people who had received organ transplants and were hospitalized from April to November 2020, either for COVID (1,682 of them) or other health issues. Those who had COVID were more likely to have complications and to die in the hospital than those who did not have it.
 

Vaccination guidelines, policies

Federal COVID-19 treatment guidelines from the National Institutes of Health state that transplant patients on immunosuppressant drugs used after the procedure should be considered at a higher risk of getting severe COVID if infected.

In a joint statement from the American Society of Transplant Surgeons, the American Society of Transplantation, and the International Society for Heart and Lung Transplantation, the organizations say they “strongly recommend that all eligible children and adult transplant candidates and recipients be vaccinated with a COVID-19 vaccine [and booster] that is approved or authorized in their jurisdiction. Whenever possible, vaccination should occur prior to transplantation.” Ideally, it should be completed at least 2 weeks before the transplant.

The organizations also “support the development of institutional policies regarding pretransplant vaccination. We believe that this is in the best interest of the transplant candidate, optimizing their chances of getting through the perioperative and posttransplant periods without severe COVID-19 disease, especially at times of greater infection prevalence.”

Officials at Brigham and Women’s Hospital, where the 31-year-old father was removed from the list, issued a statement that reads, in part: “Our Mass General Brigham health care system requires several [Centers for Disease Control and Prevention]-recommended vaccines, including the COVID-19 vaccine, and lifestyle behaviors for transplant candidates to create both the best chance for a successful operation and to optimize the patient’s survival after transplantation, given that their immune system is drastically suppressed. Patients are not active on the wait list without this.”
 

Ethics amid organ shortage

“Organs are scarce,” said Arthur L. Caplan, PhD, director of the division of medical ethics at New York University Langone Medical Center. That makes the goal of choosing the very best candidates for success even more crucial.

“You try to maximize the chance the organ will work,” he said. Pretransplant vaccination is one way.

The shortage is most severe for kidney transplants. In 2020, according to federal statistics, more than 91,000 kidney transplants were needed, but fewer than 23,000 were received. During 2021, 41,354 transplants were done, an increase of nearly 6% over the previous year. The total includes kidneys, hearts, lungs, and other organs, with kidneys accounting for more than 24,000 of the total.

Even with the rise in transplant numbers, supply does not meet demand. According to federal statistics, 17 people in the United States die each day waiting for an organ transplant. Every 9 minutes, someone is added to the waiting list.

“This isn’t and it shouldn’t be a fight about the COVID vaccine,” Dr. Caplan said. “This isn’t an issue about punishing non-COVID vaccinators. It’s deciding who is going to get a scarce organ.”

“A lot of people [opposed to removing the nonvaccinated from the list] think: ‘Oh, they are just killing those people who won’t take a COVID vaccine.’ That’s not what is going on.”

The transplant candidate must be in the best possible shape overall, Dr. Caplan and doctors agreed. Someone who is smoking, drinking heavily, or abusing drugs isn’t going to the top of the list either. And for other procedures, such as bariatric surgery or knee surgery, some patients are told first to lose weight before a surgeon will operate.

The worry about side effects from the vaccine, which some patients have cited as a concern, is misplaced, Dr. Caplan said. What transplant candidates who refuse the COVID vaccine may not be thinking about is that they are facing a serious operation and will be on numerous anti-rejection drugs, with side effects, after the surgery.

“So to be worried about the side effects of a COVID vaccine is irrational,” he said.
 

Transplants: The process

The patients who were recently removed from the transplant list could seek care and a transplant at an alternate center, said Anne Paschke, a spokesperson for the United Network for Organ Sharing, a nonprofit group that is under contract with the federal government and operates the national Organ Procurement and Transplantation Network (OPTN).

“Transplant hospitals decide which patients to add to the wait list based on their own criteria and medical judgment to create the best chance for a positive transplant outcome,” she said. That’s done with the understanding that patients will help with their medical care.

So, if one program won’t accept a patient, another may. But, if a patient turned down at one center due to refusing to get the COVID vaccine tries another center, the requirements at that hospital may be the same, she said.

OPTN maintains a list of transplant centers. As of Jan. 28, there were 251 transplant centers, according to UNOS, which manages the waiting list, matches donors and recipients, and strives for equity, among other duties.
 

Pretransplant refusers not typical

“The cases we are seeing are outliers,” Dr. Caplan said of the handful of known candidates who have refused the vaccine. Most ask their doctor exactly what they need to do to live and follow those instructions.

