Patients treated with infliximab for inflammatory bowel disease (IBD) showed significantly reduced response to COVID-19 antibodies, compared with those treated with vedolizumab, according to data from nearly 7,000 patients.

Although anti–tumor necrosis factor (anti-TNF) drugs are routinely used for patients with IBD, the impact of their immune-suppressing properties on protective immunity to COVID-19 is unknown, wrote Nicholas A. Kennedy, MD, of the University of Exeter (England) and colleagues. These drugs have been reported to impair protective immunity following vaccines for other diseases, such as those for influenza and viral hepatitis.

“By suppressing immune responses, biological and immunosuppression therapies may lead to chronic SARS-CoV-2 infection and have recently been implicated in the evolution and emergence of novel variants,” they noted, citing a study published in Cell.

In the current study, published in Gut, the researchers used data from the CLARITY IBD study to identify 6,935 patients with IBD aged 5 years and older seen at 92 hospitals in the United Kingdom between Sept. 22, 2020, and Dec. 23, 2020. Of these, 4,685 were treated with infliximab, and 2,250 received vedolizumab. The proportion of study participants with a positive anti–SARS-CoV-2 antibody test was the primary outcome, with secondary outcomes including proportion with positive antibodies following positive polymerase chain reaction test for SARS-CoV-2 and the magnitude of antibody reactivity.

Substantial seroprevalence differences seen

Overall, rates of symptomatic and proven SARS-CoV-2 infection and hospitalization were similar between infliximab-treated and vedolizumab-treated patients with IBD. However, seroprevalence was significantly lower in the infliximab group, compared with the vedolizumab group (3.4% vs. 6.0%; P < .0001). In addition, infliximab and immunomodulator use were each independently associated with lower seropositivity, compared with vedolizumab (odds ratio, 0.66 for infliximab and OR, 0.70 for immunomodulators) in a multivariate analysis.

In a sensitivity analysis, 39 of 81 infliximab-treated patients with polymerase chain reaction–confirmed COVID-19 infection seroconverted (48%), compared with 30 of 36 vedolizumab-treated patients (83%) (P < .00044). Infliximab-treated patients with confirmed infections also showed a lower magnitude of anti–SARS-CoV-2 reactivity, compared with vedolizumab-treated patients (P < .0001).

From a clinical perspective, the lower seroconversion rates and reduced levels of anti–SARS-CoV-2 antibody reactivity might increase susceptibility to recurrent COVID-19 infections in infliximab-treated IBD patients, the researchers noted. In addition, the impaired serological responses might promote chronic nasopharyngeal colonization and consequently promote the development of COVID-19 variants and drive persistent transmission, the researchers said.

The study findings were limited by several factors including lack of knowledge on the impact of attenuated immune response on infection risk, the potential for recall bias associated with patient reports, and the focus on infliximab only, the researchers pointed out. However, the key findings are likely apply to other anti-TNF monoclonal antibodies including adalimumab, certolizumab and golimumab, they suggested.

The study was strengthened by the recruitment of a large number of patients in a narrow time frame and comprehensive collection of data on patient-reported outcomes, COVID-19 testing, and serological assay results, the researchers said. Overall, the findings support the public health value of serological testing and virus surveillance to identify suboptimal vaccine response and to consider implications for practice, they added. “If attenuated serological responses following vaccination are also observed, then modified immunization strategies will need to be designed for millions of patients worldwide,” they emphasized.

Findings inform clinical practice and public health

The study is very important for many reasons, said Kim L. Isaacs, MD, PhD, AGAF, of the University of North Carolina at Chapel Hill in an interview. “It is known that there is decreased responsiveness to a number of routine vaccinations in IBD patients on immune active therapy. In terms of SARS-CoV-2, development of an immune response with infection is important in terms of severity of infection, reinfection, and possibly limiting spread of infection in this patient population,” she said. “Looking at both serum seroconversion and reactivity of immune response in patients with known SARS-CoV-2 infection will help to define clinical and public health guidance, and also may be predictive as to what might happen with SARS-CoV-2 immunization based on background biologic or immunosuppressant therapy,” she noted.

Dr. Isaacs said that she was not surprised by the study findings. “Anti-TNF, thiopurine, and methotrexate therapy are all thought to be systemically active and likely to suppress the immune response to infection and vaccination,” she said. Vedolizumab, on the other hand, is thought to be less systemically active and clinically is associated with fewer serious infections.

Data will drive patient counseling 

“These results affect counseling of IBD patients on immune active therapy who have had a SARS-CoV-2 infection,” said Dr. Isaacs. “They should be made aware that infection does not indicate protection for further infection. Although the issues that are raised in this study are of concern, patients should not have clinically beneficial therapy discontinued or switched based on these results,” she said.

“Additional research is needed to determine what the seroconversion rate is with the currently available immunizations for SARS-CoV-2,” said Dr. Isaacs. More questions to address include whether there are differences in the different products available, whether immunization after SARS-CoV-2 infection improves both seroconversion and immune reactivity, and whether there is any benefit to transiently stopping dual immune active therapy during the time of immunization, she said.

Further studies can fill knowledge gaps

“There is a knowledge gap in our understanding of susceptibility to SARS-CoV-2 infections among patients with IBD who have previously been infected,” Shirley Cohen-Mekelburg, MD, MS, staff physician and research scientist in the inflammatory bowel disease program at the Veterans Affairs Ann Arbor (Mich.) Healthcare System, said in an interview. ”This is a first step in beginning to narrow this gap – to provide patients and providers with data to drive recommendations during this COVID-19 pandemic.”

She added that, while further work needs to be done, the study findings do support potential benefit for ongoing vigilance among patients receiving infliximab for IBD. “The study findings also drive us to seek answers to more questions: For example, should we consider serological testing for patients on infliximab? How does the presence or absence of anti–SARS-CoV-2 antibodies associate with susceptibility to infection for patients with infliximab?

“Further studies examining anti–SARS-CoV-2 reactivity are necessary to better understand antibody responses between patients with IBD to the general population, or between patients on immunosuppressive therapy and the general population,” she said. “Observational studies are also not designed to examine the causal relationship between infections, medications, and antibody responses. There may be some inherent differences to patients who receive infliximab as compared to vedolizumab for IBD.”

The study was supported by Biogen (Switzerland), Celltrion Healthcare, Galapagos, F. Hoffmann-La Roche, Hull University Teaching Hospital NHS Trust, and the Royal Devon and Exeter NHS Foundation Trust. The study authors disclosed financial and nonfinancial relationships with numerous companies, including AbbVie, Biogen, Celltrion Healthcare, Galapagos, F. Hoffmann-La Roche, and Immundiagnostik, as well as Janssen, who markets infliximab, and Takeda, who markets vedolizumab. Dr. Isaacs and Dr. Cohen-Mekelburg had no relevant financial conflicts to disclose.

This article was updated 3/31/21.

Patients treated with infliximab for inflammatory bowel disease (IBD) showed significantly reduced response to COVID-19 antibodies, compared with those treated with vedolizumab, according to data from nearly 7,000 patients.

Although anti–tumor necrosis factor (anti-TNF) drugs are routinely used for patients with IBD, the impact of their immune-suppressing properties on protective immunity to COVID-19 is unknown, wrote Nicholas A. Kennedy, MD, of the University of Exeter (England) and colleagues. These drugs have been reported to impair protective immunity following vaccines for other diseases, such as those for influenza and viral hepatitis.

“By suppressing immune responses, biological and immunosuppression therapies may lead to chronic SARS-CoV-2 infection and have recently been implicated in the evolution and emergence of novel variants,” they noted, citing a study published in Cell.

In the current study, published in Gut, the researchers used data from the CLARITY IBD study to identify 6,935 patients with IBD aged 5 years and older seen at 92 hospitals in the United Kingdom between Sept. 22, 2020, and Dec. 23, 2020. Of these, 4,685 were treated with infliximab, and 2,250 received vedolizumab. The proportion of study participants with a positive anti–SARS-CoV-2 antibody test was the primary outcome, with secondary outcomes including proportion with positive antibodies following positive polymerase chain reaction test for SARS-CoV-2 and the magnitude of antibody reactivity.

Substantial seroprevalence differences seen

Overall, rates of symptomatic and proven SARS-CoV-2 infection and hospitalization were similar between infliximab-treated and vedolizumab-treated patients with IBD. However, seroprevalence was significantly lower in the infliximab group, compared with the vedolizumab group (3.4% vs. 6.0%; P < .0001). In addition, infliximab and immunomodulator use were each independently associated with lower seropositivity, compared with vedolizumab (odds ratio, 0.66 for infliximab and OR, 0.70 for immunomodulators) in a multivariate analysis.

In a sensitivity analysis, 39 of 81 infliximab-treated patients with polymerase chain reaction–confirmed COVID-19 infection seroconverted (48%), compared with 30 of 36 vedolizumab-treated patients (83%) (P < .00044). Infliximab-treated patients with confirmed infections also showed a lower magnitude of anti–SARS-CoV-2 reactivity, compared with vedolizumab-treated patients (P < .0001).

From a clinical perspective, the lower seroconversion rates and reduced levels of anti–SARS-CoV-2 antibody reactivity might increase susceptibility to recurrent COVID-19 infections in infliximab-treated IBD patients, the researchers noted. In addition, the impaired serological responses might promote chronic nasopharyngeal colonization and consequently promote the development of COVID-19 variants and drive persistent transmission, the researchers said.

The study findings were limited by several factors including lack of knowledge on the impact of attenuated immune response on infection risk, the potential for recall bias associated with patient reports, and the focus on infliximab only, the researchers pointed out. However, the key findings are likely apply to other anti-TNF monoclonal antibodies including adalimumab, certolizumab and golimumab, they suggested.

The study was strengthened by the recruitment of a large number of patients in a narrow time frame and comprehensive collection of data on patient-reported outcomes, COVID-19 testing, and serological assay results, the researchers said. Overall, the findings support the public health value of serological testing and virus surveillance to identify suboptimal vaccine response and to consider implications for practice, they added. “If attenuated serological responses following vaccination are also observed, then modified immunization strategies will need to be designed for millions of patients worldwide,” they emphasized.

Findings inform clinical practice and public health

The study is very important for many reasons, said Kim L. Isaacs, MD, PhD, AGAF, of the University of North Carolina at Chapel Hill in an interview. “It is known that there is decreased responsiveness to a number of routine vaccinations in IBD patients on immune active therapy. In terms of SARS-CoV-2, development of an immune response with infection is important in terms of severity of infection, reinfection, and possibly limiting spread of infection in this patient population,” she said. “Looking at both serum seroconversion and reactivity of immune response in patients with known SARS-CoV-2 infection will help to define clinical and public health guidance, and also may be predictive as to what might happen with SARS-CoV-2 immunization based on background biologic or immunosuppressant therapy,” she noted.

Dr. Isaacs said that she was not surprised by the study findings. “Anti-TNF, thiopurine, and methotrexate therapy are all thought to be systemically active and likely to suppress the immune response to infection and vaccination,” she said. Vedolizumab, on the other hand, is thought to be less systemically active and clinically is associated with fewer serious infections.

Data will drive patient counseling 

“These results affect counseling of IBD patients on immune active therapy who have had a SARS-CoV-2 infection,” said Dr. Isaacs. “They should be made aware that infection does not indicate protection for further infection. Although the issues that are raised in this study are of concern, patients should not have clinically beneficial therapy discontinued or switched based on these results,” she said.

“Additional research is needed to determine what the seroconversion rate is with the currently available immunizations for SARS-CoV-2,” said Dr. Isaacs. More questions to address include whether there are differences in the different products available, whether immunization after SARS-CoV-2 infection improves both seroconversion and immune reactivity, and whether there is any benefit to transiently stopping dual immune active therapy during the time of immunization, she said.

Further studies can fill knowledge gaps

“There is a knowledge gap in our understanding of susceptibility to SARS-CoV-2 infections among patients with IBD who have previously been infected,” Shirley Cohen-Mekelburg, MD, MS, staff physician and research scientist in the inflammatory bowel disease program at the Veterans Affairs Ann Arbor (Mich.) Healthcare System, said in an interview. ”This is a first step in beginning to narrow this gap – to provide patients and providers with data to drive recommendations during this COVID-19 pandemic.”

She added that, while further work needs to be done, the study findings do support potential benefit for ongoing vigilance among patients receiving infliximab for IBD. “The study findings also drive us to seek answers to more questions: For example, should we consider serological testing for patients on infliximab? How does the presence or absence of anti–SARS-CoV-2 antibodies associate with susceptibility to infection for patients with infliximab?

“Further studies examining anti–SARS-CoV-2 reactivity are necessary to better understand antibody responses between patients with IBD to the general population, or between patients on immunosuppressive therapy and the general population,” she said. “Observational studies are also not designed to examine the causal relationship between infections, medications, and antibody responses. There may be some inherent differences to patients who receive infliximab as compared to vedolizumab for IBD.”

The study was supported by Biogen (Switzerland), Celltrion Healthcare, Galapagos, F. Hoffmann-La Roche, Hull University Teaching Hospital NHS Trust, and the Royal Devon and Exeter NHS Foundation Trust. The study authors disclosed financial and nonfinancial relationships with numerous companies, including AbbVie, Biogen, Celltrion Healthcare, Galapagos, F. Hoffmann-La Roche, and Immundiagnostik, as well as Janssen, who markets infliximab, and Takeda, who markets vedolizumab. Dr. Isaacs and Dr. Cohen-Mekelburg had no relevant financial conflicts to disclose.

This article was updated 3/31/21.

Patients treated with infliximab for inflammatory bowel disease (IBD) showed significantly reduced response to COVID-19 antibodies, compared with those treated with vedolizumab, according to data from nearly 7,000 patients.

Although anti–tumor necrosis factor (anti-TNF) drugs are routinely used for patients with IBD, the impact of their immune-suppressing properties on protective immunity to COVID-19 is unknown, wrote Nicholas A. Kennedy, MD, of the University of Exeter (England) and colleagues. These drugs have been reported to impair protective immunity following vaccines for other diseases, such as those for influenza and viral hepatitis.

“By suppressing immune responses, biological and immunosuppression therapies may lead to chronic SARS-CoV-2 infection and have recently been implicated in the evolution and emergence of novel variants,” they noted, citing a study published in Cell.

In the current study, published in Gut, the researchers used data from the CLARITY IBD study to identify 6,935 patients with IBD aged 5 years and older seen at 92 hospitals in the United Kingdom between Sept. 22, 2020, and Dec. 23, 2020. Of these, 4,685 were treated with infliximab, and 2,250 received vedolizumab. The proportion of study participants with a positive anti–SARS-CoV-2 antibody test was the primary outcome, with secondary outcomes including proportion with positive antibodies following positive polymerase chain reaction test for SARS-CoV-2 and the magnitude of antibody reactivity.

Substantial seroprevalence differences seen

Overall, rates of symptomatic and proven SARS-CoV-2 infection and hospitalization were similar between infliximab-treated and vedolizumab-treated patients with IBD. However, seroprevalence was significantly lower in the infliximab group, compared with the vedolizumab group (3.4% vs. 6.0%; P < .0001). In addition, infliximab and immunomodulator use were each independently associated with lower seropositivity, compared with vedolizumab (odds ratio, 0.66 for infliximab and OR, 0.70 for immunomodulators) in a multivariate analysis.

In a sensitivity analysis, 39 of 81 infliximab-treated patients with polymerase chain reaction–confirmed COVID-19 infection seroconverted (48%), compared with 30 of 36 vedolizumab-treated patients (83%) (P < .00044). Infliximab-treated patients with confirmed infections also showed a lower magnitude of anti–SARS-CoV-2 reactivity, compared with vedolizumab-treated patients (P < .0001).

From a clinical perspective, the lower seroconversion rates and reduced levels of anti–SARS-CoV-2 antibody reactivity might increase susceptibility to recurrent COVID-19 infections in infliximab-treated IBD patients, the researchers noted. In addition, the impaired serological responses might promote chronic nasopharyngeal colonization and consequently promote the development of COVID-19 variants and drive persistent transmission, the researchers said.

The study findings were limited by several factors including lack of knowledge on the impact of attenuated immune response on infection risk, the potential for recall bias associated with patient reports, and the focus on infliximab only, the researchers pointed out. However, the key findings are likely apply to other anti-TNF monoclonal antibodies including adalimumab, certolizumab and golimumab, they suggested.

The study was strengthened by the recruitment of a large number of patients in a narrow time frame and comprehensive collection of data on patient-reported outcomes, COVID-19 testing, and serological assay results, the researchers said. Overall, the findings support the public health value of serological testing and virus surveillance to identify suboptimal vaccine response and to consider implications for practice, they added. “If attenuated serological responses following vaccination are also observed, then modified immunization strategies will need to be designed for millions of patients worldwide,” they emphasized.

Findings inform clinical practice and public health

The study is very important for many reasons, said Kim L. Isaacs, MD, PhD, AGAF, of the University of North Carolina at Chapel Hill in an interview. “It is known that there is decreased responsiveness to a number of routine vaccinations in IBD patients on immune active therapy. In terms of SARS-CoV-2, development of an immune response with infection is important in terms of severity of infection, reinfection, and possibly limiting spread of infection in this patient population,” she said. “Looking at both serum seroconversion and reactivity of immune response in patients with known SARS-CoV-2 infection will help to define clinical and public health guidance, and also may be predictive as to what might happen with SARS-CoV-2 immunization based on background biologic or immunosuppressant therapy,” she noted.

Dr. Isaacs said that she was not surprised by the study findings. “Anti-TNF, thiopurine, and methotrexate therapy are all thought to be systemically active and likely to suppress the immune response to infection and vaccination,” she said. Vedolizumab, on the other hand, is thought to be less systemically active and clinically is associated with fewer serious infections.

Data will drive patient counseling 

“These results affect counseling of IBD patients on immune active therapy who have had a SARS-CoV-2 infection,” said Dr. Isaacs. “They should be made aware that infection does not indicate protection for further infection. Although the issues that are raised in this study are of concern, patients should not have clinically beneficial therapy discontinued or switched based on these results,” she said.

“Additional research is needed to determine what the seroconversion rate is with the currently available immunizations for SARS-CoV-2,” said Dr. Isaacs. More questions to address include whether there are differences in the different products available, whether immunization after SARS-CoV-2 infection improves both seroconversion and immune reactivity, and whether there is any benefit to transiently stopping dual immune active therapy during the time of immunization, she said.

