Background: The beneficial role of high-intensity statins in secondary prevention of recurrent atherosclerotic stroke is well established. It is uncertain whether the observed benefit was from a reduction in the cholesterol level or to other pleotropic effects of atorvastatin. The ideal target cholesterol level for secondary prevention is unclear. This trial was conducted to help determine an ideal target LDL-C level in the prevention of CV events following ischemic stroke.

There were 2,860 patients enrolled, 1,430 were assigned to each target group. At the end of 3.5 years, the primary endpoint occurred in 8.5% of patients in the lower target group, compared with 10.9% in the higher target group (hazard ratio, 0.78; 95% confidence interval, 0.61-0.98; P = .04). Unfortunately, the trial was stopped early because of a lack of funding.

Bottom line: Using medications including statins to lower the LDL-C to less than 70 mg/dL leads to better cardiovascular outcomes following ischemic stroke.

Citation: Amarenco P et al. A comparison of two LDL cholesterol targets after ischemic stroke. N Engl J Med. 2020 Jan 2;382:9-19.

Dr. Garg is assistant professor in the division of hospital medicine, Loyola University Medical Center, Maywood, Ill.

Background: The beneficial role of high-intensity statins in secondary prevention of recurrent atherosclerotic stroke is well established. It is uncertain whether the observed benefit was from a reduction in the cholesterol level or to other pleotropic effects of atorvastatin. The ideal target cholesterol level for secondary prevention is unclear. This trial was conducted to help determine an ideal target LDL-C level in the prevention of CV events following ischemic stroke.

There were 2,860 patients enrolled, 1,430 were assigned to each target group. At the end of 3.5 years, the primary endpoint occurred in 8.5% of patients in the lower target group, compared with 10.9% in the higher target group (hazard ratio, 0.78; 95% confidence interval, 0.61-0.98; P = .04). Unfortunately, the trial was stopped early because of a lack of funding.

Bottom line: Using medications including statins to lower the LDL-C to less than 70 mg/dL leads to better cardiovascular outcomes following ischemic stroke.

Citation: Amarenco P et al. A comparison of two LDL cholesterol targets after ischemic stroke. N Engl J Med. 2020 Jan 2;382:9-19.

Dr. Garg is assistant professor in the division of hospital medicine, Loyola University Medical Center, Maywood, Ill.

Background: The beneficial role of high-intensity statins in secondary prevention of recurrent atherosclerotic stroke is well established. It is uncertain whether the observed benefit was from a reduction in the cholesterol level or to other pleotropic effects of atorvastatin. The ideal target cholesterol level for secondary prevention is unclear. This trial was conducted to help determine an ideal target LDL-C level in the prevention of CV events following ischemic stroke.

There were 2,860 patients enrolled, 1,430 were assigned to each target group. At the end of 3.5 years, the primary endpoint occurred in 8.5% of patients in the lower target group, compared with 10.9% in the higher target group (hazard ratio, 0.78; 95% confidence interval, 0.61-0.98; P = .04). Unfortunately, the trial was stopped early because of a lack of funding.

Bottom line: Using medications including statins to lower the LDL-C to less than 70 mg/dL leads to better cardiovascular outcomes following ischemic stroke.

Citation: Amarenco P et al. A comparison of two LDL cholesterol targets after ischemic stroke. N Engl J Med. 2020 Jan 2;382:9-19.

Dr. Garg is assistant professor in the division of hospital medicine, Loyola University Medical Center, Maywood, Ill.

Oral evobrutinib, an investigational highly selective Bruton’s tyrosine kinase inhibitor, may have a beneficial effect on reducing nerve damage in multiple sclerosis (MS), based on how it’s been found to lower levels of a key blood biomarker, according to a post hoc analysis of a placebo-controlled clinical trial reported at the American Academy of Neurology’s 2021 annual meeting.

Jens Kuhle, MD, of the department of biomedicine at University Hospital Basel, Switzerland, said the conclusion was based on reductions in blood levels of neurofilament light chain (NfL), a biomarker of neuroaxonal damage, in treated patients. “These data on the effect of evobrutinib on NfL dynamics are the first to be reported for a BTK inhibitor investigated for MS,” Dr. Kuhle said. Evobrutinib targets beta cells and myeloid cells, including macrophages and microglia, to disrupt NfL production.

The analysis consisted of three treatment arms in addition to the placebo arm: 25 and 75 mg daily, and 75 mg twice daily. The post hoc analysis included 166 patients across all arms, with 148 being evaluated at week 24.

Dr. Kuhle said the 75-mg twice-daily group exhibited significantly lower blood NfL levels as early as week 12 with lowered levels maintained to week 24, the last time point the study evaluated – specifically reductions of 18.9% (P = .01) and 16.8% (P = .040) compared with placebo, respectively.

However, the 75-mg once daily dose also showed meaningful reductions when compared with placebo: 15.4% (P = .043) and 14.1% (P = .10) at 12 and 24 weeks, respectively, Dr. Kuhle said. “There were no significant differences seen with the 25-mg once-daily group,” he said.

“These results are promising and indicate evobrutinib at an efficacious dose of 75 mg twice daily has a beneficial effect on reducing neuroaxonal damage in MS,” he said.

In an interview, Dr. Kuhle explained the importance of lower NfL levels. “The hope is that detecting subclinical disease activity in a sensitive and comprehensive way will lead to more effective treatment of the individual MS patient,” he said.

The findings may also inform future studies of evobrutinib in MS, he said. “Neurofilaments and neurons are the key substrate of permanent disability in MS and other neurodegenerative diseases,” Dr. Kuhle said. “It is anticipated that normalization of NfL to levels in same-age healthy controls should be the adequate treatment target for individual patients.”

NfL could be an “easily accessible and modifiable biomarker” for use in clinical trials of relapsing and progressive MS, he said. The researchers plan to use NfL measurements in the extension phase of the trial.

“An important next step is the development of reliable and age-adjusted reference values for NfL measurements in blood to move this biomarker further toward individual application in clinical practice,” he added, noting that his group has already collected more than 10,000 serum samples from more than 5,000 healthy controls to do that.

The analysis adds to the growing body of evidence supporting the use of blood NfL levels to gauge the effectiveness of disease-modifying therapies on neuroaxonal degeneration in MS, said Fredrik Piehl, MD, PhD, a professor at Karolinska University Hospital in Stockholm.

Oral evobrutinib, an investigational highly selective Bruton’s tyrosine kinase inhibitor, may have a beneficial effect on reducing nerve damage in multiple sclerosis (MS), based on how it’s been found to lower levels of a key blood biomarker, according to a post hoc analysis of a placebo-controlled clinical trial reported at the American Academy of Neurology’s 2021 annual meeting.

Jens Kuhle, MD, of the department of biomedicine at University Hospital Basel, Switzerland, said the conclusion was based on reductions in blood levels of neurofilament light chain (NfL), a biomarker of neuroaxonal damage, in treated patients. “These data on the effect of evobrutinib on NfL dynamics are the first to be reported for a BTK inhibitor investigated for MS,” Dr. Kuhle said. Evobrutinib targets beta cells and myeloid cells, including macrophages and microglia, to disrupt NfL production.

The analysis consisted of three treatment arms in addition to the placebo arm: 25 and 75 mg daily, and 75 mg twice daily. The post hoc analysis included 166 patients across all arms, with 148 being evaluated at week 24.

Dr. Kuhle said the 75-mg twice-daily group exhibited significantly lower blood NfL levels as early as week 12 with lowered levels maintained to week 24, the last time point the study evaluated – specifically reductions of 18.9% (P = .01) and 16.8% (P = .040) compared with placebo, respectively.

However, the 75-mg once daily dose also showed meaningful reductions when compared with placebo: 15.4% (P = .043) and 14.1% (P = .10) at 12 and 24 weeks, respectively, Dr. Kuhle said. “There were no significant differences seen with the 25-mg once-daily group,” he said.

“These results are promising and indicate evobrutinib at an efficacious dose of 75 mg twice daily has a beneficial effect on reducing neuroaxonal damage in MS,” he said.

In an interview, Dr. Kuhle explained the importance of lower NfL levels. “The hope is that detecting subclinical disease activity in a sensitive and comprehensive way will lead to more effective treatment of the individual MS patient,” he said.

The findings may also inform future studies of evobrutinib in MS, he said. “Neurofilaments and neurons are the key substrate of permanent disability in MS and other neurodegenerative diseases,” Dr. Kuhle said. “It is anticipated that normalization of NfL to levels in same-age healthy controls should be the adequate treatment target for individual patients.”

NfL could be an “easily accessible and modifiable biomarker” for use in clinical trials of relapsing and progressive MS, he said. The researchers plan to use NfL measurements in the extension phase of the trial.

“An important next step is the development of reliable and age-adjusted reference values for NfL measurements in blood to move this biomarker further toward individual application in clinical practice,” he added, noting that his group has already collected more than 10,000 serum samples from more than 5,000 healthy controls to do that.

The analysis adds to the growing body of evidence supporting the use of blood NfL levels to gauge the effectiveness of disease-modifying therapies on neuroaxonal degeneration in MS, said Fredrik Piehl, MD, PhD, a professor at Karolinska University Hospital in Stockholm.

Oral evobrutinib, an investigational highly selective Bruton’s tyrosine kinase inhibitor, may have a beneficial effect on reducing nerve damage in multiple sclerosis (MS), based on how it’s been found to lower levels of a key blood biomarker, according to a post hoc analysis of a placebo-controlled clinical trial reported at the American Academy of Neurology’s 2021 annual meeting.

Jens Kuhle, MD, of the department of biomedicine at University Hospital Basel, Switzerland, said the conclusion was based on reductions in blood levels of neurofilament light chain (NfL), a biomarker of neuroaxonal damage, in treated patients. “These data on the effect of evobrutinib on NfL dynamics are the first to be reported for a BTK inhibitor investigated for MS,” Dr. Kuhle said. Evobrutinib targets beta cells and myeloid cells, including macrophages and microglia, to disrupt NfL production.

The analysis consisted of three treatment arms in addition to the placebo arm: 25 and 75 mg daily, and 75 mg twice daily. The post hoc analysis included 166 patients across all arms, with 148 being evaluated at week 24.

Dr. Kuhle said the 75-mg twice-daily group exhibited significantly lower blood NfL levels as early as week 12 with lowered levels maintained to week 24, the last time point the study evaluated – specifically reductions of 18.9% (P = .01) and 16.8% (P = .040) compared with placebo, respectively.

However, the 75-mg once daily dose also showed meaningful reductions when compared with placebo: 15.4% (P = .043) and 14.1% (P = .10) at 12 and 24 weeks, respectively, Dr. Kuhle said. “There were no significant differences seen with the 25-mg once-daily group,” he said.

“These results are promising and indicate evobrutinib at an efficacious dose of 75 mg twice daily has a beneficial effect on reducing neuroaxonal damage in MS,” he said.

In an interview, Dr. Kuhle explained the importance of lower NfL levels. “The hope is that detecting subclinical disease activity in a sensitive and comprehensive way will lead to more effective treatment of the individual MS patient,” he said.

The findings may also inform future studies of evobrutinib in MS, he said. “Neurofilaments and neurons are the key substrate of permanent disability in MS and other neurodegenerative diseases,” Dr. Kuhle said. “It is anticipated that normalization of NfL to levels in same-age healthy controls should be the adequate treatment target for individual patients.”

NfL could be an “easily accessible and modifiable biomarker” for use in clinical trials of relapsing and progressive MS, he said. The researchers plan to use NfL measurements in the extension phase of the trial.

“An important next step is the development of reliable and age-adjusted reference values for NfL measurements in blood to move this biomarker further toward individual application in clinical practice,” he added, noting that his group has already collected more than 10,000 serum samples from more than 5,000 healthy controls to do that.

The analysis adds to the growing body of evidence supporting the use of blood NfL levels to gauge the effectiveness of disease-modifying therapies on neuroaxonal degeneration in MS, said Fredrik Piehl, MD, PhD, a professor at Karolinska University Hospital in Stockholm.

The percentage of physicians in the United States who are Black has increased only 4% in the past 120 years, and the number of Black male doctors has not changed at all since 1940, according to a new study.

In 1900, 1.3% of physicians were Black. In 1940, 2.8% of physicians were Black, and by 2018 – when almost 13% of the population was Black – 5.4% of doctors were Black, reports Dan Ly, MD, PhD, MPP, an assistant professor of medicine at the University of California, Los Angeles, in a study published online April 19, 2021, in the Journal of General Internal Medicine.

The proportion of male Black physicians was 2.7% in 1940 and 2.6% in 2018.

Dr. Ly also found a significant wage gap. The median income earned by White doctors was $50,000 more than the median income of Black physicians in 2018. Dr. Ly based his findings on the U.S. Census Decennial Census long form, accessed via IPUMS, a free database funded by the National Institutes of Health and other organizations.

“If we care about the health of the population, particularly the health of Black patients, we should care about how small the proportion of our physicians who are Black is and the extremely slow progress we have made as a medical system in increasing that proportion,” Dr. Ly said in an interview.

Dr. Ly said he took on this research in part because previous studies have shown that Black patients are more likely to seek preventive care from Black doctors. Thus, increasing the numbers of Black physicians could narrow gaps in life expectancy between Whites and Blacks.

He also wanted to see whether progress had been made as a result of various medical organizations and the Association of American Medical Colleges undertaking initiatives to increase workforce diversity. There has been “very, very little” progress, he said.

Norma Poll-Hunter, PhD, the AAMC’s senior director of workforce diversity, said Dr. Ly’s report “was not surprising at all.”

The AAMC reported in 2014 that the number of Black men who apply to and matriculate into medical schools has been declining since 1978. That year, there were 1,410 Black male applicants and 542 Black enrollees. In 2014, there were 1,337 applicants and 515 enrollees.

Since 2014, Black male enrollment has increased slightly, rising from 2.4% in the 2014-2015 school year to 2.9% in the 2019-2020 year, the AAMC reported last year.

In addition, among other historically underrepresented minorities, “we really have seen very small progress” despite the increase in the number of medical schools, Dr. Poll-Hunter said in an interview.

The AAMC and the National Medical Association consider the lack of Black male applicants and matriculants to be a national crisis. The two groups started an alliance in 2020 aimed at finding ways to amplify and support Black men’s interest in medicine and the biomedical sciences and to “develop systems-based solutions to address exclusionary practices that create barriers for Black men and prevent them from having equitable opportunities to successfully enroll in medical school.”

Solutions include requiring medical school admissions committees and application screeners to undergo implicit bias awareness and mitigation training, adopting holistic admissions reviews, and incentivizing institutions of higher learning to partner with Black communities in urban and rural school systems to establish K-12 health sciences academies, said NMA President Leon McDougle, MD, MPH.

“There are the systems factors, and racism is a big one that we have to tackle,” said Dr. Poll-Hunter.

Diversity isn’t just about numbers, said Dr. McDougle, a professor of family medicine and associate dean for diversity and inclusion at Ohio State University, Columbus. “We know that medical school graduates who are African American or Black, Hispanic or Latinx, or American Indian or Alaskan Native are more likely to serve those communities as practicing physicians.

“The COVID-19 pandemic highlighted the urgent need for more African American or Black, Hispanic or Latinx, or American Indian or Alaskan Native physicians,” he said. “Inadequate access to culturally competent care has exacerbated existing health disparities, resulting in death and hospitalization rates up to three to four times the rates of European American or White people.”

Dr. Poll-Hunter also said that studies have shown that diversity in the classroom creates a more enriched learning environment and increases civic mindedness and cognitive complexity, “as well as helps us understand people who are different than ourselves.”

The diversity goal “is not about quotas, it’s about excellence,” she said. “We know that there’s talent that exists, and we want to make sure that everyone has an opportunity to be successful.”

Dr. Ly has disclosed no relevant financial relationships.

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

The percentage of physicians in the United States who are Black has increased only 4% in the past 120 years, and the number of Black male doctors has not changed at all since 1940, according to a new study.

In 1900, 1.3% of physicians were Black. In 1940, 2.8% of physicians were Black, and by 2018 – when almost 13% of the population was Black – 5.4% of doctors were Black, reports Dan Ly, MD, PhD, MPP, an assistant professor of medicine at the University of California, Los Angeles, in a study published online April 19, 2021, in the Journal of General Internal Medicine.

The proportion of male Black physicians was 2.7% in 1940 and 2.6% in 2018.

Dr. Ly also found a significant wage gap. The median income earned by White doctors was $50,000 more than the median income of Black physicians in 2018. Dr. Ly based his findings on the U.S. Census Decennial Census long form, accessed via IPUMS, a free database funded by the National Institutes of Health and other organizations.

“If we care about the health of the population, particularly the health of Black patients, we should care about how small the proportion of our physicians who are Black is and the extremely slow progress we have made as a medical system in increasing that proportion,” Dr. Ly said in an interview.

Dr. Ly said he took on this research in part because previous studies have shown that Black patients are more likely to seek preventive care from Black doctors. Thus, increasing the numbers of Black physicians could narrow gaps in life expectancy between Whites and Blacks.

He also wanted to see whether progress had been made as a result of various medical organizations and the Association of American Medical Colleges undertaking initiatives to increase workforce diversity. There has been “very, very little” progress, he said.

Norma Poll-Hunter, PhD, the AAMC’s senior director of workforce diversity, said Dr. Ly’s report “was not surprising at all.”

The AAMC reported in 2014 that the number of Black men who apply to and matriculate into medical schools has been declining since 1978. That year, there were 1,410 Black male applicants and 542 Black enrollees. In 2014, there were 1,337 applicants and 515 enrollees.

Since 2014, Black male enrollment has increased slightly, rising from 2.4% in the 2014-2015 school year to 2.9% in the 2019-2020 year, the AAMC reported last year.

In addition, among other historically underrepresented minorities, “we really have seen very small progress” despite the increase in the number of medical schools, Dr. Poll-Hunter said in an interview.

The AAMC and the National Medical Association consider the lack of Black male applicants and matriculants to be a national crisis. The two groups started an alliance in 2020 aimed at finding ways to amplify and support Black men’s interest in medicine and the biomedical sciences and to “develop systems-based solutions to address exclusionary practices that create barriers for Black men and prevent them from having equitable opportunities to successfully enroll in medical school.”

Solutions include requiring medical school admissions committees and application screeners to undergo implicit bias awareness and mitigation training, adopting holistic admissions reviews, and incentivizing institutions of higher learning to partner with Black communities in urban and rural school systems to establish K-12 health sciences academies, said NMA President Leon McDougle, MD, MPH.

“There are the systems factors, and racism is a big one that we have to tackle,” said Dr. Poll-Hunter.

