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Bamlanivimab’s effects in COVID-19 depend on antibodies
In the randomized controlled trial, in both the group who received bamlanivimab and the group who received placebo, higher antigen and viral RNA levels were associated with a lower proportion of patients achieving recovery.
Other studies have shown that the use of monoclonal antibodies reduces hospitalization risk in outpatients with early COVID-19, and appears to promote viral load decline in the nasopharynx, wrote Jens D. Lundgren, MD, of the University of Copenhagen and colleagues in their article published in the Annals of Internal Medicine. What had been missing prior to this new research was final results from hospitalized patients, the authors said.
In the new study, the researchers randomized 314 adults hospitalized with COVID-19 but without end-organ failure to receive 7,000 mg bamlanivimab (163 patients) or a placebo (151 patients). All patients received study-supplied remdesivir unless contraindicated. The researchers compared the efficacy of bamlanivimab versus placebo, but considered remdesivir the standard of care in this study.
At baseline, 50% of patients overall had antispike endogenous neutralizing antibodies (nAbs), and 50% had SARS-CoV-2 nucleocapsid plasma antigen levels of at least 1,000 ng/L.
The median time to sustained recovery, 19 days, was not significantly different between the bamlanivimab and placebo groups (subhazard ratio, 0.99).
“As hypothesized, among those who were negative for nAb, the difference between bamlanivimab and placebo was more evident if levels of plasma antigen or nasal-swab viral RNA were above the median entry levels,” with subhazard ratios of 1.48 and 1.89, respectively, the researchers explained.
However, the hazard ratio for death for bamlanivimab vs. placebo was 0.45 for patients negative for nAb vs. 3.53 for those positive for nAb. These differences with respect to nAb status were similar across all 90 elements of a composite safety outcome, the researchers said.
Potential benefits remain unclear
The use of neutralizing monoclonal antibodies has been extensively documented as an effective treatment for COVID-19 among ambulatory patients, corresponding author Dr. Lundgren said in an interview.
“Conversely, among admitted patients with COVID-19 pneumonia, the benefit has been questionable,” he said.
The researchers examined a hypothesis that the null finding in hospitalized patients may stem from differences in underlying mechanisms, “either from uncontrolled viral replication – which would be predicted to occur in particular among those not yet been able to mount an endogenous immune response – or from hyperinflammation among those that have mounted such a response,” Dr. Lundgren said.
The study findings supported the stated hypothesis, said Dr. Lundgren. “However, it was surprising that not only was the neutralizing antibody without any benefit among those that had mounted an endogenous immune response, but it actually may have been harmful,” he said.
Bamlanivimab was effective against the viral strain that circulated at the time of enrollment in the study, but subsequent viral strains have appeared to be unaffected by the neutralizing activity of the antibody, said Dr. Lundgren.
From a practical standpoint, “the findings would suggest that use of neutralizing monoclonal antibodies for patients admitted to a hospital with COVID pneumonia should be restricted to those that have not yet mounted an endogenous immune response, as determined by lack of detectable neutralizing antibodies at the time of admission,” Dr. Lundgren said.
Looking ahead, studies are currently underway to examine how the findings translate to vaccinated patients, he added. Other questions to be addressed include whether the benefits and harms apply to some or all neutralizing antibody products, he said.
In addition, “our research consortium is currently doing field testing of several point-of-care test candidates to examine their reliability and functionality,” for how quickly they might identify an endogenous neutralizing antibody response in an admitted COVID pneumonia patient,” Dr. Lundgren noted.
Findings show bamlanivimab’s limits
“Based on the findings of the current study, no clear subgroup of patients could be identified who would benefit from bamlanivimab when hospitalized with COVID-19,” said Suman Pal, MD, of the University of New Mexico, Albuquerque, in an interview.
“The study findings also show possible harm of using bamlanivimab in hospitalized COVID-19 patients who were seropositive for neutralizing antibodies prior to receiving therapy,” Dr. Pal emphasized. “Moreover, the study did not include participants with COVID-19 from variant strains, such as delta and omicron, which currently account for a large number of cases.” “Therefore, the results of this study do not support the use of bamlanivimab in the clinical setting until further evidence is available to guide the selection of patients who may benefit from therapy,” he explained.
“The possible benefit of bamlanivimab does not outweigh the risks in patients hospitalized with COVID-19,” he concluded.
Dr. Pal emphasized the need for larger prospective studies to establish whether bamlanivimab may have benefits in a subgroup of patients, but “well-validated point-of-care tests to identify such patients need to be readily available before this therapy can be considered by clinicians at the bedside,” he concluded.
Diligent screening required before use
Monoclonal antibody treatment has been administered to individuals with diagnosis of COVID-19 infection as outpatients as well as for hospitalized inpatients, said Noel Deep, MD, an internist in Antigo, Wisc., in an interview. “This study is important because it helps physicians and health care institutions to evaluate whether continued use of the monoclonal antibodies would be beneficial and, if so, in what patient populations,” he said.
The findings present interesting implications for the care of COVID-19 patients, said Dr. Deep. “This study indicates that bamlanivimab does not provide the benefit that was initially envisioned when the monoclonal antibody infusions were initially initiated in the treatment of COVID-19 infections. “Serological screening of the patients would help to identify that subgroup of individuals who could benefit from this monoclonal antibody rather than administering it to every COVID-19–positive individual,” he explained.
However, “it is important to note that the emergency use authorization (EUA) for single-agent bamlanivimab has been revoked,” Dr. Deep said.
“The potential benefits of bamlanivimab can be realized only if adequate attention is paid to identifying the appropriate candidates based on serological screening, and administering bamlanivimab to those who are already producing endogenous antibodies could lead to increased risk to those individuals,” he said. Dr. Deep added that he would favor administration of bamlanivimab “in those appropriately screened and eligible candidates, and it is my opinion that the benefits outweigh the risks in those individuals.”
Although the EUA for single-agent bamlanivimab has been revoked, “alternative monoclonal antibody therapies remain available under EUA, including REGEN-COV (casirivimab and imdevimab, administered together), and bamlanivimab and etesevimab administered together, for the same uses as previously authorized for bamlanivimab alone,” Dr. Deep said. “The FDA believes that these alternative monoclonal antibody therapies remain appropriate to treat patients with COVID-19, and I would like to see some data about the benefits and risks of these agents,” he noted.
Limitations, funding, and disclosures
The main limitation of the study was the small size and the fact that it was a subgroup analysis of a trial that ended early because of futility, the researchers wrote. However, the Therapeutics for Inpatients With COVID-19 (TICO) platform will proceed with clinical evaluation of additional COVID-19 treatments, they said.
The study was supported primarily by the U.S. government Operation Warp Speed and the National Institute of Allergy and Infectious Diseases. Other funding sources included the Division of Clinical Research and Leidos Biomedical Research for the INSIGHT (International Network for Strategic Initiatives in Global HIV Trials) Network, as well as an agreement between the National Heart, Lung, and Blood Institute and the Research Triangle Institute for the PETAL (Prevention & Early Treatment of Acute Lung Injury) Network and CTSN (Cardiothoracic Surgical Trials Network). Other support came from the U.S. Department of Veterans Affairs and the governments of Denmark (National Research Foundation), Australia (National Health and Medical Research Council), and the United Kingdom (Medical Research Council).
The medications used in the study were donated by Gilead Sciences and Eli Lilly.
The researchers had no financial conflicts do disclose. Dr. Deep and Dr. Pal had no relevant financial conflicts to disclose.
In the randomized controlled trial, in both the group who received bamlanivimab and the group who received placebo, higher antigen and viral RNA levels were associated with a lower proportion of patients achieving recovery.
Other studies have shown that the use of monoclonal antibodies reduces hospitalization risk in outpatients with early COVID-19, and appears to promote viral load decline in the nasopharynx, wrote Jens D. Lundgren, MD, of the University of Copenhagen and colleagues in their article published in the Annals of Internal Medicine. What had been missing prior to this new research was final results from hospitalized patients, the authors said.
In the new study, the researchers randomized 314 adults hospitalized with COVID-19 but without end-organ failure to receive 7,000 mg bamlanivimab (163 patients) or a placebo (151 patients). All patients received study-supplied remdesivir unless contraindicated. The researchers compared the efficacy of bamlanivimab versus placebo, but considered remdesivir the standard of care in this study.
At baseline, 50% of patients overall had antispike endogenous neutralizing antibodies (nAbs), and 50% had SARS-CoV-2 nucleocapsid plasma antigen levels of at least 1,000 ng/L.
The median time to sustained recovery, 19 days, was not significantly different between the bamlanivimab and placebo groups (subhazard ratio, 0.99).
“As hypothesized, among those who were negative for nAb, the difference between bamlanivimab and placebo was more evident if levels of plasma antigen or nasal-swab viral RNA were above the median entry levels,” with subhazard ratios of 1.48 and 1.89, respectively, the researchers explained.
However, the hazard ratio for death for bamlanivimab vs. placebo was 0.45 for patients negative for nAb vs. 3.53 for those positive for nAb. These differences with respect to nAb status were similar across all 90 elements of a composite safety outcome, the researchers said.
Potential benefits remain unclear
The use of neutralizing monoclonal antibodies has been extensively documented as an effective treatment for COVID-19 among ambulatory patients, corresponding author Dr. Lundgren said in an interview.
“Conversely, among admitted patients with COVID-19 pneumonia, the benefit has been questionable,” he said.
The researchers examined a hypothesis that the null finding in hospitalized patients may stem from differences in underlying mechanisms, “either from uncontrolled viral replication – which would be predicted to occur in particular among those not yet been able to mount an endogenous immune response – or from hyperinflammation among those that have mounted such a response,” Dr. Lundgren said.
The study findings supported the stated hypothesis, said Dr. Lundgren. “However, it was surprising that not only was the neutralizing antibody without any benefit among those that had mounted an endogenous immune response, but it actually may have been harmful,” he said.
Bamlanivimab was effective against the viral strain that circulated at the time of enrollment in the study, but subsequent viral strains have appeared to be unaffected by the neutralizing activity of the antibody, said Dr. Lundgren.
From a practical standpoint, “the findings would suggest that use of neutralizing monoclonal antibodies for patients admitted to a hospital with COVID pneumonia should be restricted to those that have not yet mounted an endogenous immune response, as determined by lack of detectable neutralizing antibodies at the time of admission,” Dr. Lundgren said.
Looking ahead, studies are currently underway to examine how the findings translate to vaccinated patients, he added. Other questions to be addressed include whether the benefits and harms apply to some or all neutralizing antibody products, he said.
In addition, “our research consortium is currently doing field testing of several point-of-care test candidates to examine their reliability and functionality,” for how quickly they might identify an endogenous neutralizing antibody response in an admitted COVID pneumonia patient,” Dr. Lundgren noted.
Findings show bamlanivimab’s limits
“Based on the findings of the current study, no clear subgroup of patients could be identified who would benefit from bamlanivimab when hospitalized with COVID-19,” said Suman Pal, MD, of the University of New Mexico, Albuquerque, in an interview.
“The study findings also show possible harm of using bamlanivimab in hospitalized COVID-19 patients who were seropositive for neutralizing antibodies prior to receiving therapy,” Dr. Pal emphasized. “Moreover, the study did not include participants with COVID-19 from variant strains, such as delta and omicron, which currently account for a large number of cases.” “Therefore, the results of this study do not support the use of bamlanivimab in the clinical setting until further evidence is available to guide the selection of patients who may benefit from therapy,” he explained.
“The possible benefit of bamlanivimab does not outweigh the risks in patients hospitalized with COVID-19,” he concluded.
Dr. Pal emphasized the need for larger prospective studies to establish whether bamlanivimab may have benefits in a subgroup of patients, but “well-validated point-of-care tests to identify such patients need to be readily available before this therapy can be considered by clinicians at the bedside,” he concluded.
Diligent screening required before use
Monoclonal antibody treatment has been administered to individuals with diagnosis of COVID-19 infection as outpatients as well as for hospitalized inpatients, said Noel Deep, MD, an internist in Antigo, Wisc., in an interview. “This study is important because it helps physicians and health care institutions to evaluate whether continued use of the monoclonal antibodies would be beneficial and, if so, in what patient populations,” he said.
The findings present interesting implications for the care of COVID-19 patients, said Dr. Deep. “This study indicates that bamlanivimab does not provide the benefit that was initially envisioned when the monoclonal antibody infusions were initially initiated in the treatment of COVID-19 infections. “Serological screening of the patients would help to identify that subgroup of individuals who could benefit from this monoclonal antibody rather than administering it to every COVID-19–positive individual,” he explained.
However, “it is important to note that the emergency use authorization (EUA) for single-agent bamlanivimab has been revoked,” Dr. Deep said.
“The potential benefits of bamlanivimab can be realized only if adequate attention is paid to identifying the appropriate candidates based on serological screening, and administering bamlanivimab to those who are already producing endogenous antibodies could lead to increased risk to those individuals,” he said. Dr. Deep added that he would favor administration of bamlanivimab “in those appropriately screened and eligible candidates, and it is my opinion that the benefits outweigh the risks in those individuals.”
Although the EUA for single-agent bamlanivimab has been revoked, “alternative monoclonal antibody therapies remain available under EUA, including REGEN-COV (casirivimab and imdevimab, administered together), and bamlanivimab and etesevimab administered together, for the same uses as previously authorized for bamlanivimab alone,” Dr. Deep said. “The FDA believes that these alternative monoclonal antibody therapies remain appropriate to treat patients with COVID-19, and I would like to see some data about the benefits and risks of these agents,” he noted.
Limitations, funding, and disclosures
The main limitation of the study was the small size and the fact that it was a subgroup analysis of a trial that ended early because of futility, the researchers wrote. However, the Therapeutics for Inpatients With COVID-19 (TICO) platform will proceed with clinical evaluation of additional COVID-19 treatments, they said.
The study was supported primarily by the U.S. government Operation Warp Speed and the National Institute of Allergy and Infectious Diseases. Other funding sources included the Division of Clinical Research and Leidos Biomedical Research for the INSIGHT (International Network for Strategic Initiatives in Global HIV Trials) Network, as well as an agreement between the National Heart, Lung, and Blood Institute and the Research Triangle Institute for the PETAL (Prevention & Early Treatment of Acute Lung Injury) Network and CTSN (Cardiothoracic Surgical Trials Network). Other support came from the U.S. Department of Veterans Affairs and the governments of Denmark (National Research Foundation), Australia (National Health and Medical Research Council), and the United Kingdom (Medical Research Council).
The medications used in the study were donated by Gilead Sciences and Eli Lilly.
The researchers had no financial conflicts do disclose. Dr. Deep and Dr. Pal had no relevant financial conflicts to disclose.
In the randomized controlled trial, in both the group who received bamlanivimab and the group who received placebo, higher antigen and viral RNA levels were associated with a lower proportion of patients achieving recovery.
Other studies have shown that the use of monoclonal antibodies reduces hospitalization risk in outpatients with early COVID-19, and appears to promote viral load decline in the nasopharynx, wrote Jens D. Lundgren, MD, of the University of Copenhagen and colleagues in their article published in the Annals of Internal Medicine. What had been missing prior to this new research was final results from hospitalized patients, the authors said.
In the new study, the researchers randomized 314 adults hospitalized with COVID-19 but without end-organ failure to receive 7,000 mg bamlanivimab (163 patients) or a placebo (151 patients). All patients received study-supplied remdesivir unless contraindicated. The researchers compared the efficacy of bamlanivimab versus placebo, but considered remdesivir the standard of care in this study.
At baseline, 50% of patients overall had antispike endogenous neutralizing antibodies (nAbs), and 50% had SARS-CoV-2 nucleocapsid plasma antigen levels of at least 1,000 ng/L.
The median time to sustained recovery, 19 days, was not significantly different between the bamlanivimab and placebo groups (subhazard ratio, 0.99).
“As hypothesized, among those who were negative for nAb, the difference between bamlanivimab and placebo was more evident if levels of plasma antigen or nasal-swab viral RNA were above the median entry levels,” with subhazard ratios of 1.48 and 1.89, respectively, the researchers explained.
However, the hazard ratio for death for bamlanivimab vs. placebo was 0.45 for patients negative for nAb vs. 3.53 for those positive for nAb. These differences with respect to nAb status were similar across all 90 elements of a composite safety outcome, the researchers said.
Potential benefits remain unclear
The use of neutralizing monoclonal antibodies has been extensively documented as an effective treatment for COVID-19 among ambulatory patients, corresponding author Dr. Lundgren said in an interview.
“Conversely, among admitted patients with COVID-19 pneumonia, the benefit has been questionable,” he said.
The researchers examined a hypothesis that the null finding in hospitalized patients may stem from differences in underlying mechanisms, “either from uncontrolled viral replication – which would be predicted to occur in particular among those not yet been able to mount an endogenous immune response – or from hyperinflammation among those that have mounted such a response,” Dr. Lundgren said.
The study findings supported the stated hypothesis, said Dr. Lundgren. “However, it was surprising that not only was the neutralizing antibody without any benefit among those that had mounted an endogenous immune response, but it actually may have been harmful,” he said.
Bamlanivimab was effective against the viral strain that circulated at the time of enrollment in the study, but subsequent viral strains have appeared to be unaffected by the neutralizing activity of the antibody, said Dr. Lundgren.
From a practical standpoint, “the findings would suggest that use of neutralizing monoclonal antibodies for patients admitted to a hospital with COVID pneumonia should be restricted to those that have not yet mounted an endogenous immune response, as determined by lack of detectable neutralizing antibodies at the time of admission,” Dr. Lundgren said.
Looking ahead, studies are currently underway to examine how the findings translate to vaccinated patients, he added. Other questions to be addressed include whether the benefits and harms apply to some or all neutralizing antibody products, he said.
In addition, “our research consortium is currently doing field testing of several point-of-care test candidates to examine their reliability and functionality,” for how quickly they might identify an endogenous neutralizing antibody response in an admitted COVID pneumonia patient,” Dr. Lundgren noted.
Findings show bamlanivimab’s limits
“Based on the findings of the current study, no clear subgroup of patients could be identified who would benefit from bamlanivimab when hospitalized with COVID-19,” said Suman Pal, MD, of the University of New Mexico, Albuquerque, in an interview.
“The study findings also show possible harm of using bamlanivimab in hospitalized COVID-19 patients who were seropositive for neutralizing antibodies prior to receiving therapy,” Dr. Pal emphasized. “Moreover, the study did not include participants with COVID-19 from variant strains, such as delta and omicron, which currently account for a large number of cases.” “Therefore, the results of this study do not support the use of bamlanivimab in the clinical setting until further evidence is available to guide the selection of patients who may benefit from therapy,” he explained.
“The possible benefit of bamlanivimab does not outweigh the risks in patients hospitalized with COVID-19,” he concluded.
Dr. Pal emphasized the need for larger prospective studies to establish whether bamlanivimab may have benefits in a subgroup of patients, but “well-validated point-of-care tests to identify such patients need to be readily available before this therapy can be considered by clinicians at the bedside,” he concluded.
Diligent screening required before use
Monoclonal antibody treatment has been administered to individuals with diagnosis of COVID-19 infection as outpatients as well as for hospitalized inpatients, said Noel Deep, MD, an internist in Antigo, Wisc., in an interview. “This study is important because it helps physicians and health care institutions to evaluate whether continued use of the monoclonal antibodies would be beneficial and, if so, in what patient populations,” he said.
