CHEST Physician

Extended use of corticosteroids for chronic inflammatory conditions puts patients at risk for serious adverse events (AEs), including cardiovascular disease, osteoporosis, cataracts, and diabetes. Now, a growing body of evidence suggests that even short bursts of these drugs are associated with serious risks.

Most recently, a population-based study of more than 2.6 million people found that taking corticosteroids for 14 days or less was associated with a substantially greater risk for gastrointestinal (GI) bleeding, sepsis, and heart failure, particularly within the first 30 days after therapy.

In the study, Tsung-Chieh Yao, MD, PhD, a professor in the division of allergy, asthma, and rheumatology in the department of pediatrics at Chang Gung Memorial Hospital in Taoyuan, Taiwan, and colleagues used a self-controlled case series to analyze data from Taiwan’s National Health Insurance Research Database of medical claims. They compared patients’ conditions in the period from 5 to 90 days before treatment to conditions from the periods from 5 to 30 days and from 31 to 90 days after therapy.

With a median duration of 3 days of treatment, the incidence rate ratios (IRRs) were 1.80 (95% confidence interval, 1.75-1.84) for GI bleeding, 1.99 (95% CI, 1.70-2.32) for sepsis, and 2.37 (95% CI, 2.13-2.63) for heart failure.

Given the findings, physicians should weigh the benefits against the risks of rare but potentially serious consequences of these anti-inflammatory drugs, according to the authors.

“After initiating patients on oral steroid bursts, physicians should be on the lookout for these severe adverse events, particularly within the first month after initiation of steroid therapy,” Dr. Yao said in an interview.

The findings were published online July 6 in Annals of Internal Medicine.

Of the 15,859,129 adult Asians in the Taiwanese database, the study included 2,623,327 adults aged 20-64 years who received single steroid bursts (14 days or less) between Jan. 1, 2013, and Dec. 31, 2015.

Almost 60% of the indications were for skin disorders, such as eczema and urticaria, and for respiratory tract infections, such as sinusitis and acute pharyngitis. Among specialties, dermatology, otolaryngology, family practice, internal medicine, and pediatrics accounted for 88% of prescriptions.

“Our findings are important for physicians and guideline developers because short-term use of oral corticosteroids is common and the real-world safety of this approach remains unclear,” the authors wrote. They acknowledged that the database did not provide information on such potential confounders as disease severity and lifestyle factors, nor did it include children and vulnerable individuals, which may limit the generalizability of the results.

The findings echo those of a 2017 cohort study conducted by researchers at the University of Michigan in Ann Arbor. That study, by Akbar K. Waljee, MD, assistant professor of gastroenterology, University of Michigan, Ann Arbor, and colleagues, included data on more than 1.5 million privately insured U.S. adults. The researchers included somewhat longer steroid bursts of up to 30 days’ duration and found that use of the drugs was associated with a greater than fivefold increased risk for sepsis, a more than threefold increased risk for venous thromboembolism, and a nearly twofold increased risk for fracture within 30 days of starting treatment.

Furthermore, the elevated risk persisted at prednisone-equivalent doses of less than 20 mg/d (IRR, 4.02 for sepsis, 3.61 for venous thromboembolism, and 1.83 for fracture; all P < .001).

The U.S. study also found that during the 3-year period from 2012 to 2014, more than 20% of patients were prescribed short-term oral corticosteroids.

“Both studies indicate that these short-term regimens are more common in the real world than was previously thought and are not risk free,” Dr. Yao said.

Recognition that corticosteroids are associated with adverse events has been building for decades, according to the authors of an editorial that accompanies the new study.

“However, we commonly use short corticosteroid ‘bursts’ for minor ailments despite a lack of evidence for meaningful benefit. We are now learning that bursts as short as 3 days may increase risk for serious AEs, even in young and healthy people,” wrote editorialists Beth I. Wallace, MD, of the Center for Clinical Management Research at the VA Ann Arbor Healthcare System and the Institute for Healthcare Policy and Innovation at Michigan Medicine, Ann Arbor, and Dr. Waljee, who led the 2017 study.

Dr. Wallace and Dr. Waljee drew parallels between corticosteroid bursts and other short-term regimens, such as of antibiotics and opiates, in which prescriber preference and sometimes patient pressure play a role. “All of these treatments have well-defined indications but can cause net harm when used. We can thus conceive of a corticosteroid stewardship model of targeted interventions that aims to reduce inappropriate prescribing,” they wrote.

In an interview, Dr. Wallace, a rheumatologist who prescribes oral steroids fairly frequently, noted that the Taiwan study is the first to investigate steroid bursts. “Up till now, these very short courses have flown under the radar. Clinicians very commonly prescribe short courses to help relieve symptoms of self-limited conditions like bronchitis, and we assume that because the exposure duration is short, the risks are low, especially for patients who are otherwise healthy.”

She warned that the data in the current study indicate that these short bursts – even at the lower end of the 1- to 2-week courses American physicians prescribe most often – carry small but real increases in risk for serious AEs. “And these increases were seen in young, healthy people, not just in people with preexisting conditions,” she said. “So, we might need to start thinking harder about how we are prescribing even these very short courses of steroids and try to use steroids only when their meaningful benefits really outweigh the risk.”

She noted that a patient with a chronic inflammatory condition such as rheumatoid arthritis may benefit substantially from short-term steroids to treat a disease flare. In that specific case, the benefits of short-term steroids may outweigh the risks, Dr. Wallace said.

But not everyone thinks a new strategy is needed. For Whitney A. High, MD, associate professor of dermatology and pathology at the University of Colorado at Denver, Aurora, the overprescribing of short-term corticosteroids is not a problem, and dermatologists are already exercising caution.

Bruce Jancin/MDedge News

“I only prescribe these drugs short term to, at a guess, about 1 in 40 patients and only when a patient is miserable and quality of life is being seriously affected,” he said in an interview. “And that’s something that can’t be measured in a database study like the one from Taiwan but only in a risk-benefit analysis,” he said.

Furthermore, dermatologists have other drugs and technologies in their armamentarium, including topical steroids with occlusion or with wet wraps, phototherapy, phosphodiesterase inhibitors, calcipotriene, methotrexate and other immunosuppressive agents, and biologics. “In fact, many of these agents are specifically referred to as steroid-sparing,” Dr. High said.

Nor does he experience much pressure from patients to prescribe these drugs. “While occasionally I may encounter a patient who places pressure on me for oral steroids, it’s probably not nearly as frequently as providers in other fields are pressured to prescribe antibiotics or narcotics,” he said.

According to the Taiwanese researchers, the next step is to conduct more studies, including clinical trials, to determine optimal use of corticosteroids by monitoring adverse events. In the meantime, for practitioners such as Dr. Wallace and Dr. High, there is ample evidence from several recent studies of the harms of short-term corticosteroids, whereas the benefits for patients with self-limiting conditions remain uncertain. “This and other studies like it quite appropriately remind providers to avoid oral steroids when they’re not necessary and to seek alternatives where possible,” Dr. High said.

The study was supported by the National Health Research Institutes of Taiwan, the Ministry of Science and Technology of Taiwan, the Chang Gung Medical Foundation, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NIH). Dr. Yao has disclosed no relevant financial relationships. Dr. Wu has received grants from GlaxoSmithKline outside the submitted work. The editorialists and Dr. High have disclosed no relevant financial relationships. Dr. Wallace received an NIH grant during the writing of the editorial.
 

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

Extended use of corticosteroids for chronic inflammatory conditions puts patients at risk for serious adverse events (AEs), including cardiovascular disease, osteoporosis, cataracts, and diabetes. Now, a growing body of evidence suggests that even short bursts of these drugs are associated with serious risks.

Most recently, a population-based study of more than 2.6 million people found that taking corticosteroids for 14 days or less was associated with a substantially greater risk for gastrointestinal (GI) bleeding, sepsis, and heart failure, particularly within the first 30 days after therapy.

In the study, Tsung-Chieh Yao, MD, PhD, a professor in the division of allergy, asthma, and rheumatology in the department of pediatrics at Chang Gung Memorial Hospital in Taoyuan, Taiwan, and colleagues used a self-controlled case series to analyze data from Taiwan’s National Health Insurance Research Database of medical claims. They compared patients’ conditions in the period from 5 to 90 days before treatment to conditions from the periods from 5 to 30 days and from 31 to 90 days after therapy.

With a median duration of 3 days of treatment, the incidence rate ratios (IRRs) were 1.80 (95% confidence interval, 1.75-1.84) for GI bleeding, 1.99 (95% CI, 1.70-2.32) for sepsis, and 2.37 (95% CI, 2.13-2.63) for heart failure.

Given the findings, physicians should weigh the benefits against the risks of rare but potentially serious consequences of these anti-inflammatory drugs, according to the authors.

“After initiating patients on oral steroid bursts, physicians should be on the lookout for these severe adverse events, particularly within the first month after initiation of steroid therapy,” Dr. Yao said in an interview.

The findings were published online July 6 in Annals of Internal Medicine.

Of the 15,859,129 adult Asians in the Taiwanese database, the study included 2,623,327 adults aged 20-64 years who received single steroid bursts (14 days or less) between Jan. 1, 2013, and Dec. 31, 2015.

Almost 60% of the indications were for skin disorders, such as eczema and urticaria, and for respiratory tract infections, such as sinusitis and acute pharyngitis. Among specialties, dermatology, otolaryngology, family practice, internal medicine, and pediatrics accounted for 88% of prescriptions.

“Our findings are important for physicians and guideline developers because short-term use of oral corticosteroids is common and the real-world safety of this approach remains unclear,” the authors wrote. They acknowledged that the database did not provide information on such potential confounders as disease severity and lifestyle factors, nor did it include children and vulnerable individuals, which may limit the generalizability of the results.

The findings echo those of a 2017 cohort study conducted by researchers at the University of Michigan in Ann Arbor. That study, by Akbar K. Waljee, MD, assistant professor of gastroenterology, University of Michigan, Ann Arbor, and colleagues, included data on more than 1.5 million privately insured U.S. adults. The researchers included somewhat longer steroid bursts of up to 30 days’ duration and found that use of the drugs was associated with a greater than fivefold increased risk for sepsis, a more than threefold increased risk for venous thromboembolism, and a nearly twofold increased risk for fracture within 30 days of starting treatment.

Furthermore, the elevated risk persisted at prednisone-equivalent doses of less than 20 mg/d (IRR, 4.02 for sepsis, 3.61 for venous thromboembolism, and 1.83 for fracture; all P < .001).

The U.S. study also found that during the 3-year period from 2012 to 2014, more than 20% of patients were prescribed short-term oral corticosteroids.

“Both studies indicate that these short-term regimens are more common in the real world than was previously thought and are not risk free,” Dr. Yao said.

Recognition that corticosteroids are associated with adverse events has been building for decades, according to the authors of an editorial that accompanies the new study.

“However, we commonly use short corticosteroid ‘bursts’ for minor ailments despite a lack of evidence for meaningful benefit. We are now learning that bursts as short as 3 days may increase risk for serious AEs, even in young and healthy people,” wrote editorialists Beth I. Wallace, MD, of the Center for Clinical Management Research at the VA Ann Arbor Healthcare System and the Institute for Healthcare Policy and Innovation at Michigan Medicine, Ann Arbor, and Dr. Waljee, who led the 2017 study.

Dr. Wallace and Dr. Waljee drew parallels between corticosteroid bursts and other short-term regimens, such as of antibiotics and opiates, in which prescriber preference and sometimes patient pressure play a role. “All of these treatments have well-defined indications but can cause net harm when used. We can thus conceive of a corticosteroid stewardship model of targeted interventions that aims to reduce inappropriate prescribing,” they wrote.

In an interview, Dr. Wallace, a rheumatologist who prescribes oral steroids fairly frequently, noted that the Taiwan study is the first to investigate steroid bursts. “Up till now, these very short courses have flown under the radar. Clinicians very commonly prescribe short courses to help relieve symptoms of self-limited conditions like bronchitis, and we assume that because the exposure duration is short, the risks are low, especially for patients who are otherwise healthy.”

She warned that the data in the current study indicate that these short bursts – even at the lower end of the 1- to 2-week courses American physicians prescribe most often – carry small but real increases in risk for serious AEs. “And these increases were seen in young, healthy people, not just in people with preexisting conditions,” she said. “So, we might need to start thinking harder about how we are prescribing even these very short courses of steroids and try to use steroids only when their meaningful benefits really outweigh the risk.”

She noted that a patient with a chronic inflammatory condition such as rheumatoid arthritis may benefit substantially from short-term steroids to treat a disease flare. In that specific case, the benefits of short-term steroids may outweigh the risks, Dr. Wallace said.

But not everyone thinks a new strategy is needed. For Whitney A. High, MD, associate professor of dermatology and pathology at the University of Colorado at Denver, Aurora, the overprescribing of short-term corticosteroids is not a problem, and dermatologists are already exercising caution.

Bruce Jancin/MDedge News

“I only prescribe these drugs short term to, at a guess, about 1 in 40 patients and only when a patient is miserable and quality of life is being seriously affected,” he said in an interview. “And that’s something that can’t be measured in a database study like the one from Taiwan but only in a risk-benefit analysis,” he said.

Furthermore, dermatologists have other drugs and technologies in their armamentarium, including topical steroids with occlusion or with wet wraps, phototherapy, phosphodiesterase inhibitors, calcipotriene, methotrexate and other immunosuppressive agents, and biologics. “In fact, many of these agents are specifically referred to as steroid-sparing,” Dr. High said.

Nor does he experience much pressure from patients to prescribe these drugs. “While occasionally I may encounter a patient who places pressure on me for oral steroids, it’s probably not nearly as frequently as providers in other fields are pressured to prescribe antibiotics or narcotics,” he said.

According to the Taiwanese researchers, the next step is to conduct more studies, including clinical trials, to determine optimal use of corticosteroids by monitoring adverse events. In the meantime, for practitioners such as Dr. Wallace and Dr. High, there is ample evidence from several recent studies of the harms of short-term corticosteroids, whereas the benefits for patients with self-limiting conditions remain uncertain. “This and other studies like it quite appropriately remind providers to avoid oral steroids when they’re not necessary and to seek alternatives where possible,” Dr. High said.

The study was supported by the National Health Research Institutes of Taiwan, the Ministry of Science and Technology of Taiwan, the Chang Gung Medical Foundation, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NIH). Dr. Yao has disclosed no relevant financial relationships. Dr. Wu has received grants from GlaxoSmithKline outside the submitted work. The editorialists and Dr. High have disclosed no relevant financial relationships. Dr. Wallace received an NIH grant during the writing of the editorial.
 

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

Extended use of corticosteroids for chronic inflammatory conditions puts patients at risk for serious adverse events (AEs), including cardiovascular disease, osteoporosis, cataracts, and diabetes. Now, a growing body of evidence suggests that even short bursts of these drugs are associated with serious risks.

Most recently, a population-based study of more than 2.6 million people found that taking corticosteroids for 14 days or less was associated with a substantially greater risk for gastrointestinal (GI) bleeding, sepsis, and heart failure, particularly within the first 30 days after therapy.

In the study, Tsung-Chieh Yao, MD, PhD, a professor in the division of allergy, asthma, and rheumatology in the department of pediatrics at Chang Gung Memorial Hospital in Taoyuan, Taiwan, and colleagues used a self-controlled case series to analyze data from Taiwan’s National Health Insurance Research Database of medical claims. They compared patients’ conditions in the period from 5 to 90 days before treatment to conditions from the periods from 5 to 30 days and from 31 to 90 days after therapy.

With a median duration of 3 days of treatment, the incidence rate ratios (IRRs) were 1.80 (95% confidence interval, 1.75-1.84) for GI bleeding, 1.99 (95% CI, 1.70-2.32) for sepsis, and 2.37 (95% CI, 2.13-2.63) for heart failure.

Given the findings, physicians should weigh the benefits against the risks of rare but potentially serious consequences of these anti-inflammatory drugs, according to the authors.

“After initiating patients on oral steroid bursts, physicians should be on the lookout for these severe adverse events, particularly within the first month after initiation of steroid therapy,” Dr. Yao said in an interview.

The findings were published online July 6 in Annals of Internal Medicine.

Of the 15,859,129 adult Asians in the Taiwanese database, the study included 2,623,327 adults aged 20-64 years who received single steroid bursts (14 days or less) between Jan. 1, 2013, and Dec. 31, 2015.

Almost 60% of the indications were for skin disorders, such as eczema and urticaria, and for respiratory tract infections, such as sinusitis and acute pharyngitis. Among specialties, dermatology, otolaryngology, family practice, internal medicine, and pediatrics accounted for 88% of prescriptions.

“Our findings are important for physicians and guideline developers because short-term use of oral corticosteroids is common and the real-world safety of this approach remains unclear,” the authors wrote. They acknowledged that the database did not provide information on such potential confounders as disease severity and lifestyle factors, nor did it include children and vulnerable individuals, which may limit the generalizability of the results.

The findings echo those of a 2017 cohort study conducted by researchers at the University of Michigan in Ann Arbor. That study, by Akbar K. Waljee, MD, assistant professor of gastroenterology, University of Michigan, Ann Arbor, and colleagues, included data on more than 1.5 million privately insured U.S. adults. The researchers included somewhat longer steroid bursts of up to 30 days’ duration and found that use of the drugs was associated with a greater than fivefold increased risk for sepsis, a more than threefold increased risk for venous thromboembolism, and a nearly twofold increased risk for fracture within 30 days of starting treatment.

Furthermore, the elevated risk persisted at prednisone-equivalent doses of less than 20 mg/d (IRR, 4.02 for sepsis, 3.61 for venous thromboembolism, and 1.83 for fracture; all P < .001).

The U.S. study also found that during the 3-year period from 2012 to 2014, more than 20% of patients were prescribed short-term oral corticosteroids.

“Both studies indicate that these short-term regimens are more common in the real world than was previously thought and are not risk free,” Dr. Yao said.

Recognition that corticosteroids are associated with adverse events has been building for decades, according to the authors of an editorial that accompanies the new study.

“However, we commonly use short corticosteroid ‘bursts’ for minor ailments despite a lack of evidence for meaningful benefit. We are now learning that bursts as short as 3 days may increase risk for serious AEs, even in young and healthy people,” wrote editorialists Beth I. Wallace, MD, of the Center for Clinical Management Research at the VA Ann Arbor Healthcare System and the Institute for Healthcare Policy and Innovation at Michigan Medicine, Ann Arbor, and Dr. Waljee, who led the 2017 study.

Dr. Wallace and Dr. Waljee drew parallels between corticosteroid bursts and other short-term regimens, such as of antibiotics and opiates, in which prescriber preference and sometimes patient pressure play a role. “All of these treatments have well-defined indications but can cause net harm when used. We can thus conceive of a corticosteroid stewardship model of targeted interventions that aims to reduce inappropriate prescribing,” they wrote.

In an interview, Dr. Wallace, a rheumatologist who prescribes oral steroids fairly frequently, noted that the Taiwan study is the first to investigate steroid bursts. “Up till now, these very short courses have flown under the radar. Clinicians very commonly prescribe short courses to help relieve symptoms of self-limited conditions like bronchitis, and we assume that because the exposure duration is short, the risks are low, especially for patients who are otherwise healthy.”

She warned that the data in the current study indicate that these short bursts – even at the lower end of the 1- to 2-week courses American physicians prescribe most often – carry small but real increases in risk for serious AEs. “And these increases were seen in young, healthy people, not just in people with preexisting conditions,” she said. “So, we might need to start thinking harder about how we are prescribing even these very short courses of steroids and try to use steroids only when their meaningful benefits really outweigh the risk.”

She noted that a patient with a chronic inflammatory condition such as rheumatoid arthritis may benefit substantially from short-term steroids to treat a disease flare. In that specific case, the benefits of short-term steroids may outweigh the risks, Dr. Wallace said.