Further studies can fill knowledge gaps

“There is a knowledge gap in our understanding of susceptibility to SARS-CoV-2 infections among patients with IBD who have previously been infected,” Shirley Cohen-Mekelburg, MD, MS, staff physician and research scientist in the inflammatory bowel disease program at the Veterans Affairs Ann Arbor (Mich.) Healthcare System, said in an interview. ”This is a first step in beginning to narrow this gap – to provide patients and providers with data to drive recommendations during this COVID-19 pandemic.”

She added that, while further work needs to be done, the study findings do support potential benefit for ongoing vigilance among patients receiving infliximab for IBD. “The study findings also drive us to seek answers to more questions: For example, should we consider serological testing for patients on infliximab? How does the presence or absence of anti–SARS-CoV-2 antibodies associate with susceptibility to infection for patients with infliximab?

“Further studies examining anti–SARS-CoV-2 reactivity are necessary to better understand antibody responses between patients with IBD to the general population, or between patients on immunosuppressive therapy and the general population,” she said. “Observational studies are also not designed to examine the causal relationship between infections, medications, and antibody responses. There may be some inherent differences to patients who receive infliximab as compared to vedolizumab for IBD.”

The study was supported by Biogen (Switzerland), Celltrion Healthcare, Galapagos, F. Hoffmann-La Roche, Hull University Teaching Hospital NHS Trust, and the Royal Devon and Exeter NHS Foundation Trust. The study authors disclosed financial and nonfinancial relationships with numerous companies, including AbbVie, Biogen, Celltrion Healthcare, Galapagos, F. Hoffmann-La Roche, and Immundiagnostik, as well as Janssen, who markets infliximab, and Takeda, who markets vedolizumab. Dr. Isaacs and Dr. Cohen-Mekelburg had no relevant financial conflicts to disclose.

This article was updated 3/31/21.

An experimental oral Janus kinase 1 (JAK1) inhibitor, abrocitinib, showed greater itch reduction after 2 weeks of treatment than dupilumab in patients with moderate to severe atopic dermatitis (AD), in a multicenter, randomized trial.

In addition, in the study, those on 200-mg and 100-mg daily doses of abrocitinib experienced significantly greater reductions in signs and symptoms of AD at 12 and 16 weeks, than those on placebo, the authors reported.

The findings from the JADE COMPARE trial, published on March 25 in the New England Journal of Medicine, suggest abrocitinib will provide clinicians with another treatment option for patients who don’t get adequate relief from either topical medications or dupilumab. Abrocitinib is associated with a different set of adverse reactions than dupilumab, according to investigators.

In 2017, dupilumab (Dupixent) became the first systemic drug approved by the Food and Drug Administration specifically for AD, though systemic steroids and other immunosuppressant drugs are sometimes prescribed. A monoclonal antibody delivered by subcutaneous injection, dupilumab binds to interleukin-4 receptors to block signaling pathways involved in AD; it is now approved for treatment of patients with moderate to severe AD down to age 6 years.

“It is sort of the bar for efficacy and for safety in those patients, because that’s what we have right now,” said one of the JADE Compare investigators and study author, Jonathan I. Silverberg, MD, PhD, MPH, associate professor of dermatology and director of clinical research and contact dermatitis at George Washington University, Washington, said in an interview. “For any new therapy coming to market, we really do want to understand how it compares to what’s out there.”

Abrocitinib is a small molecule that inhibits JAK1, which is thought to modulate multiple cytokines involved in AD, including interleukin (IL)–4, IL-13, IL-31, IL-22, and thymic stromal lymphopoietin. Two other JAK1 inhibitors, baricitinib and upadacitinib, are also being investigated as systemic treatments for AD.

In JADE COMPARE, people with moderate to severe AD from 18 countries on four continents, entered a 28-day screening period during which they discontinued treatments. They began using emollients twice a day at least 7 days before being randomly assigned to a treatment group, and continued on topical medication once daily. Topical treatments included low- or medium-potency topical glucocorticoids, calcineurin inhibitors, and phosphodiesterase-4 inhibitors.

The researchers randomly assigned 838 to trial groups: 226 received 200 mg of abrocitinib orally once a day, 238 received 100 mg of abrocitinib once a day, 243 received a 300-mg dupilumab injection every other week, and 131 received placebo versions of both medications, for 16 weeks. The mean age of the patients overall was about 38 years; about two-thirds were White.

At 2 weeks, half of the patients on 200 mg of abrocitinib and 31.8% of those on the 100-mg dose had an itch response, defined as at least a 4-point improvement from baseline in the 0-10 Peak Pruritus Numerical Rating Scale. This was compared with 26.4% of those on dupilumab and 13.8% of those on placebo.

And at 12 weeks, more of the patients in the 200-mg abrocitinib group than in the other groups had an Investigator’s Global Assessment (IGA) response (defined as clear or almost clear) and more had an Eczema Area and Severity Index (EASI-75) response (defined as an improvement of at least 75%). (See Table) EASI-75 and IGA responses at week 12 were the primary outcomes of the study.

The overall incidence of adverse events was higher in the 200-mg abrocitinib arm than in the other groups, but the incidence of serious or severe adverse events, and the incidence of adverse events that resulted in discontinuing the medication, were similar across the trial groups.

However, nausea affected 11.1% of the patients in the 200-mg abrocitinib group and 4.2% of those in the 100-mg abrocitinib group. Acne was also reported in these groups (6.6% and 2.9%, among those on 200 mg and 100 mg, respectively, compared with 1.2% of those on dupilumab and none of those on placebo). In a few of those on abrocitinib, herpes zoster flared up. And median platelet counts decreased among the patients taking abrocitinib, although none dropped below 75,000/mm³. Serious infections were reported in two patients on abrocitinib, but resolved.

By contrast, only 2.9% of the patients on dupilumab had nausea. But 6.2% in the dupilumab group had conjunctivitis, compared with 1.3% of patients in the 200-mg abrocitinib group and 0.8 in the 100-mg abrocitinib group.

As an oral medication, abrocitinib will appeal to patients who want to avoid injections, and dosing will be easier to adjust, Dr. Silverberg said. On the other hand, he added, dupilumab will have an advantage for patients who don’t want to take a daily medication, or who are concerned about the adverse events associated with abrocitinib, particularly those with blood-clotting disorders.

On the basis of two previous JADE phase 3 trials, Pfizer has submitted a new drug application for abrocitinib for treating moderate to severe AD in patients aged 12 and older to the FDA; a decision is expected in April, according to the company. The company has also applied to market the drug in Europe and the United Kingdom.

The study was funded by Pfizer. Dr. Silverberg’s disclosures included serving as a consultant to companies including AbbVie, Pfizer, and Regeneron. Several authors are Pfizer employees; other authors had disclosures related to Pfizer and other pharmaceutical companies.

 

An experimental oral Janus kinase 1 (JAK1) inhibitor, abrocitinib, showed greater itch reduction after 2 weeks of treatment than dupilumab in patients with moderate to severe atopic dermatitis (AD), in a multicenter, randomized trial.

In addition, in the study, those on 200-mg and 100-mg daily doses of abrocitinib experienced significantly greater reductions in signs and symptoms of AD at 12 and 16 weeks, than those on placebo, the authors reported.

The findings from the JADE COMPARE trial, published on March 25 in the New England Journal of Medicine, suggest abrocitinib will provide clinicians with another treatment option for patients who don’t get adequate relief from either topical medications or dupilumab. Abrocitinib is associated with a different set of adverse reactions than dupilumab, according to investigators.

In 2017, dupilumab (Dupixent) became the first systemic drug approved by the Food and Drug Administration specifically for AD, though systemic steroids and other immunosuppressant drugs are sometimes prescribed. A monoclonal antibody delivered by subcutaneous injection, dupilumab binds to interleukin-4 receptors to block signaling pathways involved in AD; it is now approved for treatment of patients with moderate to severe AD down to age 6 years.

“It is sort of the bar for efficacy and for safety in those patients, because that’s what we have right now,” said one of the JADE Compare investigators and study author, Jonathan I. Silverberg, MD, PhD, MPH, associate professor of dermatology and director of clinical research and contact dermatitis at George Washington University, Washington, said in an interview. “For any new therapy coming to market, we really do want to understand how it compares to what’s out there.”

Abrocitinib is a small molecule that inhibits JAK1, which is thought to modulate multiple cytokines involved in AD, including interleukin (IL)–4, IL-13, IL-31, IL-22, and thymic stromal lymphopoietin. Two other JAK1 inhibitors, baricitinib and upadacitinib, are also being investigated as systemic treatments for AD.

In JADE COMPARE, people with moderate to severe AD from 18 countries on four continents, entered a 28-day screening period during which they discontinued treatments. They began using emollients twice a day at least 7 days before being randomly assigned to a treatment group, and continued on topical medication once daily. Topical treatments included low- or medium-potency topical glucocorticoids, calcineurin inhibitors, and phosphodiesterase-4 inhibitors.

The researchers randomly assigned 838 to trial groups: 226 received 200 mg of abrocitinib orally once a day, 238 received 100 mg of abrocitinib once a day, 243 received a 300-mg dupilumab injection every other week, and 131 received placebo versions of both medications, for 16 weeks. The mean age of the patients overall was about 38 years; about two-thirds were White.

At 2 weeks, half of the patients on 200 mg of abrocitinib and 31.8% of those on the 100-mg dose had an itch response, defined as at least a 4-point improvement from baseline in the 0-10 Peak Pruritus Numerical Rating Scale. This was compared with 26.4% of those on dupilumab and 13.8% of those on placebo.

And at 12 weeks, more of the patients in the 200-mg abrocitinib group than in the other groups had an Investigator’s Global Assessment (IGA) response (defined as clear or almost clear) and more had an Eczema Area and Severity Index (EASI-75) response (defined as an improvement of at least 75%). (See Table) EASI-75 and IGA responses at week 12 were the primary outcomes of the study.

The overall incidence of adverse events was higher in the 200-mg abrocitinib arm than in the other groups, but the incidence of serious or severe adverse events, and the incidence of adverse events that resulted in discontinuing the medication, were similar across the trial groups.

However, nausea affected 11.1% of the patients in the 200-mg abrocitinib group and 4.2% of those in the 100-mg abrocitinib group. Acne was also reported in these groups (6.6% and 2.9%, among those on 200 mg and 100 mg, respectively, compared with 1.2% of those on dupilumab and none of those on placebo). In a few of those on abrocitinib, herpes zoster flared up. And median platelet counts decreased among the patients taking abrocitinib, although none dropped below 75,000/mm³. Serious infections were reported in two patients on abrocitinib, but resolved.

By contrast, only 2.9% of the patients on dupilumab had nausea. But 6.2% in the dupilumab group had conjunctivitis, compared with 1.3% of patients in the 200-mg abrocitinib group and 0.8 in the 100-mg abrocitinib group.

As an oral medication, abrocitinib will appeal to patients who want to avoid injections, and dosing will be easier to adjust, Dr. Silverberg said. On the other hand, he added, dupilumab will have an advantage for patients who don’t want to take a daily medication, or who are concerned about the adverse events associated with abrocitinib, particularly those with blood-clotting disorders.

On the basis of two previous JADE phase 3 trials, Pfizer has submitted a new drug application for abrocitinib for treating moderate to severe AD in patients aged 12 and older to the FDA; a decision is expected in April, according to the company. The company has also applied to market the drug in Europe and the United Kingdom.

The study was funded by Pfizer. Dr. Silverberg’s disclosures included serving as a consultant to companies including AbbVie, Pfizer, and Regeneron. Several authors are Pfizer employees; other authors had disclosures related to Pfizer and other pharmaceutical companies.

 

An experimental oral Janus kinase 1 (JAK1) inhibitor, abrocitinib, showed greater itch reduction after 2 weeks of treatment than dupilumab in patients with moderate to severe atopic dermatitis (AD), in a multicenter, randomized trial.

In addition, in the study, those on 200-mg and 100-mg daily doses of abrocitinib experienced significantly greater reductions in signs and symptoms of AD at 12 and 16 weeks, than those on placebo, the authors reported.

The findings from the JADE COMPARE trial, published on March 25 in the New England Journal of Medicine, suggest abrocitinib will provide clinicians with another treatment option for patients who don’t get adequate relief from either topical medications or dupilumab. Abrocitinib is associated with a different set of adverse reactions than dupilumab, according to investigators.

In 2017, dupilumab (Dupixent) became the first systemic drug approved by the Food and Drug Administration specifically for AD, though systemic steroids and other immunosuppressant drugs are sometimes prescribed. A monoclonal antibody delivered by subcutaneous injection, dupilumab binds to interleukin-4 receptors to block signaling pathways involved in AD; it is now approved for treatment of patients with moderate to severe AD down to age 6 years.

“It is sort of the bar for efficacy and for safety in those patients, because that’s what we have right now,” said one of the JADE Compare investigators and study author, Jonathan I. Silverberg, MD, PhD, MPH, associate professor of dermatology and director of clinical research and contact dermatitis at George Washington University, Washington, said in an interview. “For any new therapy coming to market, we really do want to understand how it compares to what’s out there.”

Abrocitinib is a small molecule that inhibits JAK1, which is thought to modulate multiple cytokines involved in AD, including interleukin (IL)–4, IL-13, IL-31, IL-22, and thymic stromal lymphopoietin. Two other JAK1 inhibitors, baricitinib and upadacitinib, are also being investigated as systemic treatments for AD.

In JADE COMPARE, people with moderate to severe AD from 18 countries on four continents, entered a 28-day screening period during which they discontinued treatments. They began using emollients twice a day at least 7 days before being randomly assigned to a treatment group, and continued on topical medication once daily. Topical treatments included low- or medium-potency topical glucocorticoids, calcineurin inhibitors, and phosphodiesterase-4 inhibitors.

The researchers randomly assigned 838 to trial groups: 226 received 200 mg of abrocitinib orally once a day, 238 received 100 mg of abrocitinib once a day, 243 received a 300-mg dupilumab injection every other week, and 131 received placebo versions of both medications, for 16 weeks. The mean age of the patients overall was about 38 years; about two-thirds were White.

At 2 weeks, half of the patients on 200 mg of abrocitinib and 31.8% of those on the 100-mg dose had an itch response, defined as at least a 4-point improvement from baseline in the 0-10 Peak Pruritus Numerical Rating Scale. This was compared with 26.4% of those on dupilumab and 13.8% of those on placebo.

And at 12 weeks, more of the patients in the 200-mg abrocitinib group than in the other groups had an Investigator’s Global Assessment (IGA) response (defined as clear or almost clear) and more had an Eczema Area and Severity Index (EASI-75) response (defined as an improvement of at least 75%). (See Table) EASI-75 and IGA responses at week 12 were the primary outcomes of the study.

The overall incidence of adverse events was higher in the 200-mg abrocitinib arm than in the other groups, but the incidence of serious or severe adverse events, and the incidence of adverse events that resulted in discontinuing the medication, were similar across the trial groups.

However, nausea affected 11.1% of the patients in the 200-mg abrocitinib group and 4.2% of those in the 100-mg abrocitinib group. Acne was also reported in these groups (6.6% and 2.9%, among those on 200 mg and 100 mg, respectively, compared with 1.2% of those on dupilumab and none of those on placebo). In a few of those on abrocitinib, herpes zoster flared up. And median platelet counts decreased among the patients taking abrocitinib, although none dropped below 75,000/mm³. Serious infections were reported in two patients on abrocitinib, but resolved.

By contrast, only 2.9% of the patients on dupilumab had nausea. But 6.2% in the dupilumab group had conjunctivitis, compared with 1.3% of patients in the 200-mg abrocitinib group and 0.8 in the 100-mg abrocitinib group.

As an oral medication, abrocitinib will appeal to patients who want to avoid injections, and dosing will be easier to adjust, Dr. Silverberg said. On the other hand, he added, dupilumab will have an advantage for patients who don’t want to take a daily medication, or who are concerned about the adverse events associated with abrocitinib, particularly those with blood-clotting disorders.

On the basis of two previous JADE phase 3 trials, Pfizer has submitted a new drug application for abrocitinib for treating moderate to severe AD in patients aged 12 and older to the FDA; a decision is expected in April, according to the company. The company has also applied to market the drug in Europe and the United Kingdom.

The study was funded by Pfizer. Dr. Silverberg’s disclosures included serving as a consultant to companies including AbbVie, Pfizer, and Regeneron. Several authors are Pfizer employees; other authors had disclosures related to Pfizer and other pharmaceutical companies.

 

In a record year for the Match, internal medicine residencies offered and filled more positions than ever before, according to the National Resident Matching Program.

“Rather than faltering in these uncertain times, program fill rates increased across the board,” the NRMP said in a written statement. Overall, the 2021 Main Residency Match offered (35,194) and filled (33,353) record numbers of first-year (PGY-1) slots. That fill rate of 94.8% was up from 94.6% the year before.

“The application and recruitment cycle was upended as a result of the pandemic, yet the results of the Match continue to demonstrate strong and consistent outcomes for participants,” said Donna L. Lamb, DHSc, MBA, president and CEO of the NRMP.

Internal medicine offered 9,024 positions in this year’s Match, up by 3.8% over 2020, and filled 8,632, for a 1-year increase of 3.7% and a fill rate of 95.7%. Over 55% (5,005) of the available slots were given to U.S. seniors (MDs and DOs), while 37.9% went to international medical graduates. The corresponding PGY-1 numbers for the Match as a whole were 70.4% U.S. and 21.1% international medical graduates, based on NRMP data.

The number of positions offered in internal medicine residencies has increased by 1,791 (24.8%) since 2017, and such growth over time may “be a predictor of future physician workforce supply,” the NRMP suggested. Internal medicine also increased its share of all available residency positions from 24.9% in 2018 to 25.6% in 2021.

“Concerns about the impact of virtual recruitment on applicants’ matching into PGY-1 positions were not realized,” the NRMP noted, as “growth in registration was seen in every applicant group.” Compared with 2020, submissions of rank-order lists of programs were up by 2.8% for U.S. MD seniors, 7.9% for U.S. DO seniors, 2.5% among U.S.-citizen IMGs, and 15.0% for non–U.S.-citizen IMGs.

“The internal medicine workforce remains the backbone of our health care system, and expansion of this workforce is imperative to provide access to specialty and subspecialty medical care for future patients,” Philip A. Masters, MD, vice president of membership and global engagement at the American College of Physicians, said in a separate statement.