The findings present interesting implications for the care of COVID-19 patients, said Dr. Deep. “This study indicates that bamlanivimab does not provide the benefit that was initially envisioned when the monoclonal antibody infusions were initially initiated in the treatment of COVID-19 infections. “Serological screening of the patients would help to identify that subgroup of individuals who could benefit from this monoclonal antibody rather than administering it to every COVID-19–positive individual,” he explained.
However, “it is important to note that the emergency use authorization (EUA) for single-agent bamlanivimab has been revoked,” Dr. Deep said.
“The potential benefits of bamlanivimab can be realized only if adequate attention is paid to identifying the appropriate candidates based on serological screening, and administering bamlanivimab to those who are already producing endogenous antibodies could lead to increased risk to those individuals,” he said. Dr. Deep added that he would favor administration of bamlanivimab “in those appropriately screened and eligible candidates, and it is my opinion that the benefits outweigh the risks in those individuals.”
Although the EUA for single-agent bamlanivimab has been revoked, “alternative monoclonal antibody therapies remain available under EUA, including REGEN-COV (casirivimab and imdevimab, administered together), and bamlanivimab and etesevimab administered together, for the same uses as previously authorized for bamlanivimab alone,” Dr. Deep said. “The FDA believes that these alternative monoclonal antibody therapies remain appropriate to treat patients with COVID-19, and I would like to see some data about the benefits and risks of these agents,” he noted.
Limitations, funding, and disclosures
The main limitation of the study was the small size and the fact that it was a subgroup analysis of a trial that ended early because of futility, the researchers wrote. However, the Therapeutics for Inpatients With COVID-19 (TICO) platform will proceed with clinical evaluation of additional COVID-19 treatments, they said.
The study was supported primarily by the U.S. government Operation Warp Speed and the National Institute of Allergy and Infectious Diseases. Other funding sources included the Division of Clinical Research and Leidos Biomedical Research for the INSIGHT (International Network for Strategic Initiatives in Global HIV Trials) Network, as well as an agreement between the National Heart, Lung, and Blood Institute and the Research Triangle Institute for the PETAL (Prevention & Early Treatment of Acute Lung Injury) Network and CTSN (Cardiothoracic Surgical Trials Network). Other support came from the U.S. Department of Veterans Affairs and the governments of Denmark (National Research Foundation), Australia (National Health and Medical Research Council), and the United Kingdom (Medical Research Council).
The medications used in the study were donated by Gilead Sciences and Eli Lilly.
The researchers had no financial conflicts do disclose. Dr. Deep and Dr. Pal had no relevant financial conflicts to disclose.
FROM ANNALS OF INTERNAL MEDICINE
RSV resurgence likely in wake of COVID-19
The impact of respiratory syncytial virus (RSV)will likely be greater in 2021 and 2022 in the United States than in previous years as a result of the ongoing COVID-19 pandemic, based on data from a simulation-modeling study involving approximately 19 million individuals.
Although RSV usually follows consistent patterns of timing and duration, the disease all but disappeared starting in March 2020 after the introduction of measures to mitigate the spread of COVID-19, Zhe Zheng, MBBS, of Yale University, New Haven, Conn., and colleagues wrote.
However, lifting of mitigation measures has resulted in emergence of RSV in various parts of the world in early 2021, and trends may be similar in the United States, but data are needed to plan for prophylaxis and hospital use, they noted.
In a study published in JAMA Network Open, the researchers developed a simulation model for epidemics of RSV based on historical data. They acquired inpatient records from New York during 2005-2014 and from California during 2003-2011. The primary clinical outcome was the estimated monthly hospitalizations for RSV.
The simulated study population was 19.45 million individuals. After evaluating several scenarios including continued low transmission associated with social distancing and other mitigation measures, the researchers focused on the likely scenario that introduction of RSV from other regions would likely spark RSV epidemics in the United States.
They determined that spring and summer 2021 would show an increase in hospitalizations for RSV. Overall, higher rates of virus introduction from other regions were associated with more intense spring and summer RSV epidemics, with the trade-off of smaller winter epidemics. In the model, the expected RSV epidemic in spring and summer 2021 in New York was small, with a peak incidence of 419 hospitalizations per 100,000 people in April; by contrast, for states with less seasonal variability, such as Florida, the model predicted a larger summer epidemic.
In the model, the mean age of hospitalization for children younger than 5 years for January 2022 was expected to be 1.17 years, compared with 0.84 years in January 2019, the researchers noted.
Across all age groups, the greatest relative increase in the incidence of RSV infection was predicted for children aged 1-4 years (ranging from 82% to 86%), as were lower respiratory infections (87%-101%) and hospitalization (99%-119%), compared with prepandemic levels.
Hospitalizations for children aged 1 year were predicted to double compared with prepandemic seasons; 707 per 100,000 children per year for 2021 and 2022 versus 355 per 100,000 children per year in a typical prepandemic season. However, the largest incidence of lower respiratory infections (30,075 per 100,000) was predicted for infants aged 3-5 months, and the largest incidence of hospitalizations (3,116 per 100,000) was predicted for infants younger than 3 months.
“Without virus importation, the risk of RSV infections across all age groups in the winter of 2021 and 2022 would be greater, as more susceptible individuals were spared from infections in the absence of summer epidemics,” the researchers noted.
The older mean hospitalization age seen in the model was similar to the reported median patient age in Australia both before the pandemic and during the reemergent RSV epidemic.
“This makes intuitive sense, since many children born in 2020 were spared from RSV infection due to the low virus activity; these children will be older when they get infected for the first time during the reemergent epidemics,” the researchers wrote. “Consequently, stakeholders should consider modifying prophylaxis guidelines to include high-risk infants less than 2 years of age for the 2021-2022 season.”
The study findings were limited by several factors including the lack of data on level of virus introduction or on the impact of lack of boosting on infants with only transplacentally acquired RSV antibodies, the researchers noted. Other limitations include the use of historical data and the lack of data on values outside those included in the model, as well as the inability to control for other factors that could influence RSV, such as vaccines or long-lasting antibodies.
However, the results suggest that the rate of imported infections is associated with RSV hospitalizations, and the model effectively captured the RSV epidemics in the United States in spring and summer 2021.
Models can guide clinical preparations
“Health care simulation modeling is a growing field, with very exciting implications,” Lenore Jarvis, MD, of George Washington University, Washington, said in an interview. The field has the potential ability to influence health care in a data-driven way, including, but not limited to, staffing and other hospital operations, as well as patient care decision-making. “In short, accurate modeling and predictions can help us to make informed health care decisions that can lead to increased quality of care, potential cost savings, and even to help save lives,” she said.
Although the details of transmission modeling were not mentioned in the study, the authors evaluated the performances of several models and scenarios. “Scenario 4, for example, was focused on in particular because it best captured the observed dynamics [for RSV] that emerged during the spring and summer of 2021,” Dr. Jarvis said.
“Pediatricians can speak to these trends firsthand. A decrease in expected RSV infections and hospitalizations in 2020, followed by an unprecedented and early increase in RSV infections and severity in 2021, and the factors that the authors account for make sense, such as reintroduction of RSV from other regions and low immunity in the population,” she said. “It also makes sense that, in these transmission modeling scenarios, the expected mean age of hospitalization because of RSV increased with a temporary (hopefully) increase in RSV hospitalizations in the 2021 season, and potentially the 2022 RSV season.”
As for additional research, Dr. Jarvis said she would like to see follow-up data on the RSV transmission modeling. “For example, with scenario 4, does this scenario continue to perform well in other time periods, such as the winter? If the modeling continues to be accurate during other periods of evaluation and reevaluation, this modeling could be very useful in helping pediatric clinics and hospitals to prepare for RSV care and hospital capacity management.”
The study was supported by grants to various researchers from the National Institute of Allergy and Infectious Diseases/National Institutes of Health, the National Center for Advancing Translational Science at the National Institutes of Health, and NIH Roadmap for Medical Research. Lead author Ms. Zheng had no financial conflicts to disclose. Her study coauthors disclosed relationships with companies including AbbVie, Merck, Pfizer, GlaxoSmithKline, MedImmune, and Janssen. Dr. Jarvis had no financial conflicts to disclose and serves on the Pediatric News editorial advisory board.
The impact of respiratory syncytial virus (RSV)will likely be greater in 2021 and 2022 in the United States than in previous years as a result of the ongoing COVID-19 pandemic, based on data from a simulation-modeling study involving approximately 19 million individuals.
Although RSV usually follows consistent patterns of timing and duration, the disease all but disappeared starting in March 2020 after the introduction of measures to mitigate the spread of COVID-19, Zhe Zheng, MBBS, of Yale University, New Haven, Conn., and colleagues wrote.
However, lifting of mitigation measures has resulted in emergence of RSV in various parts of the world in early 2021, and trends may be similar in the United States, but data are needed to plan for prophylaxis and hospital use, they noted.
In a study published in JAMA Network Open, the researchers developed a simulation model for epidemics of RSV based on historical data. They acquired inpatient records from New York during 2005-2014 and from California during 2003-2011. The primary clinical outcome was the estimated monthly hospitalizations for RSV.
The simulated study population was 19.45 million individuals. After evaluating several scenarios including continued low transmission associated with social distancing and other mitigation measures, the researchers focused on the likely scenario that introduction of RSV from other regions would likely spark RSV epidemics in the United States.
They determined that spring and summer 2021 would show an increase in hospitalizations for RSV. Overall, higher rates of virus introduction from other regions were associated with more intense spring and summer RSV epidemics, with the trade-off of smaller winter epidemics. In the model, the expected RSV epidemic in spring and summer 2021 in New York was small, with a peak incidence of 419 hospitalizations per 100,000 people in April; by contrast, for states with less seasonal variability, such as Florida, the model predicted a larger summer epidemic.
In the model, the mean age of hospitalization for children younger than 5 years for January 2022 was expected to be 1.17 years, compared with 0.84 years in January 2019, the researchers noted.
Across all age groups, the greatest relative increase in the incidence of RSV infection was predicted for children aged 1-4 years (ranging from 82% to 86%), as were lower respiratory infections (87%-101%) and hospitalization (99%-119%), compared with prepandemic levels.
Hospitalizations for children aged 1 year were predicted to double compared with prepandemic seasons; 707 per 100,000 children per year for 2021 and 2022 versus 355 per 100,000 children per year in a typical prepandemic season. However, the largest incidence of lower respiratory infections (30,075 per 100,000) was predicted for infants aged 3-5 months, and the largest incidence of hospitalizations (3,116 per 100,000) was predicted for infants younger than 3 months.
“Without virus importation, the risk of RSV infections across all age groups in the winter of 2021 and 2022 would be greater, as more susceptible individuals were spared from infections in the absence of summer epidemics,” the researchers noted.
The older mean hospitalization age seen in the model was similar to the reported median patient age in Australia both before the pandemic and during the reemergent RSV epidemic.
“This makes intuitive sense, since many children born in 2020 were spared from RSV infection due to the low virus activity; these children will be older when they get infected for the first time during the reemergent epidemics,” the researchers wrote. “Consequently, stakeholders should consider modifying prophylaxis guidelines to include high-risk infants less than 2 years of age for the 2021-2022 season.”
The study findings were limited by several factors including the lack of data on level of virus introduction or on the impact of lack of boosting on infants with only transplacentally acquired RSV antibodies, the researchers noted. Other limitations include the use of historical data and the lack of data on values outside those included in the model, as well as the inability to control for other factors that could influence RSV, such as vaccines or long-lasting antibodies.
However, the results suggest that the rate of imported infections is associated with RSV hospitalizations, and the model effectively captured the RSV epidemics in the United States in spring and summer 2021.
Models can guide clinical preparations
“Health care simulation modeling is a growing field, with very exciting implications,” Lenore Jarvis, MD, of George Washington University, Washington, said in an interview. The field has the potential ability to influence health care in a data-driven way, including, but not limited to, staffing and other hospital operations, as well as patient care decision-making. “In short, accurate modeling and predictions can help us to make informed health care decisions that can lead to increased quality of care, potential cost savings, and even to help save lives,” she said.
Although the details of transmission modeling were not mentioned in the study, the authors evaluated the performances of several models and scenarios. “Scenario 4, for example, was focused on in particular because it best captured the observed dynamics [for RSV] that emerged during the spring and summer of 2021,” Dr. Jarvis said.
“Pediatricians can speak to these trends firsthand. A decrease in expected RSV infections and hospitalizations in 2020, followed by an unprecedented and early increase in RSV infections and severity in 2021, and the factors that the authors account for make sense, such as reintroduction of RSV from other regions and low immunity in the population,” she said. “It also makes sense that, in these transmission modeling scenarios, the expected mean age of hospitalization because of RSV increased with a temporary (hopefully) increase in RSV hospitalizations in the 2021 season, and potentially the 2022 RSV season.”
As for additional research, Dr. Jarvis said she would like to see follow-up data on the RSV transmission modeling. “For example, with scenario 4, does this scenario continue to perform well in other time periods, such as the winter? If the modeling continues to be accurate during other periods of evaluation and reevaluation, this modeling could be very useful in helping pediatric clinics and hospitals to prepare for RSV care and hospital capacity management.”
The study was supported by grants to various researchers from the National Institute of Allergy and Infectious Diseases/National Institutes of Health, the National Center for Advancing Translational Science at the National Institutes of Health, and NIH Roadmap for Medical Research. Lead author Ms. Zheng had no financial conflicts to disclose. Her study coauthors disclosed relationships with companies including AbbVie, Merck, Pfizer, GlaxoSmithKline, MedImmune, and Janssen. Dr. Jarvis had no financial conflicts to disclose and serves on the Pediatric News editorial advisory board.
The impact of respiratory syncytial virus (RSV)will likely be greater in 2021 and 2022 in the United States than in previous years as a result of the ongoing COVID-19 pandemic, based on data from a simulation-modeling study involving approximately 19 million individuals.
Although RSV usually follows consistent patterns of timing and duration, the disease all but disappeared starting in March 2020 after the introduction of measures to mitigate the spread of COVID-19, Zhe Zheng, MBBS, of Yale University, New Haven, Conn., and colleagues wrote.
However, lifting of mitigation measures has resulted in emergence of RSV in various parts of the world in early 2021, and trends may be similar in the United States, but data are needed to plan for prophylaxis and hospital use, they noted.
In a study published in JAMA Network Open, the researchers developed a simulation model for epidemics of RSV based on historical data. They acquired inpatient records from New York during 2005-2014 and from California during 2003-2011. The primary clinical outcome was the estimated monthly hospitalizations for RSV.
The simulated study population was 19.45 million individuals. After evaluating several scenarios including continued low transmission associated with social distancing and other mitigation measures, the researchers focused on the likely scenario that introduction of RSV from other regions would likely spark RSV epidemics in the United States.
They determined that spring and summer 2021 would show an increase in hospitalizations for RSV. Overall, higher rates of virus introduction from other regions were associated with more intense spring and summer RSV epidemics, with the trade-off of smaller winter epidemics. In the model, the expected RSV epidemic in spring and summer 2021 in New York was small, with a peak incidence of 419 hospitalizations per 100,000 people in April; by contrast, for states with less seasonal variability, such as Florida, the model predicted a larger summer epidemic.
In the model, the mean age of hospitalization for children younger than 5 years for January 2022 was expected to be 1.17 years, compared with 0.84 years in January 2019, the researchers noted.
Across all age groups, the greatest relative increase in the incidence of RSV infection was predicted for children aged 1-4 years (ranging from 82% to 86%), as were lower respiratory infections (87%-101%) and hospitalization (99%-119%), compared with prepandemic levels.
Hospitalizations for children aged 1 year were predicted to double compared with prepandemic seasons; 707 per 100,000 children per year for 2021 and 2022 versus 355 per 100,000 children per year in a typical prepandemic season. However, the largest incidence of lower respiratory infections (30,075 per 100,000) was predicted for infants aged 3-5 months, and the largest incidence of hospitalizations (3,116 per 100,000) was predicted for infants younger than 3 months.
“Without virus importation, the risk of RSV infections across all age groups in the winter of 2021 and 2022 would be greater, as more susceptible individuals were spared from infections in the absence of summer epidemics,” the researchers noted.
The older mean hospitalization age seen in the model was similar to the reported median patient age in Australia both before the pandemic and during the reemergent RSV epidemic.
“This makes intuitive sense, since many children born in 2020 were spared from RSV infection due to the low virus activity; these children will be older when they get infected for the first time during the reemergent epidemics,” the researchers wrote. “Consequently, stakeholders should consider modifying prophylaxis guidelines to include high-risk infants less than 2 years of age for the 2021-2022 season.”
The study findings were limited by several factors including the lack of data on level of virus introduction or on the impact of lack of boosting on infants with only transplacentally acquired RSV antibodies, the researchers noted. Other limitations include the use of historical data and the lack of data on values outside those included in the model, as well as the inability to control for other factors that could influence RSV, such as vaccines or long-lasting antibodies.
However, the results suggest that the rate of imported infections is associated with RSV hospitalizations, and the model effectively captured the RSV epidemics in the United States in spring and summer 2021.
Models can guide clinical preparations
“Health care simulation modeling is a growing field, with very exciting implications,” Lenore Jarvis, MD, of George Washington University, Washington, said in an interview. The field has the potential ability to influence health care in a data-driven way, including, but not limited to, staffing and other hospital operations, as well as patient care decision-making. “In short, accurate modeling and predictions can help us to make informed health care decisions that can lead to increased quality of care, potential cost savings, and even to help save lives,” she said.
Although the details of transmission modeling were not mentioned in the study, the authors evaluated the performances of several models and scenarios. “Scenario 4, for example, was focused on in particular because it best captured the observed dynamics [for RSV] that emerged during the spring and summer of 2021,” Dr. Jarvis said.
“Pediatricians can speak to these trends firsthand. A decrease in expected RSV infections and hospitalizations in 2020, followed by an unprecedented and early increase in RSV infections and severity in 2021, and the factors that the authors account for make sense, such as reintroduction of RSV from other regions and low immunity in the population,” she said. “It also makes sense that, in these transmission modeling scenarios, the expected mean age of hospitalization because of RSV increased with a temporary (hopefully) increase in RSV hospitalizations in the 2021 season, and potentially the 2022 RSV season.”
As for additional research, Dr. Jarvis said she would like to see follow-up data on the RSV transmission modeling. “For example, with scenario 4, does this scenario continue to perform well in other time periods, such as the winter? If the modeling continues to be accurate during other periods of evaluation and reevaluation, this modeling could be very useful in helping pediatric clinics and hospitals to prepare for RSV care and hospital capacity management.”
The study was supported by grants to various researchers from the National Institute of Allergy and Infectious Diseases/National Institutes of Health, the National Center for Advancing Translational Science at the National Institutes of Health, and NIH Roadmap for Medical Research. Lead author Ms. Zheng had no financial conflicts to disclose. Her study coauthors disclosed relationships with companies including AbbVie, Merck, Pfizer, GlaxoSmithKline, MedImmune, and Janssen. Dr. Jarvis had no financial conflicts to disclose and serves on the Pediatric News editorial advisory board.
FROM JAMA NETWORK OPEN
New option for flares in pustular psoriasis
according to a statement from manufacturer Boehringer Ingelheim. The FDA also granted Priority Review to spesolimab. Priority Review is a designation granted to medications that would offer significant improvement over the currently available treatments.