But not everyone thinks a new strategy is needed. For Whitney A. High, MD, associate professor of dermatology and pathology at the University of Colorado at Denver, Aurora, the overprescribing of short-term corticosteroids is not a problem, and dermatologists are already exercising caution.

Bruce Jancin/MDedge News

“I only prescribe these drugs short term to, at a guess, about 1 in 40 patients and only when a patient is miserable and quality of life is being seriously affected,” he said in an interview. “And that’s something that can’t be measured in a database study like the one from Taiwan but only in a risk-benefit analysis,” he said.

Furthermore, dermatologists have other drugs and technologies in their armamentarium, including topical steroids with occlusion or with wet wraps, phototherapy, phosphodiesterase inhibitors, calcipotriene, methotrexate and other immunosuppressive agents, and biologics. “In fact, many of these agents are specifically referred to as steroid-sparing,” Dr. High said.

Nor does he experience much pressure from patients to prescribe these drugs. “While occasionally I may encounter a patient who places pressure on me for oral steroids, it’s probably not nearly as frequently as providers in other fields are pressured to prescribe antibiotics or narcotics,” he said.

According to the Taiwanese researchers, the next step is to conduct more studies, including clinical trials, to determine optimal use of corticosteroids by monitoring adverse events. In the meantime, for practitioners such as Dr. Wallace and Dr. High, there is ample evidence from several recent studies of the harms of short-term corticosteroids, whereas the benefits for patients with self-limiting conditions remain uncertain. “This and other studies like it quite appropriately remind providers to avoid oral steroids when they’re not necessary and to seek alternatives where possible,” Dr. High said.

The study was supported by the National Health Research Institutes of Taiwan, the Ministry of Science and Technology of Taiwan, the Chang Gung Medical Foundation, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NIH). Dr. Yao has disclosed no relevant financial relationships. Dr. Wu has received grants from GlaxoSmithKline outside the submitted work. The editorialists and Dr. High have disclosed no relevant financial relationships. Dr. Wallace received an NIH grant during the writing of the editorial.
 

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

Among adults who drink alcohol at relatively high amounts, regular weekly physical activity may reduce the mortality risk posed by alcohol-related cancers, concludes a new observational study involving 50,000-plus British adults.

Being physically active – for example, by walking, house cleaning, or playing a sport – could be promoted as a risk-minimization measure for alcohol-related cancers, say the authors, led by Emmanuel Stamatakis, PhD, professor of Physical Activity, Lifestyle, and Population Health, University of Sydney, Australia.

The researchers found a “strong direct association between alcohol consumption and mortality risk of [10] alcohol-related cancers.”

Specifically, when compared with never drinkers, there was a significantly higher risk of dying from such cancers among drinkers who consumed “hazardous” and “harmful” amounts of alcohol, and also for ex-drinkers.

Notably, occasional drinkers and drinkers within guidelines did not have statistically significantly higher risks for alcohol-related cancer mortality.

But the analysis also found that among the bigger drinkers, the risks were “substantially attenuated” in physically active participants who met at least the lower recommended limit of activity (>7.5 metabolic equivalent task [MET]–hours/week).

That’s not a taxing amount of activity because, for example, general household cleaning results in 3 METs/hour and walking slowly translates into 2 METs/hour. However, nearly a quarter of survey participants reported no physical activity.

The study was published online May 14 in the International Journal of Cancer.

The new results require confirmation because the findings “are limited in their statistical power,” with small numbers of cases in several categories, said Alpa Patel, PhD, an epidemiologist at the American Cancer Society, who was not involved in the study. For example, there were only 55 alcohol-related cancer deaths among the 1540 harmful drinkers.

Patel stressed that, “based on the collective evidence to date, it is best to both avoid alcohol consumption and engage in sufficient amounts of physical activity.” That amount is 150-300 minutes of moderate or 75-150 minutes of vigorous activity per week for cancer prevention.

Her message about abstinence is in-line with new ACS guidelines issued last month, as reported by Medscape Medical News. The ACS’s guidance was criticized by many readers in the comments section, who repeatedly encouraged “moderation.”

However, the ACS also recommended moderation, saying, for those adults who do drink, intake should be no more than 1 drink/day for women or 2 drinks/day for men. 

Study author Dr. Stamatakis commented on the alcohol debate.

“Any advice for complete abstinence is bound to alienate many people,” he told Medscape Medical News in an email. “Alcohol drinking has been an integral part of many societies for thousands of years.”

Dr. Stamatakis, who is an occasional beer drinker, also said, “there is no healthy level of alcohol drinking.”

This was also the conclusion of a 2018 study published in the Lancet, which stated that there is “no safe limit,” as even one drink a day increases the risk of cancer. A few years earlier, the 2014 World Cancer Report found a dose-response relationship between alcohol consumption and certain cancers.

However, epidemiological findings are not necessarily “clinically relevant,” commented Jennifer Ligibel, MD, a medical oncologist at the Dana-Farber Cancer Institute, Boston, Massachusetts, in a 2018 interview with Medscape Medical News.

Dr. Ligibel explained that there are 50 years of studies linking alcohol and cancers. “With the huge amount of data we have, even small differences [in consumption] are statistically significant.”

Dr. Ligibel cited an often-repeated statistic: for the average woman, there is a 12% lifetime risk of breast cancer. “If a woman consumes a drink a day, which is considered a low-level intake, that risk may become about 13% – which is statistically significant,” Dr. Ligibel explained.

But that risk increase is not clinically relevant, she added.

Mean 10 years of follow-up

The new study is the first to examine physical activity, drinking, and the 10 cancers that have been linked to alcohol consumption (oral cavity, throat, larynx, esophagus, liver, colorectal, stomach, breast, pancreas, and lung).

The authors used data from 10 British population-based health surveys from 1994-2008 and looked at adults aged 30 years and older. The mean follow-up period was 9.9 years.

Among 54,686 participants, there were 2039 alcohol-related site-specific cancer deaths.

Alcohol consumption categories were based on U.K. guidelines, with 1 unit equal to 8 grams (about 2 ounces) of pure alcohol. The categories were as follows: drinking within guidelines (<14 units/week for women, <21 units/week for men), hazardous level (14-35 units/week for women, 21-49 units/week for men), and harmful level (> 35 units/week for women, >49 units/week for men). The survey also queried participants about being ex-drinkers, occasional drinkers, and never drinkers.

Physical activity was assessed using self-reported accounts of the 4 weeks preceding the health survey and intensity of activity (light, moderate, or vigorous) was queried. Physical activity was categorized using the upper (15 MET-hours/week) and lower (the aforementioned <7 MET-hours/week) recommended limits.

The median age of participants was 51 years; 7.9% were never drinkers and 14.7% exceeded guideline amounts. For physical activity, 23% reported none. The median level of activity was 9 MET-hours/week.

The authors say that the “increased risks [among the harmful, hazardous, and ex-drinker categories] were eliminated” among the individuals who reported physical activity >7.5 MET-hours/week. That meant the hazard ratios for cancer mortality for each category were reduced to the point that they were no longer statistically significant.

For example, for all drinkers in the “hazardous” category, the risk of cancer-related mortality was significantly higher than for nondrinkers (with a hazard ratio of 1.39), but in the subgroup of these participants who were physically active at the lower recommended limit, the hazard ratio dropped to 1.21.

These “broad patterns of effect modification by physical activity persisted when the upper physical activity limit [15 MET-hours/week] was used,” write the authors.

The new study adds to the literature on cancer mortality and alcohol consumption. In another recent study, researchers looked at eight British cohorts and reported overall cancer mortality associated with alcohol consumption was eliminated among those meeting physical activity recommendations (Br J Sports Med. 2017;51:651-7). The new study added two more cohorts to this base of eight and only focused on cancers that have been linked to alcohol consumption. The earlier study included deaths from all types of cancer.

The refinement of focus in the current study is important, say Dr. Stamatakis and colleagues.

“This specificity adds biological plausibility and permits a more immediate translation of our findings into policy and practice,” they write. 

Dr. Stamatakis practices what he advocates, but is not a teetotaler.

“I exercise (e.g., dynamic yoga, HIIT cardio workouts, run, cycle, lift weights) for 45-60 minutes a day and I walk 8,000-14,000 steps daily. That would categorize me perhaps in the top 3%-5% for my age/sex group. And I enjoy 1-2 cans of craft beer a couple of times a week,” he said in an email.

Dr. Stamatakis and Dr. Patel have reported no relevant financial relationships.

This article first appeared on Medscape.com.

Among adults who drink alcohol at relatively high amounts, regular weekly physical activity may reduce the mortality risk posed by alcohol-related cancers, concludes a new observational study involving 50,000-plus British adults.

Being physically active – for example, by walking, house cleaning, or playing a sport – could be promoted as a risk-minimization measure for alcohol-related cancers, say the authors, led by Emmanuel Stamatakis, PhD, professor of Physical Activity, Lifestyle, and Population Health, University of Sydney, Australia.

The researchers found a “strong direct association between alcohol consumption and mortality risk of [10] alcohol-related cancers.”

Specifically, when compared with never drinkers, there was a significantly higher risk of dying from such cancers among drinkers who consumed “hazardous” and “harmful” amounts of alcohol, and also for ex-drinkers.

Notably, occasional drinkers and drinkers within guidelines did not have statistically significantly higher risks for alcohol-related cancer mortality.

But the analysis also found that among the bigger drinkers, the risks were “substantially attenuated” in physically active participants who met at least the lower recommended limit of activity (>7.5 metabolic equivalent task [MET]–hours/week).

That’s not a taxing amount of activity because, for example, general household cleaning results in 3 METs/hour and walking slowly translates into 2 METs/hour. However, nearly a quarter of survey participants reported no physical activity.

The study was published online May 14 in the International Journal of Cancer.

The new results require confirmation because the findings “are limited in their statistical power,” with small numbers of cases in several categories, said Alpa Patel, PhD, an epidemiologist at the American Cancer Society, who was not involved in the study. For example, there were only 55 alcohol-related cancer deaths among the 1540 harmful drinkers.

Patel stressed that, “based on the collective evidence to date, it is best to both avoid alcohol consumption and engage in sufficient amounts of physical activity.” That amount is 150-300 minutes of moderate or 75-150 minutes of vigorous activity per week for cancer prevention.

Her message about abstinence is in-line with new ACS guidelines issued last month, as reported by Medscape Medical News. The ACS’s guidance was criticized by many readers in the comments section, who repeatedly encouraged “moderation.”

However, the ACS also recommended moderation, saying, for those adults who do drink, intake should be no more than 1 drink/day for women or 2 drinks/day for men. 

Study author Dr. Stamatakis commented on the alcohol debate.

“Any advice for complete abstinence is bound to alienate many people,” he told Medscape Medical News in an email. “Alcohol drinking has been an integral part of many societies for thousands of years.”

Dr. Stamatakis, who is an occasional beer drinker, also said, “there is no healthy level of alcohol drinking.”

This was also the conclusion of a 2018 study published in the Lancet, which stated that there is “no safe limit,” as even one drink a day increases the risk of cancer. A few years earlier, the 2014 World Cancer Report found a dose-response relationship between alcohol consumption and certain cancers.

However, epidemiological findings are not necessarily “clinically relevant,” commented Jennifer Ligibel, MD, a medical oncologist at the Dana-Farber Cancer Institute, Boston, Massachusetts, in a 2018 interview with Medscape Medical News.

Dr. Ligibel explained that there are 50 years of studies linking alcohol and cancers. “With the huge amount of data we have, even small differences [in consumption] are statistically significant.”

Dr. Ligibel cited an often-repeated statistic: for the average woman, there is a 12% lifetime risk of breast cancer. “If a woman consumes a drink a day, which is considered a low-level intake, that risk may become about 13% – which is statistically significant,” Dr. Ligibel explained.

But that risk increase is not clinically relevant, she added.

Mean 10 years of follow-up

The new study is the first to examine physical activity, drinking, and the 10 cancers that have been linked to alcohol consumption (oral cavity, throat, larynx, esophagus, liver, colorectal, stomach, breast, pancreas, and lung).

The authors used data from 10 British population-based health surveys from 1994-2008 and looked at adults aged 30 years and older. The mean follow-up period was 9.9 years.

Among 54,686 participants, there were 2039 alcohol-related site-specific cancer deaths.

Alcohol consumption categories were based on U.K. guidelines, with 1 unit equal to 8 grams (about 2 ounces) of pure alcohol. The categories were as follows: drinking within guidelines (<14 units/week for women, <21 units/week for men), hazardous level (14-35 units/week for women, 21-49 units/week for men), and harmful level (> 35 units/week for women, >49 units/week for men). The survey also queried participants about being ex-drinkers, occasional drinkers, and never drinkers.

Physical activity was assessed using self-reported accounts of the 4 weeks preceding the health survey and intensity of activity (light, moderate, or vigorous) was queried. Physical activity was categorized using the upper (15 MET-hours/week) and lower (the aforementioned <7 MET-hours/week) recommended limits.

The median age of participants was 51 years; 7.9% were never drinkers and 14.7% exceeded guideline amounts. For physical activity, 23% reported none. The median level of activity was 9 MET-hours/week.

The authors say that the “increased risks [among the harmful, hazardous, and ex-drinker categories] were eliminated” among the individuals who reported physical activity >7.5 MET-hours/week. That meant the hazard ratios for cancer mortality for each category were reduced to the point that they were no longer statistically significant.

For example, for all drinkers in the “hazardous” category, the risk of cancer-related mortality was significantly higher than for nondrinkers (with a hazard ratio of 1.39), but in the subgroup of these participants who were physically active at the lower recommended limit, the hazard ratio dropped to 1.21.

These “broad patterns of effect modification by physical activity persisted when the upper physical activity limit [15 MET-hours/week] was used,” write the authors.

The new study adds to the literature on cancer mortality and alcohol consumption. In another recent study, researchers looked at eight British cohorts and reported overall cancer mortality associated with alcohol consumption was eliminated among those meeting physical activity recommendations (Br J Sports Med. 2017;51:651-7). The new study added two more cohorts to this base of eight and only focused on cancers that have been linked to alcohol consumption. The earlier study included deaths from all types of cancer.

The refinement of focus in the current study is important, say Dr. Stamatakis and colleagues.

“This specificity adds biological plausibility and permits a more immediate translation of our findings into policy and practice,” they write. 

Dr. Stamatakis practices what he advocates, but is not a teetotaler.

“I exercise (e.g., dynamic yoga, HIIT cardio workouts, run, cycle, lift weights) for 45-60 minutes a day and I walk 8,000-14,000 steps daily. That would categorize me perhaps in the top 3%-5% for my age/sex group. And I enjoy 1-2 cans of craft beer a couple of times a week,” he said in an email.

Dr. Stamatakis and Dr. Patel have reported no relevant financial relationships.

This article first appeared on Medscape.com.

Among adults who drink alcohol at relatively high amounts, regular weekly physical activity may reduce the mortality risk posed by alcohol-related cancers, concludes a new observational study involving 50,000-plus British adults.

Being physically active – for example, by walking, house cleaning, or playing a sport – could be promoted as a risk-minimization measure for alcohol-related cancers, say the authors, led by Emmanuel Stamatakis, PhD, professor of Physical Activity, Lifestyle, and Population Health, University of Sydney, Australia.

The researchers found a “strong direct association between alcohol consumption and mortality risk of [10] alcohol-related cancers.”

Specifically, when compared with never drinkers, there was a significantly higher risk of dying from such cancers among drinkers who consumed “hazardous” and “harmful” amounts of alcohol, and also for ex-drinkers.

Notably, occasional drinkers and drinkers within guidelines did not have statistically significantly higher risks for alcohol-related cancer mortality.

But the analysis also found that among the bigger drinkers, the risks were “substantially attenuated” in physically active participants who met at least the lower recommended limit of activity (>7.5 metabolic equivalent task [MET]–hours/week).

That’s not a taxing amount of activity because, for example, general household cleaning results in 3 METs/hour and walking slowly translates into 2 METs/hour. However, nearly a quarter of survey participants reported no physical activity.

The study was published online May 14 in the International Journal of Cancer.

The new results require confirmation because the findings “are limited in their statistical power,” with small numbers of cases in several categories, said Alpa Patel, PhD, an epidemiologist at the American Cancer Society, who was not involved in the study. For example, there were only 55 alcohol-related cancer deaths among the 1540 harmful drinkers.

Patel stressed that, “based on the collective evidence to date, it is best to both avoid alcohol consumption and engage in sufficient amounts of physical activity.” That amount is 150-300 minutes of moderate or 75-150 minutes of vigorous activity per week for cancer prevention.

Her message about abstinence is in-line with new ACS guidelines issued last month, as reported by Medscape Medical News. The ACS’s guidance was criticized by many readers in the comments section, who repeatedly encouraged “moderation.”

However, the ACS also recommended moderation, saying, for those adults who do drink, intake should be no more than 1 drink/day for women or 2 drinks/day for men. 

Study author Dr. Stamatakis commented on the alcohol debate.

“Any advice for complete abstinence is bound to alienate many people,” he told Medscape Medical News in an email. “Alcohol drinking has been an integral part of many societies for thousands of years.”

Dr. Stamatakis, who is an occasional beer drinker, also said, “there is no healthy level of alcohol drinking.”

This was also the conclusion of a 2018 study published in the Lancet, which stated that there is “no safe limit,” as even one drink a day increases the risk of cancer. A few years earlier, the 2014 World Cancer Report found a dose-response relationship between alcohol consumption and certain cancers.

However, epidemiological findings are not necessarily “clinically relevant,” commented Jennifer Ligibel, MD, a medical oncologist at the Dana-Farber Cancer Institute, Boston, Massachusetts, in a 2018 interview with Medscape Medical News.

Dr. Ligibel explained that there are 50 years of studies linking alcohol and cancers. “With the huge amount of data we have, even small differences [in consumption] are statistically significant.”

Dr. Ligibel cited an often-repeated statistic: for the average woman, there is a 12% lifetime risk of breast cancer. “If a woman consumes a drink a day, which is considered a low-level intake, that risk may become about 13% – which is statistically significant,” Dr. Ligibel explained.

But that risk increase is not clinically relevant, she added.

Mean 10 years of follow-up

The new study is the first to examine physical activity, drinking, and the 10 cancers that have been linked to alcohol consumption (oral cavity, throat, larynx, esophagus, liver, colorectal, stomach, breast, pancreas, and lung).

The authors used data from 10 British population-based health surveys from 1994-2008 and looked at adults aged 30 years and older. The mean follow-up period was 9.9 years.

Among 54,686 participants, there were 2039 alcohol-related site-specific cancer deaths.

Alcohol consumption categories were based on U.K. guidelines, with 1 unit equal to 8 grams (about 2 ounces) of pure alcohol. The categories were as follows: drinking within guidelines (<14 units/week for women, <21 units/week for men), hazardous level (14-35 units/week for women, 21-49 units/week for men), and harmful level (> 35 units/week for women, >49 units/week for men). The survey also queried participants about being ex-drinkers, occasional drinkers, and never drinkers.

Physical activity was assessed using self-reported accounts of the 4 weeks preceding the health survey and intensity of activity (light, moderate, or vigorous) was queried. Physical activity was categorized using the upper (15 MET-hours/week) and lower (the aforementioned <7 MET-hours/week) recommended limits.

The median age of participants was 51 years; 7.9% were never drinkers and 14.7% exceeded guideline amounts. For physical activity, 23% reported none. The median level of activity was 9 MET-hours/week.

The authors say that the “increased risks [among the harmful, hazardous, and ex-drinker categories] were eliminated” among the individuals who reported physical activity >7.5 MET-hours/week. That meant the hazard ratios for cancer mortality for each category were reduced to the point that they were no longer statistically significant.

For example, for all drinkers in the “hazardous” category, the risk of cancer-related mortality was significantly higher than for nondrinkers (with a hazard ratio of 1.39), but in the subgroup of these participants who were physically active at the lower recommended limit, the hazard ratio dropped to 1.21.

