Neurology Reviews

Among patients with migraine who use prescription medications, the increasing use of prescription opioids is associated with chronic migraine, more severe disability, and anxiety and depression, according to an analysis published in the January issue of Headache . The use of prescription opioids also is associated with treatment-related variables such as poor acute treatment optimization and treatment in a pain clinic. The results indicate the continued need to educate patients and clinicians about the potential risks of opioids for migraineurs, according to the researchers.

A review of MAST data

Dr. Lipton and colleagues set out to identify the variables associated with the frequency of opioid use in people with migraine. Among the variables that they sought to examine were demographic characteristics, comorbidities, headache characteristics, medication use, and patterns of health care use. Dr. Lipton’s group hypothesized that migraine-related severity and burden would increase with increasing frequency of opioid use.

To conduct their research, the investigators examined data from the MAST study, a nationwide sample of American adults with migraine. They focused specifically on participants who reported receiving prescription acute medications. Participants eligible for this analysis reported 3 or more headache days in the previous 3 months and at least 1 monthly headache day in the previous month. In all, 15,133 participants met these criteria.

Dr. Lipton and colleagues categorized participants into four groups based on their frequency of opioid use. The groups had no opioid use, 3 or fewer monthly days of opioid use, 4 to 9 monthly days of opioid use, and 10 or more days of monthly opioid use. The last category is consistent with the International Classification of Headache Disorders-3 criteria for overuse of opioids in migraine.

At baseline, MAST participants provided information about variables such as gender, age, marital status, smoking status, education, and income. Participants also reported how many times in the previous 6 months they had visited a primary care doctor, a neurologist, a headache specialist, or a pain specialist. Dr. Lipton’s group calculated monthly headache days using the number of days during the previous 3 months affected by headache. The Migraine Disability Assessment (MIDAS) questionnaire was used to measure headache-related disability. The four-item Patient Health Questionnaire (PHQ-4) was used to screen for anxiety and depression, and the Migraine Treatment Optimization Questionnaire (mTOQ-4) evaluated participants’ treatment optimization.
 

Men predominated among opioid users

The investigators included 4,701 MAST participants in their analysis. The population’s mean age was 45 years, and 71.6% of participants were women. Of the entire sample, 67.5% reported no opioid use, and 32.5% reported opioid use. Of the total study population, 18.7% of patients took opioids 3 or fewer days per month, 6.5% took opioids 4 to 9 days per month, and 7.3% took opioids on 10 or more days per month.

Opioid users did not differ from nonusers on race or marital status. Men were overrepresented among all groups of opioid users, however. In addition, opioid use was more prevalent among participants with fewer than 4 years of college education (34.9%) than among participants with 4 or more years of college (30.8%). The proportion of participants with fewer than 4 years of college increased with increasing monthly opioid use. Furthermore, opioid use increased with decreasing household income. As opioid use increased, rates of employment decreased. Approximately 33% of the entire sample were obese, and the proportion of obese participants increased with increasing days per month of opioid use.

The most frequent setting during the previous 6 months for participants seeking care was primary care (49.7%). The next most frequent setting was neurology units (20.9%), pain clinics (8.3%), and headache clinics (7.7%). The prevalence of opioid use was 37.5% among participants with primary care visits, 37.3% among participants with neurologist visits, 43.0% among participants with headache clinic visits, and 53.5% with pain clinic visits.

About 15% of the population had chronic migraine. The prevalence of chronic migraine increased with increasing frequency of opioid use. About 49% of the sample had allodynia, and the prevalence of allodynia increased with increasing frequency of opioid use. Overall, disability was moderate to severe in 57.3% of participants. Participants who used opioids on 3 or fewer days per month had the lowest prevalence of moderate to severe disability (50.2%), and participants who used opioids on 10 or more days per month had the highest prevalence of moderate to severe disability (83.8%).

Approximately 21% of participants had anxiety or depression. The lowest prevalence of anxiety or depression was among participants who took opioids on 3 or fewer days per month (17.4%), and the highest prevalence was among participants who took opioids on 10 or more days per month (43.2%). About 39% of the population had very poor to poor treatment optimization. Among opioid nonusers, 35.6% had very poor to poor treatment optimization, and 59.4% of participants who used opioids on 10 or more days per month had very poor to poor treatment optimization.

Dr. Lipton and colleagues also examined the study population’s use of triptans. Overall, 51.5% of participants reported taking triptans. The prevalence of triptan use was highest among participants who did not use opioids (64.1%) and lowest among participants who used opioids on 3 or fewer days per month (20.5%). Triptan use increased as monthly days of opioid use increased.
 

Pain clinics and opioid prescription

“In the general population, women are more likely to receive opioids than men,” said Dr. Lipton. “This [finding] could reflect, in part, that women have more pain disorders than men and are more likely to seek medical care for pain than men.” In the current study, however, men with migraine were more likely to receive opioid prescriptions than were women with migraine. One potential explanation for this finding is that men with migraine are less likely to receive a migraine diagnosis, which might attenuate opioid prescribing, than women with migraine. “It may be that opioids are perceived to be serious drugs for serious pain, and that some physicians may be more likely to prescribe opioids to men because the disorder is taken more seriously in men than women,” said Dr. Lipton.

The observation that opioids were more likely to be prescribed for people treated in pain clinics “is consistent with my understanding of practice patterns,” he added. “Generally, neurologists strive to find effective acute treatment alternatives to opioids. The emergence of [drug classes known as] gepants and ditans provides a helpful set of alternatives to tritpans.”

Dr. Lipton and his colleagues plan further research into the treatment of migraineurs. “In a claims analysis, we showed that when people with migraine fail a triptan, they are most likely to get an opioid as their next drug,” he said. “Reasonable [clinicians] might disagree on the next step. The next step, in the absence of contraindications, could be a different oral triptan, a nonoral triptan, or a gepant or ditan. We are planning a randomized trial to probe this question.”
 

Why are opioids still being used?

The study’s reliance on patients’ self-report and its retrospective design are two of its weaknesses, said Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and editor-in-chief of Neurology Reviews. One strength, however, is that the stratified sampling methodology produced a study population that accurately reflects the demographic characteristics of the U.S. adult population, he added. Another strength is the investigators’ examination of opioid use by patient characteristics such as marital status, education, income, obesity, and smoking.

Given the harmful effects of opioids in migraine, it is hard to understand why as much as one-third of study participants using acute care medication for migraine were using opioids, said Dr. Rapoport. Using opioids for the acute treatment of migraine attacks often indicates inadequate treatment optimization, which leads to ongoing headache. As a consequence, patients may take more medication, which can increase headache frequency and lead to diagnoses of chronic migraine and medication overuse headache. Although the study found an association between the increased use of opioids and decreased household income and increased unemployment, smoking, and obesity, “it is not possible to assign causality to any of these associations, even though some would argue that decreased socioeconomic status was somehow related to more headache, disability, obesity, smoking, and unemployment,” he added.

“The paper suggests that future research should look at the risk factors for use of opioids and should determine if depression is a risk factor for or a consequence of opioid use,” said Dr. Rapoport. “Interventional studies designed to improve the acute care of migraine attacks might be able to reduce the use of opioids. I have not used opioids or butalbital-containing medication in my office for many years.”

This study was funded and sponsored by Dr. Reddy’s Laboratories group of companies, Princeton, N.J. Dr. Lipton has received grant support from the National Institutes of Health, the National Headache Foundation, and the Migraine Research Fund. He serves as a consultant, serves as an advisory board member, or has received honoraria from Alder, Allergan, American Headache Society, Autonomic Technologies, Biohaven, Dr. Reddy’s Laboratories, Eli Lilly, eNeura Therapeutics, Merck, Novartis, Pfizer, and Teva, Inc. He receives royalties from Wolff’s Headache, 8th Edition (New York: Oxford University Press, 2009) and holds stock options in eNeura Therapeutics and Biohaven.

SOURCE: Lipton RB, et al. Headache. https://doi.org/10.1111/head.14018. 2020;61(1):103-16.

Among patients with migraine who use prescription medications, the increasing use of prescription opioids is associated with chronic migraine, more severe disability, and anxiety and depression, according to an analysis published in the January issue of Headache . The use of prescription opioids also is associated with treatment-related variables such as poor acute treatment optimization and treatment in a pain clinic. The results indicate the continued need to educate patients and clinicians about the potential risks of opioids for migraineurs, according to the researchers.

A review of MAST data

Dr. Lipton and colleagues set out to identify the variables associated with the frequency of opioid use in people with migraine. Among the variables that they sought to examine were demographic characteristics, comorbidities, headache characteristics, medication use, and patterns of health care use. Dr. Lipton’s group hypothesized that migraine-related severity and burden would increase with increasing frequency of opioid use.

To conduct their research, the investigators examined data from the MAST study, a nationwide sample of American adults with migraine. They focused specifically on participants who reported receiving prescription acute medications. Participants eligible for this analysis reported 3 or more headache days in the previous 3 months and at least 1 monthly headache day in the previous month. In all, 15,133 participants met these criteria.

Dr. Lipton and colleagues categorized participants into four groups based on their frequency of opioid use. The groups had no opioid use, 3 or fewer monthly days of opioid use, 4 to 9 monthly days of opioid use, and 10 or more days of monthly opioid use. The last category is consistent with the International Classification of Headache Disorders-3 criteria for overuse of opioids in migraine.

At baseline, MAST participants provided information about variables such as gender, age, marital status, smoking status, education, and income. Participants also reported how many times in the previous 6 months they had visited a primary care doctor, a neurologist, a headache specialist, or a pain specialist. Dr. Lipton’s group calculated monthly headache days using the number of days during the previous 3 months affected by headache. The Migraine Disability Assessment (MIDAS) questionnaire was used to measure headache-related disability. The four-item Patient Health Questionnaire (PHQ-4) was used to screen for anxiety and depression, and the Migraine Treatment Optimization Questionnaire (mTOQ-4) evaluated participants’ treatment optimization.
 

Men predominated among opioid users

The investigators included 4,701 MAST participants in their analysis. The population’s mean age was 45 years, and 71.6% of participants were women. Of the entire sample, 67.5% reported no opioid use, and 32.5% reported opioid use. Of the total study population, 18.7% of patients took opioids 3 or fewer days per month, 6.5% took opioids 4 to 9 days per month, and 7.3% took opioids on 10 or more days per month.

Opioid users did not differ from nonusers on race or marital status. Men were overrepresented among all groups of opioid users, however. In addition, opioid use was more prevalent among participants with fewer than 4 years of college education (34.9%) than among participants with 4 or more years of college (30.8%). The proportion of participants with fewer than 4 years of college increased with increasing monthly opioid use. Furthermore, opioid use increased with decreasing household income. As opioid use increased, rates of employment decreased. Approximately 33% of the entire sample were obese, and the proportion of obese participants increased with increasing days per month of opioid use.

The most frequent setting during the previous 6 months for participants seeking care was primary care (49.7%). The next most frequent setting was neurology units (20.9%), pain clinics (8.3%), and headache clinics (7.7%). The prevalence of opioid use was 37.5% among participants with primary care visits, 37.3% among participants with neurologist visits, 43.0% among participants with headache clinic visits, and 53.5% with pain clinic visits.

About 15% of the population had chronic migraine. The prevalence of chronic migraine increased with increasing frequency of opioid use. About 49% of the sample had allodynia, and the prevalence of allodynia increased with increasing frequency of opioid use. Overall, disability was moderate to severe in 57.3% of participants. Participants who used opioids on 3 or fewer days per month had the lowest prevalence of moderate to severe disability (50.2%), and participants who used opioids on 10 or more days per month had the highest prevalence of moderate to severe disability (83.8%).

Approximately 21% of participants had anxiety or depression. The lowest prevalence of anxiety or depression was among participants who took opioids on 3 or fewer days per month (17.4%), and the highest prevalence was among participants who took opioids on 10 or more days per month (43.2%). About 39% of the population had very poor to poor treatment optimization. Among opioid nonusers, 35.6% had very poor to poor treatment optimization, and 59.4% of participants who used opioids on 10 or more days per month had very poor to poor treatment optimization.

Dr. Lipton and colleagues also examined the study population’s use of triptans. Overall, 51.5% of participants reported taking triptans. The prevalence of triptan use was highest among participants who did not use opioids (64.1%) and lowest among participants who used opioids on 3 or fewer days per month (20.5%). Triptan use increased as monthly days of opioid use increased.
 

Pain clinics and opioid prescription

“In the general population, women are more likely to receive opioids than men,” said Dr. Lipton. “This [finding] could reflect, in part, that women have more pain disorders than men and are more likely to seek medical care for pain than men.” In the current study, however, men with migraine were more likely to receive opioid prescriptions than were women with migraine. One potential explanation for this finding is that men with migraine are less likely to receive a migraine diagnosis, which might attenuate opioid prescribing, than women with migraine. “It may be that opioids are perceived to be serious drugs for serious pain, and that some physicians may be more likely to prescribe opioids to men because the disorder is taken more seriously in men than women,” said Dr. Lipton.

The observation that opioids were more likely to be prescribed for people treated in pain clinics “is consistent with my understanding of practice patterns,” he added. “Generally, neurologists strive to find effective acute treatment alternatives to opioids. The emergence of [drug classes known as] gepants and ditans provides a helpful set of alternatives to tritpans.”

Dr. Lipton and his colleagues plan further research into the treatment of migraineurs. “In a claims analysis, we showed that when people with migraine fail a triptan, they are most likely to get an opioid as their next drug,” he said. “Reasonable [clinicians] might disagree on the next step. The next step, in the absence of contraindications, could be a different oral triptan, a nonoral triptan, or a gepant or ditan. We are planning a randomized trial to probe this question.”
 

Why are opioids still being used?

The study’s reliance on patients’ self-report and its retrospective design are two of its weaknesses, said Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and editor-in-chief of Neurology Reviews. One strength, however, is that the stratified sampling methodology produced a study population that accurately reflects the demographic characteristics of the U.S. adult population, he added. Another strength is the investigators’ examination of opioid use by patient characteristics such as marital status, education, income, obesity, and smoking.

Given the harmful effects of opioids in migraine, it is hard to understand why as much as one-third of study participants using acute care medication for migraine were using opioids, said Dr. Rapoport. Using opioids for the acute treatment of migraine attacks often indicates inadequate treatment optimization, which leads to ongoing headache. As a consequence, patients may take more medication, which can increase headache frequency and lead to diagnoses of chronic migraine and medication overuse headache. Although the study found an association between the increased use of opioids and decreased household income and increased unemployment, smoking, and obesity, “it is not possible to assign causality to any of these associations, even though some would argue that decreased socioeconomic status was somehow related to more headache, disability, obesity, smoking, and unemployment,” he added.

“The paper suggests that future research should look at the risk factors for use of opioids and should determine if depression is a risk factor for or a consequence of opioid use,” said Dr. Rapoport. “Interventional studies designed to improve the acute care of migraine attacks might be able to reduce the use of opioids. I have not used opioids or butalbital-containing medication in my office for many years.”

This study was funded and sponsored by Dr. Reddy’s Laboratories group of companies, Princeton, N.J. Dr. Lipton has received grant support from the National Institutes of Health, the National Headache Foundation, and the Migraine Research Fund. He serves as a consultant, serves as an advisory board member, or has received honoraria from Alder, Allergan, American Headache Society, Autonomic Technologies, Biohaven, Dr. Reddy’s Laboratories, Eli Lilly, eNeura Therapeutics, Merck, Novartis, Pfizer, and Teva, Inc. He receives royalties from Wolff’s Headache, 8th Edition (New York: Oxford University Press, 2009) and holds stock options in eNeura Therapeutics and Biohaven.

SOURCE: Lipton RB, et al. Headache. https://doi.org/10.1111/head.14018. 2020;61(1):103-16.

Among patients with migraine who use prescription medications, the increasing use of prescription opioids is associated with chronic migraine, more severe disability, and anxiety and depression, according to an analysis published in the January issue of Headache . The use of prescription opioids also is associated with treatment-related variables such as poor acute treatment optimization and treatment in a pain clinic. The results indicate the continued need to educate patients and clinicians about the potential risks of opioids for migraineurs, according to the researchers.

A review of MAST data

Dr. Lipton and colleagues set out to identify the variables associated with the frequency of opioid use in people with migraine. Among the variables that they sought to examine were demographic characteristics, comorbidities, headache characteristics, medication use, and patterns of health care use. Dr. Lipton’s group hypothesized that migraine-related severity and burden would increase with increasing frequency of opioid use.

To conduct their research, the investigators examined data from the MAST study, a nationwide sample of American adults with migraine. They focused specifically on participants who reported receiving prescription acute medications. Participants eligible for this analysis reported 3 or more headache days in the previous 3 months and at least 1 monthly headache day in the previous month. In all, 15,133 participants met these criteria.

Dr. Lipton and colleagues categorized participants into four groups based on their frequency of opioid use. The groups had no opioid use, 3 or fewer monthly days of opioid use, 4 to 9 monthly days of opioid use, and 10 or more days of monthly opioid use. The last category is consistent with the International Classification of Headache Disorders-3 criteria for overuse of opioids in migraine.

At baseline, MAST participants provided information about variables such as gender, age, marital status, smoking status, education, and income. Participants also reported how many times in the previous 6 months they had visited a primary care doctor, a neurologist, a headache specialist, or a pain specialist. Dr. Lipton’s group calculated monthly headache days using the number of days during the previous 3 months affected by headache. The Migraine Disability Assessment (MIDAS) questionnaire was used to measure headache-related disability. The four-item Patient Health Questionnaire (PHQ-4) was used to screen for anxiety and depression, and the Migraine Treatment Optimization Questionnaire (mTOQ-4) evaluated participants’ treatment optimization.
 

Men predominated among opioid users

The investigators included 4,701 MAST participants in their analysis. The population’s mean age was 45 years, and 71.6% of participants were women. Of the entire sample, 67.5% reported no opioid use, and 32.5% reported opioid use. Of the total study population, 18.7% of patients took opioids 3 or fewer days per month, 6.5% took opioids 4 to 9 days per month, and 7.3% took opioids on 10 or more days per month.

Opioid users did not differ from nonusers on race or marital status. Men were overrepresented among all groups of opioid users, however. In addition, opioid use was more prevalent among participants with fewer than 4 years of college education (34.9%) than among participants with 4 or more years of college (30.8%). The proportion of participants with fewer than 4 years of college increased with increasing monthly opioid use. Furthermore, opioid use increased with decreasing household income. As opioid use increased, rates of employment decreased. Approximately 33% of the entire sample were obese, and the proportion of obese participants increased with increasing days per month of opioid use.

The most frequent setting during the previous 6 months for participants seeking care was primary care (49.7%). The next most frequent setting was neurology units (20.9%), pain clinics (8.3%), and headache clinics (7.7%). The prevalence of opioid use was 37.5% among participants with primary care visits, 37.3% among participants with neurologist visits, 43.0% among participants with headache clinic visits, and 53.5% with pain clinic visits.

About 15% of the population had chronic migraine. The prevalence of chronic migraine increased with increasing frequency of opioid use. About 49% of the sample had allodynia, and the prevalence of allodynia increased with increasing frequency of opioid use. Overall, disability was moderate to severe in 57.3% of participants. Participants who used opioids on 3 or fewer days per month had the lowest prevalence of moderate to severe disability (50.2%), and participants who used opioids on 10 or more days per month had the highest prevalence of moderate to severe disability (83.8%).

Approximately 21% of participants had anxiety or depression. The lowest prevalence of anxiety or depression was among participants who took opioids on 3 or fewer days per month (17.4%), and the highest prevalence was among participants who took opioids on 10 or more days per month (43.2%). About 39% of the population had very poor to poor treatment optimization. Among opioid nonusers, 35.6% had very poor to poor treatment optimization, and 59.4% of participants who used opioids on 10 or more days per month had very poor to poor treatment optimization.

Dr. Lipton and colleagues also examined the study population’s use of triptans. Overall, 51.5% of participants reported taking triptans. The prevalence of triptan use was highest among participants who did not use opioids (64.1%) and lowest among participants who used opioids on 3 or fewer days per month (20.5%). Triptan use increased as monthly days of opioid use increased.
 

Pain clinics and opioid prescription

“In the general population, women are more likely to receive opioids than men,” said Dr. Lipton. “This [finding] could reflect, in part, that women have more pain disorders than men and are more likely to seek medical care for pain than men.” In the current study, however, men with migraine were more likely to receive opioid prescriptions than were women with migraine. One potential explanation for this finding is that men with migraine are less likely to receive a migraine diagnosis, which might attenuate opioid prescribing, than women with migraine. “It may be that opioids are perceived to be serious drugs for serious pain, and that some physicians may be more likely to prescribe opioids to men because the disorder is taken more seriously in men than women,” said Dr. Lipton.