Generalized pustular psoriasis (GPP), though rare, is a potentially life-threatening condition that is distinct from plaque psoriasis. Throughout the course of the disease, which is caused by the accumulation of neutrophils in the skin, patients may experience persistent disease with intermittent flares or relapsing disease with recurrent flares. The neutrophil accumulation results in the eruption of sterile, yet painful pustules across all parts of the body.
“While the severity of GPP flares can vary, if left untreated they can be life threatening due to complications such as sepsis and multisystem organ failure,” and have a significant impact on quality of life, according to the company statement.
The FDA also has granted spesolimab an Orphan Drug Designation for the treatment of GPP, and a Breakthrough Therapy Designation for the treatment of GPP flares in adults.
A marketing authorization application for spesolimab for the treatment of GPP was accepted for evaluation by the European Medicines Agency in October 2021, according to a company press release issued at that time.
A protocol for a phase 2 study of spesolimab versus placebo for treating acute flares in GPP patients was published in October in BMJ Open, after a phase 1 proof-of-concept study published in 2019 showed the potential of an IL-36 receptor antagonist to improve disease scores in adults with GPP.
More information is available on the Boehringer Ingelheim website.
according to a statement from manufacturer Boehringer Ingelheim. The FDA also granted Priority Review to spesolimab. Priority Review is a designation granted to medications that would offer significant improvement over the currently available treatments.
Generalized pustular psoriasis (GPP), though rare, is a potentially life-threatening condition that is distinct from plaque psoriasis. Throughout the course of the disease, which is caused by the accumulation of neutrophils in the skin, patients may experience persistent disease with intermittent flares or relapsing disease with recurrent flares. The neutrophil accumulation results in the eruption of sterile, yet painful pustules across all parts of the body.
“While the severity of GPP flares can vary, if left untreated they can be life threatening due to complications such as sepsis and multisystem organ failure,” and have a significant impact on quality of life, according to the company statement.
The FDA also has granted spesolimab an Orphan Drug Designation for the treatment of GPP, and a Breakthrough Therapy Designation for the treatment of GPP flares in adults.
A marketing authorization application for spesolimab for the treatment of GPP was accepted for evaluation by the European Medicines Agency in October 2021, according to a company press release issued at that time.
A protocol for a phase 2 study of spesolimab versus placebo for treating acute flares in GPP patients was published in October in BMJ Open, after a phase 1 proof-of-concept study published in 2019 showed the potential of an IL-36 receptor antagonist to improve disease scores in adults with GPP.
More information is available on the Boehringer Ingelheim website.
according to a statement from manufacturer Boehringer Ingelheim. The FDA also granted Priority Review to spesolimab. Priority Review is a designation granted to medications that would offer significant improvement over the currently available treatments.
Generalized pustular psoriasis (GPP), though rare, is a potentially life-threatening condition that is distinct from plaque psoriasis. Throughout the course of the disease, which is caused by the accumulation of neutrophils in the skin, patients may experience persistent disease with intermittent flares or relapsing disease with recurrent flares. The neutrophil accumulation results in the eruption of sterile, yet painful pustules across all parts of the body.
“While the severity of GPP flares can vary, if left untreated they can be life threatening due to complications such as sepsis and multisystem organ failure,” and have a significant impact on quality of life, according to the company statement.
The FDA also has granted spesolimab an Orphan Drug Designation for the treatment of GPP, and a Breakthrough Therapy Designation for the treatment of GPP flares in adults.
A marketing authorization application for spesolimab for the treatment of GPP was accepted for evaluation by the European Medicines Agency in October 2021, according to a company press release issued at that time.
A protocol for a phase 2 study of spesolimab versus placebo for treating acute flares in GPP patients was published in October in BMJ Open, after a phase 1 proof-of-concept study published in 2019 showed the potential of an IL-36 receptor antagonist to improve disease scores in adults with GPP.
More information is available on the Boehringer Ingelheim website.
Delayed umbilical cord clamping improves outcomes in very preterm infants
Delayed umbilical cord clamping for at least 60 seconds after birth significantly reduced death or disability in infants of less than 30 weeks’ gestation, according to data from nearly 1,500 infants.
The burden of disability and mortality for babies born before 30 weeks’ gestation remains high, especially in low- and middle-income countries, wrote Kristy P. Robledo, PhD, of the University of Sydney, Australia, and colleagues. Delayed clamping of the umbilical cord is a simple procedure that may improve mortality in this population, but more research is needed; recommended times to delayed clamping range from 30 seconds to 3 minutes, they noted.
In a study published in The Lancet Child & Adolescent Health, the researchers randomized 767 very preterm infants to delayed clamping at least 60 seconds after birth and 764 to immediate clamping. Of these, 384 were multiple births (who were individually randomized), 862 were male, and 505 were born before 27 weeks’ gestation. The primary outcome was death or disability at 2 years of age. Major disability was defined as cerebral palsy, severe visual loss, deafness requiring a hearing aid or cochlear implants, major language or speech problems, or cognitive delay at 2 years corrected age. The median time to clamping was 60 seconds in the delayed group and 5 seconds in the immediate group.
Primary outcome data were available for 1,419 infants. Death or major disability occurred in 29% of infants assigned to delayed clamping compared to 34% of those assigned to immediate clamping (relative risk 0.83, P = .010). The infants were part of the APTS Childhood Follow-Up Study, an open-label superiority trial conducted in Australia and New Zealand.
By age 2 years, 8% of infants in the delayed group and 11% of those in the immediate group had died; 23% and 26%, respectively, met criteria for major disability. The impact of delayed clamping translates to a 30% reduction in relative risk of mortality at 2 years of age, but no significant impact on major disability, the researchers wrote.
The findings were limited by several factors including the unblinded study design, lack of data on heart rate or time to first breath, and the clamping prior to 60 seconds in 26% of infants in the delayed group based on clinical concerns for these specific infants, the researchers noted.
However, the results were strengthened by the large size, low risk of bias, and specific primary outcome, they said. The data support findings from recent systematic reviews and highlight the need for further trials to evaluate delayed clamping at different time points, with larger populations, inclusion of time to first breath and heart rate, and improved measures of disability, the researchers added.
In clinical practice, “Given that aiming to delay cord clamping for 60 seconds or more improved 2-year outcomes and short-term hematological measures with no evidence of significant harm, it seems reasonable to conclude that delayed clamping is appropriate as standard care in very preterm infants,” they concluded.
Accepting simple intervention could have great impact
This study is important in light of the overwhelming burden of preterm birth on the health care system and society as a whole, Lisette D. Tanner, MD, of Emory University, Atlanta, said in an interview.
“Preterm birth is associated with billions in health care costs each year, and a large portion of that money is directed to the complications associated with preterm birth, such as early intervention services, educational support, and ongoing medical care,” Dr. Tanner said. “This study is particularly timely, as we are quickly approaching 2030, the deadline for achieving the United Nations Sustainable Development Goal of ending preventable deaths of newborns and children under 5 years of age,” she said. The goal involves “all countries aiming to reduce neonatal mortality to at least as low as 12 per 1,000 live births and under-5 mortality to at least as low as 25 per 1,000 live births. Effective treatments to reduce infant and child mortality would make strong inroads toward this goal,” she explained.
Dr. Tanner said she was not surprised by the findings because previous studies have shown similar results. “However, the large, multicenter nature of this study provides additional weight to recommendations to delay cord clamping as standard practice,” she said.
“The findings of this study support the recommendations of a number of large organizations,” said Dr. Tanner. “The World Health Organization recommends that the umbilical cord not be clamped earlier than 1 minute after birth in term or preterm infants who do not require positive pressure ventilation. The American College of Obstetricians and Gynecologists and the American Academy of Pediatrics now recommend a delay in umbilical cord clamping in vigorous term and preterm infants for at least 30–60 seconds after birth,” she said. “The Royal College of Obstetricians and Gynaecologists also recommends deferring umbilical cord clamping for healthy term and preterm infants for at least 2 minutes after birth,” she added.
However, “the delay in adoption of this guidelines in practice appears to be related to some concerns regarding universal adoption of this approach,” Dr. Tanner noted. “Some clinicians have suggested that delayed cord clamping could delay vital neonatal resuscitative efforts, leading to worse neonatal outcomes, but this concern has not been borne out in the data, as all guidelines specifically state that this intervention is for vigorous newborns,” she said. “In fact, in preterm infants, delayed cord clamping is associated with improved transitional circulation, decreased need for blood transfusion, and lower incidence of necrotizing enterocolitis and intraventricular hemorrhage,” Dr. Tanner emphasized. “Additionally, concerns persist that delayed cord clamping could lead to excessive transfusion with resultant polycythemia. Again, no data have supported this claim to date,” she said.
“Finally, some clinicians are concerned that delayed clamping could lead to delay in addressing maternal complications of birth such as hemorrhage, but studies have shown the opposite; delayed umbilical cord clamping has not been associated with an increased risk of postpartum hemorrhage or increased blood loss at delivery, nor has it been with a difference in the need for blood transfusion,” said Dr. Tanner.
Ideally, practitioners will become more comfortable in delaying cord clamping as a routine practice as more data demonstrating the safety and benefit of this easy intervention are disseminated, she said.
Additional research delineating which gestational ages benefit most from delayed cord clamping would help direct education efforts to implement this intervention, Dr. Tanner noted.
The study was funded by the Australian National Health and Medical Research Council. The researchers and Dr. Tanner had no financial conflicts to disclose.
Delayed umbilical cord clamping for at least 60 seconds after birth significantly reduced death or disability in infants of less than 30 weeks’ gestation, according to data from nearly 1,500 infants.
The burden of disability and mortality for babies born before 30 weeks’ gestation remains high, especially in low- and middle-income countries, wrote Kristy P. Robledo, PhD, of the University of Sydney, Australia, and colleagues. Delayed clamping of the umbilical cord is a simple procedure that may improve mortality in this population, but more research is needed; recommended times to delayed clamping range from 30 seconds to 3 minutes, they noted.
In a study published in The Lancet Child & Adolescent Health, the researchers randomized 767 very preterm infants to delayed clamping at least 60 seconds after birth and 764 to immediate clamping. Of these, 384 were multiple births (who were individually randomized), 862 were male, and 505 were born before 27 weeks’ gestation. The primary outcome was death or disability at 2 years of age. Major disability was defined as cerebral palsy, severe visual loss, deafness requiring a hearing aid or cochlear implants, major language or speech problems, or cognitive delay at 2 years corrected age. The median time to clamping was 60 seconds in the delayed group and 5 seconds in the immediate group.
Primary outcome data were available for 1,419 infants. Death or major disability occurred in 29% of infants assigned to delayed clamping compared to 34% of those assigned to immediate clamping (relative risk 0.83, P = .010). The infants were part of the APTS Childhood Follow-Up Study, an open-label superiority trial conducted in Australia and New Zealand.
By age 2 years, 8% of infants in the delayed group and 11% of those in the immediate group had died; 23% and 26%, respectively, met criteria for major disability. The impact of delayed clamping translates to a 30% reduction in relative risk of mortality at 2 years of age, but no significant impact on major disability, the researchers wrote.
The findings were limited by several factors including the unblinded study design, lack of data on heart rate or time to first breath, and the clamping prior to 60 seconds in 26% of infants in the delayed group based on clinical concerns for these specific infants, the researchers noted.
However, the results were strengthened by the large size, low risk of bias, and specific primary outcome, they said. The data support findings from recent systematic reviews and highlight the need for further trials to evaluate delayed clamping at different time points, with larger populations, inclusion of time to first breath and heart rate, and improved measures of disability, the researchers added.
In clinical practice, “Given that aiming to delay cord clamping for 60 seconds or more improved 2-year outcomes and short-term hematological measures with no evidence of significant harm, it seems reasonable to conclude that delayed clamping is appropriate as standard care in very preterm infants,” they concluded.
Accepting simple intervention could have great impact
This study is important in light of the overwhelming burden of preterm birth on the health care system and society as a whole, Lisette D. Tanner, MD, of Emory University, Atlanta, said in an interview.
“Preterm birth is associated with billions in health care costs each year, and a large portion of that money is directed to the complications associated with preterm birth, such as early intervention services, educational support, and ongoing medical care,” Dr. Tanner said. “This study is particularly timely, as we are quickly approaching 2030, the deadline for achieving the United Nations Sustainable Development Goal of ending preventable deaths of newborns and children under 5 years of age,” she said. The goal involves “all countries aiming to reduce neonatal mortality to at least as low as 12 per 1,000 live births and under-5 mortality to at least as low as 25 per 1,000 live births. Effective treatments to reduce infant and child mortality would make strong inroads toward this goal,” she explained.
Dr. Tanner said she was not surprised by the findings because previous studies have shown similar results. “However, the large, multicenter nature of this study provides additional weight to recommendations to delay cord clamping as standard practice,” she said.
“The findings of this study support the recommendations of a number of large organizations,” said Dr. Tanner. “The World Health Organization recommends that the umbilical cord not be clamped earlier than 1 minute after birth in term or preterm infants who do not require positive pressure ventilation. The American College of Obstetricians and Gynecologists and the American Academy of Pediatrics now recommend a delay in umbilical cord clamping in vigorous term and preterm infants for at least 30–60 seconds after birth,” she said. “The Royal College of Obstetricians and Gynaecologists also recommends deferring umbilical cord clamping for healthy term and preterm infants for at least 2 minutes after birth,” she added.
However, “the delay in adoption of this guidelines in practice appears to be related to some concerns regarding universal adoption of this approach,” Dr. Tanner noted. “Some clinicians have suggested that delayed cord clamping could delay vital neonatal resuscitative efforts, leading to worse neonatal outcomes, but this concern has not been borne out in the data, as all guidelines specifically state that this intervention is for vigorous newborns,” she said. “In fact, in preterm infants, delayed cord clamping is associated with improved transitional circulation, decreased need for blood transfusion, and lower incidence of necrotizing enterocolitis and intraventricular hemorrhage,” Dr. Tanner emphasized. “Additionally, concerns persist that delayed cord clamping could lead to excessive transfusion with resultant polycythemia. Again, no data have supported this claim to date,” she said.
“Finally, some clinicians are concerned that delayed clamping could lead to delay in addressing maternal complications of birth such as hemorrhage, but studies have shown the opposite; delayed umbilical cord clamping has not been associated with an increased risk of postpartum hemorrhage or increased blood loss at delivery, nor has it been with a difference in the need for blood transfusion,” said Dr. Tanner.
Ideally, practitioners will become more comfortable in delaying cord clamping as a routine practice as more data demonstrating the safety and benefit of this easy intervention are disseminated, she said.
Additional research delineating which gestational ages benefit most from delayed cord clamping would help direct education efforts to implement this intervention, Dr. Tanner noted.
The study was funded by the Australian National Health and Medical Research Council. The researchers and Dr. Tanner had no financial conflicts to disclose.
Delayed umbilical cord clamping for at least 60 seconds after birth significantly reduced death or disability in infants of less than 30 weeks’ gestation, according to data from nearly 1,500 infants.
The burden of disability and mortality for babies born before 30 weeks’ gestation remains high, especially in low- and middle-income countries, wrote Kristy P. Robledo, PhD, of the University of Sydney, Australia, and colleagues. Delayed clamping of the umbilical cord is a simple procedure that may improve mortality in this population, but more research is needed; recommended times to delayed clamping range from 30 seconds to 3 minutes, they noted.
In a study published in The Lancet Child & Adolescent Health, the researchers randomized 767 very preterm infants to delayed clamping at least 60 seconds after birth and 764 to immediate clamping. Of these, 384 were multiple births (who were individually randomized), 862 were male, and 505 were born before 27 weeks’ gestation. The primary outcome was death or disability at 2 years of age. Major disability was defined as cerebral palsy, severe visual loss, deafness requiring a hearing aid or cochlear implants, major language or speech problems, or cognitive delay at 2 years corrected age. The median time to clamping was 60 seconds in the delayed group and 5 seconds in the immediate group.
Primary outcome data were available for 1,419 infants. Death or major disability occurred in 29% of infants assigned to delayed clamping compared to 34% of those assigned to immediate clamping (relative risk 0.83, P = .010). The infants were part of the APTS Childhood Follow-Up Study, an open-label superiority trial conducted in Australia and New Zealand.
By age 2 years, 8% of infants in the delayed group and 11% of those in the immediate group had died; 23% and 26%, respectively, met criteria for major disability. The impact of delayed clamping translates to a 30% reduction in relative risk of mortality at 2 years of age, but no significant impact on major disability, the researchers wrote.
The findings were limited by several factors including the unblinded study design, lack of data on heart rate or time to first breath, and the clamping prior to 60 seconds in 26% of infants in the delayed group based on clinical concerns for these specific infants, the researchers noted.
However, the results were strengthened by the large size, low risk of bias, and specific primary outcome, they said. The data support findings from recent systematic reviews and highlight the need for further trials to evaluate delayed clamping at different time points, with larger populations, inclusion of time to first breath and heart rate, and improved measures of disability, the researchers added.
In clinical practice, “Given that aiming to delay cord clamping for 60 seconds or more improved 2-year outcomes and short-term hematological measures with no evidence of significant harm, it seems reasonable to conclude that delayed clamping is appropriate as standard care in very preterm infants,” they concluded.
Accepting simple intervention could have great impact
This study is important in light of the overwhelming burden of preterm birth on the health care system and society as a whole, Lisette D. Tanner, MD, of Emory University, Atlanta, said in an interview.
“Preterm birth is associated with billions in health care costs each year, and a large portion of that money is directed to the complications associated with preterm birth, such as early intervention services, educational support, and ongoing medical care,” Dr. Tanner said. “This study is particularly timely, as we are quickly approaching 2030, the deadline for achieving the United Nations Sustainable Development Goal of ending preventable deaths of newborns and children under 5 years of age,” she said. The goal involves “all countries aiming to reduce neonatal mortality to at least as low as 12 per 1,000 live births and under-5 mortality to at least as low as 25 per 1,000 live births. Effective treatments to reduce infant and child mortality would make strong inroads toward this goal,” she explained.
Dr. Tanner said she was not surprised by the findings because previous studies have shown similar results. “However, the large, multicenter nature of this study provides additional weight to recommendations to delay cord clamping as standard practice,” she said.
“The findings of this study support the recommendations of a number of large organizations,” said Dr. Tanner. “The World Health Organization recommends that the umbilical cord not be clamped earlier than 1 minute after birth in term or preterm infants who do not require positive pressure ventilation. The American College of Obstetricians and Gynecologists and the American Academy of Pediatrics now recommend a delay in umbilical cord clamping in vigorous term and preterm infants for at least 30–60 seconds after birth,” she said. “The Royal College of Obstetricians and Gynaecologists also recommends deferring umbilical cord clamping for healthy term and preterm infants for at least 2 minutes after birth,” she added.
However, “the delay in adoption of this guidelines in practice appears to be related to some concerns regarding universal adoption of this approach,” Dr. Tanner noted. “Some clinicians have suggested that delayed cord clamping could delay vital neonatal resuscitative efforts, leading to worse neonatal outcomes, but this concern has not been borne out in the data, as all guidelines specifically state that this intervention is for vigorous newborns,” she said. “In fact, in preterm infants, delayed cord clamping is associated with improved transitional circulation, decreased need for blood transfusion, and lower incidence of necrotizing enterocolitis and intraventricular hemorrhage,” Dr. Tanner emphasized. “Additionally, concerns persist that delayed cord clamping could lead to excessive transfusion with resultant polycythemia. Again, no data have supported this claim to date,” she said.