These “broad patterns of effect modification by physical activity persisted when the upper physical activity limit [15 MET-hours/week] was used,” write the authors.

The new study adds to the literature on cancer mortality and alcohol consumption. In another recent study, researchers looked at eight British cohorts and reported overall cancer mortality associated with alcohol consumption was eliminated among those meeting physical activity recommendations (Br J Sports Med. 2017;51:651-7). The new study added two more cohorts to this base of eight and only focused on cancers that have been linked to alcohol consumption. The earlier study included deaths from all types of cancer.

The refinement of focus in the current study is important, say Dr. Stamatakis and colleagues.

“This specificity adds biological plausibility and permits a more immediate translation of our findings into policy and practice,” they write. 

Dr. Stamatakis practices what he advocates, but is not a teetotaler.

“I exercise (e.g., dynamic yoga, HIIT cardio workouts, run, cycle, lift weights) for 45-60 minutes a day and I walk 8,000-14,000 steps daily. That would categorize me perhaps in the top 3%-5% for my age/sex group. And I enjoy 1-2 cans of craft beer a couple of times a week,” he said in an email.

Dr. Stamatakis and Dr. Patel have reported no relevant financial relationships.

This article first appeared on Medscape.com.

The COVID-19 literature has been peppered with reports about myocarditis accompanying the disease. If true, this could, in part, explain some of the observed cardiac injury and arrhythmias in seriously ill patients, but also have implications for prognosis.

But endomyocardial biopsies and autopsies, the gold-standard confirmation tests, have been few and far between. That has led some cardiologists to question the true rate of myocarditis with SARS-CoV-2, or even if there is definitive proof the virus causes myocarditis.

Predictors of death in COVID-19 are older age, cardiovascular comorbidities, and elevated troponin or NT-proBNP – none of which actually fit well with the epidemiology of myocarditis due to other causes, Alida L.P. Caforio, MD, of Padua (Italy) University said in an interview. Myocarditis is traditionally a disease of the young, and most cases are immune-mediated and do not release troponin.

Moreover, myocarditis is a diagnosis of exclusion. For it to be made with any certainty requires proof, by biopsy or autopsy, of inflammatory infiltrates within the myocardium with myocyte necrosis not typical of myocardial infarction, said Dr. Caforio, who chaired the European Society of Cardiology’s writing committee for its 2013 position statement on myocardial and pericardial diseases.

“We have one biopsy-proven case, and in this case there were no viruses in the myocardium, including COVID-19,” she said. “There’s no proof that we have COVID-19 causing myocarditis because it has not been found in the cardiomyocytes.”
 

Emerging evidence

The virus-negative case from Lombardy, Italy, followed an early case series suggesting fulminant myocarditis was involved in 7% of COVID-related deaths in Wuhan, China.

Other case reports include cardiac magnetic resonance (CMR) findings typical of acute myocarditis in a man with no lung involvement or fever but a massive troponin spike, and myocarditis presenting as reverse takotsubo syndrome in a woman undergoing CMR and endomyocardial biopsy.

A CMR analysis in May said acute myocarditis, by 2018 Lake Louise Criteria, was present in eight of 10 patients with “myocarditis-like syndrome,” and a study just out June 30 said the coronavirus can infect heart cells in a lab dish.

Among the few autopsy series, a preprint on 12 patients with COVID-19 in the Seattle area showed coronavirus in the heart tissue of 1 patient.

“It was a low level, so there’s the possibility that it could be viremia, but the fact we do see actual cardiomyocyte injury associated with inflammation, that’s a myocarditis pattern. So it could be related to the SARS-CoV-2 virus,” said Desiree Marshall, MD, director of autopsy and after-death services, University of Washington Medical Center, Seattle.

The “waters are a little bit muddy,” however, because the patient had a coinfection clinically with influenza and methicillin-susceptible Staphylococcus aureus, which raises the specter that influenza could also have contributed, she said.

Data pending publication from two additional patients show no coronavirus in the heart. Acute respiratory distress syndrome pathology was common in all patients, but there was no evidence of vascular inflammation, such as endotheliitis, Dr. Marshall said.

SARS-CoV-2 cell entry depends on the angiotensin-converting enzyme 2 (ACE2) receptor, which is widely expressed in the heart and on endothelial cells and is linked to inflammatory activation. Autopsy data from three COVID-19 patients showed endothelial cell infection in the heart and diffuse endothelial inflammation, but no sign of lymphocytic myocarditis.
 

Defining myocarditis

“There are some experts who believe we’re likely still dealing with myocarditis but with atypical features, while others suggest there is no myocarditis by strict classic criteria,” said Peter Liu, MD, chief scientific officer/vice president of research, University of Ottawa Heart Institute.

“I don’t think either extreme is accurate,” he said. “The truth is likely somewhere in between, with evidence of both cardiac injury and inflammation. But nothing in COVID-19, as we know today, is classic; it’s a new disease, so we need to be more open minded as new data emerge.”

Part of the divide may indeed stem from the way myocarditis is defined. “Based on traditional Dallas criteria, classic myocarditis requires evidence of myocyte necrosis, which we have, but also inflammatory cell infiltrate, which we don’t consistently have,” he said. “But on the other hand, there is evidence of inflammation-induced cardiac damage, often aggregated around blood vessels.”

The situation is evolving in recent days, and new data under review demonstrated inflammatory infiltrates, which fits the traditional myocarditis criteria, Dr. Liu noted. Yet the viral etiology for the inflammation is still elusive in definitive proof.

In traditional myocarditis, there is an abundance of lymphocytes and foci of inflammation in the myocardium, but COVID-19 is very unusual, in that these lymphocytes are not as exuberant, he said. Lymphopenia or low lymphocyte counts occur in up to 80% of patients. Also, older patients, who initially made up the bulk of the severe COVID-19 cases, are less T-lymphocyte responsive.

“So the lower your lymphocyte count, the worse your outcome is going to be and the more likely you’re going to get cytokine storm,” Dr. Liu said. “And that may be the reason the suspected myocarditis in COVID-19 is atypical because the lymphocytes, in fact, are being suppressed and there is instead more vasculitis.”

Recent data from myocardial gene expression analysis showed that the viral receptor ACE2 is present in the myocardium, and can be upregulated in conditions such as heart failure, he said. However, the highest ACE2 expression is found in pericytes around blood vessels, not myocytes. “This may explain the preferential vascular involvement often observed.”
 

Cardiac damage in the young

Evidence started evolving in early April that young COVID-19 patients without lung disease, generally in their 20s and 30s, can have very high troponin peaks and a form of cardiac damage that does not appear to be related to sepsis, systemic shock, or cytokine storm.

“That’s the group that I do think has some myocarditis, but it’s different. It’s not lymphocytic myocarditis, like enteroviral myocarditis,” Leslie T. Cooper Jr., MD, a myocarditis expert at Mayo Clinic, Jacksonville, Florida, said in an interview.

“The data to date suggest that most SARS cardiac injury is related to stress or high circulating cytokine levels. However, myocarditis probably does affect some patients, he added. “The few published cases suggest a role for macrophages or endothelial cells, which could affect cardiac myocyte function. This type of injury could cause the ST-segment elevation MI-like patterns we have seen in young people with normal epicardial coronary arteries.”

Dr. Cooper, who coauthored a report on the management of COVID-19 cardiovascular syndrome, pointed out that it’s been hard for researchers to isolate genome from autopsy samples because of RNA degradation prior to autopsy and the use of formalin fixation for tissues prior to RNA extraction.

“Most labs are not doing next-generation sequencing, and even with that, RNA protection and fresh tissue may be required to detect viral genome,” he said.
 

No proven therapy

Although up to 50% of acute myocarditis cases undergo spontaneous healing, recognition and multidisciplinary management of clinically suspected myocarditis is important. The optimal treatment remains unclear.

An early case report suggested use of methylprednisolone and intravenous immunoglobulin helped spare the life of a 37-year-old with clinically suspected fulminant myocarditis with cardiogenic shock.

In a related commentary, Dr. Caforio and colleagues pointed out that the World Health Organization considers the use of IV corticosteroids controversial, even in pneumonia due to COVID-19, because it may reduce viral clearance and increase sepsis risk. Intravenous immunoglobulin is also questionable because there is no IgG response to COVID-19 in the plasma donors’ pool.

“Immunosuppression should be reserved for only virus-negative non-COVID myocarditis,” Dr. Caforio said in an interview. “There is no appropriate treatment nowadays for clinically suspected COVID-19 myocarditis. There is no proven therapy for COVID-19, even less for COVID-19 myocarditis.”

Although definitive publication of the RECOVERY trial is still pending, the benefits of dexamethasone – a steroid that works predominantly through its anti-inflammatory effects – appear to be in the sickest patients, such as those requiring ICU admission or respiratory support.

“Many of the same patients would have systemic inflammation and would have also shown elevated cardiac biomarkers,” Dr. Liu observed. “Therefore, it is conceivable that a subset who had cardiac inflammation also benefited from the treatment. Further data, possibly through subgroup analysis and eventually meta-analysis, may help us to understand if dexamethasone also benefited patients with dominant cardiac injury.”

Dr. Caforio, Dr. Marshall, Dr. Liu, and Dr. Cooper reported having no relevant conflicts of interest.

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

The COVID-19 literature has been peppered with reports about myocarditis accompanying the disease. If true, this could, in part, explain some of the observed cardiac injury and arrhythmias in seriously ill patients, but also have implications for prognosis.

But endomyocardial biopsies and autopsies, the gold-standard confirmation tests, have been few and far between. That has led some cardiologists to question the true rate of myocarditis with SARS-CoV-2, or even if there is definitive proof the virus causes myocarditis.

Predictors of death in COVID-19 are older age, cardiovascular comorbidities, and elevated troponin or NT-proBNP – none of which actually fit well with the epidemiology of myocarditis due to other causes, Alida L.P. Caforio, MD, of Padua (Italy) University said in an interview. Myocarditis is traditionally a disease of the young, and most cases are immune-mediated and do not release troponin.

Moreover, myocarditis is a diagnosis of exclusion. For it to be made with any certainty requires proof, by biopsy or autopsy, of inflammatory infiltrates within the myocardium with myocyte necrosis not typical of myocardial infarction, said Dr. Caforio, who chaired the European Society of Cardiology’s writing committee for its 2013 position statement on myocardial and pericardial diseases.

“We have one biopsy-proven case, and in this case there were no viruses in the myocardium, including COVID-19,” she said. “There’s no proof that we have COVID-19 causing myocarditis because it has not been found in the cardiomyocytes.”
 

Emerging evidence

The virus-negative case from Lombardy, Italy, followed an early case series suggesting fulminant myocarditis was involved in 7% of COVID-related deaths in Wuhan, China.

Other case reports include cardiac magnetic resonance (CMR) findings typical of acute myocarditis in a man with no lung involvement or fever but a massive troponin spike, and myocarditis presenting as reverse takotsubo syndrome in a woman undergoing CMR and endomyocardial biopsy.

A CMR analysis in May said acute myocarditis, by 2018 Lake Louise Criteria, was present in eight of 10 patients with “myocarditis-like syndrome,” and a study just out June 30 said the coronavirus can infect heart cells in a lab dish.

Among the few autopsy series, a preprint on 12 patients with COVID-19 in the Seattle area showed coronavirus in the heart tissue of 1 patient.

“It was a low level, so there’s the possibility that it could be viremia, but the fact we do see actual cardiomyocyte injury associated with inflammation, that’s a myocarditis pattern. So it could be related to the SARS-CoV-2 virus,” said Desiree Marshall, MD, director of autopsy and after-death services, University of Washington Medical Center, Seattle.

The “waters are a little bit muddy,” however, because the patient had a coinfection clinically with influenza and methicillin-susceptible Staphylococcus aureus, which raises the specter that influenza could also have contributed, she said.

Data pending publication from two additional patients show no coronavirus in the heart. Acute respiratory distress syndrome pathology was common in all patients, but there was no evidence of vascular inflammation, such as endotheliitis, Dr. Marshall said.

SARS-CoV-2 cell entry depends on the angiotensin-converting enzyme 2 (ACE2) receptor, which is widely expressed in the heart and on endothelial cells and is linked to inflammatory activation. Autopsy data from three COVID-19 patients showed endothelial cell infection in the heart and diffuse endothelial inflammation, but no sign of lymphocytic myocarditis.
 

Defining myocarditis

“There are some experts who believe we’re likely still dealing with myocarditis but with atypical features, while others suggest there is no myocarditis by strict classic criteria,” said Peter Liu, MD, chief scientific officer/vice president of research, University of Ottawa Heart Institute.

“I don’t think either extreme is accurate,” he said. “The truth is likely somewhere in between, with evidence of both cardiac injury and inflammation. But nothing in COVID-19, as we know today, is classic; it’s a new disease, so we need to be more open minded as new data emerge.”

Part of the divide may indeed stem from the way myocarditis is defined. “Based on traditional Dallas criteria, classic myocarditis requires evidence of myocyte necrosis, which we have, but also inflammatory cell infiltrate, which we don’t consistently have,” he said. “But on the other hand, there is evidence of inflammation-induced cardiac damage, often aggregated around blood vessels.”

The situation is evolving in recent days, and new data under review demonstrated inflammatory infiltrates, which fits the traditional myocarditis criteria, Dr. Liu noted. Yet the viral etiology for the inflammation is still elusive in definitive proof.

In traditional myocarditis, there is an abundance of lymphocytes and foci of inflammation in the myocardium, but COVID-19 is very unusual, in that these lymphocytes are not as exuberant, he said. Lymphopenia or low lymphocyte counts occur in up to 80% of patients. Also, older patients, who initially made up the bulk of the severe COVID-19 cases, are less T-lymphocyte responsive.

“So the lower your lymphocyte count, the worse your outcome is going to be and the more likely you’re going to get cytokine storm,” Dr. Liu said. “And that may be the reason the suspected myocarditis in COVID-19 is atypical because the lymphocytes, in fact, are being suppressed and there is instead more vasculitis.”

Recent data from myocardial gene expression analysis showed that the viral receptor ACE2 is present in the myocardium, and can be upregulated in conditions such as heart failure, he said. However, the highest ACE2 expression is found in pericytes around blood vessels, not myocytes. “This may explain the preferential vascular involvement often observed.”
 

Cardiac damage in the young

Evidence started evolving in early April that young COVID-19 patients without lung disease, generally in their 20s and 30s, can have very high troponin peaks and a form of cardiac damage that does not appear to be related to sepsis, systemic shock, or cytokine storm.

“That’s the group that I do think has some myocarditis, but it’s different. It’s not lymphocytic myocarditis, like enteroviral myocarditis,” Leslie T. Cooper Jr., MD, a myocarditis expert at Mayo Clinic, Jacksonville, Florida, said in an interview.

“The data to date suggest that most SARS cardiac injury is related to stress or high circulating cytokine levels. However, myocarditis probably does affect some patients, he added. “The few published cases suggest a role for macrophages or endothelial cells, which could affect cardiac myocyte function. This type of injury could cause the ST-segment elevation MI-like patterns we have seen in young people with normal epicardial coronary arteries.”

Dr. Cooper, who coauthored a report on the management of COVID-19 cardiovascular syndrome, pointed out that it’s been hard for researchers to isolate genome from autopsy samples because of RNA degradation prior to autopsy and the use of formalin fixation for tissues prior to RNA extraction.

“Most labs are not doing next-generation sequencing, and even with that, RNA protection and fresh tissue may be required to detect viral genome,” he said.
 

No proven therapy

Although up to 50% of acute myocarditis cases undergo spontaneous healing, recognition and multidisciplinary management of clinically suspected myocarditis is important. The optimal treatment remains unclear.

An early case report suggested use of methylprednisolone and intravenous immunoglobulin helped spare the life of a 37-year-old with clinically suspected fulminant myocarditis with cardiogenic shock.

In a related commentary, Dr. Caforio and colleagues pointed out that the World Health Organization considers the use of IV corticosteroids controversial, even in pneumonia due to COVID-19, because it may reduce viral clearance and increase sepsis risk. Intravenous immunoglobulin is also questionable because there is no IgG response to COVID-19 in the plasma donors’ pool.

“Immunosuppression should be reserved for only virus-negative non-COVID myocarditis,” Dr. Caforio said in an interview. “There is no appropriate treatment nowadays for clinically suspected COVID-19 myocarditis. There is no proven therapy for COVID-19, even less for COVID-19 myocarditis.”

Although definitive publication of the RECOVERY trial is still pending, the benefits of dexamethasone – a steroid that works predominantly through its anti-inflammatory effects – appear to be in the sickest patients, such as those requiring ICU admission or respiratory support.

“Many of the same patients would have systemic inflammation and would have also shown elevated cardiac biomarkers,” Dr. Liu observed. “Therefore, it is conceivable that a subset who had cardiac inflammation also benefited from the treatment. Further data, possibly through subgroup analysis and eventually meta-analysis, may help us to understand if dexamethasone also benefited patients with dominant cardiac injury.”

Dr. Caforio, Dr. Marshall, Dr. Liu, and Dr. Cooper reported having no relevant conflicts of interest.

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

The COVID-19 literature has been peppered with reports about myocarditis accompanying the disease. If true, this could, in part, explain some of the observed cardiac injury and arrhythmias in seriously ill patients, but also have implications for prognosis.

But endomyocardial biopsies and autopsies, the gold-standard confirmation tests, have been few and far between. That has led some cardiologists to question the true rate of myocarditis with SARS-CoV-2, or even if there is definitive proof the virus causes myocarditis.

Predictors of death in COVID-19 are older age, cardiovascular comorbidities, and elevated troponin or NT-proBNP – none of which actually fit well with the epidemiology of myocarditis due to other causes, Alida L.P. Caforio, MD, of Padua (Italy) University said in an interview. Myocarditis is traditionally a disease of the young, and most cases are immune-mediated and do not release troponin.

Moreover, myocarditis is a diagnosis of exclusion. For it to be made with any certainty requires proof, by biopsy or autopsy, of inflammatory infiltrates within the myocardium with myocyte necrosis not typical of myocardial infarction, said Dr. Caforio, who chaired the European Society of Cardiology’s writing committee for its 2013 position statement on myocardial and pericardial diseases.

“We have one biopsy-proven case, and in this case there were no viruses in the myocardium, including COVID-19,” she said. “There’s no proof that we have COVID-19 causing myocarditis because it has not been found in the cardiomyocytes.”
 

Emerging evidence

The virus-negative case from Lombardy, Italy, followed an early case series suggesting fulminant myocarditis was involved in 7% of COVID-related deaths in Wuhan, China.

Other case reports include cardiac magnetic resonance (CMR) findings typical of acute myocarditis in a man with no lung involvement or fever but a massive troponin spike, and myocarditis presenting as reverse takotsubo syndrome in a woman undergoing CMR and endomyocardial biopsy.

A CMR analysis in May said acute myocarditis, by 2018 Lake Louise Criteria, was present in eight of 10 patients with “myocarditis-like syndrome,” and a study just out June 30 said the coronavirus can infect heart cells in a lab dish.

Among the few autopsy series, a preprint on 12 patients with COVID-19 in the Seattle area showed coronavirus in the heart tissue of 1 patient.

“It was a low level, so there’s the possibility that it could be viremia, but the fact we do see actual cardiomyocyte injury associated with inflammation, that’s a myocarditis pattern. So it could be related to the SARS-CoV-2 virus,” said Desiree Marshall, MD, director of autopsy and after-death services, University of Washington Medical Center, Seattle.

The “waters are a little bit muddy,” however, because the patient had a coinfection clinically with influenza and methicillin-susceptible Staphylococcus aureus, which raises the specter that influenza could also have contributed, she said.

Data pending publication from two additional patients show no coronavirus in the heart. Acute respiratory distress syndrome pathology was common in all patients, but there was no evidence of vascular inflammation, such as endotheliitis, Dr. Marshall said.