The observation that opioids were more likely to be prescribed for people treated in pain clinics “is consistent with my understanding of practice patterns,” he added. “Generally, neurologists strive to find effective acute treatment alternatives to opioids. The emergence of [drug classes known as] gepants and ditans provides a helpful set of alternatives to tritpans.”

Dr. Lipton and his colleagues plan further research into the treatment of migraineurs. “In a claims analysis, we showed that when people with migraine fail a triptan, they are most likely to get an opioid as their next drug,” he said. “Reasonable [clinicians] might disagree on the next step. The next step, in the absence of contraindications, could be a different oral triptan, a nonoral triptan, or a gepant or ditan. We are planning a randomized trial to probe this question.”
 

Why are opioids still being used?

The study’s reliance on patients’ self-report and its retrospective design are two of its weaknesses, said Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and editor-in-chief of Neurology Reviews. One strength, however, is that the stratified sampling methodology produced a study population that accurately reflects the demographic characteristics of the U.S. adult population, he added. Another strength is the investigators’ examination of opioid use by patient characteristics such as marital status, education, income, obesity, and smoking.

Given the harmful effects of opioids in migraine, it is hard to understand why as much as one-third of study participants using acute care medication for migraine were using opioids, said Dr. Rapoport. Using opioids for the acute treatment of migraine attacks often indicates inadequate treatment optimization, which leads to ongoing headache. As a consequence, patients may take more medication, which can increase headache frequency and lead to diagnoses of chronic migraine and medication overuse headache. Although the study found an association between the increased use of opioids and decreased household income and increased unemployment, smoking, and obesity, “it is not possible to assign causality to any of these associations, even though some would argue that decreased socioeconomic status was somehow related to more headache, disability, obesity, smoking, and unemployment,” he added.

“The paper suggests that future research should look at the risk factors for use of opioids and should determine if depression is a risk factor for or a consequence of opioid use,” said Dr. Rapoport. “Interventional studies designed to improve the acute care of migraine attacks might be able to reduce the use of opioids. I have not used opioids or butalbital-containing medication in my office for many years.”

This study was funded and sponsored by Dr. Reddy’s Laboratories group of companies, Princeton, N.J. Dr. Lipton has received grant support from the National Institutes of Health, the National Headache Foundation, and the Migraine Research Fund. He serves as a consultant, serves as an advisory board member, or has received honoraria from Alder, Allergan, American Headache Society, Autonomic Technologies, Biohaven, Dr. Reddy’s Laboratories, Eli Lilly, eNeura Therapeutics, Merck, Novartis, Pfizer, and Teva, Inc. He receives royalties from Wolff’s Headache, 8th Edition (New York: Oxford University Press, 2009) and holds stock options in eNeura Therapeutics and Biohaven.

SOURCE: Lipton RB, et al. Headache. https://doi.org/10.1111/head.14018. 2020;61(1):103-16.

A meta-analysis of two randomized studies evaluating patent foramen ovale (PFO) closure as a treatment strategy for migraine has shown significant benefits in several key endpoints, prompting the authors to conclude the approach warrants reevaluation.
 

The pooled analysis of patient-level data from the PRIMA and PREMIUM studies, both of which evaluated the Amplatzer PFO Occluder device (Abbott Vascular), showed that PFO closure significantly reduced the mean number of monthly migraine days and monthly migraine attacks and resulted in a greater number of patients who experienced complete migraine cessation.

The study, led by Mohammad K. Mojadidi, MD, Virginia Commonwealth University, Richmond, was published online in the Journal of the American College of Cardiology on Feb. 8, 2021.

Commenting on the article, the coauthor of an accompanying editorial, Zubair Ahmed, MD, of the Cleveland Clinic said the meta-analysis gave some useful new information but is not enough to recommend PFO closure routinely for patients with migraine.

“This meta-analysis looked at different endpoints that are more relevant to current clinical practice than those in the two original studies, and the results show that we shouldn’t rule out PFO closure as a treatment strategy for some migraine patients,” Dr. Ahmed stated. “But we’re still not sure exactly which patients are most likely to benefit from this approach, and we need additional studies to gain more understanding on that.”

The study authors noted that there is an established link between the presence of PFO and migraine, especially migraine with aura. In observational studies of PFO closure for cryptogenic stroke, the vast majority of patients who also had migraine reported a more than 50% reduction in migraine days per month after PFO closure.

However, two recent randomized clinical trials evaluating the Amplatzer PFO Occluder device for reducing the frequency and duration of episodic migraine headaches did not meet their respective primary endpoints, although they did show significant benefit of PFO closure in most of their secondary endpoints.

The current meta-analysis pooled individual participant data from the two trials to increase the power to detect the effect of percutaneous PFO closure for treating patients with episodic migraine compared with medical therapy alone.

In the two studies including a total of 337 patients, 176 were randomized to PFO closure and 161 to medical treatment only. At 12 months, three of the four efficacy endpoints evaluated in the meta-analysis were significantly reduced in the PFO-closure group. These were mean reduction of monthly migraine days (–3.1 days vs. –1.9 days; P = .02), mean reduction of monthly migraine attacks (–2.0 vs. –1.4; P = .01), and number of patients who experienced complete cessation of migraine (9% vs. 0.7%; P < .001).

The responder rate, defined as more than a 50% reduction in migraine attacks, showed a trend towards an increase in the PFO-closure group but did not achieve statistical significance (38% vs. 29%; P = .13).  

For the safety analysis, nine procedure-related and four device-related adverse events occurred in 245 patients who eventually received devices. All events were transient and resolved.
 

Better effect in patients with aura

Patients with migraine with aura, in particular frequent aura, had a significantly greater reduction in migraine days and a higher incidence of complete migraine cessation following PFO closure versus no closure, the authors reported.

In those without aura, PFO closure did not significantly reduce migraine days or improve complete headache cessation. However, some patients without aura did respond to PFO closure, which was statistically significant for reduction of migraine attacks (–2.0 vs. –1.0; P = .03).

“The interaction between the brain that is susceptible to migraine and the plethora of potential triggers is complex. A PFO may be the potential pathway for a variety of chemical triggers, such as serotonin from platelets, and although less frequent, some people with migraine without aura may trigger their migraine through this mechanism,” the researchers suggested. This hypothesis will be tested in the RELIEF trial, which is now being planned.

In the accompanying editorial, Dr. Ahmed and coauthor Robert J. Sommer, MD, Columbia University Medical Center, New York, pointed out that the meta-analysis demonstrates benefit of PFO closure in the migraine population for the first time.

“Moreover, the investigators defined a population of patients who may benefit most from PFO closure, those with migraine with frequent aura, suggesting that these may be different physiologically than other migraine subtypes. The analysis also places the PRIMA and PREMIUM outcomes in the context of endpoints that are more practical and are more commonly assessed in current clinical trials,” the editorialists noted.
 

Many unanswered questions

But the editorialists highlighted several significant limitations of the analysis, including “pooling of patient cohorts, methods, and outcome measures that might not be entirely comparable,” which they say could have introduced bias.

They also pointed out that the underlying pathophysiological mechanism linking migraine symptoms to PFO remains unknown. They explain that the mechanism is thought to involve the right-to-left passage of systemic venous blood, with some component – which would normally be eliminated or reduced on passage through the pulmonary vasculature – reaching the cerebral circulation via the PFO in supranormal concentrations and acting as a trigger for migraine activity in patients with susceptible brains.

But not all patients with migraine who have PFO benefit from PFO closure, they noted, and therefore presumably have PFO-unrelated migraines. There is no verified way to distinguish between these two groups at present.

“Once we learn to identify the subset of migraine patients in whom PFOs are actually causal of headache symptoms, screening and treatment of PFO for migraine can become a reality,” they wrote.

Although the meta-analysis is a step in the right direction, “it is not a home run,” Dr. Ahmed elaborated. “This was a post hoc analysis of two studies, neither of which showed significant benefits on their primary endpoints. That weakens the findings somewhat.”

He added: “At present, PFO closure is not routinely recommended as a migraine treatment strategy as we haven’t been sure which patients are most likely to benefit. And while this meta-analysis suggests patients with aura may be more likely to benefit, one quarter of patients without aura in the PREMIUM trial responded to PFO closure, so it’s not just about aura.

“There are still many unanswered questions.

“I don’t think the new information from this meta-analysis is enough to persuade me to change my practice, but it is a small building block in the overall picture and suggests this may be a suitable strategy for some patients in future,” he concluded.

The study had no outside funding. Participant-level data were provided by Abbott. Several coauthors were on the steering committee for the PREMIUM or PRIMA trials. Dr. Ahmed reported receiving consulting fees from, Amgen, AbbVie, electroCore, and Eli Lilly; serving on advisory boards for Amgen and Supernus; serving as a speaker for AbbVie; and receiving funding for an investigator-initiated trial from Teva and Eli Lilly.

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

A meta-analysis of two randomized studies evaluating patent foramen ovale (PFO) closure as a treatment strategy for migraine has shown significant benefits in several key endpoints, prompting the authors to conclude the approach warrants reevaluation.
 

The pooled analysis of patient-level data from the PRIMA and PREMIUM studies, both of which evaluated the Amplatzer PFO Occluder device (Abbott Vascular), showed that PFO closure significantly reduced the mean number of monthly migraine days and monthly migraine attacks and resulted in a greater number of patients who experienced complete migraine cessation.

The study, led by Mohammad K. Mojadidi, MD, Virginia Commonwealth University, Richmond, was published online in the Journal of the American College of Cardiology on Feb. 8, 2021.

Commenting on the article, the coauthor of an accompanying editorial, Zubair Ahmed, MD, of the Cleveland Clinic said the meta-analysis gave some useful new information but is not enough to recommend PFO closure routinely for patients with migraine.

“This meta-analysis looked at different endpoints that are more relevant to current clinical practice than those in the two original studies, and the results show that we shouldn’t rule out PFO closure as a treatment strategy for some migraine patients,” Dr. Ahmed stated. “But we’re still not sure exactly which patients are most likely to benefit from this approach, and we need additional studies to gain more understanding on that.”

The study authors noted that there is an established link between the presence of PFO and migraine, especially migraine with aura. In observational studies of PFO closure for cryptogenic stroke, the vast majority of patients who also had migraine reported a more than 50% reduction in migraine days per month after PFO closure.

However, two recent randomized clinical trials evaluating the Amplatzer PFO Occluder device for reducing the frequency and duration of episodic migraine headaches did not meet their respective primary endpoints, although they did show significant benefit of PFO closure in most of their secondary endpoints.

The current meta-analysis pooled individual participant data from the two trials to increase the power to detect the effect of percutaneous PFO closure for treating patients with episodic migraine compared with medical therapy alone.

In the two studies including a total of 337 patients, 176 were randomized to PFO closure and 161 to medical treatment only. At 12 months, three of the four efficacy endpoints evaluated in the meta-analysis were significantly reduced in the PFO-closure group. These were mean reduction of monthly migraine days (–3.1 days vs. –1.9 days; P = .02), mean reduction of monthly migraine attacks (–2.0 vs. –1.4; P = .01), and number of patients who experienced complete cessation of migraine (9% vs. 0.7%; P < .001).

The responder rate, defined as more than a 50% reduction in migraine attacks, showed a trend towards an increase in the PFO-closure group but did not achieve statistical significance (38% vs. 29%; P = .13).  

For the safety analysis, nine procedure-related and four device-related adverse events occurred in 245 patients who eventually received devices. All events were transient and resolved.
 

Better effect in patients with aura

Patients with migraine with aura, in particular frequent aura, had a significantly greater reduction in migraine days and a higher incidence of complete migraine cessation following PFO closure versus no closure, the authors reported.

In those without aura, PFO closure did not significantly reduce migraine days or improve complete headache cessation. However, some patients without aura did respond to PFO closure, which was statistically significant for reduction of migraine attacks (–2.0 vs. –1.0; P = .03).

“The interaction between the brain that is susceptible to migraine and the plethora of potential triggers is complex. A PFO may be the potential pathway for a variety of chemical triggers, such as serotonin from platelets, and although less frequent, some people with migraine without aura may trigger their migraine through this mechanism,” the researchers suggested. This hypothesis will be tested in the RELIEF trial, which is now being planned.

In the accompanying editorial, Dr. Ahmed and coauthor Robert J. Sommer, MD, Columbia University Medical Center, New York, pointed out that the meta-analysis demonstrates benefit of PFO closure in the migraine population for the first time.

“Moreover, the investigators defined a population of patients who may benefit most from PFO closure, those with migraine with frequent aura, suggesting that these may be different physiologically than other migraine subtypes. The analysis also places the PRIMA and PREMIUM outcomes in the context of endpoints that are more practical and are more commonly assessed in current clinical trials,” the editorialists noted.
 

Many unanswered questions

But the editorialists highlighted several significant limitations of the analysis, including “pooling of patient cohorts, methods, and outcome measures that might not be entirely comparable,” which they say could have introduced bias.

They also pointed out that the underlying pathophysiological mechanism linking migraine symptoms to PFO remains unknown. They explain that the mechanism is thought to involve the right-to-left passage of systemic venous blood, with some component – which would normally be eliminated or reduced on passage through the pulmonary vasculature – reaching the cerebral circulation via the PFO in supranormal concentrations and acting as a trigger for migraine activity in patients with susceptible brains.

But not all patients with migraine who have PFO benefit from PFO closure, they noted, and therefore presumably have PFO-unrelated migraines. There is no verified way to distinguish between these two groups at present.

“Once we learn to identify the subset of migraine patients in whom PFOs are actually causal of headache symptoms, screening and treatment of PFO for migraine can become a reality,” they wrote.

Although the meta-analysis is a step in the right direction, “it is not a home run,” Dr. Ahmed elaborated. “This was a post hoc analysis of two studies, neither of which showed significant benefits on their primary endpoints. That weakens the findings somewhat.”

He added: “At present, PFO closure is not routinely recommended as a migraine treatment strategy as we haven’t been sure which patients are most likely to benefit. And while this meta-analysis suggests patients with aura may be more likely to benefit, one quarter of patients without aura in the PREMIUM trial responded to PFO closure, so it’s not just about aura.

“There are still many unanswered questions.

“I don’t think the new information from this meta-analysis is enough to persuade me to change my practice, but it is a small building block in the overall picture and suggests this may be a suitable strategy for some patients in future,” he concluded.

The study had no outside funding. Participant-level data were provided by Abbott. Several coauthors were on the steering committee for the PREMIUM or PRIMA trials. Dr. Ahmed reported receiving consulting fees from, Amgen, AbbVie, electroCore, and Eli Lilly; serving on advisory boards for Amgen and Supernus; serving as a speaker for AbbVie; and receiving funding for an investigator-initiated trial from Teva and Eli Lilly.

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

A meta-analysis of two randomized studies evaluating patent foramen ovale (PFO) closure as a treatment strategy for migraine has shown significant benefits in several key endpoints, prompting the authors to conclude the approach warrants reevaluation.
 

The pooled analysis of patient-level data from the PRIMA and PREMIUM studies, both of which evaluated the Amplatzer PFO Occluder device (Abbott Vascular), showed that PFO closure significantly reduced the mean number of monthly migraine days and monthly migraine attacks and resulted in a greater number of patients who experienced complete migraine cessation.

The study, led by Mohammad K. Mojadidi, MD, Virginia Commonwealth University, Richmond, was published online in the Journal of the American College of Cardiology on Feb. 8, 2021.

Commenting on the article, the coauthor of an accompanying editorial, Zubair Ahmed, MD, of the Cleveland Clinic said the meta-analysis gave some useful new information but is not enough to recommend PFO closure routinely for patients with migraine.

“This meta-analysis looked at different endpoints that are more relevant to current clinical practice than those in the two original studies, and the results show that we shouldn’t rule out PFO closure as a treatment strategy for some migraine patients,” Dr. Ahmed stated. “But we’re still not sure exactly which patients are most likely to benefit from this approach, and we need additional studies to gain more understanding on that.”

The study authors noted that there is an established link between the presence of PFO and migraine, especially migraine with aura. In observational studies of PFO closure for cryptogenic stroke, the vast majority of patients who also had migraine reported a more than 50% reduction in migraine days per month after PFO closure.

However, two recent randomized clinical trials evaluating the Amplatzer PFO Occluder device for reducing the frequency and duration of episodic migraine headaches did not meet their respective primary endpoints, although they did show significant benefit of PFO closure in most of their secondary endpoints.

The current meta-analysis pooled individual participant data from the two trials to increase the power to detect the effect of percutaneous PFO closure for treating patients with episodic migraine compared with medical therapy alone.

In the two studies including a total of 337 patients, 176 were randomized to PFO closure and 161 to medical treatment only. At 12 months, three of the four efficacy endpoints evaluated in the meta-analysis were significantly reduced in the PFO-closure group. These were mean reduction of monthly migraine days (–3.1 days vs. –1.9 days; P = .02), mean reduction of monthly migraine attacks (–2.0 vs. –1.4; P = .01), and number of patients who experienced complete cessation of migraine (9% vs. 0.7%; P < .001).

The responder rate, defined as more than a 50% reduction in migraine attacks, showed a trend towards an increase in the PFO-closure group but did not achieve statistical significance (38% vs. 29%; P = .13).  

For the safety analysis, nine procedure-related and four device-related adverse events occurred in 245 patients who eventually received devices. All events were transient and resolved.
 

Better effect in patients with aura

Patients with migraine with aura, in particular frequent aura, had a significantly greater reduction in migraine days and a higher incidence of complete migraine cessation following PFO closure versus no closure, the authors reported.

In those without aura, PFO closure did not significantly reduce migraine days or improve complete headache cessation. However, some patients without aura did respond to PFO closure, which was statistically significant for reduction of migraine attacks (–2.0 vs. –1.0; P = .03).

“The interaction between the brain that is susceptible to migraine and the plethora of potential triggers is complex. A PFO may be the potential pathway for a variety of chemical triggers, such as serotonin from platelets, and although less frequent, some people with migraine without aura may trigger their migraine through this mechanism,” the researchers suggested. This hypothesis will be tested in the RELIEF trial, which is now being planned.

In the accompanying editorial, Dr. Ahmed and coauthor Robert J. Sommer, MD, Columbia University Medical Center, New York, pointed out that the meta-analysis demonstrates benefit of PFO closure in the migraine population for the first time.

“Moreover, the investigators defined a population of patients who may benefit most from PFO closure, those with migraine with frequent aura, suggesting that these may be different physiologically than other migraine subtypes. The analysis also places the PRIMA and PREMIUM outcomes in the context of endpoints that are more practical and are more commonly assessed in current clinical trials,” the editorialists noted.
 

Many unanswered questions

But the editorialists highlighted several significant limitations of the analysis, including “pooling of patient cohorts, methods, and outcome measures that might not be entirely comparable,” which they say could have introduced bias.

They also pointed out that the underlying pathophysiological mechanism linking migraine symptoms to PFO remains unknown. They explain that the mechanism is thought to involve the right-to-left passage of systemic venous blood, with some component – which would normally be eliminated or reduced on passage through the pulmonary vasculature – reaching the cerebral circulation via the PFO in supranormal concentrations and acting as a trigger for migraine activity in patients with susceptible brains.

But not all patients with migraine who have PFO benefit from PFO closure, they noted, and therefore presumably have PFO-unrelated migraines. There is no verified way to distinguish between these two groups at present.

“Once we learn to identify the subset of migraine patients in whom PFOs are actually causal of headache symptoms, screening and treatment of PFO for migraine can become a reality,” they wrote.

Although the meta-analysis is a step in the right direction, “it is not a home run,” Dr. Ahmed elaborated. “This was a post hoc analysis of two studies, neither of which showed significant benefits on their primary endpoints. That weakens the findings somewhat.”

He added: “At present, PFO closure is not routinely recommended as a migraine treatment strategy as we haven’t been sure which patients are most likely to benefit. And while this meta-analysis suggests patients with aura may be more likely to benefit, one quarter of patients without aura in the PREMIUM trial responded to PFO closure, so it’s not just about aura.

“There are still many unanswered questions.

“I don’t think the new information from this meta-analysis is enough to persuade me to change my practice, but it is a small building block in the overall picture and suggests this may be a suitable strategy for some patients in future,” he concluded.