[email protected]

In a record year for the Match, internal medicine residencies offered and filled more positions than ever before, according to the National Resident Matching Program.

“Rather than faltering in these uncertain times, program fill rates increased across the board,” the NRMP said in a written statement. Overall, the 2021 Main Residency Match offered (35,194) and filled (33,353) record numbers of first-year (PGY-1) slots. That fill rate of 94.8% was up from 94.6% the year before.

“The application and recruitment cycle was upended as a result of the pandemic, yet the results of the Match continue to demonstrate strong and consistent outcomes for participants,” said Donna L. Lamb, DHSc, MBA, president and CEO of the NRMP.

Internal medicine offered 9,024 positions in this year’s Match, up by 3.8% over 2020, and filled 8,632, for a 1-year increase of 3.7% and a fill rate of 95.7%. Over 55% (5,005) of the available slots were given to U.S. seniors (MDs and DOs), while 37.9% went to international medical graduates. The corresponding PGY-1 numbers for the Match as a whole were 70.4% U.S. and 21.1% international medical graduates, based on NRMP data.

The number of positions offered in internal medicine residencies has increased by 1,791 (24.8%) since 2017, and such growth over time may “be a predictor of future physician workforce supply,” the NRMP suggested. Internal medicine also increased its share of all available residency positions from 24.9% in 2018 to 25.6% in 2021.

“Concerns about the impact of virtual recruitment on applicants’ matching into PGY-1 positions were not realized,” the NRMP noted, as “growth in registration was seen in every applicant group.” Compared with 2020, submissions of rank-order lists of programs were up by 2.8% for U.S. MD seniors, 7.9% for U.S. DO seniors, 2.5% among U.S.-citizen IMGs, and 15.0% for non–U.S.-citizen IMGs.

“The internal medicine workforce remains the backbone of our health care system, and expansion of this workforce is imperative to provide access to specialty and subspecialty medical care for future patients,” Philip A. Masters, MD, vice president of membership and global engagement at the American College of Physicians, said in a separate statement.

[email protected]

In a record year for the Match, internal medicine residencies offered and filled more positions than ever before, according to the National Resident Matching Program.

“Rather than faltering in these uncertain times, program fill rates increased across the board,” the NRMP said in a written statement. Overall, the 2021 Main Residency Match offered (35,194) and filled (33,353) record numbers of first-year (PGY-1) slots. That fill rate of 94.8% was up from 94.6% the year before.

“The application and recruitment cycle was upended as a result of the pandemic, yet the results of the Match continue to demonstrate strong and consistent outcomes for participants,” said Donna L. Lamb, DHSc, MBA, president and CEO of the NRMP.

Internal medicine offered 9,024 positions in this year’s Match, up by 3.8% over 2020, and filled 8,632, for a 1-year increase of 3.7% and a fill rate of 95.7%. Over 55% (5,005) of the available slots were given to U.S. seniors (MDs and DOs), while 37.9% went to international medical graduates. The corresponding PGY-1 numbers for the Match as a whole were 70.4% U.S. and 21.1% international medical graduates, based on NRMP data.

The number of positions offered in internal medicine residencies has increased by 1,791 (24.8%) since 2017, and such growth over time may “be a predictor of future physician workforce supply,” the NRMP suggested. Internal medicine also increased its share of all available residency positions from 24.9% in 2018 to 25.6% in 2021.

“Concerns about the impact of virtual recruitment on applicants’ matching into PGY-1 positions were not realized,” the NRMP noted, as “growth in registration was seen in every applicant group.” Compared with 2020, submissions of rank-order lists of programs were up by 2.8% for U.S. MD seniors, 7.9% for U.S. DO seniors, 2.5% among U.S.-citizen IMGs, and 15.0% for non–U.S.-citizen IMGs.

“The internal medicine workforce remains the backbone of our health care system, and expansion of this workforce is imperative to provide access to specialty and subspecialty medical care for future patients,” Philip A. Masters, MD, vice president of membership and global engagement at the American College of Physicians, said in a separate statement.

[email protected]

Postintubation laryngeal and tracheal injuries may be yet another part of recovery from severe COVID-19 infection for some patients.

Evidence has been accumulating on the link between prolonged intubation and lingering breathing and speaking difficulties, a concern that has become more germane in the wake of the COVID-19 pandemic. Now, researchers in Italy led by Giacomo Fiacchini, MD, and Luca Bruschini, MD, of the University of Pisa have published new research suggesting tracheal complications were particularly common in COVID-19 patients intubated for prolonged periods during the pandemic.

The study may be revealing effects of the pandemic itself, as resources and staff were at times overwhelmed by critical care patients. Of the 98 patients admitted from March 1 to May 31, 47% intubated for longer than 14 days developed full-thickness tracheal lesions, compared with 2.2% of a control group treated during the same time frame in 2019. The difference is eye-popping, but may not be generalizable. “I have not observed an increased rate of tracheal injury, but we haven’t carefully studied that outcome as far as I know,” said Daniel Ouellette, MD, FCCP, who is a senior staff physician and director of the pulmonary inpatient unit at Henry Ford Health System, and an associate professor at Wayne State University, Detroit.

He expressed concern about the retrospective nature of the study, and wondered if the different outcomes might be because of disruptions caused by the pandemic. “It’s not hard to imagine that these patients were seen [during] a great rush of patients, whereas the control group was looked at during a period where that kind of volume didn’t exist. There might have been a tendency for more inexperienced practitioners to be intubating patients because they were in the middle of the epidemic. There might have been less supervision of trainees. Individuals, physicians, teams may have been more rushed. Protocols may not have been followed as closely. It may all be an effect of the epidemic itself,” said Dr. Ouellette.

The investigators suggested that implementation of pronation maneuvers may have increased cuff pressure on the tracheal walls leading to some injuries. In addition, the prothrombotic and antifibrinolytic state of patients with COVID-19 may have contributed, along with the impact of systemic steroids that may have altered normal healing of tracheal wall microwounds caused by intubation, cuff pressure, or tracheostomy.

Other research has suggested increased complications from intubation among COVID-19 patients, including a case series that found heightened frequency of pneumomediastinum. The authors of that study suggested that aggressive disease pathophysiology and accompanying risk of alveolar damage and tracheobronchial injury may be to blame, along with larger-bore tracheal tubes and higher ventilation pressures. That study may also be reflecting the conditions of intubation during the pandemic.

Not all institutions saw an uptick in tracheal injury or pneumomediastinum. Mary Jo S. Farmer, MD, PhD, FCCP, of the department of medicine at University of Massachusetts, Springfield, asked one of the institute’s statisticians to examine pneumothorax frequency from March 15, 2020, to March 1, 2021, comparing the rates between patients who tested positive for SARS-CoV-2 within 14 days of admission, and those who tested negative. The rate was 0.5% in patients who tested positive versus 0.4% in those who tested negative. “My division chief’s gut sense is it’s just the same. The prevalence [of pneumomediastinum] is what we were seeing before,” said Dr. Farmer.

Shortly before the COVID-19 pandemic, researchers at Vanderbilt University Medical Center found that more than half of patients undergoing prolonged intubation experience breathing and speaking difficulties at 10 weeks post intubation. The group has followed up that study with another study looking at treatment timing and outcomes.

The researchers reviewed the experiences of 29 patients with laryngeal injury from endotracheal intubation between May 1, 2014,- and June 1, 2018. Ten patients with posterior glottis injury received early treatment, at a median of 34.7 days to presentation (interquartile range, 1.5-44.8 days). Nineteen patients with posterior glottis stenosis received treatment at a median of 341.9 days (absolute difference, 307.2 days; 95% confidence interval, 124.4-523.3 days). Demographic characteristics and comorbidities were similar between the two groups. At last follow-up, 90% of the early-treatment group were decannulated, compared with 58% of the late group (absolute difference, 32%; 95% CI, –3% to 68%). The early group required a mean of 2.2 interventions, compared with 11.5 in the late group (absolute difference, 9.3; 95% CI, 6.4-12.1). No patients in the early group required an open procedure, compared with 90% of the late-treatment group.

Although early treatment seems promising, the timing of laryngeal injury repair would be a key consideration. “You would worry about patient stability, [making] sure they’re clinically stable and didn’t have any acute ill effects from the injury itself or the underlying illness that led to intubation,” said Dr. Ouellette. For COVID-19 patients, that would mean recovery from pneumonia or any other lung problems, he added.

Together, the studies raise concerns and questions over tracheal and laryngeal injury in the context of COVID-19, but fall short of providing clinical guidance. “It raises the awareness in the mind of the critical care physician about these potential injuries to the larynx surrounding intubation,” said Dr. Farmer.

The studies received no funding. Dr. Ouellette and Dr. Farmer reported no relevant financial disclosures.

Postintubation laryngeal and tracheal injuries may be yet another part of recovery from severe COVID-19 infection for some patients.

Evidence has been accumulating on the link between prolonged intubation and lingering breathing and speaking difficulties, a concern that has become more germane in the wake of the COVID-19 pandemic. Now, researchers in Italy led by Giacomo Fiacchini, MD, and Luca Bruschini, MD, of the University of Pisa have published new research suggesting tracheal complications were particularly common in COVID-19 patients intubated for prolonged periods during the pandemic.

The study may be revealing effects of the pandemic itself, as resources and staff were at times overwhelmed by critical care patients. Of the 98 patients admitted from March 1 to May 31, 47% intubated for longer than 14 days developed full-thickness tracheal lesions, compared with 2.2% of a control group treated during the same time frame in 2019. The difference is eye-popping, but may not be generalizable. “I have not observed an increased rate of tracheal injury, but we haven’t carefully studied that outcome as far as I know,” said Daniel Ouellette, MD, FCCP, who is a senior staff physician and director of the pulmonary inpatient unit at Henry Ford Health System, and an associate professor at Wayne State University, Detroit.

He expressed concern about the retrospective nature of the study, and wondered if the different outcomes might be because of disruptions caused by the pandemic. “It’s not hard to imagine that these patients were seen [during] a great rush of patients, whereas the control group was looked at during a period where that kind of volume didn’t exist. There might have been a tendency for more inexperienced practitioners to be intubating patients because they were in the middle of the epidemic. There might have been less supervision of trainees. Individuals, physicians, teams may have been more rushed. Protocols may not have been followed as closely. It may all be an effect of the epidemic itself,” said Dr. Ouellette.

The investigators suggested that implementation of pronation maneuvers may have increased cuff pressure on the tracheal walls leading to some injuries. In addition, the prothrombotic and antifibrinolytic state of patients with COVID-19 may have contributed, along with the impact of systemic steroids that may have altered normal healing of tracheal wall microwounds caused by intubation, cuff pressure, or tracheostomy.

Other research has suggested increased complications from intubation among COVID-19 patients, including a case series that found heightened frequency of pneumomediastinum. The authors of that study suggested that aggressive disease pathophysiology and accompanying risk of alveolar damage and tracheobronchial injury may be to blame, along with larger-bore tracheal tubes and higher ventilation pressures. That study may also be reflecting the conditions of intubation during the pandemic.

Not all institutions saw an uptick in tracheal injury or pneumomediastinum. Mary Jo S. Farmer, MD, PhD, FCCP, of the department of medicine at University of Massachusetts, Springfield, asked one of the institute’s statisticians to examine pneumothorax frequency from March 15, 2020, to March 1, 2021, comparing the rates between patients who tested positive for SARS-CoV-2 within 14 days of admission, and those who tested negative. The rate was 0.5% in patients who tested positive versus 0.4% in those who tested negative. “My division chief’s gut sense is it’s just the same. The prevalence [of pneumomediastinum] is what we were seeing before,” said Dr. Farmer.

Shortly before the COVID-19 pandemic, researchers at Vanderbilt University Medical Center found that more than half of patients undergoing prolonged intubation experience breathing and speaking difficulties at 10 weeks post intubation. The group has followed up that study with another study looking at treatment timing and outcomes.

The researchers reviewed the experiences of 29 patients with laryngeal injury from endotracheal intubation between May 1, 2014,- and June 1, 2018. Ten patients with posterior glottis injury received early treatment, at a median of 34.7 days to presentation (interquartile range, 1.5-44.8 days). Nineteen patients with posterior glottis stenosis received treatment at a median of 341.9 days (absolute difference, 307.2 days; 95% confidence interval, 124.4-523.3 days). Demographic characteristics and comorbidities were similar between the two groups. At last follow-up, 90% of the early-treatment group were decannulated, compared with 58% of the late group (absolute difference, 32%; 95% CI, –3% to 68%). The early group required a mean of 2.2 interventions, compared with 11.5 in the late group (absolute difference, 9.3; 95% CI, 6.4-12.1). No patients in the early group required an open procedure, compared with 90% of the late-treatment group.

Although early treatment seems promising, the timing of laryngeal injury repair would be a key consideration. “You would worry about patient stability, [making] sure they’re clinically stable and didn’t have any acute ill effects from the injury itself or the underlying illness that led to intubation,” said Dr. Ouellette. For COVID-19 patients, that would mean recovery from pneumonia or any other lung problems, he added.

Together, the studies raise concerns and questions over tracheal and laryngeal injury in the context of COVID-19, but fall short of providing clinical guidance. “It raises the awareness in the mind of the critical care physician about these potential injuries to the larynx surrounding intubation,” said Dr. Farmer.

The studies received no funding. Dr. Ouellette and Dr. Farmer reported no relevant financial disclosures.

Postintubation laryngeal and tracheal injuries may be yet another part of recovery from severe COVID-19 infection for some patients.

Evidence has been accumulating on the link between prolonged intubation and lingering breathing and speaking difficulties, a concern that has become more germane in the wake of the COVID-19 pandemic. Now, researchers in Italy led by Giacomo Fiacchini, MD, and Luca Bruschini, MD, of the University of Pisa have published new research suggesting tracheal complications were particularly common in COVID-19 patients intubated for prolonged periods during the pandemic.

The study may be revealing effects of the pandemic itself, as resources and staff were at times overwhelmed by critical care patients. Of the 98 patients admitted from March 1 to May 31, 47% intubated for longer than 14 days developed full-thickness tracheal lesions, compared with 2.2% of a control group treated during the same time frame in 2019. The difference is eye-popping, but may not be generalizable. “I have not observed an increased rate of tracheal injury, but we haven’t carefully studied that outcome as far as I know,” said Daniel Ouellette, MD, FCCP, who is a senior staff physician and director of the pulmonary inpatient unit at Henry Ford Health System, and an associate professor at Wayne State University, Detroit.

He expressed concern about the retrospective nature of the study, and wondered if the different outcomes might be because of disruptions caused by the pandemic. “It’s not hard to imagine that these patients were seen [during] a great rush of patients, whereas the control group was looked at during a period where that kind of volume didn’t exist. There might have been a tendency for more inexperienced practitioners to be intubating patients because they were in the middle of the epidemic. There might have been less supervision of trainees. Individuals, physicians, teams may have been more rushed. Protocols may not have been followed as closely. It may all be an effect of the epidemic itself,” said Dr. Ouellette.

The investigators suggested that implementation of pronation maneuvers may have increased cuff pressure on the tracheal walls leading to some injuries. In addition, the prothrombotic and antifibrinolytic state of patients with COVID-19 may have contributed, along with the impact of systemic steroids that may have altered normal healing of tracheal wall microwounds caused by intubation, cuff pressure, or tracheostomy.

Other research has suggested increased complications from intubation among COVID-19 patients, including a case series that found heightened frequency of pneumomediastinum. The authors of that study suggested that aggressive disease pathophysiology and accompanying risk of alveolar damage and tracheobronchial injury may be to blame, along with larger-bore tracheal tubes and higher ventilation pressures. That study may also be reflecting the conditions of intubation during the pandemic.

Not all institutions saw an uptick in tracheal injury or pneumomediastinum. Mary Jo S. Farmer, MD, PhD, FCCP, of the department of medicine at University of Massachusetts, Springfield, asked one of the institute’s statisticians to examine pneumothorax frequency from March 15, 2020, to March 1, 2021, comparing the rates between patients who tested positive for SARS-CoV-2 within 14 days of admission, and those who tested negative. The rate was 0.5% in patients who tested positive versus 0.4% in those who tested negative. “My division chief’s gut sense is it’s just the same. The prevalence [of pneumomediastinum] is what we were seeing before,” said Dr. Farmer.

Shortly before the COVID-19 pandemic, researchers at Vanderbilt University Medical Center found that more than half of patients undergoing prolonged intubation experience breathing and speaking difficulties at 10 weeks post intubation. The group has followed up that study with another study looking at treatment timing and outcomes.

The researchers reviewed the experiences of 29 patients with laryngeal injury from endotracheal intubation between May 1, 2014,- and June 1, 2018. Ten patients with posterior glottis injury received early treatment, at a median of 34.7 days to presentation (interquartile range, 1.5-44.8 days). Nineteen patients with posterior glottis stenosis received treatment at a median of 341.9 days (absolute difference, 307.2 days; 95% confidence interval, 124.4-523.3 days). Demographic characteristics and comorbidities were similar between the two groups. At last follow-up, 90% of the early-treatment group were decannulated, compared with 58% of the late group (absolute difference, 32%; 95% CI, –3% to 68%). The early group required a mean of 2.2 interventions, compared with 11.5 in the late group (absolute difference, 9.3; 95% CI, 6.4-12.1). No patients in the early group required an open procedure, compared with 90% of the late-treatment group.

Although early treatment seems promising, the timing of laryngeal injury repair would be a key consideration. “You would worry about patient stability, [making] sure they’re clinically stable and didn’t have any acute ill effects from the injury itself or the underlying illness that led to intubation,” said Dr. Ouellette. For COVID-19 patients, that would mean recovery from pneumonia or any other lung problems, he added.

Together, the studies raise concerns and questions over tracheal and laryngeal injury in the context of COVID-19, but fall short of providing clinical guidance. “It raises the awareness in the mind of the critical care physician about these potential injuries to the larynx surrounding intubation,” said Dr. Farmer.

The studies received no funding. Dr. Ouellette and Dr. Farmer reported no relevant financial disclosures.

The use of allogeneic hematopoietic stem cell transplantation (allo-HSCT) can improve survival in minimal residual disease (MRD)–negative remission patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) after the start of monoclonal antibody treatment, according to the results of a landmark analysis presented at the virtual meeting of the European Society for Blood and Marrow Transplantation.