Diversity isn’t just about numbers, said Dr. McDougle, a professor of family medicine and associate dean for diversity and inclusion at Ohio State University, Columbus. “We know that medical school graduates who are African American or Black, Hispanic or Latinx, or American Indian or Alaskan Native are more likely to serve those communities as practicing physicians.

“The COVID-19 pandemic highlighted the urgent need for more African American or Black, Hispanic or Latinx, or American Indian or Alaskan Native physicians,” he said. “Inadequate access to culturally competent care has exacerbated existing health disparities, resulting in death and hospitalization rates up to three to four times the rates of European American or White people.”

Dr. Poll-Hunter also said that studies have shown that diversity in the classroom creates a more enriched learning environment and increases civic mindedness and cognitive complexity, “as well as helps us understand people who are different than ourselves.”

The diversity goal “is not about quotas, it’s about excellence,” she said. “We know that there’s talent that exists, and we want to make sure that everyone has an opportunity to be successful.”

Dr. Ly has disclosed no relevant financial relationships.

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

The percentage of physicians in the United States who are Black has increased only 4% in the past 120 years, and the number of Black male doctors has not changed at all since 1940, according to a new study.

In 1900, 1.3% of physicians were Black. In 1940, 2.8% of physicians were Black, and by 2018 – when almost 13% of the population was Black – 5.4% of doctors were Black, reports Dan Ly, MD, PhD, MPP, an assistant professor of medicine at the University of California, Los Angeles, in a study published online April 19, 2021, in the Journal of General Internal Medicine.

The proportion of male Black physicians was 2.7% in 1940 and 2.6% in 2018.

Dr. Ly also found a significant wage gap. The median income earned by White doctors was $50,000 more than the median income of Black physicians in 2018. Dr. Ly based his findings on the U.S. Census Decennial Census long form, accessed via IPUMS, a free database funded by the National Institutes of Health and other organizations.

“If we care about the health of the population, particularly the health of Black patients, we should care about how small the proportion of our physicians who are Black is and the extremely slow progress we have made as a medical system in increasing that proportion,” Dr. Ly said in an interview.

Dr. Ly said he took on this research in part because previous studies have shown that Black patients are more likely to seek preventive care from Black doctors. Thus, increasing the numbers of Black physicians could narrow gaps in life expectancy between Whites and Blacks.

He also wanted to see whether progress had been made as a result of various medical organizations and the Association of American Medical Colleges undertaking initiatives to increase workforce diversity. There has been “very, very little” progress, he said.

Norma Poll-Hunter, PhD, the AAMC’s senior director of workforce diversity, said Dr. Ly’s report “was not surprising at all.”

The AAMC reported in 2014 that the number of Black men who apply to and matriculate into medical schools has been declining since 1978. That year, there were 1,410 Black male applicants and 542 Black enrollees. In 2014, there were 1,337 applicants and 515 enrollees.

Since 2014, Black male enrollment has increased slightly, rising from 2.4% in the 2014-2015 school year to 2.9% in the 2019-2020 year, the AAMC reported last year.

In addition, among other historically underrepresented minorities, “we really have seen very small progress” despite the increase in the number of medical schools, Dr. Poll-Hunter said in an interview.

The AAMC and the National Medical Association consider the lack of Black male applicants and matriculants to be a national crisis. The two groups started an alliance in 2020 aimed at finding ways to amplify and support Black men’s interest in medicine and the biomedical sciences and to “develop systems-based solutions to address exclusionary practices that create barriers for Black men and prevent them from having equitable opportunities to successfully enroll in medical school.”

Solutions include requiring medical school admissions committees and application screeners to undergo implicit bias awareness and mitigation training, adopting holistic admissions reviews, and incentivizing institutions of higher learning to partner with Black communities in urban and rural school systems to establish K-12 health sciences academies, said NMA President Leon McDougle, MD, MPH.

“There are the systems factors, and racism is a big one that we have to tackle,” said Dr. Poll-Hunter.

Diversity isn’t just about numbers, said Dr. McDougle, a professor of family medicine and associate dean for diversity and inclusion at Ohio State University, Columbus. “We know that medical school graduates who are African American or Black, Hispanic or Latinx, or American Indian or Alaskan Native are more likely to serve those communities as practicing physicians.

“The COVID-19 pandemic highlighted the urgent need for more African American or Black, Hispanic or Latinx, or American Indian or Alaskan Native physicians,” he said. “Inadequate access to culturally competent care has exacerbated existing health disparities, resulting in death and hospitalization rates up to three to four times the rates of European American or White people.”

Dr. Poll-Hunter also said that studies have shown that diversity in the classroom creates a more enriched learning environment and increases civic mindedness and cognitive complexity, “as well as helps us understand people who are different than ourselves.”

The diversity goal “is not about quotas, it’s about excellence,” she said. “We know that there’s talent that exists, and we want to make sure that everyone has an opportunity to be successful.”

Dr. Ly has disclosed no relevant financial relationships.

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

The Food and Drug Administration has approved a new indication for ALK’s under-the-tongue immunotherapy tablet Ragwitek (Ambrosia artemisiifolia) to treat ragweed pollen–induced hay fever in children aged 5-17 years.

Olivier Le Moal/Getty Images

Ragwitek received FDA approval in 2014 to treat short ragweed pollen–induced hay fever, with or without allergic rhinoconjunctivitis, in adults aged 18-65 years. This new indication expanded that age group to include children.

The approval for Ragwitek comes with a boxed warning regarding a risk for life-threatening allergic reactions associated with the immunotherapy treatment, including anaphylaxis and severe laryngopharyngeal restriction. The package insert specifies that physicians should prescribe autoinjectable epinephrine with the drug.

“Ragwitek tablets provide a new immunotherapy treatment option for children and adolescents with seasonal ragweed allergies which often causes uncomfortable nasal symptoms and red, itchy eyes during the late summer and early fall,” David I. Bernstein, MD, University of Cincinnati, Bernstein Clinical Research, said in a company press release. 

Short ragweed pollen is one of the most common weed allergies. Allergic rhinitis, or hay fever, affects 10%-30% of the population worldwide, according to the American Academy of Allergy Asthma & Immunology. In the United States, approximately 7.7% of adults and 7.2% of children were diagnosed with it annually, according to the Centers for Disease Control and Prevention.

The new indication was based partly on data from a phase 3 clinical trial in children with short ragweed–induced allergic rhinitis, or hay fever, published in the Journal of Allergy and Clinical Immunology. In the study, researchers evaluated the efficacy and safety of the treatment in 1,022 participants aged 5-17 years with a history of ragweed-induced rhinoconjunctivitis and sensitivity to ragweed over a 20- to 28-week treatment period.

Researchers found that Ragwitek improved symptoms in children and adolescents and decreased their use of symptom-relieving medication, compared with placebo.

Among children and adolescents aged 5-17 years, the most common adverse reactions reported were throat irritation/tickle (48.3% in the Ragwitek group vs. 17.7% in the placebo group), itching in the mouth (47.8% vs. 11.2%), itching in the ear (33.9% vs. 6.3%), mouth pain (18.9% vs. 4.5%), swelling of the lips (13.8% vs. 1.2%), nausea (11.5% vs. 3.3%), swelling of the tongue (11.3% vs. 0.8%), throat swelling (10.7% vs. 1.6%), and stomach pain (10.1% vs. 4.5%).

The FDA also recommends that Ragwitek not be prescribed to people with severe, unstable, or uncontrolled asthma, those with a history of severe systemic allergic reactions, and those with a history of eosinophilic esophagitis. The immunotherapy treatment also may not be suitable for people who are unresponsive to epinephrine or inhaled bronchodilators.

In addition, the treatment is not approved for the immediate relief of allergic symptoms in children or adults. The once-daily treatment, which contains an extract from short ragweed pollen, should begin 12 weeks before the start of ragweed pollen season and continue throughout the season, according to the FDA.

Dr. Bernstein said that the under-the-tongue immunotherapy works by targeting the specific allergy trigger and reducing allergy symptoms by “stimulating the immune system.”

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

The Food and Drug Administration has approved a new indication for ALK’s under-the-tongue immunotherapy tablet Ragwitek (Ambrosia artemisiifolia) to treat ragweed pollen–induced hay fever in children aged 5-17 years.

Olivier Le Moal/Getty Images

Ragwitek received FDA approval in 2014 to treat short ragweed pollen–induced hay fever, with or without allergic rhinoconjunctivitis, in adults aged 18-65 years. This new indication expanded that age group to include children.

The approval for Ragwitek comes with a boxed warning regarding a risk for life-threatening allergic reactions associated with the immunotherapy treatment, including anaphylaxis and severe laryngopharyngeal restriction. The package insert specifies that physicians should prescribe autoinjectable epinephrine with the drug.

“Ragwitek tablets provide a new immunotherapy treatment option for children and adolescents with seasonal ragweed allergies which often causes uncomfortable nasal symptoms and red, itchy eyes during the late summer and early fall,” David I. Bernstein, MD, University of Cincinnati, Bernstein Clinical Research, said in a company press release. 

Short ragweed pollen is one of the most common weed allergies. Allergic rhinitis, or hay fever, affects 10%-30% of the population worldwide, according to the American Academy of Allergy Asthma & Immunology. In the United States, approximately 7.7% of adults and 7.2% of children were diagnosed with it annually, according to the Centers for Disease Control and Prevention.

The new indication was based partly on data from a phase 3 clinical trial in children with short ragweed–induced allergic rhinitis, or hay fever, published in the Journal of Allergy and Clinical Immunology. In the study, researchers evaluated the efficacy and safety of the treatment in 1,022 participants aged 5-17 years with a history of ragweed-induced rhinoconjunctivitis and sensitivity to ragweed over a 20- to 28-week treatment period.

Researchers found that Ragwitek improved symptoms in children and adolescents and decreased their use of symptom-relieving medication, compared with placebo.

Among children and adolescents aged 5-17 years, the most common adverse reactions reported were throat irritation/tickle (48.3% in the Ragwitek group vs. 17.7% in the placebo group), itching in the mouth (47.8% vs. 11.2%), itching in the ear (33.9% vs. 6.3%), mouth pain (18.9% vs. 4.5%), swelling of the lips (13.8% vs. 1.2%), nausea (11.5% vs. 3.3%), swelling of the tongue (11.3% vs. 0.8%), throat swelling (10.7% vs. 1.6%), and stomach pain (10.1% vs. 4.5%).

The FDA also recommends that Ragwitek not be prescribed to people with severe, unstable, or uncontrolled asthma, those with a history of severe systemic allergic reactions, and those with a history of eosinophilic esophagitis. The immunotherapy treatment also may not be suitable for people who are unresponsive to epinephrine or inhaled bronchodilators.

In addition, the treatment is not approved for the immediate relief of allergic symptoms in children or adults. The once-daily treatment, which contains an extract from short ragweed pollen, should begin 12 weeks before the start of ragweed pollen season and continue throughout the season, according to the FDA.

Dr. Bernstein said that the under-the-tongue immunotherapy works by targeting the specific allergy trigger and reducing allergy symptoms by “stimulating the immune system.”

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

The Food and Drug Administration has approved a new indication for ALK’s under-the-tongue immunotherapy tablet Ragwitek (Ambrosia artemisiifolia) to treat ragweed pollen–induced hay fever in children aged 5-17 years.

Olivier Le Moal/Getty Images

Ragwitek received FDA approval in 2014 to treat short ragweed pollen–induced hay fever, with or without allergic rhinoconjunctivitis, in adults aged 18-65 years. This new indication expanded that age group to include children.

The approval for Ragwitek comes with a boxed warning regarding a risk for life-threatening allergic reactions associated with the immunotherapy treatment, including anaphylaxis and severe laryngopharyngeal restriction. The package insert specifies that physicians should prescribe autoinjectable epinephrine with the drug.

“Ragwitek tablets provide a new immunotherapy treatment option for children and adolescents with seasonal ragweed allergies which often causes uncomfortable nasal symptoms and red, itchy eyes during the late summer and early fall,” David I. Bernstein, MD, University of Cincinnati, Bernstein Clinical Research, said in a company press release. 

Short ragweed pollen is one of the most common weed allergies. Allergic rhinitis, or hay fever, affects 10%-30% of the population worldwide, according to the American Academy of Allergy Asthma & Immunology. In the United States, approximately 7.7% of adults and 7.2% of children were diagnosed with it annually, according to the Centers for Disease Control and Prevention.

The new indication was based partly on data from a phase 3 clinical trial in children with short ragweed–induced allergic rhinitis, or hay fever, published in the Journal of Allergy and Clinical Immunology. In the study, researchers evaluated the efficacy and safety of the treatment in 1,022 participants aged 5-17 years with a history of ragweed-induced rhinoconjunctivitis and sensitivity to ragweed over a 20- to 28-week treatment period.

Researchers found that Ragwitek improved symptoms in children and adolescents and decreased their use of symptom-relieving medication, compared with placebo.

Among children and adolescents aged 5-17 years, the most common adverse reactions reported were throat irritation/tickle (48.3% in the Ragwitek group vs. 17.7% in the placebo group), itching in the mouth (47.8% vs. 11.2%), itching in the ear (33.9% vs. 6.3%), mouth pain (18.9% vs. 4.5%), swelling of the lips (13.8% vs. 1.2%), nausea (11.5% vs. 3.3%), swelling of the tongue (11.3% vs. 0.8%), throat swelling (10.7% vs. 1.6%), and stomach pain (10.1% vs. 4.5%).

The FDA also recommends that Ragwitek not be prescribed to people with severe, unstable, or uncontrolled asthma, those with a history of severe systemic allergic reactions, and those with a history of eosinophilic esophagitis. The immunotherapy treatment also may not be suitable for people who are unresponsive to epinephrine or inhaled bronchodilators.

In addition, the treatment is not approved for the immediate relief of allergic symptoms in children or adults. The once-daily treatment, which contains an extract from short ragweed pollen, should begin 12 weeks before the start of ragweed pollen season and continue throughout the season, according to the FDA.

Dr. Bernstein said that the under-the-tongue immunotherapy works by targeting the specific allergy trigger and reducing allergy symptoms by “stimulating the immune system.”

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

Do your patients think that getting COVID-19 is fully protective against subsequent reinfection? Tell it to the Marines.

A study of U.S. Marine recruits on their way to boot camp at Parris Island, S.C., showed that those who were seropositive at baseline, indicating prior exposure to SARS-CoV-2, remained at some risk for reinfection. They had about one-fifth the risk of subsequent infection, compared with seronegative recruits during basic training, but reinfections did occur.

The study, by Stuart C. Sealfon, MD, of Icahn School of Medicine at Mount Sinai in New York, and colleagues, was published in The Lancet Respiratory Medicine.

“Although antibodies induced by initial infection are largely protective, they do not guarantee effective SARS-CoV-2 neutralization activity or immunity against subsequent infection,” they wrote.

An infectious disease specialist who was not involved in the study said that the findings provide further evidence about the level of immunity acquired after an infection.

“It’s quite clear that reinfections do occur, they are of public health importance, and they’re something we need to be mindful of in terms of advising patients about whether a prior infection protects them from reinfection,” Mark Siedner, MD, MPH, a clinician and researcher in the division of infectious diseases at Massachusetts General Hospital, Boston, said in an interview.

The study results reinforce that “not all antibodies are the same,” said Sachin Gupta, MD, an attending physician in pulmonary and critical care medicine at Alameda Health System in Oakland, Calif. “We’re seeing still that 10% of folks who have antibodies can get infected again,” he said in an interview.

CHARM initiative

Dr. Sealfon and colleagues presented an analysis of data from the ironically named CHARM (COVID-19 Health Action Response for Marines) prospective study.

CHARM included U.S. Marine recruits, most of them male, aged 18-20 years, who were instructed to follow a 2-week unsupervised quarantine at home, after which they reported to a Marine-supervised facility for an additional 2-week quarantine.

At baseline, participants were tested for SARS-CoV-2 immunoglobulin G (IgG) seropositivity, defined as a dilution of 1:150 or more on receptor-binding domain and full-length spike protein enzyme-linked immunosorbent assay (ELISA).

The recruits filled out questionnaires asking them to report any of 14 specific COVID-19–related symptoms or any other unspecified symptom, as well as demographic information, risk factors, and a brief medical history.

Investigators tested recruits for SARS-CoV-2 infection by polymerase chain reaction (PCR) assay at weeks 0, 1, and 2 of quarantine, and any who had positive PCR results during quarantine were excluded.

Participants who had three negative swab PCR results during quarantine and a baseline serology test at the beginning of the supervised quarantine period – either seronegative or seropositive – then went on to enjoy their basic training at the Marine Corps Recruit Depot, Parris Island, S.C.

The participants were followed prospectively with PCR tests at weeks 2, 4, and 6 in both the seropositive and seronegative groups, and sera were obtained at the same time.
 

Holes in immunologic armor

Full data were available for a total of 189 participants who were seropositive and 2,247 who were seronegative at enrollment.

In all, 19 of 189 seropositive recruits (10%) had at least one PCR test positive for SARS-CoV-2 infection during the 6-week follow-up period. This translated into an incidence of 1.1 cases per person-year.

Of the 2,247 participants seronegative at baseline, 1,079 tested positive (6.2 cases per person-year; incidence rate ratio 0.18).

It appeared that antibodies provided some protection for seropositive recruits, as evidenced by a higher likelihood of infection among those with lower baseline full-length spike protein IgG titers than in those with higher baseline titers (hazard ratio 0.4, P < .001).

Among the seropositive participants who did acquire a second SARS-CoV-2 infection, viral loads in mid-turbinate nasal swabs were about 10-fold lower than in seronegative recruits who acquired infections during follow-up.

“This finding suggests that some reinfected individuals could have a similar capacity to transmit infection as those who are infected for the first time. The rate at which reinfection occurs after vaccines and natural immunity is important for estimating the proportion of the population that needs to be vaccinated to suppress the pandemic,” the investigators wrote.

Baseline neutralizing antibody titers were detected in 45 of the first 54 seropositive recruits who remained PCR negative throughout follow-up, but also in 6 of 19 seropositive participants who became infected during the 6 weeks of observation.
 

Lessons

Both Dr. Siedner and Dr. Gupta agreed with the authors that the risks for reinfection that were observed in young, physically fit people may differ for other populations, such as women (only 10% of seropositive recruits and 8% of seronegative recruits were female), older patients, or those who are immunocompromised.

Given that the adjusted odds ratio for reinfection in this study was nearly identical to that of a recent British study comparing infection rates between seropositive and seronegative health care workers, the risk of reinfection for other young adults and for the general population may be similar, Dr. Sealfon and colleagues wrote.

Adding to the challenge of reaching herd immunity is the observation that some patients who have recovered from COVID-19 are skeptical about the need for further protection.