SARS-CoV-2 cell entry depends on the angiotensin-converting enzyme 2 (ACE2) receptor, which is widely expressed in the heart and on endothelial cells and is linked to inflammatory activation. Autopsy data from three COVID-19 patients showed endothelial cell infection in the heart and diffuse endothelial inflammation, but no sign of lymphocytic myocarditis.
 

Defining myocarditis

“There are some experts who believe we’re likely still dealing with myocarditis but with atypical features, while others suggest there is no myocarditis by strict classic criteria,” said Peter Liu, MD, chief scientific officer/vice president of research, University of Ottawa Heart Institute.

“I don’t think either extreme is accurate,” he said. “The truth is likely somewhere in between, with evidence of both cardiac injury and inflammation. But nothing in COVID-19, as we know today, is classic; it’s a new disease, so we need to be more open minded as new data emerge.”

Part of the divide may indeed stem from the way myocarditis is defined. “Based on traditional Dallas criteria, classic myocarditis requires evidence of myocyte necrosis, which we have, but also inflammatory cell infiltrate, which we don’t consistently have,” he said. “But on the other hand, there is evidence of inflammation-induced cardiac damage, often aggregated around blood vessels.”

The situation is evolving in recent days, and new data under review demonstrated inflammatory infiltrates, which fits the traditional myocarditis criteria, Dr. Liu noted. Yet the viral etiology for the inflammation is still elusive in definitive proof.

In traditional myocarditis, there is an abundance of lymphocytes and foci of inflammation in the myocardium, but COVID-19 is very unusual, in that these lymphocytes are not as exuberant, he said. Lymphopenia or low lymphocyte counts occur in up to 80% of patients. Also, older patients, who initially made up the bulk of the severe COVID-19 cases, are less T-lymphocyte responsive.

“So the lower your lymphocyte count, the worse your outcome is going to be and the more likely you’re going to get cytokine storm,” Dr. Liu said. “And that may be the reason the suspected myocarditis in COVID-19 is atypical because the lymphocytes, in fact, are being suppressed and there is instead more vasculitis.”

Recent data from myocardial gene expression analysis showed that the viral receptor ACE2 is present in the myocardium, and can be upregulated in conditions such as heart failure, he said. However, the highest ACE2 expression is found in pericytes around blood vessels, not myocytes. “This may explain the preferential vascular involvement often observed.”
 

Cardiac damage in the young

Evidence started evolving in early April that young COVID-19 patients without lung disease, generally in their 20s and 30s, can have very high troponin peaks and a form of cardiac damage that does not appear to be related to sepsis, systemic shock, or cytokine storm.

“That’s the group that I do think has some myocarditis, but it’s different. It’s not lymphocytic myocarditis, like enteroviral myocarditis,” Leslie T. Cooper Jr., MD, a myocarditis expert at Mayo Clinic, Jacksonville, Florida, said in an interview.

“The data to date suggest that most SARS cardiac injury is related to stress or high circulating cytokine levels. However, myocarditis probably does affect some patients, he added. “The few published cases suggest a role for macrophages or endothelial cells, which could affect cardiac myocyte function. This type of injury could cause the ST-segment elevation MI-like patterns we have seen in young people with normal epicardial coronary arteries.”

Dr. Cooper, who coauthored a report on the management of COVID-19 cardiovascular syndrome, pointed out that it’s been hard for researchers to isolate genome from autopsy samples because of RNA degradation prior to autopsy and the use of formalin fixation for tissues prior to RNA extraction.

“Most labs are not doing next-generation sequencing, and even with that, RNA protection and fresh tissue may be required to detect viral genome,” he said.
 

No proven therapy

Although up to 50% of acute myocarditis cases undergo spontaneous healing, recognition and multidisciplinary management of clinically suspected myocarditis is important. The optimal treatment remains unclear.

An early case report suggested use of methylprednisolone and intravenous immunoglobulin helped spare the life of a 37-year-old with clinically suspected fulminant myocarditis with cardiogenic shock.

In a related commentary, Dr. Caforio and colleagues pointed out that the World Health Organization considers the use of IV corticosteroids controversial, even in pneumonia due to COVID-19, because it may reduce viral clearance and increase sepsis risk. Intravenous immunoglobulin is also questionable because there is no IgG response to COVID-19 in the plasma donors’ pool.

“Immunosuppression should be reserved for only virus-negative non-COVID myocarditis,” Dr. Caforio said in an interview. “There is no appropriate treatment nowadays for clinically suspected COVID-19 myocarditis. There is no proven therapy for COVID-19, even less for COVID-19 myocarditis.”

Although definitive publication of the RECOVERY trial is still pending, the benefits of dexamethasone – a steroid that works predominantly through its anti-inflammatory effects – appear to be in the sickest patients, such as those requiring ICU admission or respiratory support.

“Many of the same patients would have systemic inflammation and would have also shown elevated cardiac biomarkers,” Dr. Liu observed. “Therefore, it is conceivable that a subset who had cardiac inflammation also benefited from the treatment. Further data, possibly through subgroup analysis and eventually meta-analysis, may help us to understand if dexamethasone also benefited patients with dominant cardiac injury.”

Dr. Caforio, Dr. Marshall, Dr. Liu, and Dr. Cooper reported having no relevant conflicts of interest.

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

As more jurisdictions mandate facial coverings in public, questions have arisen about whether it’s safe for everyone – including those with lung disease – to wear masks. Stories about people who claim to be unable to wear masks because of breathing problems are appearing in the news with increasing frequency, and patients are starting to call their doctors to request medical exemptions to public mask requirements.

David Fuentes Prieto/Shutterstock

To address these issues, Medscape spoke with the chief medical officer of the American Lung Association, Dr. Albert Rizzo.
 

The CDC recommendations on mask wearing say, “Cloth face coverings should not be placed on young children under age 2, anyone who has trouble breathing, or is unconscious, incapacitated, or otherwise unable to remove the mask without assistance.” Does this language suggest that there indeed is a subset of the adult population with lung disease who shouldn’t wear masks?

It makes sense to say that if it makes you uncomfortable to wear a mask because it affects your breathing, you should think twice about getting in a situation where you would have to wear a mask.

I’ve told many of my high-risk patients, “The best way to avoid getting COVID-19 is to stay home and stay away from sick people, especially if you feel that you are not going to be able to wear a mask or facial covering of some sort.”

The reason that some people have trouble with a mask is that they haven’t tried the right style of mask – by that I mean how tightly it fits and the material it’s made out of. Sometimes it really is just that people with lung disease don’t like to have anything covering their faces. Many of these patients feel better where there is air blowing across their faces – they will have a fan blowing even in the middle of winter because they feel more comfortable.

I won’t say it’s all in their heads, but sometimes it’s a matter of desensitizing themselves to wearing a mask. I liken it to people who have sleep apnea. We often have to desensitize them to wearing a mask for sleeping. We tell them to put it on while they are watching TV — don’t hook it up to anything yet, just get used to having something on your face.

I’ve told my patients the same thing about masks for COVID-19. Put on the mask, see how it feels. If you become uncomfortable breathing with it on, take it off, but maybe you can handle it for a half hour or 45 minutes. Find out how much time you have for a trip to the grocery store based on how comfortable you are wearing it at home.

It’s a matter of training the patient, giving them options of how to get comfortable with it, and then making them realize that they have to weigh the benefits and risks of wearing the mask and feeling out of breath versus going out in public and being potentially exposed to coronavirus. And the bottom line is, anybody who is wearing a mask and starts to feel uncomfortable, they can take the mask off.
 

You mentioned different types of masks. Is there a type of mask that is typically more breathable that clinicians can recommend to patients with lung disease?

First, I remind patients who think they will have trouble breathing with a mask on that they are choosing a mask not so much to protect themselves – that would take an N95 mask to filter out the virus. The mask is worn so that when they cough or drink or speak, they aren’t sending respiratory droplets out into the environment. Even when we speak, respiratory droplets can easily go out as far as 6 feet, or further with coughing or sneezing. With facial coverings, we try to keep those respiratory droplets from getting out and infecting others.

So when choosing a mask, you don’t have to worry as much about a tight-fitting mask. I recommend a loose-fitting mask that covers the nose and mouth and isn’t going to fall off but isn’t so tight around the ears and neck to make them feel uncomfortable. Even though it doesn’t really protect the wearer, it is cutting down on the ability to breathe in droplets – maybe not microscopic particles, but it’s better than nothing.
 

Is a face shield a reasonable alternative for someone who feels they can’t breathe with a mask on?

Yes. I’m surprised that face shields don’t get more attention. I’ve tried them out, and they are actually more comfortable than masks. They do impede the spilling out of droplets into the public, but they are not as close fitting to the face as a mask. If you want to protect others, the face shield should be adequate. It is not as good at preventing you from breathing in viral particles.

Some people have claimed that wearing a mask makes them hyperventilate and feel like they are going to pass out, or the mask causes them to become hypoxic. Are these valid concerns?

We get two questions about masks from patients who feel that they are short of breath or are worried about wearing a mask. One is whether their oxygen level is dropping. It’s usually not that. It’s usually because they feel that the mask is an impediment to getting air in. Their oxygen levels are stable.

The other question is whether the mask causes CO₂ retention. For the mask to trap enough exhaled CO₂ and for us to breathe enough of that CO₂ back in to raise our CO₂ level, it has to be a pretty tight-fitting mask. With the type of masks we are suggesting that people wear, that’s very unlikely to occur.
 

What can clinicians do to reassure patients with some type of lung disease that they can safely wear masks?

There are a few things they can do right in the office. Have them put the mask on for a few minutes and make sure they feel comfortable with it. With an oximeter, patients can see that their oxygen levels don’t change when they are breathing through the mask for a period of time.

You can’t really measure CO₂ retention that easily, but most patients with chronic obstructive pulmonary disease or pulmonary fibrosis don’t have an elevated CO₂ at baseline. A little more education is helpful in those situations. In most cases, they aren’t going to retain enough CO₂ to have problems wearing a mask.

Only a small percentage of patients with lung disease are CO₂ retainers, and many of those patients are being seen by pulmonary specialists. Those are the patients you might want to be more cautious with, to make sure they aren’t wearing anything that is tight fitting or that makes them work harder to breathe. It’s not that the mask is causing CO₂ retention, but the increased work of breathing may make it harder to exhale the CO₂.
 

Does a mask interfere with supplemental oxygen in any way?

Supplemental oxygen is typically supplied through a nasal cannula, so 100% oxygen is still getting to the nasal passages and entrained down into the airway, so it shouldn’t be a problem.

Some of the resistance to wearing masks has come from people with asthma. Is it safe for patients with asthma to wear masks, or should these patients be exempt from wearing masks?

In general, the breathing of people with mild asthma, both young and old, should not be impeded by the wearing of facial coverings. The concerns about oxygen and carbon dioxide among patients with more severe lung disease should not play a role in asthma.

Since younger adults with COVID-19 seem to have fewer or no symptoms and may actually be carrying the virus unknowingly, this should be the main population who should wear masks to prevent transmission to others.

Exemptions for mask wearing for mild asthma should be discouraged and dealt with on a case-by-case basis if there is a particular concern for that individual.
 

How do you respond if a patient asks you for a formal medical exemption to wearing a mask?

We’ve been asked to do a lot of letter writing for patients around going back to work, as well as the issue of wearing masks. The discussion usually revolves around trying to avoid going somewhere where you would have to wear a mask if it makes you feel uncomfortable.

I do not recommend automatically exempting individuals from wearing masks, even many of my pulmonary patients. There needs to be an understanding by the patient regarding the purpose of the mask and the overall advice to stay out of situations where social distancing is not being practiced. If you can take the time to discuss options as mentioned above – mask styles, desensitization, etc – the patient usually understands and will try wearing a mask.

On a case-by-case basis, some individuals may need to be exempted, but I feel this is a small number. I prefer my high-risk (older, chronic disease, etc) patients do everything they can to avoid infection – handwashing, mask wearing, and socially distancing.

They should also realize that even with a note, it is not going to help if they are in the middle of the grocery store and someone confronts them about not wearing a mask. It may help as they enter a store that says “masks required” and they can show it to someone monitoring the door. But I’m not really sure in what situations having that note is going to be helpful if confrontations occur.

Patients are also asking how safe is it for them to go back to work and be out in public. I tell them, nothing is going to be 100% safe. Until we have an effective vaccine, we are all going to have to weigh the potential risks of going to an area where social distancing isn’t maintained, people aren’t wearing face masks, and you can’t wash your hands as much as you’d like to. That’s going to be a struggle for all of us to get back out into situations where people interact socially.

Albert A. Rizzo, MD, is chief medical officer for the American Lung Association, chief of the Section of Pulmonary and Critical Care Medicine at the Christiana Care Health System in Newark, Delaware, and a member of Christiana Care Pulmonary Associates. He is board certified in internal medicine, pulmonary medicine, critical care medicine, and sleep medicine and is a clinical assistant professor of medicine at Thomas Jefferson University Medical School, Philadelphia.

This article first appeared on Medscape.com.

As more jurisdictions mandate facial coverings in public, questions have arisen about whether it’s safe for everyone – including those with lung disease – to wear masks. Stories about people who claim to be unable to wear masks because of breathing problems are appearing in the news with increasing frequency, and patients are starting to call their doctors to request medical exemptions to public mask requirements.

David Fuentes Prieto/Shutterstock

To address these issues, Medscape spoke with the chief medical officer of the American Lung Association, Dr. Albert Rizzo.
 

The CDC recommendations on mask wearing say, “Cloth face coverings should not be placed on young children under age 2, anyone who has trouble breathing, or is unconscious, incapacitated, or otherwise unable to remove the mask without assistance.” Does this language suggest that there indeed is a subset of the adult population with lung disease who shouldn’t wear masks?

It makes sense to say that if it makes you uncomfortable to wear a mask because it affects your breathing, you should think twice about getting in a situation where you would have to wear a mask.

I’ve told many of my high-risk patients, “The best way to avoid getting COVID-19 is to stay home and stay away from sick people, especially if you feel that you are not going to be able to wear a mask or facial covering of some sort.”

The reason that some people have trouble with a mask is that they haven’t tried the right style of mask – by that I mean how tightly it fits and the material it’s made out of. Sometimes it really is just that people with lung disease don’t like to have anything covering their faces. Many of these patients feel better where there is air blowing across their faces – they will have a fan blowing even in the middle of winter because they feel more comfortable.

I won’t say it’s all in their heads, but sometimes it’s a matter of desensitizing themselves to wearing a mask. I liken it to people who have sleep apnea. We often have to desensitize them to wearing a mask for sleeping. We tell them to put it on while they are watching TV — don’t hook it up to anything yet, just get used to having something on your face.

I’ve told my patients the same thing about masks for COVID-19. Put on the mask, see how it feels. If you become uncomfortable breathing with it on, take it off, but maybe you can handle it for a half hour or 45 minutes. Find out how much time you have for a trip to the grocery store based on how comfortable you are wearing it at home.

It’s a matter of training the patient, giving them options of how to get comfortable with it, and then making them realize that they have to weigh the benefits and risks of wearing the mask and feeling out of breath versus going out in public and being potentially exposed to coronavirus. And the bottom line is, anybody who is wearing a mask and starts to feel uncomfortable, they can take the mask off.
 

You mentioned different types of masks. Is there a type of mask that is typically more breathable that clinicians can recommend to patients with lung disease?

First, I remind patients who think they will have trouble breathing with a mask on that they are choosing a mask not so much to protect themselves – that would take an N95 mask to filter out the virus. The mask is worn so that when they cough or drink or speak, they aren’t sending respiratory droplets out into the environment. Even when we speak, respiratory droplets can easily go out as far as 6 feet, or further with coughing or sneezing. With facial coverings, we try to keep those respiratory droplets from getting out and infecting others.

So when choosing a mask, you don’t have to worry as much about a tight-fitting mask. I recommend a loose-fitting mask that covers the nose and mouth and isn’t going to fall off but isn’t so tight around the ears and neck to make them feel uncomfortable. Even though it doesn’t really protect the wearer, it is cutting down on the ability to breathe in droplets – maybe not microscopic particles, but it’s better than nothing.
 

Is a face shield a reasonable alternative for someone who feels they can’t breathe with a mask on?

Yes. I’m surprised that face shields don’t get more attention. I’ve tried them out, and they are actually more comfortable than masks. They do impede the spilling out of droplets into the public, but they are not as close fitting to the face as a mask. If you want to protect others, the face shield should be adequate. It is not as good at preventing you from breathing in viral particles.

Some people have claimed that wearing a mask makes them hyperventilate and feel like they are going to pass out, or the mask causes them to become hypoxic. Are these valid concerns?

We get two questions about masks from patients who feel that they are short of breath or are worried about wearing a mask. One is whether their oxygen level is dropping. It’s usually not that. It’s usually because they feel that the mask is an impediment to getting air in. Their oxygen levels are stable.

The other question is whether the mask causes CO₂ retention. For the mask to trap enough exhaled CO₂ and for us to breathe enough of that CO₂ back in to raise our CO₂ level, it has to be a pretty tight-fitting mask. With the type of masks we are suggesting that people wear, that’s very unlikely to occur.
 

What can clinicians do to reassure patients with some type of lung disease that they can safely wear masks?

There are a few things they can do right in the office. Have them put the mask on for a few minutes and make sure they feel comfortable with it. With an oximeter, patients can see that their oxygen levels don’t change when they are breathing through the mask for a period of time.

You can’t really measure CO₂ retention that easily, but most patients with chronic obstructive pulmonary disease or pulmonary fibrosis don’t have an elevated CO₂ at baseline. A little more education is helpful in those situations. In most cases, they aren’t going to retain enough CO₂ to have problems wearing a mask.

Only a small percentage of patients with lung disease are CO₂ retainers, and many of those patients are being seen by pulmonary specialists. Those are the patients you might want to be more cautious with, to make sure they aren’t wearing anything that is tight fitting or that makes them work harder to breathe. It’s not that the mask is causing CO₂ retention, but the increased work of breathing may make it harder to exhale the CO₂.
 

Does a mask interfere with supplemental oxygen in any way?

Supplemental oxygen is typically supplied through a nasal cannula, so 100% oxygen is still getting to the nasal passages and entrained down into the airway, so it shouldn’t be a problem.

Some of the resistance to wearing masks has come from people with asthma. Is it safe for patients with asthma to wear masks, or should these patients be exempt from wearing masks?

In general, the breathing of people with mild asthma, both young and old, should not be impeded by the wearing of facial coverings. The concerns about oxygen and carbon dioxide among patients with more severe lung disease should not play a role in asthma.

Since younger adults with COVID-19 seem to have fewer or no symptoms and may actually be carrying the virus unknowingly, this should be the main population who should wear masks to prevent transmission to others.

Exemptions for mask wearing for mild asthma should be discouraged and dealt with on a case-by-case basis if there is a particular concern for that individual.
 

How do you respond if a patient asks you for a formal medical exemption to wearing a mask?

We’ve been asked to do a lot of letter writing for patients around going back to work, as well as the issue of wearing masks. The discussion usually revolves around trying to avoid going somewhere where you would have to wear a mask if it makes you feel uncomfortable.

I do not recommend automatically exempting individuals from wearing masks, even many of my pulmonary patients. There needs to be an understanding by the patient regarding the purpose of the mask and the overall advice to stay out of situations where social distancing is not being practiced. If you can take the time to discuss options as mentioned above – mask styles, desensitization, etc – the patient usually understands and will try wearing a mask.

On a case-by-case basis, some individuals may need to be exempted, but I feel this is a small number. I prefer my high-risk (older, chronic disease, etc) patients do everything they can to avoid infection – handwashing, mask wearing, and socially distancing.

They should also realize that even with a note, it is not going to help if they are in the middle of the grocery store and someone confronts them about not wearing a mask. It may help as they enter a store that says “masks required” and they can show it to someone monitoring the door. But I’m not really sure in what situations having that note is going to be helpful if confrontations occur.