VashiDonsk/Wikimedia Commons/Creative Commons 3.0

Previous studies have indicated that allo-HSCT improves the results of treatment in r/r B-ALL patients, compared with chemotherapy alone. In addition, it has been found that the monoclonal antibodies (Mab), anti-CD19-blinatumomab and anti-CD22-inotuzumab ozogamicin, induced remission in a significant proportion of such patients.

To determine if the use of allo-HSCT improves the outcome of patients in MRD-negative remission with or without Mab treatment, researchers performed a landmark analysis of 110 patients who achieved MRD-negative status after Mab treatment. The analysis examined results at 2, 4, and 6 months subsequent to the initiation of Mab treatment, according to poster presentation by Inna V. Markova, MD, and colleagues at Pavlov University, Saint Petersburg, Russian Federation.
 

Study details

The researchers included 110 patients who achieved MRD-negative status outside of clinical trials at a single institution in the analysis. Forty of the patients (36%) were children and 70 (64%) were adults. The median age for all patients was 23 years and the median follow up was 24 months. Fifty-seven (52%) and 53 (48%) patients received Mab for hematological relapse and persistent measurable residual disease or for molecular relapse, respectively. Therapy with Mab alone without subsequent allo-HSCT was used in 36 (31%) patients (30 received blinatumomab and 6 received inotuzumab ozogamicin). A total of 74 (69%) patients received allo-HSCT from a matched related or unrelated donor (MD-HSCT, n = 38) or haploidentical donor (Haplo-HSCT, n = 36). All patients received posttransplantation cyclophosphamide (PTCY)–based graft-versus host disease (GVHD) prophylaxis. Landmark analysis was performed at 2, 4, and 6 months after Mab therapy initiation to determine the effect of allo-HSCT on the outcome and the optimal timing of HSCT. Overall survival and disease-free survival (DFS) were used as outcomes.
 

Promising results

No significant differences between the MD-HSCT, Mab alone, and Haplo-HSCT groups were observed in 2-month landmark analysis (P = .4 for OS and P =.65 for DFS). However, the 4-month landmark analysis demonstrated superior overall survival and DFS in patients after MD-HSCT, but not Haplo-HSCT, compared with Mab alone: 2-year OS was 75%, 50%, and 27,7% (P = .032) and DFS was 53.5%, 51.3%, and 16.6% (P = .02) for MD-HSCT, Mab alone and Haplo-HSCT groups, respectively. In addition, 6-month analysis showed that there was no benefit from subsequent transplantation, according to the authors, with regard to overall survival (P = .11).

“Our study demonstrated that at least MD-HSCT with PTCY platform improves survival in MRD-negative remission if performed during the first 4 months after Mab initiation. Haplo-HSCT or MD-HSCT beyond 4 months are not associated with improved outcomes in this groups of patients,” the researchers concluded.

The researchers reported they had no conflicts of interest to declare.

[email protected]

The use of allogeneic hematopoietic stem cell transplantation (allo-HSCT) can improve survival in minimal residual disease (MRD)–negative remission patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) after the start of monoclonal antibody treatment, according to the results of a landmark analysis presented at the virtual meeting of the European Society for Blood and Marrow Transplantation.

VashiDonsk/Wikimedia Commons/Creative Commons 3.0

Previous studies have indicated that allo-HSCT improves the results of treatment in r/r B-ALL patients, compared with chemotherapy alone. In addition, it has been found that the monoclonal antibodies (Mab), anti-CD19-blinatumomab and anti-CD22-inotuzumab ozogamicin, induced remission in a significant proportion of such patients.

To determine if the use of allo-HSCT improves the outcome of patients in MRD-negative remission with or without Mab treatment, researchers performed a landmark analysis of 110 patients who achieved MRD-negative status after Mab treatment. The analysis examined results at 2, 4, and 6 months subsequent to the initiation of Mab treatment, according to poster presentation by Inna V. Markova, MD, and colleagues at Pavlov University, Saint Petersburg, Russian Federation.
 

Study details

The researchers included 110 patients who achieved MRD-negative status outside of clinical trials at a single institution in the analysis. Forty of the patients (36%) were children and 70 (64%) were adults. The median age for all patients was 23 years and the median follow up was 24 months. Fifty-seven (52%) and 53 (48%) patients received Mab for hematological relapse and persistent measurable residual disease or for molecular relapse, respectively. Therapy with Mab alone without subsequent allo-HSCT was used in 36 (31%) patients (30 received blinatumomab and 6 received inotuzumab ozogamicin). A total of 74 (69%) patients received allo-HSCT from a matched related or unrelated donor (MD-HSCT, n = 38) or haploidentical donor (Haplo-HSCT, n = 36). All patients received posttransplantation cyclophosphamide (PTCY)–based graft-versus host disease (GVHD) prophylaxis. Landmark analysis was performed at 2, 4, and 6 months after Mab therapy initiation to determine the effect of allo-HSCT on the outcome and the optimal timing of HSCT. Overall survival and disease-free survival (DFS) were used as outcomes.
 

Promising results

No significant differences between the MD-HSCT, Mab alone, and Haplo-HSCT groups were observed in 2-month landmark analysis (P = .4 for OS and P =.65 for DFS). However, the 4-month landmark analysis demonstrated superior overall survival and DFS in patients after MD-HSCT, but not Haplo-HSCT, compared with Mab alone: 2-year OS was 75%, 50%, and 27,7% (P = .032) and DFS was 53.5%, 51.3%, and 16.6% (P = .02) for MD-HSCT, Mab alone and Haplo-HSCT groups, respectively. In addition, 6-month analysis showed that there was no benefit from subsequent transplantation, according to the authors, with regard to overall survival (P = .11).

“Our study demonstrated that at least MD-HSCT with PTCY platform improves survival in MRD-negative remission if performed during the first 4 months after Mab initiation. Haplo-HSCT or MD-HSCT beyond 4 months are not associated with improved outcomes in this groups of patients,” the researchers concluded.

The researchers reported they had no conflicts of interest to declare.

[email protected]

The use of allogeneic hematopoietic stem cell transplantation (allo-HSCT) can improve survival in minimal residual disease (MRD)–negative remission patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) after the start of monoclonal antibody treatment, according to the results of a landmark analysis presented at the virtual meeting of the European Society for Blood and Marrow Transplantation.

VashiDonsk/Wikimedia Commons/Creative Commons 3.0

Previous studies have indicated that allo-HSCT improves the results of treatment in r/r B-ALL patients, compared with chemotherapy alone. In addition, it has been found that the monoclonal antibodies (Mab), anti-CD19-blinatumomab and anti-CD22-inotuzumab ozogamicin, induced remission in a significant proportion of such patients.

To determine if the use of allo-HSCT improves the outcome of patients in MRD-negative remission with or without Mab treatment, researchers performed a landmark analysis of 110 patients who achieved MRD-negative status after Mab treatment. The analysis examined results at 2, 4, and 6 months subsequent to the initiation of Mab treatment, according to poster presentation by Inna V. Markova, MD, and colleagues at Pavlov University, Saint Petersburg, Russian Federation.
 

Study details

The researchers included 110 patients who achieved MRD-negative status outside of clinical trials at a single institution in the analysis. Forty of the patients (36%) were children and 70 (64%) were adults. The median age for all patients was 23 years and the median follow up was 24 months. Fifty-seven (52%) and 53 (48%) patients received Mab for hematological relapse and persistent measurable residual disease or for molecular relapse, respectively. Therapy with Mab alone without subsequent allo-HSCT was used in 36 (31%) patients (30 received blinatumomab and 6 received inotuzumab ozogamicin). A total of 74 (69%) patients received allo-HSCT from a matched related or unrelated donor (MD-HSCT, n = 38) or haploidentical donor (Haplo-HSCT, n = 36). All patients received posttransplantation cyclophosphamide (PTCY)–based graft-versus host disease (GVHD) prophylaxis. Landmark analysis was performed at 2, 4, and 6 months after Mab therapy initiation to determine the effect of allo-HSCT on the outcome and the optimal timing of HSCT. Overall survival and disease-free survival (DFS) were used as outcomes.
 

Promising results

No significant differences between the MD-HSCT, Mab alone, and Haplo-HSCT groups were observed in 2-month landmark analysis (P = .4 for OS and P =.65 for DFS). However, the 4-month landmark analysis demonstrated superior overall survival and DFS in patients after MD-HSCT, but not Haplo-HSCT, compared with Mab alone: 2-year OS was 75%, 50%, and 27,7% (P = .032) and DFS was 53.5%, 51.3%, and 16.6% (P = .02) for MD-HSCT, Mab alone and Haplo-HSCT groups, respectively. In addition, 6-month analysis showed that there was no benefit from subsequent transplantation, according to the authors, with regard to overall survival (P = .11).

“Our study demonstrated that at least MD-HSCT with PTCY platform improves survival in MRD-negative remission if performed during the first 4 months after Mab initiation. Haplo-HSCT or MD-HSCT beyond 4 months are not associated with improved outcomes in this groups of patients,” the researchers concluded.

The researchers reported they had no conflicts of interest to declare.

[email protected]

Baseball great Satchel Paige’s famous adage, “Age is a case of mind over matter. If you don’t mind, it don’t matter,” may also apply to candidates for ovarian cancer surgery. That’s because investigators have found that physical frailty is a better determinant of fitness for surgery than is calendar age.

Investigators conducted a retrospective analysis of 591 patients considered for primary resection of stage II to IV high-grade ovarian, fallopian tube, or peritoneal cancer. Results showed that a 10-item modified frailty index was better than patient age for predicting survival outcomes.

“Frailty does seem to correlate with age and increase with age, but it is not synonymous with age,” said investigator Katelyn F. Handley, MD, of the University of Texas MD Anderson Cancer Center in Houston.

“Frailty is a spectrum, and we can see patients of the same chronological age, but one may be a 76-year-old, ultra-distance triathlete, while another is in failing health and diminishing function,” Dr. Handley said at the Society of Gynecologic Oncology’s Virtual Annual Meeting on Women’s Cancer (Abstract 10463).

Dr. Handley cited a consensus definition of frailty, published in 2013, as “a medical syndrome with multiple causes and contributors that is characterized by diminished strength, endurance, and reduced physiologic function that increases an individual’s vulnerability for developing increased dependency and/or death.”
 

Ten-item score

To assess the effect of frailty in ovarian cancer patients on surgical procedures and outcomes, the investigators retrospectively applied a modified frailty index (mFI) to patients who were treated at MD Anderson Cancer Center from April 2013 through September 2017.

The index is a sum of 10 items: Chronic obstructive pulmonary disease or recent pneumonia, heart failure, myocardial infarction, coronary artery disease, diabetes, hypertension, peripheral vascular disease, cerebrovascular disease, cerebrovascular accident with neurologic deficit, and poor Eastern Cooperative Oncology Group performance status (3 or 4).

Of the 591 patients who met inclusion criteria, 57% had mFI scores of 0, indicating no frailty, 29% had one frailty factor, and 14% had two or more factors.

Patient age did significantly correlate with mFI scores. Patients with an mFI score of 0 had a median age of 62 years, the median age in those with a score of 1 was 69 years, and the median age for those with scores of 2 or higher was 70.5 years (P <. 001).

Charlson comorbidity index scores also significantly increased with age, with mean scores of 3.00, 3.83, and 5.14 in patients with mFI scores of 0, 1, or 2, respectively (P <. 001).

“But if you look at the age ranges in each category, you’ll notice that there are patients as young as 47 with an mFI of greater than or equal to 2, and as old as 89 with an mFI of 0,” Dr. Handley pointed out.
 

Higher scores, fewer assessments

The investigators found that patients with suspected ovarian cancer with frailty scores of 2 or higher were less likely to be offered laparoscopic assessment to determine primary resectability than were those with scores of 1 or 0 (28% vs. 43% and 49%, respectively, P = .004).

Among all patients who underwent laparoscopic assessment, the predictive index score (modified Fagotti score) was more likely to be 8 or higher in patients with high frailty scores (58%, 48%, and 34% for scores of 2 or greater, 1, and 0, respectively; P = .038).

Only 17% of the most frail patients went on to primary debulking surgery, compared with 26% of patients with a single frailty factor and 34% of those with none (P = .015).

Patients with higher frailty scores were less likely to undergo primary or interval tumor reductive surgery (59% vs. 74% for those with mFI scores of 1 and 85% for those with scores of 0; P <. 001). The frailest patients were significantly more likely to undergo splenectomy (20%, 3%, and 6%, respectively; P = .001) and small bowel resection (14%, 8%, and 3%, respectively; P = .006).

Two-thirds of the most frail patients (64%) had postoperative complications, primarily gastrointestinal and renal complications, compared with 56% and 44% of patients with mFI scores of 1 or 0, respectively (P = .014).

Frailty was predictive of 30-day postoperative mortality (P = .005) but not postoperative length of stay.

Frailer patients were more likely to receive neoadjuvant chemotherapy (P = .033) but less likely to receive adjuvant chemotherapy (P <. 001).

mFI scores of 2 or greater and 1 were both associated with significantly worse progression-free survival (P < .001 and P = .022, respectively), but only an mFI of 2 or greater was associated with significantly worse overall survival (P <. 001).

On multivariate analysis controlling for frailty, age, stage, BRCA status, and tumor reductive surgery status, high frailty was associated with worse progression-free survival (P = .009) and a trend toward worse overall survival (P = .079).

High frailty was better than age for predicting worse progression-free survival (hazard ratio, 1.50; P = .017) and overall survival (HR, 1.57; P = .047)
 

Volume counts

In a separate presentation during the same session, Morcos Nakhla, of the University of California, Los Angeles, reported finding similar associations between frailty and worse surgical outcomes for ovarian cancer patients (Abstract 11016).

Mr. Nakhla and colleagues found that frail patients had a twofold increase in the risk of postoperative complications, a threefold increase in the risk for non-home dismissal, and a threefold increased risk of death (P <. 001 for all).

The team also found, however, that mortality improved from 2005 through 2017, despite an increase in frail patients over that time period.

In addition, higher surgical volumes were associated with decreased mortality among frail patients undergoing ovarian cancer surgery.
 

Navigating treatment

“Frailty syndrome is a medical syndrome. It’s not a disability,” said Jamie N. Bakkum-Gamez, MD, of the Mayo Clinic in Rochester, Minn., the invited discussant. “No patient or human wants to be frail, but at some point, we may all be at risk for frailty syndrome, and as we navigate much-needed novel ways to treat this medical syndrome, it’s imperative that we listen to the voice of the customer and that our communication and technology doesn’t add unanticipated stress.”

Dr. Bakkum-Gamez emphasized the importance of shared decision-making, screening for frailty syndrome, referral to higher volume surgical centers when practical, and surgical alternatives such as neoadjuvant chemotherapy with or without interval debulking surgery and palliative care.

Interventions for ameliorating frailty may include exercise, high-protein calorie supplementation, reduction of polypharmacy, and vitamin D supplementation.

“Sometimes, shared decision-making means deciding not to operate,” Dr. Bakkum-Gamez said. “This is sometimes amongst the hardest decisions for a surgeon. We know when we make the wrong decision in operating if our patient experiences a major, life-shortening complication, but it’s less clear to know if we make the wrong decision to not operate.”

The study by Dr. Handley and colleagues was funded by the Gulf Coast Consortia, MD Anderson, National Institutes of Health, American Cancer Society, and GOG Foundation. Mr. Nakhla and colleagues did not disclose a funding source. Dr. Handley, Mr. Nakhla, and Dr. Bakkum-Gamez all reported no relevant conflicts of interest.

Baseball great Satchel Paige’s famous adage, “Age is a case of mind over matter. If you don’t mind, it don’t matter,” may also apply to candidates for ovarian cancer surgery. That’s because investigators have found that physical frailty is a better determinant of fitness for surgery than is calendar age.

Investigators conducted a retrospective analysis of 591 patients considered for primary resection of stage II to IV high-grade ovarian, fallopian tube, or peritoneal cancer. Results showed that a 10-item modified frailty index was better than patient age for predicting survival outcomes.

“Frailty does seem to correlate with age and increase with age, but it is not synonymous with age,” said investigator Katelyn F. Handley, MD, of the University of Texas MD Anderson Cancer Center in Houston.

“Frailty is a spectrum, and we can see patients of the same chronological age, but one may be a 76-year-old, ultra-distance triathlete, while another is in failing health and diminishing function,” Dr. Handley said at the Society of Gynecologic Oncology’s Virtual Annual Meeting on Women’s Cancer (Abstract 10463).

Dr. Handley cited a consensus definition of frailty, published in 2013, as “a medical syndrome with multiple causes and contributors that is characterized by diminished strength, endurance, and reduced physiologic function that increases an individual’s vulnerability for developing increased dependency and/or death.”
 

Ten-item score

To assess the effect of frailty in ovarian cancer patients on surgical procedures and outcomes, the investigators retrospectively applied a modified frailty index (mFI) to patients who were treated at MD Anderson Cancer Center from April 2013 through September 2017.

The index is a sum of 10 items: Chronic obstructive pulmonary disease or recent pneumonia, heart failure, myocardial infarction, coronary artery disease, diabetes, hypertension, peripheral vascular disease, cerebrovascular disease, cerebrovascular accident with neurologic deficit, and poor Eastern Cooperative Oncology Group performance status (3 or 4).

Of the 591 patients who met inclusion criteria, 57% had mFI scores of 0, indicating no frailty, 29% had one frailty factor, and 14% had two or more factors.

Patient age did significantly correlate with mFI scores. Patients with an mFI score of 0 had a median age of 62 years, the median age in those with a score of 1 was 69 years, and the median age for those with scores of 2 or higher was 70.5 years (P <. 001).

Charlson comorbidity index scores also significantly increased with age, with mean scores of 3.00, 3.83, and 5.14 in patients with mFI scores of 0, 1, or 2, respectively (P <. 001).

“But if you look at the age ranges in each category, you’ll notice that there are patients as young as 47 with an mFI of greater than or equal to 2, and as old as 89 with an mFI of 0,” Dr. Handley pointed out.
 

Higher scores, fewer assessments

The investigators found that patients with suspected ovarian cancer with frailty scores of 2 or higher were less likely to be offered laparoscopic assessment to determine primary resectability than were those with scores of 1 or 0 (28% vs. 43% and 49%, respectively, P = .004).