“There are patients who feel like vaccination is of low benefit to them, and I think these are the same people who would be hesitant to get the vaccine anyway,” Dr. Gupta said.

Although no vaccine is perfect – the vaccine failure rate from the mRNA-based vaccines from Moderna and Pfizer/Biontech is about 5% – the protections they afford are unmistakable, Dr. Siedner said.

“I think it’s important to make the distinction that most postvaccination infections by and large have been very mild,” he said. “In people with normal immune systems, we have not seen an onslaught of postvaccination infections requiring hospitalization. Even if people do get infected after vaccination, the vaccines protect people from severe infection, and that’s what we want them to do.”

The investigators stated, “Young adults, of whom a high proportion are asymptomatically infected and become seropositive in the absence of known infection, can be an important source of transmission to more vulnerable populations. Evaluating the protection against subsequent SARS-CoV-2 infection conferred by seropositivity in young adults is important for determining the need for vaccinating previously infected individuals in this age group.”

The study was funded by the Defense Health Agency and Defense Advanced Research Projects Agency. Dr. Sealfon, Dr. Siedner, and Dr. Gupta have no conflicts of interest to report. Dr. Gupta is a member of the editorial advisory board for this publication.

Do your patients think that getting COVID-19 is fully protective against subsequent reinfection? Tell it to the Marines.

A study of U.S. Marine recruits on their way to boot camp at Parris Island, S.C., showed that those who were seropositive at baseline, indicating prior exposure to SARS-CoV-2, remained at some risk for reinfection. They had about one-fifth the risk of subsequent infection, compared with seronegative recruits during basic training, but reinfections did occur.

The study, by Stuart C. Sealfon, MD, of Icahn School of Medicine at Mount Sinai in New York, and colleagues, was published in The Lancet Respiratory Medicine.

“Although antibodies induced by initial infection are largely protective, they do not guarantee effective SARS-CoV-2 neutralization activity or immunity against subsequent infection,” they wrote.

An infectious disease specialist who was not involved in the study said that the findings provide further evidence about the level of immunity acquired after an infection.

“It’s quite clear that reinfections do occur, they are of public health importance, and they’re something we need to be mindful of in terms of advising patients about whether a prior infection protects them from reinfection,” Mark Siedner, MD, MPH, a clinician and researcher in the division of infectious diseases at Massachusetts General Hospital, Boston, said in an interview.

The study results reinforce that “not all antibodies are the same,” said Sachin Gupta, MD, an attending physician in pulmonary and critical care medicine at Alameda Health System in Oakland, Calif. “We’re seeing still that 10% of folks who have antibodies can get infected again,” he said in an interview.

CHARM initiative

Dr. Sealfon and colleagues presented an analysis of data from the ironically named CHARM (COVID-19 Health Action Response for Marines) prospective study.

CHARM included U.S. Marine recruits, most of them male, aged 18-20 years, who were instructed to follow a 2-week unsupervised quarantine at home, after which they reported to a Marine-supervised facility for an additional 2-week quarantine.

At baseline, participants were tested for SARS-CoV-2 immunoglobulin G (IgG) seropositivity, defined as a dilution of 1:150 or more on receptor-binding domain and full-length spike protein enzyme-linked immunosorbent assay (ELISA).

The recruits filled out questionnaires asking them to report any of 14 specific COVID-19–related symptoms or any other unspecified symptom, as well as demographic information, risk factors, and a brief medical history.

Investigators tested recruits for SARS-CoV-2 infection by polymerase chain reaction (PCR) assay at weeks 0, 1, and 2 of quarantine, and any who had positive PCR results during quarantine were excluded.

Participants who had three negative swab PCR results during quarantine and a baseline serology test at the beginning of the supervised quarantine period – either seronegative or seropositive – then went on to enjoy their basic training at the Marine Corps Recruit Depot, Parris Island, S.C.

The participants were followed prospectively with PCR tests at weeks 2, 4, and 6 in both the seropositive and seronegative groups, and sera were obtained at the same time.
 

Holes in immunologic armor

Full data were available for a total of 189 participants who were seropositive and 2,247 who were seronegative at enrollment.

In all, 19 of 189 seropositive recruits (10%) had at least one PCR test positive for SARS-CoV-2 infection during the 6-week follow-up period. This translated into an incidence of 1.1 cases per person-year.

Of the 2,247 participants seronegative at baseline, 1,079 tested positive (6.2 cases per person-year; incidence rate ratio 0.18).

It appeared that antibodies provided some protection for seropositive recruits, as evidenced by a higher likelihood of infection among those with lower baseline full-length spike protein IgG titers than in those with higher baseline titers (hazard ratio 0.4, P < .001).

Among the seropositive participants who did acquire a second SARS-CoV-2 infection, viral loads in mid-turbinate nasal swabs were about 10-fold lower than in seronegative recruits who acquired infections during follow-up.

“This finding suggests that some reinfected individuals could have a similar capacity to transmit infection as those who are infected for the first time. The rate at which reinfection occurs after vaccines and natural immunity is important for estimating the proportion of the population that needs to be vaccinated to suppress the pandemic,” the investigators wrote.

Baseline neutralizing antibody titers were detected in 45 of the first 54 seropositive recruits who remained PCR negative throughout follow-up, but also in 6 of 19 seropositive participants who became infected during the 6 weeks of observation.
 

Lessons

Both Dr. Siedner and Dr. Gupta agreed with the authors that the risks for reinfection that were observed in young, physically fit people may differ for other populations, such as women (only 10% of seropositive recruits and 8% of seronegative recruits were female), older patients, or those who are immunocompromised.

Given that the adjusted odds ratio for reinfection in this study was nearly identical to that of a recent British study comparing infection rates between seropositive and seronegative health care workers, the risk of reinfection for other young adults and for the general population may be similar, Dr. Sealfon and colleagues wrote.

Adding to the challenge of reaching herd immunity is the observation that some patients who have recovered from COVID-19 are skeptical about the need for further protection.

“There are patients who feel like vaccination is of low benefit to them, and I think these are the same people who would be hesitant to get the vaccine anyway,” Dr. Gupta said.

Although no vaccine is perfect – the vaccine failure rate from the mRNA-based vaccines from Moderna and Pfizer/Biontech is about 5% – the protections they afford are unmistakable, Dr. Siedner said.

“I think it’s important to make the distinction that most postvaccination infections by and large have been very mild,” he said. “In people with normal immune systems, we have not seen an onslaught of postvaccination infections requiring hospitalization. Even if people do get infected after vaccination, the vaccines protect people from severe infection, and that’s what we want them to do.”

The investigators stated, “Young adults, of whom a high proportion are asymptomatically infected and become seropositive in the absence of known infection, can be an important source of transmission to more vulnerable populations. Evaluating the protection against subsequent SARS-CoV-2 infection conferred by seropositivity in young adults is important for determining the need for vaccinating previously infected individuals in this age group.”

The study was funded by the Defense Health Agency and Defense Advanced Research Projects Agency. Dr. Sealfon, Dr. Siedner, and Dr. Gupta have no conflicts of interest to report. Dr. Gupta is a member of the editorial advisory board for this publication.

Do your patients think that getting COVID-19 is fully protective against subsequent reinfection? Tell it to the Marines.

A study of U.S. Marine recruits on their way to boot camp at Parris Island, S.C., showed that those who were seropositive at baseline, indicating prior exposure to SARS-CoV-2, remained at some risk for reinfection. They had about one-fifth the risk of subsequent infection, compared with seronegative recruits during basic training, but reinfections did occur.

The study, by Stuart C. Sealfon, MD, of Icahn School of Medicine at Mount Sinai in New York, and colleagues, was published in The Lancet Respiratory Medicine.

“Although antibodies induced by initial infection are largely protective, they do not guarantee effective SARS-CoV-2 neutralization activity or immunity against subsequent infection,” they wrote.

An infectious disease specialist who was not involved in the study said that the findings provide further evidence about the level of immunity acquired after an infection.

“It’s quite clear that reinfections do occur, they are of public health importance, and they’re something we need to be mindful of in terms of advising patients about whether a prior infection protects them from reinfection,” Mark Siedner, MD, MPH, a clinician and researcher in the division of infectious diseases at Massachusetts General Hospital, Boston, said in an interview.

The study results reinforce that “not all antibodies are the same,” said Sachin Gupta, MD, an attending physician in pulmonary and critical care medicine at Alameda Health System in Oakland, Calif. “We’re seeing still that 10% of folks who have antibodies can get infected again,” he said in an interview.

CHARM initiative

Dr. Sealfon and colleagues presented an analysis of data from the ironically named CHARM (COVID-19 Health Action Response for Marines) prospective study.

CHARM included U.S. Marine recruits, most of them male, aged 18-20 years, who were instructed to follow a 2-week unsupervised quarantine at home, after which they reported to a Marine-supervised facility for an additional 2-week quarantine.

At baseline, participants were tested for SARS-CoV-2 immunoglobulin G (IgG) seropositivity, defined as a dilution of 1:150 or more on receptor-binding domain and full-length spike protein enzyme-linked immunosorbent assay (ELISA).

The recruits filled out questionnaires asking them to report any of 14 specific COVID-19–related symptoms or any other unspecified symptom, as well as demographic information, risk factors, and a brief medical history.

Investigators tested recruits for SARS-CoV-2 infection by polymerase chain reaction (PCR) assay at weeks 0, 1, and 2 of quarantine, and any who had positive PCR results during quarantine were excluded.

Participants who had three negative swab PCR results during quarantine and a baseline serology test at the beginning of the supervised quarantine period – either seronegative or seropositive – then went on to enjoy their basic training at the Marine Corps Recruit Depot, Parris Island, S.C.

The participants were followed prospectively with PCR tests at weeks 2, 4, and 6 in both the seropositive and seronegative groups, and sera were obtained at the same time.
 

Holes in immunologic armor

Full data were available for a total of 189 participants who were seropositive and 2,247 who were seronegative at enrollment.

In all, 19 of 189 seropositive recruits (10%) had at least one PCR test positive for SARS-CoV-2 infection during the 6-week follow-up period. This translated into an incidence of 1.1 cases per person-year.

Of the 2,247 participants seronegative at baseline, 1,079 tested positive (6.2 cases per person-year; incidence rate ratio 0.18).

It appeared that antibodies provided some protection for seropositive recruits, as evidenced by a higher likelihood of infection among those with lower baseline full-length spike protein IgG titers than in those with higher baseline titers (hazard ratio 0.4, P < .001).

Among the seropositive participants who did acquire a second SARS-CoV-2 infection, viral loads in mid-turbinate nasal swabs were about 10-fold lower than in seronegative recruits who acquired infections during follow-up.

“This finding suggests that some reinfected individuals could have a similar capacity to transmit infection as those who are infected for the first time. The rate at which reinfection occurs after vaccines and natural immunity is important for estimating the proportion of the population that needs to be vaccinated to suppress the pandemic,” the investigators wrote.

Baseline neutralizing antibody titers were detected in 45 of the first 54 seropositive recruits who remained PCR negative throughout follow-up, but also in 6 of 19 seropositive participants who became infected during the 6 weeks of observation.
 

Lessons

Both Dr. Siedner and Dr. Gupta agreed with the authors that the risks for reinfection that were observed in young, physically fit people may differ for other populations, such as women (only 10% of seropositive recruits and 8% of seronegative recruits were female), older patients, or those who are immunocompromised.

Given that the adjusted odds ratio for reinfection in this study was nearly identical to that of a recent British study comparing infection rates between seropositive and seronegative health care workers, the risk of reinfection for other young adults and for the general population may be similar, Dr. Sealfon and colleagues wrote.

Adding to the challenge of reaching herd immunity is the observation that some patients who have recovered from COVID-19 are skeptical about the need for further protection.

“There are patients who feel like vaccination is of low benefit to them, and I think these are the same people who would be hesitant to get the vaccine anyway,” Dr. Gupta said.

Although no vaccine is perfect – the vaccine failure rate from the mRNA-based vaccines from Moderna and Pfizer/Biontech is about 5% – the protections they afford are unmistakable, Dr. Siedner said.

“I think it’s important to make the distinction that most postvaccination infections by and large have been very mild,” he said. “In people with normal immune systems, we have not seen an onslaught of postvaccination infections requiring hospitalization. Even if people do get infected after vaccination, the vaccines protect people from severe infection, and that’s what we want them to do.”

The investigators stated, “Young adults, of whom a high proportion are asymptomatically infected and become seropositive in the absence of known infection, can be an important source of transmission to more vulnerable populations. Evaluating the protection against subsequent SARS-CoV-2 infection conferred by seropositivity in young adults is important for determining the need for vaccinating previously infected individuals in this age group.”

The study was funded by the Defense Health Agency and Defense Advanced Research Projects Agency. Dr. Sealfon, Dr. Siedner, and Dr. Gupta have no conflicts of interest to report. Dr. Gupta is a member of the editorial advisory board for this publication.

Mitochondrial DNA (mtDNA) copy number alterations are known to occur in acute myeloid leukemia (AML), however their biological significance has not been well studied. Pediatric AML has a distinct biology, different from adults, and with heterogeneous clinical outcomes, the biological basis of which are not well understood, according to researchers Shilpi Chaudhary, PhD, of the All India Institute of Medical Sciences, New Delhi, and colleagues.

wir0man/GettyImages

Their analysis of 123 pediatric patients with AML found that mtDNA copy number was an independent predictor of aggressive disease, lower event-free survival, and overall survival, according to a report published in Mitochondrion.

In an attempt to find the biological factors involved in the increased mtDNA copy numbers and their effect on the development and aggressiveness of pediatric AML, the researchers studied the regulation and significance of mtDNA copy number in pediatric AML patients using quantitative real time–polymerase chain reaction, as well as in vitro studies. For patients, results were correlated with clinical outcomes.

Mitochondrial biogenesis genes (TFAM, POLG, POLRMT) and two regulator of mitochondrial biogenesis, MYC and PGC1A, were also assessed, according to Dr. Chaudhary and colleagues.
 

Predictive results

MtDNA copy number was significantly higher in patients, compared with controls (P < .001) and was found to be an independent predictor of aggressive disease (P = .006), lower event-free survival (P = .033), and overall survival (P = .007).

TFAM, POLG & POLRMT and ND3 were also found to be significantly up-regulated in patients, compared with controls as was the expression of the mitochondrial biogenesis regulator MYC (P < .001). However, correlation analysis showed that mtDNA copy number was not associated with the expression of these genes.

In contrast, PGC1A expression was not significantly different in patients, compared with controls overall, although there was a subset of patients whose PGC1A expression was extremely high, according to the researchers.

Importantly, however, in the subset of patients with high PGC1A expression (n = 28), mtDNA copy number had a positive correlation with PGC1A expression (P = .013). On the other hand, among patients with low MYC expression (n = 27), there was no correlation of mtDNA copy number with either PGC1A or MYC expression.

These results were corroborated in in vitro studies, where treatment with the inhibitor tigecycline led to a significant decrease in expression of MYC (P < .001), TFAM (P = .037) and ND3 (P = .010) but resulted in no significant change in mtDNA copy number (P = .23) or expression of PGC1A (P = .10).
 

Therapeutic candidate?

In contrast to the case of MYC, in vitro PGC1A inhibition significantly reduced mtDNA copy number in along with expression of TFAM and even expression of POLG and POLRMT at higher concentration.

“This observation is in line with our finding in patient samples as well that PGC1A expression positively correlated with mtDNA copy number, more so in patients with higher PGC1A expression,” the researchers stated.

“This makes it plausible to infer that PGC1A may have a possible role in enhancing mtDNA copy number in AML patients, likely independent of MYC,” they added. “Therefore, a strategy of designing therapeutics using already approved inhibitors targeting PGC1A may be an exciting area of therapeutic intervention.”

The authors reported that they have no competing financial conflicts of interests.

mlesney@mdedge.com

Mitochondrial DNA (mtDNA) copy number alterations are known to occur in acute myeloid leukemia (AML), however their biological significance has not been well studied. Pediatric AML has a distinct biology, different from adults, and with heterogeneous clinical outcomes, the biological basis of which are not well understood, according to researchers Shilpi Chaudhary, PhD, of the All India Institute of Medical Sciences, New Delhi, and colleagues.

wir0man/GettyImages

Their analysis of 123 pediatric patients with AML found that mtDNA copy number was an independent predictor of aggressive disease, lower event-free survival, and overall survival, according to a report published in Mitochondrion.

In an attempt to find the biological factors involved in the increased mtDNA copy numbers and their effect on the development and aggressiveness of pediatric AML, the researchers studied the regulation and significance of mtDNA copy number in pediatric AML patients using quantitative real time–polymerase chain reaction, as well as in vitro studies. For patients, results were correlated with clinical outcomes.

Mitochondrial biogenesis genes (TFAM, POLG, POLRMT) and two regulator of mitochondrial biogenesis, MYC and PGC1A, were also assessed, according to Dr. Chaudhary and colleagues.
 

Predictive results

MtDNA copy number was significantly higher in patients, compared with controls (P < .001) and was found to be an independent predictor of aggressive disease (P = .006), lower event-free survival (P = .033), and overall survival (P = .007).

TFAM, POLG & POLRMT and ND3 were also found to be significantly up-regulated in patients, compared with controls as was the expression of the mitochondrial biogenesis regulator MYC (P < .001). However, correlation analysis showed that mtDNA copy number was not associated with the expression of these genes.

In contrast, PGC1A expression was not significantly different in patients, compared with controls overall, although there was a subset of patients whose PGC1A expression was extremely high, according to the researchers.

Importantly, however, in the subset of patients with high PGC1A expression (n = 28), mtDNA copy number had a positive correlation with PGC1A expression (P = .013). On the other hand, among patients with low MYC expression (n = 27), there was no correlation of mtDNA copy number with either PGC1A or MYC expression.

These results were corroborated in in vitro studies, where treatment with the inhibitor tigecycline led to a significant decrease in expression of MYC (P < .001), TFAM (P = .037) and ND3 (P = .010) but resulted in no significant change in mtDNA copy number (P = .23) or expression of PGC1A (P = .10).
 

Therapeutic candidate?

In contrast to the case of MYC, in vitro PGC1A inhibition significantly reduced mtDNA copy number in along with expression of TFAM and even expression of POLG and POLRMT at higher concentration.

“This observation is in line with our finding in patient samples as well that PGC1A expression positively correlated with mtDNA copy number, more so in patients with higher PGC1A expression,” the researchers stated.

“This makes it plausible to infer that PGC1A may have a possible role in enhancing mtDNA copy number in AML patients, likely independent of MYC,” they added. “Therefore, a strategy of designing therapeutics using already approved inhibitors targeting PGC1A may be an exciting area of therapeutic intervention.”