The study had no outside funding. Participant-level data were provided by Abbott. Several coauthors were on the steering committee for the PREMIUM or PRIMA trials. Dr. Ahmed reported receiving consulting fees from, Amgen, AbbVie, electroCore, and Eli Lilly; serving on advisory boards for Amgen and Supernus; serving as a speaker for AbbVie; and receiving funding for an investigator-initiated trial from Teva and Eli Lilly.

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

This time of year I spend weekend afternoons in my hot tub, catching up on medical journals, CME, paperbacks, and generally anything worth reading that shows up in my mailbox.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

This time of year I spend weekend afternoons in my hot tub, catching up on medical journals, CME, paperbacks, and generally anything worth reading that shows up in my mailbox.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

This time of year I spend weekend afternoons in my hot tub, catching up on medical journals, CME, paperbacks, and generally anything worth reading that shows up in my mailbox.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

In outpatients with COVID-19, peginterferon lambda has the potential to prevent clinical deterioration and shorten the duration of viral shedding, according to results of a double-blind, placebo-controlled trial (NCT04354259).

Reductions in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA were greater with peginterferon lambda than with placebo from day 3 onward in the phase 2 study led by Jordan J. Feld, MD, of the Toronto Centre for Liver Disease. The findings were reported in The Lancet Respiratory Medicine.
 

Fewer side effects

To date in randomized clinical trials, efficacy in treatment of COVID-19 has been shown only for remdesivir and dexamethasone in hospitalized patients, and in an interim analysis of accelerated viral clearance for a monoclonal antibody infusion in outpatients.

Activity against respiratory pathogens has been demonstrated for interferon lambda-1, a type III interferon shown to be involved in innate antiviral responses. Interferons, Dr. Feld and coauthors stated, drive induction of genes with antiviral, antiproliferative and immunoregulatory properties, and early treatment with interferons might halt clinical progression and shorten the duration of viral shedding with reduced onward transmission. In addition, interferon lambdas (type III) use a distinct receptor complex with high expression levels limited to epithelial cells in the lung, liver, and intestine, leading to fewer side effects than other interferons, including avoiding risk of promoting cytokine storm syndrome.

The researchers investigated peginterferon lambda safety and efficacy in treatment of patients with laboratory-confirmed, mild to moderate COVID-19. Sixty patients (median age 46 years, about 60% female, about 50% White) were recruited from outpatient testing centers at six institutions in Toronto, and referred to a single ambulatory site. Patients were randomly assigned 1:1 to a single subcutaneous injection of peginterferon lambda 180 mcg or placebo within 7 days of symptom onset or, if asymptomatic, of their first positive swab. Mean time from symptom onset to injection was about 4.5 days, and about 18.5% were asymptomatic. The primary outcome was the proportion of patients negative for SARS-CoV-2 RNA on day 7 after the injection.
 

Greater benefit with higher baseline load

A higher baseline SARS-CoV-2 RNA concentration found in the peginterferon lambda group was found to be significantly associated with day 7 clearance (odds ratio [OR] 0.69 [95% confidence interval 0.51-0.87]; P = ·001). In the peginterferon lambda group, also, the mean decline in SARS-CoV-2 RNA was significantly larger than in the placebo group across all time points (days 3, 5, 7, and14). While viral load decline was 0.81 log greater in the treatment group (P = .14) by day 3, viral load decline increased to 1.67 log copies per mL by day 5 (P = .013) and 2.42 log copies per mL by day 7 (P = .0041). At day 14, the viral decline was 1.77 log copies per mL larger in the peginterferon lambda group (P = .048). The investigators pointed out that the difference in viral load decline between groups was greater in patients with high baseline viral load (at or above 106 copies per mL). In the peginterferon lambda high baseline viral load group, the reduction was 7.17 log copies per mL, versus 4.92 log copies per mL in the placebo group (P = .004).
 

More patients SARS-CoV-2 RNA negative

By day 7, 80% of patients in the peginterferon lambda group were negative for SARS-CoV-2 RNA, compared with 63% in the placebo group (P = .15). After baseline load adjustment, however, the peginterferon lambda treatment was significantly associated with day 7 clearance (OR 4·12 [95% CI 1·15-16·73]; P = .029).
 

Respiratory symptoms improved faster

Most symptoms in both groups were mild to moderate, without difference in frequency or severity. While symptom improvement was generally similar over time for both groups, respiratory symptoms improved faster with peginterferon lambda, with the effect more pronounced in the high baseline viral load group (OR 5·88 (0·81-42·46; P =. 079).

Laboratory adverse events, similar for both groups, were mild.

“Peginterferon lambda has potential to prevent clinical deterioration and shorten duration of viral shedding,” the investigators concluded.

“This clinical trial is important” because it suggests that a single intravenous dose of peginterferon lambda administered to outpatients with a positive SARS-CoV-2 nasopharyngeal swab speeds reduction of SARS-CoV-2 viral load, David L. Bowton, MD, FCCP, professor emeritus, Wake Forest Baptist Health, Winston-Salem, N.C., said in an interview. He observed that the smaller viral load difference observed at day 14 likely reflects host immune responses.

Dr. Bowton also noted that two placebo group baseline characteristics (five placebo group patients with anti-SARS-CoV-2 S protein IgG antibodies; two times more undetectable SARS-CoV-2 RNA at baseline assessment) would tend to reduce differences between the peginterferon lambda and placebo groups. He added that the study findings were concordant with another phase 2 trial of hospitalized COVID-19 patients receiving inhaled interferon beta-1a.

“Thus, interferons may find a place in the treatment of COVID-19 and perhaps other severe viral illnesses,” Dr. Bowton said.

The study was funded by the Toronto COVID-19 Action Initiative, University of Toronto, and the Ontario First COVID-19 Rapid Research Fund, Toronto General & Western Hospital Foundation.

Dr. Bowton had no disclosures. Disclosures for Dr. Feld and coauthors are listed on the Lancet Respiratory Medicine website.

In outpatients with COVID-19, peginterferon lambda has the potential to prevent clinical deterioration and shorten the duration of viral shedding, according to results of a double-blind, placebo-controlled trial (NCT04354259).

Reductions in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA were greater with peginterferon lambda than with placebo from day 3 onward in the phase 2 study led by Jordan J. Feld, MD, of the Toronto Centre for Liver Disease. The findings were reported in The Lancet Respiratory Medicine.
 

Fewer side effects

To date in randomized clinical trials, efficacy in treatment of COVID-19 has been shown only for remdesivir and dexamethasone in hospitalized patients, and in an interim analysis of accelerated viral clearance for a monoclonal antibody infusion in outpatients.

Activity against respiratory pathogens has been demonstrated for interferon lambda-1, a type III interferon shown to be involved in innate antiviral responses. Interferons, Dr. Feld and coauthors stated, drive induction of genes with antiviral, antiproliferative and immunoregulatory properties, and early treatment with interferons might halt clinical progression and shorten the duration of viral shedding with reduced onward transmission. In addition, interferon lambdas (type III) use a distinct receptor complex with high expression levels limited to epithelial cells in the lung, liver, and intestine, leading to fewer side effects than other interferons, including avoiding risk of promoting cytokine storm syndrome.

The researchers investigated peginterferon lambda safety and efficacy in treatment of patients with laboratory-confirmed, mild to moderate COVID-19. Sixty patients (median age 46 years, about 60% female, about 50% White) were recruited from outpatient testing centers at six institutions in Toronto, and referred to a single ambulatory site. Patients were randomly assigned 1:1 to a single subcutaneous injection of peginterferon lambda 180 mcg or placebo within 7 days of symptom onset or, if asymptomatic, of their first positive swab. Mean time from symptom onset to injection was about 4.5 days, and about 18.5% were asymptomatic. The primary outcome was the proportion of patients negative for SARS-CoV-2 RNA on day 7 after the injection.
 

Greater benefit with higher baseline load

A higher baseline SARS-CoV-2 RNA concentration found in the peginterferon lambda group was found to be significantly associated with day 7 clearance (odds ratio [OR] 0.69 [95% confidence interval 0.51-0.87]; P = ·001). In the peginterferon lambda group, also, the mean decline in SARS-CoV-2 RNA was significantly larger than in the placebo group across all time points (days 3, 5, 7, and14). While viral load decline was 0.81 log greater in the treatment group (P = .14) by day 3, viral load decline increased to 1.67 log copies per mL by day 5 (P = .013) and 2.42 log copies per mL by day 7 (P = .0041). At day 14, the viral decline was 1.77 log copies per mL larger in the peginterferon lambda group (P = .048). The investigators pointed out that the difference in viral load decline between groups was greater in patients with high baseline viral load (at or above 106 copies per mL). In the peginterferon lambda high baseline viral load group, the reduction was 7.17 log copies per mL, versus 4.92 log copies per mL in the placebo group (P = .004).
 

More patients SARS-CoV-2 RNA negative

By day 7, 80% of patients in the peginterferon lambda group were negative for SARS-CoV-2 RNA, compared with 63% in the placebo group (P = .15). After baseline load adjustment, however, the peginterferon lambda treatment was significantly associated with day 7 clearance (OR 4·12 [95% CI 1·15-16·73]; P = .029).
 

Respiratory symptoms improved faster

Most symptoms in both groups were mild to moderate, without difference in frequency or severity. While symptom improvement was generally similar over time for both groups, respiratory symptoms improved faster with peginterferon lambda, with the effect more pronounced in the high baseline viral load group (OR 5·88 (0·81-42·46; P =. 079).

Laboratory adverse events, similar for both groups, were mild.

“Peginterferon lambda has potential to prevent clinical deterioration and shorten duration of viral shedding,” the investigators concluded.

“This clinical trial is important” because it suggests that a single intravenous dose of peginterferon lambda administered to outpatients with a positive SARS-CoV-2 nasopharyngeal swab speeds reduction of SARS-CoV-2 viral load, David L. Bowton, MD, FCCP, professor emeritus, Wake Forest Baptist Health, Winston-Salem, N.C., said in an interview. He observed that the smaller viral load difference observed at day 14 likely reflects host immune responses.

Dr. Bowton also noted that two placebo group baseline characteristics (five placebo group patients with anti-SARS-CoV-2 S protein IgG antibodies; two times more undetectable SARS-CoV-2 RNA at baseline assessment) would tend to reduce differences between the peginterferon lambda and placebo groups. He added that the study findings were concordant with another phase 2 trial of hospitalized COVID-19 patients receiving inhaled interferon beta-1a.

“Thus, interferons may find a place in the treatment of COVID-19 and perhaps other severe viral illnesses,” Dr. Bowton said.

The study was funded by the Toronto COVID-19 Action Initiative, University of Toronto, and the Ontario First COVID-19 Rapid Research Fund, Toronto General & Western Hospital Foundation.

Dr. Bowton had no disclosures. Disclosures for Dr. Feld and coauthors are listed on the Lancet Respiratory Medicine website.

In outpatients with COVID-19, peginterferon lambda has the potential to prevent clinical deterioration and shorten the duration of viral shedding, according to results of a double-blind, placebo-controlled trial (NCT04354259).

Reductions in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA were greater with peginterferon lambda than with placebo from day 3 onward in the phase 2 study led by Jordan J. Feld, MD, of the Toronto Centre for Liver Disease. The findings were reported in The Lancet Respiratory Medicine.
 

Fewer side effects

To date in randomized clinical trials, efficacy in treatment of COVID-19 has been shown only for remdesivir and dexamethasone in hospitalized patients, and in an interim analysis of accelerated viral clearance for a monoclonal antibody infusion in outpatients.

Activity against respiratory pathogens has been demonstrated for interferon lambda-1, a type III interferon shown to be involved in innate antiviral responses. Interferons, Dr. Feld and coauthors stated, drive induction of genes with antiviral, antiproliferative and immunoregulatory properties, and early treatment with interferons might halt clinical progression and shorten the duration of viral shedding with reduced onward transmission. In addition, interferon lambdas (type III) use a distinct receptor complex with high expression levels limited to epithelial cells in the lung, liver, and intestine, leading to fewer side effects than other interferons, including avoiding risk of promoting cytokine storm syndrome.

The researchers investigated peginterferon lambda safety and efficacy in treatment of patients with laboratory-confirmed, mild to moderate COVID-19. Sixty patients (median age 46 years, about 60% female, about 50% White) were recruited from outpatient testing centers at six institutions in Toronto, and referred to a single ambulatory site. Patients were randomly assigned 1:1 to a single subcutaneous injection of peginterferon lambda 180 mcg or placebo within 7 days of symptom onset or, if asymptomatic, of their first positive swab. Mean time from symptom onset to injection was about 4.5 days, and about 18.5% were asymptomatic. The primary outcome was the proportion of patients negative for SARS-CoV-2 RNA on day 7 after the injection.
 

Greater benefit with higher baseline load

A higher baseline SARS-CoV-2 RNA concentration found in the peginterferon lambda group was found to be significantly associated with day 7 clearance (odds ratio [OR] 0.69 [95% confidence interval 0.51-0.87]; P = ·001). In the peginterferon lambda group, also, the mean decline in SARS-CoV-2 RNA was significantly larger than in the placebo group across all time points (days 3, 5, 7, and14). While viral load decline was 0.81 log greater in the treatment group (P = .14) by day 3, viral load decline increased to 1.67 log copies per mL by day 5 (P = .013) and 2.42 log copies per mL by day 7 (P = .0041). At day 14, the viral decline was 1.77 log copies per mL larger in the peginterferon lambda group (P = .048). The investigators pointed out that the difference in viral load decline between groups was greater in patients with high baseline viral load (at or above 106 copies per mL). In the peginterferon lambda high baseline viral load group, the reduction was 7.17 log copies per mL, versus 4.92 log copies per mL in the placebo group (P = .004).
 

More patients SARS-CoV-2 RNA negative

By day 7, 80% of patients in the peginterferon lambda group were negative for SARS-CoV-2 RNA, compared with 63% in the placebo group (P = .15). After baseline load adjustment, however, the peginterferon lambda treatment was significantly associated with day 7 clearance (OR 4·12 [95% CI 1·15-16·73]; P = .029).
 

Respiratory symptoms improved faster

Most symptoms in both groups were mild to moderate, without difference in frequency or severity. While symptom improvement was generally similar over time for both groups, respiratory symptoms improved faster with peginterferon lambda, with the effect more pronounced in the high baseline viral load group (OR 5·88 (0·81-42·46; P =. 079).

Laboratory adverse events, similar for both groups, were mild.

“Peginterferon lambda has potential to prevent clinical deterioration and shorten duration of viral shedding,” the investigators concluded.

“This clinical trial is important” because it suggests that a single intravenous dose of peginterferon lambda administered to outpatients with a positive SARS-CoV-2 nasopharyngeal swab speeds reduction of SARS-CoV-2 viral load, David L. Bowton, MD, FCCP, professor emeritus, Wake Forest Baptist Health, Winston-Salem, N.C., said in an interview. He observed that the smaller viral load difference observed at day 14 likely reflects host immune responses.

Dr. Bowton also noted that two placebo group baseline characteristics (five placebo group patients with anti-SARS-CoV-2 S protein IgG antibodies; two times more undetectable SARS-CoV-2 RNA at baseline assessment) would tend to reduce differences between the peginterferon lambda and placebo groups. He added that the study findings were concordant with another phase 2 trial of hospitalized COVID-19 patients receiving inhaled interferon beta-1a.

“Thus, interferons may find a place in the treatment of COVID-19 and perhaps other severe viral illnesses,” Dr. Bowton said.

The study was funded by the Toronto COVID-19 Action Initiative, University of Toronto, and the Ontario First COVID-19 Rapid Research Fund, Toronto General & Western Hospital Foundation.

Dr. Bowton had no disclosures. Disclosures for Dr. Feld and coauthors are listed on the Lancet Respiratory Medicine website.

When 42-year-old Danielle Simone Brand started having hormonal migraines, she first turned to cannabidiol (CBD) oil, eventually adding an occasional pull on a prefilled tetrahydrocannabinol (THC) vape for nighttime use. She was careful to avoid THC during work hours. A parenting and cannabis writer, Ms. Brand had more than a cursory background in cannabinoid medicine and had spent time at her local California dispensary discussing various cannabinoid components that might help alleviate her pain.

Anatoliy Sizov/Getty Images

A self-professed “do-it-yourselfer,” Ms. Brand continues to use cannabinoids for her monthly headaches, forgoing any other pain medication. “There are times for conventional medicine in partnership with your doctor, but when it comes to health and wellness, women should be empowered to make decisions and self-experiment,” she said in an interview.

Ms. Brand is not alone. Significant numbers of women are replacing or supplementing prescription medications with cannabinoids, often without consulting their primary care physician, ob.gyn., or other specialist. At times, women have tried to have these conversations, only to be met with silence or worse.

Take Linda Fuller, a 58-year-old yoga instructor from Long Island who says that she uses CBD and THC for chronic sacroiliac pain after a car accident and to alleviate stress-triggered eczema flares. “I’ve had doctors turn their backs on me; I’ve had nurse practitioners walk out on me in the middle of a sentence,” she said in an interview.

Ms. Fuller said her conversion to cannabinoid medicine is relatively new; she never used cannabis recreationally before her accident but now considers it a gift. She doesn’t keep aspirin in the house and refused pain medication immediately after she injured her back.

Diana Krach, a 34-year-old writer from Maryland, says she’s encountered roadblocks about her decision to use cannabinoids for endometriosis and for pain from Crohn’s disease. When she tried to discuss her CBD use with a gastroenterologist, he interrupted her: “Whatever pot you’re smoking isn’t going to work, you’re going on biologics.”

Ms. Krach had not been smoking anything but had turned to a CBD tincture for symptom relief after prescription pain medications failed to help.

Ms. Brand, Ms. Fuller, and Ms. Krach are the tip of the iceberg when it comes to women seeking symptom relief outside the medicine cabinet. A recent survey in the Journal of Women’s Health of almost 1,000 women show that 90% (most between the ages of 35 and 44) had used cannabis and would consider using it to treat gynecologic pain. Roughly 80% said they would consider using it for procedure-related pain or other conditions. Additionally, women have reported using cannabinoids for PTSD, sleep disturbances or insomnia, anxiety, and migraine headaches.

Observational survey data have likewise shown that 80% of women with advanced or recurrent gynecologic malignancies who were prescribed cannabis reported that it was equivalent or superior to other medications for relieving pain, neuropathy, nausea, insomnia, decreased appetite, and anxiety.

In another survey, almost half (45%) of women with gynecologic malignancies who used nonprescribed cannabis for the same symptoms reported that they had reduced their use of prescription narcotics after initiating use of cannabis.
 

The gray zone

There has been a surge in self-reported cannabis use among pregnant women in particular. The National Survey on Drug Use and Health findings for the periods 2002-2003 and 2016-2017 highlight increases in adjusted prevalence rates from 3.4% to 7% in past-month use among pregnant women overall and from 5.7% to 12.1% during the first trimester alone.

“The more that you talk to pregnant women, the more that you realize that a lot are using cannabinoids for something that is basically medicinal, for sleep, for anxiety, or for nausea,” Katrina Mark, MD, an ob.gyn. and associate professor of medicine at the University of Maryland, College Park, said in an interview. “I’m not saying it’s fine to use drugs in pregnancy, but it is a grayer conversation than a lot of colleagues want to believe. Telling women to quit seems foolish since the alternative is to be anxious, don’t sleep, don’t eat, or use a medication that also has risks to it.”

One observational study shows that pregnant women themselves are conflicted. Although the majority believe that cannabis is “natural” and “safe,” compared with prescription drugs, they aren’t entirely in the dark about potential risks. They often express frustration with practitioners’ responses when these topics are broached during office visits. An observational survey among women and practitioners published in 2020 highlights that only half of doctors openly discouraged perinatal cannabis use and that others opted out of the discussion entirely.

This is the experience of many of the women that this news organization spoke with. Ms. Krach pointed out that “there’s a big deficit in listening; the doctor is supposed to be working for our behalf, especially when it comes to reproductive health.”

Dr. Mark believed that a lot of the conversation has been clouded by the illegality of the substance but that cannabinoids deserve as much of a fair chance for discussion and consideration as other medicines, which also carry risks in pregnancy. “There’s literally no evidence that it will work in pregnancy [for these symptoms], but there’s no evidence that it doesn’t, either,” she said in an interview. “When I have this conversation with colleagues who do not share my views, I try to encourage them to look at the actual risks versus the benefits versus the alternatives.”