Among all patients who underwent laparoscopic assessment, the predictive index score (modified Fagotti score) was more likely to be 8 or higher in patients with high frailty scores (58%, 48%, and 34% for scores of 2 or greater, 1, and 0, respectively; P = .038).

Only 17% of the most frail patients went on to primary debulking surgery, compared with 26% of patients with a single frailty factor and 34% of those with none (P = .015).

Patients with higher frailty scores were less likely to undergo primary or interval tumor reductive surgery (59% vs. 74% for those with mFI scores of 1 and 85% for those with scores of 0; P <. 001). The frailest patients were significantly more likely to undergo splenectomy (20%, 3%, and 6%, respectively; P = .001) and small bowel resection (14%, 8%, and 3%, respectively; P = .006).

Two-thirds of the most frail patients (64%) had postoperative complications, primarily gastrointestinal and renal complications, compared with 56% and 44% of patients with mFI scores of 1 or 0, respectively (P = .014).

Frailty was predictive of 30-day postoperative mortality (P = .005) but not postoperative length of stay.

Frailer patients were more likely to receive neoadjuvant chemotherapy (P = .033) but less likely to receive adjuvant chemotherapy (P <. 001).

mFI scores of 2 or greater and 1 were both associated with significantly worse progression-free survival (P < .001 and P = .022, respectively), but only an mFI of 2 or greater was associated with significantly worse overall survival (P <. 001).

On multivariate analysis controlling for frailty, age, stage, BRCA status, and tumor reductive surgery status, high frailty was associated with worse progression-free survival (P = .009) and a trend toward worse overall survival (P = .079).

High frailty was better than age for predicting worse progression-free survival (hazard ratio, 1.50; P = .017) and overall survival (HR, 1.57; P = .047)
 

Volume counts

In a separate presentation during the same session, Morcos Nakhla, of the University of California, Los Angeles, reported finding similar associations between frailty and worse surgical outcomes for ovarian cancer patients (Abstract 11016).

Mr. Nakhla and colleagues found that frail patients had a twofold increase in the risk of postoperative complications, a threefold increase in the risk for non-home dismissal, and a threefold increased risk of death (P <. 001 for all).

The team also found, however, that mortality improved from 2005 through 2017, despite an increase in frail patients over that time period.

In addition, higher surgical volumes were associated with decreased mortality among frail patients undergoing ovarian cancer surgery.
 

Navigating treatment

“Frailty syndrome is a medical syndrome. It’s not a disability,” said Jamie N. Bakkum-Gamez, MD, of the Mayo Clinic in Rochester, Minn., the invited discussant. “No patient or human wants to be frail, but at some point, we may all be at risk for frailty syndrome, and as we navigate much-needed novel ways to treat this medical syndrome, it’s imperative that we listen to the voice of the customer and that our communication and technology doesn’t add unanticipated stress.”

Dr. Bakkum-Gamez emphasized the importance of shared decision-making, screening for frailty syndrome, referral to higher volume surgical centers when practical, and surgical alternatives such as neoadjuvant chemotherapy with or without interval debulking surgery and palliative care.

Interventions for ameliorating frailty may include exercise, high-protein calorie supplementation, reduction of polypharmacy, and vitamin D supplementation.

“Sometimes, shared decision-making means deciding not to operate,” Dr. Bakkum-Gamez said. “This is sometimes amongst the hardest decisions for a surgeon. We know when we make the wrong decision in operating if our patient experiences a major, life-shortening complication, but it’s less clear to know if we make the wrong decision to not operate.”

The study by Dr. Handley and colleagues was funded by the Gulf Coast Consortia, MD Anderson, National Institutes of Health, American Cancer Society, and GOG Foundation. Mr. Nakhla and colleagues did not disclose a funding source. Dr. Handley, Mr. Nakhla, and Dr. Bakkum-Gamez all reported no relevant conflicts of interest.

Baseball great Satchel Paige’s famous adage, “Age is a case of mind over matter. If you don’t mind, it don’t matter,” may also apply to candidates for ovarian cancer surgery. That’s because investigators have found that physical frailty is a better determinant of fitness for surgery than is calendar age.

Investigators conducted a retrospective analysis of 591 patients considered for primary resection of stage II to IV high-grade ovarian, fallopian tube, or peritoneal cancer. Results showed that a 10-item modified frailty index was better than patient age for predicting survival outcomes.

“Frailty does seem to correlate with age and increase with age, but it is not synonymous with age,” said investigator Katelyn F. Handley, MD, of the University of Texas MD Anderson Cancer Center in Houston.

“Frailty is a spectrum, and we can see patients of the same chronological age, but one may be a 76-year-old, ultra-distance triathlete, while another is in failing health and diminishing function,” Dr. Handley said at the Society of Gynecologic Oncology’s Virtual Annual Meeting on Women’s Cancer (Abstract 10463).

Dr. Handley cited a consensus definition of frailty, published in 2013, as “a medical syndrome with multiple causes and contributors that is characterized by diminished strength, endurance, and reduced physiologic function that increases an individual’s vulnerability for developing increased dependency and/or death.”
 

Ten-item score

To assess the effect of frailty in ovarian cancer patients on surgical procedures and outcomes, the investigators retrospectively applied a modified frailty index (mFI) to patients who were treated at MD Anderson Cancer Center from April 2013 through September 2017.

The index is a sum of 10 items: Chronic obstructive pulmonary disease or recent pneumonia, heart failure, myocardial infarction, coronary artery disease, diabetes, hypertension, peripheral vascular disease, cerebrovascular disease, cerebrovascular accident with neurologic deficit, and poor Eastern Cooperative Oncology Group performance status (3 or 4).

Of the 591 patients who met inclusion criteria, 57% had mFI scores of 0, indicating no frailty, 29% had one frailty factor, and 14% had two or more factors.

Patient age did significantly correlate with mFI scores. Patients with an mFI score of 0 had a median age of 62 years, the median age in those with a score of 1 was 69 years, and the median age for those with scores of 2 or higher was 70.5 years (P <. 001).

Charlson comorbidity index scores also significantly increased with age, with mean scores of 3.00, 3.83, and 5.14 in patients with mFI scores of 0, 1, or 2, respectively (P <. 001).

“But if you look at the age ranges in each category, you’ll notice that there are patients as young as 47 with an mFI of greater than or equal to 2, and as old as 89 with an mFI of 0,” Dr. Handley pointed out.
 

Higher scores, fewer assessments

The investigators found that patients with suspected ovarian cancer with frailty scores of 2 or higher were less likely to be offered laparoscopic assessment to determine primary resectability than were those with scores of 1 or 0 (28% vs. 43% and 49%, respectively, P = .004).

Among all patients who underwent laparoscopic assessment, the predictive index score (modified Fagotti score) was more likely to be 8 or higher in patients with high frailty scores (58%, 48%, and 34% for scores of 2 or greater, 1, and 0, respectively; P = .038).

Only 17% of the most frail patients went on to primary debulking surgery, compared with 26% of patients with a single frailty factor and 34% of those with none (P = .015).

Patients with higher frailty scores were less likely to undergo primary or interval tumor reductive surgery (59% vs. 74% for those with mFI scores of 1 and 85% for those with scores of 0; P <. 001). The frailest patients were significantly more likely to undergo splenectomy (20%, 3%, and 6%, respectively; P = .001) and small bowel resection (14%, 8%, and 3%, respectively; P = .006).

Two-thirds of the most frail patients (64%) had postoperative complications, primarily gastrointestinal and renal complications, compared with 56% and 44% of patients with mFI scores of 1 or 0, respectively (P = .014).

Frailty was predictive of 30-day postoperative mortality (P = .005) but not postoperative length of stay.

Frailer patients were more likely to receive neoadjuvant chemotherapy (P = .033) but less likely to receive adjuvant chemotherapy (P <. 001).

mFI scores of 2 or greater and 1 were both associated with significantly worse progression-free survival (P < .001 and P = .022, respectively), but only an mFI of 2 or greater was associated with significantly worse overall survival (P <. 001).

On multivariate analysis controlling for frailty, age, stage, BRCA status, and tumor reductive surgery status, high frailty was associated with worse progression-free survival (P = .009) and a trend toward worse overall survival (P = .079).

High frailty was better than age for predicting worse progression-free survival (hazard ratio, 1.50; P = .017) and overall survival (HR, 1.57; P = .047)
 

Volume counts

In a separate presentation during the same session, Morcos Nakhla, of the University of California, Los Angeles, reported finding similar associations between frailty and worse surgical outcomes for ovarian cancer patients (Abstract 11016).

Mr. Nakhla and colleagues found that frail patients had a twofold increase in the risk of postoperative complications, a threefold increase in the risk for non-home dismissal, and a threefold increased risk of death (P <. 001 for all).

The team also found, however, that mortality improved from 2005 through 2017, despite an increase in frail patients over that time period.

In addition, higher surgical volumes were associated with decreased mortality among frail patients undergoing ovarian cancer surgery.
 

Navigating treatment

“Frailty syndrome is a medical syndrome. It’s not a disability,” said Jamie N. Bakkum-Gamez, MD, of the Mayo Clinic in Rochester, Minn., the invited discussant. “No patient or human wants to be frail, but at some point, we may all be at risk for frailty syndrome, and as we navigate much-needed novel ways to treat this medical syndrome, it’s imperative that we listen to the voice of the customer and that our communication and technology doesn’t add unanticipated stress.”

Dr. Bakkum-Gamez emphasized the importance of shared decision-making, screening for frailty syndrome, referral to higher volume surgical centers when practical, and surgical alternatives such as neoadjuvant chemotherapy with or without interval debulking surgery and palliative care.

Interventions for ameliorating frailty may include exercise, high-protein calorie supplementation, reduction of polypharmacy, and vitamin D supplementation.

“Sometimes, shared decision-making means deciding not to operate,” Dr. Bakkum-Gamez said. “This is sometimes amongst the hardest decisions for a surgeon. We know when we make the wrong decision in operating if our patient experiences a major, life-shortening complication, but it’s less clear to know if we make the wrong decision to not operate.”

The study by Dr. Handley and colleagues was funded by the Gulf Coast Consortia, MD Anderson, National Institutes of Health, American Cancer Society, and GOG Foundation. Mr. Nakhla and colleagues did not disclose a funding source. Dr. Handley, Mr. Nakhla, and Dr. Bakkum-Gamez all reported no relevant conflicts of interest.

The COVID-19 pandemic has stressed all aspects of the world’s health care systems. The sheer volume of pandemic-related research produced over the past year has been challenging to process. This is as it should be, given its unprecedented spread and related morbidity and mortality. However, such rapid production and application leaves little time for proper vetting. Large numbers of providers adopted suggested, but largely unproven, practices that deviated from pre–COVID-19 guidelines. These “early adopters” theorized that COVID-19–related disease processes were different, necessitating a modification to existing practices.

While many unproven approaches were suggested and implemented, I’ll focus on two approaches. First, throughout the pandemic, many have argued that COVID-19 causes a novel acute respiratory distress syndrome (ARDS) phenotype. Early on, a group of prominent Italian ARDS researchers made a compelling case for physiological differences, concluding that early intubation was required to avoid large transpulmonary pressure swings. The logic was that COVID-19 causes significant gas-exchange abnormality without the typical effect on elastance. The resulting increase in respiratory drive would generate vigorous inspiratory effort, overstretch a relatively compliant lung, and lead to further injury.

Other equally prominent researchers countered this argument. Martin Tobin drew on physiology, while Arthur Slutsky and Niall Ferguson used emerging data to make their case. Tobin and colleagues cautioned against early intubation for anyone who could be maintained using noninvasive support. In August 2020 (well into the pandemic and after more data were available), Slutsky and colleagues argued that ARDS caused by COVID-19 wasn’t much different from lung injury due to other causes.

Two more recent studies published online recently are relevant to the debate over COVID-19 ARDS. One was a prospective study and the other a retrospective study; both had comparison groups, and both came to the same conclusions. Overall, COVID-19 ARDS isn’t much different from ARDS due to other causes. These studies were comprehensive in their comparisons and measures of outcomes, but they were both rather small and included patients from one and two hospitals, respectively. The discussions of both provide a nice review of the existing literature on COVID-19 ARDS.

A second controversial, but unproven, COVID-19 practice is aggressive anticoagulation. Early reports of a high prevalence of venous thromboembolism (VTE) in patients with COVID-19 pushed many to recommend empirically increasing prophylaxis. Most of the data guiding this approach were from retrospective, observational studies that suffered from selection bias. Early on, many of the studies were from China, where baseline VTE prophylaxis rates were low. Despite these limitations, many physicians acted on the basis of these data. An arbitrarily defined “intermediate” or treatment dose for prophylaxis was used, with some measuring D-dimer to guide their approach. An evidence-based argument against this practice, published in the New England Journal of Medicine, failed to sway readers. (Look at the poll at the end of the article and you’ll see how readers answered.)

Two articles recently published online in CHEST attempted to bring clarity to the debate over COVID-19 and VTE prophylaxis. The first study evaluated critically ill patients in France, and researchers found that higher doses of anticoagulation reduced thrombotic complications without an associated increase in bleeding events. The study is well done but certainly has its flaws. It is observational and retrospective, and it essentially uses a before-after comparison technique. Such an approach is particularly prone to bias during COVID-19, given that practice patterns change quickly.

The second paper is a systematic review looking at VTE and bleeding rates among patients hospitalized with COVID-19. The authors found high rates of VTE (17.0% overall), with screening, admission to the ICU, and the prospective study design all being associated with increased rates. Of importance, unlike the retrospective trial cited in the previous paragraph, the authors of the systematic review found treatment-dose anticoagulation was associated with higher bleeding rates.

I admit, the title of this piece is a bit of a misnomer. The “late adopters” would truly have their revenge if deviation from guidelines for COVID-19–related ARDS and VTE prophylaxis proves to be harmful. It’s not clear that’s the case, and at least for VTE prophylaxis, results from several randomized, controlled trials (REMAP-CAP, ATTACC, and ACTIV-4a) will be released soon. These are sure to provide more definitive answers. If nothing else, the COVID-19–related ARDS and VTE data reinforce how difficult it is to obtain high-quality data that yield clear results. Until something more definitive is published and released, I will remain a “late adopter.” Standard non–COVID-19 guidelines for ARDS and VTE prophylaxis are good enough for me.

Dr. Holley is program director of the Pulmonary and Critical Care Medical Fellowship at Walter Reed National Military Medical Center, Bethesda, Md.

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

The COVID-19 pandemic has stressed all aspects of the world’s health care systems. The sheer volume of pandemic-related research produced over the past year has been challenging to process. This is as it should be, given its unprecedented spread and related morbidity and mortality. However, such rapid production and application leaves little time for proper vetting. Large numbers of providers adopted suggested, but largely unproven, practices that deviated from pre–COVID-19 guidelines. These “early adopters” theorized that COVID-19–related disease processes were different, necessitating a modification to existing practices.

While many unproven approaches were suggested and implemented, I’ll focus on two approaches. First, throughout the pandemic, many have argued that COVID-19 causes a novel acute respiratory distress syndrome (ARDS) phenotype. Early on, a group of prominent Italian ARDS researchers made a compelling case for physiological differences, concluding that early intubation was required to avoid large transpulmonary pressure swings. The logic was that COVID-19 causes significant gas-exchange abnormality without the typical effect on elastance. The resulting increase in respiratory drive would generate vigorous inspiratory effort, overstretch a relatively compliant lung, and lead to further injury.

Other equally prominent researchers countered this argument. Martin Tobin drew on physiology, while Arthur Slutsky and Niall Ferguson used emerging data to make their case. Tobin and colleagues cautioned against early intubation for anyone who could be maintained using noninvasive support. In August 2020 (well into the pandemic and after more data were available), Slutsky and colleagues argued that ARDS caused by COVID-19 wasn’t much different from lung injury due to other causes.

Two more recent studies published online recently are relevant to the debate over COVID-19 ARDS. One was a prospective study and the other a retrospective study; both had comparison groups, and both came to the same conclusions. Overall, COVID-19 ARDS isn’t much different from ARDS due to other causes. These studies were comprehensive in their comparisons and measures of outcomes, but they were both rather small and included patients from one and two hospitals, respectively. The discussions of both provide a nice review of the existing literature on COVID-19 ARDS.

A second controversial, but unproven, COVID-19 practice is aggressive anticoagulation. Early reports of a high prevalence of venous thromboembolism (VTE) in patients with COVID-19 pushed many to recommend empirically increasing prophylaxis. Most of the data guiding this approach were from retrospective, observational studies that suffered from selection bias. Early on, many of the studies were from China, where baseline VTE prophylaxis rates were low. Despite these limitations, many physicians acted on the basis of these data. An arbitrarily defined “intermediate” or treatment dose for prophylaxis was used, with some measuring D-dimer to guide their approach. An evidence-based argument against this practice, published in the New England Journal of Medicine, failed to sway readers. (Look at the poll at the end of the article and you’ll see how readers answered.)

Two articles recently published online in CHEST attempted to bring clarity to the debate over COVID-19 and VTE prophylaxis. The first study evaluated critically ill patients in France, and researchers found that higher doses of anticoagulation reduced thrombotic complications without an associated increase in bleeding events. The study is well done but certainly has its flaws. It is observational and retrospective, and it essentially uses a before-after comparison technique. Such an approach is particularly prone to bias during COVID-19, given that practice patterns change quickly.

The second paper is a systematic review looking at VTE and bleeding rates among patients hospitalized with COVID-19. The authors found high rates of VTE (17.0% overall), with screening, admission to the ICU, and the prospective study design all being associated with increased rates. Of importance, unlike the retrospective trial cited in the previous paragraph, the authors of the systematic review found treatment-dose anticoagulation was associated with higher bleeding rates.

I admit, the title of this piece is a bit of a misnomer. The “late adopters” would truly have their revenge if deviation from guidelines for COVID-19–related ARDS and VTE prophylaxis proves to be harmful. It’s not clear that’s the case, and at least for VTE prophylaxis, results from several randomized, controlled trials (REMAP-CAP, ATTACC, and ACTIV-4a) will be released soon. These are sure to provide more definitive answers. If nothing else, the COVID-19–related ARDS and VTE data reinforce how difficult it is to obtain high-quality data that yield clear results. Until something more definitive is published and released, I will remain a “late adopter.” Standard non–COVID-19 guidelines for ARDS and VTE prophylaxis are good enough for me.