“Finally, some clinicians are concerned that delayed clamping could lead to delay in addressing maternal complications of birth such as hemorrhage, but studies have shown the opposite; delayed umbilical cord clamping has not been associated with an increased risk of postpartum hemorrhage or increased blood loss at delivery, nor has it been with a difference in the need for blood transfusion,” said Dr. Tanner.
Ideally, practitioners will become more comfortable in delaying cord clamping as a routine practice as more data demonstrating the safety and benefit of this easy intervention are disseminated, she said.
Additional research delineating which gestational ages benefit most from delayed cord clamping would help direct education efforts to implement this intervention, Dr. Tanner noted.
The study was funded by the Australian National Health and Medical Research Council. The researchers and Dr. Tanner had no financial conflicts to disclose.
FROM THE LANCET CHILD & ADOLESCENT HEALTH
COVID-19 asymptomatic infection rate remains high
Based on data from a meta-analysis of 95 studies that included nearly 30,000,000 individuals, the pooled percentage of asymptomatic COVID-19 infections was 0.25% in the tested population and 40.5% among confirmed cases.
, wrote Qiuyue Ma, PhD, and colleagues of Peking University, Beijing.
In a study published in JAMA Network Open the researchers identified 44 cross-sectional studies, 41 cohort studies, seven case series, and three case series on transmission studies. A total of 74 studies were conducted in developed countries, including those in Europe, North America, and Asia. Approximately one-third (37) of the studies were conducted among health care workers or in-hospital patients, 17 among nursing home staff or residents, and 14 among community residents. In addition, 13 studies involved pregnant women, eight involved air or cruise ship travelers, and six involved close contacts of individuals with confirmed infections.
The meta-analysis included 29,776,306 tested individuals; 11,516 of them had asymptomatic infections.
Overall, the pooled percentage of asymptomatic infections among the tested population was 0.25%. In an analysis of different study populations, the percentage was higher in nursing home residents or staff (4.52%), air or cruise ship travelers (2.02%), and pregnant women (2.34%), compared against the pooled percentage.
The pooled percentage of asymptomatic infections among the confirmed population was 40.50%, and this percentage was higher in pregnant women (54.11%), air or cruise ship travelers (52.91%), and nursing home residents or staff (47.53%).
The pooled percentage in the tested population was higher than the overall percentage when the mean age of the study population was 60 years or older (3.69%). By contrast, in the confirmed population, the pooled percentage was higher than the overall percentage when the study population was younger than 20 years (60.2%) or aged 20 to 39 years (49.5%).
The researchers noted in their discussion that the varying percentage of asymptomatic individuals according to community prevalence might impact the heterogeneity of the included studies. They also noted the high number of studies conducted in nursing home populations, groups in which asymptomatic individuals were more likely to be tested.
The study findings were limited by several factors, including the potential for missed studies that were not published at the time of the meta-analysis, as well as the exclusion of studies written in Chinese, the researchers noted. Other limitations included lack of follow-up on presymptomatic and covert infections, and the focus on specific populations, factors that may limit the degree to which the results can be generalized.
However, the results highlight the need to screen for asymptomatic infections, especially in countries where COVID-19 has been better controlled, the researchers said. Management strategies for asymptomatic infections, when identified, should include isolation and contact tracing similar to strategies used with confirmed cases, they added.
More testing needed to catch cases early
“During the initial phase of [the] COVID-19 pandemic, testing was not widely available in the United States or the rest of the world,” Setu Patolia, MD, of Saint Louis University School of Medicine, Missouri, said in an interview. Much of the world still lacks access to COVID-19 testing, and early in the pandemic only severely symptomatic patients were tested, he said. “With new variants, particularly the Omicron variant, which may have mild or minimally symptomatic disease, asymptomatic carriers play an important role in propagation of the pandemic,” he explained. “It is important to know the asymptomatic carrier rate among the general population for the future control of [the] pandemic,” he added.
Dr. Patolia said he was surprised by the study finding that one in 400 people in the general population could be asymptomatic carriers of COVID-19.
“Also, nursing home patients are more at risk of complications of COVID, and I expected that they would have a higher rate of symptomatic disease as compared to [the] general population,” said Dr. Patolia. He was also surprised by the high rate of asymptomatic infections in travelers.
“Physicians should be more aware about the asymptomatic carrier rate, particularly in travelers and nursing home patients,” he noted. “Travelers carry high risk of transferring infection from one region to another region of the world, and physicians should advise them to get tested despite the absence of symptoms,” Dr. Patolia emphasized. “Similarly, once any nursing home patient has been diagnosed with COVID-19, physicians should be more careful with the rest of the nursing home patients and test them despite the absence of the symptoms,” he added.
Dr. Patolia also recommended that pregnant women wear masks to help prevent disease transmission when visiting a doctor’s office or labor unit.
Looking ahead, there is a need for cheaper at-home testing kits so that all vulnerable populations can be tested fast and frequently, Dr. Patolia said.
The study was supported by the National Natural Science Foundation of China. The researchers had no financial conflicts to disclose. Dr. Patolia has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Based on data from a meta-analysis of 95 studies that included nearly 30,000,000 individuals, the pooled percentage of asymptomatic COVID-19 infections was 0.25% in the tested population and 40.5% among confirmed cases.
, wrote Qiuyue Ma, PhD, and colleagues of Peking University, Beijing.
In a study published in JAMA Network Open the researchers identified 44 cross-sectional studies, 41 cohort studies, seven case series, and three case series on transmission studies. A total of 74 studies were conducted in developed countries, including those in Europe, North America, and Asia. Approximately one-third (37) of the studies were conducted among health care workers or in-hospital patients, 17 among nursing home staff or residents, and 14 among community residents. In addition, 13 studies involved pregnant women, eight involved air or cruise ship travelers, and six involved close contacts of individuals with confirmed infections.
The meta-analysis included 29,776,306 tested individuals; 11,516 of them had asymptomatic infections.
Overall, the pooled percentage of asymptomatic infections among the tested population was 0.25%. In an analysis of different study populations, the percentage was higher in nursing home residents or staff (4.52%), air or cruise ship travelers (2.02%), and pregnant women (2.34%), compared against the pooled percentage.
The pooled percentage of asymptomatic infections among the confirmed population was 40.50%, and this percentage was higher in pregnant women (54.11%), air or cruise ship travelers (52.91%), and nursing home residents or staff (47.53%).
The pooled percentage in the tested population was higher than the overall percentage when the mean age of the study population was 60 years or older (3.69%). By contrast, in the confirmed population, the pooled percentage was higher than the overall percentage when the study population was younger than 20 years (60.2%) or aged 20 to 39 years (49.5%).
The researchers noted in their discussion that the varying percentage of asymptomatic individuals according to community prevalence might impact the heterogeneity of the included studies. They also noted the high number of studies conducted in nursing home populations, groups in which asymptomatic individuals were more likely to be tested.
The study findings were limited by several factors, including the potential for missed studies that were not published at the time of the meta-analysis, as well as the exclusion of studies written in Chinese, the researchers noted. Other limitations included lack of follow-up on presymptomatic and covert infections, and the focus on specific populations, factors that may limit the degree to which the results can be generalized.
However, the results highlight the need to screen for asymptomatic infections, especially in countries where COVID-19 has been better controlled, the researchers said. Management strategies for asymptomatic infections, when identified, should include isolation and contact tracing similar to strategies used with confirmed cases, they added.
More testing needed to catch cases early
“During the initial phase of [the] COVID-19 pandemic, testing was not widely available in the United States or the rest of the world,” Setu Patolia, MD, of Saint Louis University School of Medicine, Missouri, said in an interview. Much of the world still lacks access to COVID-19 testing, and early in the pandemic only severely symptomatic patients were tested, he said. “With new variants, particularly the Omicron variant, which may have mild or minimally symptomatic disease, asymptomatic carriers play an important role in propagation of the pandemic,” he explained. “It is important to know the asymptomatic carrier rate among the general population for the future control of [the] pandemic,” he added.
Dr. Patolia said he was surprised by the study finding that one in 400 people in the general population could be asymptomatic carriers of COVID-19.
“Also, nursing home patients are more at risk of complications of COVID, and I expected that they would have a higher rate of symptomatic disease as compared to [the] general population,” said Dr. Patolia. He was also surprised by the high rate of asymptomatic infections in travelers.
“Physicians should be more aware about the asymptomatic carrier rate, particularly in travelers and nursing home patients,” he noted. “Travelers carry high risk of transferring infection from one region to another region of the world, and physicians should advise them to get tested despite the absence of symptoms,” Dr. Patolia emphasized. “Similarly, once any nursing home patient has been diagnosed with COVID-19, physicians should be more careful with the rest of the nursing home patients and test them despite the absence of the symptoms,” he added.
Dr. Patolia also recommended that pregnant women wear masks to help prevent disease transmission when visiting a doctor’s office or labor unit.
Looking ahead, there is a need for cheaper at-home testing kits so that all vulnerable populations can be tested fast and frequently, Dr. Patolia said.
The study was supported by the National Natural Science Foundation of China. The researchers had no financial conflicts to disclose. Dr. Patolia has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Based on data from a meta-analysis of 95 studies that included nearly 30,000,000 individuals, the pooled percentage of asymptomatic COVID-19 infections was 0.25% in the tested population and 40.5% among confirmed cases.
, wrote Qiuyue Ma, PhD, and colleagues of Peking University, Beijing.
In a study published in JAMA Network Open the researchers identified 44 cross-sectional studies, 41 cohort studies, seven case series, and three case series on transmission studies. A total of 74 studies were conducted in developed countries, including those in Europe, North America, and Asia. Approximately one-third (37) of the studies were conducted among health care workers or in-hospital patients, 17 among nursing home staff or residents, and 14 among community residents. In addition, 13 studies involved pregnant women, eight involved air or cruise ship travelers, and six involved close contacts of individuals with confirmed infections.
The meta-analysis included 29,776,306 tested individuals; 11,516 of them had asymptomatic infections.
Overall, the pooled percentage of asymptomatic infections among the tested population was 0.25%. In an analysis of different study populations, the percentage was higher in nursing home residents or staff (4.52%), air or cruise ship travelers (2.02%), and pregnant women (2.34%), compared against the pooled percentage.
The pooled percentage of asymptomatic infections among the confirmed population was 40.50%, and this percentage was higher in pregnant women (54.11%), air or cruise ship travelers (52.91%), and nursing home residents or staff (47.53%).
The pooled percentage in the tested population was higher than the overall percentage when the mean age of the study population was 60 years or older (3.69%). By contrast, in the confirmed population, the pooled percentage was higher than the overall percentage when the study population was younger than 20 years (60.2%) or aged 20 to 39 years (49.5%).
The researchers noted in their discussion that the varying percentage of asymptomatic individuals according to community prevalence might impact the heterogeneity of the included studies. They also noted the high number of studies conducted in nursing home populations, groups in which asymptomatic individuals were more likely to be tested.
The study findings were limited by several factors, including the potential for missed studies that were not published at the time of the meta-analysis, as well as the exclusion of studies written in Chinese, the researchers noted. Other limitations included lack of follow-up on presymptomatic and covert infections, and the focus on specific populations, factors that may limit the degree to which the results can be generalized.
However, the results highlight the need to screen for asymptomatic infections, especially in countries where COVID-19 has been better controlled, the researchers said. Management strategies for asymptomatic infections, when identified, should include isolation and contact tracing similar to strategies used with confirmed cases, they added.
More testing needed to catch cases early
“During the initial phase of [the] COVID-19 pandemic, testing was not widely available in the United States or the rest of the world,” Setu Patolia, MD, of Saint Louis University School of Medicine, Missouri, said in an interview. Much of the world still lacks access to COVID-19 testing, and early in the pandemic only severely symptomatic patients were tested, he said. “With new variants, particularly the Omicron variant, which may have mild or minimally symptomatic disease, asymptomatic carriers play an important role in propagation of the pandemic,” he explained. “It is important to know the asymptomatic carrier rate among the general population for the future control of [the] pandemic,” he added.
Dr. Patolia said he was surprised by the study finding that one in 400 people in the general population could be asymptomatic carriers of COVID-19.
“Also, nursing home patients are more at risk of complications of COVID, and I expected that they would have a higher rate of symptomatic disease as compared to [the] general population,” said Dr. Patolia. He was also surprised by the high rate of asymptomatic infections in travelers.
“Physicians should be more aware about the asymptomatic carrier rate, particularly in travelers and nursing home patients,” he noted. “Travelers carry high risk of transferring infection from one region to another region of the world, and physicians should advise them to get tested despite the absence of symptoms,” Dr. Patolia emphasized. “Similarly, once any nursing home patient has been diagnosed with COVID-19, physicians should be more careful with the rest of the nursing home patients and test them despite the absence of the symptoms,” he added.
Dr. Patolia also recommended that pregnant women wear masks to help prevent disease transmission when visiting a doctor’s office or labor unit.
Looking ahead, there is a need for cheaper at-home testing kits so that all vulnerable populations can be tested fast and frequently, Dr. Patolia said.
The study was supported by the National Natural Science Foundation of China. The researchers had no financial conflicts to disclose. Dr. Patolia has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Microbiota may predict success on low FODMAP diet
Two distinct gut microbiota subtypes showed an enhanced clinical response to a low FODMAP diet in an analysis of 41 adults with irritable bowel syndrome and household controls.
Irritable bowel syndrome (IBS) has a significant impact on quality of life, and some patients find relief on a low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) diet, wrote Kevin Vervier, PhD, of Wellcome Sanger Institute, Hinxton, England, and colleagues. However, the mechanism of action for the success of low FODMAP diets remains unclear, the diet is hard for many patients to follow, and the long-term impact on health is unknown. Therefore, research is needed to identify patients who would derive the most benefit, they said.
In a study published in Gut, the researchers used metagenomics and functional analysis to identify potential biomarkers of response to a low FODMAP diet. They analyzed stool samples from 41 pairs of IBS patients and household contacts. Stool samples were collected at baseline while on usual diets, and again after 4 weeks and 12 weeks on a low FODMAP diet. The patients were divided into two groups based on microbiota clusters; baseline demographics and clinical characteristics were similar between the clusters. In addition, symptom severity was measured using the IBS Severity Scoring System (IBS-SSS).
Cluster 1 was referred to as IBSP microbiome type because of its pathogenic properties, and cluster 2 as IBSH microbiome type because of its resemblance to the microbiome of healthy household controls, the researchers wrote.
“We found a significant enrichment of 109 functional pathways and significant depletion of 13 functional pathways in IBSP microbiomes compared with IBSH microbiomes,” the researchers said.
More specifically, the IBSP microbiomes were enriched in Firmicutes and in genes for amino acid and carbohydrate metabolism, at baseline, while the IBSH microbiomes were similar to healthy controls.
After 4 weeks on the low FODMAP diet, the IBSP microbiomes normalized, with increased levels of Bacterioides and decreased levels of pathobionts (including Clostridium difficile, Streptococcus parasanguinis, and Paeniclostridium sordellii) to create a microbiome profile resembling the IBSH microbiomes and healthy controls. The taxonomic profile of microbiomes observed in IBSH and healthy controls did not demonstrate a significant shift.
Although both microbiome groups showed improvement in IBS-SSS scores from baseline on the low FODMAP diet, decreasing from a mean baseline score of 278 to a diet score of 128, the improvement was greater in the IBSP group than the IBSH group (delta, 194 vs. 114, respectively; P = .02), the researchers noted. “The shift in the IBSP microbiota to a healthy profile appeared stable for at least 3 months and correlated with continuing symptomatic well-being,” they wrote.
The distinct responses of the IBSP and IBSH microbiomes to the low FODMAP diet suggest a potential mode of action, the researchers said in their discussion. Based on their findings, “it is possible that removal of the eliciting dietary component starves the pathobionts, leading to reduction in their growth and metabolism and a consequent decrease in symptoms, accompanied by an expansion of commensal or symbiotic species leading to a health-associated microbiome,” but more research is needed to prove causality, they said.
The study findings were limited by several factors, including the relatively small sample size, strict inclusion criteria, restriction of medications, and need for participation by household controls, the researchers noted. Other limitations include the inability to control for other factors that could have impacted the gut microbiota, such as the placebo effect and psychological factors, they said.
However, the findings provide a foundation for more research and should be validated in other populations involving different geographical regions and dietary habits, they said. “The identification of a microbial signature ‘biomarker’ that correlates with improved response to a low FODMAP diet may, if validated, allow better stratification and selection of patients likely to benefit from the diet,” they concluded.
Setting the stage for focused studies
The low FODMAP diet has demonstrated effectiveness for symptom relief in IBS, although potential risks include exacerbation of disordered eating, nutrition deficiencies, and disrupting gut microbiota, wrote Peter R. Gibson, MD, and Emma P. Halmos, MD, of Monash University and Alfred Health, Melbourne, in an accompanying editorial. However, the current study takes a new step on the journey to identifying patients most likely to respond to a low FODMAP diet, they said.
The editorialists noted three key takeaway points. First, the fecal microbiome may predict response to a low FODMAP diet. Second, the correction of the microbiome through the low FODMAP diet appeared to continue even after the diet was discontinued. “The other intriguing finding was that trehalose metabolic pathways were ‘activated’ in those with dysbiosis,” suggesting that trehalose might be an unrecognized FODMAP, the researchers noted. Trehalose has not been well studied but has been associated with pathogenicity, they said.
Although the study may overemphasize the impact of the low FODMAP diet given the relatively poor assessment of FODMAP intake, “the beauty of Vervier’s work is not in its definitive nature but in that it enables the creation of feasible innovative hypotheses that can be examined by focused studies,” they concluded.
The current study is important because IBS and related disorders of gut-brain interaction are common and greatly impact the quality of life of affected individuals, Jatin Roper, MD, of Duke University in Durham, N.C., said in an interview. Although the mechanisms for improvement are unknown, he said, “The low FODMAP diet is widely used to treat IBS, based on the hypothesis that this diet modifies the gut microbiome in a beneficial way.”
The study authors made two important discoveries, said Dr. Roper. “First, they found that they were able to distinguish IBS versus household controls based on their gut microbial signatures as well expression of key metabolic genes,” he said. “Second, they identified a unique microbiota subtype that was associated with a significant clinical response to the low FODMAP diet in IBS patients; IBS patients with a ‘pathogenic’ microbiome consisting of high Firmicutes and low Bacteroidetes responded to a greater degree to the low FODMAP diet compared to IBS patients with a ‘healthy’ microbiome that was similar to controls,” he explained. “Furthermore, after time on the low FODMAP diet, the IBS patients with pathogenic microbiome signatures developed a microbiome with low Firmicutes and high Bacteroidetes, which is thought to be healthy,” he added.
“These findings are exciting because they suggest that a patient’s microbial signature might be used clinically to predict response to the low FODMAP diet,” said Dr. Roper. “The surprising aspect of these results is that the microbial signature alone was able to predict response to a low FODMAP diet, despite the complex effects of the diet on host physiology and metabolism and the multifactorial etiology of IBS,” he noted.
However, larger clinical studies are needed to confirm the study findings results in larger patient cohorts and to show that standardized clinical assays can be used to prospectively predict response to dietary interventions such as low FODMAP in IBS, Dr. Roper emphasized.