The authors reported that they have no competing financial conflicts of interests.

mlesney@mdedge.com

Mitochondrial DNA (mtDNA) copy number alterations are known to occur in acute myeloid leukemia (AML), however their biological significance has not been well studied. Pediatric AML has a distinct biology, different from adults, and with heterogeneous clinical outcomes, the biological basis of which are not well understood, according to researchers Shilpi Chaudhary, PhD, of the All India Institute of Medical Sciences, New Delhi, and colleagues.

wir0man/GettyImages

Their analysis of 123 pediatric patients with AML found that mtDNA copy number was an independent predictor of aggressive disease, lower event-free survival, and overall survival, according to a report published in Mitochondrion.

In an attempt to find the biological factors involved in the increased mtDNA copy numbers and their effect on the development and aggressiveness of pediatric AML, the researchers studied the regulation and significance of mtDNA copy number in pediatric AML patients using quantitative real time–polymerase chain reaction, as well as in vitro studies. For patients, results were correlated with clinical outcomes.

Mitochondrial biogenesis genes (TFAM, POLG, POLRMT) and two regulator of mitochondrial biogenesis, MYC and PGC1A, were also assessed, according to Dr. Chaudhary and colleagues.
 

Predictive results

MtDNA copy number was significantly higher in patients, compared with controls (P < .001) and was found to be an independent predictor of aggressive disease (P = .006), lower event-free survival (P = .033), and overall survival (P = .007).

TFAM, POLG & POLRMT and ND3 were also found to be significantly up-regulated in patients, compared with controls as was the expression of the mitochondrial biogenesis regulator MYC (P < .001). However, correlation analysis showed that mtDNA copy number was not associated with the expression of these genes.

In contrast, PGC1A expression was not significantly different in patients, compared with controls overall, although there was a subset of patients whose PGC1A expression was extremely high, according to the researchers.

Importantly, however, in the subset of patients with high PGC1A expression (n = 28), mtDNA copy number had a positive correlation with PGC1A expression (P = .013). On the other hand, among patients with low MYC expression (n = 27), there was no correlation of mtDNA copy number with either PGC1A or MYC expression.

These results were corroborated in in vitro studies, where treatment with the inhibitor tigecycline led to a significant decrease in expression of MYC (P < .001), TFAM (P = .037) and ND3 (P = .010) but resulted in no significant change in mtDNA copy number (P = .23) or expression of PGC1A (P = .10).
 

Therapeutic candidate?

In contrast to the case of MYC, in vitro PGC1A inhibition significantly reduced mtDNA copy number in along with expression of TFAM and even expression of POLG and POLRMT at higher concentration.

“This observation is in line with our finding in patient samples as well that PGC1A expression positively correlated with mtDNA copy number, more so in patients with higher PGC1A expression,” the researchers stated.

“This makes it plausible to infer that PGC1A may have a possible role in enhancing mtDNA copy number in AML patients, likely independent of MYC,” they added. “Therefore, a strategy of designing therapeutics using already approved inhibitors targeting PGC1A may be an exciting area of therapeutic intervention.”

The authors reported that they have no competing financial conflicts of interests.

mlesney@mdedge.com

In the United States, the rate of mortality caused by severe maternal morbidity has improved over time, but failure to rescue is significantly more common among racial and ethnic minorities.

These failures are a “major contributing factor” to the disproportionately higher rate of maternal mortality among women of color, reported lead author Jean Guglielminotti, MD, PhD, of Columbia University, New York, and colleagues.

“Racial and ethnic disparities in severe maternal morbidity are a growing public health concern in the United States,” the investigators wrote in Obstetrics & Gynecology.

“The reported incidence of severe maternal morbidity is twofold to threefold higher among Black American women, compared with non-Hispanic White women; and although the difference is less pronounced, the incidence of severe maternal morbidity also is higher among Hispanic, Asian and Pacific Islander, and Native American women.”

The ensuant, disproportionate risk of maternal mortality may be further exacerbated by disparities in hospitals, according to the investigators. They noted that non-Hispanic White women tend to give birth in different hospitals than racial and ethnic minorities, and the hospitals serving people of color “are characterized by lower performance on maternal safety indicators.”

Even within hospitals that most often serve minorities, severe maternal morbidity is more common among women of color than women who are White, they added.

“However, the simple severe maternal morbidity rate is insufficient to assess hospital performance and should be complemented with the rate of failure to rescue,” wrote Dr. Guglielminotti and colleagues.
 

Measuring failure to rescue across racial and ethnic groups

According to the investigators, failure-to-rescue rate advances focus from complications themselves – which can occur when care is appropriate and may stem from patient characteristics – to a hospital’s response to such complications.

Using this metric, a 2016 study by Friedman and colleagues, which included data from 1998 to 2010, showed failure to rescue was more common among Hispanic and non-Hispanic Black women than white women.

The present study built upon these findings with data from almost 74 million delivery hospitalizations in the National Inpatient Sample (1999-2017). The population included 993,864 women with severe maternal morbidity, among whom 4,328 died.

Overall, the failure-to-rescue rate decreased over the course of the study from 13.2% in 1999-2000 to 4.5% in 2017 (P < .001).

Yet racial and ethnic inequities were apparent.

Compared with White women, non-Hispanic Black women had a significantly higher failure-to-rescue rate ratio (1.79; 95% CI, 1.77-1.81), as did Hispanic women (RR, 1.08; 95% CI, 1.06-1.09), women of other non-White racial/ethnic backgrounds (RR, 1.39; 95% CI, 1.37-1.41), and women documented without racial/ethnic designations (RR, 1.43; 95% CI, 1.42-1.45).

“Failure to rescue from severe maternal morbidity remains a major contributing factor to the excess maternal mortality in racial and ethnic minority women in the United States,” the investigators concluded. “This finding underscores the need to identify factors accounting for these disparities and develop hospital-based interventions to reduce excess maternal mortality in racial and ethnic minority women.”
 

Striving for progress through systemic change

According to Eve Espey, MD, MPH, of the University of New Mexico, Albuquerque, “this study adds to the literature demonstrating that structural racism and implicit bias have profound negative impacts,” which “has implications for action.”

“We must increase efforts to improve maternal safety, including the rollout of Alliance for Innovation on Maternal Health [AIM] bundles through statewide perinatal quality collaboratives,” Dr. Espey said. “AIM bundle implementation must focus on the context of health inequities related to racism and bias. Similarly, we must consider large scale public policy changes building on the Affordable Care Act, such as universal health coverage throughout the life span, [which] equitably increases access to quality health care for all.”

Constance Bohon, MD, of Sibley Memorial Hospital, Washington, offered a similar viewpoint, and suggested that further analyses could reveal the impacts of systemic changes, thereby guiding future interventions.

“It would be interesting to determine if declines in failure to rescue rates were greatest in states that implemented AIM safety bundles [in 2012] as compared with the states that did not,” Dr. Bohon said. “The same assessment could be made with a comparison between the states that did and those that did not approve the Medicaid expansion [in 2014]. Other beneficial data would be a comparison of the failure-to-rescue rates in hospitals that provide the same obstetrical level of care. Further studies need to be done in order to identify factors that have the greatest impact on the failure-to-rescue rate. Subsequently, proposals can be suggested for actions that can be taken to decrease the excess maternal mortality in racial and ethnic minorities.”
 

Comparing the U.S. with the rest of the world

In an accompanying editorial, Marian F. MacDorman, PhD, of the University of Maryland, College Park, and Eugene Declercq, PhD, of Boston University, put the findings in a global context.

They noted that, in the United States over the past 2 decades, the rate of maternal mortality has either remained flat or increased, depending on study methodology; however, the relative state of affairs between the United States and the rest of the world is more straightforward.

“What is clear is that U.S. maternal mortality did not decline from 2000 to 2018,” wrote Dr. MacDorman and Dr. Declercq. “This contrasts with World Health Organization data showing that maternal mortality declined by 38% worldwide and by 53% in Europe from 2000 to 2017. In fact, North America was the only world region to not show substantial declines in maternal mortality during the period, and U.S. maternal mortality rates are nearly twice those in Europe.”

Within the US, these shortcomings are felt most acutely among racial and ethnic minorities, they noted, as the present study suggests.

“The U.S. is still plagued by wide racial disparities, with similar or larger Black-White maternal mortality disparities in 2018 than existed in the 1940s,” they wrote. “Thus, any euphoria generated by the lack of increase in maternal mortality (if accurate) must be set in the context of worldwide improvements, in which the U.S. is an outlier with no improvement. The U.S. can and should do better!”

To this end, Dr. MacDorman and Dr. Declercq wrote, “additional training and vigilance among clinicians can help to avert these largely preventable deaths. In addition, applying this same rigor to preventing deaths that occur in the community before and after birth, combined with a focus on social determinants among women during the reproductive years, will be essential to lowering U.S. maternal mortality overall and eliminating longstanding racial inequities.”

The study received no external funding. The investigators reported no conflicts of interest.

In the United States, the rate of mortality caused by severe maternal morbidity has improved over time, but failure to rescue is significantly more common among racial and ethnic minorities.

These failures are a “major contributing factor” to the disproportionately higher rate of maternal mortality among women of color, reported lead author Jean Guglielminotti, MD, PhD, of Columbia University, New York, and colleagues.

“Racial and ethnic disparities in severe maternal morbidity are a growing public health concern in the United States,” the investigators wrote in Obstetrics & Gynecology.

“The reported incidence of severe maternal morbidity is twofold to threefold higher among Black American women, compared with non-Hispanic White women; and although the difference is less pronounced, the incidence of severe maternal morbidity also is higher among Hispanic, Asian and Pacific Islander, and Native American women.”

The ensuant, disproportionate risk of maternal mortality may be further exacerbated by disparities in hospitals, according to the investigators. They noted that non-Hispanic White women tend to give birth in different hospitals than racial and ethnic minorities, and the hospitals serving people of color “are characterized by lower performance on maternal safety indicators.”

Even within hospitals that most often serve minorities, severe maternal morbidity is more common among women of color than women who are White, they added.

“However, the simple severe maternal morbidity rate is insufficient to assess hospital performance and should be complemented with the rate of failure to rescue,” wrote Dr. Guglielminotti and colleagues.
 

Measuring failure to rescue across racial and ethnic groups

According to the investigators, failure-to-rescue rate advances focus from complications themselves – which can occur when care is appropriate and may stem from patient characteristics – to a hospital’s response to such complications.

Using this metric, a 2016 study by Friedman and colleagues, which included data from 1998 to 2010, showed failure to rescue was more common among Hispanic and non-Hispanic Black women than white women.

The present study built upon these findings with data from almost 74 million delivery hospitalizations in the National Inpatient Sample (1999-2017). The population included 993,864 women with severe maternal morbidity, among whom 4,328 died.

Overall, the failure-to-rescue rate decreased over the course of the study from 13.2% in 1999-2000 to 4.5% in 2017 (P < .001).

Yet racial and ethnic inequities were apparent.

Compared with White women, non-Hispanic Black women had a significantly higher failure-to-rescue rate ratio (1.79; 95% CI, 1.77-1.81), as did Hispanic women (RR, 1.08; 95% CI, 1.06-1.09), women of other non-White racial/ethnic backgrounds (RR, 1.39; 95% CI, 1.37-1.41), and women documented without racial/ethnic designations (RR, 1.43; 95% CI, 1.42-1.45).

“Failure to rescue from severe maternal morbidity remains a major contributing factor to the excess maternal mortality in racial and ethnic minority women in the United States,” the investigators concluded. “This finding underscores the need to identify factors accounting for these disparities and develop hospital-based interventions to reduce excess maternal mortality in racial and ethnic minority women.”
 

Striving for progress through systemic change

According to Eve Espey, MD, MPH, of the University of New Mexico, Albuquerque, “this study adds to the literature demonstrating that structural racism and implicit bias have profound negative impacts,” which “has implications for action.”

“We must increase efforts to improve maternal safety, including the rollout of Alliance for Innovation on Maternal Health [AIM] bundles through statewide perinatal quality collaboratives,” Dr. Espey said. “AIM bundle implementation must focus on the context of health inequities related to racism and bias. Similarly, we must consider large scale public policy changes building on the Affordable Care Act, such as universal health coverage throughout the life span, [which] equitably increases access to quality health care for all.”

Constance Bohon, MD, of Sibley Memorial Hospital, Washington, offered a similar viewpoint, and suggested that further analyses could reveal the impacts of systemic changes, thereby guiding future interventions.

“It would be interesting to determine if declines in failure to rescue rates were greatest in states that implemented AIM safety bundles [in 2012] as compared with the states that did not,” Dr. Bohon said. “The same assessment could be made with a comparison between the states that did and those that did not approve the Medicaid expansion [in 2014]. Other beneficial data would be a comparison of the failure-to-rescue rates in hospitals that provide the same obstetrical level of care. Further studies need to be done in order to identify factors that have the greatest impact on the failure-to-rescue rate. Subsequently, proposals can be suggested for actions that can be taken to decrease the excess maternal mortality in racial and ethnic minorities.”
 

Comparing the U.S. with the rest of the world

In an accompanying editorial, Marian F. MacDorman, PhD, of the University of Maryland, College Park, and Eugene Declercq, PhD, of Boston University, put the findings in a global context.

They noted that, in the United States over the past 2 decades, the rate of maternal mortality has either remained flat or increased, depending on study methodology; however, the relative state of affairs between the United States and the rest of the world is more straightforward.

“What is clear is that U.S. maternal mortality did not decline from 2000 to 2018,” wrote Dr. MacDorman and Dr. Declercq. “This contrasts with World Health Organization data showing that maternal mortality declined by 38% worldwide and by 53% in Europe from 2000 to 2017. In fact, North America was the only world region to not show substantial declines in maternal mortality during the period, and U.S. maternal mortality rates are nearly twice those in Europe.”

Within the US, these shortcomings are felt most acutely among racial and ethnic minorities, they noted, as the present study suggests.

“The U.S. is still plagued by wide racial disparities, with similar or larger Black-White maternal mortality disparities in 2018 than existed in the 1940s,” they wrote. “Thus, any euphoria generated by the lack of increase in maternal mortality (if accurate) must be set in the context of worldwide improvements, in which the U.S. is an outlier with no improvement. The U.S. can and should do better!”

To this end, Dr. MacDorman and Dr. Declercq wrote, “additional training and vigilance among clinicians can help to avert these largely preventable deaths. In addition, applying this same rigor to preventing deaths that occur in the community before and after birth, combined with a focus on social determinants among women during the reproductive years, will be essential to lowering U.S. maternal mortality overall and eliminating longstanding racial inequities.”

The study received no external funding. The investigators reported no conflicts of interest.

In the United States, the rate of mortality caused by severe maternal morbidity has improved over time, but failure to rescue is significantly more common among racial and ethnic minorities.

These failures are a “major contributing factor” to the disproportionately higher rate of maternal mortality among women of color, reported lead author Jean Guglielminotti, MD, PhD, of Columbia University, New York, and colleagues.

“Racial and ethnic disparities in severe maternal morbidity are a growing public health concern in the United States,” the investigators wrote in Obstetrics & Gynecology.

“The reported incidence of severe maternal morbidity is twofold to threefold higher among Black American women, compared with non-Hispanic White women; and although the difference is less pronounced, the incidence of severe maternal morbidity also is higher among Hispanic, Asian and Pacific Islander, and Native American women.”

The ensuant, disproportionate risk of maternal mortality may be further exacerbated by disparities in hospitals, according to the investigators. They noted that non-Hispanic White women tend to give birth in different hospitals than racial and ethnic minorities, and the hospitals serving people of color “are characterized by lower performance on maternal safety indicators.”

Even within hospitals that most often serve minorities, severe maternal morbidity is more common among women of color than women who are White, they added.

“However, the simple severe maternal morbidity rate is insufficient to assess hospital performance and should be complemented with the rate of failure to rescue,” wrote Dr. Guglielminotti and colleagues.
 

Measuring failure to rescue across racial and ethnic groups

According to the investigators, failure-to-rescue rate advances focus from complications themselves – which can occur when care is appropriate and may stem from patient characteristics – to a hospital’s response to such complications.

Using this metric, a 2016 study by Friedman and colleagues, which included data from 1998 to 2010, showed failure to rescue was more common among Hispanic and non-Hispanic Black women than white women.

The present study built upon these findings with data from almost 74 million delivery hospitalizations in the National Inpatient Sample (1999-2017). The population included 993,864 women with severe maternal morbidity, among whom 4,328 died.

Overall, the failure-to-rescue rate decreased over the course of the study from 13.2% in 1999-2000 to 4.5% in 2017 (P < .001).

Yet racial and ethnic inequities were apparent.

Compared with White women, non-Hispanic Black women had a significantly higher failure-to-rescue rate ratio (1.79; 95% CI, 1.77-1.81), as did Hispanic women (RR, 1.08; 95% CI, 1.06-1.09), women of other non-White racial/ethnic backgrounds (RR, 1.39; 95% CI, 1.37-1.41), and women documented without racial/ethnic designations (RR, 1.43; 95% CI, 1.42-1.45).

“Failure to rescue from severe maternal morbidity remains a major contributing factor to the excess maternal mortality in racial and ethnic minority women in the United States,” the investigators concluded. “This finding underscores the need to identify factors accounting for these disparities and develop hospital-based interventions to reduce excess maternal mortality in racial and ethnic minority women.”
 

Striving for progress through systemic change

According to Eve Espey, MD, MPH, of the University of New Mexico, Albuquerque, “this study adds to the literature demonstrating that structural racism and implicit bias have profound negative impacts,” which “has implications for action.”

“We must increase efforts to improve maternal safety, including the rollout of Alliance for Innovation on Maternal Health [AIM] bundles through statewide perinatal quality collaboratives,” Dr. Espey said. “AIM bundle implementation must focus on the context of health inequities related to racism and bias. Similarly, we must consider large scale public policy changes building on the Affordable Care Act, such as universal health coverage throughout the life span, [which] equitably increases access to quality health care for all.”

Constance Bohon, MD, of Sibley Memorial Hospital, Washington, offered a similar viewpoint, and suggested that further analyses could reveal the impacts of systemic changes, thereby guiding future interventions.

“It would be interesting to determine if declines in failure to rescue rates were greatest in states that implemented AIM safety bundles [in 2012] as compared with the states that did not,” Dr. Bohon said. “The same assessment could be made with a comparison between the states that did and those that did not approve the Medicaid expansion [in 2014]. Other beneficial data would be a comparison of the failure-to-rescue rates in hospitals that provide the same obstetrical level of care. Further studies need to be done in order to identify factors that have the greatest impact on the failure-to-rescue rate. Subsequently, proposals can be suggested for actions that can be taken to decrease the excess maternal mortality in racial and ethnic minorities.”
 