Patients are also asking how safe is it for them to go back to work and be out in public. I tell them, nothing is going to be 100% safe. Until we have an effective vaccine, we are all going to have to weigh the potential risks of going to an area where social distancing isn’t maintained, people aren’t wearing face masks, and you can’t wash your hands as much as you’d like to. That’s going to be a struggle for all of us to get back out into situations where people interact socially.

Albert A. Rizzo, MD, is chief medical officer for the American Lung Association, chief of the Section of Pulmonary and Critical Care Medicine at the Christiana Care Health System in Newark, Delaware, and a member of Christiana Care Pulmonary Associates. He is board certified in internal medicine, pulmonary medicine, critical care medicine, and sleep medicine and is a clinical assistant professor of medicine at Thomas Jefferson University Medical School, Philadelphia.

This article first appeared on Medscape.com.

As more jurisdictions mandate facial coverings in public, questions have arisen about whether it’s safe for everyone – including those with lung disease – to wear masks. Stories about people who claim to be unable to wear masks because of breathing problems are appearing in the news with increasing frequency, and patients are starting to call their doctors to request medical exemptions to public mask requirements.

David Fuentes Prieto/Shutterstock

To address these issues, Medscape spoke with the chief medical officer of the American Lung Association, Dr. Albert Rizzo.
 

The CDC recommendations on mask wearing say, “Cloth face coverings should not be placed on young children under age 2, anyone who has trouble breathing, or is unconscious, incapacitated, or otherwise unable to remove the mask without assistance.” Does this language suggest that there indeed is a subset of the adult population with lung disease who shouldn’t wear masks?

It makes sense to say that if it makes you uncomfortable to wear a mask because it affects your breathing, you should think twice about getting in a situation where you would have to wear a mask.

I’ve told many of my high-risk patients, “The best way to avoid getting COVID-19 is to stay home and stay away from sick people, especially if you feel that you are not going to be able to wear a mask or facial covering of some sort.”

The reason that some people have trouble with a mask is that they haven’t tried the right style of mask – by that I mean how tightly it fits and the material it’s made out of. Sometimes it really is just that people with lung disease don’t like to have anything covering their faces. Many of these patients feel better where there is air blowing across their faces – they will have a fan blowing even in the middle of winter because they feel more comfortable.

I won’t say it’s all in their heads, but sometimes it’s a matter of desensitizing themselves to wearing a mask. I liken it to people who have sleep apnea. We often have to desensitize them to wearing a mask for sleeping. We tell them to put it on while they are watching TV — don’t hook it up to anything yet, just get used to having something on your face.

I’ve told my patients the same thing about masks for COVID-19. Put on the mask, see how it feels. If you become uncomfortable breathing with it on, take it off, but maybe you can handle it for a half hour or 45 minutes. Find out how much time you have for a trip to the grocery store based on how comfortable you are wearing it at home.

It’s a matter of training the patient, giving them options of how to get comfortable with it, and then making them realize that they have to weigh the benefits and risks of wearing the mask and feeling out of breath versus going out in public and being potentially exposed to coronavirus. And the bottom line is, anybody who is wearing a mask and starts to feel uncomfortable, they can take the mask off.
 

You mentioned different types of masks. Is there a type of mask that is typically more breathable that clinicians can recommend to patients with lung disease?

First, I remind patients who think they will have trouble breathing with a mask on that they are choosing a mask not so much to protect themselves – that would take an N95 mask to filter out the virus. The mask is worn so that when they cough or drink or speak, they aren’t sending respiratory droplets out into the environment. Even when we speak, respiratory droplets can easily go out as far as 6 feet, or further with coughing or sneezing. With facial coverings, we try to keep those respiratory droplets from getting out and infecting others.

So when choosing a mask, you don’t have to worry as much about a tight-fitting mask. I recommend a loose-fitting mask that covers the nose and mouth and isn’t going to fall off but isn’t so tight around the ears and neck to make them feel uncomfortable. Even though it doesn’t really protect the wearer, it is cutting down on the ability to breathe in droplets – maybe not microscopic particles, but it’s better than nothing.
 

Is a face shield a reasonable alternative for someone who feels they can’t breathe with a mask on?

Yes. I’m surprised that face shields don’t get more attention. I’ve tried them out, and they are actually more comfortable than masks. They do impede the spilling out of droplets into the public, but they are not as close fitting to the face as a mask. If you want to protect others, the face shield should be adequate. It is not as good at preventing you from breathing in viral particles.

Some people have claimed that wearing a mask makes them hyperventilate and feel like they are going to pass out, or the mask causes them to become hypoxic. Are these valid concerns?

We get two questions about masks from patients who feel that they are short of breath or are worried about wearing a mask. One is whether their oxygen level is dropping. It’s usually not that. It’s usually because they feel that the mask is an impediment to getting air in. Their oxygen levels are stable.

The other question is whether the mask causes CO₂ retention. For the mask to trap enough exhaled CO₂ and for us to breathe enough of that CO₂ back in to raise our CO₂ level, it has to be a pretty tight-fitting mask. With the type of masks we are suggesting that people wear, that’s very unlikely to occur.
 

What can clinicians do to reassure patients with some type of lung disease that they can safely wear masks?

There are a few things they can do right in the office. Have them put the mask on for a few minutes and make sure they feel comfortable with it. With an oximeter, patients can see that their oxygen levels don’t change when they are breathing through the mask for a period of time.

You can’t really measure CO₂ retention that easily, but most patients with chronic obstructive pulmonary disease or pulmonary fibrosis don’t have an elevated CO₂ at baseline. A little more education is helpful in those situations. In most cases, they aren’t going to retain enough CO₂ to have problems wearing a mask.

Only a small percentage of patients with lung disease are CO₂ retainers, and many of those patients are being seen by pulmonary specialists. Those are the patients you might want to be more cautious with, to make sure they aren’t wearing anything that is tight fitting or that makes them work harder to breathe. It’s not that the mask is causing CO₂ retention, but the increased work of breathing may make it harder to exhale the CO₂.
 

Does a mask interfere with supplemental oxygen in any way?

Supplemental oxygen is typically supplied through a nasal cannula, so 100% oxygen is still getting to the nasal passages and entrained down into the airway, so it shouldn’t be a problem.

Some of the resistance to wearing masks has come from people with asthma. Is it safe for patients with asthma to wear masks, or should these patients be exempt from wearing masks?

In general, the breathing of people with mild asthma, both young and old, should not be impeded by the wearing of facial coverings. The concerns about oxygen and carbon dioxide among patients with more severe lung disease should not play a role in asthma.

Since younger adults with COVID-19 seem to have fewer or no symptoms and may actually be carrying the virus unknowingly, this should be the main population who should wear masks to prevent transmission to others.

Exemptions for mask wearing for mild asthma should be discouraged and dealt with on a case-by-case basis if there is a particular concern for that individual.
 

How do you respond if a patient asks you for a formal medical exemption to wearing a mask?

We’ve been asked to do a lot of letter writing for patients around going back to work, as well as the issue of wearing masks. The discussion usually revolves around trying to avoid going somewhere where you would have to wear a mask if it makes you feel uncomfortable.

I do not recommend automatically exempting individuals from wearing masks, even many of my pulmonary patients. There needs to be an understanding by the patient regarding the purpose of the mask and the overall advice to stay out of situations where social distancing is not being practiced. If you can take the time to discuss options as mentioned above – mask styles, desensitization, etc – the patient usually understands and will try wearing a mask.

On a case-by-case basis, some individuals may need to be exempted, but I feel this is a small number. I prefer my high-risk (older, chronic disease, etc) patients do everything they can to avoid infection – handwashing, mask wearing, and socially distancing.

They should also realize that even with a note, it is not going to help if they are in the middle of the grocery store and someone confronts them about not wearing a mask. It may help as they enter a store that says “masks required” and they can show it to someone monitoring the door. But I’m not really sure in what situations having that note is going to be helpful if confrontations occur.

Patients are also asking how safe is it for them to go back to work and be out in public. I tell them, nothing is going to be 100% safe. Until we have an effective vaccine, we are all going to have to weigh the potential risks of going to an area where social distancing isn’t maintained, people aren’t wearing face masks, and you can’t wash your hands as much as you’d like to. That’s going to be a struggle for all of us to get back out into situations where people interact socially.

Albert A. Rizzo, MD, is chief medical officer for the American Lung Association, chief of the Section of Pulmonary and Critical Care Medicine at the Christiana Care Health System in Newark, Delaware, and a member of Christiana Care Pulmonary Associates. He is board certified in internal medicine, pulmonary medicine, critical care medicine, and sleep medicine and is a clinical assistant professor of medicine at Thomas Jefferson University Medical School, Philadelphia.

This article first appeared on Medscape.com.

During a family medicine rotation at Oregon Health & Sciences University, Portland, third-year medical students are preparing for a patient visit. Only, instead of entering a clinic room, students sit down at a computer. The patient they’re virtually examining – a 42-year-old male cattle rancher with knee problems – is an actor.

He asks for an MRI. A student explains that kneecap pain calls for rehab rather than a scan. The patient pushes back. “It would ease my mind,” he says. “I really need to make sure I can keep the ranch running.” The student must now try to digitally maintain rapport while explaining why imaging isn’t necessary.

When COVID-19 hit, telehealth training and remote learning became major parts of medical education, seemingly overnight. Since the start of the pandemic, students have contended with canceled classes, missed rotations, and revised training timelines, even as the demand for new doctors grows ever more pressing.

Institutions have been forced to rethink how to best establish solid, long-term foundations to ensure that young doctors are adequately trained. “They may find themselves the only doctors to be practicing in a small town,” said Stephen G. Post, PhD, bioethicist and professor at Stony Brook (N.Y.) University. “They have to be ready.”

With limited hands-on access to patients, students must learn in ways most never have before. Medical schools are now test-driving a mix of new and reimagined teaching strategies that aim to produce doctors who will enter medicine just as prepared as their more seasoned peers.

Hands-off education

Soon after starting her pediatrics rotation in March, recent Stanford (Calif.) University graduate Paloma Marin-Nevarez, MD, heard that children were being admitted to her hospital for evaluation to rule out COVID-19. Dr. Marin-Nevarez was assigned to help care for them but never physically met any – an approach called “virtual rounding.”

In virtual rounding, a provider typically goes in, examines a patient, and uses a portable device such as an iPad to send video or take notes about the encounter. Students or others in another room then give input on the patient’s care. “It was bizarre doing rounds on patients I had not met yet, discussing their treatment plans in one of the team rooms,” Dr. Marin-Nevarez said. “There was something very eerie about passing that particular unit that said: ‘Do not enter,’ and never being able to go inside.”

Within weeks, the Association of American Medical Colleges advised medical schools to suspend any activities – including clinical rotations – that involved direct student contact with patients, even those who weren’t COVID-19 positive.

Many schools hope to have students back and participating in some degree of patient care at non–COVID-19 hospital wards as early as July 1, said Michael Gisondi, MD, vice chair of education at Stanford’s department of emergency medicine. Returning students must now adapt to a restricted training environment, often while scrambling to make up training time. “This is uncharted territory for medical schools. Elective cases are down, surgical cases are down. That’s potentially going to decrease exposure to training opportunities.”

When students come back, lectures are still likely to remain on hold at most schools, replaced by Zoom conferences and virtual presentations. That’s not completely new: A trend away from large, traditional classes predated the pandemic. In a 2017-2018 AAMC survey, one in four second-year medical students said they almost never went to in-person lectures. COVID-19 has accelerated this shift.

For faculty who have long emphasized hands-on, in-person learning, the shift presents “a whole pedagogical issue – you don’t necessarily know how to adjust your practices to an online format,” Dr. Gisondi said. Instructors have to be even more flexible in order to engage students. “Every week I ask the students: ‘What’s working? What’s not working?’ ” Dr. Gisondi said about his online classes. “We have to solicit feedback.”

Changes to lectures are the easy part, says Elisabeth Fassas, a second-year student at the University of Maryland, Baltimore County. Before the pandemic, she was taking a clinical medicine course that involved time in the hospital, something that helped link the academic with the practical. “You really get to see the stuff you’re learning being relevant: ‘Here’s a patient who has a cardiology problem,’ ” she said. “[Capturing] that piece of connection to what you’re working toward is going to be tricky, I think.”

Some students who graduated this past spring worry about that clinical time they lost. Many remain acutely conscious of specific knowledge gaps. “I did not get a ton of experience examining crying children or holding babies,” said Dr. Marin-Nevarez, who starts an emergency medicine residency this year. “I am going to have to be transparent with my future instructors and let them know I missed out because of the pandemic.”

Such knowledge gaps mean new doctors will have to make up ground, said Jeremiah Tao, MD, who trains ophthalmology residents at the University of California, Irvine. But Dr. Tao doesn’t see these setbacks as a major long-term problem. His residents are already starting to make up the patient hours they missed in the spring and are refining the skills that got short shrift earlier on. For eligibility, “most boards require a certain number of days of experience. But most of the message from our board is [that] they’re understanding, and they’re going to leave it to the program directors to declare someone competent.”

Robert Johnson, MD, dean of New Jersey Medical School, Newark, said short-term setbacks in training likely won’t translate into longer-term skill deficits. “What most schools have done is overprepare students. We’re sure they have acquired all the skills they need to practice.”

Closing the gaps

To fill existing knowledge gaps and prevent future deficits, institutions hope to strike a balance between keeping trainees safe and providing necessary on-site learning. In line with ongoing AAMC recommendations, which suggest schools curtail student involvement in direct patient care in areas with significant COVID-19 spread, virtual rounding will likely continue.

Many schools may use a hybrid approach, in which students take turns entering patient rooms to perform checkups or observations while other students and instructors watch a video broadcast. “It’s not that different from when I go into the room and supervise a trainee,” Dr. Gisondi said.

Some schools are going even further, transforming education in ways that reflect the demands of a COVID-19–era medical marketplace. Institutions such as Weill Cornell Medicine, New York, and OHSU have invested in telemedicine training for years, but COVID-19 has given telehealth education an additional boost. These types of visits have surged dramatically, underscoring the importance of preparing new doctors to practice in a virtual setting – something that wasn’t common previously. In a 2019 survey, only about a quarter of sampled medical schools offered a telemedicine curriculum.

Simulated telehealth consults such as OHSU’s knee-pain scenario serve several purposes, says Ryan Palmer, EdD, associate dean of education at Northeast Ohio Universities, Rootstown. They virtually teach skills that students need – such as clearly explaining to patients why a care plan is called for – while allowing the trainees to practice forging an emotional connection with patients they are treating remotely.

“It’s less about how you use a specific system,” said Dr. Palmer, who developed OHSU’s TeleOSCE, a telehealth training system that has interested other schools. He sees this as an opportunity, inasmuch as telemedicine is likely to remain an important part of practice for the foreseeable future.

To that end, the AAMC recently hosted an online seminar to help faculty with telehealth instruction. But training such as this can only go so far, said Dr. Johnson. “There are techniques you do have to learn at the patient’s side.”

Dr. Johnson says that a traditional part of medical school at Rutgers has been having students spend time in general practitioners’ offices early on to see what the experience is like. “That’s going to be a problem – I expect many primary care practices will go out of business. Those types of shadowing experiences will probably go away. They may be replaced by experiences at larger clinics.”

Some learning in clinics may soon resume. Although fears about COVID-19 still loom large, Dr. Tao’s ophthalmology residents have started taking on something closer to a normal workload, thanks to patients returning for regular office visits. As people return to medical facilities in larger numbers, hospitals around the country have started separating patients with COVID-19 from others. Dr. Gisondi suggested that this means medical students may be able to circulate in non–COVID-19 wards, provided the institution has enough personal protective equipment. “The inpatient wards are really safe – there’s a low risk of transmission. That’s where core rotations occur.”

The road ahead

In settings where patients’ viral status remains uncertain, such as emergency wards and off-site clinics without rapid testing, in-person learning may be slower to resume. That’s where longer-term changes may come into play. Some schools are preparing digital learning platforms that have the potential to transform medical education.

For example, Haru Okuda, MD, an emergency medicine doctor and director of the Center for Advanced Medical Learning and Simulation at the University of South Florida, Tampa, is testing a new virtual-reality platform called Immertec. Dr. Okuda said that, unlike older teaching tools, the system is not a stale, static virtual environment that will become obsolete. Instead, it uses a live camera to visually teleport students into the space of a real clinic or operating room.

“Let’s say you have students learning gross anatomy, how to dissect the chest. You’d have a cadaver on the table, demonstrating anatomy. The student has a headset – you can see like you’re in the room.” The wraparound visual device allows students to watch surgical maneuvers close up or view additional input from devices such as laparoscopes.

Dr. Okuda acknowledges that educators don’t yet know whether this works as well as older, hands-on methods. As yet, no virtual reality system has touch-based sensors sophisticated enough to simulate even skills such as tying a basic surgical knot, Dr. Gisondi said. And immersive platforms are expensive, which means a gap may occur between schools that can afford them and those that can’t.

The long-term consequences of COVID-19 go beyond costs that institutions may have to bear. Some students are concerned that the pandemic is affecting their mental well-being in ways that may make training a tougher slog. A few students graduated early to serve on the COVID-19 front lines. Others, rather than planning trips to celebrate the gap between medical school and residency, watched from home as young doctors they knew worked under abusive and unsafe conditions.

“Many of us felt powerless, given what we saw happening around us,” said recent University of Michigan, Ann Arbor, graduate Marina Haque, MD. She thinks those feelings, along with the rigors of practicing medicine during a pandemic, may leave her and her colleagues more prone to burnout.

The pandemic has also had a galvanizing effect on students – some excited new doctors are eager to line up for duty on COVID-19 wards. But supervisors say they must weigh young doctors’ desire to serve against the possible risks. “You don’t want people who have a big future ahead of them rushing into these situations and getting severely ill,” said Dr. Post. “There is a balance.”

All these changes, temporary or lasting, have led many to question whether doctors who complete their training under the cloud of the pandemic will be more – or less – prepared than those who came before them. But it’s not really a question of better or worse, says Dr. Johnson, who stresses that medical education has always required flexibility.

“You come into medicine with a plan in mind, but things happen,” he said. He reflected on the HIV pandemic of the late 1980s and early 1990s that influenced his medical career. He hopes young doctors come through the COVID-19 crucible more seasoned, resilient, and confident in crisis situations. “This is a pivotal event in their lives, and it will shape many careers.”

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

During a family medicine rotation at Oregon Health & Sciences University, Portland, third-year medical students are preparing for a patient visit. Only, instead of entering a clinic room, students sit down at a computer. The patient they’re virtually examining – a 42-year-old male cattle rancher with knee problems – is an actor.

He asks for an MRI. A student explains that kneecap pain calls for rehab rather than a scan. The patient pushes back. “It would ease my mind,” he says. “I really need to make sure I can keep the ranch running.” The student must now try to digitally maintain rapport while explaining why imaging isn’t necessary.

When COVID-19 hit, telehealth training and remote learning became major parts of medical education, seemingly overnight. Since the start of the pandemic, students have contended with canceled classes, missed rotations, and revised training timelines, even as the demand for new doctors grows ever more pressing.

Institutions have been forced to rethink how to best establish solid, long-term foundations to ensure that young doctors are adequately trained. “They may find themselves the only doctors to be practicing in a small town,” said Stephen G. Post, PhD, bioethicist and professor at Stony Brook (N.Y.) University. “They have to be ready.”

With limited hands-on access to patients, students must learn in ways most never have before. Medical schools are now test-driving a mix of new and reimagined teaching strategies that aim to produce doctors who will enter medicine just as prepared as their more seasoned peers.

Hands-off education

Soon after starting her pediatrics rotation in March, recent Stanford (Calif.) University graduate Paloma Marin-Nevarez, MD, heard that children were being admitted to her hospital for evaluation to rule out COVID-19. Dr. Marin-Nevarez was assigned to help care for them but never physically met any – an approach called “virtual rounding.”