The ‘entourage effect’

Data supporting cannabinoids have been mostly laboratory based, case based, or observational. However, several well-designed (albeit small) trials have demonstrated efficacy for chronic pain conditions, including neuropathic and headache pain, as well as in Crohn’s disease. Most investigators have concluded that dosage is important and that there is a synergistic interaction between compounds (known as the “entourage effect”) that relates to cannabinoid efficacy or lack thereof, as well as possible adverse effects.

In addition to legality issues, the entourage effect is one of the most important factors related to the medical use of cannabinoids. “There are literally thousands of cultivars of cannabis, each with their own phytocannabinoid and terpenic profiles that may produce distinct therapeutic effects, [so] it is misguided to speak of cannabis in monolithic terms. It is like making broad claims about soup,” wrote coauthor Samoon Ahmad, MD, in Medical Marijuana: A Clinical Handbook.

Additionally, the role that reproductive hormones play is not entirely understood. Reproductive-aged women appear to be more susceptible to a “telescoping” (gender-related progression to dependence) effect in comparison with men. Ziva Cooper, PhD, director of the Cannabis Research Initiative at the University of California, Los Angeles, said in an interview. She explained that research has shown that factors such as the degree of exposure, frequency of use, and menses confound this susceptibility.
 

It’s the data

Frustration over cannabinoid therapeutics abound, especially when it comes to data, legal issues, and lack of training. “The feedback that I hear from providers is that there isn’t enough information; we just don’t know enough about it,” Dr. Mark said, “but there is information that we do have, and ignoring it is not beneficial.”

Dr. Cooper concurred. Although she readily acknowledges that data from randomized, placebo-controlled trials are mostly lacking, she says, “There are signals in the literature providing evidence for the utility of cannabis and cannabinoids for pain and some other effects.”

Other practitioners said in an interview that some patients admit to using cannabinoids but that they lack the ample information to guide these patients. By and large, many women equate “natural” with “safe,” and some will experiment on their own to see what works.

Those experiments are not without risk, which is why “it’s just as important for physicians to talk to their patients about cannabis use as it is for patients to be forthcoming about that use,” said Dr. Cooper. “It could have implications on their overall health as well as interactions with other drugs that they’re using.”

That balance from a clinical perspective on cannabis is crucial, wrote coauthor Kenneth Hill, MD, in Medical Marijuana: A Clinical Handbook. “Without it,” he wrote, “the window of opportunity for a patient to accept treatment that she needs may not be open very long.”

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

When 42-year-old Danielle Simone Brand started having hormonal migraines, she first turned to cannabidiol (CBD) oil, eventually adding an occasional pull on a prefilled tetrahydrocannabinol (THC) vape for nighttime use. She was careful to avoid THC during work hours. A parenting and cannabis writer, Ms. Brand had more than a cursory background in cannabinoid medicine and had spent time at her local California dispensary discussing various cannabinoid components that might help alleviate her pain.

Anatoliy Sizov/Getty Images

A self-professed “do-it-yourselfer,” Ms. Brand continues to use cannabinoids for her monthly headaches, forgoing any other pain medication. “There are times for conventional medicine in partnership with your doctor, but when it comes to health and wellness, women should be empowered to make decisions and self-experiment,” she said in an interview.

Ms. Brand is not alone. Significant numbers of women are replacing or supplementing prescription medications with cannabinoids, often without consulting their primary care physician, ob.gyn., or other specialist. At times, women have tried to have these conversations, only to be met with silence or worse.

Take Linda Fuller, a 58-year-old yoga instructor from Long Island who says that she uses CBD and THC for chronic sacroiliac pain after a car accident and to alleviate stress-triggered eczema flares. “I’ve had doctors turn their backs on me; I’ve had nurse practitioners walk out on me in the middle of a sentence,” she said in an interview.

Ms. Fuller said her conversion to cannabinoid medicine is relatively new; she never used cannabis recreationally before her accident but now considers it a gift. She doesn’t keep aspirin in the house and refused pain medication immediately after she injured her back.

Diana Krach, a 34-year-old writer from Maryland, says she’s encountered roadblocks about her decision to use cannabinoids for endometriosis and for pain from Crohn’s disease. When she tried to discuss her CBD use with a gastroenterologist, he interrupted her: “Whatever pot you’re smoking isn’t going to work, you’re going on biologics.”

Ms. Krach had not been smoking anything but had turned to a CBD tincture for symptom relief after prescription pain medications failed to help.

Ms. Brand, Ms. Fuller, and Ms. Krach are the tip of the iceberg when it comes to women seeking symptom relief outside the medicine cabinet. A recent survey in the Journal of Women’s Health of almost 1,000 women show that 90% (most between the ages of 35 and 44) had used cannabis and would consider using it to treat gynecologic pain. Roughly 80% said they would consider using it for procedure-related pain or other conditions. Additionally, women have reported using cannabinoids for PTSD, sleep disturbances or insomnia, anxiety, and migraine headaches.

Observational survey data have likewise shown that 80% of women with advanced or recurrent gynecologic malignancies who were prescribed cannabis reported that it was equivalent or superior to other medications for relieving pain, neuropathy, nausea, insomnia, decreased appetite, and anxiety.

In another survey, almost half (45%) of women with gynecologic malignancies who used nonprescribed cannabis for the same symptoms reported that they had reduced their use of prescription narcotics after initiating use of cannabis.
 

The gray zone

There has been a surge in self-reported cannabis use among pregnant women in particular. The National Survey on Drug Use and Health findings for the periods 2002-2003 and 2016-2017 highlight increases in adjusted prevalence rates from 3.4% to 7% in past-month use among pregnant women overall and from 5.7% to 12.1% during the first trimester alone.

“The more that you talk to pregnant women, the more that you realize that a lot are using cannabinoids for something that is basically medicinal, for sleep, for anxiety, or for nausea,” Katrina Mark, MD, an ob.gyn. and associate professor of medicine at the University of Maryland, College Park, said in an interview. “I’m not saying it’s fine to use drugs in pregnancy, but it is a grayer conversation than a lot of colleagues want to believe. Telling women to quit seems foolish since the alternative is to be anxious, don’t sleep, don’t eat, or use a medication that also has risks to it.”

One observational study shows that pregnant women themselves are conflicted. Although the majority believe that cannabis is “natural” and “safe,” compared with prescription drugs, they aren’t entirely in the dark about potential risks. They often express frustration with practitioners’ responses when these topics are broached during office visits. An observational survey among women and practitioners published in 2020 highlights that only half of doctors openly discouraged perinatal cannabis use and that others opted out of the discussion entirely.

This is the experience of many of the women that this news organization spoke with. Ms. Krach pointed out that “there’s a big deficit in listening; the doctor is supposed to be working for our behalf, especially when it comes to reproductive health.”

Dr. Mark believed that a lot of the conversation has been clouded by the illegality of the substance but that cannabinoids deserve as much of a fair chance for discussion and consideration as other medicines, which also carry risks in pregnancy. “There’s literally no evidence that it will work in pregnancy [for these symptoms], but there’s no evidence that it doesn’t, either,” she said in an interview. “When I have this conversation with colleagues who do not share my views, I try to encourage them to look at the actual risks versus the benefits versus the alternatives.”

The ‘entourage effect’

Data supporting cannabinoids have been mostly laboratory based, case based, or observational. However, several well-designed (albeit small) trials have demonstrated efficacy for chronic pain conditions, including neuropathic and headache pain, as well as in Crohn’s disease. Most investigators have concluded that dosage is important and that there is a synergistic interaction between compounds (known as the “entourage effect”) that relates to cannabinoid efficacy or lack thereof, as well as possible adverse effects.

In addition to legality issues, the entourage effect is one of the most important factors related to the medical use of cannabinoids. “There are literally thousands of cultivars of cannabis, each with their own phytocannabinoid and terpenic profiles that may produce distinct therapeutic effects, [so] it is misguided to speak of cannabis in monolithic terms. It is like making broad claims about soup,” wrote coauthor Samoon Ahmad, MD, in Medical Marijuana: A Clinical Handbook.

Additionally, the role that reproductive hormones play is not entirely understood. Reproductive-aged women appear to be more susceptible to a “telescoping” (gender-related progression to dependence) effect in comparison with men. Ziva Cooper, PhD, director of the Cannabis Research Initiative at the University of California, Los Angeles, said in an interview. She explained that research has shown that factors such as the degree of exposure, frequency of use, and menses confound this susceptibility.
 

It’s the data

Frustration over cannabinoid therapeutics abound, especially when it comes to data, legal issues, and lack of training. “The feedback that I hear from providers is that there isn’t enough information; we just don’t know enough about it,” Dr. Mark said, “but there is information that we do have, and ignoring it is not beneficial.”

Dr. Cooper concurred. Although she readily acknowledges that data from randomized, placebo-controlled trials are mostly lacking, she says, “There are signals in the literature providing evidence for the utility of cannabis and cannabinoids for pain and some other effects.”

Other practitioners said in an interview that some patients admit to using cannabinoids but that they lack the ample information to guide these patients. By and large, many women equate “natural” with “safe,” and some will experiment on their own to see what works.

Those experiments are not without risk, which is why “it’s just as important for physicians to talk to their patients about cannabis use as it is for patients to be forthcoming about that use,” said Dr. Cooper. “It could have implications on their overall health as well as interactions with other drugs that they’re using.”

That balance from a clinical perspective on cannabis is crucial, wrote coauthor Kenneth Hill, MD, in Medical Marijuana: A Clinical Handbook. “Without it,” he wrote, “the window of opportunity for a patient to accept treatment that she needs may not be open very long.”

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

When 42-year-old Danielle Simone Brand started having hormonal migraines, she first turned to cannabidiol (CBD) oil, eventually adding an occasional pull on a prefilled tetrahydrocannabinol (THC) vape for nighttime use. She was careful to avoid THC during work hours. A parenting and cannabis writer, Ms. Brand had more than a cursory background in cannabinoid medicine and had spent time at her local California dispensary discussing various cannabinoid components that might help alleviate her pain.

Anatoliy Sizov/Getty Images

A self-professed “do-it-yourselfer,” Ms. Brand continues to use cannabinoids for her monthly headaches, forgoing any other pain medication. “There are times for conventional medicine in partnership with your doctor, but when it comes to health and wellness, women should be empowered to make decisions and self-experiment,” she said in an interview.

Ms. Brand is not alone. Significant numbers of women are replacing or supplementing prescription medications with cannabinoids, often without consulting their primary care physician, ob.gyn., or other specialist. At times, women have tried to have these conversations, only to be met with silence or worse.

Take Linda Fuller, a 58-year-old yoga instructor from Long Island who says that she uses CBD and THC for chronic sacroiliac pain after a car accident and to alleviate stress-triggered eczema flares. “I’ve had doctors turn their backs on me; I’ve had nurse practitioners walk out on me in the middle of a sentence,” she said in an interview.

Ms. Fuller said her conversion to cannabinoid medicine is relatively new; she never used cannabis recreationally before her accident but now considers it a gift. She doesn’t keep aspirin in the house and refused pain medication immediately after she injured her back.

Diana Krach, a 34-year-old writer from Maryland, says she’s encountered roadblocks about her decision to use cannabinoids for endometriosis and for pain from Crohn’s disease. When she tried to discuss her CBD use with a gastroenterologist, he interrupted her: “Whatever pot you’re smoking isn’t going to work, you’re going on biologics.”

Ms. Krach had not been smoking anything but had turned to a CBD tincture for symptom relief after prescription pain medications failed to help.

Ms. Brand, Ms. Fuller, and Ms. Krach are the tip of the iceberg when it comes to women seeking symptom relief outside the medicine cabinet. A recent survey in the Journal of Women’s Health of almost 1,000 women show that 90% (most between the ages of 35 and 44) had used cannabis and would consider using it to treat gynecologic pain. Roughly 80% said they would consider using it for procedure-related pain or other conditions. Additionally, women have reported using cannabinoids for PTSD, sleep disturbances or insomnia, anxiety, and migraine headaches.

Observational survey data have likewise shown that 80% of women with advanced or recurrent gynecologic malignancies who were prescribed cannabis reported that it was equivalent or superior to other medications for relieving pain, neuropathy, nausea, insomnia, decreased appetite, and anxiety.

In another survey, almost half (45%) of women with gynecologic malignancies who used nonprescribed cannabis for the same symptoms reported that they had reduced their use of prescription narcotics after initiating use of cannabis.
 

The gray zone

There has been a surge in self-reported cannabis use among pregnant women in particular. The National Survey on Drug Use and Health findings for the periods 2002-2003 and 2016-2017 highlight increases in adjusted prevalence rates from 3.4% to 7% in past-month use among pregnant women overall and from 5.7% to 12.1% during the first trimester alone.

“The more that you talk to pregnant women, the more that you realize that a lot are using cannabinoids for something that is basically medicinal, for sleep, for anxiety, or for nausea,” Katrina Mark, MD, an ob.gyn. and associate professor of medicine at the University of Maryland, College Park, said in an interview. “I’m not saying it’s fine to use drugs in pregnancy, but it is a grayer conversation than a lot of colleagues want to believe. Telling women to quit seems foolish since the alternative is to be anxious, don’t sleep, don’t eat, or use a medication that also has risks to it.”

One observational study shows that pregnant women themselves are conflicted. Although the majority believe that cannabis is “natural” and “safe,” compared with prescription drugs, they aren’t entirely in the dark about potential risks. They often express frustration with practitioners’ responses when these topics are broached during office visits. An observational survey among women and practitioners published in 2020 highlights that only half of doctors openly discouraged perinatal cannabis use and that others opted out of the discussion entirely.

This is the experience of many of the women that this news organization spoke with. Ms. Krach pointed out that “there’s a big deficit in listening; the doctor is supposed to be working for our behalf, especially when it comes to reproductive health.”

Dr. Mark believed that a lot of the conversation has been clouded by the illegality of the substance but that cannabinoids deserve as much of a fair chance for discussion and consideration as other medicines, which also carry risks in pregnancy. “There’s literally no evidence that it will work in pregnancy [for these symptoms], but there’s no evidence that it doesn’t, either,” she said in an interview. “When I have this conversation with colleagues who do not share my views, I try to encourage them to look at the actual risks versus the benefits versus the alternatives.”

The ‘entourage effect’

Data supporting cannabinoids have been mostly laboratory based, case based, or observational. However, several well-designed (albeit small) trials have demonstrated efficacy for chronic pain conditions, including neuropathic and headache pain, as well as in Crohn’s disease. Most investigators have concluded that dosage is important and that there is a synergistic interaction between compounds (known as the “entourage effect”) that relates to cannabinoid efficacy or lack thereof, as well as possible adverse effects.

In addition to legality issues, the entourage effect is one of the most important factors related to the medical use of cannabinoids. “There are literally thousands of cultivars of cannabis, each with their own phytocannabinoid and terpenic profiles that may produce distinct therapeutic effects, [so] it is misguided to speak of cannabis in monolithic terms. It is like making broad claims about soup,” wrote coauthor Samoon Ahmad, MD, in Medical Marijuana: A Clinical Handbook.

Additionally, the role that reproductive hormones play is not entirely understood. Reproductive-aged women appear to be more susceptible to a “telescoping” (gender-related progression to dependence) effect in comparison with men. Ziva Cooper, PhD, director of the Cannabis Research Initiative at the University of California, Los Angeles, said in an interview. She explained that research has shown that factors such as the degree of exposure, frequency of use, and menses confound this susceptibility.
 

It’s the data

Frustration over cannabinoid therapeutics abound, especially when it comes to data, legal issues, and lack of training. “The feedback that I hear from providers is that there isn’t enough information; we just don’t know enough about it,” Dr. Mark said, “but there is information that we do have, and ignoring it is not beneficial.”

Dr. Cooper concurred. Although she readily acknowledges that data from randomized, placebo-controlled trials are mostly lacking, she says, “There are signals in the literature providing evidence for the utility of cannabis and cannabinoids for pain and some other effects.”

Other practitioners said in an interview that some patients admit to using cannabinoids but that they lack the ample information to guide these patients. By and large, many women equate “natural” with “safe,” and some will experiment on their own to see what works.

Those experiments are not without risk, which is why “it’s just as important for physicians to talk to their patients about cannabis use as it is for patients to be forthcoming about that use,” said Dr. Cooper. “It could have implications on their overall health as well as interactions with other drugs that they’re using.”

That balance from a clinical perspective on cannabis is crucial, wrote coauthor Kenneth Hill, MD, in Medical Marijuana: A Clinical Handbook. “Without it,” he wrote, “the window of opportunity for a patient to accept treatment that she needs may not be open very long.”

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

The emergence of multiple inflammatory syndrome in children (MIS-C) in association with COVID-19 may be complicating the investigation and diagnosis of more common viral and bacterial infections, potentially delaying treatment and prolonging hospital stays.

Two recent articles published online in Hospital Pediatrics provide evidence of this phenomenon. The articles outlined case studies of children who underwent extensive investigation for MIS-C when in fact they had less severe and more common infections. MIS-C is a severe but rare syndrome that involves systemic hyperinflammation with fever and multisystem organ dysfunction similar to that of Kawasaki disease (KD).

In one of the articles, Matthew Molloy, MD, MPH, of the division of pediatric hospital medicine at Cincinnati Children’s Hospital Medical Center, and colleagues aptly asked: “What are we missing in our search for MIS-C?”
 

E. coli, not SARS-CoV-2

That question arose from a case involving a 3-year-old boy who had a 6-day history of fever and fatigue. Three days earlier, he had tested negative for strep antigen and COVID-19. He had a persistent, high fever, reduced appetite, and reduced urine output and was taken to the ED. On physical examination, there was no rash, skin peeling, redness of the eye or oral mucosa, congestion, rhinorrhea, cough, shortness of breath, chest pain, abdominal pain, nausea, vomiting, or diarrhea.

Urinalysis results and exam findings were suspicious for pyelonephritis. Other findings from an extensive laboratory workup raised the alarm that the boy was suffering from MIS-C as opposed to incomplete KD. After admission to hospital medicine, the cardiology, rheumatology, and infectious disease teams were called in to consult.

Repeat labs were planned for the following day before initiating therapy. On day 2, the child’s urine culture was positive for gram-negative rods, later identified as Escherichia coli. The boy was started on ceftriaxone. Left renal scarring was apparent on ultrasound. The patient’s condition resolved after 36 hours, and he was discharged home with antibiotics.
 

‘Diagnosis derailed’

Calling this a case of “diagnosis derailed,” the authors noted that, in the pre-COVID era, this child’s signs and symptoms would likely have triggered a more targeted and less costly evaluation for more common infectious and noninfectious causes, including pyelonephritis, absent any physical exam findings consistent with KD.

“However, the patient presented in the midst of the COVID-19 pandemic with growing awareness of a new clinical entity,” Dr. Molloy and colleagues wrote. “Anchored to the patient’s persistent fever, the medical team initiated an extensive, costly, and ultimately unnecessary workup to avoid missing the diagnosis of MIS-C; a not yet well-described diagnosis with potentially severe morbidity.”

Confirmation bias and diagnostic momentum likely contributed to the early focus on MIS-C rather than more common alternatives, the authors acknowledged. The addition of mildly abnormal laboratory data not typically obtained in the evaluation of fever led the team astray. “The diagnosis and definitive treatment may have been made earlier had the focus on concern for MIS-C not been present,” Dr. Molloy said in an interview.
 

Keeping value in care

The authors recognized that their initial approach to evaluating for MIS-C provided low-value care. “In our desire to not ‘miss’ MIS-C, we were performing costly evaluations that at times produced mildly abnormal, nonspecific results,” they wrote. That triggered a cascade of specialty consultations, follow-up testing, and an unwarranted diagnostic preoccupation with MIS-C.

Determining the extra price tag for the child’s workup would be complex and difficult because there is a difference in the cost to the hospital and the cost to the family, Dr. Molloy said. “However, there are potential cost savings that would be related to making a correct diagnosis in a timely manner in terms of preventing downstream effects from delayed diagnoses.”

Even as clinicians struggle with the challenging SARS-CoV-2 learning curve, Dr. Molloy and associates urged them to continue to strive for high-value care, with an unwavering focus on using only necessary resources, a stewardship the pandemic has shown to be critical.

“The COVID-19 pandemic has been an incredibly stressful time for physicians and for families,” Dr. Molloy said. “COVID-19 and related conditions like MIS-C are new, and we are learning more and more about them every week. These diagnoses are understandably on the minds of physicians and families when children present with fever.” Notwithstanding, the boy’s case underscores the need for clinicians to consider alternate diagnoses and the value of the care provided.
 