Comparing the U.S. with the rest of the world

In an accompanying editorial, Marian F. MacDorman, PhD, of the University of Maryland, College Park, and Eugene Declercq, PhD, of Boston University, put the findings in a global context.

They noted that, in the United States over the past 2 decades, the rate of maternal mortality has either remained flat or increased, depending on study methodology; however, the relative state of affairs between the United States and the rest of the world is more straightforward.

“What is clear is that U.S. maternal mortality did not decline from 2000 to 2018,” wrote Dr. MacDorman and Dr. Declercq. “This contrasts with World Health Organization data showing that maternal mortality declined by 38% worldwide and by 53% in Europe from 2000 to 2017. In fact, North America was the only world region to not show substantial declines in maternal mortality during the period, and U.S. maternal mortality rates are nearly twice those in Europe.”

Within the US, these shortcomings are felt most acutely among racial and ethnic minorities, they noted, as the present study suggests.

“The U.S. is still plagued by wide racial disparities, with similar or larger Black-White maternal mortality disparities in 2018 than existed in the 1940s,” they wrote. “Thus, any euphoria generated by the lack of increase in maternal mortality (if accurate) must be set in the context of worldwide improvements, in which the U.S. is an outlier with no improvement. The U.S. can and should do better!”

To this end, Dr. MacDorman and Dr. Declercq wrote, “additional training and vigilance among clinicians can help to avert these largely preventable deaths. In addition, applying this same rigor to preventing deaths that occur in the community before and after birth, combined with a focus on social determinants among women during the reproductive years, will be essential to lowering U.S. maternal mortality overall and eliminating longstanding racial inequities.”

The study received no external funding. The investigators reported no conflicts of interest.

A study of U.S. children across ethnic and racial groups found that Asians were least likely to receive therapy for ADHD, compared with White children – who had the highest odds of getting some kind of treatment over other groups.

Other studies have identified disparity problems in ADHD diagnosis, although results have varied on inequality metrics. Few studies have looked at Asians separately, according to the study’s lead author, Yu Shi, MD, MPH. “They were usually just classified as ‘other’ or as non-White,” Dr. Shi, a consultant with the Mayo Clinic’s division of pediatric anesthesia in Rochester, Minn., said in an interview.

Disparities might stem from cultural and socioeconomic factors, and the way in which clinicians interpret behavior and apply diagnostic criteria.

“Further understanding of how treatment patterns for ADHD may differ based on race, at the time of initial diagnosis and in the early stages of treatment, may help all children receive appropriate evidence-based care,” Dr. Shi and colleagues reported in JAMA Network Open.
 

Researchers develop large birth cohort

Dr. Shi and colleagues hypothesized that non-Hispanic White children had a greater chance of getting diagnosed and treated within the first year of diagnosis than that of other ethnic and racial cohorts. Using administrative claims data with socioeconomic status information from a national commercial insurance warehouse, they constructed a retrospective birth cohort of children born between Jan. 1, 2006, and Dec. 31, 2012. The children had continuous insurance coverage for at least 4 years, and represented non-Hispanic Whites, Blacks, Hispanics, and Asians. Self-reporting identified the race/ethnicity groups.

Investigators analyzed ADHD diagnosis and treatment data on 238,011 children between October 2019 and December 2020, using a multivariate Cox regression model to adjust for sex, region, and household income. Primary and secondary outcomes included ADHD diagnosis as defined by recent ICD codes, ADHD behavior, and medication therapies in the clinical setting after initial diagnosis, respectively.

Whites made up most of the cohort (72.7%), followed by Hispanics (9.8%), Asians (6.7%), and Blacks (6.2%). Nearly half the population was female (48.8%). During the follow-up period with these children, 11,401, or 4.8%, had received an ADHD diagnosis. Mean age of diagnosis was 6.5 years, and overall incidence of ADHD was 69 per 10,000 person years (95% confidence interval, 68-70).

Pediatricians were most likely to make an ADHD diagnosis, although the study cited other clinicians, such as psychiatrists, neurologists, psychologists, and family practice clinicians, as responsible for these decisions.

Children diagnosed with ADHD had more years of coverage in the data set, and were more likely to be White and male. The Southern census region had a higher representation of diagnoses (50.6%) than did the Northeast region (11.8%).
 

Asians at highest odds for no treatment

Taking a closer look at race and ethnicity, Whites had the highest cumulative incidence of ADHD (14.19%), versus Asian children, who had lowest incidence (6.08%). “The curves for Black and Hispanic children were similar in shape and slightly lower than that for White children,” reported the investigators.

White children had higher odds of receiving some kind of treatment, compared with the other groups.

Incidence of medication treatment was lower among Asians and Hispanics. In a striking finding, Asians were most likely to receive no treatment at all (odds ratio compared with White children, 0.54; 95% confidence interval, 0.42-0.70). “However, the percentage of Asian children receiving psychotherapy was not significantly lower than other groups, which is different than a 2013 study finding that Asian children with ADHD were less likely to use mental health services,” they noted.

Most of the patients received medication (32.4%) in the first year after diagnosis, whereas (19.4%) received behavioral therapy only. Nineteen percent had both. More than 29% of these cases had no claims associated with either treatment. Among school-aged children, 65.5% were prescribed medications, compared with just 14.4% who received therapy. Twenty percent had no treatment.

Diagnosis with another disorder often preceded ADHD diagnosis. Results varied among racial groups. White children were more likely than were Black children to be diagnosed with an anxiety or adjustment disorder. Relative to White children, Asians were more likely to be diagnosed with autism spectrum disorder, speech sound disorders, or unspecified neurodevelopmental disorders. Even after an ADHD diagnosis, clinicians were more likely to diagnose Asian children with autism.
 

Parents may influence treatment decisions

Parental views and preferences may explain some of the variations in diagnosis and treatment among the racial/ethnic groups.

“In order for a diagnosis of ADHD to happen, a parent has first to recognize a problem and bring a child for clinical evaluation,” said Dr. Shi. “A certain behavior could be viewed as normal or a problem depending on a person’s cultural or racial background.” It’s unclear whether clinicians played any role in diagnosis disparities, he added. Patients’ concerns about racism might also influence the desire to get treated in health care systems.

Overall, the findings underscore the presence of racial and ethnic disparities in ADHD diagnosis and treatment. Future research should explore the underlying mechanisms, Dr. Shi suggested. While he and his colleagues have no immediate plans to do another ADHD study, “we’re planning on research to understand disparities in surgery in children,” he said.

The authors cited numerous limitations with their study. Use of ICD codes to identify cases might not have represented true clinical diagnosis, since the data were collected for billing, not research purposes. Investigators drew participants from a commercial insurance database, which did not necessarily reflect all U.S. children. The results might not represent a large number of children covered by Medicaid, for example, noted Dr. Shi. “It is more difficult to work with Medicaid data because there’s no national-level Medicaid data for research. Only state-level data is available.”

Because of other data gaps, Dr. Shi and colleagues might have underestimated the number of children in therapy.
 

A need for ‘culturally sensitive care’

The findings “ultimately demonstrate the need for culturally sensitive care in the diagnosis and treatment of children and adolescents,” said Tiffani L. Bell, MD, a psychiatrist in Winston-Salem, N.C., who was not involved with the study. She specializes in child and adolescent psychiatry.

The exact cause for racial disparity in diagnosis and treatment of ADHD is unknown and likely multifaceted, she continued. “It may be due to differences in the way that disruptive behaviors are interrupted based on factors such as race. This study found that Asian parents often brought their children in for evaluation for reasons other than ADHD. Concerns surrounding the stigma of mental health treatment and racism also could contribute to the disparity in diagnosis and treatment,” she said.

Dr. Bell said she hopes to see future studies that address the impact of social determinants of health on mental illness and investigate underlying causes that contribute to disparities in treatment and diagnosis.

The Mayo Clinic supported the study but had no role in its design or research methods. The authors reported no conflicts of interest.

A study of U.S. children across ethnic and racial groups found that Asians were least likely to receive therapy for ADHD, compared with White children – who had the highest odds of getting some kind of treatment over other groups.

Other studies have identified disparity problems in ADHD diagnosis, although results have varied on inequality metrics. Few studies have looked at Asians separately, according to the study’s lead author, Yu Shi, MD, MPH. “They were usually just classified as ‘other’ or as non-White,” Dr. Shi, a consultant with the Mayo Clinic’s division of pediatric anesthesia in Rochester, Minn., said in an interview.

Disparities might stem from cultural and socioeconomic factors, and the way in which clinicians interpret behavior and apply diagnostic criteria.

“Further understanding of how treatment patterns for ADHD may differ based on race, at the time of initial diagnosis and in the early stages of treatment, may help all children receive appropriate evidence-based care,” Dr. Shi and colleagues reported in JAMA Network Open.
 

Researchers develop large birth cohort

Dr. Shi and colleagues hypothesized that non-Hispanic White children had a greater chance of getting diagnosed and treated within the first year of diagnosis than that of other ethnic and racial cohorts. Using administrative claims data with socioeconomic status information from a national commercial insurance warehouse, they constructed a retrospective birth cohort of children born between Jan. 1, 2006, and Dec. 31, 2012. The children had continuous insurance coverage for at least 4 years, and represented non-Hispanic Whites, Blacks, Hispanics, and Asians. Self-reporting identified the race/ethnicity groups.

Investigators analyzed ADHD diagnosis and treatment data on 238,011 children between October 2019 and December 2020, using a multivariate Cox regression model to adjust for sex, region, and household income. Primary and secondary outcomes included ADHD diagnosis as defined by recent ICD codes, ADHD behavior, and medication therapies in the clinical setting after initial diagnosis, respectively.

Whites made up most of the cohort (72.7%), followed by Hispanics (9.8%), Asians (6.7%), and Blacks (6.2%). Nearly half the population was female (48.8%). During the follow-up period with these children, 11,401, or 4.8%, had received an ADHD diagnosis. Mean age of diagnosis was 6.5 years, and overall incidence of ADHD was 69 per 10,000 person years (95% confidence interval, 68-70).

Pediatricians were most likely to make an ADHD diagnosis, although the study cited other clinicians, such as psychiatrists, neurologists, psychologists, and family practice clinicians, as responsible for these decisions.

Children diagnosed with ADHD had more years of coverage in the data set, and were more likely to be White and male. The Southern census region had a higher representation of diagnoses (50.6%) than did the Northeast region (11.8%).
 

Asians at highest odds for no treatment

Taking a closer look at race and ethnicity, Whites had the highest cumulative incidence of ADHD (14.19%), versus Asian children, who had lowest incidence (6.08%). “The curves for Black and Hispanic children were similar in shape and slightly lower than that for White children,” reported the investigators.

White children had higher odds of receiving some kind of treatment, compared with the other groups.

Incidence of medication treatment was lower among Asians and Hispanics. In a striking finding, Asians were most likely to receive no treatment at all (odds ratio compared with White children, 0.54; 95% confidence interval, 0.42-0.70). “However, the percentage of Asian children receiving psychotherapy was not significantly lower than other groups, which is different than a 2013 study finding that Asian children with ADHD were less likely to use mental health services,” they noted.

Most of the patients received medication (32.4%) in the first year after diagnosis, whereas (19.4%) received behavioral therapy only. Nineteen percent had both. More than 29% of these cases had no claims associated with either treatment. Among school-aged children, 65.5% were prescribed medications, compared with just 14.4% who received therapy. Twenty percent had no treatment.

Diagnosis with another disorder often preceded ADHD diagnosis. Results varied among racial groups. White children were more likely than were Black children to be diagnosed with an anxiety or adjustment disorder. Relative to White children, Asians were more likely to be diagnosed with autism spectrum disorder, speech sound disorders, or unspecified neurodevelopmental disorders. Even after an ADHD diagnosis, clinicians were more likely to diagnose Asian children with autism.
 

Parents may influence treatment decisions

Parental views and preferences may explain some of the variations in diagnosis and treatment among the racial/ethnic groups.

“In order for a diagnosis of ADHD to happen, a parent has first to recognize a problem and bring a child for clinical evaluation,” said Dr. Shi. “A certain behavior could be viewed as normal or a problem depending on a person’s cultural or racial background.” It’s unclear whether clinicians played any role in diagnosis disparities, he added. Patients’ concerns about racism might also influence the desire to get treated in health care systems.

Overall, the findings underscore the presence of racial and ethnic disparities in ADHD diagnosis and treatment. Future research should explore the underlying mechanisms, Dr. Shi suggested. While he and his colleagues have no immediate plans to do another ADHD study, “we’re planning on research to understand disparities in surgery in children,” he said.

The authors cited numerous limitations with their study. Use of ICD codes to identify cases might not have represented true clinical diagnosis, since the data were collected for billing, not research purposes. Investigators drew participants from a commercial insurance database, which did not necessarily reflect all U.S. children. The results might not represent a large number of children covered by Medicaid, for example, noted Dr. Shi. “It is more difficult to work with Medicaid data because there’s no national-level Medicaid data for research. Only state-level data is available.”

Because of other data gaps, Dr. Shi and colleagues might have underestimated the number of children in therapy.
 

A need for ‘culturally sensitive care’

The findings “ultimately demonstrate the need for culturally sensitive care in the diagnosis and treatment of children and adolescents,” said Tiffani L. Bell, MD, a psychiatrist in Winston-Salem, N.C., who was not involved with the study. She specializes in child and adolescent psychiatry.

The exact cause for racial disparity in diagnosis and treatment of ADHD is unknown and likely multifaceted, she continued. “It may be due to differences in the way that disruptive behaviors are interrupted based on factors such as race. This study found that Asian parents often brought their children in for evaluation for reasons other than ADHD. Concerns surrounding the stigma of mental health treatment and racism also could contribute to the disparity in diagnosis and treatment,” she said.

Dr. Bell said she hopes to see future studies that address the impact of social determinants of health on mental illness and investigate underlying causes that contribute to disparities in treatment and diagnosis.

The Mayo Clinic supported the study but had no role in its design or research methods. The authors reported no conflicts of interest.

A study of U.S. children across ethnic and racial groups found that Asians were least likely to receive therapy for ADHD, compared with White children – who had the highest odds of getting some kind of treatment over other groups.

Other studies have identified disparity problems in ADHD diagnosis, although results have varied on inequality metrics. Few studies have looked at Asians separately, according to the study’s lead author, Yu Shi, MD, MPH. “They were usually just classified as ‘other’ or as non-White,” Dr. Shi, a consultant with the Mayo Clinic’s division of pediatric anesthesia in Rochester, Minn., said in an interview.

Disparities might stem from cultural and socioeconomic factors, and the way in which clinicians interpret behavior and apply diagnostic criteria.

“Further understanding of how treatment patterns for ADHD may differ based on race, at the time of initial diagnosis and in the early stages of treatment, may help all children receive appropriate evidence-based care,” Dr. Shi and colleagues reported in JAMA Network Open.
 

Researchers develop large birth cohort

Dr. Shi and colleagues hypothesized that non-Hispanic White children had a greater chance of getting diagnosed and treated within the first year of diagnosis than that of other ethnic and racial cohorts. Using administrative claims data with socioeconomic status information from a national commercial insurance warehouse, they constructed a retrospective birth cohort of children born between Jan. 1, 2006, and Dec. 31, 2012. The children had continuous insurance coverage for at least 4 years, and represented non-Hispanic Whites, Blacks, Hispanics, and Asians. Self-reporting identified the race/ethnicity groups.

Investigators analyzed ADHD diagnosis and treatment data on 238,011 children between October 2019 and December 2020, using a multivariate Cox regression model to adjust for sex, region, and household income. Primary and secondary outcomes included ADHD diagnosis as defined by recent ICD codes, ADHD behavior, and medication therapies in the clinical setting after initial diagnosis, respectively.

Whites made up most of the cohort (72.7%), followed by Hispanics (9.8%), Asians (6.7%), and Blacks (6.2%). Nearly half the population was female (48.8%). During the follow-up period with these children, 11,401, or 4.8%, had received an ADHD diagnosis. Mean age of diagnosis was 6.5 years, and overall incidence of ADHD was 69 per 10,000 person years (95% confidence interval, 68-70).

Pediatricians were most likely to make an ADHD diagnosis, although the study cited other clinicians, such as psychiatrists, neurologists, psychologists, and family practice clinicians, as responsible for these decisions.

Children diagnosed with ADHD had more years of coverage in the data set, and were more likely to be White and male. The Southern census region had a higher representation of diagnoses (50.6%) than did the Northeast region (11.8%).
 

Asians at highest odds for no treatment

Taking a closer look at race and ethnicity, Whites had the highest cumulative incidence of ADHD (14.19%), versus Asian children, who had lowest incidence (6.08%). “The curves for Black and Hispanic children were similar in shape and slightly lower than that for White children,” reported the investigators.

White children had higher odds of receiving some kind of treatment, compared with the other groups.

Incidence of medication treatment was lower among Asians and Hispanics. In a striking finding, Asians were most likely to receive no treatment at all (odds ratio compared with White children, 0.54; 95% confidence interval, 0.42-0.70). “However, the percentage of Asian children receiving psychotherapy was not significantly lower than other groups, which is different than a 2013 study finding that Asian children with ADHD were less likely to use mental health services,” they noted.

Most of the patients received medication (32.4%) in the first year after diagnosis, whereas (19.4%) received behavioral therapy only. Nineteen percent had both. More than 29% of these cases had no claims associated with either treatment. Among school-aged children, 65.5% were prescribed medications, compared with just 14.4% who received therapy. Twenty percent had no treatment.

Diagnosis with another disorder often preceded ADHD diagnosis. Results varied among racial groups. White children were more likely than were Black children to be diagnosed with an anxiety or adjustment disorder. Relative to White children, Asians were more likely to be diagnosed with autism spectrum disorder, speech sound disorders, or unspecified neurodevelopmental disorders. Even after an ADHD diagnosis, clinicians were more likely to diagnose Asian children with autism.
 

Parents may influence treatment decisions

Parental views and preferences may explain some of the variations in diagnosis and treatment among the racial/ethnic groups.

“In order for a diagnosis of ADHD to happen, a parent has first to recognize a problem and bring a child for clinical evaluation,” said Dr. Shi. “A certain behavior could be viewed as normal or a problem depending on a person’s cultural or racial background.” It’s unclear whether clinicians played any role in diagnosis disparities, he added. Patients’ concerns about racism might also influence the desire to get treated in health care systems.

Overall, the findings underscore the presence of racial and ethnic disparities in ADHD diagnosis and treatment. Future research should explore the underlying mechanisms, Dr. Shi suggested. While he and his colleagues have no immediate plans to do another ADHD study, “we’re planning on research to understand disparities in surgery in children,” he said.