In virtual rounding, a provider typically goes in, examines a patient, and uses a portable device such as an iPad to send video or take notes about the encounter. Students or others in another room then give input on the patient’s care. “It was bizarre doing rounds on patients I had not met yet, discussing their treatment plans in one of the team rooms,” Dr. Marin-Nevarez said. “There was something very eerie about passing that particular unit that said: ‘Do not enter,’ and never being able to go inside.”

Within weeks, the Association of American Medical Colleges advised medical schools to suspend any activities – including clinical rotations – that involved direct student contact with patients, even those who weren’t COVID-19 positive.

Many schools hope to have students back and participating in some degree of patient care at non–COVID-19 hospital wards as early as July 1, said Michael Gisondi, MD, vice chair of education at Stanford’s department of emergency medicine. Returning students must now adapt to a restricted training environment, often while scrambling to make up training time. “This is uncharted territory for medical schools. Elective cases are down, surgical cases are down. That’s potentially going to decrease exposure to training opportunities.”

When students come back, lectures are still likely to remain on hold at most schools, replaced by Zoom conferences and virtual presentations. That’s not completely new: A trend away from large, traditional classes predated the pandemic. In a 2017-2018 AAMC survey, one in four second-year medical students said they almost never went to in-person lectures. COVID-19 has accelerated this shift.

For faculty who have long emphasized hands-on, in-person learning, the shift presents “a whole pedagogical issue – you don’t necessarily know how to adjust your practices to an online format,” Dr. Gisondi said. Instructors have to be even more flexible in order to engage students. “Every week I ask the students: ‘What’s working? What’s not working?’ ” Dr. Gisondi said about his online classes. “We have to solicit feedback.”

Changes to lectures are the easy part, says Elisabeth Fassas, a second-year student at the University of Maryland, Baltimore County. Before the pandemic, she was taking a clinical medicine course that involved time in the hospital, something that helped link the academic with the practical. “You really get to see the stuff you’re learning being relevant: ‘Here’s a patient who has a cardiology problem,’ ” she said. “[Capturing] that piece of connection to what you’re working toward is going to be tricky, I think.”

Some students who graduated this past spring worry about that clinical time they lost. Many remain acutely conscious of specific knowledge gaps. “I did not get a ton of experience examining crying children or holding babies,” said Dr. Marin-Nevarez, who starts an emergency medicine residency this year. “I am going to have to be transparent with my future instructors and let them know I missed out because of the pandemic.”

Such knowledge gaps mean new doctors will have to make up ground, said Jeremiah Tao, MD, who trains ophthalmology residents at the University of California, Irvine. But Dr. Tao doesn’t see these setbacks as a major long-term problem. His residents are already starting to make up the patient hours they missed in the spring and are refining the skills that got short shrift earlier on. For eligibility, “most boards require a certain number of days of experience. But most of the message from our board is [that] they’re understanding, and they’re going to leave it to the program directors to declare someone competent.”

Robert Johnson, MD, dean of New Jersey Medical School, Newark, said short-term setbacks in training likely won’t translate into longer-term skill deficits. “What most schools have done is overprepare students. We’re sure they have acquired all the skills they need to practice.”

Closing the gaps

To fill existing knowledge gaps and prevent future deficits, institutions hope to strike a balance between keeping trainees safe and providing necessary on-site learning. In line with ongoing AAMC recommendations, which suggest schools curtail student involvement in direct patient care in areas with significant COVID-19 spread, virtual rounding will likely continue.

Many schools may use a hybrid approach, in which students take turns entering patient rooms to perform checkups or observations while other students and instructors watch a video broadcast. “It’s not that different from when I go into the room and supervise a trainee,” Dr. Gisondi said.

Some schools are going even further, transforming education in ways that reflect the demands of a COVID-19–era medical marketplace. Institutions such as Weill Cornell Medicine, New York, and OHSU have invested in telemedicine training for years, but COVID-19 has given telehealth education an additional boost. These types of visits have surged dramatically, underscoring the importance of preparing new doctors to practice in a virtual setting – something that wasn’t common previously. In a 2019 survey, only about a quarter of sampled medical schools offered a telemedicine curriculum.

Simulated telehealth consults such as OHSU’s knee-pain scenario serve several purposes, says Ryan Palmer, EdD, associate dean of education at Northeast Ohio Universities, Rootstown. They virtually teach skills that students need – such as clearly explaining to patients why a care plan is called for – while allowing the trainees to practice forging an emotional connection with patients they are treating remotely.

“It’s less about how you use a specific system,” said Dr. Palmer, who developed OHSU’s TeleOSCE, a telehealth training system that has interested other schools. He sees this as an opportunity, inasmuch as telemedicine is likely to remain an important part of practice for the foreseeable future.

To that end, the AAMC recently hosted an online seminar to help faculty with telehealth instruction. But training such as this can only go so far, said Dr. Johnson. “There are techniques you do have to learn at the patient’s side.”

Dr. Johnson says that a traditional part of medical school at Rutgers has been having students spend time in general practitioners’ offices early on to see what the experience is like. “That’s going to be a problem – I expect many primary care practices will go out of business. Those types of shadowing experiences will probably go away. They may be replaced by experiences at larger clinics.”

Some learning in clinics may soon resume. Although fears about COVID-19 still loom large, Dr. Tao’s ophthalmology residents have started taking on something closer to a normal workload, thanks to patients returning for regular office visits. As people return to medical facilities in larger numbers, hospitals around the country have started separating patients with COVID-19 from others. Dr. Gisondi suggested that this means medical students may be able to circulate in non–COVID-19 wards, provided the institution has enough personal protective equipment. “The inpatient wards are really safe – there’s a low risk of transmission. That’s where core rotations occur.”

The road ahead

In settings where patients’ viral status remains uncertain, such as emergency wards and off-site clinics without rapid testing, in-person learning may be slower to resume. That’s where longer-term changes may come into play. Some schools are preparing digital learning platforms that have the potential to transform medical education.

For example, Haru Okuda, MD, an emergency medicine doctor and director of the Center for Advanced Medical Learning and Simulation at the University of South Florida, Tampa, is testing a new virtual-reality platform called Immertec. Dr. Okuda said that, unlike older teaching tools, the system is not a stale, static virtual environment that will become obsolete. Instead, it uses a live camera to visually teleport students into the space of a real clinic or operating room.

“Let’s say you have students learning gross anatomy, how to dissect the chest. You’d have a cadaver on the table, demonstrating anatomy. The student has a headset – you can see like you’re in the room.” The wraparound visual device allows students to watch surgical maneuvers close up or view additional input from devices such as laparoscopes.

Dr. Okuda acknowledges that educators don’t yet know whether this works as well as older, hands-on methods. As yet, no virtual reality system has touch-based sensors sophisticated enough to simulate even skills such as tying a basic surgical knot, Dr. Gisondi said. And immersive platforms are expensive, which means a gap may occur between schools that can afford them and those that can’t.

The long-term consequences of COVID-19 go beyond costs that institutions may have to bear. Some students are concerned that the pandemic is affecting their mental well-being in ways that may make training a tougher slog. A few students graduated early to serve on the COVID-19 front lines. Others, rather than planning trips to celebrate the gap between medical school and residency, watched from home as young doctors they knew worked under abusive and unsafe conditions.

“Many of us felt powerless, given what we saw happening around us,” said recent University of Michigan, Ann Arbor, graduate Marina Haque, MD. She thinks those feelings, along with the rigors of practicing medicine during a pandemic, may leave her and her colleagues more prone to burnout.

The pandemic has also had a galvanizing effect on students – some excited new doctors are eager to line up for duty on COVID-19 wards. But supervisors say they must weigh young doctors’ desire to serve against the possible risks. “You don’t want people who have a big future ahead of them rushing into these situations and getting severely ill,” said Dr. Post. “There is a balance.”

All these changes, temporary or lasting, have led many to question whether doctors who complete their training under the cloud of the pandemic will be more – or less – prepared than those who came before them. But it’s not really a question of better or worse, says Dr. Johnson, who stresses that medical education has always required flexibility.

“You come into medicine with a plan in mind, but things happen,” he said. He reflected on the HIV pandemic of the late 1980s and early 1990s that influenced his medical career. He hopes young doctors come through the COVID-19 crucible more seasoned, resilient, and confident in crisis situations. “This is a pivotal event in their lives, and it will shape many careers.”

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

During a family medicine rotation at Oregon Health & Sciences University, Portland, third-year medical students are preparing for a patient visit. Only, instead of entering a clinic room, students sit down at a computer. The patient they’re virtually examining – a 42-year-old male cattle rancher with knee problems – is an actor.

He asks for an MRI. A student explains that kneecap pain calls for rehab rather than a scan. The patient pushes back. “It would ease my mind,” he says. “I really need to make sure I can keep the ranch running.” The student must now try to digitally maintain rapport while explaining why imaging isn’t necessary.

When COVID-19 hit, telehealth training and remote learning became major parts of medical education, seemingly overnight. Since the start of the pandemic, students have contended with canceled classes, missed rotations, and revised training timelines, even as the demand for new doctors grows ever more pressing.

Institutions have been forced to rethink how to best establish solid, long-term foundations to ensure that young doctors are adequately trained. “They may find themselves the only doctors to be practicing in a small town,” said Stephen G. Post, PhD, bioethicist and professor at Stony Brook (N.Y.) University. “They have to be ready.”

With limited hands-on access to patients, students must learn in ways most never have before. Medical schools are now test-driving a mix of new and reimagined teaching strategies that aim to produce doctors who will enter medicine just as prepared as their more seasoned peers.

Hands-off education

Soon after starting her pediatrics rotation in March, recent Stanford (Calif.) University graduate Paloma Marin-Nevarez, MD, heard that children were being admitted to her hospital for evaluation to rule out COVID-19. Dr. Marin-Nevarez was assigned to help care for them but never physically met any – an approach called “virtual rounding.”

In virtual rounding, a provider typically goes in, examines a patient, and uses a portable device such as an iPad to send video or take notes about the encounter. Students or others in another room then give input on the patient’s care. “It was bizarre doing rounds on patients I had not met yet, discussing their treatment plans in one of the team rooms,” Dr. Marin-Nevarez said. “There was something very eerie about passing that particular unit that said: ‘Do not enter,’ and never being able to go inside.”

Within weeks, the Association of American Medical Colleges advised medical schools to suspend any activities – including clinical rotations – that involved direct student contact with patients, even those who weren’t COVID-19 positive.

Many schools hope to have students back and participating in some degree of patient care at non–COVID-19 hospital wards as early as July 1, said Michael Gisondi, MD, vice chair of education at Stanford’s department of emergency medicine. Returning students must now adapt to a restricted training environment, often while scrambling to make up training time. “This is uncharted territory for medical schools. Elective cases are down, surgical cases are down. That’s potentially going to decrease exposure to training opportunities.”

When students come back, lectures are still likely to remain on hold at most schools, replaced by Zoom conferences and virtual presentations. That’s not completely new: A trend away from large, traditional classes predated the pandemic. In a 2017-2018 AAMC survey, one in four second-year medical students said they almost never went to in-person lectures. COVID-19 has accelerated this shift.

For faculty who have long emphasized hands-on, in-person learning, the shift presents “a whole pedagogical issue – you don’t necessarily know how to adjust your practices to an online format,” Dr. Gisondi said. Instructors have to be even more flexible in order to engage students. “Every week I ask the students: ‘What’s working? What’s not working?’ ” Dr. Gisondi said about his online classes. “We have to solicit feedback.”

Changes to lectures are the easy part, says Elisabeth Fassas, a second-year student at the University of Maryland, Baltimore County. Before the pandemic, she was taking a clinical medicine course that involved time in the hospital, something that helped link the academic with the practical. “You really get to see the stuff you’re learning being relevant: ‘Here’s a patient who has a cardiology problem,’ ” she said. “[Capturing] that piece of connection to what you’re working toward is going to be tricky, I think.”

Some students who graduated this past spring worry about that clinical time they lost. Many remain acutely conscious of specific knowledge gaps. “I did not get a ton of experience examining crying children or holding babies,” said Dr. Marin-Nevarez, who starts an emergency medicine residency this year. “I am going to have to be transparent with my future instructors and let them know I missed out because of the pandemic.”

Such knowledge gaps mean new doctors will have to make up ground, said Jeremiah Tao, MD, who trains ophthalmology residents at the University of California, Irvine. But Dr. Tao doesn’t see these setbacks as a major long-term problem. His residents are already starting to make up the patient hours they missed in the spring and are refining the skills that got short shrift earlier on. For eligibility, “most boards require a certain number of days of experience. But most of the message from our board is [that] they’re understanding, and they’re going to leave it to the program directors to declare someone competent.”

Robert Johnson, MD, dean of New Jersey Medical School, Newark, said short-term setbacks in training likely won’t translate into longer-term skill deficits. “What most schools have done is overprepare students. We’re sure they have acquired all the skills they need to practice.”

Closing the gaps

To fill existing knowledge gaps and prevent future deficits, institutions hope to strike a balance between keeping trainees safe and providing necessary on-site learning. In line with ongoing AAMC recommendations, which suggest schools curtail student involvement in direct patient care in areas with significant COVID-19 spread, virtual rounding will likely continue.

Many schools may use a hybrid approach, in which students take turns entering patient rooms to perform checkups or observations while other students and instructors watch a video broadcast. “It’s not that different from when I go into the room and supervise a trainee,” Dr. Gisondi said.

Some schools are going even further, transforming education in ways that reflect the demands of a COVID-19–era medical marketplace. Institutions such as Weill Cornell Medicine, New York, and OHSU have invested in telemedicine training for years, but COVID-19 has given telehealth education an additional boost. These types of visits have surged dramatically, underscoring the importance of preparing new doctors to practice in a virtual setting – something that wasn’t common previously. In a 2019 survey, only about a quarter of sampled medical schools offered a telemedicine curriculum.

Simulated telehealth consults such as OHSU’s knee-pain scenario serve several purposes, says Ryan Palmer, EdD, associate dean of education at Northeast Ohio Universities, Rootstown. They virtually teach skills that students need – such as clearly explaining to patients why a care plan is called for – while allowing the trainees to practice forging an emotional connection with patients they are treating remotely.

“It’s less about how you use a specific system,” said Dr. Palmer, who developed OHSU’s TeleOSCE, a telehealth training system that has interested other schools. He sees this as an opportunity, inasmuch as telemedicine is likely to remain an important part of practice for the foreseeable future.

To that end, the AAMC recently hosted an online seminar to help faculty with telehealth instruction. But training such as this can only go so far, said Dr. Johnson. “There are techniques you do have to learn at the patient’s side.”

Dr. Johnson says that a traditional part of medical school at Rutgers has been having students spend time in general practitioners’ offices early on to see what the experience is like. “That’s going to be a problem – I expect many primary care practices will go out of business. Those types of shadowing experiences will probably go away. They may be replaced by experiences at larger clinics.”

Some learning in clinics may soon resume. Although fears about COVID-19 still loom large, Dr. Tao’s ophthalmology residents have started taking on something closer to a normal workload, thanks to patients returning for regular office visits. As people return to medical facilities in larger numbers, hospitals around the country have started separating patients with COVID-19 from others. Dr. Gisondi suggested that this means medical students may be able to circulate in non–COVID-19 wards, provided the institution has enough personal protective equipment. “The inpatient wards are really safe – there’s a low risk of transmission. That’s where core rotations occur.”

The road ahead

In settings where patients’ viral status remains uncertain, such as emergency wards and off-site clinics without rapid testing, in-person learning may be slower to resume. That’s where longer-term changes may come into play. Some schools are preparing digital learning platforms that have the potential to transform medical education.

For example, Haru Okuda, MD, an emergency medicine doctor and director of the Center for Advanced Medical Learning and Simulation at the University of South Florida, Tampa, is testing a new virtual-reality platform called Immertec. Dr. Okuda said that, unlike older teaching tools, the system is not a stale, static virtual environment that will become obsolete. Instead, it uses a live camera to visually teleport students into the space of a real clinic or operating room.

“Let’s say you have students learning gross anatomy, how to dissect the chest. You’d have a cadaver on the table, demonstrating anatomy. The student has a headset – you can see like you’re in the room.” The wraparound visual device allows students to watch surgical maneuvers close up or view additional input from devices such as laparoscopes.

Dr. Okuda acknowledges that educators don’t yet know whether this works as well as older, hands-on methods. As yet, no virtual reality system has touch-based sensors sophisticated enough to simulate even skills such as tying a basic surgical knot, Dr. Gisondi said. And immersive platforms are expensive, which means a gap may occur between schools that can afford them and those that can’t.

The long-term consequences of COVID-19 go beyond costs that institutions may have to bear. Some students are concerned that the pandemic is affecting their mental well-being in ways that may make training a tougher slog. A few students graduated early to serve on the COVID-19 front lines. Others, rather than planning trips to celebrate the gap between medical school and residency, watched from home as young doctors they knew worked under abusive and unsafe conditions.

“Many of us felt powerless, given what we saw happening around us,” said recent University of Michigan, Ann Arbor, graduate Marina Haque, MD. She thinks those feelings, along with the rigors of practicing medicine during a pandemic, may leave her and her colleagues more prone to burnout.

The pandemic has also had a galvanizing effect on students – some excited new doctors are eager to line up for duty on COVID-19 wards. But supervisors say they must weigh young doctors’ desire to serve against the possible risks. “You don’t want people who have a big future ahead of them rushing into these situations and getting severely ill,” said Dr. Post. “There is a balance.”

All these changes, temporary or lasting, have led many to question whether doctors who complete their training under the cloud of the pandemic will be more – or less – prepared than those who came before them. But it’s not really a question of better or worse, says Dr. Johnson, who stresses that medical education has always required flexibility.

“You come into medicine with a plan in mind, but things happen,” he said. He reflected on the HIV pandemic of the late 1980s and early 1990s that influenced his medical career. He hopes young doctors come through the COVID-19 crucible more seasoned, resilient, and confident in crisis situations. “This is a pivotal event in their lives, and it will shape many careers.”

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

Brensocatib, an experimental small-molecule inhibitor targeted to inflammation-regulating neutrophil serine proteases, may be a novel, nonantibiotic option for reducing exacerbations in patients with bronchiectasis, investigators in the phase 2 WILLOW study said.

Among 256 adults with a recent history of bronchiectasis exacerbations, oral brensocatib at doses of both 10 mg and 25 mg daily for 24 weeks was associated with significantly longer time to first exacerbation than placebo, and the 10-mg dose was associated with a significant reduction in the annualized rate of exacerbations, reported James Chalmers, MB, ChB, PhD of Ninewells Hospital and Medical School in Dundee (England).

“We also observed a dose-dependent reduction in neutrophil elastase levels in sputum, which supports the mechanism of action of this drug, and importantly showed a link between reducing neutrophil serine protease activity and clinical benefits in people with bronchiectasis,” he said in at the American Thoracic Society’s virtual clinical trial session.

“This is a very important trial, a landmark trial for people with bronchiectasis, because this is a drug that for the first time appears to be able to target directly neutrophilic inflammation, resulting in clinical benefit,” he said.

Pulmonologist Jennifer L. Taylor-Cousar, MD, MSCS, of National Jewish Health in Denver, who was facilitator for the online presentation but was not involved in the study, said that it offered welcome news.

“For those of us who treat bronchiectasis, a safe and effective anti-inflammatory has really been the Holy Grail, so this is really exciting,” she said.
 

Novel mechanism of action

Frequent exacerbations in bronchiectasis are related to uncontrolled neutrophilic inflammation, and proinflammatory neutrophil serine proteases (NSPs), including neutrophil elastase, are seen at increased levels in sputum of patients with bronchiectasis. In addition, the presence in sputum of elevated NSPs are associated with exacerbations and poor quality of life, Dr. Chalmers said.