Impact of bias

Dr. Molloy’s group brings home the cognitive biases practitioners often suffer from, including anchoring and confirmation bias and diagnostic momentum, according to J. Howard Smart, MD, chief of pediatrics at Sharp Mary Birch Hospital for Women and Newborns, San Diego, and an assistant clinical professor of pediatrics at University of California, San Diego.

“But it is one thing to recognize these in retrospect and quite another to consider whether they may be happening to you yourself in real time,” he said in an interview. “It is almost as if we need to have a ‘time out,’ where we stop and ask ourselves whether there is something else that could be explaining our patient’s presentation, something that would be more common and more likely to be occurring.”

According to Dr. Smart, who was not involved in Dr. Molloy’s study, the team’s premature diagnostic focus on MIS-C was almost the inverse of what typically happens with KD. “It is usually the case that Kawasaki disease does not enter the differential diagnosis until late in the course of the fever, typically on day 5 or later, when it may have been better to think of it earlier,” he said.

In the second article, Andrea Dean, MD, of the department of pediatrics at Baylor College of Medicine and Texas Children’s Hospital, both in Houston, and colleagues outlined the cases of five patients aged 8-17 years who were hospitalized in May 2020 for suspected MIS-C. They exhibited inflammatory and other concerning indicators but were eventually discharged with a diagnosis of murine typhus.

This flea-borne infection, most commonly reported in the United States in the southeastern Gulf Coast region, Hawaii, and California, is often associated with a triad of fever, rash, and headache.

Cases have been rising in southern Texas, and Dr. Dean and colleagues postulated that school closures and social distancing may have increased exposure as a result of children spending more time outdoors or with pets. “Alternatively, parental concern for SARS-CoV-2 infection could mean children with symptoms are presenting to care and being referred or admitted to the hospital more frequently due to provider concern for MIS-C,” they wrote.
 

Cardiac involvement

The most concerning of the five cases in terms of possible MIS-C, Dr. Dean said in an interview, was that of a 12-year-old boy who had fever for 6 days in association with headache, eczematous rash, dry lips, and conjunctivitis. Laboratory tests showed a mildly elevated C-reactive protein level, hyponatremia, and thrombocytopenia, as well as sterile pyuria and mildly elevated prothrombin time. He was treated empirically with doxycycline, and his fever resolved over the next 24 hours.

An echocardiogram at initial evaluation, however, revealed mild dilation of the left anterior descending and right coronary arteries, which led to the administration of intravenous immunoglobulin and aspirin for atypical KD, in contrast to MIS-C. The authors postulated that mild cardiac involvement in disorders other than MIS-C and KD may be underrecognized.

The lesson from these cases, Dr. Dean and associates concluded, is that hospitalists must maintain a wide differential diagnosis when assessing a child with prolonged fever and evidence of systemic inflammation. The CDC stipulates that a diagnosis of MIS-C requires the absence of a plausible alternative diagnosis.

In addition to common viral, bacterial, and noninfectious disorders, a range of regional endemic rickettsial and parasitic infections must be considered as alternative diagnoses to MIS-C. “Many of these diseases cannot be reliably differentiated from MIS-C on presentation, and as community exposure to SARS-CoV-2 grows, hospitalists should be prepared to admit febrile children with evidence of systemic inflammation for brief observation periods to evaluate for MIS-C,” Dr. Dean’s group wrote. In this context, however, empiric treatment for common or even uncommon infectious diseases may avoid overdiagnosis and overtreatment of MIS-C as well as improve patient outcomes.

“We do have specific MIS-C guidelines at our institution,” Dr. Dean said, “but like all institutions, we are dealing with the broad definition of MIS-C according to the World Health Organization and the CDC, which is really the takeaway from this paper.”
 

More difficult differentiation

Both groups of authors pointed out that, as SARS-CoV-2 spreads throughout a community, a higher percentage of the population will have positive results on antibody testing, and such results will become less useful for differentiating between MIS-C and other conditions.

Despite these series’ cautionary lessons, other experts point to the critical importance of including MIS-C early on in the interest of efficient diagnosis and therapy. “In the cases cited, other pathologies were evaluated for and treated accordingly,” said Kara Gross Margolis, MD, AGAF, an associate professor of pediatrics in the division of pediatric gastroenterology, hepatology, and nutrition at Morgan Stanley Children’s Hospital,New York. “These papers stress the need for a balance that is important, and all potential diagnoses need to be considered, but MIS-C, due to its potential severe consequences, also needs to be on our differential now.”

In her view, as this new high-morbidity entity becomes more widespread during the pandemic, it will be increasingly important to keep this condition on the diagnostic radar.

Interestingly, in a converse example of diagnostic clouding, Dr. Gross Margolis’s group reported (Gastroenterology. 2020 Oct;159[4]:1571-4.e2) last year on a pediatric case series in which the presence of gastrointestinal symptoms in children with COVID-19–related MIS-C muddied the diagnosis by confusing this potentially severe syndrome with more common and less toxic gastrointestinal infections.

According to Dr. Smart, although the two reports don’t offer evidence for a particular diagnostic practice, they can inform the decision-making process. “It may be that we will have enough evidence shortly to say what the best practice is regarding diagnostic evaluation of possible MIS-C cases,” he said. “Until then, we must remember that common things occur commonly, even during a global pandemic.”

Neither of the two reports received any specific funding. The authors disclosed no relevant financial relationships.

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

The emergence of multiple inflammatory syndrome in children (MIS-C) in association with COVID-19 may be complicating the investigation and diagnosis of more common viral and bacterial infections, potentially delaying treatment and prolonging hospital stays.

Two recent articles published online in Hospital Pediatrics provide evidence of this phenomenon. The articles outlined case studies of children who underwent extensive investigation for MIS-C when in fact they had less severe and more common infections. MIS-C is a severe but rare syndrome that involves systemic hyperinflammation with fever and multisystem organ dysfunction similar to that of Kawasaki disease (KD).

In one of the articles, Matthew Molloy, MD, MPH, of the division of pediatric hospital medicine at Cincinnati Children’s Hospital Medical Center, and colleagues aptly asked: “What are we missing in our search for MIS-C?”
 

E. coli, not SARS-CoV-2

That question arose from a case involving a 3-year-old boy who had a 6-day history of fever and fatigue. Three days earlier, he had tested negative for strep antigen and COVID-19. He had a persistent, high fever, reduced appetite, and reduced urine output and was taken to the ED. On physical examination, there was no rash, skin peeling, redness of the eye or oral mucosa, congestion, rhinorrhea, cough, shortness of breath, chest pain, abdominal pain, nausea, vomiting, or diarrhea.

Urinalysis results and exam findings were suspicious for pyelonephritis. Other findings from an extensive laboratory workup raised the alarm that the boy was suffering from MIS-C as opposed to incomplete KD. After admission to hospital medicine, the cardiology, rheumatology, and infectious disease teams were called in to consult.

Repeat labs were planned for the following day before initiating therapy. On day 2, the child’s urine culture was positive for gram-negative rods, later identified as Escherichia coli. The boy was started on ceftriaxone. Left renal scarring was apparent on ultrasound. The patient’s condition resolved after 36 hours, and he was discharged home with antibiotics.
 

‘Diagnosis derailed’

Calling this a case of “diagnosis derailed,” the authors noted that, in the pre-COVID era, this child’s signs and symptoms would likely have triggered a more targeted and less costly evaluation for more common infectious and noninfectious causes, including pyelonephritis, absent any physical exam findings consistent with KD.

“However, the patient presented in the midst of the COVID-19 pandemic with growing awareness of a new clinical entity,” Dr. Molloy and colleagues wrote. “Anchored to the patient’s persistent fever, the medical team initiated an extensive, costly, and ultimately unnecessary workup to avoid missing the diagnosis of MIS-C; a not yet well-described diagnosis with potentially severe morbidity.”

Confirmation bias and diagnostic momentum likely contributed to the early focus on MIS-C rather than more common alternatives, the authors acknowledged. The addition of mildly abnormal laboratory data not typically obtained in the evaluation of fever led the team astray. “The diagnosis and definitive treatment may have been made earlier had the focus on concern for MIS-C not been present,” Dr. Molloy said in an interview.
 

Keeping value in care

The authors recognized that their initial approach to evaluating for MIS-C provided low-value care. “In our desire to not ‘miss’ MIS-C, we were performing costly evaluations that at times produced mildly abnormal, nonspecific results,” they wrote. That triggered a cascade of specialty consultations, follow-up testing, and an unwarranted diagnostic preoccupation with MIS-C.

Determining the extra price tag for the child’s workup would be complex and difficult because there is a difference in the cost to the hospital and the cost to the family, Dr. Molloy said. “However, there are potential cost savings that would be related to making a correct diagnosis in a timely manner in terms of preventing downstream effects from delayed diagnoses.”

Even as clinicians struggle with the challenging SARS-CoV-2 learning curve, Dr. Molloy and associates urged them to continue to strive for high-value care, with an unwavering focus on using only necessary resources, a stewardship the pandemic has shown to be critical.

“The COVID-19 pandemic has been an incredibly stressful time for physicians and for families,” Dr. Molloy said. “COVID-19 and related conditions like MIS-C are new, and we are learning more and more about them every week. These diagnoses are understandably on the minds of physicians and families when children present with fever.” Notwithstanding, the boy’s case underscores the need for clinicians to consider alternate diagnoses and the value of the care provided.
 

Impact of bias

Dr. Molloy’s group brings home the cognitive biases practitioners often suffer from, including anchoring and confirmation bias and diagnostic momentum, according to J. Howard Smart, MD, chief of pediatrics at Sharp Mary Birch Hospital for Women and Newborns, San Diego, and an assistant clinical professor of pediatrics at University of California, San Diego.

“But it is one thing to recognize these in retrospect and quite another to consider whether they may be happening to you yourself in real time,” he said in an interview. “It is almost as if we need to have a ‘time out,’ where we stop and ask ourselves whether there is something else that could be explaining our patient’s presentation, something that would be more common and more likely to be occurring.”

According to Dr. Smart, who was not involved in Dr. Molloy’s study, the team’s premature diagnostic focus on MIS-C was almost the inverse of what typically happens with KD. “It is usually the case that Kawasaki disease does not enter the differential diagnosis until late in the course of the fever, typically on day 5 or later, when it may have been better to think of it earlier,” he said.

In the second article, Andrea Dean, MD, of the department of pediatrics at Baylor College of Medicine and Texas Children’s Hospital, both in Houston, and colleagues outlined the cases of five patients aged 8-17 years who were hospitalized in May 2020 for suspected MIS-C. They exhibited inflammatory and other concerning indicators but were eventually discharged with a diagnosis of murine typhus.

This flea-borne infection, most commonly reported in the United States in the southeastern Gulf Coast region, Hawaii, and California, is often associated with a triad of fever, rash, and headache.

Cases have been rising in southern Texas, and Dr. Dean and colleagues postulated that school closures and social distancing may have increased exposure as a result of children spending more time outdoors or with pets. “Alternatively, parental concern for SARS-CoV-2 infection could mean children with symptoms are presenting to care and being referred or admitted to the hospital more frequently due to provider concern for MIS-C,” they wrote.
 

Cardiac involvement

The most concerning of the five cases in terms of possible MIS-C, Dr. Dean said in an interview, was that of a 12-year-old boy who had fever for 6 days in association with headache, eczematous rash, dry lips, and conjunctivitis. Laboratory tests showed a mildly elevated C-reactive protein level, hyponatremia, and thrombocytopenia, as well as sterile pyuria and mildly elevated prothrombin time. He was treated empirically with doxycycline, and his fever resolved over the next 24 hours.

An echocardiogram at initial evaluation, however, revealed mild dilation of the left anterior descending and right coronary arteries, which led to the administration of intravenous immunoglobulin and aspirin for atypical KD, in contrast to MIS-C. The authors postulated that mild cardiac involvement in disorders other than MIS-C and KD may be underrecognized.

The lesson from these cases, Dr. Dean and associates concluded, is that hospitalists must maintain a wide differential diagnosis when assessing a child with prolonged fever and evidence of systemic inflammation. The CDC stipulates that a diagnosis of MIS-C requires the absence of a plausible alternative diagnosis.

In addition to common viral, bacterial, and noninfectious disorders, a range of regional endemic rickettsial and parasitic infections must be considered as alternative diagnoses to MIS-C. “Many of these diseases cannot be reliably differentiated from MIS-C on presentation, and as community exposure to SARS-CoV-2 grows, hospitalists should be prepared to admit febrile children with evidence of systemic inflammation for brief observation periods to evaluate for MIS-C,” Dr. Dean’s group wrote. In this context, however, empiric treatment for common or even uncommon infectious diseases may avoid overdiagnosis and overtreatment of MIS-C as well as improve patient outcomes.

“We do have specific MIS-C guidelines at our institution,” Dr. Dean said, “but like all institutions, we are dealing with the broad definition of MIS-C according to the World Health Organization and the CDC, which is really the takeaway from this paper.”
 

More difficult differentiation

Both groups of authors pointed out that, as SARS-CoV-2 spreads throughout a community, a higher percentage of the population will have positive results on antibody testing, and such results will become less useful for differentiating between MIS-C and other conditions.

Despite these series’ cautionary lessons, other experts point to the critical importance of including MIS-C early on in the interest of efficient diagnosis and therapy. “In the cases cited, other pathologies were evaluated for and treated accordingly,” said Kara Gross Margolis, MD, AGAF, an associate professor of pediatrics in the division of pediatric gastroenterology, hepatology, and nutrition at Morgan Stanley Children’s Hospital,New York. “These papers stress the need for a balance that is important, and all potential diagnoses need to be considered, but MIS-C, due to its potential severe consequences, also needs to be on our differential now.”

In her view, as this new high-morbidity entity becomes more widespread during the pandemic, it will be increasingly important to keep this condition on the diagnostic radar.

Interestingly, in a converse example of diagnostic clouding, Dr. Gross Margolis’s group reported (Gastroenterology. 2020 Oct;159[4]:1571-4.e2) last year on a pediatric case series in which the presence of gastrointestinal symptoms in children with COVID-19–related MIS-C muddied the diagnosis by confusing this potentially severe syndrome with more common and less toxic gastrointestinal infections.

According to Dr. Smart, although the two reports don’t offer evidence for a particular diagnostic practice, they can inform the decision-making process. “It may be that we will have enough evidence shortly to say what the best practice is regarding diagnostic evaluation of possible MIS-C cases,” he said. “Until then, we must remember that common things occur commonly, even during a global pandemic.”

Neither of the two reports received any specific funding. The authors disclosed no relevant financial relationships.

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

The emergence of multiple inflammatory syndrome in children (MIS-C) in association with COVID-19 may be complicating the investigation and diagnosis of more common viral and bacterial infections, potentially delaying treatment and prolonging hospital stays.

Two recent articles published online in Hospital Pediatrics provide evidence of this phenomenon. The articles outlined case studies of children who underwent extensive investigation for MIS-C when in fact they had less severe and more common infections. MIS-C is a severe but rare syndrome that involves systemic hyperinflammation with fever and multisystem organ dysfunction similar to that of Kawasaki disease (KD).

In one of the articles, Matthew Molloy, MD, MPH, of the division of pediatric hospital medicine at Cincinnati Children’s Hospital Medical Center, and colleagues aptly asked: “What are we missing in our search for MIS-C?”
 

E. coli, not SARS-CoV-2

That question arose from a case involving a 3-year-old boy who had a 6-day history of fever and fatigue. Three days earlier, he had tested negative for strep antigen and COVID-19. He had a persistent, high fever, reduced appetite, and reduced urine output and was taken to the ED. On physical examination, there was no rash, skin peeling, redness of the eye or oral mucosa, congestion, rhinorrhea, cough, shortness of breath, chest pain, abdominal pain, nausea, vomiting, or diarrhea.

Urinalysis results and exam findings were suspicious for pyelonephritis. Other findings from an extensive laboratory workup raised the alarm that the boy was suffering from MIS-C as opposed to incomplete KD. After admission to hospital medicine, the cardiology, rheumatology, and infectious disease teams were called in to consult.

Repeat labs were planned for the following day before initiating therapy. On day 2, the child’s urine culture was positive for gram-negative rods, later identified as Escherichia coli. The boy was started on ceftriaxone. Left renal scarring was apparent on ultrasound. The patient’s condition resolved after 36 hours, and he was discharged home with antibiotics.
 

‘Diagnosis derailed’

Calling this a case of “diagnosis derailed,” the authors noted that, in the pre-COVID era, this child’s signs and symptoms would likely have triggered a more targeted and less costly evaluation for more common infectious and noninfectious causes, including pyelonephritis, absent any physical exam findings consistent with KD.

“However, the patient presented in the midst of the COVID-19 pandemic with growing awareness of a new clinical entity,” Dr. Molloy and colleagues wrote. “Anchored to the patient’s persistent fever, the medical team initiated an extensive, costly, and ultimately unnecessary workup to avoid missing the diagnosis of MIS-C; a not yet well-described diagnosis with potentially severe morbidity.”

Confirmation bias and diagnostic momentum likely contributed to the early focus on MIS-C rather than more common alternatives, the authors acknowledged. The addition of mildly abnormal laboratory data not typically obtained in the evaluation of fever led the team astray. “The diagnosis and definitive treatment may have been made earlier had the focus on concern for MIS-C not been present,” Dr. Molloy said in an interview.
 

Keeping value in care

The authors recognized that their initial approach to evaluating for MIS-C provided low-value care. “In our desire to not ‘miss’ MIS-C, we were performing costly evaluations that at times produced mildly abnormal, nonspecific results,” they wrote. That triggered a cascade of specialty consultations, follow-up testing, and an unwarranted diagnostic preoccupation with MIS-C.

Determining the extra price tag for the child’s workup would be complex and difficult because there is a difference in the cost to the hospital and the cost to the family, Dr. Molloy said. “However, there are potential cost savings that would be related to making a correct diagnosis in a timely manner in terms of preventing downstream effects from delayed diagnoses.”

Even as clinicians struggle with the challenging SARS-CoV-2 learning curve, Dr. Molloy and associates urged them to continue to strive for high-value care, with an unwavering focus on using only necessary resources, a stewardship the pandemic has shown to be critical.

“The COVID-19 pandemic has been an incredibly stressful time for physicians and for families,” Dr. Molloy said. “COVID-19 and related conditions like MIS-C are new, and we are learning more and more about them every week. These diagnoses are understandably on the minds of physicians and families when children present with fever.” Notwithstanding, the boy’s case underscores the need for clinicians to consider alternate diagnoses and the value of the care provided.
 

Impact of bias

Dr. Molloy’s group brings home the cognitive biases practitioners often suffer from, including anchoring and confirmation bias and diagnostic momentum, according to J. Howard Smart, MD, chief of pediatrics at Sharp Mary Birch Hospital for Women and Newborns, San Diego, and an assistant clinical professor of pediatrics at University of California, San Diego.

“But it is one thing to recognize these in retrospect and quite another to consider whether they may be happening to you yourself in real time,” he said in an interview. “It is almost as if we need to have a ‘time out,’ where we stop and ask ourselves whether there is something else that could be explaining our patient’s presentation, something that would be more common and more likely to be occurring.”

According to Dr. Smart, who was not involved in Dr. Molloy’s study, the team’s premature diagnostic focus on MIS-C was almost the inverse of what typically happens with KD. “It is usually the case that Kawasaki disease does not enter the differential diagnosis until late in the course of the fever, typically on day 5 or later, when it may have been better to think of it earlier,” he said.

In the second article, Andrea Dean, MD, of the department of pediatrics at Baylor College of Medicine and Texas Children’s Hospital, both in Houston, and colleagues outlined the cases of five patients aged 8-17 years who were hospitalized in May 2020 for suspected MIS-C. They exhibited inflammatory and other concerning indicators but were eventually discharged with a diagnosis of murine typhus.

This flea-borne infection, most commonly reported in the United States in the southeastern Gulf Coast region, Hawaii, and California, is often associated with a triad of fever, rash, and headache.

Cases have been rising in southern Texas, and Dr. Dean and colleagues postulated that school closures and social distancing may have increased exposure as a result of children spending more time outdoors or with pets. “Alternatively, parental concern for SARS-CoV-2 infection could mean children with symptoms are presenting to care and being referred or admitted to the hospital more frequently due to provider concern for MIS-C,” they wrote.
 