Dr. Norman agreed. Most of the kidney patients he cares for who are hoping for a transplant have been on dialysis, “which they do not like. They are doing whatever they can to make sure they don’t go back on dialysis. As a group, they tend to be very adherent, very safety conscious because they understand their risk and they understand the gift they have received [or will receive] through transplantation. They want to do everything they can to respect and protect that gift.”

Not surprisingly, some on the transplant list who are vaccinated have strong opinions about those who refuse to get the vaccine. Dana J. Ufkes, 61, a Seattle realtor, has been on the kidney transplant list – this time – since 2003, hoping for her third transplant. When asked if potential recipients should be removed from the list if they refuse the COVID vaccine, her answer was immediate: “Absolutely.”

At age 17, Ms. Ufkes got a serious kidney infection that went undiagnosed and untreated. Her kidney health worsened, and she needed a transplant. She got her first one in 1986, then again in 1992.

“They last longer than they used to,” she said. But not forever. (According to the American Kidney Fund, transplants from a living kidney donor last about 15-20 years; from a deceased donor, 10-15.)

The decision to decline the vaccine is, of course, each person’s choice, Ms. Ufkes said. But “if they don’t want to be vaccinated [and still want to be on the list], I think that’s BS.”

Citing the lack of organs, “it’s not like they are handing these out like jellybeans.”

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

Right now, more than 106,600 people in the United States are on the national transplant waiting list, each hoping to hear soon that a lung, kidney, heart, or other vital organ has been found for them. It’s the promise not just of a new organ, but a new life.

Well before they are placed on that list, transplant candidates, as they’re known, are evaluated with a battery of tests and exams to be sure they are infection free, their other organs are healthy, and that all their vaccinations are up to date.

Now, COVID vaccinations – and some people’s resistance to them – have turned what used to be routine preparation controversial.

In January, a 31-year-old Boston father of two declined to get the COVID-19 vaccine, and Brigham and Women’s Hospital officials removed him from the heart transplant waiting list. And in North Carolina, a 38-year-old man in need of a kidney transplant said he, too, was denied the organ when he declined to get the vaccination.

Those are just two of the most recent cases. The decisions by the transplant centers to remove the candidates from the waiting list have set off a national debate among ethicists, family members, doctors, patients, and others.

On social media and in conversation, the question persists: Is removing them from the list unfair and cruel, or simply business as usual to keep the patient as healthy as possible and the transplant as successful as possible?

Two recent tweets sum up the debate.

“The people responsible for this should be charged with attempted homicide,” one Twitter user said, while another suggested that the more accurate way to headline the news about a transplant candidate refusing the COVID-19 vaccine would be: “Patient voluntarily forfeits donor organ.”

Doctors and ethics experts, as well as other patients on the waiting list, say it’s simply good medicine to require the COVID vaccine, along with a host of other pretransplant requirements.
 

Transplant protocols

“Transplant medicine has always been a strong promoter of vaccination,” said Silas Prescod Norman, MD, a clinical associate professor of nephrology and internal medicine at the University of Michigan, Ann Arbor. He is a kidney specialist who works in the university’s transplant clinic.

Requiring the COVID vaccine is in line with requirements to get numerous other vaccines, he said.“Promoting the COVID vaccine among our transplant candidates and recipients is just an extension of our usual practice.

“In transplantation, first and foremost is patient safety,” Dr. Norman said. “And we know that solid organ transplant patients are at substantially higher risk of contracting COVID than nontransplant patients.”

After the transplant, they are placed on immunosuppressant drugs, that weaken the immune system while also decreasing the body’s ability to reject the new organ.

“We know now, because there is good data about the vaccine to show that people who are on transplant medications are less likely to make detectable antibodies after vaccination,” said Dr. Norman, who’s also a medical adviser for the American Kidney Fund, a nonprofit that provides kidney health information and financial assistance for dialysis.

And this is not a surprise because of the immunosuppressive effects, he said. “So it only makes sense to get people vaccinated before transplantation.”

Researchers compared the cases of more than 17,000 people who had received organ transplants and were hospitalized from April to November 2020, either for COVID (1,682 of them) or other health issues. Those who had COVID were more likely to have complications and to die in the hospital than those who did not have it.
 

Vaccination guidelines, policies

Federal COVID-19 treatment guidelines from the National Institutes of Health state that transplant patients on immunosuppressant drugs used after the procedure should be considered at a higher risk of getting severe COVID if infected.