“This paper provides preliminary and provocative findings that suggest that gut microbiota metabolites may play a role in the pathogenesis of IBS,” said Dr. Roper. “Future basic science and translational research is needed to study the mechanisms by which specific bacterial metabolites regulate intestinal function and disorders such as IBS. I hope that this research will eventually lead to metabolite-based therapies for IBS and other gastrointestinal disorders,” he said.
The study received no outside funding. Lead author Dr. Vervier had no financial conflicts to disclose. Dr. Gibson disclosed authoring two educational/recipe books on the low FODMAP diet, and Monash University financially benefits from the sales of a digital application, booklets, and online courses on the low FODMAP diet. Dr. Halmos had no financial conflicts to disclose. Dr. Roper had no financial conflicts to disclose.
Through the AGA Center for Gut Microbiome Research and Education, AGA is committed to keeping you up-to-speed on the latest news, research and policy updates related to the gut microbiome: www.gastro.org/microbiome.
Two distinct gut microbiota subtypes showed an enhanced clinical response to a low FODMAP diet in an analysis of 41 adults with irritable bowel syndrome and household controls.
Irritable bowel syndrome (IBS) has a significant impact on quality of life, and some patients find relief on a low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) diet, wrote Kevin Vervier, PhD, of Wellcome Sanger Institute, Hinxton, England, and colleagues. However, the mechanism of action for the success of low FODMAP diets remains unclear, the diet is hard for many patients to follow, and the long-term impact on health is unknown. Therefore, research is needed to identify patients who would derive the most benefit, they said.
In a study published in Gut, the researchers used metagenomics and functional analysis to identify potential biomarkers of response to a low FODMAP diet. They analyzed stool samples from 41 pairs of IBS patients and household contacts. Stool samples were collected at baseline while on usual diets, and again after 4 weeks and 12 weeks on a low FODMAP diet. The patients were divided into two groups based on microbiota clusters; baseline demographics and clinical characteristics were similar between the clusters. In addition, symptom severity was measured using the IBS Severity Scoring System (IBS-SSS).
Cluster 1 was referred to as IBSP microbiome type because of its pathogenic properties, and cluster 2 as IBSH microbiome type because of its resemblance to the microbiome of healthy household controls, the researchers wrote.
“We found a significant enrichment of 109 functional pathways and significant depletion of 13 functional pathways in IBSP microbiomes compared with IBSH microbiomes,” the researchers said.
More specifically, the IBSP microbiomes were enriched in Firmicutes and in genes for amino acid and carbohydrate metabolism, at baseline, while the IBSH microbiomes were similar to healthy controls.
After 4 weeks on the low FODMAP diet, the IBSP microbiomes normalized, with increased levels of Bacterioides and decreased levels of pathobionts (including Clostridium difficile, Streptococcus parasanguinis, and Paeniclostridium sordellii) to create a microbiome profile resembling the IBSH microbiomes and healthy controls. The taxonomic profile of microbiomes observed in IBSH and healthy controls did not demonstrate a significant shift.
Although both microbiome groups showed improvement in IBS-SSS scores from baseline on the low FODMAP diet, decreasing from a mean baseline score of 278 to a diet score of 128, the improvement was greater in the IBSP group than the IBSH group (delta, 194 vs. 114, respectively; P = .02), the researchers noted. “The shift in the IBSP microbiota to a healthy profile appeared stable for at least 3 months and correlated with continuing symptomatic well-being,” they wrote.
The distinct responses of the IBSP and IBSH microbiomes to the low FODMAP diet suggest a potential mode of action, the researchers said in their discussion. Based on their findings, “it is possible that removal of the eliciting dietary component starves the pathobionts, leading to reduction in their growth and metabolism and a consequent decrease in symptoms, accompanied by an expansion of commensal or symbiotic species leading to a health-associated microbiome,” but more research is needed to prove causality, they said.
The study findings were limited by several factors, including the relatively small sample size, strict inclusion criteria, restriction of medications, and need for participation by household controls, the researchers noted. Other limitations include the inability to control for other factors that could have impacted the gut microbiota, such as the placebo effect and psychological factors, they said.
However, the findings provide a foundation for more research and should be validated in other populations involving different geographical regions and dietary habits, they said. “The identification of a microbial signature ‘biomarker’ that correlates with improved response to a low FODMAP diet may, if validated, allow better stratification and selection of patients likely to benefit from the diet,” they concluded.
Setting the stage for focused studies
The low FODMAP diet has demonstrated effectiveness for symptom relief in IBS, although potential risks include exacerbation of disordered eating, nutrition deficiencies, and disrupting gut microbiota, wrote Peter R. Gibson, MD, and Emma P. Halmos, MD, of Monash University and Alfred Health, Melbourne, in an accompanying editorial. However, the current study takes a new step on the journey to identifying patients most likely to respond to a low FODMAP diet, they said.
The editorialists noted three key takeaway points. First, the fecal microbiome may predict response to a low FODMAP diet. Second, the correction of the microbiome through the low FODMAP diet appeared to continue even after the diet was discontinued. “The other intriguing finding was that trehalose metabolic pathways were ‘activated’ in those with dysbiosis,” suggesting that trehalose might be an unrecognized FODMAP, the researchers noted. Trehalose has not been well studied but has been associated with pathogenicity, they said.
Although the study may overemphasize the impact of the low FODMAP diet given the relatively poor assessment of FODMAP intake, “the beauty of Vervier’s work is not in its definitive nature but in that it enables the creation of feasible innovative hypotheses that can be examined by focused studies,” they concluded.
The current study is important because IBS and related disorders of gut-brain interaction are common and greatly impact the quality of life of affected individuals, Jatin Roper, MD, of Duke University in Durham, N.C., said in an interview. Although the mechanisms for improvement are unknown, he said, “The low FODMAP diet is widely used to treat IBS, based on the hypothesis that this diet modifies the gut microbiome in a beneficial way.”
The study authors made two important discoveries, said Dr. Roper. “First, they found that they were able to distinguish IBS versus household controls based on their gut microbial signatures as well expression of key metabolic genes,” he said. “Second, they identified a unique microbiota subtype that was associated with a significant clinical response to the low FODMAP diet in IBS patients; IBS patients with a ‘pathogenic’ microbiome consisting of high Firmicutes and low Bacteroidetes responded to a greater degree to the low FODMAP diet compared to IBS patients with a ‘healthy’ microbiome that was similar to controls,” he explained. “Furthermore, after time on the low FODMAP diet, the IBS patients with pathogenic microbiome signatures developed a microbiome with low Firmicutes and high Bacteroidetes, which is thought to be healthy,” he added.
“These findings are exciting because they suggest that a patient’s microbial signature might be used clinically to predict response to the low FODMAP diet,” said Dr. Roper. “The surprising aspect of these results is that the microbial signature alone was able to predict response to a low FODMAP diet, despite the complex effects of the diet on host physiology and metabolism and the multifactorial etiology of IBS,” he noted.
However, larger clinical studies are needed to confirm the study findings results in larger patient cohorts and to show that standardized clinical assays can be used to prospectively predict response to dietary interventions such as low FODMAP in IBS, Dr. Roper emphasized.
“This paper provides preliminary and provocative findings that suggest that gut microbiota metabolites may play a role in the pathogenesis of IBS,” said Dr. Roper. “Future basic science and translational research is needed to study the mechanisms by which specific bacterial metabolites regulate intestinal function and disorders such as IBS. I hope that this research will eventually lead to metabolite-based therapies for IBS and other gastrointestinal disorders,” he said.
The study received no outside funding. Lead author Dr. Vervier had no financial conflicts to disclose. Dr. Gibson disclosed authoring two educational/recipe books on the low FODMAP diet, and Monash University financially benefits from the sales of a digital application, booklets, and online courses on the low FODMAP diet. Dr. Halmos had no financial conflicts to disclose. Dr. Roper had no financial conflicts to disclose.
Through the AGA Center for Gut Microbiome Research and Education, AGA is committed to keeping you up-to-speed on the latest news, research and policy updates related to the gut microbiome: www.gastro.org/microbiome.
Two distinct gut microbiota subtypes showed an enhanced clinical response to a low FODMAP diet in an analysis of 41 adults with irritable bowel syndrome and household controls.
Irritable bowel syndrome (IBS) has a significant impact on quality of life, and some patients find relief on a low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) diet, wrote Kevin Vervier, PhD, of Wellcome Sanger Institute, Hinxton, England, and colleagues. However, the mechanism of action for the success of low FODMAP diets remains unclear, the diet is hard for many patients to follow, and the long-term impact on health is unknown. Therefore, research is needed to identify patients who would derive the most benefit, they said.
In a study published in Gut, the researchers used metagenomics and functional analysis to identify potential biomarkers of response to a low FODMAP diet. They analyzed stool samples from 41 pairs of IBS patients and household contacts. Stool samples were collected at baseline while on usual diets, and again after 4 weeks and 12 weeks on a low FODMAP diet. The patients were divided into two groups based on microbiota clusters; baseline demographics and clinical characteristics were similar between the clusters. In addition, symptom severity was measured using the IBS Severity Scoring System (IBS-SSS).
Cluster 1 was referred to as IBSP microbiome type because of its pathogenic properties, and cluster 2 as IBSH microbiome type because of its resemblance to the microbiome of healthy household controls, the researchers wrote.
“We found a significant enrichment of 109 functional pathways and significant depletion of 13 functional pathways in IBSP microbiomes compared with IBSH microbiomes,” the researchers said.
More specifically, the IBSP microbiomes were enriched in Firmicutes and in genes for amino acid and carbohydrate metabolism, at baseline, while the IBSH microbiomes were similar to healthy controls.
After 4 weeks on the low FODMAP diet, the IBSP microbiomes normalized, with increased levels of Bacterioides and decreased levels of pathobionts (including Clostridium difficile, Streptococcus parasanguinis, and Paeniclostridium sordellii) to create a microbiome profile resembling the IBSH microbiomes and healthy controls. The taxonomic profile of microbiomes observed in IBSH and healthy controls did not demonstrate a significant shift.
Although both microbiome groups showed improvement in IBS-SSS scores from baseline on the low FODMAP diet, decreasing from a mean baseline score of 278 to a diet score of 128, the improvement was greater in the IBSP group than the IBSH group (delta, 194 vs. 114, respectively; P = .02), the researchers noted. “The shift in the IBSP microbiota to a healthy profile appeared stable for at least 3 months and correlated with continuing symptomatic well-being,” they wrote.
The distinct responses of the IBSP and IBSH microbiomes to the low FODMAP diet suggest a potential mode of action, the researchers said in their discussion. Based on their findings, “it is possible that removal of the eliciting dietary component starves the pathobionts, leading to reduction in their growth and metabolism and a consequent decrease in symptoms, accompanied by an expansion of commensal or symbiotic species leading to a health-associated microbiome,” but more research is needed to prove causality, they said.
The study findings were limited by several factors, including the relatively small sample size, strict inclusion criteria, restriction of medications, and need for participation by household controls, the researchers noted. Other limitations include the inability to control for other factors that could have impacted the gut microbiota, such as the placebo effect and psychological factors, they said.
However, the findings provide a foundation for more research and should be validated in other populations involving different geographical regions and dietary habits, they said. “The identification of a microbial signature ‘biomarker’ that correlates with improved response to a low FODMAP diet may, if validated, allow better stratification and selection of patients likely to benefit from the diet,” they concluded.
Setting the stage for focused studies
The low FODMAP diet has demonstrated effectiveness for symptom relief in IBS, although potential risks include exacerbation of disordered eating, nutrition deficiencies, and disrupting gut microbiota, wrote Peter R. Gibson, MD, and Emma P. Halmos, MD, of Monash University and Alfred Health, Melbourne, in an accompanying editorial. However, the current study takes a new step on the journey to identifying patients most likely to respond to a low FODMAP diet, they said.
The editorialists noted three key takeaway points. First, the fecal microbiome may predict response to a low FODMAP diet. Second, the correction of the microbiome through the low FODMAP diet appeared to continue even after the diet was discontinued. “The other intriguing finding was that trehalose metabolic pathways were ‘activated’ in those with dysbiosis,” suggesting that trehalose might be an unrecognized FODMAP, the researchers noted. Trehalose has not been well studied but has been associated with pathogenicity, they said.
Although the study may overemphasize the impact of the low FODMAP diet given the relatively poor assessment of FODMAP intake, “the beauty of Vervier’s work is not in its definitive nature but in that it enables the creation of feasible innovative hypotheses that can be examined by focused studies,” they concluded.
The current study is important because IBS and related disorders of gut-brain interaction are common and greatly impact the quality of life of affected individuals, Jatin Roper, MD, of Duke University in Durham, N.C., said in an interview. Although the mechanisms for improvement are unknown, he said, “The low FODMAP diet is widely used to treat IBS, based on the hypothesis that this diet modifies the gut microbiome in a beneficial way.”
The study authors made two important discoveries, said Dr. Roper. “First, they found that they were able to distinguish IBS versus household controls based on their gut microbial signatures as well expression of key metabolic genes,” he said. “Second, they identified a unique microbiota subtype that was associated with a significant clinical response to the low FODMAP diet in IBS patients; IBS patients with a ‘pathogenic’ microbiome consisting of high Firmicutes and low Bacteroidetes responded to a greater degree to the low FODMAP diet compared to IBS patients with a ‘healthy’ microbiome that was similar to controls,” he explained. “Furthermore, after time on the low FODMAP diet, the IBS patients with pathogenic microbiome signatures developed a microbiome with low Firmicutes and high Bacteroidetes, which is thought to be healthy,” he added.
“These findings are exciting because they suggest that a patient’s microbial signature might be used clinically to predict response to the low FODMAP diet,” said Dr. Roper. “The surprising aspect of these results is that the microbial signature alone was able to predict response to a low FODMAP diet, despite the complex effects of the diet on host physiology and metabolism and the multifactorial etiology of IBS,” he noted.
However, larger clinical studies are needed to confirm the study findings results in larger patient cohorts and to show that standardized clinical assays can be used to prospectively predict response to dietary interventions such as low FODMAP in IBS, Dr. Roper emphasized.
“This paper provides preliminary and provocative findings that suggest that gut microbiota metabolites may play a role in the pathogenesis of IBS,” said Dr. Roper. “Future basic science and translational research is needed to study the mechanisms by which specific bacterial metabolites regulate intestinal function and disorders such as IBS. I hope that this research will eventually lead to metabolite-based therapies for IBS and other gastrointestinal disorders,” he said.
The study received no outside funding. Lead author Dr. Vervier had no financial conflicts to disclose. Dr. Gibson disclosed authoring two educational/recipe books on the low FODMAP diet, and Monash University financially benefits from the sales of a digital application, booklets, and online courses on the low FODMAP diet. Dr. Halmos had no financial conflicts to disclose. Dr. Roper had no financial conflicts to disclose.
Through the AGA Center for Gut Microbiome Research and Education, AGA is committed to keeping you up-to-speed on the latest news, research and policy updates related to the gut microbiome: www.gastro.org/microbiome.
FROM GUT
D-dimer thresholds rule out PE in meta-analysis
In a patient suspected to have a PE, “diagnosis is made radiographically, usually with CT pulmonary angiogram, or V/Q scan,” Suman Pal, MD, of the University of New Mexico, Albuquerque, said in an interview.
“Validated clinical decision tools such as Wells’ score or Geneva score may be used to identify patients at low pretest probability of PE who may initially get a D-dimer level check, followed by imaging only if D-dimer level is elevated,” explained Dr. Pal, who was not involved with the new research, which was published in the Annals of Internal Medicine.
According to the authors of the new paper, while current diagnostic strategies in patients with suspected PE include use of a validated clinical decision rule (CDR) and D-dimer testing to rule out PE without imaging tests, the effectiveness of D-dimer tests in older patients, inpatients, cancer patients, and other high-risk groups has not been well-studied.
Lead author of the paper, Milou A.M. Stals, MD, and colleagues said their goal was to evaluate the safety and efficiency of the Wells rule and revised Geneva score in combination with D-dimer tests, and also the YEARS algorithm for D-dimer thresholds, in their paper.
Dr. Stals, of Leiden (the Netherlands) University Medical Center, and the coinvestigators conducted an international systemic review and individual patient data meta-analysis that included 16 studies and 20,553 patients, with all studies having been published between Jan. 1, 1995, and Jan. 1, 2021. Their primary outcomes were the safety and efficiency of each of these three strategies.
In the review, the researchers defined safety as the 3-month incidence of venous thromboembolism after PE was ruled out without imaging at baseline. They defined efficiency as the proportion patients for whom PE was ruled out based on D-dimer thresholds without imaging.
Overall, efficiency was highest in the subset of patients aged younger than 40 years, ranging from 47% to 68% in this group. Efficiency was lowest in patients aged 80 years and older (6.0%-23%), and in patients with cancer (9.6%-26%).
The efficiency was higher when D-dimer thresholds based on pretest probability were used, compared with when fixed or age-adjusted D-dimer thresholds were used.
The key finding was the significant variability in performance of the diagnostic strategies, the researchers said.
“The predicted failure rate was generally highest for strategies incorporating adapted D-dimer thresholds. However, at the same time, predicted overall efficiency was substantially higher with these strategies versus strategies with a fixed D-dimer threshold as well,” they said. Given that the benefits of each of the three diagnostic strategies depends on their correct application, the researchers recommended that an individual hospitalist choose one strategy for their institution.
“Whether clinicians should rely on the Wells rule, the YEARS algorithm, or the revised Geneva score becomes a matter of local preference and experience,” Dr. Stals and colleagues wrote.
The study findings were limited by several factors including between-study differences in scoring predictors and D-dimer assays. Another limitation was that differential verification biases for classifying fatal events and PE may have contributed to overestimation of failure rates of the adapted D-dimer thresholds.
Strengths of the study included its large sample size and original data on pretest probability, and that data support the use of any of the three strategies for ruling out PE in the identified subgroups without the need for imaging tests, the authors wrote.
“Pending the results of ongoing diagnostic randomized trials, physicians and guideline committees should balance the interlink between safety and efficiency of available diagnostic strategies,” they concluded.
Adapted D-dimer benefits some patients
“Clearly, increasing the D-dimer cutoff will lower the number of patients who require radiographic imaging (improved specificity), but this comes with a risk for missing PE (lower sensitivity). Is this risk worth taking?” Daniel J. Brotman, MD, of Johns Hopkins University, Baltimore, asked in an editorial accompanying the new study.
Dr. Brotman was not surprised by the study findings.
“Conditions that predispose to thrombosis through activated hemostasis – such as advanced age, cancer, inflammation, prolonged hospitalization, and trauma – drive D-dimer levels higher independent of the presence or absence of radiographically apparent thrombosis,” he said. However, these patients are unlikely to have normal D-dimer levels regardless of the cutoff used.
Adapted D-dimer cutoffs may benefit some patients, including those with contraindications or limited access to imaging, said Dr. Brotman. D-dimer may be used for risk stratification regardless of PE, since patients with marginally elevated D-dimers have better prognoses than those with higher D-dimer elevations, even if a small PE is missed.
Dr. Brotman wrote that increasing D-dimer cutoffs for high-risk patients in the subgroups analyzed may spare some patients radiographic testing, but doing so carries an increased risk for diagnostic failure. Overall, “the important work by Stals and colleagues offers reassurance that modifying D-dimer thresholds according to age or pretest probability is safe enough for widespread practice, even in high-risk groups.”