Cardiac involvement

The most concerning of the five cases in terms of possible MIS-C, Dr. Dean said in an interview, was that of a 12-year-old boy who had fever for 6 days in association with headache, eczematous rash, dry lips, and conjunctivitis. Laboratory tests showed a mildly elevated C-reactive protein level, hyponatremia, and thrombocytopenia, as well as sterile pyuria and mildly elevated prothrombin time. He was treated empirically with doxycycline, and his fever resolved over the next 24 hours.

An echocardiogram at initial evaluation, however, revealed mild dilation of the left anterior descending and right coronary arteries, which led to the administration of intravenous immunoglobulin and aspirin for atypical KD, in contrast to MIS-C. The authors postulated that mild cardiac involvement in disorders other than MIS-C and KD may be underrecognized.

The lesson from these cases, Dr. Dean and associates concluded, is that hospitalists must maintain a wide differential diagnosis when assessing a child with prolonged fever and evidence of systemic inflammation. The CDC stipulates that a diagnosis of MIS-C requires the absence of a plausible alternative diagnosis.

In addition to common viral, bacterial, and noninfectious disorders, a range of regional endemic rickettsial and parasitic infections must be considered as alternative diagnoses to MIS-C. “Many of these diseases cannot be reliably differentiated from MIS-C on presentation, and as community exposure to SARS-CoV-2 grows, hospitalists should be prepared to admit febrile children with evidence of systemic inflammation for brief observation periods to evaluate for MIS-C,” Dr. Dean’s group wrote. In this context, however, empiric treatment for common or even uncommon infectious diseases may avoid overdiagnosis and overtreatment of MIS-C as well as improve patient outcomes.

“We do have specific MIS-C guidelines at our institution,” Dr. Dean said, “but like all institutions, we are dealing with the broad definition of MIS-C according to the World Health Organization and the CDC, which is really the takeaway from this paper.”
 

More difficult differentiation

Both groups of authors pointed out that, as SARS-CoV-2 spreads throughout a community, a higher percentage of the population will have positive results on antibody testing, and such results will become less useful for differentiating between MIS-C and other conditions.

Despite these series’ cautionary lessons, other experts point to the critical importance of including MIS-C early on in the interest of efficient diagnosis and therapy. “In the cases cited, other pathologies were evaluated for and treated accordingly,” said Kara Gross Margolis, MD, AGAF, an associate professor of pediatrics in the division of pediatric gastroenterology, hepatology, and nutrition at Morgan Stanley Children’s Hospital,New York. “These papers stress the need for a balance that is important, and all potential diagnoses need to be considered, but MIS-C, due to its potential severe consequences, also needs to be on our differential now.”

In her view, as this new high-morbidity entity becomes more widespread during the pandemic, it will be increasingly important to keep this condition on the diagnostic radar.

Interestingly, in a converse example of diagnostic clouding, Dr. Gross Margolis’s group reported (Gastroenterology. 2020 Oct;159[4]:1571-4.e2) last year on a pediatric case series in which the presence of gastrointestinal symptoms in children with COVID-19–related MIS-C muddied the diagnosis by confusing this potentially severe syndrome with more common and less toxic gastrointestinal infections.

According to Dr. Smart, although the two reports don’t offer evidence for a particular diagnostic practice, they can inform the decision-making process. “It may be that we will have enough evidence shortly to say what the best practice is regarding diagnostic evaluation of possible MIS-C cases,” he said. “Until then, we must remember that common things occur commonly, even during a global pandemic.”

Neither of the two reports received any specific funding. The authors disclosed no relevant financial relationships.

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

States that implemented mask mandates in 2020 saw a decline in the growth of COVID-19 hospitalizations between March and October 2020, according to a new study published Feb. 5 in the CDC’s Morbidity and Mortality Weekly Report.

Hospitalization growth rates declined by 5.5 percentage points for adults between ages 18-64 about 3 weeks after the mandates were implemented, compared with climbing growth rates in the 4 weeks before mandates.

CDC Director Rochelle Walensky said she was pleased to see the results, but that it’s “too early” to tell whether President Joe Biden’s recent mask orders have had an effect on cases and hospitalizations in 2021.

“We’re going to be watching the mask data very carefully,” she said during a news briefing with the White House COVID-19 Response Team on Feb. 5. “I think it’s probably still a bit too early to tell, but I’m encouraged with the decrease in case rates right now.”

In another study published Feb. 5 in the Morbidity and Mortality Weekly Report, trained observers tracked mask use at six universities with mask mandates between September and November 2020. Overall, observers reported that about 92% of people wore masks correctly indoors, which varied based on the type of mask.

About 97% of people used N95 masks correctly, compared with 92% who used cloth masks, and 79% who used bandanas, scarves, or neck gaiters. Cloth masks were most common, and bandanas and scarves were least common.

The Biden administration is considering whether to send masks directly to American households to encourage people to wear them, according to NBC News. The White House COVID-19 Response Team is debating the logistics of mailing out masks, including how many to send and what the mask material would be, the news outlet reported.

Wisconsin Gov. Tony Evers reissued a new statewide mask mandate on Feb. 4, just an hour after the Republican-controlled legislature voted to repeal his previous mandate, according to The Associated Press. Gov. Evers said his priority is to keep people safe and that wearing a mask is the easiest way to do so.

“If the legislature keeps playing politics and we don’t keep wearing masks, we’re going to see more preventable deaths,” he said. “It’s going to take even longer to get our state and our economy back on track.”

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

States that implemented mask mandates in 2020 saw a decline in the growth of COVID-19 hospitalizations between March and October 2020, according to a new study published Feb. 5 in the CDC’s Morbidity and Mortality Weekly Report.

Hospitalization growth rates declined by 5.5 percentage points for adults between ages 18-64 about 3 weeks after the mandates were implemented, compared with climbing growth rates in the 4 weeks before mandates.

CDC Director Rochelle Walensky said she was pleased to see the results, but that it’s “too early” to tell whether President Joe Biden’s recent mask orders have had an effect on cases and hospitalizations in 2021.

“We’re going to be watching the mask data very carefully,” she said during a news briefing with the White House COVID-19 Response Team on Feb. 5. “I think it’s probably still a bit too early to tell, but I’m encouraged with the decrease in case rates right now.”

In another study published Feb. 5 in the Morbidity and Mortality Weekly Report, trained observers tracked mask use at six universities with mask mandates between September and November 2020. Overall, observers reported that about 92% of people wore masks correctly indoors, which varied based on the type of mask.

About 97% of people used N95 masks correctly, compared with 92% who used cloth masks, and 79% who used bandanas, scarves, or neck gaiters. Cloth masks were most common, and bandanas and scarves were least common.

The Biden administration is considering whether to send masks directly to American households to encourage people to wear them, according to NBC News. The White House COVID-19 Response Team is debating the logistics of mailing out masks, including how many to send and what the mask material would be, the news outlet reported.

Wisconsin Gov. Tony Evers reissued a new statewide mask mandate on Feb. 4, just an hour after the Republican-controlled legislature voted to repeal his previous mandate, according to The Associated Press. Gov. Evers said his priority is to keep people safe and that wearing a mask is the easiest way to do so.

“If the legislature keeps playing politics and we don’t keep wearing masks, we’re going to see more preventable deaths,” he said. “It’s going to take even longer to get our state and our economy back on track.”

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

States that implemented mask mandates in 2020 saw a decline in the growth of COVID-19 hospitalizations between March and October 2020, according to a new study published Feb. 5 in the CDC’s Morbidity and Mortality Weekly Report.

Hospitalization growth rates declined by 5.5 percentage points for adults between ages 18-64 about 3 weeks after the mandates were implemented, compared with climbing growth rates in the 4 weeks before mandates.

CDC Director Rochelle Walensky said she was pleased to see the results, but that it’s “too early” to tell whether President Joe Biden’s recent mask orders have had an effect on cases and hospitalizations in 2021.

“We’re going to be watching the mask data very carefully,” she said during a news briefing with the White House COVID-19 Response Team on Feb. 5. “I think it’s probably still a bit too early to tell, but I’m encouraged with the decrease in case rates right now.”

In another study published Feb. 5 in the Morbidity and Mortality Weekly Report, trained observers tracked mask use at six universities with mask mandates between September and November 2020. Overall, observers reported that about 92% of people wore masks correctly indoors, which varied based on the type of mask.

About 97% of people used N95 masks correctly, compared with 92% who used cloth masks, and 79% who used bandanas, scarves, or neck gaiters. Cloth masks were most common, and bandanas and scarves were least common.

The Biden administration is considering whether to send masks directly to American households to encourage people to wear them, according to NBC News. The White House COVID-19 Response Team is debating the logistics of mailing out masks, including how many to send and what the mask material would be, the news outlet reported.

Wisconsin Gov. Tony Evers reissued a new statewide mask mandate on Feb. 4, just an hour after the Republican-controlled legislature voted to repeal his previous mandate, according to The Associated Press. Gov. Evers said his priority is to keep people safe and that wearing a mask is the easiest way to do so.

“If the legislature keeps playing politics and we don’t keep wearing masks, we’re going to see more preventable deaths,” he said. “It’s going to take even longer to get our state and our economy back on track.”

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

Among critically ill patients pulseless after planned withdrawal of life-sustaining therapies, cardiac activity restarted in 14% of cases, research shows.

Reassuringly, most resumption of heart activity happened in the first 1-2 minutes and most lasted 1 or 2 seconds.

“The reason we wanted to look at death determination specifically is we know that the stories persist about people coming back to life following death, and that’s not just in the public, it’s in the medical community as well,” lead author Sonny Dhanani, MD, of Children’s Hospital of Eastern Ontario, Ottawa, said in an interview.

“We thought that if we provided scientific evidence of whether this happened or not, we might dispel some myths and misunderstanding, which would hopefully promote organ donation.”

About 70% of organ donations occur after brain death, but an increasing number follow circulatory determination of death, he noted. Most protocols recommend 5 minutes of apnea and pulselessness by arterial catheter monitor before declaring death. But practices vary from 10 minutes in some European countries to 75 seconds in infant heart donors at one Colorado hospital.

Reports of patients recovering 10 minutes after pulselessness have raised concerns about the Lazarus phenomenon, or autoresuscitation, but are based in patients after cardiopulmonary resuscitation was terminated.

The present study, known as Death Prediction and Physiology after Removal of Therapy (DePParRT), enrolled patients at 20 intensive care sites in Canada, the Czech Republic, and the Netherlands, only if surrogate decision-makers agreed on withdrawal of life-sustaining measures without CPR and imminent death was anticipated.

As reported Jan. 28 in the New England Journal of Medicine, physicians observed resumption of circulation or cardiac activity prospectively in 1% of 631 patients based on bedside ECG, arterial pressure catheter monitors, palpated arterial pulse, breaths, or physical movements.

A retrospective review of data from 480 patients with complete ECG and arterial waveforms and at least 5 minutes of continuous waveform monitoring after pulselessness showed resumption of cardiac activity in 14% of patients.

The longest period of pulselessness before the heart showed signs of activity again was 4 minutes and 20 seconds. “So that was a reassuring number, because that’s within our 5-minute window that we currently use,” Dr. Dhanani said.

Importantly, “nobody woke up, nobody ended up being resuscitated, and all of these individuals died. And I think that’s going to be very helpful in this context,” he added.

In all, there were 77 cessations and resumptions in 67 of the 480 patients. The median duration of resumed cardiac activity was 3.9 seconds but, notably, ranged from 1 second to 13 minutes and 14 seconds.

“Though surprising, I think maybe not unreasonable,” observed Dr. Dhanani. “The heart is a very robust organ, and we maybe should anticipate these things happening, where at the end of life the heart may restart for minutes.”

In this situation, it’s important to wait the 13 minutes for the heart to stop again and then “wait another 5 minutes to make sure it doesn’t restart before determining death,” he said. “I think that’s where this study is going to now inform policy makers and guidelines, especially in the context of donations.”

The findings will be taken as strong support for the 5-minute window, said Robert Truog, MD, director of the Harvard Medical School Center for Bioethics and the Frances Glessner Lee Professor of Medical Ethics, Anaesthesia, and Pediatrics, Boston.

“I think it’s a safe point, I think people will refer to it, and it will be used to support the 5-minute window, and that’s probably reasonable,” he told this news organization. “Certainly, if it’s read in Europe it will cut the time from 10 minutes to 5 minutes, and that’s a good thing because 10 minutes is a very long time to wait.”

He noted that the 5-minute window provides reasonable assurance to the public and, with new technologies, permits most organs to be usable for donation after cardiac death. That said, there’s nothing magical about the number.

“In some ways I see this paper as providing interesting data but not actually providing an answer, because from the patient’s perspective and from the recipient’s perspective, waiting until the heart has made its last squeeze may not be the most relevant ethical question,” Dr. Truog said. “It may be, once we know this patient is not going to have return of cardiorespiratory function, is not going to wake up, that’s the point at which we ought to focus on organ preservation and organ retrieval, and that can be much sooner than 5 minutes.”

Dr. Dhanani and colleagues note that the generalizability of the results might be limited because patients without arterial pressure catheters were excluded, and 24% of enrolled patients could not be included in the retrospective waveform analysis owing to incomplete data.

“Our study definition of cardiac activity used an arbitrary threshold of pulse pressure (less than 5 mm Hg) that does not imply meaningful circulation,” they add. “This conservative consensus definition may have been partially responsible for the ostensibly high incidence (14%) of transient resumptions of cardiac activity identified through waveform adjudication.”

The study was supported by the Canadian Institutes for Health Research as part of the Canadian Donation and Transplantation Research Program, CHEO Research Institute, and Karel Pavlík Foundation. Dr. Dhanani has consulted for Canadian Blood Services. Dr. Truog reports no relevant conflicts of interest.

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

Among critically ill patients pulseless after planned withdrawal of life-sustaining therapies, cardiac activity restarted in 14% of cases, research shows.

Reassuringly, most resumption of heart activity happened in the first 1-2 minutes and most lasted 1 or 2 seconds.

“The reason we wanted to look at death determination specifically is we know that the stories persist about people coming back to life following death, and that’s not just in the public, it’s in the medical community as well,” lead author Sonny Dhanani, MD, of Children’s Hospital of Eastern Ontario, Ottawa, said in an interview.

“We thought that if we provided scientific evidence of whether this happened or not, we might dispel some myths and misunderstanding, which would hopefully promote organ donation.”

About 70% of organ donations occur after brain death, but an increasing number follow circulatory determination of death, he noted. Most protocols recommend 5 minutes of apnea and pulselessness by arterial catheter monitor before declaring death. But practices vary from 10 minutes in some European countries to 75 seconds in infant heart donors at one Colorado hospital.

Reports of patients recovering 10 minutes after pulselessness have raised concerns about the Lazarus phenomenon, or autoresuscitation, but are based in patients after cardiopulmonary resuscitation was terminated.

The present study, known as Death Prediction and Physiology after Removal of Therapy (DePParRT), enrolled patients at 20 intensive care sites in Canada, the Czech Republic, and the Netherlands, only if surrogate decision-makers agreed on withdrawal of life-sustaining measures without CPR and imminent death was anticipated.

As reported Jan. 28 in the New England Journal of Medicine, physicians observed resumption of circulation or cardiac activity prospectively in 1% of 631 patients based on bedside ECG, arterial pressure catheter monitors, palpated arterial pulse, breaths, or physical movements.

A retrospective review of data from 480 patients with complete ECG and arterial waveforms and at least 5 minutes of continuous waveform monitoring after pulselessness showed resumption of cardiac activity in 14% of patients.

The longest period of pulselessness before the heart showed signs of activity again was 4 minutes and 20 seconds. “So that was a reassuring number, because that’s within our 5-minute window that we currently use,” Dr. Dhanani said.

Importantly, “nobody woke up, nobody ended up being resuscitated, and all of these individuals died. And I think that’s going to be very helpful in this context,” he added.

In all, there were 77 cessations and resumptions in 67 of the 480 patients. The median duration of resumed cardiac activity was 3.9 seconds but, notably, ranged from 1 second to 13 minutes and 14 seconds.

“Though surprising, I think maybe not unreasonable,” observed Dr. Dhanani. “The heart is a very robust organ, and we maybe should anticipate these things happening, where at the end of life the heart may restart for minutes.”

In this situation, it’s important to wait the 13 minutes for the heart to stop again and then “wait another 5 minutes to make sure it doesn’t restart before determining death,” he said. “I think that’s where this study is going to now inform policy makers and guidelines, especially in the context of donations.”

The findings will be taken as strong support for the 5-minute window, said Robert Truog, MD, director of the Harvard Medical School Center for Bioethics and the Frances Glessner Lee Professor of Medical Ethics, Anaesthesia, and Pediatrics, Boston.

“I think it’s a safe point, I think people will refer to it, and it will be used to support the 5-minute window, and that’s probably reasonable,” he told this news organization. “Certainly, if it’s read in Europe it will cut the time from 10 minutes to 5 minutes, and that’s a good thing because 10 minutes is a very long time to wait.”

He noted that the 5-minute window provides reasonable assurance to the public and, with new technologies, permits most organs to be usable for donation after cardiac death. That said, there’s nothing magical about the number.

“In some ways I see this paper as providing interesting data but not actually providing an answer, because from the patient’s perspective and from the recipient’s perspective, waiting until the heart has made its last squeeze may not be the most relevant ethical question,” Dr. Truog said. “It may be, once we know this patient is not going to have return of cardiorespiratory function, is not going to wake up, that’s the point at which we ought to focus on organ preservation and organ retrieval, and that can be much sooner than 5 minutes.”

Dr. Dhanani and colleagues note that the generalizability of the results might be limited because patients without arterial pressure catheters were excluded, and 24% of enrolled patients could not be included in the retrospective waveform analysis owing to incomplete data.

“Our study definition of cardiac activity used an arbitrary threshold of pulse pressure (less than 5 mm Hg) that does not imply meaningful circulation,” they add. “This conservative consensus definition may have been partially responsible for the ostensibly high incidence (14%) of transient resumptions of cardiac activity identified through waveform adjudication.”

The study was supported by the Canadian Institutes for Health Research as part of the Canadian Donation and Transplantation Research Program, CHEO Research Institute, and Karel Pavlík Foundation. Dr. Dhanani has consulted for Canadian Blood Services. Dr. Truog reports no relevant conflicts of interest.

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

Among critically ill patients pulseless after planned withdrawal of life-sustaining therapies, cardiac activity restarted in 14% of cases, research shows.

Reassuringly, most resumption of heart activity happened in the first 1-2 minutes and most lasted 1 or 2 seconds.

“The reason we wanted to look at death determination specifically is we know that the stories persist about people coming back to life following death, and that’s not just in the public, it’s in the medical community as well,” lead author Sonny Dhanani, MD, of Children’s Hospital of Eastern Ontario, Ottawa, said in an interview.

“We thought that if we provided scientific evidence of whether this happened or not, we might dispel some myths and misunderstanding, which would hopefully promote organ donation.”

About 70% of organ donations occur after brain death, but an increasing number follow circulatory determination of death, he noted. Most protocols recommend 5 minutes of apnea and pulselessness by arterial catheter monitor before declaring death. But practices vary from 10 minutes in some European countries to 75 seconds in infant heart donors at one Colorado hospital.

Reports of patients recovering 10 minutes after pulselessness have raised concerns about the Lazarus phenomenon, or autoresuscitation, but are based in patients after cardiopulmonary resuscitation was terminated.

The present study, known as Death Prediction and Physiology after Removal of Therapy (DePParRT), enrolled patients at 20 intensive care sites in Canada, the Czech Republic, and the Netherlands, only if surrogate decision-makers agreed on withdrawal of life-sustaining measures without CPR and imminent death was anticipated.

As reported Jan. 28 in the New England Journal of Medicine, physicians observed resumption of circulation or cardiac activity prospectively in 1% of 631 patients based on bedside ECG, arterial pressure catheter monitors, palpated arterial pulse, breaths, or physical movements.

A retrospective review of data from 480 patients with complete ECG and arterial waveforms and at least 5 minutes of continuous waveform monitoring after pulselessness showed resumption of cardiac activity in 14% of patients.

The longest period of pulselessness before the heart showed signs of activity again was 4 minutes and 20 seconds. “So that was a reassuring number, because that’s within our 5-minute window that we currently use,” Dr. Dhanani said.

Importantly, “nobody woke up, nobody ended up being resuscitated, and all of these individuals died. And I think that’s going to be very helpful in this context,” he added.

In all, there were 77 cessations and resumptions in 67 of the 480 patients. The median duration of resumed cardiac activity was 3.9 seconds but, notably, ranged from 1 second to 13 minutes and 14 seconds.