The authors cited numerous limitations with their study. Use of ICD codes to identify cases might not have represented true clinical diagnosis, since the data were collected for billing, not research purposes. Investigators drew participants from a commercial insurance database, which did not necessarily reflect all U.S. children. The results might not represent a large number of children covered by Medicaid, for example, noted Dr. Shi. “It is more difficult to work with Medicaid data because there’s no national-level Medicaid data for research. Only state-level data is available.”

Because of other data gaps, Dr. Shi and colleagues might have underestimated the number of children in therapy.
 

A need for ‘culturally sensitive care’

The findings “ultimately demonstrate the need for culturally sensitive care in the diagnosis and treatment of children and adolescents,” said Tiffani L. Bell, MD, a psychiatrist in Winston-Salem, N.C., who was not involved with the study. She specializes in child and adolescent psychiatry.

The exact cause for racial disparity in diagnosis and treatment of ADHD is unknown and likely multifaceted, she continued. “It may be due to differences in the way that disruptive behaviors are interrupted based on factors such as race. This study found that Asian parents often brought their children in for evaluation for reasons other than ADHD. Concerns surrounding the stigma of mental health treatment and racism also could contribute to the disparity in diagnosis and treatment,” she said.

Dr. Bell said she hopes to see future studies that address the impact of social determinants of health on mental illness and investigate underlying causes that contribute to disparities in treatment and diagnosis.

The Mayo Clinic supported the study but had no role in its design or research methods. The authors reported no conflicts of interest.

It has been more than 120 years since Ernst Wertheim, a Viennese surgeon, performed and described what is considered to have been the first radical total hysterectomy with lymphadenectomy for early-stage cervical cancer, yet this morbid procedure remains the standard of care for most early-stage cervical cancers. The rationale for this procedure, which included removal of the parametrial tissue, uterosacral and cardinal ligaments, and upper vagina en bloc with the cervix and uterus, was to obtain margins around a cancer that has a dominant radial growth pattern. The morbidity associated with this procedure is substantial. The parametrium houses important vascular, neural, and urologic structures. Unlike extrafascial hysterectomy, often referred to as “simple” hysterectomy, in which surgeons follow a fascial plane, and therefore a relatively avascular dissection, surgeons performing radical hysterectomy must venture outside of these embryologic fusion planes into less well–defined anatomy. Therefore, surgical complications are relatively common including hemorrhage, ureteral and bladder injury, as well as late-onset devastating complications such as fistula, urinary retention, or incontinence, and sexual dysfunction.¹ More recently, variations of the Wertheim-Meigs radical hysterectomy have been described, and objective classifications created, which include modified radical procedures (removing less parametria) and nerve-sparing procedures to facilitate standardized nomenclature for tailoring the most appropriate procedure for any given tumor.²

Courtesy Dr. Emma Rossi

The trend, and a positive one at that, over the course of the past century, has been a move away from routine radical surgical procedures for most clinical stage 1 cancers. No better example exists than breast cancer, in which the Halsted radical mastectomy has been largely replaced by less morbid breast-conserving or nonradical procedures with adjunct medical and radiation therapies offered to achieve high rates of cure with far more acceptable patient-centered outcomes.³ And so why is it that radical hysterectomy is still considered the standard of care for all but the smallest of microscopic cervical cancers?

The risk of lymph node metastases or recurrence is exceptionally low for women with microscopic (stage IA1) cervical cancers that are less than 3 mm in depth. Therefore, the National Comprehensive Cancer Network guidelines recommend nonradical surgical remedies (such as extrafascial hysterectomy, or cone biopsy or trachelectomy if fertility preservation is desired) for this earlier stage of disease.⁴ If there is lymphovascular space invasion (an indicator of poor prognosis and potential lymphatic involvement), a lymphadenectomy or sentinel lymph node biopsy is also recommended. For women with stage IA2 or IB lesions, radical excisions (either trachelectomy or hysterectomy) are considered the standard of care. However, this “gold standard” was achieved largely through legacy, and not a result of randomized trials comparing its outcomes with nonradical procedures.

Initial strides away from radical cervical cancer surgery focused on the goal of fertility preservation via radical trachelectomy which allowed women to preserve an intact uterine fundus. This was initially met with skepticism and concern that surgeons could be sacrificing oncologic outcomes in order to preserve a woman’s fertility. Thanks to pioneering work, including prospective research studies by surgeon innovators it has been shown that, in appropriately selected candidates with tumors less than 2 cm, it is an accepted standard of care.⁴ Radical vaginal or abdominal trachelectomy is associated with cancer recurrence rates of less than 5% and successful pregnancy in approximately three-quarters of patients in whom this is desired.^5,6 However, full-term pregnancy is achieved in 50%-75% of cases, reflecting increased obstetric risk, and radical trachelectomy still subjects patients to the morbidity of a radical parametrial resection, despite the fact that many of them will have no residual carcinoma in their final pathological specimens.

Therefore, can we be even more conservative in our surgery for these patients? Are simple hysterectomy or conization potentially adequate treatments for small (<2 cm) stage IA2 and IB1 lesions that have favorable histology (<10 mm stromal invasion, low-risk histology, no lymphovascular space involvement, negative margins on conization and no lymph node metastases)? In patients whose tumor exhibits these histologic features, the likelihood of parametrial involvement is approximately 1%, calling into question the virtue of parametrial resection.⁷ Observational studies have identified mixed results on the safety of conservative surgical techniques in early-stage cervical cancer. In a study of the National Cancer Database, the outcomes of 2,543 radical hysterectomies and 1,388 extrafascial hysterectomies for women with stage IB1 disease were evaluated and observed a difference in 5-year survival (92.4% vs. 95.3%) favoring the radical procedure.⁸ Unfortunately, database analyses such as these are limited by potential confounders and discordance between the groups such as rates of lymphadenectomy, known involvement of oncologic surgeon specialists, and margin status. An alternative evaluation of the Surveillance, Epidemiology, and End Results database including 2,571 patients with stage IB1 disease, all of whom had lymphadenectomy performed, showed no difference in 10-year disease-specific survival between the two surgical approaches.⁹

Ultimately, whether conservative procedures (such as conization or extrafascial hysterectomy) can be offered to women with small, low-risk IB1 or IA2 cervical cancers will be best determined by prospective single-arm or randomized trials. Fortunately, these are underway. Preliminary results from the ConCerv trial in which 100 women with early-stage, low-risk stage IA2 and IB1 cervical cancer were treated with either repeat conization or extrafascial hysterectomy with sentinel lymph node biopsy showed acceptably low rates of recurrence (3%) with this approach.¹⁰ If the mature data supports this finding, it seems that, for appropriately selected and well-counseled patients, conservative surgery may become more broadly accepted as a reasonable option for treatment that spares women not only loss of fertility, but also the early and late surgical morbidity from radical procedures.

In the meantime, until more is known about the oncologic safety of nonradical procedures for stage IA2 and IB1 cervical cancer, this option should not be considered standard of care, and only offered to patients with favorable tumor factors who are well counseled regarding the uncertainty of this approach. It is critical that patients with early-stage cervical cancer be evaluated by a gynecologic cancer specialist prior to definitive surgical treatment as they are best equipped to evaluate risk profiles and counsel about her options for surgery, its known and unknown consequences, and the appropriateness of fertility preservation or radicality of surgery. We eagerly await the results of trials evaluating the safety of conservative cervical cancer surgery, which promise to advance us from 19th-century practices, preserving not only fertility, but also quality of life.

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no disclosures and can be contacted at obnews@mdedge.com.

References

1. Trimbos JB et al. Eur J Cancer. 2004;40(3):375-8.

2. Querleu D and Morrow CP. Lancet Oncol. 2008;9:297-303.

3. Sakorafas GH and Safioleas M. Eur J Cancer Care. 2010 Mar;19(2):145-66.

4. National Comprehensive Cancer Network. Cervical Cancer (Version 1.2021). https://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf. Accessed 2021 Apr 21.

5. Plante M et al. Gynecol Oncol. 2011;121:290-7.

6. Wethington SL et al. Int J Gynecol Cancer. 2012;22:1251-7.

7. Domgue J and Schmeler K. Best Pract Res Clin Obstet Gynaecol. 2019 Feb;55:79-92.

8. Sia TY et al. Obstet Gyenecol. 2019;134(6):1132.

9. Tseng J et al. Gynecol Oncol. 2018;150(1):44.

10. Schmeler K et al. Int J Gynecol Cancer. 2019;29:A14-5.

It has been more than 120 years since Ernst Wertheim, a Viennese surgeon, performed and described what is considered to have been the first radical total hysterectomy with lymphadenectomy for early-stage cervical cancer, yet this morbid procedure remains the standard of care for most early-stage cervical cancers. The rationale for this procedure, which included removal of the parametrial tissue, uterosacral and cardinal ligaments, and upper vagina en bloc with the cervix and uterus, was to obtain margins around a cancer that has a dominant radial growth pattern. The morbidity associated with this procedure is substantial. The parametrium houses important vascular, neural, and urologic structures. Unlike extrafascial hysterectomy, often referred to as “simple” hysterectomy, in which surgeons follow a fascial plane, and therefore a relatively avascular dissection, surgeons performing radical hysterectomy must venture outside of these embryologic fusion planes into less well–defined anatomy. Therefore, surgical complications are relatively common including hemorrhage, ureteral and bladder injury, as well as late-onset devastating complications such as fistula, urinary retention, or incontinence, and sexual dysfunction.¹ More recently, variations of the Wertheim-Meigs radical hysterectomy have been described, and objective classifications created, which include modified radical procedures (removing less parametria) and nerve-sparing procedures to facilitate standardized nomenclature for tailoring the most appropriate procedure for any given tumor.²

Courtesy Dr. Emma Rossi

The trend, and a positive one at that, over the course of the past century, has been a move away from routine radical surgical procedures for most clinical stage 1 cancers. No better example exists than breast cancer, in which the Halsted radical mastectomy has been largely replaced by less morbid breast-conserving or nonradical procedures with adjunct medical and radiation therapies offered to achieve high rates of cure with far more acceptable patient-centered outcomes.³ And so why is it that radical hysterectomy is still considered the standard of care for all but the smallest of microscopic cervical cancers?

The risk of lymph node metastases or recurrence is exceptionally low for women with microscopic (stage IA1) cervical cancers that are less than 3 mm in depth. Therefore, the National Comprehensive Cancer Network guidelines recommend nonradical surgical remedies (such as extrafascial hysterectomy, or cone biopsy or trachelectomy if fertility preservation is desired) for this earlier stage of disease.⁴ If there is lymphovascular space invasion (an indicator of poor prognosis and potential lymphatic involvement), a lymphadenectomy or sentinel lymph node biopsy is also recommended. For women with stage IA2 or IB lesions, radical excisions (either trachelectomy or hysterectomy) are considered the standard of care. However, this “gold standard” was achieved largely through legacy, and not a result of randomized trials comparing its outcomes with nonradical procedures.

Initial strides away from radical cervical cancer surgery focused on the goal of fertility preservation via radical trachelectomy which allowed women to preserve an intact uterine fundus. This was initially met with skepticism and concern that surgeons could be sacrificing oncologic outcomes in order to preserve a woman’s fertility. Thanks to pioneering work, including prospective research studies by surgeon innovators it has been shown that, in appropriately selected candidates with tumors less than 2 cm, it is an accepted standard of care.⁴ Radical vaginal or abdominal trachelectomy is associated with cancer recurrence rates of less than 5% and successful pregnancy in approximately three-quarters of patients in whom this is desired.^5,6 However, full-term pregnancy is achieved in 50%-75% of cases, reflecting increased obstetric risk, and radical trachelectomy still subjects patients to the morbidity of a radical parametrial resection, despite the fact that many of them will have no residual carcinoma in their final pathological specimens.

Therefore, can we be even more conservative in our surgery for these patients? Are simple hysterectomy or conization potentially adequate treatments for small (<2 cm) stage IA2 and IB1 lesions that have favorable histology (<10 mm stromal invasion, low-risk histology, no lymphovascular space involvement, negative margins on conization and no lymph node metastases)? In patients whose tumor exhibits these histologic features, the likelihood of parametrial involvement is approximately 1%, calling into question the virtue of parametrial resection.⁷ Observational studies have identified mixed results on the safety of conservative surgical techniques in early-stage cervical cancer. In a study of the National Cancer Database, the outcomes of 2,543 radical hysterectomies and 1,388 extrafascial hysterectomies for women with stage IB1 disease were evaluated and observed a difference in 5-year survival (92.4% vs. 95.3%) favoring the radical procedure.⁸ Unfortunately, database analyses such as these are limited by potential confounders and discordance between the groups such as rates of lymphadenectomy, known involvement of oncologic surgeon specialists, and margin status. An alternative evaluation of the Surveillance, Epidemiology, and End Results database including 2,571 patients with stage IB1 disease, all of whom had lymphadenectomy performed, showed no difference in 10-year disease-specific survival between the two surgical approaches.⁹

Ultimately, whether conservative procedures (such as conization or extrafascial hysterectomy) can be offered to women with small, low-risk IB1 or IA2 cervical cancers will be best determined by prospective single-arm or randomized trials. Fortunately, these are underway. Preliminary results from the ConCerv trial in which 100 women with early-stage, low-risk stage IA2 and IB1 cervical cancer were treated with either repeat conization or extrafascial hysterectomy with sentinel lymph node biopsy showed acceptably low rates of recurrence (3%) with this approach.¹⁰ If the mature data supports this finding, it seems that, for appropriately selected and well-counseled patients, conservative surgery may become more broadly accepted as a reasonable option for treatment that spares women not only loss of fertility, but also the early and late surgical morbidity from radical procedures.

In the meantime, until more is known about the oncologic safety of nonradical procedures for stage IA2 and IB1 cervical cancer, this option should not be considered standard of care, and only offered to patients with favorable tumor factors who are well counseled regarding the uncertainty of this approach. It is critical that patients with early-stage cervical cancer be evaluated by a gynecologic cancer specialist prior to definitive surgical treatment as they are best equipped to evaluate risk profiles and counsel about her options for surgery, its known and unknown consequences, and the appropriateness of fertility preservation or radicality of surgery. We eagerly await the results of trials evaluating the safety of conservative cervical cancer surgery, which promise to advance us from 19th-century practices, preserving not only fertility, but also quality of life.

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no disclosures and can be contacted at obnews@mdedge.com.

References

1. Trimbos JB et al. Eur J Cancer. 2004;40(3):375-8.

2. Querleu D and Morrow CP. Lancet Oncol. 2008;9:297-303.

3. Sakorafas GH and Safioleas M. Eur J Cancer Care. 2010 Mar;19(2):145-66.

4. National Comprehensive Cancer Network. Cervical Cancer (Version 1.2021). https://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf. Accessed 2021 Apr 21.

5. Plante M et al. Gynecol Oncol. 2011;121:290-7.

6. Wethington SL et al. Int J Gynecol Cancer. 2012;22:1251-7.

7. Domgue J and Schmeler K. Best Pract Res Clin Obstet Gynaecol. 2019 Feb;55:79-92.

8. Sia TY et al. Obstet Gyenecol. 2019;134(6):1132.

9. Tseng J et al. Gynecol Oncol. 2018;150(1):44.

10. Schmeler K et al. Int J Gynecol Cancer. 2019;29:A14-5.

It has been more than 120 years since Ernst Wertheim, a Viennese surgeon, performed and described what is considered to have been the first radical total hysterectomy with lymphadenectomy for early-stage cervical cancer, yet this morbid procedure remains the standard of care for most early-stage cervical cancers. The rationale for this procedure, which included removal of the parametrial tissue, uterosacral and cardinal ligaments, and upper vagina en bloc with the cervix and uterus, was to obtain margins around a cancer that has a dominant radial growth pattern. The morbidity associated with this procedure is substantial. The parametrium houses important vascular, neural, and urologic structures. Unlike extrafascial hysterectomy, often referred to as “simple” hysterectomy, in which surgeons follow a fascial plane, and therefore a relatively avascular dissection, surgeons performing radical hysterectomy must venture outside of these embryologic fusion planes into less well–defined anatomy. Therefore, surgical complications are relatively common including hemorrhage, ureteral and bladder injury, as well as late-onset devastating complications such as fistula, urinary retention, or incontinence, and sexual dysfunction.¹ More recently, variations of the Wertheim-Meigs radical hysterectomy have been described, and objective classifications created, which include modified radical procedures (removing less parametria) and nerve-sparing procedures to facilitate standardized nomenclature for tailoring the most appropriate procedure for any given tumor.²

Courtesy Dr. Emma Rossi

The trend, and a positive one at that, over the course of the past century, has been a move away from routine radical surgical procedures for most clinical stage 1 cancers. No better example exists than breast cancer, in which the Halsted radical mastectomy has been largely replaced by less morbid breast-conserving or nonradical procedures with adjunct medical and radiation therapies offered to achieve high rates of cure with far more acceptable patient-centered outcomes.³ And so why is it that radical hysterectomy is still considered the standard of care for all but the smallest of microscopic cervical cancers?

The risk of lymph node metastases or recurrence is exceptionally low for women with microscopic (stage IA1) cervical cancers that are less than 3 mm in depth. Therefore, the National Comprehensive Cancer Network guidelines recommend nonradical surgical remedies (such as extrafascial hysterectomy, or cone biopsy or trachelectomy if fertility preservation is desired) for this earlier stage of disease.⁴ If there is lymphovascular space invasion (an indicator of poor prognosis and potential lymphatic involvement), a lymphadenectomy or sentinel lymph node biopsy is also recommended. For women with stage IA2 or IB lesions, radical excisions (either trachelectomy or hysterectomy) are considered the standard of care. However, this “gold standard” was achieved largely through legacy, and not a result of randomized trials comparing its outcomes with nonradical procedures.

Initial strides away from radical cervical cancer surgery focused on the goal of fertility preservation via radical trachelectomy which allowed women to preserve an intact uterine fundus. This was initially met with skepticism and concern that surgeons could be sacrificing oncologic outcomes in order to preserve a woman’s fertility. Thanks to pioneering work, including prospective research studies by surgeon innovators it has been shown that, in appropriately selected candidates with tumors less than 2 cm, it is an accepted standard of care.⁴ Radical vaginal or abdominal trachelectomy is associated with cancer recurrence rates of less than 5% and successful pregnancy in approximately three-quarters of patients in whom this is desired.^5,6 However, full-term pregnancy is achieved in 50%-75% of cases, reflecting increased obstetric risk, and radical trachelectomy still subjects patients to the morbidity of a radical parametrial resection, despite the fact that many of them will have no residual carcinoma in their final pathological specimens.