Dr. Holley is program director of the Pulmonary and Critical Care Medical Fellowship at Walter Reed National Military Medical Center, Bethesda, Md.

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

The COVID-19 pandemic has stressed all aspects of the world’s health care systems. The sheer volume of pandemic-related research produced over the past year has been challenging to process. This is as it should be, given its unprecedented spread and related morbidity and mortality. However, such rapid production and application leaves little time for proper vetting. Large numbers of providers adopted suggested, but largely unproven, practices that deviated from pre–COVID-19 guidelines. These “early adopters” theorized that COVID-19–related disease processes were different, necessitating a modification to existing practices.

While many unproven approaches were suggested and implemented, I’ll focus on two approaches. First, throughout the pandemic, many have argued that COVID-19 causes a novel acute respiratory distress syndrome (ARDS) phenotype. Early on, a group of prominent Italian ARDS researchers made a compelling case for physiological differences, concluding that early intubation was required to avoid large transpulmonary pressure swings. The logic was that COVID-19 causes significant gas-exchange abnormality without the typical effect on elastance. The resulting increase in respiratory drive would generate vigorous inspiratory effort, overstretch a relatively compliant lung, and lead to further injury.

Other equally prominent researchers countered this argument. Martin Tobin drew on physiology, while Arthur Slutsky and Niall Ferguson used emerging data to make their case. Tobin and colleagues cautioned against early intubation for anyone who could be maintained using noninvasive support. In August 2020 (well into the pandemic and after more data were available), Slutsky and colleagues argued that ARDS caused by COVID-19 wasn’t much different from lung injury due to other causes.

Two more recent studies published online recently are relevant to the debate over COVID-19 ARDS. One was a prospective study and the other a retrospective study; both had comparison groups, and both came to the same conclusions. Overall, COVID-19 ARDS isn’t much different from ARDS due to other causes. These studies were comprehensive in their comparisons and measures of outcomes, but they were both rather small and included patients from one and two hospitals, respectively. The discussions of both provide a nice review of the existing literature on COVID-19 ARDS.

A second controversial, but unproven, COVID-19 practice is aggressive anticoagulation. Early reports of a high prevalence of venous thromboembolism (VTE) in patients with COVID-19 pushed many to recommend empirically increasing prophylaxis. Most of the data guiding this approach were from retrospective, observational studies that suffered from selection bias. Early on, many of the studies were from China, where baseline VTE prophylaxis rates were low. Despite these limitations, many physicians acted on the basis of these data. An arbitrarily defined “intermediate” or treatment dose for prophylaxis was used, with some measuring D-dimer to guide their approach. An evidence-based argument against this practice, published in the New England Journal of Medicine, failed to sway readers. (Look at the poll at the end of the article and you’ll see how readers answered.)

Two articles recently published online in CHEST attempted to bring clarity to the debate over COVID-19 and VTE prophylaxis. The first study evaluated critically ill patients in France, and researchers found that higher doses of anticoagulation reduced thrombotic complications without an associated increase in bleeding events. The study is well done but certainly has its flaws. It is observational and retrospective, and it essentially uses a before-after comparison technique. Such an approach is particularly prone to bias during COVID-19, given that practice patterns change quickly.

The second paper is a systematic review looking at VTE and bleeding rates among patients hospitalized with COVID-19. The authors found high rates of VTE (17.0% overall), with screening, admission to the ICU, and the prospective study design all being associated with increased rates. Of importance, unlike the retrospective trial cited in the previous paragraph, the authors of the systematic review found treatment-dose anticoagulation was associated with higher bleeding rates.

I admit, the title of this piece is a bit of a misnomer. The “late adopters” would truly have their revenge if deviation from guidelines for COVID-19–related ARDS and VTE prophylaxis proves to be harmful. It’s not clear that’s the case, and at least for VTE prophylaxis, results from several randomized, controlled trials (REMAP-CAP, ATTACC, and ACTIV-4a) will be released soon. These are sure to provide more definitive answers. If nothing else, the COVID-19–related ARDS and VTE data reinforce how difficult it is to obtain high-quality data that yield clear results. Until something more definitive is published and released, I will remain a “late adopter.” Standard non–COVID-19 guidelines for ARDS and VTE prophylaxis are good enough for me.

Dr. Holley is program director of the Pulmonary and Critical Care Medical Fellowship at Walter Reed National Military Medical Center, Bethesda, Md.

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

Seasonal time change is now up for consideration in the U.S. Congress, prompting sleep medicine specialists to weigh in on the health impact of a major policy change.

As lawmakers in Washington propose an end to seasonal time changes by permanently establishing daylight saving time (DST), the American Academy of Sleep Medicine (AASM) is pushing for a Congressional hearing so scientists can present evidence in favor of converse legislation – to make standard time the new norm.

According to the AASM, seasonal time changes in either direction have been associated with a range of detrimental health effects; however, the switch from standard time to DST incurs more risk.

“Current evidence best supports the adoption of year-round standard time, which aligns best with human circadian biology and provides distinct benefits for public health and safety,” the AASM noted in a 2020 position statement on DST.

The statement cites a number of studies that have reported associations between the switch to DST and acute, negative health outcomes, including higher rates of hospital admission, cardiovascular morbidity, atrial fibrillation, and stroke. The time shift has been associated with a spectrum of cellular, metabolic, and circadian derangements, from increased production of inflammatory markers, to higher blood pressure, and loss of sleep. These biological effects may have far-reaching consequences, including increased rates of fatal motor accidents in the days following the time change, and even increased volatility in the stock market, which may stem from cognitive deficits.

U.S. Senator Marco Rubio (R-Fla.) and others in the U.S. Congress have reintroduced the 2019 Sunshine Protection Act, legislation that would make DST permanent across the country. According to a statement on Sen. Rubio’s website, “The bill reflects the Florida legislature’s 2018 enactment of year-round DST; however, for Florida’s change to apply, a change in the federal statute is required. Fifteen other states – Arkansas, Alabama, California, Delaware, Georgia, Idaho, Louisiana, Maine, Ohio, Oregon, South Carolina, Tennessee, Utah, Washington, and Wyoming – have passed similar laws, resolutions, or voter initiatives, and dozens more are looking. The legislation, if enacted, would apply to those states [that] currently participate in DST, which most states observe for eight months out of the year.”
 

A stitch in time

“The sudden change in clock time disrupts sleep/wake patterns, decreasing total sleep time and sleep quality, leading to decrements in daytime cognition,” said Kannan Ramar, MBBS, MD, president of the AASM and a sleep medicine specialist at Mayo Clinic, Rochester, Minn. 

Emphasizing this point, Dr. Ramar noted a recent study that reported an 18% increase in “patient safety-related incidents associated with human error” among health care workers within a week of the spring time change.

“Irregular bedtimes and wake times disrupt the timing of our circadian rhythms, which can lead to symptoms of insomnia or long-term, excessive daytime sleepiness. Lack of sleep can lead to numerous adverse effects on our minds, including decreased cognitive function, trouble concentrating, and general moodiness,” Dr. Ramar said.

He noted that these impacts may be more significant among certain individuals.

“The daylight saving time changes can be especially problematic for any populations that already experience chronic insufficient sleep or other sleep difficulties,” Dr. Ramar said. “Populations at greatest risk include teenagers, who tend to experience chronic sleep restriction during the school week, and night shift workers, who often struggle to sleep well during daytime hours.”

While fewer studies have evaluated the long-term effects of seasonal time changes, the AASM position statement cited evidence that “the body clock does not adjust to daylight saving time after several months,” possibly because “daylight saving time is less well-aligned with intrinsic human circadian physiology, and it disrupts the natural seasonal adjustment of the human clock due to the effect of late-evening light on the circadian rhythm.”

According to the AASM, permanent DST, as proposed by Sen. Rubio and colleagues, could “result in permanent phase delay, a condition that can also lead to a perpetual discrepancy between the innate biological clock and the extrinsic environmental clock, as well as chronic sleep loss due to early morning social demands that truncate the opportunity to sleep.” This mismatch between sleep/wake cycles and social demands, known as “social jet lag,” has been associated with chronic health risks, including metabolic syndrome, obesity, depression, and cardiovascular disease.
 

Cardiac impacts of seasonal time change

Muhammad Adeel Rishi, MD, a sleep specialist at Mayo Clinic, Eau Claire, Wis., and lead author of the AASM position statement, highlighted cardiovascular risks in a written statement for this article, noting increased rates of heart attack following the spring time change, and a higher risk of atrial fibrillation.

“Mayo Clinic has not taken a position on this issue,” Dr. Rishi noted. Still, he advocated for permanent standard time as the author of the AASM position statement and vice chair of the AASM public safety committee.

Jay Chudow, MD, and Andrew K. Krumerman, MD, of Montefiore Medical Center, New York, lead author and principal author, respectively, of a recent study that reported increased rates of atrial fibrillation admissions after DST transitions, had the same stance.

Pros and cons

Not all sleep experts are convinced. Mary Jo Farmer, MD, PhD, FCCP, a sleep specialist and director of pulmonary hypertension services at Baystate Medical Center, and assistant professor of medicine at the University of Massachusetts, Springfield, considers perspectives from both sides of the issue.

“Daylight saving time promotes active lifestyles as people engage in more outdoor activities after work and school, [and] daylight saving time produces economic and safety benefits to society as retail revenues are higher and crimes are lower,” Dr. Farmer said. “Alternatively, moving the clocks forward is a cost burden to the U.S. economy when health issues, decreased productivity, and workplace injuries are considered.”

If one time system is permanently established, Dr. Farmer anticipates divided opinions from patients with sleep issues, regardless of which system is chosen.

“I can tell you, I have a cohort of sleep patients who prefer more evening light and look forward to the spring time change to daylight saving time,” she said. “However, they would not want the sun coming up at 9:00 a.m. in the winter months if we stayed on daylight saving time year-round. Similarly, patients would not want the sun coming up at 4:00 a.m. on the longest day of the year if we stayed on standard time all year round.”

Dr. Farmer called for more research before a decision is made.

“I suggest we need more information about the dangers of staying on daylight saving or standard time year-round because perhaps the current strategy of keeping morning light consistent is not so bad,” she said.
 

Time for a Congressional hearing?

According to Dr. Ramar, the time is now for a Congressional hearing, as lawmakers and the public need to be adequately informed when considering new legislation.

“There are public misconceptions about daylight saving time and standard time,” Dr. Ramar said. “People often like the idea of daylight saving time because they think it provides more light, and they dislike the concept of standard time because they think it provides more darkness. The reality is that neither time system provides more light or darkness than the other; it is only the timing that changes.”

Until new legislation is introduced, Dr. Ramar offered some practical advice for navigating seasonal time shifts.

“Beginning 2-3 days before the time change, it can be helpful to gradually adjust sleep and wake times, as well as other daily routines such as meal times,” he said. “After the time change, going outside for some morning light can help adjust the timing of your internal body clock.”

The investigators reported no conflicts of interest.

Seasonal time change is now up for consideration in the U.S. Congress, prompting sleep medicine specialists to weigh in on the health impact of a major policy change.

As lawmakers in Washington propose an end to seasonal time changes by permanently establishing daylight saving time (DST), the American Academy of Sleep Medicine (AASM) is pushing for a Congressional hearing so scientists can present evidence in favor of converse legislation – to make standard time the new norm.

According to the AASM, seasonal time changes in either direction have been associated with a range of detrimental health effects; however, the switch from standard time to DST incurs more risk.

“Current evidence best supports the adoption of year-round standard time, which aligns best with human circadian biology and provides distinct benefits for public health and safety,” the AASM noted in a 2020 position statement on DST.

The statement cites a number of studies that have reported associations between the switch to DST and acute, negative health outcomes, including higher rates of hospital admission, cardiovascular morbidity, atrial fibrillation, and stroke. The time shift has been associated with a spectrum of cellular, metabolic, and circadian derangements, from increased production of inflammatory markers, to higher blood pressure, and loss of sleep. These biological effects may have far-reaching consequences, including increased rates of fatal motor accidents in the days following the time change, and even increased volatility in the stock market, which may stem from cognitive deficits.

U.S. Senator Marco Rubio (R-Fla.) and others in the U.S. Congress have reintroduced the 2019 Sunshine Protection Act, legislation that would make DST permanent across the country. According to a statement on Sen. Rubio’s website, “The bill reflects the Florida legislature’s 2018 enactment of year-round DST; however, for Florida’s change to apply, a change in the federal statute is required. Fifteen other states – Arkansas, Alabama, California, Delaware, Georgia, Idaho, Louisiana, Maine, Ohio, Oregon, South Carolina, Tennessee, Utah, Washington, and Wyoming – have passed similar laws, resolutions, or voter initiatives, and dozens more are looking. The legislation, if enacted, would apply to those states [that] currently participate in DST, which most states observe for eight months out of the year.”
 

A stitch in time

“The sudden change in clock time disrupts sleep/wake patterns, decreasing total sleep time and sleep quality, leading to decrements in daytime cognition,” said Kannan Ramar, MBBS, MD, president of the AASM and a sleep medicine specialist at Mayo Clinic, Rochester, Minn. 

Emphasizing this point, Dr. Ramar noted a recent study that reported an 18% increase in “patient safety-related incidents associated with human error” among health care workers within a week of the spring time change.

“Irregular bedtimes and wake times disrupt the timing of our circadian rhythms, which can lead to symptoms of insomnia or long-term, excessive daytime sleepiness. Lack of sleep can lead to numerous adverse effects on our minds, including decreased cognitive function, trouble concentrating, and general moodiness,” Dr. Ramar said.

He noted that these impacts may be more significant among certain individuals.

“The daylight saving time changes can be especially problematic for any populations that already experience chronic insufficient sleep or other sleep difficulties,” Dr. Ramar said. “Populations at greatest risk include teenagers, who tend to experience chronic sleep restriction during the school week, and night shift workers, who often struggle to sleep well during daytime hours.”

While fewer studies have evaluated the long-term effects of seasonal time changes, the AASM position statement cited evidence that “the body clock does not adjust to daylight saving time after several months,” possibly because “daylight saving time is less well-aligned with intrinsic human circadian physiology, and it disrupts the natural seasonal adjustment of the human clock due to the effect of late-evening light on the circadian rhythm.”

According to the AASM, permanent DST, as proposed by Sen. Rubio and colleagues, could “result in permanent phase delay, a condition that can also lead to a perpetual discrepancy between the innate biological clock and the extrinsic environmental clock, as well as chronic sleep loss due to early morning social demands that truncate the opportunity to sleep.” This mismatch between sleep/wake cycles and social demands, known as “social jet lag,” has been associated with chronic health risks, including metabolic syndrome, obesity, depression, and cardiovascular disease.
 

Cardiac impacts of seasonal time change

Muhammad Adeel Rishi, MD, a sleep specialist at Mayo Clinic, Eau Claire, Wis., and lead author of the AASM position statement, highlighted cardiovascular risks in a written statement for this article, noting increased rates of heart attack following the spring time change, and a higher risk of atrial fibrillation.

“Mayo Clinic has not taken a position on this issue,” Dr. Rishi noted. Still, he advocated for permanent standard time as the author of the AASM position statement and vice chair of the AASM public safety committee.

Jay Chudow, MD, and Andrew K. Krumerman, MD, of Montefiore Medical Center, New York, lead author and principal author, respectively, of a recent study that reported increased rates of atrial fibrillation admissions after DST transitions, had the same stance.

Pros and cons

Not all sleep experts are convinced. Mary Jo Farmer, MD, PhD, FCCP, a sleep specialist and director of pulmonary hypertension services at Baystate Medical Center, and assistant professor of medicine at the University of Massachusetts, Springfield, considers perspectives from both sides of the issue.

“Daylight saving time promotes active lifestyles as people engage in more outdoor activities after work and school, [and] daylight saving time produces economic and safety benefits to society as retail revenues are higher and crimes are lower,” Dr. Farmer said. “Alternatively, moving the clocks forward is a cost burden to the U.S. economy when health issues, decreased productivity, and workplace injuries are considered.”

If one time system is permanently established, Dr. Farmer anticipates divided opinions from patients with sleep issues, regardless of which system is chosen.

“I can tell you, I have a cohort of sleep patients who prefer more evening light and look forward to the spring time change to daylight saving time,” she said. “However, they would not want the sun coming up at 9:00 a.m. in the winter months if we stayed on daylight saving time year-round. Similarly, patients would not want the sun coming up at 4:00 a.m. on the longest day of the year if we stayed on standard time all year round.”

Dr. Farmer called for more research before a decision is made.

“I suggest we need more information about the dangers of staying on daylight saving or standard time year-round because perhaps the current strategy of keeping morning light consistent is not so bad,” she said.
 

Time for a Congressional hearing?

According to Dr. Ramar, the time is now for a Congressional hearing, as lawmakers and the public need to be adequately informed when considering new legislation.

“There are public misconceptions about daylight saving time and standard time,” Dr. Ramar said. “People often like the idea of daylight saving time because they think it provides more light, and they dislike the concept of standard time because they think it provides more darkness. The reality is that neither time system provides more light or darkness than the other; it is only the timing that changes.”

Until new legislation is introduced, Dr. Ramar offered some practical advice for navigating seasonal time shifts.

“Beginning 2-3 days before the time change, it can be helpful to gradually adjust sleep and wake times, as well as other daily routines such as meal times,” he said. “After the time change, going outside for some morning light can help adjust the timing of your internal body clock.”

The investigators reported no conflicts of interest.

Seasonal time change is now up for consideration in the U.S. Congress, prompting sleep medicine specialists to weigh in on the health impact of a major policy change.

As lawmakers in Washington propose an end to seasonal time changes by permanently establishing daylight saving time (DST), the American Academy of Sleep Medicine (AASM) is pushing for a Congressional hearing so scientists can present evidence in favor of converse legislation – to make standard time the new norm.

According to the AASM, seasonal time changes in either direction have been associated with a range of detrimental health effects; however, the switch from standard time to DST incurs more risk.

“Current evidence best supports the adoption of year-round standard time, which aligns best with human circadian biology and provides distinct benefits for public health and safety,” the AASM noted in a 2020 position statement on DST.

The statement cites a number of studies that have reported associations between the switch to DST and acute, negative health outcomes, including higher rates of hospital admission, cardiovascular morbidity, atrial fibrillation, and stroke. The time shift has been associated with a spectrum of cellular, metabolic, and circadian derangements, from increased production of inflammatory markers, to higher blood pressure, and loss of sleep. These biological effects may have far-reaching consequences, including increased rates of fatal motor accidents in the days following the time change, and even increased volatility in the stock market, which may stem from cognitive deficits.