Brensocatib is an inhibitor of dipeptidyl peptidase 1 (DPP1), a lysosomal cysteine protease that is responsible for NSP activation in bone marrow during the neutrophil maturation cycle.

In phase 1 trials, brensocatib was associated with a dose-dependent reduction in neutrophil elastase in healthy volunteers.
 

Three WILLOW branches

In the phase 2 WILLOW trial, patients with bronchiectasis not related to cystic fibrosis were screened and stratified by Pseudomonas aeruginosa on sputum culture and use of macrolide antibiotics and then randomized in equal proportions to receive either brensocatib at daily oral doses of 25 mg or 10 mg, or placebo for 24 weeks, followed by a 4-week off-treatment period.

Both doses of brensocatib met the primary endpoint of time to first exacerbation, compared with placebo. The hazard ratio (HR) for the 10-mg brensocatib dose, compared with placebo was 0.58 (P = .029), and the HR for the 25-mg dose was 0.62 (P = .046).

The exacerbation rate over 24 weeks among patients on placebo was 48.3%, compared with 31.7% of patients on 10 mg brensocatib (P = .033) and 33.3% of patients on the 25 mg dose (P = .038).

The annualized exacerbation rate was 1.37 for patients on placebo, compared with 0.88 with 10 mg brensocatib (P = .041) and 1.03 with 25 mg brensocatib (nonsignificant).

In both brensocatib groups there were significant reductions from baseline neutrophil elastase concentrations in sputum, compared with placebo (P = .034 for 10 mg and .021 for 25 mg). During the 4-week period following treatment neutrophil elastase levels in both active drug arms rose rapidly and returned to baseline.

The importance of these reductions was reflected in pooled data from the two brensocatib cohorts, which showed that patients who achieved neutrophil elastase levels below the limit of quantification had a significantly lower incidence of bronchiectasis exacerbations (HR 0.28, P < .0001).

Although the study was not powered to compare changes in postbronchodilator forced expiratory volume in 1 second (FEV₁) levels, placebo-treated patients had a numerically larger decline in lung function from baseline, compared with brensocatib-treated patients.
 

Safety

Expected adverse events with brensocatib included those associated with Papillon-Lefèvre syndrome, a rare congenital condition caused by the absence of the gene coding for DPP1, resulting in keratinization leading to redness, thickening of soles and palms, and severe, destructive periodontal disease, as well as reduced immune response to bacterial infection.

Treatment-emergent adverse events (TEAEs) resulting in study discontinuation occurred in only three patients on placebo and 10 mg brensocatib, and four on the 25-mg dose. TEAEs resulting in treatment discontinuation were more common in the placebo arm, occurring in nine patients compared with six each in the brensocatib arms.

Serious TEAEs occurring in more than 3% of patients in any group included infective exacerbations in three patients on placebo, none on the 10-mg dose, and four on the 25-mg dose of brensocatib. Respective numbers of patients with treatment-emergent pneumonia were three, zero, and four.

Other TEAEs included cough, headache, sputum increase, dyspnea, and diarrhea.

Adverse events of special interest included skin events in 10 patients on placebo, 12 on the 10-mg dose, and 21 on the 25-mg brensocatib dose. Dental changes occurred in 3, 13, and 9 patients, and infections in 9, 12, and 14 patients, respectively.

A phase 3 study to confirm efficacy and establish the optimal dose of brensocatib is planned for the end of 2020, “COVID willing,” Dr. Chalmers said.

Dr. Chalmers disclosed consultancy with and research funding from Insmed, which funded the study. Dr. Taylor-Cousar has disclosed grants and/or personal fees from various companies.

Brensocatib, an experimental small-molecule inhibitor targeted to inflammation-regulating neutrophil serine proteases, may be a novel, nonantibiotic option for reducing exacerbations in patients with bronchiectasis, investigators in the phase 2 WILLOW study said.

Among 256 adults with a recent history of bronchiectasis exacerbations, oral brensocatib at doses of both 10 mg and 25 mg daily for 24 weeks was associated with significantly longer time to first exacerbation than placebo, and the 10-mg dose was associated with a significant reduction in the annualized rate of exacerbations, reported James Chalmers, MB, ChB, PhD of Ninewells Hospital and Medical School in Dundee (England).

“We also observed a dose-dependent reduction in neutrophil elastase levels in sputum, which supports the mechanism of action of this drug, and importantly showed a link between reducing neutrophil serine protease activity and clinical benefits in people with bronchiectasis,” he said in at the American Thoracic Society’s virtual clinical trial session.

“This is a very important trial, a landmark trial for people with bronchiectasis, because this is a drug that for the first time appears to be able to target directly neutrophilic inflammation, resulting in clinical benefit,” he said.

Pulmonologist Jennifer L. Taylor-Cousar, MD, MSCS, of National Jewish Health in Denver, who was facilitator for the online presentation but was not involved in the study, said that it offered welcome news.

“For those of us who treat bronchiectasis, a safe and effective anti-inflammatory has really been the Holy Grail, so this is really exciting,” she said.
 

Novel mechanism of action

Frequent exacerbations in bronchiectasis are related to uncontrolled neutrophilic inflammation, and proinflammatory neutrophil serine proteases (NSPs), including neutrophil elastase, are seen at increased levels in sputum of patients with bronchiectasis. In addition, the presence in sputum of elevated NSPs are associated with exacerbations and poor quality of life, Dr. Chalmers said.

Brensocatib is an inhibitor of dipeptidyl peptidase 1 (DPP1), a lysosomal cysteine protease that is responsible for NSP activation in bone marrow during the neutrophil maturation cycle.

In phase 1 trials, brensocatib was associated with a dose-dependent reduction in neutrophil elastase in healthy volunteers.
 

Three WILLOW branches

In the phase 2 WILLOW trial, patients with bronchiectasis not related to cystic fibrosis were screened and stratified by Pseudomonas aeruginosa on sputum culture and use of macrolide antibiotics and then randomized in equal proportions to receive either brensocatib at daily oral doses of 25 mg or 10 mg, or placebo for 24 weeks, followed by a 4-week off-treatment period.

Both doses of brensocatib met the primary endpoint of time to first exacerbation, compared with placebo. The hazard ratio (HR) for the 10-mg brensocatib dose, compared with placebo was 0.58 (P = .029), and the HR for the 25-mg dose was 0.62 (P = .046).

The exacerbation rate over 24 weeks among patients on placebo was 48.3%, compared with 31.7% of patients on 10 mg brensocatib (P = .033) and 33.3% of patients on the 25 mg dose (P = .038).

The annualized exacerbation rate was 1.37 for patients on placebo, compared with 0.88 with 10 mg brensocatib (P = .041) and 1.03 with 25 mg brensocatib (nonsignificant).

In both brensocatib groups there were significant reductions from baseline neutrophil elastase concentrations in sputum, compared with placebo (P = .034 for 10 mg and .021 for 25 mg). During the 4-week period following treatment neutrophil elastase levels in both active drug arms rose rapidly and returned to baseline.

The importance of these reductions was reflected in pooled data from the two brensocatib cohorts, which showed that patients who achieved neutrophil elastase levels below the limit of quantification had a significantly lower incidence of bronchiectasis exacerbations (HR 0.28, P < .0001).

Although the study was not powered to compare changes in postbronchodilator forced expiratory volume in 1 second (FEV₁) levels, placebo-treated patients had a numerically larger decline in lung function from baseline, compared with brensocatib-treated patients.
 

Safety

Expected adverse events with brensocatib included those associated with Papillon-Lefèvre syndrome, a rare congenital condition caused by the absence of the gene coding for DPP1, resulting in keratinization leading to redness, thickening of soles and palms, and severe, destructive periodontal disease, as well as reduced immune response to bacterial infection.

Treatment-emergent adverse events (TEAEs) resulting in study discontinuation occurred in only three patients on placebo and 10 mg brensocatib, and four on the 25-mg dose. TEAEs resulting in treatment discontinuation were more common in the placebo arm, occurring in nine patients compared with six each in the brensocatib arms.

Serious TEAEs occurring in more than 3% of patients in any group included infective exacerbations in three patients on placebo, none on the 10-mg dose, and four on the 25-mg dose of brensocatib. Respective numbers of patients with treatment-emergent pneumonia were three, zero, and four.

Other TEAEs included cough, headache, sputum increase, dyspnea, and diarrhea.

Adverse events of special interest included skin events in 10 patients on placebo, 12 on the 10-mg dose, and 21 on the 25-mg brensocatib dose. Dental changes occurred in 3, 13, and 9 patients, and infections in 9, 12, and 14 patients, respectively.

A phase 3 study to confirm efficacy and establish the optimal dose of brensocatib is planned for the end of 2020, “COVID willing,” Dr. Chalmers said.

Dr. Chalmers disclosed consultancy with and research funding from Insmed, which funded the study. Dr. Taylor-Cousar has disclosed grants and/or personal fees from various companies.

Brensocatib, an experimental small-molecule inhibitor targeted to inflammation-regulating neutrophil serine proteases, may be a novel, nonantibiotic option for reducing exacerbations in patients with bronchiectasis, investigators in the phase 2 WILLOW study said.

Among 256 adults with a recent history of bronchiectasis exacerbations, oral brensocatib at doses of both 10 mg and 25 mg daily for 24 weeks was associated with significantly longer time to first exacerbation than placebo, and the 10-mg dose was associated with a significant reduction in the annualized rate of exacerbations, reported James Chalmers, MB, ChB, PhD of Ninewells Hospital and Medical School in Dundee (England).

“We also observed a dose-dependent reduction in neutrophil elastase levels in sputum, which supports the mechanism of action of this drug, and importantly showed a link between reducing neutrophil serine protease activity and clinical benefits in people with bronchiectasis,” he said in at the American Thoracic Society’s virtual clinical trial session.

“This is a very important trial, a landmark trial for people with bronchiectasis, because this is a drug that for the first time appears to be able to target directly neutrophilic inflammation, resulting in clinical benefit,” he said.

Pulmonologist Jennifer L. Taylor-Cousar, MD, MSCS, of National Jewish Health in Denver, who was facilitator for the online presentation but was not involved in the study, said that it offered welcome news.

“For those of us who treat bronchiectasis, a safe and effective anti-inflammatory has really been the Holy Grail, so this is really exciting,” she said.
 

Novel mechanism of action

Frequent exacerbations in bronchiectasis are related to uncontrolled neutrophilic inflammation, and proinflammatory neutrophil serine proteases (NSPs), including neutrophil elastase, are seen at increased levels in sputum of patients with bronchiectasis. In addition, the presence in sputum of elevated NSPs are associated with exacerbations and poor quality of life, Dr. Chalmers said.

Brensocatib is an inhibitor of dipeptidyl peptidase 1 (DPP1), a lysosomal cysteine protease that is responsible for NSP activation in bone marrow during the neutrophil maturation cycle.

In phase 1 trials, brensocatib was associated with a dose-dependent reduction in neutrophil elastase in healthy volunteers.
 

Three WILLOW branches

In the phase 2 WILLOW trial, patients with bronchiectasis not related to cystic fibrosis were screened and stratified by Pseudomonas aeruginosa on sputum culture and use of macrolide antibiotics and then randomized in equal proportions to receive either brensocatib at daily oral doses of 25 mg or 10 mg, or placebo for 24 weeks, followed by a 4-week off-treatment period.

Both doses of brensocatib met the primary endpoint of time to first exacerbation, compared with placebo. The hazard ratio (HR) for the 10-mg brensocatib dose, compared with placebo was 0.58 (P = .029), and the HR for the 25-mg dose was 0.62 (P = .046).

The exacerbation rate over 24 weeks among patients on placebo was 48.3%, compared with 31.7% of patients on 10 mg brensocatib (P = .033) and 33.3% of patients on the 25 mg dose (P = .038).

The annualized exacerbation rate was 1.37 for patients on placebo, compared with 0.88 with 10 mg brensocatib (P = .041) and 1.03 with 25 mg brensocatib (nonsignificant).

In both brensocatib groups there were significant reductions from baseline neutrophil elastase concentrations in sputum, compared with placebo (P = .034 for 10 mg and .021 for 25 mg). During the 4-week period following treatment neutrophil elastase levels in both active drug arms rose rapidly and returned to baseline.

The importance of these reductions was reflected in pooled data from the two brensocatib cohorts, which showed that patients who achieved neutrophil elastase levels below the limit of quantification had a significantly lower incidence of bronchiectasis exacerbations (HR 0.28, P < .0001).

Although the study was not powered to compare changes in postbronchodilator forced expiratory volume in 1 second (FEV₁) levels, placebo-treated patients had a numerically larger decline in lung function from baseline, compared with brensocatib-treated patients.
 

Safety

Expected adverse events with brensocatib included those associated with Papillon-Lefèvre syndrome, a rare congenital condition caused by the absence of the gene coding for DPP1, resulting in keratinization leading to redness, thickening of soles and palms, and severe, destructive periodontal disease, as well as reduced immune response to bacterial infection.

Treatment-emergent adverse events (TEAEs) resulting in study discontinuation occurred in only three patients on placebo and 10 mg brensocatib, and four on the 25-mg dose. TEAEs resulting in treatment discontinuation were more common in the placebo arm, occurring in nine patients compared with six each in the brensocatib arms.

Serious TEAEs occurring in more than 3% of patients in any group included infective exacerbations in three patients on placebo, none on the 10-mg dose, and four on the 25-mg dose of brensocatib. Respective numbers of patients with treatment-emergent pneumonia were three, zero, and four.

Other TEAEs included cough, headache, sputum increase, dyspnea, and diarrhea.

Adverse events of special interest included skin events in 10 patients on placebo, 12 on the 10-mg dose, and 21 on the 25-mg brensocatib dose. Dental changes occurred in 3, 13, and 9 patients, and infections in 9, 12, and 14 patients, respectively.

A phase 3 study to confirm efficacy and establish the optimal dose of brensocatib is planned for the end of 2020, “COVID willing,” Dr. Chalmers said.

Dr. Chalmers disclosed consultancy with and research funding from Insmed, which funded the study. Dr. Taylor-Cousar has disclosed grants and/or personal fees from various companies.

The World Health Organization is preparing a scientific brief to address the continually emerging evidence on transmission of COVID-19 and plans to release its guidance “in the coming days.”

WHO will likely address airborne transmission of the virus after a commentary from almost 240 multidisciplinary scientists raised the alarm that virus particles could remain airborne longer that previously appreciated, particularly in poorly ventilated indoor spaces.

“Airborne route of infection transmission is significant, but so far completely undermined, and not recognized by the decision makers and bodies responsible for infection control,” lead commentary author Lidia Morawska, PhD, told Medscape Medical News.

“This means that no control measures are taken to mitigate airborne transmission and, as a consequence, people are infected and can die,” said Morawska, director of the International Laboratory for Air Quality and Health at Queensland University of Technology in Brisbane, Australia. “We wanted to bring this to the attention of the world to prevent this from happening.”

The commentary was published July 6 in Clinical Infectious Diseases.

WHO leaders defended their progress in announcing any changes regarding how COVID-19 can be transmitted during a virtual press briefing today. They have collaborated since April with some of the scientists who coauthored the commentary, for example, said Maria Van Kerkhove, PhD, WHO technical lead on COVID-19.

“We have been working on a scientific brief ... to consolidate knowledge around transmission,” she added.

One focus will be on how masks protect healthcare workers. “We are also looking at the possible role of airborne transmission in other settings,” Van Kerkhove said. “We will be releasing our brief in the coming days.”

“We acknowledge there is emerging evidence in this field,” Benedetta Allegranzi, MD, WHO technical lead on COVID-19, said during the briefing from Geneva. “Therefore, we believe we have to be open to this evidence and its implications.”

WHO participated in an international research meeting last week that addressed means for controlling modes of COVID-19 transmission, Allegranzi said. “Our group and others really highlighted importance of research on different modes of transmission, including droplets of different sizes and their relative importance,” she said. Another aim was determining the dose of the virus required for airborne transmission.

“These fields of research are really growing but not definitive. More evidence needs to be gathered and evaluated,” she explained.

In the meantime, Allegranzi said, “the possibility of airborne transmission in public settings – especially closed, poorly ventilated settings – cannot be ruled out.”

Morawska said the evidence already exists. “A continuous surprise is that it takes the world such a long time to accept this, while this has such solid scientific foundation.” As an example, she cited an April report she coauthored in the journal Environment International. She and colleagues call for “national authorities to acknowledge the reality that the virus spreads through air and recommend that adequate control measures be implemented to prevent further spread of the SARS-CoV-2 virus, in particularly removal of the virus-laden droplets from indoor air by ventilation.”

The take-home message from the commentary, Morawska said, is a call to action. The authors state there is a need “to provide sufficient and effective ventilation (supply clean outdoor air, minimize recirculating air) particularly in public buildings, workplace environments, schools, hospitals, and aged care homes.”

WHO Chief Scientist Soumya Swaminathan, MD, explained why the organization remains cautious about making premature pronouncements regarding airborne transmission. “Any guidance we put out has implications for billions of people around the world, so we want to be as careful as possible,” she said during the press briefing. “We have to consider the weight of the evidence.”

“We are constantly looking for information on how we can do better,” Swaminathan added. WHO officials are reviewing hundreds of scientific reports every day, she said, and not all are of good quality. For this reason, she and other scientists at WHO perform a “living systematic review” – updating the consensus of evidence on a weekly basis.  

“This process on COVID-19 will, I am sure, continue for the weeks and months to come,” she added.

This article first appeared on Medscape.com.

The World Health Organization is preparing a scientific brief to address the continually emerging evidence on transmission of COVID-19 and plans to release its guidance “in the coming days.”

WHO will likely address airborne transmission of the virus after a commentary from almost 240 multidisciplinary scientists raised the alarm that virus particles could remain airborne longer that previously appreciated, particularly in poorly ventilated indoor spaces.

“Airborne route of infection transmission is significant, but so far completely undermined, and not recognized by the decision makers and bodies responsible for infection control,” lead commentary author Lidia Morawska, PhD, told Medscape Medical News.

“This means that no control measures are taken to mitigate airborne transmission and, as a consequence, people are infected and can die,” said Morawska, director of the International Laboratory for Air Quality and Health at Queensland University of Technology in Brisbane, Australia. “We wanted to bring this to the attention of the world to prevent this from happening.”

The commentary was published July 6 in Clinical Infectious Diseases.

WHO leaders defended their progress in announcing any changes regarding how COVID-19 can be transmitted during a virtual press briefing today. They have collaborated since April with some of the scientists who coauthored the commentary, for example, said Maria Van Kerkhove, PhD, WHO technical lead on COVID-19.

“We have been working on a scientific brief ... to consolidate knowledge around transmission,” she added.

One focus will be on how masks protect healthcare workers. “We are also looking at the possible role of airborne transmission in other settings,” Van Kerkhove said. “We will be releasing our brief in the coming days.”

“We acknowledge there is emerging evidence in this field,” Benedetta Allegranzi, MD, WHO technical lead on COVID-19, said during the briefing from Geneva. “Therefore, we believe we have to be open to this evidence and its implications.”

WHO participated in an international research meeting last week that addressed means for controlling modes of COVID-19 transmission, Allegranzi said. “Our group and others really highlighted importance of research on different modes of transmission, including droplets of different sizes and their relative importance,” she said. Another aim was determining the dose of the virus required for airborne transmission.

“These fields of research are really growing but not definitive. More evidence needs to be gathered and evaluated,” she explained.

In the meantime, Allegranzi said, “the possibility of airborne transmission in public settings – especially closed, poorly ventilated settings – cannot be ruled out.”

Morawska said the evidence already exists. “A continuous surprise is that it takes the world such a long time to accept this, while this has such solid scientific foundation.” As an example, she cited an April report she coauthored in the journal Environment International. She and colleagues call for “national authorities to acknowledge the reality that the virus spreads through air and recommend that adequate control measures be implemented to prevent further spread of the SARS-CoV-2 virus, in particularly removal of the virus-laden droplets from indoor air by ventilation.”