Therefore, can we be even more conservative in our surgery for these patients? Are simple hysterectomy or conization potentially adequate treatments for small (<2 cm) stage IA2 and IB1 lesions that have favorable histology (<10 mm stromal invasion, low-risk histology, no lymphovascular space involvement, negative margins on conization and no lymph node metastases)? In patients whose tumor exhibits these histologic features, the likelihood of parametrial involvement is approximately 1%, calling into question the virtue of parametrial resection.⁷ Observational studies have identified mixed results on the safety of conservative surgical techniques in early-stage cervical cancer. In a study of the National Cancer Database, the outcomes of 2,543 radical hysterectomies and 1,388 extrafascial hysterectomies for women with stage IB1 disease were evaluated and observed a difference in 5-year survival (92.4% vs. 95.3%) favoring the radical procedure.⁸ Unfortunately, database analyses such as these are limited by potential confounders and discordance between the groups such as rates of lymphadenectomy, known involvement of oncologic surgeon specialists, and margin status. An alternative evaluation of the Surveillance, Epidemiology, and End Results database including 2,571 patients with stage IB1 disease, all of whom had lymphadenectomy performed, showed no difference in 10-year disease-specific survival between the two surgical approaches.⁹

Ultimately, whether conservative procedures (such as conization or extrafascial hysterectomy) can be offered to women with small, low-risk IB1 or IA2 cervical cancers will be best determined by prospective single-arm or randomized trials. Fortunately, these are underway. Preliminary results from the ConCerv trial in which 100 women with early-stage, low-risk stage IA2 and IB1 cervical cancer were treated with either repeat conization or extrafascial hysterectomy with sentinel lymph node biopsy showed acceptably low rates of recurrence (3%) with this approach.¹⁰ If the mature data supports this finding, it seems that, for appropriately selected and well-counseled patients, conservative surgery may become more broadly accepted as a reasonable option for treatment that spares women not only loss of fertility, but also the early and late surgical morbidity from radical procedures.

In the meantime, until more is known about the oncologic safety of nonradical procedures for stage IA2 and IB1 cervical cancer, this option should not be considered standard of care, and only offered to patients with favorable tumor factors who are well counseled regarding the uncertainty of this approach. It is critical that patients with early-stage cervical cancer be evaluated by a gynecologic cancer specialist prior to definitive surgical treatment as they are best equipped to evaluate risk profiles and counsel about her options for surgery, its known and unknown consequences, and the appropriateness of fertility preservation or radicality of surgery. We eagerly await the results of trials evaluating the safety of conservative cervical cancer surgery, which promise to advance us from 19th-century practices, preserving not only fertility, but also quality of life.

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no disclosures and can be contacted at obnews@mdedge.com.

References

1. Trimbos JB et al. Eur J Cancer. 2004;40(3):375-8.

2. Querleu D and Morrow CP. Lancet Oncol. 2008;9:297-303.

3. Sakorafas GH and Safioleas M. Eur J Cancer Care. 2010 Mar;19(2):145-66.

4. National Comprehensive Cancer Network. Cervical Cancer (Version 1.2021). https://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf. Accessed 2021 Apr 21.

5. Plante M et al. Gynecol Oncol. 2011;121:290-7.

6. Wethington SL et al. Int J Gynecol Cancer. 2012;22:1251-7.

7. Domgue J and Schmeler K. Best Pract Res Clin Obstet Gynaecol. 2019 Feb;55:79-92.

8. Sia TY et al. Obstet Gyenecol. 2019;134(6):1132.

9. Tseng J et al. Gynecol Oncol. 2018;150(1):44.

10. Schmeler K et al. Int J Gynecol Cancer. 2019;29:A14-5.

Dear colleagues and friends,

The Perspectives series returns, this time with an exciting discussion about antibiotic use in acute uncomplicated diverticulitis. It has been fascinating to witness this field evolve from an era where not using antibiotics was inconceivable! Dr. Anne F. Peery and Dr. Neil Stollman, both recognized experts in the matter, provide arguments to both sides of the debate, as well as much-needed nuance. As always, I welcome your comments and suggestions for future topics at ginews@gastro.org. Thank you for your support, and I hope you will enjoy the reading and learning from this as much as I did.

Charles J. Kahi, MD, MS, AGAF, is a professor of medicine at Indiana University, Indianapolis. He is also an associate editor for GI & Hepatology News.

Think carefully about when to withhold

For decades, it was standard practice to give antibiotics to all patients with acute uncomplicated diverticulitis (AUD). While most patients with a first diagnosis of AUD recover within a few weeks, a small proportion will develop a complication.¹ Among generally healthy patients with an initial diagnosis of AUD, about 3% will progress to complicated diverticulitis, and about 1% will require emergency surgery within 6 months. Around another 6% of cases will develop chronic diverticulitis with ongoing diverticular inflammation that persists for weeks to months.

Because the complications are uncommon, we don’t know if antibiotics reduce the risk of progression to complicated diverticulitis, emergency surgery, or the development of chronic diverticulitis. Investigating these patient-centered and morbid outcomes would require trials enrolling thousands of patients and to following these patients for months. This trial hasn’t happened yet.

To date, only small studies have compared the use of antibiotics with no antibiotics in patients with AUD. A review sponsored by the Agency for Healthcare Research and Quality published last year concluded that the current evidence was too sparse or too inconsistent to make strong conclusions about the use of antibiotics for patients with uncomplicated diverticulitis.²

With little evidence for or against antibiotics, recent guidelines have begun to recommend that antibiotics be used selectively, rather than routinely, in patients with diverticulitis.³ “Selectively” clearly means that there are some patients who should receive antibiotics, but the guidelines are vague about who those patients are. To this end, it is safest to refer to those small, underpowered trials to identify which patients are at the greatest risk of developing a complication.^1,4 The authors of those trials considered a number of groups high risk and therefore excluded them from those trials. In the absence of further definitive research, it seems clear that those groups, listed below, should therefore be selected for antibiotic treatment:

• Patients with complicated diverticulitis including paracolic extraluminal air on CT scan.
• Patients who are immunocompromised.
• Patients with a high fever, affected general condition, or clinical suspicion of sepsis.
• Patients with inflammatory bowel disease.
• Patients who are pregnant or breast feeding.

As with most clinical trials, participants in these smaller trials were younger (median age, late 50s) and healthier (63% normal, healthy patient; 34% mild systemic disease; 4% severe systemic disease) than the general population. In secondary analyses, however, several factors were independently associated with a complicated disease course after an initial diagnosis of acute uncomplicated diverticulitis. As with the first list above, the following high-risk patients should also be treated with antibiotics at diagnosis:

• Patients with American Society of Anesthesiologists scores III or IV were 4.4 times more likely to have a poor outcome, compared with those with ASA score I.
• Patients with ASA score II were 2.0 times more likely to have a poor outcome, compared with ASA score I.
• Patients with symptoms for more than 5 days at diagnosis were 3.3 times more likely to have a poor outcome, compared with those with symptoms for 5 days or less.
• Patients with vomiting at diagnosis were 3.9 times more likely to have a poor outcome, compared with those who were not vomiting.
• Patients with C-reactive protein levels higher than 140 mg/L at diagnosis were 2.9 times more likely to have a poor outcome, compared with C-reactive protein level of 140 mg/L or less.
• Patients with white blood cell count greater than 15 x 10⁹ cells/L at diagnosis were 3.7 times more likely to have a poor outcome, compared with those with 15 x 10⁹ cells/L.
• Patients with a longer segment (>86mm) of inflamed colon on CT scan were more likely to have a poor outcome, compared those who had a shorter segment (<65mm).

To help clinicians think about antibiotic treatment in patients with AUD, a recent American Gastroenterological Association clinical practice update provided the following advice: First, antibiotic treatment is advised in patients with uncomplicated diverticulitis who have comorbidities or are frail, who present with refractory symptoms or vomiting, or who have a C-reactive protein level greater than 140 mg/L, or baseline white blood cell count greater than 15 x 10⁹ cells/L.⁵ Also, antibiotic treatment is advised in patients with complicated diverticulitis or uncomplicated diverticulitis with a fluid collection or longer segment of inflammation on CT scan. Finally, patients with uncomplicated diverticulitis who are immunosuppressed are high risk for progression to complicated diverticulitis or sepsis and should be treated with antibiotics.

The lists above clearly leave some patients with AUD who may be managed without antibiotics. These patients are otherwise healthy, have good social support, access to health care, and are experiencing a mild, self-limited episode. Avoiding antibiotics requires shared decision-making with a well-informed patient. I have patients who have embraced this approach, while others found this unacceptable. Given the current level of uncertainty in the literature, I make it my practice to offer antibiotics to any patient who feels strongly about receiving them.

As with many issues in modern medicine, the use of antibiotics in AUD is an unsettled question. Given the known harms of progression of diverticulitis, it is clearly safest to treat patients who were excluded from the small studies we have or flagged by those same studies as being at increased risk of progression. Our uncertainty also demands a shared decision-making model, filling in our patients on what we can and cannot say with confidence. As is often the case, further research is desperately needed. Until that happens, antibiotics for AUD will remain a regular part of my practice.

Anne F. Peery, MD, MSCR, is with the center for gastrointestinal biology and disease at the University of North Carolina at Chapel Hill. She has no conflicts to disclose.

References

1. Daniels L et al. Br J Surg. 2017 Jan;104(1):52-61.

2. Balk EM et al. Management of Colonic Diverticulitis. Comparative Effectiveness Review No. 233. Agency for Healthcare Research and Quality. 2020 Oct. doi: 10.23970/AHRQEPCCER233.

3. Stollman N et al. Gastroenterology. 2015 Dec;149(7):1944-9.

4. Chabok A et al. Br J Surg. 2012 Jan 30;99(4):532-9.

5. Peery AF et al. Gastroenterology. 2021 Feb;160(3):906-11.e1.

The data are robust for withholding more often

That we are engaged in a legitimate debate about the role of antibiotics in acute uncomplicated diverticulitis (AUD) is itself quite notable. In the 1999 American College of Gastroenterology Practice Guidelines,¹ we did not even entertain the concept of withholding antibiotics; the only discussion points were intravenous versus oral. Fast forward 15 years, and in the 2015 American Gastroenterological Association practice guidelines (which the other contributor for this installment of Perspectives, Anne F. Peery, MD, and I worked on together) our first recommendation was that antibiotics should be used “selectively,” rather than routinely.² This did generate some raised eyebrows and hand-wringing in the community, but our position was the result of a rigorous data analysis process and we stood by it.

In fact, Dr. Peery and I also coauthored an accompanying editorial that concluded with an important endorsement “allowing the clinician to consider withholding antibiotics from select uncomplicated patients with mild disease.” I suspect, then, that Dr. Peery and I are very much coincident in our overall thoughts here, and I’m pretty sure that neither of us would defend an “always” or “never” stance on this issue, so for this educational debate, we’re really talking about where in the middle to draw the line (that is, how to define “selectively”). To that end, I will defend the supposition that the subsequent data in support of withholding antibiotics remains robust and even more supportive of this practice in many (but certainly not all) patients with acute, uncomplicated diverticulitis.

The logic underlying selective use was based on two drivers over the past decade, one being an emerging concept that diverticular pathology was often inflammatory rather than solely infectious, coupled with a timely and very important worldwide push toward restraint of antibiotic use. A recent retrospective claims analysis of outpatient antibiotic use for immunocompetent patients with AUD did reported that the dominant antibiotic combination used, metronidazole plus a fluoroquinolone, was associated with an increased risk of Clostridioides difficile infection, compared with the far less frequently used amoxicillin/clavulanate regimen, which highlights that routine antibiotics are not without risk.³

Recently, the U.S. Agency for Healthcare Research and Quality performed a rigorous meta-analysis of this body of evidence, and summarized that “antibiotic treatment may not affect pain symptoms, length of hospital stay, recurrence risk, quality of life, or need for surgery, compared to no antibiotic treatment,” with an admitted low strength of evidence (based on four randomized, controlled trials).⁴

Finally, I’ll close my evidence-based case with a quote from a Clinical Practice Update just published in February 2021 in Gastroenterology: “Antibiotic treatment can be used selectively, rather than routinely, in immunocompetent patients with mild uncomplicated diverticulitis. ... Antibiotic treatment is advised in patients with uncomplicated diverticulitis who have comorbidities or are frail, who present with refractory symptoms or vomiting, or who have a [C-reactive protein] >140 mg/L or baseline [white blood cell count] > 15 x 10⁹. Antibiotic treatment is advised in patients with complicated diverticulitis or uncomplicated diverticulitis with a fluid collection or longer segment of inflammation on CT scan.”⁵ I think this is most excellent advice, providing a practical and clinically useful framework for those in whom antibiotics absolutely should be used, but permitting a fairly large group to avoid antibiotics, which may carry significant harm, based on strong consistent data that does not support a benefit.

So, practically speaking, things are a bit harder for us now when our patient shows up in the ED and if found to have AUD on CT. In the “old days” (that is, the early 2000s), a patient with either clinically suspected or CT-confirmed AUD was simply given antibiotics, mostly a fluoroquinolone, and this was community standard. The only real decision tree was inpatient or outpatient. But now, I would respectfully suggest, we need to invest a bit more time on a nuanced discussion with the potential “no antibiotics” patient (for example, one without immunosuppression, severe comorbidities, or lab or imaging markers of aggressive disease). It is now appropriate to inform such a patient that the data suggest that a conservative approach will not increase their risk of complications and may well spare them antibiotic-related morbidity.

In the context of that informed discussion, factually framed by the practitioner, many patients should (and will, in my experience, although the San Francisco Bay Area may not entirely reflect the country as a whole) choose a strategy of observation. Of course, close follow-up with such patients is required, as is clear reassurance that if things “turn bad” that we’re available and antibiotics remain a salvage option. The “write a script and be done” days are over, and while withholding antibiotics may still feel dangerous or uncomfortable to the patient (or to us), the data is the data, and our patients deserve to at least be offered that option.

Neil Stollman, MD, AGAF, FACG, is chairman of the division of gastroenterology at Alta Bates Summit Medical Center in Oakland, Calif., and an associate clinical professor of medicine in the division of gastroenterology at the University of California, San Francisco. He discloses being a consultant for Cosmo Pharmaceuticals, which has a potential future diverticulitis study of a rifampin-class antibiotic.

References

1. Stollman N and Raskin JB. Am J Gastroenterol. 1999 Nov;94(11):3110-21.

2. Peery AF and Stollman N. Gastroenterology. 2015 Dec;149(7):1944-9.

3. Gaber CE et al. Ann Intern Med. 2021 Feb 23. doi: 10.7326/M20-6315.

4. Balk EM et al. Management of Colonic Diverticulitis. Comparative Effectiveness Review No. 233. Agency for Healthcare Research and Quality. October 2020. doi: 10.23970/AHRQEPCCER233.

5. Peery AF et al. Gastroenterology. 2021 Feb;160(3):906-11.e1.

Dear colleagues and friends,

The Perspectives series returns, this time with an exciting discussion about antibiotic use in acute uncomplicated diverticulitis. It has been fascinating to witness this field evolve from an era where not using antibiotics was inconceivable! Dr. Anne F. Peery and Dr. Neil Stollman, both recognized experts in the matter, provide arguments to both sides of the debate, as well as much-needed nuance. As always, I welcome your comments and suggestions for future topics at ginews@gastro.org. Thank you for your support, and I hope you will enjoy the reading and learning from this as much as I did.

Charles J. Kahi, MD, MS, AGAF, is a professor of medicine at Indiana University, Indianapolis. He is also an associate editor for GI & Hepatology News.

Think carefully about when to withhold

For decades, it was standard practice to give antibiotics to all patients with acute uncomplicated diverticulitis (AUD). While most patients with a first diagnosis of AUD recover within a few weeks, a small proportion will develop a complication.¹ Among generally healthy patients with an initial diagnosis of AUD, about 3% will progress to complicated diverticulitis, and about 1% will require emergency surgery within 6 months. Around another 6% of cases will develop chronic diverticulitis with ongoing diverticular inflammation that persists for weeks to months.

Because the complications are uncommon, we don’t know if antibiotics reduce the risk of progression to complicated diverticulitis, emergency surgery, or the development of chronic diverticulitis. Investigating these patient-centered and morbid outcomes would require trials enrolling thousands of patients and to following these patients for months. This trial hasn’t happened yet.

To date, only small studies have compared the use of antibiotics with no antibiotics in patients with AUD. A review sponsored by the Agency for Healthcare Research and Quality published last year concluded that the current evidence was too sparse or too inconsistent to make strong conclusions about the use of antibiotics for patients with uncomplicated diverticulitis.²

With little evidence for or against antibiotics, recent guidelines have begun to recommend that antibiotics be used selectively, rather than routinely, in patients with diverticulitis.³ “Selectively” clearly means that there are some patients who should receive antibiotics, but the guidelines are vague about who those patients are. To this end, it is safest to refer to those small, underpowered trials to identify which patients are at the greatest risk of developing a complication.^1,4 The authors of those trials considered a number of groups high risk and therefore excluded them from those trials. In the absence of further definitive research, it seems clear that those groups, listed below, should therefore be selected for antibiotic treatment:

• Patients with complicated diverticulitis including paracolic extraluminal air on CT scan.
• Patients who are immunocompromised.
• Patients with a high fever, affected general condition, or clinical suspicion of sepsis.
• Patients with inflammatory bowel disease.
• Patients who are pregnant or breast feeding.

As with most clinical trials, participants in these smaller trials were younger (median age, late 50s) and healthier (63% normal, healthy patient; 34% mild systemic disease; 4% severe systemic disease) than the general population. In secondary analyses, however, several factors were independently associated with a complicated disease course after an initial diagnosis of acute uncomplicated diverticulitis. As with the first list above, the following high-risk patients should also be treated with antibiotics at diagnosis:

• Patients with American Society of Anesthesiologists scores III or IV were 4.4 times more likely to have a poor outcome, compared with those with ASA score I.
• Patients with ASA score II were 2.0 times more likely to have a poor outcome, compared with ASA score I.
• Patients with symptoms for more than 5 days at diagnosis were 3.3 times more likely to have a poor outcome, compared with those with symptoms for 5 days or less.
• Patients with vomiting at diagnosis were 3.9 times more likely to have a poor outcome, compared with those who were not vomiting.
• Patients with C-reactive protein levels higher than 140 mg/L at diagnosis were 2.9 times more likely to have a poor outcome, compared with C-reactive protein level of 140 mg/L or less.
• Patients with white blood cell count greater than 15 x 10⁹ cells/L at diagnosis were 3.7 times more likely to have a poor outcome, compared with those with 15 x 10⁹ cells/L.
• Patients with a longer segment (>86mm) of inflamed colon on CT scan were more likely to have a poor outcome, compared those who had a shorter segment (<65mm).