U.S. Senator Marco Rubio (R-Fla.) and others in the U.S. Congress have reintroduced the 2019 Sunshine Protection Act, legislation that would make DST permanent across the country. According to a statement on Sen. Rubio’s website, “The bill reflects the Florida legislature’s 2018 enactment of year-round DST; however, for Florida’s change to apply, a change in the federal statute is required. Fifteen other states – Arkansas, Alabama, California, Delaware, Georgia, Idaho, Louisiana, Maine, Ohio, Oregon, South Carolina, Tennessee, Utah, Washington, and Wyoming – have passed similar laws, resolutions, or voter initiatives, and dozens more are looking. The legislation, if enacted, would apply to those states [that] currently participate in DST, which most states observe for eight months out of the year.”
 

A stitch in time

“The sudden change in clock time disrupts sleep/wake patterns, decreasing total sleep time and sleep quality, leading to decrements in daytime cognition,” said Kannan Ramar, MBBS, MD, president of the AASM and a sleep medicine specialist at Mayo Clinic, Rochester, Minn. 

Emphasizing this point, Dr. Ramar noted a recent study that reported an 18% increase in “patient safety-related incidents associated with human error” among health care workers within a week of the spring time change.

“Irregular bedtimes and wake times disrupt the timing of our circadian rhythms, which can lead to symptoms of insomnia or long-term, excessive daytime sleepiness. Lack of sleep can lead to numerous adverse effects on our minds, including decreased cognitive function, trouble concentrating, and general moodiness,” Dr. Ramar said.

He noted that these impacts may be more significant among certain individuals.

“The daylight saving time changes can be especially problematic for any populations that already experience chronic insufficient sleep or other sleep difficulties,” Dr. Ramar said. “Populations at greatest risk include teenagers, who tend to experience chronic sleep restriction during the school week, and night shift workers, who often struggle to sleep well during daytime hours.”

While fewer studies have evaluated the long-term effects of seasonal time changes, the AASM position statement cited evidence that “the body clock does not adjust to daylight saving time after several months,” possibly because “daylight saving time is less well-aligned with intrinsic human circadian physiology, and it disrupts the natural seasonal adjustment of the human clock due to the effect of late-evening light on the circadian rhythm.”

According to the AASM, permanent DST, as proposed by Sen. Rubio and colleagues, could “result in permanent phase delay, a condition that can also lead to a perpetual discrepancy between the innate biological clock and the extrinsic environmental clock, as well as chronic sleep loss due to early morning social demands that truncate the opportunity to sleep.” This mismatch between sleep/wake cycles and social demands, known as “social jet lag,” has been associated with chronic health risks, including metabolic syndrome, obesity, depression, and cardiovascular disease.
 

Cardiac impacts of seasonal time change

Muhammad Adeel Rishi, MD, a sleep specialist at Mayo Clinic, Eau Claire, Wis., and lead author of the AASM position statement, highlighted cardiovascular risks in a written statement for this article, noting increased rates of heart attack following the spring time change, and a higher risk of atrial fibrillation.

“Mayo Clinic has not taken a position on this issue,” Dr. Rishi noted. Still, he advocated for permanent standard time as the author of the AASM position statement and vice chair of the AASM public safety committee.

Jay Chudow, MD, and Andrew K. Krumerman, MD, of Montefiore Medical Center, New York, lead author and principal author, respectively, of a recent study that reported increased rates of atrial fibrillation admissions after DST transitions, had the same stance.

Pros and cons

Not all sleep experts are convinced. Mary Jo Farmer, MD, PhD, FCCP, a sleep specialist and director of pulmonary hypertension services at Baystate Medical Center, and assistant professor of medicine at the University of Massachusetts, Springfield, considers perspectives from both sides of the issue.

“Daylight saving time promotes active lifestyles as people engage in more outdoor activities after work and school, [and] daylight saving time produces economic and safety benefits to society as retail revenues are higher and crimes are lower,” Dr. Farmer said. “Alternatively, moving the clocks forward is a cost burden to the U.S. economy when health issues, decreased productivity, and workplace injuries are considered.”

If one time system is permanently established, Dr. Farmer anticipates divided opinions from patients with sleep issues, regardless of which system is chosen.

“I can tell you, I have a cohort of sleep patients who prefer more evening light and look forward to the spring time change to daylight saving time,” she said. “However, they would not want the sun coming up at 9:00 a.m. in the winter months if we stayed on daylight saving time year-round. Similarly, patients would not want the sun coming up at 4:00 a.m. on the longest day of the year if we stayed on standard time all year round.”

Dr. Farmer called for more research before a decision is made.

“I suggest we need more information about the dangers of staying on daylight saving or standard time year-round because perhaps the current strategy of keeping morning light consistent is not so bad,” she said.
 

Time for a Congressional hearing?

According to Dr. Ramar, the time is now for a Congressional hearing, as lawmakers and the public need to be adequately informed when considering new legislation.

“There are public misconceptions about daylight saving time and standard time,” Dr. Ramar said. “People often like the idea of daylight saving time because they think it provides more light, and they dislike the concept of standard time because they think it provides more darkness. The reality is that neither time system provides more light or darkness than the other; it is only the timing that changes.”

Until new legislation is introduced, Dr. Ramar offered some practical advice for navigating seasonal time shifts.

“Beginning 2-3 days before the time change, it can be helpful to gradually adjust sleep and wake times, as well as other daily routines such as meal times,” he said. “After the time change, going outside for some morning light can help adjust the timing of your internal body clock.”

The investigators reported no conflicts of interest.

Individuals who experience inflammation of the thyroid gland during acute COVID-19 illness may still have subacute thyroiditis months later, even if thyroid function has normalized, new research suggests.

Furthermore, the thyroiditis seems to be different from thyroid inflammation caused by other viruses, said Ilaria Muller, MD, PhD, when presenting her findings March 21 at the virtual ENDO 2021 meeting.

“SARS-CoV-2 seems to have multifactorial action on thyroid function,” said Dr. Muller, of the University of Milan, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Italy.

In July 2020, Dr. Muller and colleagues described patients hospitalized at their institution with severe COVID-19, 15% of whom had thyrotoxicosis due to atypical subacute thyroiditis, compared with just 1% of a comparison group hospitalized in the same subintensive care units during the spring of 2019, as reported by this news organization.

The “atypical” thyroiditis that occurred in the patients with COVID-19 was not associated with neck pain and affected more men than women. Moreover, it was associated with low TSH and free-triiodothyronine (T3) levels, and normal or elevated levels of free-thyroxine (T4), which is a very different presentation to classic nonthyroidal illness syndrome (NTIS) usually seen in critically ill patients, she explained.

Although transient T4 elevations can occur in acute illness, that phenomenon is not associated with low TSH. This newly described scenario appears to be a combination of thyrotoxicosis and NTIS, Dr. Muller and colleagues had speculated last summer.
 

Follow patients with COVID-19 and thyroid dysfunction for a year

Now, in an assessment of 51 patients 3 months after hospitalization for moderate-to-severe COVID-19 reported by Dr. Muller at ENDO 2021, both inflammatory markers and thyroid function had normalized, yet on imaging, a third of patients still exhibited focal hypoechoic areas suggestive of thyroiditis.

Of those, two-thirds had reduced uptake on thyroid scintigraphy, but few had antithyroid autoantibodies.

“The thyroid dysfunction induced by COVID-19 seems not mediated by autoimmunity. It is important to continue to follow these patients since they might develop thyroid dysfunction during the following months,” Dr. Muller emphasized.

Asked to comment, session moderator Robert W. Lash, MD, the Endocrine Society’s chief professional & clinical affairs officer, told this news organization: “When you’re ICU-level sick, it’s not unusual to have weird thyroid tests. Some viruses cause thyroid problems as well ... What makes this different is that while a lot of thyroid inflammation is caused by antibodies, this was not.”

“It looks like this was [SARS-CoV-2] causing damage to the thyroid gland, which is interesting,” he noted, adding that the thyroid gland expresses high levels of angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2), which allow SARS-CoV-2 to infect human cells.

“This is probably part of that same story,” Dr. Lash said.  

For patients who had thyroid abnormalities during acute COVID-19 illness or develop symptoms that might be thyroid-related afterward, he advises: “You should keep an eye on thyroid tests. It just raises your awareness ... You might check their thyroid tests every 6 months for a year.”
 

Signs of focal thyroiditis despite normalized thyroid function

The 51 patients (33 men and 18 women) hospitalized with moderate-to-severe COVID-19 had no history of thyroid disease and had not been taking thyroid medications, amiodarone, or steroids before baseline TSH was measured.

From baseline to 3 months, TSH rose from 1.2 to 1.6 mIU/L, while serum concentrations of T4, T3, C-reactive protein, and full blood counts had all normalized (all P < 0.01 vs. baseline).

Thyroid ultrasound at 3 months in 49 patients showed signs of focal thyroiditis in 16 (33%).

Among 14 patients of those who further underwent thyroid 99mTc or I123 uptake scans, four (29%) were normal, eight (57%) had focally reduced uptake, and two (14%) had diffusely reduced uptake.

Of the 16 patients with focal thyroiditis, only three were positive for autoantibodies to thyroglobulin (TgAb) or thyroid peroxidase (TPOAb). All were negative for autoantibodies to the TSH receptor.

“Importantly, of the two with diffusely reduced uptake, only one was positive for TPOAb or TgAb,” Dr. Muller noted, adding, “SARS-CoV-2 disease seems to trigger some dysfunction which very likely has complex and multifactorial mechanisms.”

In response to a question about a possible role for biopsies and thyroid cytology, Dr. Muller replied: “That’s definitely the key ... So far we’re just making guesses, so the key will be cytological or histological studies to see what is really going on in the thyroid.”

“What we know is that [unlike] classical thyroiditis that has been described after viral diseases including SARS-CoV-2, these patients have a different scenario ... Probably something is going on within the thyroid with a different mechanism, so surely cytology and histology studies are what we need,” she concluded.

The study was funded by Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, and by a COVID-19 research grant from the European Society of Endocrinology. Dr. Muller and Dr. Lash have reported no relevant financial relationships.

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

Individuals who experience inflammation of the thyroid gland during acute COVID-19 illness may still have subacute thyroiditis months later, even if thyroid function has normalized, new research suggests.

Furthermore, the thyroiditis seems to be different from thyroid inflammation caused by other viruses, said Ilaria Muller, MD, PhD, when presenting her findings March 21 at the virtual ENDO 2021 meeting.

“SARS-CoV-2 seems to have multifactorial action on thyroid function,” said Dr. Muller, of the University of Milan, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Italy.

In July 2020, Dr. Muller and colleagues described patients hospitalized at their institution with severe COVID-19, 15% of whom had thyrotoxicosis due to atypical subacute thyroiditis, compared with just 1% of a comparison group hospitalized in the same subintensive care units during the spring of 2019, as reported by this news organization.

The “atypical” thyroiditis that occurred in the patients with COVID-19 was not associated with neck pain and affected more men than women. Moreover, it was associated with low TSH and free-triiodothyronine (T3) levels, and normal or elevated levels of free-thyroxine (T4), which is a very different presentation to classic nonthyroidal illness syndrome (NTIS) usually seen in critically ill patients, she explained.

Although transient T4 elevations can occur in acute illness, that phenomenon is not associated with low TSH. This newly described scenario appears to be a combination of thyrotoxicosis and NTIS, Dr. Muller and colleagues had speculated last summer.
 

Follow patients with COVID-19 and thyroid dysfunction for a year

Now, in an assessment of 51 patients 3 months after hospitalization for moderate-to-severe COVID-19 reported by Dr. Muller at ENDO 2021, both inflammatory markers and thyroid function had normalized, yet on imaging, a third of patients still exhibited focal hypoechoic areas suggestive of thyroiditis.

Of those, two-thirds had reduced uptake on thyroid scintigraphy, but few had antithyroid autoantibodies.

“The thyroid dysfunction induced by COVID-19 seems not mediated by autoimmunity. It is important to continue to follow these patients since they might develop thyroid dysfunction during the following months,” Dr. Muller emphasized.

Asked to comment, session moderator Robert W. Lash, MD, the Endocrine Society’s chief professional & clinical affairs officer, told this news organization: “When you’re ICU-level sick, it’s not unusual to have weird thyroid tests. Some viruses cause thyroid problems as well ... What makes this different is that while a lot of thyroid inflammation is caused by antibodies, this was not.”

“It looks like this was [SARS-CoV-2] causing damage to the thyroid gland, which is interesting,” he noted, adding that the thyroid gland expresses high levels of angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2), which allow SARS-CoV-2 to infect human cells.

“This is probably part of that same story,” Dr. Lash said.  

For patients who had thyroid abnormalities during acute COVID-19 illness or develop symptoms that might be thyroid-related afterward, he advises: “You should keep an eye on thyroid tests. It just raises your awareness ... You might check their thyroid tests every 6 months for a year.”
 

Signs of focal thyroiditis despite normalized thyroid function

The 51 patients (33 men and 18 women) hospitalized with moderate-to-severe COVID-19 had no history of thyroid disease and had not been taking thyroid medications, amiodarone, or steroids before baseline TSH was measured.

From baseline to 3 months, TSH rose from 1.2 to 1.6 mIU/L, while serum concentrations of T4, T3, C-reactive protein, and full blood counts had all normalized (all P < 0.01 vs. baseline).

Thyroid ultrasound at 3 months in 49 patients showed signs of focal thyroiditis in 16 (33%).

Among 14 patients of those who further underwent thyroid 99mTc or I123 uptake scans, four (29%) were normal, eight (57%) had focally reduced uptake, and two (14%) had diffusely reduced uptake.

Of the 16 patients with focal thyroiditis, only three were positive for autoantibodies to thyroglobulin (TgAb) or thyroid peroxidase (TPOAb). All were negative for autoantibodies to the TSH receptor.

“Importantly, of the two with diffusely reduced uptake, only one was positive for TPOAb or TgAb,” Dr. Muller noted, adding, “SARS-CoV-2 disease seems to trigger some dysfunction which very likely has complex and multifactorial mechanisms.”

In response to a question about a possible role for biopsies and thyroid cytology, Dr. Muller replied: “That’s definitely the key ... So far we’re just making guesses, so the key will be cytological or histological studies to see what is really going on in the thyroid.”

“What we know is that [unlike] classical thyroiditis that has been described after viral diseases including SARS-CoV-2, these patients have a different scenario ... Probably something is going on within the thyroid with a different mechanism, so surely cytology and histology studies are what we need,” she concluded.

The study was funded by Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, and by a COVID-19 research grant from the European Society of Endocrinology. Dr. Muller and Dr. Lash have reported no relevant financial relationships.

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

Individuals who experience inflammation of the thyroid gland during acute COVID-19 illness may still have subacute thyroiditis months later, even if thyroid function has normalized, new research suggests.

Furthermore, the thyroiditis seems to be different from thyroid inflammation caused by other viruses, said Ilaria Muller, MD, PhD, when presenting her findings March 21 at the virtual ENDO 2021 meeting.

“SARS-CoV-2 seems to have multifactorial action on thyroid function,” said Dr. Muller, of the University of Milan, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Italy.

In July 2020, Dr. Muller and colleagues described patients hospitalized at their institution with severe COVID-19, 15% of whom had thyrotoxicosis due to atypical subacute thyroiditis, compared with just 1% of a comparison group hospitalized in the same subintensive care units during the spring of 2019, as reported by this news organization.

The “atypical” thyroiditis that occurred in the patients with COVID-19 was not associated with neck pain and affected more men than women. Moreover, it was associated with low TSH and free-triiodothyronine (T3) levels, and normal or elevated levels of free-thyroxine (T4), which is a very different presentation to classic nonthyroidal illness syndrome (NTIS) usually seen in critically ill patients, she explained.

Although transient T4 elevations can occur in acute illness, that phenomenon is not associated with low TSH. This newly described scenario appears to be a combination of thyrotoxicosis and NTIS, Dr. Muller and colleagues had speculated last summer.
 

Follow patients with COVID-19 and thyroid dysfunction for a year

Now, in an assessment of 51 patients 3 months after hospitalization for moderate-to-severe COVID-19 reported by Dr. Muller at ENDO 2021, both inflammatory markers and thyroid function had normalized, yet on imaging, a third of patients still exhibited focal hypoechoic areas suggestive of thyroiditis.

Of those, two-thirds had reduced uptake on thyroid scintigraphy, but few had antithyroid autoantibodies.

“The thyroid dysfunction induced by COVID-19 seems not mediated by autoimmunity. It is important to continue to follow these patients since they might develop thyroid dysfunction during the following months,” Dr. Muller emphasized.

Asked to comment, session moderator Robert W. Lash, MD, the Endocrine Society’s chief professional & clinical affairs officer, told this news organization: “When you’re ICU-level sick, it’s not unusual to have weird thyroid tests. Some viruses cause thyroid problems as well ... What makes this different is that while a lot of thyroid inflammation is caused by antibodies, this was not.”

“It looks like this was [SARS-CoV-2] causing damage to the thyroid gland, which is interesting,” he noted, adding that the thyroid gland expresses high levels of angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2), which allow SARS-CoV-2 to infect human cells.

“This is probably part of that same story,” Dr. Lash said.  

For patients who had thyroid abnormalities during acute COVID-19 illness or develop symptoms that might be thyroid-related afterward, he advises: “You should keep an eye on thyroid tests. It just raises your awareness ... You might check their thyroid tests every 6 months for a year.”
 

Signs of focal thyroiditis despite normalized thyroid function

The 51 patients (33 men and 18 women) hospitalized with moderate-to-severe COVID-19 had no history of thyroid disease and had not been taking thyroid medications, amiodarone, or steroids before baseline TSH was measured.

From baseline to 3 months, TSH rose from 1.2 to 1.6 mIU/L, while serum concentrations of T4, T3, C-reactive protein, and full blood counts had all normalized (all P < 0.01 vs. baseline).

Thyroid ultrasound at 3 months in 49 patients showed signs of focal thyroiditis in 16 (33%).

Among 14 patients of those who further underwent thyroid 99mTc or I123 uptake scans, four (29%) were normal, eight (57%) had focally reduced uptake, and two (14%) had diffusely reduced uptake.