Focus on single strategy ‘based on local needs’
“Several validated clinical decision tools, along with age or pretest probability adjusted D-dimer threshold are currently in use as diagnostic strategies for ruling out pulmonary embolism,” Dr. Pal said in an interview.
The current study is important because of limited data on the performance of these strategies in specific subgroups of patients whose risk of PE may differ from the overall patient population, he noted.
“Different diagnostic strategies for PE have a variable performance in patients with differences of age, active cancer, and history of VTE,” said Dr. Pal. “However, in this study, no clear preference for one strategy over others could be established for these subgroups, and clinicians should continue to follow institution-specific guidance.
“A single strategy should be adopted at each institution based on local needs and used as the standard of care until further data are available,” he said.
“The use of D-dimer to rule out PE, either with fixed threshold or age-adjusted thresholds, can be confounded in clinical settings by other comorbid conditions such as sepsis, recent surgery, and more recently, COVID-19,” he said.
“Since the findings of this study do not show a clear benefit of one diagnostic strategy over others in the analyzed subgroups of patients, further prospective head-to-head comparison among the subgroups of interest would be helpful to guide clinical decision making,” Dr. Pal added.
YEARS-specific study supports D-dimer safety and value
A recent paper published in JAMA supported the results of the meta-analysis. In that study, Yonathan Freund, MD, of Sorbonne Université, Paris, and colleagues focused on the YEARS strategy combined with age-adjusted D-dimer thresholds as a way to rule out PE in PERC-positive ED patients.
The authors of this paper randomized 18 EDs to either a protocol of intervention followed by control, or control followed by intervention. The study population included 726 patients in the intervention group and 688 in the control group.
The intervention strategy to rule out PE consisted of assessing the YEARS criteria and D-dimer testing. PE was ruled out in patients with no YEARS criteria and a D-dimer level below 1,000 ng/mL and in patients with one or more YEARS criteria and D-dimers below an age-adjusted threshold (defined as age times 10 ng/mL in patients aged 50 years and older).
The control strategy consisted of D-dimer testing for all patients with the threshold at age-adjusted levels; D-dimers about these levels prompted chest imaging.
Overall, the risk of a missed VTE at 3 months was noninferior between the groups (0.15% in the intervention group and 0.80% in the controls).
“The intervention was associated with a statistically significant reduction in chest imaging use,” the researchers wrote.
This study’s findings were limited by randomization at the center level, rather than the patient level, and the use of imaging on some patients despite negative D-dimer tests, the researchers wrote. However, their findings support those of previous studies and especially support the safety of the intervention, in an emergency medicine setting, as no PEs occurred in patients with a YEARS score of zero who underwent the intervention.
Downsides to applying algorithms to every patient explained
In an editorial accompanying the JAMA study, Marcel Levi, MD, and Nick van Es, MD, of Amsterdam University Medical Center, emphasized the challenges of diagnosing PE given that many patients present with nonspecific clinical manifestations and without typical signs and symptoms. High-resolution CT pulmonary angiography allows for a fast and easy diagnosis in an emergency setting. However, efforts are ongoing to develop alternative strategies that avoid unnecessary scanning for potential PE patients, many of whom have alternative diagnoses such as pulmonary infections, cardiac conditions, pleural disease, or musculoskeletal problems.
On review of the JAMA study using the YEARS rule with adjusted D-dimer thresholds, the editorialists noted that the data were robust and indicated a 10% reduction in chest imaging. They also emphasized the potential to overwhelm busy clinicians with more algorithms.
“Blindly applying algorithms to every patient may be less appropriate or even undesirable in specific situations in which deviation from the rules on clinical grounds is indicated,” but a complex imaging approach may be time consuming and challenging in the acute setting, and a simple algorithm may be safe and efficient in many cases, they wrote. “From a patient perspective, a negative diagnostic algorithm for pulmonary embolism does not diminish the physician’s obligation to consider other diagnoses that explain the symptoms, for which chest CT scans may still be needed and helpful.”
The Annals of Internal Medicine study was supported by the Dutch Research Council. The JAMA study was supported by the French Health Ministry. Dr. Stals, Dr. Freund, Dr. Pal, Dr. Levi, and Dr. van Es had no financial conflicts to disclose.
In a patient suspected to have a PE, “diagnosis is made radiographically, usually with CT pulmonary angiogram, or V/Q scan,” Suman Pal, MD, of the University of New Mexico, Albuquerque, said in an interview.
“Validated clinical decision tools such as Wells’ score or Geneva score may be used to identify patients at low pretest probability of PE who may initially get a D-dimer level check, followed by imaging only if D-dimer level is elevated,” explained Dr. Pal, who was not involved with the new research, which was published in the Annals of Internal Medicine.
According to the authors of the new paper, while current diagnostic strategies in patients with suspected PE include use of a validated clinical decision rule (CDR) and D-dimer testing to rule out PE without imaging tests, the effectiveness of D-dimer tests in older patients, inpatients, cancer patients, and other high-risk groups has not been well-studied.
Lead author of the paper, Milou A.M. Stals, MD, and colleagues said their goal was to evaluate the safety and efficiency of the Wells rule and revised Geneva score in combination with D-dimer tests, and also the YEARS algorithm for D-dimer thresholds, in their paper.
Dr. Stals, of Leiden (the Netherlands) University Medical Center, and the coinvestigators conducted an international systemic review and individual patient data meta-analysis that included 16 studies and 20,553 patients, with all studies having been published between Jan. 1, 1995, and Jan. 1, 2021. Their primary outcomes were the safety and efficiency of each of these three strategies.
In the review, the researchers defined safety as the 3-month incidence of venous thromboembolism after PE was ruled out without imaging at baseline. They defined efficiency as the proportion patients for whom PE was ruled out based on D-dimer thresholds without imaging.
Overall, efficiency was highest in the subset of patients aged younger than 40 years, ranging from 47% to 68% in this group. Efficiency was lowest in patients aged 80 years and older (6.0%-23%), and in patients with cancer (9.6%-26%).
The efficiency was higher when D-dimer thresholds based on pretest probability were used, compared with when fixed or age-adjusted D-dimer thresholds were used.
The key finding was the significant variability in performance of the diagnostic strategies, the researchers said.
“The predicted failure rate was generally highest for strategies incorporating adapted D-dimer thresholds. However, at the same time, predicted overall efficiency was substantially higher with these strategies versus strategies with a fixed D-dimer threshold as well,” they said. Given that the benefits of each of the three diagnostic strategies depends on their correct application, the researchers recommended that an individual hospitalist choose one strategy for their institution.
“Whether clinicians should rely on the Wells rule, the YEARS algorithm, or the revised Geneva score becomes a matter of local preference and experience,” Dr. Stals and colleagues wrote.
The study findings were limited by several factors including between-study differences in scoring predictors and D-dimer assays. Another limitation was that differential verification biases for classifying fatal events and PE may have contributed to overestimation of failure rates of the adapted D-dimer thresholds.
Strengths of the study included its large sample size and original data on pretest probability, and that data support the use of any of the three strategies for ruling out PE in the identified subgroups without the need for imaging tests, the authors wrote.
“Pending the results of ongoing diagnostic randomized trials, physicians and guideline committees should balance the interlink between safety and efficiency of available diagnostic strategies,” they concluded.
Adapted D-dimer benefits some patients
“Clearly, increasing the D-dimer cutoff will lower the number of patients who require radiographic imaging (improved specificity), but this comes with a risk for missing PE (lower sensitivity). Is this risk worth taking?” Daniel J. Brotman, MD, of Johns Hopkins University, Baltimore, asked in an editorial accompanying the new study.
Dr. Brotman was not surprised by the study findings.
“Conditions that predispose to thrombosis through activated hemostasis – such as advanced age, cancer, inflammation, prolonged hospitalization, and trauma – drive D-dimer levels higher independent of the presence or absence of radiographically apparent thrombosis,” he said. However, these patients are unlikely to have normal D-dimer levels regardless of the cutoff used.
Adapted D-dimer cutoffs may benefit some patients, including those with contraindications or limited access to imaging, said Dr. Brotman. D-dimer may be used for risk stratification regardless of PE, since patients with marginally elevated D-dimers have better prognoses than those with higher D-dimer elevations, even if a small PE is missed.
Dr. Brotman wrote that increasing D-dimer cutoffs for high-risk patients in the subgroups analyzed may spare some patients radiographic testing, but doing so carries an increased risk for diagnostic failure. Overall, “the important work by Stals and colleagues offers reassurance that modifying D-dimer thresholds according to age or pretest probability is safe enough for widespread practice, even in high-risk groups.”
Focus on single strategy ‘based on local needs’
“Several validated clinical decision tools, along with age or pretest probability adjusted D-dimer threshold are currently in use as diagnostic strategies for ruling out pulmonary embolism,” Dr. Pal said in an interview.
The current study is important because of limited data on the performance of these strategies in specific subgroups of patients whose risk of PE may differ from the overall patient population, he noted.
“Different diagnostic strategies for PE have a variable performance in patients with differences of age, active cancer, and history of VTE,” said Dr. Pal. “However, in this study, no clear preference for one strategy over others could be established for these subgroups, and clinicians should continue to follow institution-specific guidance.
“A single strategy should be adopted at each institution based on local needs and used as the standard of care until further data are available,” he said.
“The use of D-dimer to rule out PE, either with fixed threshold or age-adjusted thresholds, can be confounded in clinical settings by other comorbid conditions such as sepsis, recent surgery, and more recently, COVID-19,” he said.
“Since the findings of this study do not show a clear benefit of one diagnostic strategy over others in the analyzed subgroups of patients, further prospective head-to-head comparison among the subgroups of interest would be helpful to guide clinical decision making,” Dr. Pal added.
YEARS-specific study supports D-dimer safety and value
A recent paper published in JAMA supported the results of the meta-analysis. In that study, Yonathan Freund, MD, of Sorbonne Université, Paris, and colleagues focused on the YEARS strategy combined with age-adjusted D-dimer thresholds as a way to rule out PE in PERC-positive ED patients.
The authors of this paper randomized 18 EDs to either a protocol of intervention followed by control, or control followed by intervention. The study population included 726 patients in the intervention group and 688 in the control group.
The intervention strategy to rule out PE consisted of assessing the YEARS criteria and D-dimer testing. PE was ruled out in patients with no YEARS criteria and a D-dimer level below 1,000 ng/mL and in patients with one or more YEARS criteria and D-dimers below an age-adjusted threshold (defined as age times 10 ng/mL in patients aged 50 years and older).
The control strategy consisted of D-dimer testing for all patients with the threshold at age-adjusted levels; D-dimers about these levels prompted chest imaging.
Overall, the risk of a missed VTE at 3 months was noninferior between the groups (0.15% in the intervention group and 0.80% in the controls).
“The intervention was associated with a statistically significant reduction in chest imaging use,” the researchers wrote.
This study’s findings were limited by randomization at the center level, rather than the patient level, and the use of imaging on some patients despite negative D-dimer tests, the researchers wrote. However, their findings support those of previous studies and especially support the safety of the intervention, in an emergency medicine setting, as no PEs occurred in patients with a YEARS score of zero who underwent the intervention.
Downsides to applying algorithms to every patient explained
In an editorial accompanying the JAMA study, Marcel Levi, MD, and Nick van Es, MD, of Amsterdam University Medical Center, emphasized the challenges of diagnosing PE given that many patients present with nonspecific clinical manifestations and without typical signs and symptoms. High-resolution CT pulmonary angiography allows for a fast and easy diagnosis in an emergency setting. However, efforts are ongoing to develop alternative strategies that avoid unnecessary scanning for potential PE patients, many of whom have alternative diagnoses such as pulmonary infections, cardiac conditions, pleural disease, or musculoskeletal problems.
On review of the JAMA study using the YEARS rule with adjusted D-dimer thresholds, the editorialists noted that the data were robust and indicated a 10% reduction in chest imaging. They also emphasized the potential to overwhelm busy clinicians with more algorithms.
“Blindly applying algorithms to every patient may be less appropriate or even undesirable in specific situations in which deviation from the rules on clinical grounds is indicated,” but a complex imaging approach may be time consuming and challenging in the acute setting, and a simple algorithm may be safe and efficient in many cases, they wrote. “From a patient perspective, a negative diagnostic algorithm for pulmonary embolism does not diminish the physician’s obligation to consider other diagnoses that explain the symptoms, for which chest CT scans may still be needed and helpful.”
The Annals of Internal Medicine study was supported by the Dutch Research Council. The JAMA study was supported by the French Health Ministry. Dr. Stals, Dr. Freund, Dr. Pal, Dr. Levi, and Dr. van Es had no financial conflicts to disclose.
In a patient suspected to have a PE, “diagnosis is made radiographically, usually with CT pulmonary angiogram, or V/Q scan,” Suman Pal, MD, of the University of New Mexico, Albuquerque, said in an interview.
“Validated clinical decision tools such as Wells’ score or Geneva score may be used to identify patients at low pretest probability of PE who may initially get a D-dimer level check, followed by imaging only if D-dimer level is elevated,” explained Dr. Pal, who was not involved with the new research, which was published in the Annals of Internal Medicine.
According to the authors of the new paper, while current diagnostic strategies in patients with suspected PE include use of a validated clinical decision rule (CDR) and D-dimer testing to rule out PE without imaging tests, the effectiveness of D-dimer tests in older patients, inpatients, cancer patients, and other high-risk groups has not been well-studied.
Lead author of the paper, Milou A.M. Stals, MD, and colleagues said their goal was to evaluate the safety and efficiency of the Wells rule and revised Geneva score in combination with D-dimer tests, and also the YEARS algorithm for D-dimer thresholds, in their paper.
Dr. Stals, of Leiden (the Netherlands) University Medical Center, and the coinvestigators conducted an international systemic review and individual patient data meta-analysis that included 16 studies and 20,553 patients, with all studies having been published between Jan. 1, 1995, and Jan. 1, 2021. Their primary outcomes were the safety and efficiency of each of these three strategies.
In the review, the researchers defined safety as the 3-month incidence of venous thromboembolism after PE was ruled out without imaging at baseline. They defined efficiency as the proportion patients for whom PE was ruled out based on D-dimer thresholds without imaging.
Overall, efficiency was highest in the subset of patients aged younger than 40 years, ranging from 47% to 68% in this group. Efficiency was lowest in patients aged 80 years and older (6.0%-23%), and in patients with cancer (9.6%-26%).
The efficiency was higher when D-dimer thresholds based on pretest probability were used, compared with when fixed or age-adjusted D-dimer thresholds were used.
The key finding was the significant variability in performance of the diagnostic strategies, the researchers said.
“The predicted failure rate was generally highest for strategies incorporating adapted D-dimer thresholds. However, at the same time, predicted overall efficiency was substantially higher with these strategies versus strategies with a fixed D-dimer threshold as well,” they said. Given that the benefits of each of the three diagnostic strategies depends on their correct application, the researchers recommended that an individual hospitalist choose one strategy for their institution.
“Whether clinicians should rely on the Wells rule, the YEARS algorithm, or the revised Geneva score becomes a matter of local preference and experience,” Dr. Stals and colleagues wrote.
The study findings were limited by several factors including between-study differences in scoring predictors and D-dimer assays. Another limitation was that differential verification biases for classifying fatal events and PE may have contributed to overestimation of failure rates of the adapted D-dimer thresholds.
Strengths of the study included its large sample size and original data on pretest probability, and that data support the use of any of the three strategies for ruling out PE in the identified subgroups without the need for imaging tests, the authors wrote.
“Pending the results of ongoing diagnostic randomized trials, physicians and guideline committees should balance the interlink between safety and efficiency of available diagnostic strategies,” they concluded.
Adapted D-dimer benefits some patients
“Clearly, increasing the D-dimer cutoff will lower the number of patients who require radiographic imaging (improved specificity), but this comes with a risk for missing PE (lower sensitivity). Is this risk worth taking?” Daniel J. Brotman, MD, of Johns Hopkins University, Baltimore, asked in an editorial accompanying the new study.
Dr. Brotman was not surprised by the study findings.
“Conditions that predispose to thrombosis through activated hemostasis – such as advanced age, cancer, inflammation, prolonged hospitalization, and trauma – drive D-dimer levels higher independent of the presence or absence of radiographically apparent thrombosis,” he said. However, these patients are unlikely to have normal D-dimer levels regardless of the cutoff used.
Adapted D-dimer cutoffs may benefit some patients, including those with contraindications or limited access to imaging, said Dr. Brotman. D-dimer may be used for risk stratification regardless of PE, since patients with marginally elevated D-dimers have better prognoses than those with higher D-dimer elevations, even if a small PE is missed.
Dr. Brotman wrote that increasing D-dimer cutoffs for high-risk patients in the subgroups analyzed may spare some patients radiographic testing, but doing so carries an increased risk for diagnostic failure. Overall, “the important work by Stals and colleagues offers reassurance that modifying D-dimer thresholds according to age or pretest probability is safe enough for widespread practice, even in high-risk groups.”
Focus on single strategy ‘based on local needs’
“Several validated clinical decision tools, along with age or pretest probability adjusted D-dimer threshold are currently in use as diagnostic strategies for ruling out pulmonary embolism,” Dr. Pal said in an interview.
The current study is important because of limited data on the performance of these strategies in specific subgroups of patients whose risk of PE may differ from the overall patient population, he noted.
“Different diagnostic strategies for PE have a variable performance in patients with differences of age, active cancer, and history of VTE,” said Dr. Pal. “However, in this study, no clear preference for one strategy over others could be established for these subgroups, and clinicians should continue to follow institution-specific guidance.
“A single strategy should be adopted at each institution based on local needs and used as the standard of care until further data are available,” he said.
“The use of D-dimer to rule out PE, either with fixed threshold or age-adjusted thresholds, can be confounded in clinical settings by other comorbid conditions such as sepsis, recent surgery, and more recently, COVID-19,” he said.
“Since the findings of this study do not show a clear benefit of one diagnostic strategy over others in the analyzed subgroups of patients, further prospective head-to-head comparison among the subgroups of interest would be helpful to guide clinical decision making,” Dr. Pal added.
YEARS-specific study supports D-dimer safety and value
A recent paper published in JAMA supported the results of the meta-analysis. In that study, Yonathan Freund, MD, of Sorbonne Université, Paris, and colleagues focused on the YEARS strategy combined with age-adjusted D-dimer thresholds as a way to rule out PE in PERC-positive ED patients.
The authors of this paper randomized 18 EDs to either a protocol of intervention followed by control, or control followed by intervention. The study population included 726 patients in the intervention group and 688 in the control group.
The intervention strategy to rule out PE consisted of assessing the YEARS criteria and D-dimer testing. PE was ruled out in patients with no YEARS criteria and a D-dimer level below 1,000 ng/mL and in patients with one or more YEARS criteria and D-dimers below an age-adjusted threshold (defined as age times 10 ng/mL in patients aged 50 years and older).
The control strategy consisted of D-dimer testing for all patients with the threshold at age-adjusted levels; D-dimers about these levels prompted chest imaging.
Overall, the risk of a missed VTE at 3 months was noninferior between the groups (0.15% in the intervention group and 0.80% in the controls).
“The intervention was associated with a statistically significant reduction in chest imaging use,” the researchers wrote.
This study’s findings were limited by randomization at the center level, rather than the patient level, and the use of imaging on some patients despite negative D-dimer tests, the researchers wrote. However, their findings support those of previous studies and especially support the safety of the intervention, in an emergency medicine setting, as no PEs occurred in patients with a YEARS score of zero who underwent the intervention.