“Though surprising, I think maybe not unreasonable,” observed Dr. Dhanani. “The heart is a very robust organ, and we maybe should anticipate these things happening, where at the end of life the heart may restart for minutes.”

In this situation, it’s important to wait the 13 minutes for the heart to stop again and then “wait another 5 minutes to make sure it doesn’t restart before determining death,” he said. “I think that’s where this study is going to now inform policy makers and guidelines, especially in the context of donations.”

The findings will be taken as strong support for the 5-minute window, said Robert Truog, MD, director of the Harvard Medical School Center for Bioethics and the Frances Glessner Lee Professor of Medical Ethics, Anaesthesia, and Pediatrics, Boston.

“I think it’s a safe point, I think people will refer to it, and it will be used to support the 5-minute window, and that’s probably reasonable,” he told this news organization. “Certainly, if it’s read in Europe it will cut the time from 10 minutes to 5 minutes, and that’s a good thing because 10 minutes is a very long time to wait.”

He noted that the 5-minute window provides reasonable assurance to the public and, with new technologies, permits most organs to be usable for donation after cardiac death. That said, there’s nothing magical about the number.

“In some ways I see this paper as providing interesting data but not actually providing an answer, because from the patient’s perspective and from the recipient’s perspective, waiting until the heart has made its last squeeze may not be the most relevant ethical question,” Dr. Truog said. “It may be, once we know this patient is not going to have return of cardiorespiratory function, is not going to wake up, that’s the point at which we ought to focus on organ preservation and organ retrieval, and that can be much sooner than 5 minutes.”

Dr. Dhanani and colleagues note that the generalizability of the results might be limited because patients without arterial pressure catheters were excluded, and 24% of enrolled patients could not be included in the retrospective waveform analysis owing to incomplete data.

“Our study definition of cardiac activity used an arbitrary threshold of pulse pressure (less than 5 mm Hg) that does not imply meaningful circulation,” they add. “This conservative consensus definition may have been partially responsible for the ostensibly high incidence (14%) of transient resumptions of cardiac activity identified through waveform adjudication.”

The study was supported by the Canadian Institutes for Health Research as part of the Canadian Donation and Transplantation Research Program, CHEO Research Institute, and Karel Pavlík Foundation. Dr. Dhanani has consulted for Canadian Blood Services. Dr. Truog reports no relevant conflicts of interest.

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

People with rheumatic and musculoskeletal diseases (RMDs) who contract the SARS-CoV-2 virus appear more likely to die from COVID-19 if their rheumatologic condition is not being well controlled at the time of their infection.

New data from the COVID-19 Global Rheumatology Alliance (GRA) physician registry reported in Annals of the Rheumatic Diseases have found that the odds of dying from COVID-19 were 87% higher in individuals recorded as having moderate to high disease activity versus those reported to be in remission or having low disease activity.

“I think this really highlights the importance of continuing to appropriately, and actively, treat our patients, and the importance of controlling their disease,” Pedro Machado, MD, PhD, said in an interview. Dr. Machado, an associate professor in rheumatology and muscle diseases at University College London and a consultant rheumatologist at several U.K. hospitals, has been involved in the GRA physician registry from the start, and sits on the GRA steering committee.

Alongside higher disease activity, several other important factors were found to be associated with increased odds of dying from COVID-19 – older age, male gender, and the presence of one or more comorbidities, such as hypertension combined with cardiovascular disease or chronic lung disease.

These demographic and disease-based factors have been linked to an increased risk for COVID-19–related hospitalization before, both in people with RMDs and in the general population, but the latest GRA physician registry data now take that a step further, and link them also to an increased risk for death, together with several other factors more specific to RMDs.
 

Logging COVID-19 rheumatologic cases

Since the start of the global pandemic, the potential effects that SARS-CoV-2 infection might have on people with RMDs in particular has concerned the rheumatology community. The main worries being that, either because of the underlying RMD itself or to its treatment, there may be immunoregulatory deficits or other risk factors that would make individuals more susceptible to not only infection but also to developing more severe COVID-19 than the general population.

These concerns led to the rapid formation of the GRA and the COVID-19 GRA physician registry in March 2020 to collect and analyze data on adults with rheumatic disease and confirmed or presumptive COVID-19. Entries into the registry are made by or under the direction of rheumatologists, and this is a voluntary process.

“This population cannot ever be entirely representative of the population of patients with rheumatic diseases,” Dr. Machado acknowledged. There will be selection and other biases that affect the reported data. That said, it’s the largest database of reported COVID-19 cases in adult rheumatology patients across the world, with more than 9,000 cases so far included from multiple registries, including those based in Europe and North and South America. Data from one of these – the French RMD cohort – have also recently been published in Annals of the Rheumatic Diseases, showing much the same findings but on a national level.

Hospitalization was the focus of a previous report because “you need large sample sizes” to look at endpoints that occur less frequently. When the first analysis was done, there were around 600 cases from 40 countries in the registry with sufficient data that could be used. Now, with a greater number of recorded cases, factors influencing the risk for death could be examined.

Death rate and risk factors found

Data on 3,729 COVID-19 cases in people with RMDs were included in the current analysis, all recorded in the first few months of the registry being open and up until July 1, 2020. In all, 390 (10.5%) of people died. While this is “clearly higher” than reported in the general population in most countries, the analysis was not designed to calculate a precise estimate.

“It should not be taken as an estimate of the overall death rate among patients with rheumatic diseases and COVID-19,” Dr. Machado and coauthors have been keen to point out.

“Age is always the biggest risk factor,” Dr. Machado explained. “There’s always a gradient: the older the patient, the worse the outcome.”

Indeed, there was a threefold increased risk for death among those aged 66-75 years versus those who were 65 years or younger (odds ratio, 3.00), and a sixfold increased risk for patients older than 75, compared with the younger age group (OR, 6.18).

Having both hypertension and cardiovascular disease was associated with an OR of 1.89, and coexisting chronic lung disease also significantly increased the chances of dying from COVID-19 (OR, 1.68).

Being of male sex was associated with a 46% increased risk for death from COVID-19 versus being of female sex.

The risk for COVID-19 death also rose with the use of corticosteroids. Compared with no steroid use, there was a 69% increased risk for with death at doses of 10 mg or more prednisolone equivalent per day.

“The finding about moderate to high doses of steroids being associated with a worse outcome is consistent with the first report; it was the same for hospitalization,” Dr. Machado observed.

The general consensus on steroid use in the COVID-19 setting is that they should be continued as needed, but at the lowest possible dose, as outlined in provisional recommendations set out by the recently renamed European Alliance of Associations for Rheumatology.

The GRA physician registry findings provide further support for this, suggesting that disease control should be optimized with disease-modifying antirheumatic drugs, ideally without increasing the dose of steroids.

Surprise over sulfasalazine risk

“Taking all medications into account – such as methotrexate, leflunomide, hydroxychloroquine, [tumor necrosis factor] blockers, interleukin-6 blockers, and [Janus kinase] inhibitors – it is quite reassuring because we did not see an association with worse outcome with those drugs overall,” Dr. Machado said.

However, treatment with rituximab (OR, 4.0), sulfasalazine (OR, 3.6), and immunosuppressive agents such as azathioprine, cyclophosphamide, cyclosporine, mycophenolate, or tacrolimus (OR, 2.2), were associated with higher odds of dying from COVID-19 when compared with treatment with methotrexate alone.

The findings for rituximab and immunosuppressant use were perhaps not unexpected, but the possible association between sulfasalazine and COVID-19 death was “a bit intriguing,” Dr. Machado observed. “Sulfasalazine is believed to have low immunosuppressive effect.”

This warrants further investigation, but there are likely a range of confounding factors at play. One could be that people considered to be at higher risk may have been more often prescribed sulfasalazine because it was thought to be less immunosuppressive. Another might be because people taking sulfasalazine were more likely to be smokers, and they were also not advised to protect themselves from exposure to the virus (shielding) during the first wave of the pandemic, at least not in the United Kingdom.
 

Rituximab caution and vaccination

“Rituximab is a concern,” Dr. Machado acknowledged. “It is a concern that rheumatologists are now aware of and they are addressing, but then it’s a concern for a very specific subgroup of patients.”

While rheumatologists are, and will continue to prescribe it, there will be even more careful consideration over when, in whom, and how to use it during, and possibly even after, the pandemic.

“COVID is here to stay, it will become endemic, and it’s going to be part of our lives like the flu virus is,” Dr. Machado predicted.

Then there is the issue on vaccinating people against COVID-19, should those on rituximab still receive it? The answer is a yes, but, as with other vaccinations it’s all about the timing of when the vaccination is given.

Societies such as the British Society for Rheumatology have already begun to include guidance on this, recommending one of the available COVID-19 vaccines is given at least a month before the next or first dose of rituximab is due. As rituximab is given every few months, with doses sometimes spaced as much as 9 months or even a year apart, this should not be too much of a problem, but it is “better to have the vaccine first,” Dr. Machado said.
 

Has COVID-19 care improved in RMDs?

In separate research published in The Lancet Rheumatology, April Jorge, MD, of Massachusetts General Hospital and Harvard Medical School, both in Boston, and associates found that the risks of severe COVID-19 outcomes have improved over time, although they still “remain substantial.”

Dr. Jorge and colleagues looked at temporal trends in COVID-19 outcomes in patients with RMDs over the course of the first 6 months of the pandemic in 2020, using data from a large, multicenter, electronic health record network (TriNetX).

They formed two patient cohorts – a late (diagnosed from April 20 to July 20) and an early (diagnosed from January 20 to April 20) cohort – to see if outcomes had improved and discovered lower relative risks among patients in the late cohort for hospitalization (0.67), admission to the ICU (0.56), mechanical ventilation (0.39), acute kidney injury (0.66), renal replacement (0.53), and death (0.39).

“These results are encouraging,” but it’s difficult to match these different populations of patients, Dr. Machado said. “There are always factors that you cannot match for” and were not included in the U.S. analysis.

While there are important caveats in how the analysis was performed and thus in interpreting these data, they do “suggest that one of the reasons why outcomes have improved is because we have become better at treating these patients,” Dr. Machado added.

“Our treatment has improved, and our capacity to treat the complications has improved. We understand better how the disease behaves – we know that they can have thromboembolic complications that we can manage, and we are now able to manage ventilation issues better.”

Moreover, Dr. Machado said that, not only were clinicians more aware of what they should or should not do, there were treatments that were being used routinely or in some cases based on recent clinical trial results. “I think we are indeed treating these patients better.”

The COVID-19 GRA physician registry is financially supported by the American College of Rheumatology and EULAR. Dr. Machado had no relevant conflicts of interest.

People with rheumatic and musculoskeletal diseases (RMDs) who contract the SARS-CoV-2 virus appear more likely to die from COVID-19 if their rheumatologic condition is not being well controlled at the time of their infection.

New data from the COVID-19 Global Rheumatology Alliance (GRA) physician registry reported in Annals of the Rheumatic Diseases have found that the odds of dying from COVID-19 were 87% higher in individuals recorded as having moderate to high disease activity versus those reported to be in remission or having low disease activity.

“I think this really highlights the importance of continuing to appropriately, and actively, treat our patients, and the importance of controlling their disease,” Pedro Machado, MD, PhD, said in an interview. Dr. Machado, an associate professor in rheumatology and muscle diseases at University College London and a consultant rheumatologist at several U.K. hospitals, has been involved in the GRA physician registry from the start, and sits on the GRA steering committee.

Alongside higher disease activity, several other important factors were found to be associated with increased odds of dying from COVID-19 – older age, male gender, and the presence of one or more comorbidities, such as hypertension combined with cardiovascular disease or chronic lung disease.

These demographic and disease-based factors have been linked to an increased risk for COVID-19–related hospitalization before, both in people with RMDs and in the general population, but the latest GRA physician registry data now take that a step further, and link them also to an increased risk for death, together with several other factors more specific to RMDs.
 

Logging COVID-19 rheumatologic cases

Since the start of the global pandemic, the potential effects that SARS-CoV-2 infection might have on people with RMDs in particular has concerned the rheumatology community. The main worries being that, either because of the underlying RMD itself or to its treatment, there may be immunoregulatory deficits or other risk factors that would make individuals more susceptible to not only infection but also to developing more severe COVID-19 than the general population.

These concerns led to the rapid formation of the GRA and the COVID-19 GRA physician registry in March 2020 to collect and analyze data on adults with rheumatic disease and confirmed or presumptive COVID-19. Entries into the registry are made by or under the direction of rheumatologists, and this is a voluntary process.

“This population cannot ever be entirely representative of the population of patients with rheumatic diseases,” Dr. Machado acknowledged. There will be selection and other biases that affect the reported data. That said, it’s the largest database of reported COVID-19 cases in adult rheumatology patients across the world, with more than 9,000 cases so far included from multiple registries, including those based in Europe and North and South America. Data from one of these – the French RMD cohort – have also recently been published in Annals of the Rheumatic Diseases, showing much the same findings but on a national level.

Hospitalization was the focus of a previous report because “you need large sample sizes” to look at endpoints that occur less frequently. When the first analysis was done, there were around 600 cases from 40 countries in the registry with sufficient data that could be used. Now, with a greater number of recorded cases, factors influencing the risk for death could be examined.

Death rate and risk factors found

Data on 3,729 COVID-19 cases in people with RMDs were included in the current analysis, all recorded in the first few months of the registry being open and up until July 1, 2020. In all, 390 (10.5%) of people died. While this is “clearly higher” than reported in the general population in most countries, the analysis was not designed to calculate a precise estimate.

“It should not be taken as an estimate of the overall death rate among patients with rheumatic diseases and COVID-19,” Dr. Machado and coauthors have been keen to point out.

“Age is always the biggest risk factor,” Dr. Machado explained. “There’s always a gradient: the older the patient, the worse the outcome.”

Indeed, there was a threefold increased risk for death among those aged 66-75 years versus those who were 65 years or younger (odds ratio, 3.00), and a sixfold increased risk for patients older than 75, compared with the younger age group (OR, 6.18).

Having both hypertension and cardiovascular disease was associated with an OR of 1.89, and coexisting chronic lung disease also significantly increased the chances of dying from COVID-19 (OR, 1.68).

Being of male sex was associated with a 46% increased risk for death from COVID-19 versus being of female sex.

The risk for COVID-19 death also rose with the use of corticosteroids. Compared with no steroid use, there was a 69% increased risk for with death at doses of 10 mg or more prednisolone equivalent per day.

“The finding about moderate to high doses of steroids being associated with a worse outcome is consistent with the first report; it was the same for hospitalization,” Dr. Machado observed.

The general consensus on steroid use in the COVID-19 setting is that they should be continued as needed, but at the lowest possible dose, as outlined in provisional recommendations set out by the recently renamed European Alliance of Associations for Rheumatology.

The GRA physician registry findings provide further support for this, suggesting that disease control should be optimized with disease-modifying antirheumatic drugs, ideally without increasing the dose of steroids.

Surprise over sulfasalazine risk

“Taking all medications into account – such as methotrexate, leflunomide, hydroxychloroquine, [tumor necrosis factor] blockers, interleukin-6 blockers, and [Janus kinase] inhibitors – it is quite reassuring because we did not see an association with worse outcome with those drugs overall,” Dr. Machado said.

However, treatment with rituximab (OR, 4.0), sulfasalazine (OR, 3.6), and immunosuppressive agents such as azathioprine, cyclophosphamide, cyclosporine, mycophenolate, or tacrolimus (OR, 2.2), were associated with higher odds of dying from COVID-19 when compared with treatment with methotrexate alone.

The findings for rituximab and immunosuppressant use were perhaps not unexpected, but the possible association between sulfasalazine and COVID-19 death was “a bit intriguing,” Dr. Machado observed. “Sulfasalazine is believed to have low immunosuppressive effect.”

This warrants further investigation, but there are likely a range of confounding factors at play. One could be that people considered to be at higher risk may have been more often prescribed sulfasalazine because it was thought to be less immunosuppressive. Another might be because people taking sulfasalazine were more likely to be smokers, and they were also not advised to protect themselves from exposure to the virus (shielding) during the first wave of the pandemic, at least not in the United Kingdom.
 

Rituximab caution and vaccination

“Rituximab is a concern,” Dr. Machado acknowledged. “It is a concern that rheumatologists are now aware of and they are addressing, but then it’s a concern for a very specific subgroup of patients.”

While rheumatologists are, and will continue to prescribe it, there will be even more careful consideration over when, in whom, and how to use it during, and possibly even after, the pandemic.

“COVID is here to stay, it will become endemic, and it’s going to be part of our lives like the flu virus is,” Dr. Machado predicted.

Then there is the issue on vaccinating people against COVID-19, should those on rituximab still receive it? The answer is a yes, but, as with other vaccinations it’s all about the timing of when the vaccination is given.

Societies such as the British Society for Rheumatology have already begun to include guidance on this, recommending one of the available COVID-19 vaccines is given at least a month before the next or first dose of rituximab is due. As rituximab is given every few months, with doses sometimes spaced as much as 9 months or even a year apart, this should not be too much of a problem, but it is “better to have the vaccine first,” Dr. Machado said.
 

Has COVID-19 care improved in RMDs?

In separate research published in The Lancet Rheumatology, April Jorge, MD, of Massachusetts General Hospital and Harvard Medical School, both in Boston, and associates found that the risks of severe COVID-19 outcomes have improved over time, although they still “remain substantial.”

Dr. Jorge and colleagues looked at temporal trends in COVID-19 outcomes in patients with RMDs over the course of the first 6 months of the pandemic in 2020, using data from a large, multicenter, electronic health record network (TriNetX).

They formed two patient cohorts – a late (diagnosed from April 20 to July 20) and an early (diagnosed from January 20 to April 20) cohort – to see if outcomes had improved and discovered lower relative risks among patients in the late cohort for hospitalization (0.67), admission to the ICU (0.56), mechanical ventilation (0.39), acute kidney injury (0.66), renal replacement (0.53), and death (0.39).

“These results are encouraging,” but it’s difficult to match these different populations of patients, Dr. Machado said. “There are always factors that you cannot match for” and were not included in the U.S. analysis.

While there are important caveats in how the analysis was performed and thus in interpreting these data, they do “suggest that one of the reasons why outcomes have improved is because we have become better at treating these patients,” Dr. Machado added.

“Our treatment has improved, and our capacity to treat the complications has improved. We understand better how the disease behaves – we know that they can have thromboembolic complications that we can manage, and we are now able to manage ventilation issues better.”

Moreover, Dr. Machado said that, not only were clinicians more aware of what they should or should not do, there were treatments that were being used routinely or in some cases based on recent clinical trial results. “I think we are indeed treating these patients better.”

The COVID-19 GRA physician registry is financially supported by the American College of Rheumatology and EULAR. Dr. Machado had no relevant conflicts of interest.

People with rheumatic and musculoskeletal diseases (RMDs) who contract the SARS-CoV-2 virus appear more likely to die from COVID-19 if their rheumatologic condition is not being well controlled at the time of their infection.

New data from the COVID-19 Global Rheumatology Alliance (GRA) physician registry reported in Annals of the Rheumatic Diseases have found that the odds of dying from COVID-19 were 87% higher in individuals recorded as having moderate to high disease activity versus those reported to be in remission or having low disease activity.

“I think this really highlights the importance of continuing to appropriately, and actively, treat our patients, and the importance of controlling their disease,” Pedro Machado, MD, PhD, said in an interview. Dr. Machado, an associate professor in rheumatology and muscle diseases at University College London and a consultant rheumatologist at several U.K. hospitals, has been involved in the GRA physician registry from the start, and sits on the GRA steering committee.

Alongside higher disease activity, several other important factors were found to be associated with increased odds of dying from COVID-19 – older age, male gender, and the presence of one or more comorbidities, such as hypertension combined with cardiovascular disease or chronic lung disease.

These demographic and disease-based factors have been linked to an increased risk for COVID-19–related hospitalization before, both in people with RMDs and in the general population, but the latest GRA physician registry data now take that a step further, and link them also to an increased risk for death, together with several other factors more specific to RMDs.
 

Logging COVID-19 rheumatologic cases

Since the start of the global pandemic, the potential effects that SARS-CoV-2 infection might have on people with RMDs in particular has concerned the rheumatology community. The main worries being that, either because of the underlying RMD itself or to its treatment, there may be immunoregulatory deficits or other risk factors that would make individuals more susceptible to not only infection but also to developing more severe COVID-19 than the general population.