In a joint statement from the American Society of Transplant Surgeons, the American Society of Transplantation, and the International Society for Heart and Lung Transplantation, the organizations say they “strongly recommend that all eligible children and adult transplant candidates and recipients be vaccinated with a COVID-19 vaccine [and booster] that is approved or authorized in their jurisdiction. Whenever possible, vaccination should occur prior to transplantation.” Ideally, it should be completed at least 2 weeks before the transplant.

The organizations also “support the development of institutional policies regarding pretransplant vaccination. We believe that this is in the best interest of the transplant candidate, optimizing their chances of getting through the perioperative and posttransplant periods without severe COVID-19 disease, especially at times of greater infection prevalence.”

Officials at Brigham and Women’s Hospital, where the 31-year-old father was removed from the list, issued a statement that reads, in part: “Our Mass General Brigham health care system requires several [Centers for Disease Control and Prevention]-recommended vaccines, including the COVID-19 vaccine, and lifestyle behaviors for transplant candidates to create both the best chance for a successful operation and to optimize the patient’s survival after transplantation, given that their immune system is drastically suppressed. Patients are not active on the wait list without this.”
 

Ethics amid organ shortage

“Organs are scarce,” said Arthur L. Caplan, PhD, director of the division of medical ethics at New York University Langone Medical Center. That makes the goal of choosing the very best candidates for success even more crucial.

“You try to maximize the chance the organ will work,” he said. Pretransplant vaccination is one way.

The shortage is most severe for kidney transplants. In 2020, according to federal statistics, more than 91,000 kidney transplants were needed, but fewer than 23,000 were received. During 2021, 41,354 transplants were done, an increase of nearly 6% over the previous year. The total includes kidneys, hearts, lungs, and other organs, with kidneys accounting for more than 24,000 of the total.

Even with the rise in transplant numbers, supply does not meet demand. According to federal statistics, 17 people in the United States die each day waiting for an organ transplant. Every 9 minutes, someone is added to the waiting list.

“This isn’t and it shouldn’t be a fight about the COVID vaccine,” Dr. Caplan said. “This isn’t an issue about punishing non-COVID vaccinators. It’s deciding who is going to get a scarce organ.”

“A lot of people [opposed to removing the nonvaccinated from the list] think: ‘Oh, they are just killing those people who won’t take a COVID vaccine.’ That’s not what is going on.”

The transplant candidate must be in the best possible shape overall, Dr. Caplan and doctors agreed. Someone who is smoking, drinking heavily, or abusing drugs isn’t going to the top of the list either. And for other procedures, such as bariatric surgery or knee surgery, some patients are told first to lose weight before a surgeon will operate.

The worry about side effects from the vaccine, which some patients have cited as a concern, is misplaced, Dr. Caplan said. What transplant candidates who refuse the COVID vaccine may not be thinking about is that they are facing a serious operation and will be on numerous anti-rejection drugs, with side effects, after the surgery.

“So to be worried about the side effects of a COVID vaccine is irrational,” he said.
 

Transplants: The process

The patients who were recently removed from the transplant list could seek care and a transplant at an alternate center, said Anne Paschke, a spokesperson for the United Network for Organ Sharing, a nonprofit group that is under contract with the federal government and operates the national Organ Procurement and Transplantation Network (OPTN).

“Transplant hospitals decide which patients to add to the wait list based on their own criteria and medical judgment to create the best chance for a positive transplant outcome,” she said. That’s done with the understanding that patients will help with their medical care.

So, if one program won’t accept a patient, another may. But, if a patient turned down at one center due to refusing to get the COVID vaccine tries another center, the requirements at that hospital may be the same, she said.

OPTN maintains a list of transplant centers. As of Jan. 28, there were 251 transplant centers, according to UNOS, which manages the waiting list, matches donors and recipients, and strives for equity, among other duties.
 

Pretransplant refusers not typical

“The cases we are seeing are outliers,” Dr. Caplan said of the handful of known candidates who have refused the vaccine. Most ask their doctor exactly what they need to do to live and follow those instructions.

Dr. Norman agreed. Most of the kidney patients he cares for who are hoping for a transplant have been on dialysis, “which they do not like. They are doing whatever they can to make sure they don’t go back on dialysis. As a group, they tend to be very adherent, very safety conscious because they understand their risk and they understand the gift they have received [or will receive] through transplantation. They want to do everything they can to respect and protect that gift.”

Not surprisingly, some on the transplant list who are vaccinated have strong opinions about those who refuse to get the vaccine. Dana J. Ufkes, 61, a Seattle realtor, has been on the kidney transplant list – this time – since 2003, hoping for her third transplant. When asked if potential recipients should be removed from the list if they refuse the COVID vaccine, her answer was immediate: “Absolutely.”