Downsides to applying algorithms to every patient explained
In an editorial accompanying the JAMA study, Marcel Levi, MD, and Nick van Es, MD, of Amsterdam University Medical Center, emphasized the challenges of diagnosing PE given that many patients present with nonspecific clinical manifestations and without typical signs and symptoms. High-resolution CT pulmonary angiography allows for a fast and easy diagnosis in an emergency setting. However, efforts are ongoing to develop alternative strategies that avoid unnecessary scanning for potential PE patients, many of whom have alternative diagnoses such as pulmonary infections, cardiac conditions, pleural disease, or musculoskeletal problems.
On review of the JAMA study using the YEARS rule with adjusted D-dimer thresholds, the editorialists noted that the data were robust and indicated a 10% reduction in chest imaging. They also emphasized the potential to overwhelm busy clinicians with more algorithms.
“Blindly applying algorithms to every patient may be less appropriate or even undesirable in specific situations in which deviation from the rules on clinical grounds is indicated,” but a complex imaging approach may be time consuming and challenging in the acute setting, and a simple algorithm may be safe and efficient in many cases, they wrote. “From a patient perspective, a negative diagnostic algorithm for pulmonary embolism does not diminish the physician’s obligation to consider other diagnoses that explain the symptoms, for which chest CT scans may still be needed and helpful.”
The Annals of Internal Medicine study was supported by the Dutch Research Council. The JAMA study was supported by the French Health Ministry. Dr. Stals, Dr. Freund, Dr. Pal, Dr. Levi, and Dr. van Es had no financial conflicts to disclose.
FROM THE ANNALS OF INTERNAL MEDICINE
Microbiota may predict success on low FODMAP diet
Two distinct gut microbiota subtypes showed an enhanced clinical response to a low FODMAP diet in an analysis of 41 adults with irritable bowel syndrome and household controls.
Irritable bowel syndrome (IBS) has a significant impact on quality of life, and some patients find relief on a low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) diet, wrote Kevin Vervier, PhD, of Wellcome Sanger Institute, Hinxton, England, and colleagues. However, the mechanism of action for the success of low FODMAP diets remains unclear, the diet is hard for many patients to follow, and the long-term impact on health is unknown. Therefore, research is needed to identify patients who would derive the most benefit, they said.
In a study published in Gut, the researchers used metagenomics and functional analysis to identify potential biomarkers of response to a low FODMAP diet. They analyzed stool samples from 41 pairs of IBS patients and household contacts. Stool samples were collected at baseline while on usual diets, and again after 4 weeks and 12 weeks on a low FODMAP diet. The patients were divided into two groups based on microbiota clusters; baseline demographics and clinical characteristics were similar between the clusters. In addition, symptom severity was measured using the IBS Severity Scoring System (IBS-SSS).
Cluster 1 was referred to as IBSP microbiome type because of its pathogenic properties, and cluster 2 as IBSH microbiome type because of its resemblance to the microbiome of healthy household controls, the researchers wrote.
“We found a significant enrichment of 109 functional pathways and significant depletion of 13 functional pathways in IBSP microbiomes compared with IBSH microbiomes,” the researchers said.
More specifically, the IBSP microbiomes were enriched in Firmicutes and in genes for amino acid and carbohydrate metabolism, at baseline, while the IBSH microbiomes were similar to healthy controls.
After 4 weeks on the low FODMAP diet, the IBSP microbiomes normalized, with increased levels of Bacterioides and decreased levels of pathobionts (including Clostridium difficile, Streptococcus parasanguinis, and Paeniclostridium sordellii) to create a microbiome profile resembling the IBSH microbiomes and healthy controls. The taxonomic profile of microbiomes observed in IBSH and healthy controls did not demonstrate a significant shift.
Although both microbiome groups showed improvement in IBS-SSS scores from baseline on the low FODMAP diet, decreasing from a mean baseline score of 278 to a diet score of 128, the improvement was greater in the IBSP group than the IBSH group (delta, 194 vs. 114, respectively; P = .02), the researchers noted. “The shift in the IBSP microbiota to a healthy profile appeared stable for at least 3 months and correlated with continuing symptomatic well-being,” they wrote.
The distinct responses of the IBSP and IBSH microbiomes to the low FODMAP diet suggest a potential mode of action, the researchers said in their discussion. Based on their findings, “it is possible that removal of the eliciting dietary component starves the pathobionts, leading to reduction in their growth and metabolism and a consequent decrease in symptoms, accompanied by an expansion of commensal or symbiotic species leading to a health-associated microbiome,” but more research is needed to prove causality, they said.
The study findings were limited by several factors, including the relatively small sample size, strict inclusion criteria, restriction of medications, and need for participation by household controls, the researchers noted. Other limitations include the inability to control for other factors that could have impacted the gut microbiota, such as the placebo effect and psychological factors, they said.
However, the findings provide a foundation for more research and should be validated in other populations involving different geographical regions and dietary habits, they said. “The identification of a microbial signature ‘biomarker’ that correlates with improved response to a low FODMAP diet may, if validated, allow better stratification and selection of patients likely to benefit from the diet,” they concluded.
Setting the stage for focused studies
The low FODMAP diet has demonstrated effectiveness for symptom relief in IBS, although potential risks include exacerbation of disordered eating, nutrition deficiencies, and disrupting gut microbiota, wrote Peter R. Gibson, MD, and Emma P. Halmos, MD, of Monash University and Alfred Health, Melbourne, in an accompanying editorial. However, the current study takes a new step on the journey to identifying patients most likely to respond to a low FODMAP diet, they said.
The editorialists noted three key takeaway points. First, the fecal microbiome may predict response to a low FODMAP diet. Second, the correction of the microbiome through the low FODMAP diet appeared to continue even after the diet was discontinued. “The other intriguing finding was that trehalose metabolic pathways were ‘activated’ in those with dysbiosis,” suggesting that trehalose might be an unrecognized FODMAP, the researchers noted. Trehalose has not been well studied but has been associated with pathogenicity, they said.
Although the study may overemphasize the impact of the low FODMAP diet given the relatively poor assessment of FODMAP intake, “the beauty of Vervier’s work is not in its definitive nature but in that it enables the creation of feasible innovative hypotheses that can be examined by focused studies,” they concluded.
The current study is important because IBS and related disorders of gut-brain interaction are common and greatly impact the quality of life of affected individuals, Jatin Roper, MD, of Duke University in Durham, N.C., said in an interview. Although the mechanisms for improvement are unknown, he said, “The low FODMAP diet is widely used to treat IBS, based on the hypothesis that this diet modifies the gut microbiome in a beneficial way.”
The study authors made two important discoveries, said Dr. Roper. “First, they found that they were able to distinguish IBS versus household controls based on their gut microbial signatures as well expression of key metabolic genes,” he said. “Second, they identified a unique microbiota subtype that was associated with a significant clinical response to the low FODMAP diet in IBS patients; IBS patients with a ‘pathogenic’ microbiome consisting of high Firmicutes and low Bacteroidetes responded to a greater degree to the low FODMAP diet compared to IBS patients with a ‘healthy’ microbiome that was similar to controls,” he explained. “Furthermore, after time on the low FODMAP diet, the IBS patients with pathogenic microbiome signatures developed a microbiome with low Firmicutes and high Bacteroidetes, which is thought to be healthy,” he added.
“These findings are exciting because they suggest that a patient’s microbial signature might be used clinically to predict response to the low FODMAP diet,” said Dr. Roper. “The surprising aspect of these results is that the microbial signature alone was able to predict response to a low FODMAP diet, despite the complex effects of the diet on host physiology and metabolism and the multifactorial etiology of IBS,” he noted.
However, larger clinical studies are needed to confirm the study findings results in larger patient cohorts and to show that standardized clinical assays can be used to prospectively predict response to dietary interventions such as low FODMAP in IBS, Dr. Roper emphasized.
“This paper provides preliminary and provocative findings that suggest that gut microbiota metabolites may play a role in the pathogenesis of IBS,” said Dr. Roper. “Future basic science and translational research is needed to study the mechanisms by which specific bacterial metabolites regulate intestinal function and disorders such as IBS. I hope that this research will eventually lead to metabolite-based therapies for IBS and other gastrointestinal disorders,” he said.
The study received no outside funding. Lead author Dr. Vervier had no financial conflicts to disclose. Dr. Gibson disclosed authoring two educational/recipe books on the low FODMAP diet, and Monash University financially benefits from the sales of a digital application, booklets, and online courses on the low FODMAP diet. Dr. Halmos had no financial conflicts to disclose. Dr. Roper had no financial conflicts to disclose.
Two distinct gut microbiota subtypes showed an enhanced clinical response to a low FODMAP diet in an analysis of 41 adults with irritable bowel syndrome and household controls.
Irritable bowel syndrome (IBS) has a significant impact on quality of life, and some patients find relief on a low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) diet, wrote Kevin Vervier, PhD, of Wellcome Sanger Institute, Hinxton, England, and colleagues. However, the mechanism of action for the success of low FODMAP diets remains unclear, the diet is hard for many patients to follow, and the long-term impact on health is unknown. Therefore, research is needed to identify patients who would derive the most benefit, they said.
In a study published in Gut, the researchers used metagenomics and functional analysis to identify potential biomarkers of response to a low FODMAP diet. They analyzed stool samples from 41 pairs of IBS patients and household contacts. Stool samples were collected at baseline while on usual diets, and again after 4 weeks and 12 weeks on a low FODMAP diet. The patients were divided into two groups based on microbiota clusters; baseline demographics and clinical characteristics were similar between the clusters. In addition, symptom severity was measured using the IBS Severity Scoring System (IBS-SSS).
Cluster 1 was referred to as IBSP microbiome type because of its pathogenic properties, and cluster 2 as IBSH microbiome type because of its resemblance to the microbiome of healthy household controls, the researchers wrote.
“We found a significant enrichment of 109 functional pathways and significant depletion of 13 functional pathways in IBSP microbiomes compared with IBSH microbiomes,” the researchers said.
More specifically, the IBSP microbiomes were enriched in Firmicutes and in genes for amino acid and carbohydrate metabolism, at baseline, while the IBSH microbiomes were similar to healthy controls.
After 4 weeks on the low FODMAP diet, the IBSP microbiomes normalized, with increased levels of Bacterioides and decreased levels of pathobionts (including Clostridium difficile, Streptococcus parasanguinis, and Paeniclostridium sordellii) to create a microbiome profile resembling the IBSH microbiomes and healthy controls. The taxonomic profile of microbiomes observed in IBSH and healthy controls did not demonstrate a significant shift.
Although both microbiome groups showed improvement in IBS-SSS scores from baseline on the low FODMAP diet, decreasing from a mean baseline score of 278 to a diet score of 128, the improvement was greater in the IBSP group than the IBSH group (delta, 194 vs. 114, respectively; P = .02), the researchers noted. “The shift in the IBSP microbiota to a healthy profile appeared stable for at least 3 months and correlated with continuing symptomatic well-being,” they wrote.
The distinct responses of the IBSP and IBSH microbiomes to the low FODMAP diet suggest a potential mode of action, the researchers said in their discussion. Based on their findings, “it is possible that removal of the eliciting dietary component starves the pathobionts, leading to reduction in their growth and metabolism and a consequent decrease in symptoms, accompanied by an expansion of commensal or symbiotic species leading to a health-associated microbiome,” but more research is needed to prove causality, they said.
The study findings were limited by several factors, including the relatively small sample size, strict inclusion criteria, restriction of medications, and need for participation by household controls, the researchers noted. Other limitations include the inability to control for other factors that could have impacted the gut microbiota, such as the placebo effect and psychological factors, they said.
However, the findings provide a foundation for more research and should be validated in other populations involving different geographical regions and dietary habits, they said. “The identification of a microbial signature ‘biomarker’ that correlates with improved response to a low FODMAP diet may, if validated, allow better stratification and selection of patients likely to benefit from the diet,” they concluded.
Setting the stage for focused studies
The low FODMAP diet has demonstrated effectiveness for symptom relief in IBS, although potential risks include exacerbation of disordered eating, nutrition deficiencies, and disrupting gut microbiota, wrote Peter R. Gibson, MD, and Emma P. Halmos, MD, of Monash University and Alfred Health, Melbourne, in an accompanying editorial. However, the current study takes a new step on the journey to identifying patients most likely to respond to a low FODMAP diet, they said.
The editorialists noted three key takeaway points. First, the fecal microbiome may predict response to a low FODMAP diet. Second, the correction of the microbiome through the low FODMAP diet appeared to continue even after the diet was discontinued. “The other intriguing finding was that trehalose metabolic pathways were ‘activated’ in those with dysbiosis,” suggesting that trehalose might be an unrecognized FODMAP, the researchers noted. Trehalose has not been well studied but has been associated with pathogenicity, they said.
Although the study may overemphasize the impact of the low FODMAP diet given the relatively poor assessment of FODMAP intake, “the beauty of Vervier’s work is not in its definitive nature but in that it enables the creation of feasible innovative hypotheses that can be examined by focused studies,” they concluded.
The current study is important because IBS and related disorders of gut-brain interaction are common and greatly impact the quality of life of affected individuals, Jatin Roper, MD, of Duke University in Durham, N.C., said in an interview. Although the mechanisms for improvement are unknown, he said, “The low FODMAP diet is widely used to treat IBS, based on the hypothesis that this diet modifies the gut microbiome in a beneficial way.”
The study authors made two important discoveries, said Dr. Roper. “First, they found that they were able to distinguish IBS versus household controls based on their gut microbial signatures as well expression of key metabolic genes,” he said. “Second, they identified a unique microbiota subtype that was associated with a significant clinical response to the low FODMAP diet in IBS patients; IBS patients with a ‘pathogenic’ microbiome consisting of high Firmicutes and low Bacteroidetes responded to a greater degree to the low FODMAP diet compared to IBS patients with a ‘healthy’ microbiome that was similar to controls,” he explained. “Furthermore, after time on the low FODMAP diet, the IBS patients with pathogenic microbiome signatures developed a microbiome with low Firmicutes and high Bacteroidetes, which is thought to be healthy,” he added.
“These findings are exciting because they suggest that a patient’s microbial signature might be used clinically to predict response to the low FODMAP diet,” said Dr. Roper. “The surprising aspect of these results is that the microbial signature alone was able to predict response to a low FODMAP diet, despite the complex effects of the diet on host physiology and metabolism and the multifactorial etiology of IBS,” he noted.
However, larger clinical studies are needed to confirm the study findings results in larger patient cohorts and to show that standardized clinical assays can be used to prospectively predict response to dietary interventions such as low FODMAP in IBS, Dr. Roper emphasized.
“This paper provides preliminary and provocative findings that suggest that gut microbiota metabolites may play a role in the pathogenesis of IBS,” said Dr. Roper. “Future basic science and translational research is needed to study the mechanisms by which specific bacterial metabolites regulate intestinal function and disorders such as IBS. I hope that this research will eventually lead to metabolite-based therapies for IBS and other gastrointestinal disorders,” he said.
The study received no outside funding. Lead author Dr. Vervier had no financial conflicts to disclose. Dr. Gibson disclosed authoring two educational/recipe books on the low FODMAP diet, and Monash University financially benefits from the sales of a digital application, booklets, and online courses on the low FODMAP diet. Dr. Halmos had no financial conflicts to disclose. Dr. Roper had no financial conflicts to disclose.
Two distinct gut microbiota subtypes showed an enhanced clinical response to a low FODMAP diet in an analysis of 41 adults with irritable bowel syndrome and household controls.
Irritable bowel syndrome (IBS) has a significant impact on quality of life, and some patients find relief on a low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) diet, wrote Kevin Vervier, PhD, of Wellcome Sanger Institute, Hinxton, England, and colleagues. However, the mechanism of action for the success of low FODMAP diets remains unclear, the diet is hard for many patients to follow, and the long-term impact on health is unknown. Therefore, research is needed to identify patients who would derive the most benefit, they said.
In a study published in Gut, the researchers used metagenomics and functional analysis to identify potential biomarkers of response to a low FODMAP diet. They analyzed stool samples from 41 pairs of IBS patients and household contacts. Stool samples were collected at baseline while on usual diets, and again after 4 weeks and 12 weeks on a low FODMAP diet. The patients were divided into two groups based on microbiota clusters; baseline demographics and clinical characteristics were similar between the clusters. In addition, symptom severity was measured using the IBS Severity Scoring System (IBS-SSS).
Cluster 1 was referred to as IBSP microbiome type because of its pathogenic properties, and cluster 2 as IBSH microbiome type because of its resemblance to the microbiome of healthy household controls, the researchers wrote.
“We found a significant enrichment of 109 functional pathways and significant depletion of 13 functional pathways in IBSP microbiomes compared with IBSH microbiomes,” the researchers said.
More specifically, the IBSP microbiomes were enriched in Firmicutes and in genes for amino acid and carbohydrate metabolism, at baseline, while the IBSH microbiomes were similar to healthy controls.
After 4 weeks on the low FODMAP diet, the IBSP microbiomes normalized, with increased levels of Bacterioides and decreased levels of pathobionts (including Clostridium difficile, Streptococcus parasanguinis, and Paeniclostridium sordellii) to create a microbiome profile resembling the IBSH microbiomes and healthy controls. The taxonomic profile of microbiomes observed in IBSH and healthy controls did not demonstrate a significant shift.
Although both microbiome groups showed improvement in IBS-SSS scores from baseline on the low FODMAP diet, decreasing from a mean baseline score of 278 to a diet score of 128, the improvement was greater in the IBSP group than the IBSH group (delta, 194 vs. 114, respectively; P = .02), the researchers noted. “The shift in the IBSP microbiota to a healthy profile appeared stable for at least 3 months and correlated with continuing symptomatic well-being,” they wrote.
The distinct responses of the IBSP and IBSH microbiomes to the low FODMAP diet suggest a potential mode of action, the researchers said in their discussion. Based on their findings, “it is possible that removal of the eliciting dietary component starves the pathobionts, leading to reduction in their growth and metabolism and a consequent decrease in symptoms, accompanied by an expansion of commensal or symbiotic species leading to a health-associated microbiome,” but more research is needed to prove causality, they said.
The study findings were limited by several factors, including the relatively small sample size, strict inclusion criteria, restriction of medications, and need for participation by household controls, the researchers noted. Other limitations include the inability to control for other factors that could have impacted the gut microbiota, such as the placebo effect and psychological factors, they said.
However, the findings provide a foundation for more research and should be validated in other populations involving different geographical regions and dietary habits, they said. “The identification of a microbial signature ‘biomarker’ that correlates with improved response to a low FODMAP diet may, if validated, allow better stratification and selection of patients likely to benefit from the diet,” they concluded.
Setting the stage for focused studies
The low FODMAP diet has demonstrated effectiveness for symptom relief in IBS, although potential risks include exacerbation of disordered eating, nutrition deficiencies, and disrupting gut microbiota, wrote Peter R. Gibson, MD, and Emma P. Halmos, MD, of Monash University and Alfred Health, Melbourne, in an accompanying editorial. However, the current study takes a new step on the journey to identifying patients most likely to respond to a low FODMAP diet, they said.