Of the 16 patients with focal thyroiditis, only three were positive for autoantibodies to thyroglobulin (TgAb) or thyroid peroxidase (TPOAb). All were negative for autoantibodies to the TSH receptor.

“Importantly, of the two with diffusely reduced uptake, only one was positive for TPOAb or TgAb,” Dr. Muller noted, adding, “SARS-CoV-2 disease seems to trigger some dysfunction which very likely has complex and multifactorial mechanisms.”

In response to a question about a possible role for biopsies and thyroid cytology, Dr. Muller replied: “That’s definitely the key ... So far we’re just making guesses, so the key will be cytological or histological studies to see what is really going on in the thyroid.”

“What we know is that [unlike] classical thyroiditis that has been described after viral diseases including SARS-CoV-2, these patients have a different scenario ... Probably something is going on within the thyroid with a different mechanism, so surely cytology and histology studies are what we need,” she concluded.

The study was funded by Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, and by a COVID-19 research grant from the European Society of Endocrinology. Dr. Muller and Dr. Lash have reported no relevant financial relationships.

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

More sleep at night, fewer or no sleep problems, and low levels of professional burnout were associated with a lower risk of developing COVID-19 among health care workers considered to be at high risk for exposure to patients with COVID-19, new evidence reveals.

PRImageFactory/iStock/Getty Images

For each additional hour of sleep at night, for example, risk for COVID-19 dropped by 12% in a study of 2844 frontline health care workers.

Furthermore, those who reported experiencing work-related burnout every day were 2.6 times more likely to report having COVID-19, to report having COVID-19 for a longer time, and to experience COVID-19 of more severity.

“This study underscores the importance of non–hygiene-related risk factors for COVID-19 and supports a holistic approach to health – including optimal sleep and job stress reduction to protect our health care workers from this and future pandemics,” senior author Sara B. Seidelmann, MD, said in an interview.

“Our findings add to the literature that sleep duration at night, sleep problems, and burnout may be risk factors for viral illnesses like COVID-19,” wrote Dr. Seidelmann and colleagues.

This is the first study to link COVID-19 risk to sleep habits – including number of hours of sleep at night, daytime napping hours, and severe sleep problems – among health care workers across multiple countries.

The study was published online March 22 in BMJ Nutrition, Prevention, and Health.

The researchers surveyed health care professionals in specialties considered to place personnel at high risk for exposure to SARS-CoV-2: critical care, emergency care, and internal medicine.

The association between sleep and burnout risk factors and COVID-19 did not vary significantly by specialty. “We didn’t detect any significant interactions between age, sex, specialty, or country,” said Dr. Seidelmann, assistant professor of clinical medicine at Columbia University College of Physicians and Surgeons, New York, and an internist at Stamford (Conn.) Hospital.

In addition to the 12% lower risk associated with each additional hour of sleep at night, each 1 additional hour of daytime napping was linked with a 6% increased risk for COVID-19 in an adjusted analysis (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.01-1.12).

Daytime napping slightly increased risk for COVID-19 in five of the six countries included in the study: France, Germany, Italy, the United Kingdom, and the United States. In contrast, in Spain, napping had a nonsignificant protective effect.

The survey asked health care workers to recall nighttime sleep duration, sleep disorders, and burnout in the year prior to onset of the COVID-19 pandemic.
 

‘Significant, close contact’ with COVID-19?

Lead author Hyunju Kim, NP, Dr. Seidelmann, and colleagues conducted the population-based, case-control study from July 17 to Sept. 25, 2020. They identified health care workers from the SurveyHealthcareGlobus (SHG) network.

Of the respondents, 72% were men. The mean age of the participants was 48 years, and the study population was 77% White, 12% Asian, 6% mixed background, 2% Black, and 1% other. (The remainder preferred not to say).

The 568 health care workers considered to have COVID-19 were classified on the basis of self-reported symptoms. Control participants had no symptoms associated with COVID-19.

All 2,844 participants answered yes to a question about having “significant close contact” with COVID-19 patients in their workplace.

Compared to reporting no sleep problems, having three such problems – difficulty sleeping at night, poor sleep continuity, and frequent use of sleeping pills – was associated with 88% greater odds of COVID-19 (OR, 1.88; 95% CI, 1.17–3.01).

Having one sleep problem was not associated with COVID-19.
 

More burnout, greater risk

The health care workers reported the severity of any work-related burnout. “There was a significant dose-response relationship between frequency of burnout and COVID-19,” the researchers noted.

Those who reported having burnout rarely or weekly had a 1.3-1.4 greater chance of reporting COVID-19 compared to those who reported having no burnout, for example.

In addition, reporting a high level of burnout was linked to about three times the risk for having COVID-19 of longer duration and of greater severity.

What drives the association between sleep problems, burnout, and higher risk for COVID-19 and severe COVID-19 remains unknown.

“The mechanism underlying these associations isn’t clear, but suboptimal sleep, sleep disorders, and stress may result in immune system dysregulation, increased inflammation, and alterations in hormones such as cortisol and melatonin that may increase vulnerability to viral infections,” Dr. Seidelmann said.
 

Strengths and limitations

Using a large network of health care workers in the early phase of the pandemic is a strength of the study. How generalizable the findings are outside the SHG database of 1.5 million health care workers remains unknown.

Another limitation was reliance on self-reporting of COVID-19 patient exposure, outcomes, and covariates, which could have introduced bias.

“However,” the researchers noted, “health care workers are likely a reliable source of information.”
 

Insomnia a common challenge

A 2020 meta-analysis examined the effect of insomnia and psychological factors on COVID-19 risk among health care workers. Lead author Kavita Batra, PhD, of the University of Nevada, Las Vegas (UNLV), and colleagues found that the pooled prevalence of insomnia was almost 28%.

“The recent six-country study by Kim and colleagues also underscores this relationship between lack of sleep and having higher odds of COVID-19 infection,” Manoj Sharma, MBBS, PhD, professor of social and behavioral health in the UNLV department of environmental and occupational health, and one of the study authors, said in an interview.

More research is warranted to learn the direction of the association, he said. Does reduced sleep lower immunity and make a health care worker more susceptible to SARS-CoV-2 infection, or does the anxiety associated with COVID-19 contribute to insomnia?

“Practicing sleep hygiene is a must not only for health workers but also for everyone,” Dr. Sharma added. Recommendations include having fixed hours of going to bed, fixed hours of waking up, not overdoing naps, having at least 30 minutes of winding down before sleeping, having a dark bedroom devoid of all electronics and other disturbances, avoiding smoking, alcohol, and stimulants (such as caffeine) before sleeping, and practicing relaxation right before sleeping, he said.

“It is hard for some health care workers, especially those who work night shifts, but it must be a priority to follow as many sleep hygiene measures as possible,” Dr. Sharma said. “After all, if you do not take care of yourself how can you take care of others?”

Dr. Seidelmann, Dr. Batra, and Dr. Sharma have disclosed no relevant financial relationships.

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

More sleep at night, fewer or no sleep problems, and low levels of professional burnout were associated with a lower risk of developing COVID-19 among health care workers considered to be at high risk for exposure to patients with COVID-19, new evidence reveals.

PRImageFactory/iStock/Getty Images

For each additional hour of sleep at night, for example, risk for COVID-19 dropped by 12% in a study of 2844 frontline health care workers.

Furthermore, those who reported experiencing work-related burnout every day were 2.6 times more likely to report having COVID-19, to report having COVID-19 for a longer time, and to experience COVID-19 of more severity.

“This study underscores the importance of non–hygiene-related risk factors for COVID-19 and supports a holistic approach to health – including optimal sleep and job stress reduction to protect our health care workers from this and future pandemics,” senior author Sara B. Seidelmann, MD, said in an interview.

“Our findings add to the literature that sleep duration at night, sleep problems, and burnout may be risk factors for viral illnesses like COVID-19,” wrote Dr. Seidelmann and colleagues.

This is the first study to link COVID-19 risk to sleep habits – including number of hours of sleep at night, daytime napping hours, and severe sleep problems – among health care workers across multiple countries.

The study was published online March 22 in BMJ Nutrition, Prevention, and Health.

The researchers surveyed health care professionals in specialties considered to place personnel at high risk for exposure to SARS-CoV-2: critical care, emergency care, and internal medicine.

The association between sleep and burnout risk factors and COVID-19 did not vary significantly by specialty. “We didn’t detect any significant interactions between age, sex, specialty, or country,” said Dr. Seidelmann, assistant professor of clinical medicine at Columbia University College of Physicians and Surgeons, New York, and an internist at Stamford (Conn.) Hospital.

In addition to the 12% lower risk associated with each additional hour of sleep at night, each 1 additional hour of daytime napping was linked with a 6% increased risk for COVID-19 in an adjusted analysis (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.01-1.12).

Daytime napping slightly increased risk for COVID-19 in five of the six countries included in the study: France, Germany, Italy, the United Kingdom, and the United States. In contrast, in Spain, napping had a nonsignificant protective effect.

The survey asked health care workers to recall nighttime sleep duration, sleep disorders, and burnout in the year prior to onset of the COVID-19 pandemic.
 

‘Significant, close contact’ with COVID-19?

Lead author Hyunju Kim, NP, Dr. Seidelmann, and colleagues conducted the population-based, case-control study from July 17 to Sept. 25, 2020. They identified health care workers from the SurveyHealthcareGlobus (SHG) network.

Of the respondents, 72% were men. The mean age of the participants was 48 years, and the study population was 77% White, 12% Asian, 6% mixed background, 2% Black, and 1% other. (The remainder preferred not to say).

The 568 health care workers considered to have COVID-19 were classified on the basis of self-reported symptoms. Control participants had no symptoms associated with COVID-19.

All 2,844 participants answered yes to a question about having “significant close contact” with COVID-19 patients in their workplace.

Compared to reporting no sleep problems, having three such problems – difficulty sleeping at night, poor sleep continuity, and frequent use of sleeping pills – was associated with 88% greater odds of COVID-19 (OR, 1.88; 95% CI, 1.17–3.01).

Having one sleep problem was not associated with COVID-19.
 

More burnout, greater risk

The health care workers reported the severity of any work-related burnout. “There was a significant dose-response relationship between frequency of burnout and COVID-19,” the researchers noted.

Those who reported having burnout rarely or weekly had a 1.3-1.4 greater chance of reporting COVID-19 compared to those who reported having no burnout, for example.

In addition, reporting a high level of burnout was linked to about three times the risk for having COVID-19 of longer duration and of greater severity.

What drives the association between sleep problems, burnout, and higher risk for COVID-19 and severe COVID-19 remains unknown.

“The mechanism underlying these associations isn’t clear, but suboptimal sleep, sleep disorders, and stress may result in immune system dysregulation, increased inflammation, and alterations in hormones such as cortisol and melatonin that may increase vulnerability to viral infections,” Dr. Seidelmann said.
 

Strengths and limitations

Using a large network of health care workers in the early phase of the pandemic is a strength of the study. How generalizable the findings are outside the SHG database of 1.5 million health care workers remains unknown.

Another limitation was reliance on self-reporting of COVID-19 patient exposure, outcomes, and covariates, which could have introduced bias.

“However,” the researchers noted, “health care workers are likely a reliable source of information.”
 

Insomnia a common challenge

A 2020 meta-analysis examined the effect of insomnia and psychological factors on COVID-19 risk among health care workers. Lead author Kavita Batra, PhD, of the University of Nevada, Las Vegas (UNLV), and colleagues found that the pooled prevalence of insomnia was almost 28%.

“The recent six-country study by Kim and colleagues also underscores this relationship between lack of sleep and having higher odds of COVID-19 infection,” Manoj Sharma, MBBS, PhD, professor of social and behavioral health in the UNLV department of environmental and occupational health, and one of the study authors, said in an interview.

More research is warranted to learn the direction of the association, he said. Does reduced sleep lower immunity and make a health care worker more susceptible to SARS-CoV-2 infection, or does the anxiety associated with COVID-19 contribute to insomnia?

“Practicing sleep hygiene is a must not only for health workers but also for everyone,” Dr. Sharma added. Recommendations include having fixed hours of going to bed, fixed hours of waking up, not overdoing naps, having at least 30 minutes of winding down before sleeping, having a dark bedroom devoid of all electronics and other disturbances, avoiding smoking, alcohol, and stimulants (such as caffeine) before sleeping, and practicing relaxation right before sleeping, he said.

“It is hard for some health care workers, especially those who work night shifts, but it must be a priority to follow as many sleep hygiene measures as possible,” Dr. Sharma said. “After all, if you do not take care of yourself how can you take care of others?”

Dr. Seidelmann, Dr. Batra, and Dr. Sharma have disclosed no relevant financial relationships.

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

More sleep at night, fewer or no sleep problems, and low levels of professional burnout were associated with a lower risk of developing COVID-19 among health care workers considered to be at high risk for exposure to patients with COVID-19, new evidence reveals.

PRImageFactory/iStock/Getty Images

For each additional hour of sleep at night, for example, risk for COVID-19 dropped by 12% in a study of 2844 frontline health care workers.

Furthermore, those who reported experiencing work-related burnout every day were 2.6 times more likely to report having COVID-19, to report having COVID-19 for a longer time, and to experience COVID-19 of more severity.

“This study underscores the importance of non–hygiene-related risk factors for COVID-19 and supports a holistic approach to health – including optimal sleep and job stress reduction to protect our health care workers from this and future pandemics,” senior author Sara B. Seidelmann, MD, said in an interview.

“Our findings add to the literature that sleep duration at night, sleep problems, and burnout may be risk factors for viral illnesses like COVID-19,” wrote Dr. Seidelmann and colleagues.

This is the first study to link COVID-19 risk to sleep habits – including number of hours of sleep at night, daytime napping hours, and severe sleep problems – among health care workers across multiple countries.

The study was published online March 22 in BMJ Nutrition, Prevention, and Health.

The researchers surveyed health care professionals in specialties considered to place personnel at high risk for exposure to SARS-CoV-2: critical care, emergency care, and internal medicine.

The association between sleep and burnout risk factors and COVID-19 did not vary significantly by specialty. “We didn’t detect any significant interactions between age, sex, specialty, or country,” said Dr. Seidelmann, assistant professor of clinical medicine at Columbia University College of Physicians and Surgeons, New York, and an internist at Stamford (Conn.) Hospital.

In addition to the 12% lower risk associated with each additional hour of sleep at night, each 1 additional hour of daytime napping was linked with a 6% increased risk for COVID-19 in an adjusted analysis (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.01-1.12).

Daytime napping slightly increased risk for COVID-19 in five of the six countries included in the study: France, Germany, Italy, the United Kingdom, and the United States. In contrast, in Spain, napping had a nonsignificant protective effect.

The survey asked health care workers to recall nighttime sleep duration, sleep disorders, and burnout in the year prior to onset of the COVID-19 pandemic.
 

‘Significant, close contact’ with COVID-19?

Lead author Hyunju Kim, NP, Dr. Seidelmann, and colleagues conducted the population-based, case-control study from July 17 to Sept. 25, 2020. They identified health care workers from the SurveyHealthcareGlobus (SHG) network.

Of the respondents, 72% were men. The mean age of the participants was 48 years, and the study population was 77% White, 12% Asian, 6% mixed background, 2% Black, and 1% other. (The remainder preferred not to say).

The 568 health care workers considered to have COVID-19 were classified on the basis of self-reported symptoms. Control participants had no symptoms associated with COVID-19.

All 2,844 participants answered yes to a question about having “significant close contact” with COVID-19 patients in their workplace.

Compared to reporting no sleep problems, having three such problems – difficulty sleeping at night, poor sleep continuity, and frequent use of sleeping pills – was associated with 88% greater odds of COVID-19 (OR, 1.88; 95% CI, 1.17–3.01).

Having one sleep problem was not associated with COVID-19.
 

More burnout, greater risk

The health care workers reported the severity of any work-related burnout. “There was a significant dose-response relationship between frequency of burnout and COVID-19,” the researchers noted.

Those who reported having burnout rarely or weekly had a 1.3-1.4 greater chance of reporting COVID-19 compared to those who reported having no burnout, for example.

In addition, reporting a high level of burnout was linked to about three times the risk for having COVID-19 of longer duration and of greater severity.

What drives the association between sleep problems, burnout, and higher risk for COVID-19 and severe COVID-19 remains unknown.

“The mechanism underlying these associations isn’t clear, but suboptimal sleep, sleep disorders, and stress may result in immune system dysregulation, increased inflammation, and alterations in hormones such as cortisol and melatonin that may increase vulnerability to viral infections,” Dr. Seidelmann said.
 

Strengths and limitations

Using a large network of health care workers in the early phase of the pandemic is a strength of the study. How generalizable the findings are outside the SHG database of 1.5 million health care workers remains unknown.

Another limitation was reliance on self-reporting of COVID-19 patient exposure, outcomes, and covariates, which could have introduced bias.

“However,” the researchers noted, “health care workers are likely a reliable source of information.”
 

Insomnia a common challenge

A 2020 meta-analysis examined the effect of insomnia and psychological factors on COVID-19 risk among health care workers. Lead author Kavita Batra, PhD, of the University of Nevada, Las Vegas (UNLV), and colleagues found that the pooled prevalence of insomnia was almost 28%.

“The recent six-country study by Kim and colleagues also underscores this relationship between lack of sleep and having higher odds of COVID-19 infection,” Manoj Sharma, MBBS, PhD, professor of social and behavioral health in the UNLV department of environmental and occupational health, and one of the study authors, said in an interview.

More research is warranted to learn the direction of the association, he said. Does reduced sleep lower immunity and make a health care worker more susceptible to SARS-CoV-2 infection, or does the anxiety associated with COVID-19 contribute to insomnia?

“Practicing sleep hygiene is a must not only for health workers but also for everyone,” Dr. Sharma added. Recommendations include having fixed hours of going to bed, fixed hours of waking up, not overdoing naps, having at least 30 minutes of winding down before sleeping, having a dark bedroom devoid of all electronics and other disturbances, avoiding smoking, alcohol, and stimulants (such as caffeine) before sleeping, and practicing relaxation right before sleeping, he said.

“It is hard for some health care workers, especially those who work night shifts, but it must be a priority to follow as many sleep hygiene measures as possible,” Dr. Sharma said. “After all, if you do not take care of yourself how can you take care of others?”

Dr. Seidelmann, Dr. Batra, and Dr. Sharma have disclosed no relevant financial relationships.

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