These concerns led to the rapid formation of the GRA and the COVID-19 GRA physician registry in March 2020 to collect and analyze data on adults with rheumatic disease and confirmed or presumptive COVID-19. Entries into the registry are made by or under the direction of rheumatologists, and this is a voluntary process.

“This population cannot ever be entirely representative of the population of patients with rheumatic diseases,” Dr. Machado acknowledged. There will be selection and other biases that affect the reported data. That said, it’s the largest database of reported COVID-19 cases in adult rheumatology patients across the world, with more than 9,000 cases so far included from multiple registries, including those based in Europe and North and South America. Data from one of these – the French RMD cohort – have also recently been published in Annals of the Rheumatic Diseases, showing much the same findings but on a national level.

Hospitalization was the focus of a previous report because “you need large sample sizes” to look at endpoints that occur less frequently. When the first analysis was done, there were around 600 cases from 40 countries in the registry with sufficient data that could be used. Now, with a greater number of recorded cases, factors influencing the risk for death could be examined.

Death rate and risk factors found

Data on 3,729 COVID-19 cases in people with RMDs were included in the current analysis, all recorded in the first few months of the registry being open and up until July 1, 2020. In all, 390 (10.5%) of people died. While this is “clearly higher” than reported in the general population in most countries, the analysis was not designed to calculate a precise estimate.

“It should not be taken as an estimate of the overall death rate among patients with rheumatic diseases and COVID-19,” Dr. Machado and coauthors have been keen to point out.

“Age is always the biggest risk factor,” Dr. Machado explained. “There’s always a gradient: the older the patient, the worse the outcome.”

Indeed, there was a threefold increased risk for death among those aged 66-75 years versus those who were 65 years or younger (odds ratio, 3.00), and a sixfold increased risk for patients older than 75, compared with the younger age group (OR, 6.18).

Having both hypertension and cardiovascular disease was associated with an OR of 1.89, and coexisting chronic lung disease also significantly increased the chances of dying from COVID-19 (OR, 1.68).

Being of male sex was associated with a 46% increased risk for death from COVID-19 versus being of female sex.

The risk for COVID-19 death also rose with the use of corticosteroids. Compared with no steroid use, there was a 69% increased risk for with death at doses of 10 mg or more prednisolone equivalent per day.

“The finding about moderate to high doses of steroids being associated with a worse outcome is consistent with the first report; it was the same for hospitalization,” Dr. Machado observed.

The general consensus on steroid use in the COVID-19 setting is that they should be continued as needed, but at the lowest possible dose, as outlined in provisional recommendations set out by the recently renamed European Alliance of Associations for Rheumatology.

The GRA physician registry findings provide further support for this, suggesting that disease control should be optimized with disease-modifying antirheumatic drugs, ideally without increasing the dose of steroids.

Surprise over sulfasalazine risk

“Taking all medications into account – such as methotrexate, leflunomide, hydroxychloroquine, [tumor necrosis factor] blockers, interleukin-6 blockers, and [Janus kinase] inhibitors – it is quite reassuring because we did not see an association with worse outcome with those drugs overall,” Dr. Machado said.

However, treatment with rituximab (OR, 4.0), sulfasalazine (OR, 3.6), and immunosuppressive agents such as azathioprine, cyclophosphamide, cyclosporine, mycophenolate, or tacrolimus (OR, 2.2), were associated with higher odds of dying from COVID-19 when compared with treatment with methotrexate alone.

The findings for rituximab and immunosuppressant use were perhaps not unexpected, but the possible association between sulfasalazine and COVID-19 death was “a bit intriguing,” Dr. Machado observed. “Sulfasalazine is believed to have low immunosuppressive effect.”

This warrants further investigation, but there are likely a range of confounding factors at play. One could be that people considered to be at higher risk may have been more often prescribed sulfasalazine because it was thought to be less immunosuppressive. Another might be because people taking sulfasalazine were more likely to be smokers, and they were also not advised to protect themselves from exposure to the virus (shielding) during the first wave of the pandemic, at least not in the United Kingdom.
 

Rituximab caution and vaccination

“Rituximab is a concern,” Dr. Machado acknowledged. “It is a concern that rheumatologists are now aware of and they are addressing, but then it’s a concern for a very specific subgroup of patients.”

While rheumatologists are, and will continue to prescribe it, there will be even more careful consideration over when, in whom, and how to use it during, and possibly even after, the pandemic.

“COVID is here to stay, it will become endemic, and it’s going to be part of our lives like the flu virus is,” Dr. Machado predicted.

Then there is the issue on vaccinating people against COVID-19, should those on rituximab still receive it? The answer is a yes, but, as with other vaccinations it’s all about the timing of when the vaccination is given.

Societies such as the British Society for Rheumatology have already begun to include guidance on this, recommending one of the available COVID-19 vaccines is given at least a month before the next or first dose of rituximab is due. As rituximab is given every few months, with doses sometimes spaced as much as 9 months or even a year apart, this should not be too much of a problem, but it is “better to have the vaccine first,” Dr. Machado said.
 

Has COVID-19 care improved in RMDs?

In separate research published in The Lancet Rheumatology, April Jorge, MD, of Massachusetts General Hospital and Harvard Medical School, both in Boston, and associates found that the risks of severe COVID-19 outcomes have improved over time, although they still “remain substantial.”

Dr. Jorge and colleagues looked at temporal trends in COVID-19 outcomes in patients with RMDs over the course of the first 6 months of the pandemic in 2020, using data from a large, multicenter, electronic health record network (TriNetX).

They formed two patient cohorts – a late (diagnosed from April 20 to July 20) and an early (diagnosed from January 20 to April 20) cohort – to see if outcomes had improved and discovered lower relative risks among patients in the late cohort for hospitalization (0.67), admission to the ICU (0.56), mechanical ventilation (0.39), acute kidney injury (0.66), renal replacement (0.53), and death (0.39).

“These results are encouraging,” but it’s difficult to match these different populations of patients, Dr. Machado said. “There are always factors that you cannot match for” and were not included in the U.S. analysis.

While there are important caveats in how the analysis was performed and thus in interpreting these data, they do “suggest that one of the reasons why outcomes have improved is because we have become better at treating these patients,” Dr. Machado added.

“Our treatment has improved, and our capacity to treat the complications has improved. We understand better how the disease behaves – we know that they can have thromboembolic complications that we can manage, and we are now able to manage ventilation issues better.”

Moreover, Dr. Machado said that, not only were clinicians more aware of what they should or should not do, there were treatments that were being used routinely or in some cases based on recent clinical trial results. “I think we are indeed treating these patients better.”

The COVID-19 GRA physician registry is financially supported by the American College of Rheumatology and EULAR. Dr. Machado had no relevant conflicts of interest.

Multiple sclerosis (MS) may not pose a higher risk for complications in pregnant women, according to a new study published online Feb. 3 in Neurology Clinical Practice. While pregnancy and childbirth are not regarded as conditions that engender high-risk pregnancy in the MS population, previous studies evaluating the effects of MS on pregnancy and parturition have yet to fully elucidate some outcomes for pregnant women and their babies in multiple sclerosis.

“Women with multiple sclerosis may be understandably concerned about the risk of pregnancy,” said Melinda Magyari, MD, PhD, a consultant at the University of Copenhagen. “While previous research has shown there is no higher risk of birth defect for babies born to women with MS, we wanted to find out if women with MS are at risk for a variety of pregnancy complications.”

MS is regarded as a progressive, neurological disease mediated by the immune system that demands careful consideration of numerous situations and life changes including family planning. The MS population is overwhelmingly female, as women account for three out of every four cases of MS. The majority of these women range from 20 to 40 years of age at the time of being diagnosed with MS. Despite the unknown risks of pregnancy-related complications and various perinatal complications in this patient population, women who have MS are not discouraged from conceiving.
 

Assessing pregnancy outcomes

This nationwide, population-based, cross-sectional study evaluated the pregnancies of 2,930 women with MS between Jan. 1, 1997, and Dec. 31, 2016, registered in the Danish Multiple Sclerosis Registry. The researchers compared pregnancy-related and prenatal outcomes to a 5% random sample of 56,958 randomly-selected pregnant women from Denmark’s general population who did not have MS. They found no differences in the risks associated with several pregnancy-related complications (e.g., preeclampsia, gestational diabetes, or placental complications), emergency Cesarean section (C-section), instrumental delivery, stillbirth, preterm birth, or congenital malformation. Apgar scores were low in both groups. A composite of various biometrics in newborns such as reflexes, muscle tone, and heart rate immediately following birth, the Apgar score is used to help assess the neonatal health, with a value of less than 7 considered low. Here, preterm birth is defined as delivery occurring before 37 weeks of gestation, and stillbirth describes a fetus born dead after 22 weeks of gestation.

Women in the MS cohort were more likely to have elective C-sections (odds ratio, 2.89 [95% confidence interval, 1.65-2.16]), induced labor (OR, 1.15 [95%CI, 1.01-1.31]) and have babies with low birth weight based on their gestational age (OR, 1.29 [95% CI, 1.04-1.60]). Nearly 30% of babies born in the cohort (n = 851) were born to mothers who had received disease-modifying therapy (DMT). Neonates exposed to DMT weighed an average of 116 g less than babies born to mothers who had not received DMT (3,378 g vs. 3,494 g) with a slightly lower gestational age (39 weeks as opposed to 40 weeks). However, babies born to mothers with MS were less likely to show signs of asphyxia (OR, 0.87 [95% CI, 0.78-0.97]) than the comparison cohort.

“We found overall, their pregnancies were just as healthy as those of the moms without MS,” Dr. Magyari said.
 

Comprehensive data

Denmark’s health care system has two key features that make it an attractive setting in which to conduct such a study – the first being its universal health care. The second advantage is that the country enacted several health registries in the 1970s and 1980s that enable the collection of more comprehensive data. For example, the Danish National Patient Register is a population-based registry that spans the entire nation, facilitating epidemiological research with what the study’s authors describe as “high generalizability.” Providing additional insights regarding the patient story helps add context to pregnancy and outcomes. Among the data collected on the women studied were demographics, contact information, and abortions, both spontaneous and medically induced. The country uses other databases and registries to capture additional data. For example, the Register of Legally Induced Abortions provides data regarding the context of medically induced abortions. In contrast, the Danish Medical Birth Registry provides context regarding specified variables regarding women’s pregnancies, delivery, and perinatal outcomes. Finally, the population’s education register offers information regarding patients’ educational history.

A key strength of this study is that the long duration of follow-up data from the Danish Medical Birth Registry, along with its comprehensive data collection, eliminates recall bias. Universal access to health care also improves the generalizability of data. A limitation of the study is its lack of data on maternal smoking and its effects on low gestational weights. The study also has some data gaps, including body mass index information missing from a large portion of the cohort. Finally, the sample size of newborns born to mothers who had received DMT therapy within the last 6 months of gestation was too underpowered to stratify based on first on first-line or second-line treatment.

Dr. Magyari served on scientific advisory boards for Biogen, Sanofi, Teva, Roche, Novartis, and Merck. She has also received honoraria for lecturing from Biogen, Merck, Novartis, Sanofi, Genzyme, and has received research support and support for congress participation from Biogen, Genzyme, Teva, Roche, Merck, and Novartis. Coauthors disclosed various fees received from Merck, Novartis, Biogen, Roche, Sanofi Genzyme, and Teva.

Multiple sclerosis (MS) may not pose a higher risk for complications in pregnant women, according to a new study published online Feb. 3 in Neurology Clinical Practice. While pregnancy and childbirth are not regarded as conditions that engender high-risk pregnancy in the MS population, previous studies evaluating the effects of MS on pregnancy and parturition have yet to fully elucidate some outcomes for pregnant women and their babies in multiple sclerosis.

“Women with multiple sclerosis may be understandably concerned about the risk of pregnancy,” said Melinda Magyari, MD, PhD, a consultant at the University of Copenhagen. “While previous research has shown there is no higher risk of birth defect for babies born to women with MS, we wanted to find out if women with MS are at risk for a variety of pregnancy complications.”

MS is regarded as a progressive, neurological disease mediated by the immune system that demands careful consideration of numerous situations and life changes including family planning. The MS population is overwhelmingly female, as women account for three out of every four cases of MS. The majority of these women range from 20 to 40 years of age at the time of being diagnosed with MS. Despite the unknown risks of pregnancy-related complications and various perinatal complications in this patient population, women who have MS are not discouraged from conceiving.
 

Assessing pregnancy outcomes

This nationwide, population-based, cross-sectional study evaluated the pregnancies of 2,930 women with MS between Jan. 1, 1997, and Dec. 31, 2016, registered in the Danish Multiple Sclerosis Registry. The researchers compared pregnancy-related and prenatal outcomes to a 5% random sample of 56,958 randomly-selected pregnant women from Denmark’s general population who did not have MS. They found no differences in the risks associated with several pregnancy-related complications (e.g., preeclampsia, gestational diabetes, or placental complications), emergency Cesarean section (C-section), instrumental delivery, stillbirth, preterm birth, or congenital malformation. Apgar scores were low in both groups. A composite of various biometrics in newborns such as reflexes, muscle tone, and heart rate immediately following birth, the Apgar score is used to help assess the neonatal health, with a value of less than 7 considered low. Here, preterm birth is defined as delivery occurring before 37 weeks of gestation, and stillbirth describes a fetus born dead after 22 weeks of gestation.

Women in the MS cohort were more likely to have elective C-sections (odds ratio, 2.89 [95% confidence interval, 1.65-2.16]), induced labor (OR, 1.15 [95%CI, 1.01-1.31]) and have babies with low birth weight based on their gestational age (OR, 1.29 [95% CI, 1.04-1.60]). Nearly 30% of babies born in the cohort (n = 851) were born to mothers who had received disease-modifying therapy (DMT). Neonates exposed to DMT weighed an average of 116 g less than babies born to mothers who had not received DMT (3,378 g vs. 3,494 g) with a slightly lower gestational age (39 weeks as opposed to 40 weeks). However, babies born to mothers with MS were less likely to show signs of asphyxia (OR, 0.87 [95% CI, 0.78-0.97]) than the comparison cohort.

“We found overall, their pregnancies were just as healthy as those of the moms without MS,” Dr. Magyari said.
 

Comprehensive data

Denmark’s health care system has two key features that make it an attractive setting in which to conduct such a study – the first being its universal health care. The second advantage is that the country enacted several health registries in the 1970s and 1980s that enable the collection of more comprehensive data. For example, the Danish National Patient Register is a population-based registry that spans the entire nation, facilitating epidemiological research with what the study’s authors describe as “high generalizability.” Providing additional insights regarding the patient story helps add context to pregnancy and outcomes. Among the data collected on the women studied were demographics, contact information, and abortions, both spontaneous and medically induced. The country uses other databases and registries to capture additional data. For example, the Register of Legally Induced Abortions provides data regarding the context of medically induced abortions. In contrast, the Danish Medical Birth Registry provides context regarding specified variables regarding women’s pregnancies, delivery, and perinatal outcomes. Finally, the population’s education register offers information regarding patients’ educational history.

A key strength of this study is that the long duration of follow-up data from the Danish Medical Birth Registry, along with its comprehensive data collection, eliminates recall bias. Universal access to health care also improves the generalizability of data. A limitation of the study is its lack of data on maternal smoking and its effects on low gestational weights. The study also has some data gaps, including body mass index information missing from a large portion of the cohort. Finally, the sample size of newborns born to mothers who had received DMT therapy within the last 6 months of gestation was too underpowered to stratify based on first on first-line or second-line treatment.

Dr. Magyari served on scientific advisory boards for Biogen, Sanofi, Teva, Roche, Novartis, and Merck. She has also received honoraria for lecturing from Biogen, Merck, Novartis, Sanofi, Genzyme, and has received research support and support for congress participation from Biogen, Genzyme, Teva, Roche, Merck, and Novartis. Coauthors disclosed various fees received from Merck, Novartis, Biogen, Roche, Sanofi Genzyme, and Teva.

Multiple sclerosis (MS) may not pose a higher risk for complications in pregnant women, according to a new study published online Feb. 3 in Neurology Clinical Practice. While pregnancy and childbirth are not regarded as conditions that engender high-risk pregnancy in the MS population, previous studies evaluating the effects of MS on pregnancy and parturition have yet to fully elucidate some outcomes for pregnant women and their babies in multiple sclerosis.

“Women with multiple sclerosis may be understandably concerned about the risk of pregnancy,” said Melinda Magyari, MD, PhD, a consultant at the University of Copenhagen. “While previous research has shown there is no higher risk of birth defect for babies born to women with MS, we wanted to find out if women with MS are at risk for a variety of pregnancy complications.”

MS is regarded as a progressive, neurological disease mediated by the immune system that demands careful consideration of numerous situations and life changes including family planning. The MS population is overwhelmingly female, as women account for three out of every four cases of MS. The majority of these women range from 20 to 40 years of age at the time of being diagnosed with MS. Despite the unknown risks of pregnancy-related complications and various perinatal complications in this patient population, women who have MS are not discouraged from conceiving.
 

Assessing pregnancy outcomes

This nationwide, population-based, cross-sectional study evaluated the pregnancies of 2,930 women with MS between Jan. 1, 1997, and Dec. 31, 2016, registered in the Danish Multiple Sclerosis Registry. The researchers compared pregnancy-related and prenatal outcomes to a 5% random sample of 56,958 randomly-selected pregnant women from Denmark’s general population who did not have MS. They found no differences in the risks associated with several pregnancy-related complications (e.g., preeclampsia, gestational diabetes, or placental complications), emergency Cesarean section (C-section), instrumental delivery, stillbirth, preterm birth, or congenital malformation. Apgar scores were low in both groups. A composite of various biometrics in newborns such as reflexes, muscle tone, and heart rate immediately following birth, the Apgar score is used to help assess the neonatal health, with a value of less than 7 considered low. Here, preterm birth is defined as delivery occurring before 37 weeks of gestation, and stillbirth describes a fetus born dead after 22 weeks of gestation.

Women in the MS cohort were more likely to have elective C-sections (odds ratio, 2.89 [95% confidence interval, 1.65-2.16]), induced labor (OR, 1.15 [95%CI, 1.01-1.31]) and have babies with low birth weight based on their gestational age (OR, 1.29 [95% CI, 1.04-1.60]). Nearly 30% of babies born in the cohort (n = 851) were born to mothers who had received disease-modifying therapy (DMT). Neonates exposed to DMT weighed an average of 116 g less than babies born to mothers who had not received DMT (3,378 g vs. 3,494 g) with a slightly lower gestational age (39 weeks as opposed to 40 weeks). However, babies born to mothers with MS were less likely to show signs of asphyxia (OR, 0.87 [95% CI, 0.78-0.97]) than the comparison cohort.

“We found overall, their pregnancies were just as healthy as those of the moms without MS,” Dr. Magyari said.
 

Comprehensive data

Denmark’s health care system has two key features that make it an attractive setting in which to conduct such a study – the first being its universal health care. The second advantage is that the country enacted several health registries in the 1970s and 1980s that enable the collection of more comprehensive data. For example, the Danish National Patient Register is a population-based registry that spans the entire nation, facilitating epidemiological research with what the study’s authors describe as “high generalizability.” Providing additional insights regarding the patient story helps add context to pregnancy and outcomes. Among the data collected on the women studied were demographics, contact information, and abortions, both spontaneous and medically induced. The country uses other databases and registries to capture additional data. For example, the Register of Legally Induced Abortions provides data regarding the context of medically induced abortions. In contrast, the Danish Medical Birth Registry provides context regarding specified variables regarding women’s pregnancies, delivery, and perinatal outcomes. Finally, the population’s education register offers information regarding patients’ educational history.

A key strength of this study is that the long duration of follow-up data from the Danish Medical Birth Registry, along with its comprehensive data collection, eliminates recall bias. Universal access to health care also improves the generalizability of data. A limitation of the study is its lack of data on maternal smoking and its effects on low gestational weights. The study also has some data gaps, including body mass index information missing from a large portion of the cohort. Finally, the sample size of newborns born to mothers who had received DMT therapy within the last 6 months of gestation was too underpowered to stratify based on first on first-line or second-line treatment.

Dr. Magyari served on scientific advisory boards for Biogen, Sanofi, Teva, Roche, Novartis, and Merck. She has also received honoraria for lecturing from Biogen, Merck, Novartis, Sanofi, Genzyme, and has received research support and support for congress participation from Biogen, Genzyme, Teva, Roche, Merck, and Novartis. Coauthors disclosed various fees received from Merck, Novartis, Biogen, Roche, Sanofi Genzyme, and Teva.