At age 17, Ms. Ufkes got a serious kidney infection that went undiagnosed and untreated. Her kidney health worsened, and she needed a transplant. She got her first one in 1986, then again in 1992.

“They last longer than they used to,” she said. But not forever. (According to the American Kidney Fund, transplants from a living kidney donor last about 15-20 years; from a deceased donor, 10-15.)

The decision to decline the vaccine is, of course, each person’s choice, Ms. Ufkes said. But “if they don’t want to be vaccinated [and still want to be on the list], I think that’s BS.”

Citing the lack of organs, “it’s not like they are handing these out like jellybeans.”

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

Right now, more than 106,600 people in the United States are on the national transplant waiting list, each hoping to hear soon that a lung, kidney, heart, or other vital organ has been found for them. It’s the promise not just of a new organ, but a new life.

Well before they are placed on that list, transplant candidates, as they’re known, are evaluated with a battery of tests and exams to be sure they are infection free, their other organs are healthy, and that all their vaccinations are up to date.

Now, COVID vaccinations – and some people’s resistance to them – have turned what used to be routine preparation controversial.

In January, a 31-year-old Boston father of two declined to get the COVID-19 vaccine, and Brigham and Women’s Hospital officials removed him from the heart transplant waiting list. And in North Carolina, a 38-year-old man in need of a kidney transplant said he, too, was denied the organ when he declined to get the vaccination.

Those are just two of the most recent cases. The decisions by the transplant centers to remove the candidates from the waiting list have set off a national debate among ethicists, family members, doctors, patients, and others.

On social media and in conversation, the question persists: Is removing them from the list unfair and cruel, or simply business as usual to keep the patient as healthy as possible and the transplant as successful as possible?

Two recent tweets sum up the debate.

“The people responsible for this should be charged with attempted homicide,” one Twitter user said, while another suggested that the more accurate way to headline the news about a transplant candidate refusing the COVID-19 vaccine would be: “Patient voluntarily forfeits donor organ.”

Doctors and ethics experts, as well as other patients on the waiting list, say it’s simply good medicine to require the COVID vaccine, along with a host of other pretransplant requirements.
 

Transplant protocols

“Transplant medicine has always been a strong promoter of vaccination,” said Silas Prescod Norman, MD, a clinical associate professor of nephrology and internal medicine at the University of Michigan, Ann Arbor. He is a kidney specialist who works in the university’s transplant clinic.

Requiring the COVID vaccine is in line with requirements to get numerous other vaccines, he said.“Promoting the COVID vaccine among our transplant candidates and recipients is just an extension of our usual practice.

“In transplantation, first and foremost is patient safety,” Dr. Norman said. “And we know that solid organ transplant patients are at substantially higher risk of contracting COVID than nontransplant patients.”

After the transplant, they are placed on immunosuppressant drugs, that weaken the immune system while also decreasing the body’s ability to reject the new organ.

“We know now, because there is good data about the vaccine to show that people who are on transplant medications are less likely to make detectable antibodies after vaccination,” said Dr. Norman, who’s also a medical adviser for the American Kidney Fund, a nonprofit that provides kidney health information and financial assistance for dialysis.

And this is not a surprise because of the immunosuppressive effects, he said. “So it only makes sense to get people vaccinated before transplantation.”

Researchers compared the cases of more than 17,000 people who had received organ transplants and were hospitalized from April to November 2020, either for COVID (1,682 of them) or other health issues. Those who had COVID were more likely to have complications and to die in the hospital than those who did not have it.
 

Vaccination guidelines, policies

Federal COVID-19 treatment guidelines from the National Institutes of Health state that transplant patients on immunosuppressant drugs used after the procedure should be considered at a higher risk of getting severe COVID if infected.

In a joint statement from the American Society of Transplant Surgeons, the American Society of Transplantation, and the International Society for Heart and Lung Transplantation, the organizations say they “strongly recommend that all eligible children and adult transplant candidates and recipients be vaccinated with a COVID-19 vaccine [and booster] that is approved or authorized in their jurisdiction. Whenever possible, vaccination should occur prior to transplantation.” Ideally, it should be completed at least 2 weeks before the transplant.

The organizations also “support the development of institutional policies regarding pretransplant vaccination. We believe that this is in the best interest of the transplant candidate, optimizing their chances of getting through the perioperative and posttransplant periods without severe COVID-19 disease, especially at times of greater infection prevalence.”