To help clinicians think about antibiotic treatment in patients with AUD, a recent American Gastroenterological Association clinical practice update provided the following advice: First, antibiotic treatment is advised in patients with uncomplicated diverticulitis who have comorbidities or are frail, who present with refractory symptoms or vomiting, or who have a C-reactive protein level greater than 140 mg/L, or baseline white blood cell count greater than 15 x 10⁹ cells/L.⁵ Also, antibiotic treatment is advised in patients with complicated diverticulitis or uncomplicated diverticulitis with a fluid collection or longer segment of inflammation on CT scan. Finally, patients with uncomplicated diverticulitis who are immunosuppressed are high risk for progression to complicated diverticulitis or sepsis and should be treated with antibiotics.

The lists above clearly leave some patients with AUD who may be managed without antibiotics. These patients are otherwise healthy, have good social support, access to health care, and are experiencing a mild, self-limited episode. Avoiding antibiotics requires shared decision-making with a well-informed patient. I have patients who have embraced this approach, while others found this unacceptable. Given the current level of uncertainty in the literature, I make it my practice to offer antibiotics to any patient who feels strongly about receiving them.

As with many issues in modern medicine, the use of antibiotics in AUD is an unsettled question. Given the known harms of progression of diverticulitis, it is clearly safest to treat patients who were excluded from the small studies we have or flagged by those same studies as being at increased risk of progression. Our uncertainty also demands a shared decision-making model, filling in our patients on what we can and cannot say with confidence. As is often the case, further research is desperately needed. Until that happens, antibiotics for AUD will remain a regular part of my practice.

Anne F. Peery, MD, MSCR, is with the center for gastrointestinal biology and disease at the University of North Carolina at Chapel Hill. She has no conflicts to disclose.

References

1. Daniels L et al. Br J Surg. 2017 Jan;104(1):52-61.

2. Balk EM et al. Management of Colonic Diverticulitis. Comparative Effectiveness Review No. 233. Agency for Healthcare Research and Quality. 2020 Oct. doi: 10.23970/AHRQEPCCER233.

3. Stollman N et al. Gastroenterology. 2015 Dec;149(7):1944-9.

4. Chabok A et al. Br J Surg. 2012 Jan 30;99(4):532-9.

5. Peery AF et al. Gastroenterology. 2021 Feb;160(3):906-11.e1.

The data are robust for withholding more often

That we are engaged in a legitimate debate about the role of antibiotics in acute uncomplicated diverticulitis (AUD) is itself quite notable. In the 1999 American College of Gastroenterology Practice Guidelines,¹ we did not even entertain the concept of withholding antibiotics; the only discussion points were intravenous versus oral. Fast forward 15 years, and in the 2015 American Gastroenterological Association practice guidelines (which the other contributor for this installment of Perspectives, Anne F. Peery, MD, and I worked on together) our first recommendation was that antibiotics should be used “selectively,” rather than routinely.² This did generate some raised eyebrows and hand-wringing in the community, but our position was the result of a rigorous data analysis process and we stood by it.

In fact, Dr. Peery and I also coauthored an accompanying editorial that concluded with an important endorsement “allowing the clinician to consider withholding antibiotics from select uncomplicated patients with mild disease.” I suspect, then, that Dr. Peery and I are very much coincident in our overall thoughts here, and I’m pretty sure that neither of us would defend an “always” or “never” stance on this issue, so for this educational debate, we’re really talking about where in the middle to draw the line (that is, how to define “selectively”). To that end, I will defend the supposition that the subsequent data in support of withholding antibiotics remains robust and even more supportive of this practice in many (but certainly not all) patients with acute, uncomplicated diverticulitis.

The logic underlying selective use was based on two drivers over the past decade, one being an emerging concept that diverticular pathology was often inflammatory rather than solely infectious, coupled with a timely and very important worldwide push toward restraint of antibiotic use. A recent retrospective claims analysis of outpatient antibiotic use for immunocompetent patients with AUD did reported that the dominant antibiotic combination used, metronidazole plus a fluoroquinolone, was associated with an increased risk of Clostridioides difficile infection, compared with the far less frequently used amoxicillin/clavulanate regimen, which highlights that routine antibiotics are not without risk.³

Recently, the U.S. Agency for Healthcare Research and Quality performed a rigorous meta-analysis of this body of evidence, and summarized that “antibiotic treatment may not affect pain symptoms, length of hospital stay, recurrence risk, quality of life, or need for surgery, compared to no antibiotic treatment,” with an admitted low strength of evidence (based on four randomized, controlled trials).⁴

Finally, I’ll close my evidence-based case with a quote from a Clinical Practice Update just published in February 2021 in Gastroenterology: “Antibiotic treatment can be used selectively, rather than routinely, in immunocompetent patients with mild uncomplicated diverticulitis. ... Antibiotic treatment is advised in patients with uncomplicated diverticulitis who have comorbidities or are frail, who present with refractory symptoms or vomiting, or who have a [C-reactive protein] >140 mg/L or baseline [white blood cell count] > 15 x 10⁹. Antibiotic treatment is advised in patients with complicated diverticulitis or uncomplicated diverticulitis with a fluid collection or longer segment of inflammation on CT scan.”⁵ I think this is most excellent advice, providing a practical and clinically useful framework for those in whom antibiotics absolutely should be used, but permitting a fairly large group to avoid antibiotics, which may carry significant harm, based on strong consistent data that does not support a benefit.

So, practically speaking, things are a bit harder for us now when our patient shows up in the ED and if found to have AUD on CT. In the “old days” (that is, the early 2000s), a patient with either clinically suspected or CT-confirmed AUD was simply given antibiotics, mostly a fluoroquinolone, and this was community standard. The only real decision tree was inpatient or outpatient. But now, I would respectfully suggest, we need to invest a bit more time on a nuanced discussion with the potential “no antibiotics” patient (for example, one without immunosuppression, severe comorbidities, or lab or imaging markers of aggressive disease). It is now appropriate to inform such a patient that the data suggest that a conservative approach will not increase their risk of complications and may well spare them antibiotic-related morbidity.

In the context of that informed discussion, factually framed by the practitioner, many patients should (and will, in my experience, although the San Francisco Bay Area may not entirely reflect the country as a whole) choose a strategy of observation. Of course, close follow-up with such patients is required, as is clear reassurance that if things “turn bad” that we’re available and antibiotics remain a salvage option. The “write a script and be done” days are over, and while withholding antibiotics may still feel dangerous or uncomfortable to the patient (or to us), the data is the data, and our patients deserve to at least be offered that option.

Neil Stollman, MD, AGAF, FACG, is chairman of the division of gastroenterology at Alta Bates Summit Medical Center in Oakland, Calif., and an associate clinical professor of medicine in the division of gastroenterology at the University of California, San Francisco. He discloses being a consultant for Cosmo Pharmaceuticals, which has a potential future diverticulitis study of a rifampin-class antibiotic.

References

1. Stollman N and Raskin JB. Am J Gastroenterol. 1999 Nov;94(11):3110-21.

2. Peery AF and Stollman N. Gastroenterology. 2015 Dec;149(7):1944-9.

3. Gaber CE et al. Ann Intern Med. 2021 Feb 23. doi: 10.7326/M20-6315.

4. Balk EM et al. Management of Colonic Diverticulitis. Comparative Effectiveness Review No. 233. Agency for Healthcare Research and Quality. October 2020. doi: 10.23970/AHRQEPCCER233.

5. Peery AF et al. Gastroenterology. 2021 Feb;160(3):906-11.e1.

Dear colleagues and friends,

The Perspectives series returns, this time with an exciting discussion about antibiotic use in acute uncomplicated diverticulitis. It has been fascinating to witness this field evolve from an era where not using antibiotics was inconceivable! Dr. Anne F. Peery and Dr. Neil Stollman, both recognized experts in the matter, provide arguments to both sides of the debate, as well as much-needed nuance. As always, I welcome your comments and suggestions for future topics at ginews@gastro.org. Thank you for your support, and I hope you will enjoy the reading and learning from this as much as I did.

Charles J. Kahi, MD, MS, AGAF, is a professor of medicine at Indiana University, Indianapolis. He is also an associate editor for GI & Hepatology News.

Think carefully about when to withhold

For decades, it was standard practice to give antibiotics to all patients with acute uncomplicated diverticulitis (AUD). While most patients with a first diagnosis of AUD recover within a few weeks, a small proportion will develop a complication.¹ Among generally healthy patients with an initial diagnosis of AUD, about 3% will progress to complicated diverticulitis, and about 1% will require emergency surgery within 6 months. Around another 6% of cases will develop chronic diverticulitis with ongoing diverticular inflammation that persists for weeks to months.

Because the complications are uncommon, we don’t know if antibiotics reduce the risk of progression to complicated diverticulitis, emergency surgery, or the development of chronic diverticulitis. Investigating these patient-centered and morbid outcomes would require trials enrolling thousands of patients and to following these patients for months. This trial hasn’t happened yet.

To date, only small studies have compared the use of antibiotics with no antibiotics in patients with AUD. A review sponsored by the Agency for Healthcare Research and Quality published last year concluded that the current evidence was too sparse or too inconsistent to make strong conclusions about the use of antibiotics for patients with uncomplicated diverticulitis.²

With little evidence for or against antibiotics, recent guidelines have begun to recommend that antibiotics be used selectively, rather than routinely, in patients with diverticulitis.³ “Selectively” clearly means that there are some patients who should receive antibiotics, but the guidelines are vague about who those patients are. To this end, it is safest to refer to those small, underpowered trials to identify which patients are at the greatest risk of developing a complication.^1,4 The authors of those trials considered a number of groups high risk and therefore excluded them from those trials. In the absence of further definitive research, it seems clear that those groups, listed below, should therefore be selected for antibiotic treatment:

• Patients with complicated diverticulitis including paracolic extraluminal air on CT scan.
• Patients who are immunocompromised.
• Patients with a high fever, affected general condition, or clinical suspicion of sepsis.
• Patients with inflammatory bowel disease.
• Patients who are pregnant or breast feeding.

As with most clinical trials, participants in these smaller trials were younger (median age, late 50s) and healthier (63% normal, healthy patient; 34% mild systemic disease; 4% severe systemic disease) than the general population. In secondary analyses, however, several factors were independently associated with a complicated disease course after an initial diagnosis of acute uncomplicated diverticulitis. As with the first list above, the following high-risk patients should also be treated with antibiotics at diagnosis:

• Patients with American Society of Anesthesiologists scores III or IV were 4.4 times more likely to have a poor outcome, compared with those with ASA score I.
• Patients with ASA score II were 2.0 times more likely to have a poor outcome, compared with ASA score I.
• Patients with symptoms for more than 5 days at diagnosis were 3.3 times more likely to have a poor outcome, compared with those with symptoms for 5 days or less.
• Patients with vomiting at diagnosis were 3.9 times more likely to have a poor outcome, compared with those who were not vomiting.
• Patients with C-reactive protein levels higher than 140 mg/L at diagnosis were 2.9 times more likely to have a poor outcome, compared with C-reactive protein level of 140 mg/L or less.
• Patients with white blood cell count greater than 15 x 10⁹ cells/L at diagnosis were 3.7 times more likely to have a poor outcome, compared with those with 15 x 10⁹ cells/L.
• Patients with a longer segment (>86mm) of inflamed colon on CT scan were more likely to have a poor outcome, compared those who had a shorter segment (<65mm).

To help clinicians think about antibiotic treatment in patients with AUD, a recent American Gastroenterological Association clinical practice update provided the following advice: First, antibiotic treatment is advised in patients with uncomplicated diverticulitis who have comorbidities or are frail, who present with refractory symptoms or vomiting, or who have a C-reactive protein level greater than 140 mg/L, or baseline white blood cell count greater than 15 x 10⁹ cells/L.⁵ Also, antibiotic treatment is advised in patients with complicated diverticulitis or uncomplicated diverticulitis with a fluid collection or longer segment of inflammation on CT scan. Finally, patients with uncomplicated diverticulitis who are immunosuppressed are high risk for progression to complicated diverticulitis or sepsis and should be treated with antibiotics.

The lists above clearly leave some patients with AUD who may be managed without antibiotics. These patients are otherwise healthy, have good social support, access to health care, and are experiencing a mild, self-limited episode. Avoiding antibiotics requires shared decision-making with a well-informed patient. I have patients who have embraced this approach, while others found this unacceptable. Given the current level of uncertainty in the literature, I make it my practice to offer antibiotics to any patient who feels strongly about receiving them.

As with many issues in modern medicine, the use of antibiotics in AUD is an unsettled question. Given the known harms of progression of diverticulitis, it is clearly safest to treat patients who were excluded from the small studies we have or flagged by those same studies as being at increased risk of progression. Our uncertainty also demands a shared decision-making model, filling in our patients on what we can and cannot say with confidence. As is often the case, further research is desperately needed. Until that happens, antibiotics for AUD will remain a regular part of my practice.

Anne F. Peery, MD, MSCR, is with the center for gastrointestinal biology and disease at the University of North Carolina at Chapel Hill. She has no conflicts to disclose.

References

1. Daniels L et al. Br J Surg. 2017 Jan;104(1):52-61.

2. Balk EM et al. Management of Colonic Diverticulitis. Comparative Effectiveness Review No. 233. Agency for Healthcare Research and Quality. 2020 Oct. doi: 10.23970/AHRQEPCCER233.

3. Stollman N et al. Gastroenterology. 2015 Dec;149(7):1944-9.

4. Chabok A et al. Br J Surg. 2012 Jan 30;99(4):532-9.

5. Peery AF et al. Gastroenterology. 2021 Feb;160(3):906-11.e1.

The data are robust for withholding more often

That we are engaged in a legitimate debate about the role of antibiotics in acute uncomplicated diverticulitis (AUD) is itself quite notable. In the 1999 American College of Gastroenterology Practice Guidelines,¹ we did not even entertain the concept of withholding antibiotics; the only discussion points were intravenous versus oral. Fast forward 15 years, and in the 2015 American Gastroenterological Association practice guidelines (which the other contributor for this installment of Perspectives, Anne F. Peery, MD, and I worked on together) our first recommendation was that antibiotics should be used “selectively,” rather than routinely.² This did generate some raised eyebrows and hand-wringing in the community, but our position was the result of a rigorous data analysis process and we stood by it.

In fact, Dr. Peery and I also coauthored an accompanying editorial that concluded with an important endorsement “allowing the clinician to consider withholding antibiotics from select uncomplicated patients with mild disease.” I suspect, then, that Dr. Peery and I are very much coincident in our overall thoughts here, and I’m pretty sure that neither of us would defend an “always” or “never” stance on this issue, so for this educational debate, we’re really talking about where in the middle to draw the line (that is, how to define “selectively”). To that end, I will defend the supposition that the subsequent data in support of withholding antibiotics remains robust and even more supportive of this practice in many (but certainly not all) patients with acute, uncomplicated diverticulitis.

The logic underlying selective use was based on two drivers over the past decade, one being an emerging concept that diverticular pathology was often inflammatory rather than solely infectious, coupled with a timely and very important worldwide push toward restraint of antibiotic use. A recent retrospective claims analysis of outpatient antibiotic use for immunocompetent patients with AUD did reported that the dominant antibiotic combination used, metronidazole plus a fluoroquinolone, was associated with an increased risk of Clostridioides difficile infection, compared with the far less frequently used amoxicillin/clavulanate regimen, which highlights that routine antibiotics are not without risk.³

Recently, the U.S. Agency for Healthcare Research and Quality performed a rigorous meta-analysis of this body of evidence, and summarized that “antibiotic treatment may not affect pain symptoms, length of hospital stay, recurrence risk, quality of life, or need for surgery, compared to no antibiotic treatment,” with an admitted low strength of evidence (based on four randomized, controlled trials).⁴

Finally, I’ll close my evidence-based case with a quote from a Clinical Practice Update just published in February 2021 in Gastroenterology: “Antibiotic treatment can be used selectively, rather than routinely, in immunocompetent patients with mild uncomplicated diverticulitis. ... Antibiotic treatment is advised in patients with uncomplicated diverticulitis who have comorbidities or are frail, who present with refractory symptoms or vomiting, or who have a [C-reactive protein] >140 mg/L or baseline [white blood cell count] > 15 x 10⁹. Antibiotic treatment is advised in patients with complicated diverticulitis or uncomplicated diverticulitis with a fluid collection or longer segment of inflammation on CT scan.”⁵ I think this is most excellent advice, providing a practical and clinically useful framework for those in whom antibiotics absolutely should be used, but permitting a fairly large group to avoid antibiotics, which may carry significant harm, based on strong consistent data that does not support a benefit.

So, practically speaking, things are a bit harder for us now when our patient shows up in the ED and if found to have AUD on CT. In the “old days” (that is, the early 2000s), a patient with either clinically suspected or CT-confirmed AUD was simply given antibiotics, mostly a fluoroquinolone, and this was community standard. The only real decision tree was inpatient or outpatient. But now, I would respectfully suggest, we need to invest a bit more time on a nuanced discussion with the potential “no antibiotics” patient (for example, one without immunosuppression, severe comorbidities, or lab or imaging markers of aggressive disease). It is now appropriate to inform such a patient that the data suggest that a conservative approach will not increase their risk of complications and may well spare them antibiotic-related morbidity.

In the context of that informed discussion, factually framed by the practitioner, many patients should (and will, in my experience, although the San Francisco Bay Area may not entirely reflect the country as a whole) choose a strategy of observation. Of course, close follow-up with such patients is required, as is clear reassurance that if things “turn bad” that we’re available and antibiotics remain a salvage option. The “write a script and be done” days are over, and while withholding antibiotics may still feel dangerous or uncomfortable to the patient (or to us), the data is the data, and our patients deserve to at least be offered that option.

Neil Stollman, MD, AGAF, FACG, is chairman of the division of gastroenterology at Alta Bates Summit Medical Center in Oakland, Calif., and an associate clinical professor of medicine in the division of gastroenterology at the University of California, San Francisco. He discloses being a consultant for Cosmo Pharmaceuticals, which has a potential future diverticulitis study of a rifampin-class antibiotic.

References

1. Stollman N and Raskin JB. Am J Gastroenterol. 1999 Nov;94(11):3110-21.

2. Peery AF and Stollman N. Gastroenterology. 2015 Dec;149(7):1944-9.

3. Gaber CE et al. Ann Intern Med. 2021 Feb 23. doi: 10.7326/M20-6315.

4. Balk EM et al. Management of Colonic Diverticulitis. Comparative Effectiveness Review No. 233. Agency for Healthcare Research and Quality. October 2020. doi: 10.23970/AHRQEPCCER233.

5. Peery AF et al. Gastroenterology. 2021 Feb;160(3):906-11.e1.