The editorialists noted three key takeaway points. First, the fecal microbiome may predict response to a low FODMAP diet. Second, the correction of the microbiome through the low FODMAP diet appeared to continue even after the diet was discontinued. “The other intriguing finding was that trehalose metabolic pathways were ‘activated’ in those with dysbiosis,” suggesting that trehalose might be an unrecognized FODMAP, the researchers noted. Trehalose has not been well studied but has been associated with pathogenicity, they said.
Although the study may overemphasize the impact of the low FODMAP diet given the relatively poor assessment of FODMAP intake, “the beauty of Vervier’s work is not in its definitive nature but in that it enables the creation of feasible innovative hypotheses that can be examined by focused studies,” they concluded.
The current study is important because IBS and related disorders of gut-brain interaction are common and greatly impact the quality of life of affected individuals, Jatin Roper, MD, of Duke University in Durham, N.C., said in an interview. Although the mechanisms for improvement are unknown, he said, “The low FODMAP diet is widely used to treat IBS, based on the hypothesis that this diet modifies the gut microbiome in a beneficial way.”
The study authors made two important discoveries, said Dr. Roper. “First, they found that they were able to distinguish IBS versus household controls based on their gut microbial signatures as well expression of key metabolic genes,” he said. “Second, they identified a unique microbiota subtype that was associated with a significant clinical response to the low FODMAP diet in IBS patients; IBS patients with a ‘pathogenic’ microbiome consisting of high Firmicutes and low Bacteroidetes responded to a greater degree to the low FODMAP diet compared to IBS patients with a ‘healthy’ microbiome that was similar to controls,” he explained. “Furthermore, after time on the low FODMAP diet, the IBS patients with pathogenic microbiome signatures developed a microbiome with low Firmicutes and high Bacteroidetes, which is thought to be healthy,” he added.
“These findings are exciting because they suggest that a patient’s microbial signature might be used clinically to predict response to the low FODMAP diet,” said Dr. Roper. “The surprising aspect of these results is that the microbial signature alone was able to predict response to a low FODMAP diet, despite the complex effects of the diet on host physiology and metabolism and the multifactorial etiology of IBS,” he noted.
However, larger clinical studies are needed to confirm the study findings results in larger patient cohorts and to show that standardized clinical assays can be used to prospectively predict response to dietary interventions such as low FODMAP in IBS, Dr. Roper emphasized.
“This paper provides preliminary and provocative findings that suggest that gut microbiota metabolites may play a role in the pathogenesis of IBS,” said Dr. Roper. “Future basic science and translational research is needed to study the mechanisms by which specific bacterial metabolites regulate intestinal function and disorders such as IBS. I hope that this research will eventually lead to metabolite-based therapies for IBS and other gastrointestinal disorders,” he said.
The study received no outside funding. Lead author Dr. Vervier had no financial conflicts to disclose. Dr. Gibson disclosed authoring two educational/recipe books on the low FODMAP diet, and Monash University financially benefits from the sales of a digital application, booklets, and online courses on the low FODMAP diet. Dr. Halmos had no financial conflicts to disclose. Dr. Roper had no financial conflicts to disclose.
FROM GUT
Underinsurance rises among U.S. children
The proportion of U.S. children who are underinsured for health care increased by 3.4% from 2016 to 2019, reflecting approximately 2.4 million underinsured children, based on data from the National Survey of Children’s Health.
Children with inconsistent or inadequate medical coverage are more likely to forgo medical care, including preventive well-child visits, and to have unmet medical needs such as prescription medications, Justin Yu, MD, of the Children’s Hospital of Pittsburgh, and colleagues wrote. Although the American Academy of Pediatrics and the Healthy People 2030 guidelines have endorsed increasing the proportion of children with adequate coverage, recent studies suggest that advances in insuring children in the wake of the Affordable Care Act have stalled, and trends in child insurance have not been well described, the researchers said.
In a study published in Pediatrics, the researchers reviewed data from the combined 2016-2019 datasets of the National Survey of Children’s Health, a survey funded by the Maternal and Child Health Bureau of the Health Resources and Services Administration.
Adequate insurance was defined as a composite with three questions; whether the benefits “usually” or “always” meet the child’s needs; the benefits “usually” or “always” allow the child to see needed providers; and whether out-of-pocket expenses are either absent or “usually” or “always” reasonable.
Overall, the proportion of children with underinsurance increased from 30.6% in 2016 to 34.0% in 2019.
Underinsurance was significantly associated with increased health complexity and private insurance, with adjusted odds ratios of 1.9 and 3.5, respectively. In addition, underinsurance was significantly associated with child age of 6 years or older, non-Black racial identity, U.S. nonnative status, and a family income of at least 100% above the Federal Poverty Level. Notably, underinsurance grew significantly among White children living in “middle-income” families, the researchers said.
The increase in underinsurance was driven primarily by increased insurance inadequacy, which rose from 24.8% to 27.9% over the study period. The increase in insurance inadequacy was described primarily as unreasonable out-of-pocket medical expenses, according to the survey respondents.
The study findings were limited by several factors including the inability to show causality or to describe changes in outcomes for individual children, the researchers noted. Other limitations include the reliance on parent reports and the lack of a definitive definition of underinsurance.
However, the results highlight the ongoing problem of underinsurance in children, and the need to address the factors that contribute to inadequate insurance for children, the researchers said.
“Our data, demonstrating a shift from public to private insurance that is more likely to be inadequate, in conjunction with existing literature linking Medicaid/CHIP [Children’s Health Insurance Program] coverage with improved access to medical care as well as improved long-term outcomes in adulthood, should give policy makers and payers pause as they contemplate strategies to improve child health,” they concluded.
Nationwide action needed to fight underinsurance
The authors should be commended for highlighting the disturbing trend in underinsurance among children in the United States, Tim Joos, MD, a Seattle-based clinician with a combination internal medicine/pediatrics practice, said in an interview.
“With the passage of the Affordable Care Act, the population of uninsured and underinsured had shrunk quite a bit, but in the past few years, the numbers are growing again. This population has often been called the working poor; the vast majority are legal residents who make too much to qualify for Medicaid/CHIP programs, and whose employers don’t offer affordable robust health care coverage,” Dr. Joos said.
“These families have to make the risky decisions of how much of the family budget to spend on insurance plans, often to the detriment of their own and their children’s health,” he explained. “If you believe the old adage about ‘an ounce of prevention,’ then the money we spend on preserving the health of our children will more than pay for itself in benefits of increased productivity and health care savings in the 1-2 decades later when they reach adulthood. It is time for us as a nation to come up with a more comprehensive baseline coverage for all pediatric patients and take away any barriers for families to access basic health care for children.”
The study received no outside funding. The researchers had no financial conflicts to disclose. Dr. Joos had no financial conflicts to disclose and serves on the editorial advisory board of Pediatric News.
The proportion of U.S. children who are underinsured for health care increased by 3.4% from 2016 to 2019, reflecting approximately 2.4 million underinsured children, based on data from the National Survey of Children’s Health.
Children with inconsistent or inadequate medical coverage are more likely to forgo medical care, including preventive well-child visits, and to have unmet medical needs such as prescription medications, Justin Yu, MD, of the Children’s Hospital of Pittsburgh, and colleagues wrote. Although the American Academy of Pediatrics and the Healthy People 2030 guidelines have endorsed increasing the proportion of children with adequate coverage, recent studies suggest that advances in insuring children in the wake of the Affordable Care Act have stalled, and trends in child insurance have not been well described, the researchers said.
In a study published in Pediatrics, the researchers reviewed data from the combined 2016-2019 datasets of the National Survey of Children’s Health, a survey funded by the Maternal and Child Health Bureau of the Health Resources and Services Administration.
Adequate insurance was defined as a composite with three questions; whether the benefits “usually” or “always” meet the child’s needs; the benefits “usually” or “always” allow the child to see needed providers; and whether out-of-pocket expenses are either absent or “usually” or “always” reasonable.
Overall, the proportion of children with underinsurance increased from 30.6% in 2016 to 34.0% in 2019.
Underinsurance was significantly associated with increased health complexity and private insurance, with adjusted odds ratios of 1.9 and 3.5, respectively. In addition, underinsurance was significantly associated with child age of 6 years or older, non-Black racial identity, U.S. nonnative status, and a family income of at least 100% above the Federal Poverty Level. Notably, underinsurance grew significantly among White children living in “middle-income” families, the researchers said.
The increase in underinsurance was driven primarily by increased insurance inadequacy, which rose from 24.8% to 27.9% over the study period. The increase in insurance inadequacy was described primarily as unreasonable out-of-pocket medical expenses, according to the survey respondents.
The study findings were limited by several factors including the inability to show causality or to describe changes in outcomes for individual children, the researchers noted. Other limitations include the reliance on parent reports and the lack of a definitive definition of underinsurance.
However, the results highlight the ongoing problem of underinsurance in children, and the need to address the factors that contribute to inadequate insurance for children, the researchers said.
“Our data, demonstrating a shift from public to private insurance that is more likely to be inadequate, in conjunction with existing literature linking Medicaid/CHIP [Children’s Health Insurance Program] coverage with improved access to medical care as well as improved long-term outcomes in adulthood, should give policy makers and payers pause as they contemplate strategies to improve child health,” they concluded.
Nationwide action needed to fight underinsurance
The authors should be commended for highlighting the disturbing trend in underinsurance among children in the United States, Tim Joos, MD, a Seattle-based clinician with a combination internal medicine/pediatrics practice, said in an interview.
“With the passage of the Affordable Care Act, the population of uninsured and underinsured had shrunk quite a bit, but in the past few years, the numbers are growing again. This population has often been called the working poor; the vast majority are legal residents who make too much to qualify for Medicaid/CHIP programs, and whose employers don’t offer affordable robust health care coverage,” Dr. Joos said.
“These families have to make the risky decisions of how much of the family budget to spend on insurance plans, often to the detriment of their own and their children’s health,” he explained. “If you believe the old adage about ‘an ounce of prevention,’ then the money we spend on preserving the health of our children will more than pay for itself in benefits of increased productivity and health care savings in the 1-2 decades later when they reach adulthood. It is time for us as a nation to come up with a more comprehensive baseline coverage for all pediatric patients and take away any barriers for families to access basic health care for children.”
The study received no outside funding. The researchers had no financial conflicts to disclose. Dr. Joos had no financial conflicts to disclose and serves on the editorial advisory board of Pediatric News.
The proportion of U.S. children who are underinsured for health care increased by 3.4% from 2016 to 2019, reflecting approximately 2.4 million underinsured children, based on data from the National Survey of Children’s Health.
Children with inconsistent or inadequate medical coverage are more likely to forgo medical care, including preventive well-child visits, and to have unmet medical needs such as prescription medications, Justin Yu, MD, of the Children’s Hospital of Pittsburgh, and colleagues wrote. Although the American Academy of Pediatrics and the Healthy People 2030 guidelines have endorsed increasing the proportion of children with adequate coverage, recent studies suggest that advances in insuring children in the wake of the Affordable Care Act have stalled, and trends in child insurance have not been well described, the researchers said.
In a study published in Pediatrics, the researchers reviewed data from the combined 2016-2019 datasets of the National Survey of Children’s Health, a survey funded by the Maternal and Child Health Bureau of the Health Resources and Services Administration.
Adequate insurance was defined as a composite with three questions; whether the benefits “usually” or “always” meet the child’s needs; the benefits “usually” or “always” allow the child to see needed providers; and whether out-of-pocket expenses are either absent or “usually” or “always” reasonable.
Overall, the proportion of children with underinsurance increased from 30.6% in 2016 to 34.0% in 2019.
Underinsurance was significantly associated with increased health complexity and private insurance, with adjusted odds ratios of 1.9 and 3.5, respectively. In addition, underinsurance was significantly associated with child age of 6 years or older, non-Black racial identity, U.S. nonnative status, and a family income of at least 100% above the Federal Poverty Level. Notably, underinsurance grew significantly among White children living in “middle-income” families, the researchers said.
The increase in underinsurance was driven primarily by increased insurance inadequacy, which rose from 24.8% to 27.9% over the study period. The increase in insurance inadequacy was described primarily as unreasonable out-of-pocket medical expenses, according to the survey respondents.
The study findings were limited by several factors including the inability to show causality or to describe changes in outcomes for individual children, the researchers noted. Other limitations include the reliance on parent reports and the lack of a definitive definition of underinsurance.
However, the results highlight the ongoing problem of underinsurance in children, and the need to address the factors that contribute to inadequate insurance for children, the researchers said.
“Our data, demonstrating a shift from public to private insurance that is more likely to be inadequate, in conjunction with existing literature linking Medicaid/CHIP [Children’s Health Insurance Program] coverage with improved access to medical care as well as improved long-term outcomes in adulthood, should give policy makers and payers pause as they contemplate strategies to improve child health,” they concluded.
Nationwide action needed to fight underinsurance
The authors should be commended for highlighting the disturbing trend in underinsurance among children in the United States, Tim Joos, MD, a Seattle-based clinician with a combination internal medicine/pediatrics practice, said in an interview.
“With the passage of the Affordable Care Act, the population of uninsured and underinsured had shrunk quite a bit, but in the past few years, the numbers are growing again. This population has often been called the working poor; the vast majority are legal residents who make too much to qualify for Medicaid/CHIP programs, and whose employers don’t offer affordable robust health care coverage,” Dr. Joos said.
“These families have to make the risky decisions of how much of the family budget to spend on insurance plans, often to the detriment of their own and their children’s health,” he explained. “If you believe the old adage about ‘an ounce of prevention,’ then the money we spend on preserving the health of our children will more than pay for itself in benefits of increased productivity and health care savings in the 1-2 decades later when they reach adulthood. It is time for us as a nation to come up with a more comprehensive baseline coverage for all pediatric patients and take away any barriers for families to access basic health care for children.”
The study received no outside funding. The researchers had no financial conflicts to disclose. Dr. Joos had no financial conflicts to disclose and serves on the editorial advisory board of Pediatric News.
FROM PEDIATRICS
Pink or red actinic keratoses signal more inflammation
lesions.
Data suggest that up to 65% of squamous cell carcinomas (SCCs) were at some point diagnosed as AKs, wrote Jessica G. Labadie, MD, of the department of dermatology at Northwestern University, Chicago, and colleagues. Early identification of AKs is important to prevent progression to SCCs; previous studies have used histology or morphology, but not color, to characterize AK lesions, they said. In the study published in Dermatologic Surgery, the researchers analyzed images and histopathology slides to characterize AKs by color and to examine associations with inflammation and vasculature. They identified AKs from patients diagnosed between January 2018 and October 2019. The lesions were classified as white (4), brown (9), red (15), or pink (21).
Overall, white AKs had an absence of erythema and were significantly less likely to show inflammation on histopathology, compared with other colors. Brown AKs showed no significant increase in vascularity, but were significantly associated with pigment incontinence, basilar pigment presence, and absence of inflammation.
Notably, dermoscopy of red AKs revealed a distinctive polymorphous vessel pattern in most samples, as well as erythema in all. Similarly, all pink AKs showed erythema, and all showed inflammatory infiltrate on histology, although most did not show increased vascularity.
For all colors of AKs, there was a significant association between the presence of erythema on dermoscopy and the presence of inflammation on histology, while the absence of erythema on dermoscopy corresponded to a significant absence of inflammation on histology, the researchers noted.
“This report adds to the armamentarium of a dermatologist by proposing a novel way to characterize AK lesions,” the researchers wrote.
The study findings were limited by several factors including the inability to confirm which AKs would transform into SCCs based on color, and the inclusion of a study population with advanced AKs that may not generalize to typical AKs, the researchers noted. More research is needed to explore the impact of AK color on SCC development, they emphasized.
However, the results represent a novel way to characterize AK lesions, and triage them in a way that may spare some patients from unneeded biopsies, they concluded.
The study received no outside funding. The researchers had no financial conflicts to disclose.
lesions.
Data suggest that up to 65% of squamous cell carcinomas (SCCs) were at some point diagnosed as AKs, wrote Jessica G. Labadie, MD, of the department of dermatology at Northwestern University, Chicago, and colleagues. Early identification of AKs is important to prevent progression to SCCs; previous studies have used histology or morphology, but not color, to characterize AK lesions, they said. In the study published in Dermatologic Surgery, the researchers analyzed images and histopathology slides to characterize AKs by color and to examine associations with inflammation and vasculature. They identified AKs from patients diagnosed between January 2018 and October 2019. The lesions were classified as white (4), brown (9), red (15), or pink (21).
Overall, white AKs had an absence of erythema and were significantly less likely to show inflammation on histopathology, compared with other colors. Brown AKs showed no significant increase in vascularity, but were significantly associated with pigment incontinence, basilar pigment presence, and absence of inflammation.
Notably, dermoscopy of red AKs revealed a distinctive polymorphous vessel pattern in most samples, as well as erythema in all. Similarly, all pink AKs showed erythema, and all showed inflammatory infiltrate on histology, although most did not show increased vascularity.
For all colors of AKs, there was a significant association between the presence of erythema on dermoscopy and the presence of inflammation on histology, while the absence of erythema on dermoscopy corresponded to a significant absence of inflammation on histology, the researchers noted.
“This report adds to the armamentarium of a dermatologist by proposing a novel way to characterize AK lesions,” the researchers wrote.
The study findings were limited by several factors including the inability to confirm which AKs would transform into SCCs based on color, and the inclusion of a study population with advanced AKs that may not generalize to typical AKs, the researchers noted. More research is needed to explore the impact of AK color on SCC development, they emphasized.
However, the results represent a novel way to characterize AK lesions, and triage them in a way that may spare some patients from unneeded biopsies, they concluded.
The study received no outside funding. The researchers had no financial conflicts to disclose.
lesions.
Data suggest that up to 65% of squamous cell carcinomas (SCCs) were at some point diagnosed as AKs, wrote Jessica G. Labadie, MD, of the department of dermatology at Northwestern University, Chicago, and colleagues. Early identification of AKs is important to prevent progression to SCCs; previous studies have used histology or morphology, but not color, to characterize AK lesions, they said. In the study published in Dermatologic Surgery, the researchers analyzed images and histopathology slides to characterize AKs by color and to examine associations with inflammation and vasculature. They identified AKs from patients diagnosed between January 2018 and October 2019. The lesions were classified as white (4), brown (9), red (15), or pink (21).
Overall, white AKs had an absence of erythema and were significantly less likely to show inflammation on histopathology, compared with other colors. Brown AKs showed no significant increase in vascularity, but were significantly associated with pigment incontinence, basilar pigment presence, and absence of inflammation.
Notably, dermoscopy of red AKs revealed a distinctive polymorphous vessel pattern in most samples, as well as erythema in all. Similarly, all pink AKs showed erythema, and all showed inflammatory infiltrate on histology, although most did not show increased vascularity.
For all colors of AKs, there was a significant association between the presence of erythema on dermoscopy and the presence of inflammation on histology, while the absence of erythema on dermoscopy corresponded to a significant absence of inflammation on histology, the researchers noted.
“This report adds to the armamentarium of a dermatologist by proposing a novel way to characterize AK lesions,” the researchers wrote.
The study findings were limited by several factors including the inability to confirm which AKs would transform into SCCs based on color, and the inclusion of a study population with advanced AKs that may not generalize to typical AKs, the researchers noted. More research is needed to explore the impact of AK color on SCC development, they emphasized.
However, the results represent a novel way to characterize AK lesions, and triage them in a way that may spare some patients from unneeded biopsies, they concluded.
The study received no outside funding. The researchers had no financial conflicts to disclose.
FROM DERMATOLOGIC SURGERY