Officials at Brigham and Women’s Hospital, where the 31-year-old father was removed from the list, issued a statement that reads, in part: “Our Mass General Brigham health care system requires several [Centers for Disease Control and Prevention]-recommended vaccines, including the COVID-19 vaccine, and lifestyle behaviors for transplant candidates to create both the best chance for a successful operation and to optimize the patient’s survival after transplantation, given that their immune system is drastically suppressed. Patients are not active on the wait list without this.”
 

Ethics amid organ shortage

“Organs are scarce,” said Arthur L. Caplan, PhD, director of the division of medical ethics at New York University Langone Medical Center. That makes the goal of choosing the very best candidates for success even more crucial.

“You try to maximize the chance the organ will work,” he said. Pretransplant vaccination is one way.

The shortage is most severe for kidney transplants. In 2020, according to federal statistics, more than 91,000 kidney transplants were needed, but fewer than 23,000 were received. During 2021, 41,354 transplants were done, an increase of nearly 6% over the previous year. The total includes kidneys, hearts, lungs, and other organs, with kidneys accounting for more than 24,000 of the total.

Even with the rise in transplant numbers, supply does not meet demand. According to federal statistics, 17 people in the United States die each day waiting for an organ transplant. Every 9 minutes, someone is added to the waiting list.

“This isn’t and it shouldn’t be a fight about the COVID vaccine,” Dr. Caplan said. “This isn’t an issue about punishing non-COVID vaccinators. It’s deciding who is going to get a scarce organ.”

“A lot of people [opposed to removing the nonvaccinated from the list] think: ‘Oh, they are just killing those people who won’t take a COVID vaccine.’ That’s not what is going on.”

The transplant candidate must be in the best possible shape overall, Dr. Caplan and doctors agreed. Someone who is smoking, drinking heavily, or abusing drugs isn’t going to the top of the list either. And for other procedures, such as bariatric surgery or knee surgery, some patients are told first to lose weight before a surgeon will operate.

The worry about side effects from the vaccine, which some patients have cited as a concern, is misplaced, Dr. Caplan said. What transplant candidates who refuse the COVID vaccine may not be thinking about is that they are facing a serious operation and will be on numerous anti-rejection drugs, with side effects, after the surgery.

“So to be worried about the side effects of a COVID vaccine is irrational,” he said.
 

Transplants: The process

The patients who were recently removed from the transplant list could seek care and a transplant at an alternate center, said Anne Paschke, a spokesperson for the United Network for Organ Sharing, a nonprofit group that is under contract with the federal government and operates the national Organ Procurement and Transplantation Network (OPTN).

“Transplant hospitals decide which patients to add to the wait list based on their own criteria and medical judgment to create the best chance for a positive transplant outcome,” she said. That’s done with the understanding that patients will help with their medical care.

So, if one program won’t accept a patient, another may. But, if a patient turned down at one center due to refusing to get the COVID vaccine tries another center, the requirements at that hospital may be the same, she said.

OPTN maintains a list of transplant centers. As of Jan. 28, there were 251 transplant centers, according to UNOS, which manages the waiting list, matches donors and recipients, and strives for equity, among other duties.
 

Pretransplant refusers not typical

“The cases we are seeing are outliers,” Dr. Caplan said of the handful of known candidates who have refused the vaccine. Most ask their doctor exactly what they need to do to live and follow those instructions.

Dr. Norman agreed. Most of the kidney patients he cares for who are hoping for a transplant have been on dialysis, “which they do not like. They are doing whatever they can to make sure they don’t go back on dialysis. As a group, they tend to be very adherent, very safety conscious because they understand their risk and they understand the gift they have received [or will receive] through transplantation. They want to do everything they can to respect and protect that gift.”

Not surprisingly, some on the transplant list who are vaccinated have strong opinions about those who refuse to get the vaccine. Dana J. Ufkes, 61, a Seattle realtor, has been on the kidney transplant list – this time – since 2003, hoping for her third transplant. When asked if potential recipients should be removed from the list if they refuse the COVID vaccine, her answer was immediate: “Absolutely.”

At age 17, Ms. Ufkes got a serious kidney infection that went undiagnosed and untreated. Her kidney health worsened, and she needed a transplant. She got her first one in 1986, then again in 1992.

“They last longer than they used to,” she said. But not forever. (According to the American Kidney Fund, transplants from a living kidney donor last about 15-20 years; from a deceased donor, 10-15.)

The decision to decline the vaccine is, of course, each person’s choice, Ms. Ufkes said. But “if they don’t want to be vaccinated [and still want to be on the list], I think that’s BS.”

Citing the lack of organs, “it’s not like they are handing these out like jellybeans.”

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