The take-home message from the commentary, Morawska said, is a call to action. The authors state there is a need “to provide sufficient and effective ventilation (supply clean outdoor air, minimize recirculating air) particularly in public buildings, workplace environments, schools, hospitals, and aged care homes.”

WHO Chief Scientist Soumya Swaminathan, MD, explained why the organization remains cautious about making premature pronouncements regarding airborne transmission. “Any guidance we put out has implications for billions of people around the world, so we want to be as careful as possible,” she said during the press briefing. “We have to consider the weight of the evidence.”

“We are constantly looking for information on how we can do better,” Swaminathan added. WHO officials are reviewing hundreds of scientific reports every day, she said, and not all are of good quality. For this reason, she and other scientists at WHO perform a “living systematic review” – updating the consensus of evidence on a weekly basis.  

“This process on COVID-19 will, I am sure, continue for the weeks and months to come,” she added.

This article first appeared on Medscape.com.

The World Health Organization is preparing a scientific brief to address the continually emerging evidence on transmission of COVID-19 and plans to release its guidance “in the coming days.”

WHO will likely address airborne transmission of the virus after a commentary from almost 240 multidisciplinary scientists raised the alarm that virus particles could remain airborne longer that previously appreciated, particularly in poorly ventilated indoor spaces.

“Airborne route of infection transmission is significant, but so far completely undermined, and not recognized by the decision makers and bodies responsible for infection control,” lead commentary author Lidia Morawska, PhD, told Medscape Medical News.

“This means that no control measures are taken to mitigate airborne transmission and, as a consequence, people are infected and can die,” said Morawska, director of the International Laboratory for Air Quality and Health at Queensland University of Technology in Brisbane, Australia. “We wanted to bring this to the attention of the world to prevent this from happening.”

The commentary was published July 6 in Clinical Infectious Diseases.

WHO leaders defended their progress in announcing any changes regarding how COVID-19 can be transmitted during a virtual press briefing today. They have collaborated since April with some of the scientists who coauthored the commentary, for example, said Maria Van Kerkhove, PhD, WHO technical lead on COVID-19.

“We have been working on a scientific brief ... to consolidate knowledge around transmission,” she added.

One focus will be on how masks protect healthcare workers. “We are also looking at the possible role of airborne transmission in other settings,” Van Kerkhove said. “We will be releasing our brief in the coming days.”

“We acknowledge there is emerging evidence in this field,” Benedetta Allegranzi, MD, WHO technical lead on COVID-19, said during the briefing from Geneva. “Therefore, we believe we have to be open to this evidence and its implications.”

WHO participated in an international research meeting last week that addressed means for controlling modes of COVID-19 transmission, Allegranzi said. “Our group and others really highlighted importance of research on different modes of transmission, including droplets of different sizes and their relative importance,” she said. Another aim was determining the dose of the virus required for airborne transmission.

“These fields of research are really growing but not definitive. More evidence needs to be gathered and evaluated,” she explained.

In the meantime, Allegranzi said, “the possibility of airborne transmission in public settings – especially closed, poorly ventilated settings – cannot be ruled out.”

Morawska said the evidence already exists. “A continuous surprise is that it takes the world such a long time to accept this, while this has such solid scientific foundation.” As an example, she cited an April report she coauthored in the journal Environment International. She and colleagues call for “national authorities to acknowledge the reality that the virus spreads through air and recommend that adequate control measures be implemented to prevent further spread of the SARS-CoV-2 virus, in particularly removal of the virus-laden droplets from indoor air by ventilation.”

The take-home message from the commentary, Morawska said, is a call to action. The authors state there is a need “to provide sufficient and effective ventilation (supply clean outdoor air, minimize recirculating air) particularly in public buildings, workplace environments, schools, hospitals, and aged care homes.”

WHO Chief Scientist Soumya Swaminathan, MD, explained why the organization remains cautious about making premature pronouncements regarding airborne transmission. “Any guidance we put out has implications for billions of people around the world, so we want to be as careful as possible,” she said during the press briefing. “We have to consider the weight of the evidence.”

“We are constantly looking for information on how we can do better,” Swaminathan added. WHO officials are reviewing hundreds of scientific reports every day, she said, and not all are of good quality. For this reason, she and other scientists at WHO perform a “living systematic review” – updating the consensus of evidence on a weekly basis.  

“This process on COVID-19 will, I am sure, continue for the weeks and months to come,” she added.

This article first appeared on Medscape.com.

Radiomics, a growing area of cancer research that extracts noninvasive biomarkers from medical imaging, may be able to improve lung cancer screening by identifying patients with early stage disease at high risk for poorer outcomes.

This is the conclusion from a group of researchers who used data from the National Lung Screening Trial (NLST) to develop and validate a model based on radiomics that could identify a vulnerable high-risk group of early stage patients associated with poor outcomes. These patients would generally require aggressive follow-up and/or adjuvant therapy.

The study was published June 29 in Nature Scientific Reports.

Radiomics, also known as quantitative image features, are noninvasive biomarkers that are generated from medical imaging. An emerging translational field of research, radiomics extracts large amounts of features from radiographic medical images using data-characterization algorithms, which reflect the underlying tumor pathophysiology and heterogeneity.

The authors note that radiomics has many advantages over circulating and tissue-based biomarkers, as these quantitative image features are rapidly calculated from standard-of-care imaging and reflect the entire tumor burden – and not just a sample as is the case with tissue-based biomarkers.

“We view radiomics as a decision support tool across the cancer control continuum, whether it be screening and early detection, diagnosis, prognostication, or treatment response,” said lead author Matthew B. Schabath, PhD, associate member in cancer epidemiology at the H. Lee Moffitt Cancer Center & Research Institute in Tampa, Florida.

“Radiomic features are generated from standard-of-care imaging and validated radiomic models can provide real-time decision support information to clinicians,” he explained.

Last year, another study showed that combining radiomics and imaging may be able to determine which patients with lung cancer were most likely to respond to chemotherapy. The researchers used CT imaging of radiomic features from within and outside the lung nodule and found it could predict time to progression and overall survival, as well as response to chemotherapy, in patients with non–small cell lung cancer (NSCLC).

Anant Madabhushi, PhD, a professor of biomedical engineering and director of the Center for Computational Imaging and Personalized Diagnostics at Case Western Reserve University, Cleveland, commented that the new study is “complementary and supports the premise that radiomics both from inside and outside the tumor can tell us about outcome and treatment response.”

Dr. Madabhushi also noted his group has released several other studies along similar lines, including a study showing how radiomics can predict the benefit of adjuvant therapy in lung cancer, a study showing how radiomics can predict recurrence in early stage NSCLC, and a study showing that radiomics can predict survival and response to immunotherapy in NSCLC.

Improving current lung cancer screening

The landmark NLST showed that, as compared with chest x-rays, low-dose helical computed tomography (LDCT) was associated with a 20% relative reduction in lung cancer mortality in high-risk individuals. However, LDCT screening can lead to overdiagnosis and subsequent overtreatment of slow-growing, indolent cancers.

“Current lung cancer screening inclusion criteria in the US are largely based on the criteria used in the NLST,” Dr. Schabath told Medscape Medical News. “Though the NLST clearly demonstrated that screening LDCT is a lifesaving tool, the NLST was not designed to create public policy.”

He pointed out that fewer than 30% of Americans diagnosed with lung cancer meet the current screening entry criteria and that subsequent trials (e.g., NELSON, LUSI, or MILD) used broader and more inclusive criteria and also showed the efficacy of LDCT for early detection of lung cancer. “Thus, there should be consideration in making the lung cancer screening guidelines more inclusive,” said Dr. Schabath.

“Additionally, adjunct risk-stratification tools, such as blood-based biomarkers, could be an important complement to determine who should be part of a lung cancer screening program,” he said. “This could be particularly salient for people who have no or very few risk factors, such as never smokers.”

Pinpointing poor outcomes

In the current study, Dr. Schabath and colleagues used publicly available data and LDCT images from the NLST to generate radiomic features from screen detected, incidentally-diagnosed lung cancers. Radiomic features describing size, shape, volume, and textural characteristics were then calculated from both the intratumoral and peritumoral regions.

Patients were divided into training and test cohorts, and an external cohort of non-screen-detected lung cancer patients was used for further validation. There were no statistically significant differences between training and test cohorts for most demographics, including age, sex, smoking status, number of pack-years smoked, treatment, stage, and baseline screening result. However, self-reported chronic obstructive pulmonary disease (COPD) was significantly higher in the test cohort compared with the training group (16% vs. 7%; P = .02).

A total of 91 stable and reproducible radiomics features (peritumoral and intratumoral) were identified and 40 (26 peritumoral and 14 intratumoral) were significantly associated with overall survival in the training cohort. The features were subsequently narrowed to four, and backward elimination analyses identified a single model. Patients were then stratified into three risk-groups: low risk, intermediate risk, and high risk.

According to their model, the high-risk group had worse overall survival (hazard ratio, 9.91; 25% 2.5-year and 0% 5-year OS) as compared with the low-risk group (HR, 1.00; 93% 2.5-year and 78% 5-year OS).

The final model was validated in the test group and then replicated in the non–screen-detected patients with adenocarcinoma patients. Since the disease stage differed significantly across the risk groups, the model was stratified by stage and the authors found “compelling” results among early-stage patients, who generally have good outcomes. In this subset, the high-risk group was associated with a worse overall survival (HR, 2.63; 56% 2.5-year and 42% 5-year OS) vs. the low-risk group (HR, 1.00; 75% 2.5-year and 75% 5-year OS).

“We have ongoing studies to determine if these results are consistent in the real-world setting of lung cancer screening across multiple centers,” said Dr. Schabath. “If the NELSON, LUSI, or MILD trial data become publicly available, we will certainly pursue validating our results in those clinical trials.”

The study was funded by the National Cancer Institute. Dr. Schabath and Dr. Madabhushi have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Radiomics, a growing area of cancer research that extracts noninvasive biomarkers from medical imaging, may be able to improve lung cancer screening by identifying patients with early stage disease at high risk for poorer outcomes.

This is the conclusion from a group of researchers who used data from the National Lung Screening Trial (NLST) to develop and validate a model based on radiomics that could identify a vulnerable high-risk group of early stage patients associated with poor outcomes. These patients would generally require aggressive follow-up and/or adjuvant therapy.

The study was published June 29 in Nature Scientific Reports.

Radiomics, also known as quantitative image features, are noninvasive biomarkers that are generated from medical imaging. An emerging translational field of research, radiomics extracts large amounts of features from radiographic medical images using data-characterization algorithms, which reflect the underlying tumor pathophysiology and heterogeneity.

The authors note that radiomics has many advantages over circulating and tissue-based biomarkers, as these quantitative image features are rapidly calculated from standard-of-care imaging and reflect the entire tumor burden – and not just a sample as is the case with tissue-based biomarkers.

“We view radiomics as a decision support tool across the cancer control continuum, whether it be screening and early detection, diagnosis, prognostication, or treatment response,” said lead author Matthew B. Schabath, PhD, associate member in cancer epidemiology at the H. Lee Moffitt Cancer Center & Research Institute in Tampa, Florida.

“Radiomic features are generated from standard-of-care imaging and validated radiomic models can provide real-time decision support information to clinicians,” he explained.

Last year, another study showed that combining radiomics and imaging may be able to determine which patients with lung cancer were most likely to respond to chemotherapy. The researchers used CT imaging of radiomic features from within and outside the lung nodule and found it could predict time to progression and overall survival, as well as response to chemotherapy, in patients with non–small cell lung cancer (NSCLC).

Anant Madabhushi, PhD, a professor of biomedical engineering and director of the Center for Computational Imaging and Personalized Diagnostics at Case Western Reserve University, Cleveland, commented that the new study is “complementary and supports the premise that radiomics both from inside and outside the tumor can tell us about outcome and treatment response.”

Dr. Madabhushi also noted his group has released several other studies along similar lines, including a study showing how radiomics can predict the benefit of adjuvant therapy in lung cancer, a study showing how radiomics can predict recurrence in early stage NSCLC, and a study showing that radiomics can predict survival and response to immunotherapy in NSCLC.

Improving current lung cancer screening

The landmark NLST showed that, as compared with chest x-rays, low-dose helical computed tomography (LDCT) was associated with a 20% relative reduction in lung cancer mortality in high-risk individuals. However, LDCT screening can lead to overdiagnosis and subsequent overtreatment of slow-growing, indolent cancers.

“Current lung cancer screening inclusion criteria in the US are largely based on the criteria used in the NLST,” Dr. Schabath told Medscape Medical News. “Though the NLST clearly demonstrated that screening LDCT is a lifesaving tool, the NLST was not designed to create public policy.”

He pointed out that fewer than 30% of Americans diagnosed with lung cancer meet the current screening entry criteria and that subsequent trials (e.g., NELSON, LUSI, or MILD) used broader and more inclusive criteria and also showed the efficacy of LDCT for early detection of lung cancer. “Thus, there should be consideration in making the lung cancer screening guidelines more inclusive,” said Dr. Schabath.

“Additionally, adjunct risk-stratification tools, such as blood-based biomarkers, could be an important complement to determine who should be part of a lung cancer screening program,” he said. “This could be particularly salient for people who have no or very few risk factors, such as never smokers.”

Pinpointing poor outcomes

In the current study, Dr. Schabath and colleagues used publicly available data and LDCT images from the NLST to generate radiomic features from screen detected, incidentally-diagnosed lung cancers. Radiomic features describing size, shape, volume, and textural characteristics were then calculated from both the intratumoral and peritumoral regions.

Patients were divided into training and test cohorts, and an external cohort of non-screen-detected lung cancer patients was used for further validation. There were no statistically significant differences between training and test cohorts for most demographics, including age, sex, smoking status, number of pack-years smoked, treatment, stage, and baseline screening result. However, self-reported chronic obstructive pulmonary disease (COPD) was significantly higher in the test cohort compared with the training group (16% vs. 7%; P = .02).

A total of 91 stable and reproducible radiomics features (peritumoral and intratumoral) were identified and 40 (26 peritumoral and 14 intratumoral) were significantly associated with overall survival in the training cohort. The features were subsequently narrowed to four, and backward elimination analyses identified a single model. Patients were then stratified into three risk-groups: low risk, intermediate risk, and high risk.

According to their model, the high-risk group had worse overall survival (hazard ratio, 9.91; 25% 2.5-year and 0% 5-year OS) as compared with the low-risk group (HR, 1.00; 93% 2.5-year and 78% 5-year OS).

The final model was validated in the test group and then replicated in the non–screen-detected patients with adenocarcinoma patients. Since the disease stage differed significantly across the risk groups, the model was stratified by stage and the authors found “compelling” results among early-stage patients, who generally have good outcomes. In this subset, the high-risk group was associated with a worse overall survival (HR, 2.63; 56% 2.5-year and 42% 5-year OS) vs. the low-risk group (HR, 1.00; 75% 2.5-year and 75% 5-year OS).

“We have ongoing studies to determine if these results are consistent in the real-world setting of lung cancer screening across multiple centers,” said Dr. Schabath. “If the NELSON, LUSI, or MILD trial data become publicly available, we will certainly pursue validating our results in those clinical trials.”

The study was funded by the National Cancer Institute. Dr. Schabath and Dr. Madabhushi have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Radiomics, a growing area of cancer research that extracts noninvasive biomarkers from medical imaging, may be able to improve lung cancer screening by identifying patients with early stage disease at high risk for poorer outcomes.

This is the conclusion from a group of researchers who used data from the National Lung Screening Trial (NLST) to develop and validate a model based on radiomics that could identify a vulnerable high-risk group of early stage patients associated with poor outcomes. These patients would generally require aggressive follow-up and/or adjuvant therapy.

The study was published June 29 in Nature Scientific Reports.

Radiomics, also known as quantitative image features, are noninvasive biomarkers that are generated from medical imaging. An emerging translational field of research, radiomics extracts large amounts of features from radiographic medical images using data-characterization algorithms, which reflect the underlying tumor pathophysiology and heterogeneity.

The authors note that radiomics has many advantages over circulating and tissue-based biomarkers, as these quantitative image features are rapidly calculated from standard-of-care imaging and reflect the entire tumor burden – and not just a sample as is the case with tissue-based biomarkers.

“We view radiomics as a decision support tool across the cancer control continuum, whether it be screening and early detection, diagnosis, prognostication, or treatment response,” said lead author Matthew B. Schabath, PhD, associate member in cancer epidemiology at the H. Lee Moffitt Cancer Center & Research Institute in Tampa, Florida.

“Radiomic features are generated from standard-of-care imaging and validated radiomic models can provide real-time decision support information to clinicians,” he explained.

Last year, another study showed that combining radiomics and imaging may be able to determine which patients with lung cancer were most likely to respond to chemotherapy. The researchers used CT imaging of radiomic features from within and outside the lung nodule and found it could predict time to progression and overall survival, as well as response to chemotherapy, in patients with non–small cell lung cancer (NSCLC).

Anant Madabhushi, PhD, a professor of biomedical engineering and director of the Center for Computational Imaging and Personalized Diagnostics at Case Western Reserve University, Cleveland, commented that the new study is “complementary and supports the premise that radiomics both from inside and outside the tumor can tell us about outcome and treatment response.”

Dr. Madabhushi also noted his group has released several other studies along similar lines, including a study showing how radiomics can predict the benefit of adjuvant therapy in lung cancer, a study showing how radiomics can predict recurrence in early stage NSCLC, and a study showing that radiomics can predict survival and response to immunotherapy in NSCLC.

Improving current lung cancer screening

The landmark NLST showed that, as compared with chest x-rays, low-dose helical computed tomography (LDCT) was associated with a 20% relative reduction in lung cancer mortality in high-risk individuals. However, LDCT screening can lead to overdiagnosis and subsequent overtreatment of slow-growing, indolent cancers.

“Current lung cancer screening inclusion criteria in the US are largely based on the criteria used in the NLST,” Dr. Schabath told Medscape Medical News. “Though the NLST clearly demonstrated that screening LDCT is a lifesaving tool, the NLST was not designed to create public policy.”

He pointed out that fewer than 30% of Americans diagnosed with lung cancer meet the current screening entry criteria and that subsequent trials (e.g., NELSON, LUSI, or MILD) used broader and more inclusive criteria and also showed the efficacy of LDCT for early detection of lung cancer. “Thus, there should be consideration in making the lung cancer screening guidelines more inclusive,” said Dr. Schabath.

“Additionally, adjunct risk-stratification tools, such as blood-based biomarkers, could be an important complement to determine who should be part of a lung cancer screening program,” he said. “This could be particularly salient for people who have no or very few risk factors, such as never smokers.”

Pinpointing poor outcomes

In the current study, Dr. Schabath and colleagues used publicly available data and LDCT images from the NLST to generate radiomic features from screen detected, incidentally-diagnosed lung cancers. Radiomic features describing size, shape, volume, and textural characteristics were then calculated from both the intratumoral and peritumoral regions.

Patients were divided into training and test cohorts, and an external cohort of non-screen-detected lung cancer patients was used for further validation. There were no statistically significant differences between training and test cohorts for most demographics, including age, sex, smoking status, number of pack-years smoked, treatment, stage, and baseline screening result. However, self-reported chronic obstructive pulmonary disease (COPD) was significantly higher in the test cohort compared with the training group (16% vs. 7%; P = .02).

A total of 91 stable and reproducible radiomics features (peritumoral and intratumoral) were identified and 40 (26 peritumoral and 14 intratumoral) were significantly associated with overall survival in the training cohort. The features were subsequently narrowed to four, and backward elimination analyses identified a single model. Patients were then stratified into three risk-groups: low risk, intermediate risk, and high risk.

According to their model, the high-risk group had worse overall survival (hazard ratio, 9.91; 25% 2.5-year and 0% 5-year OS) as compared with the low-risk group (HR, 1.00; 93% 2.5-year and 78% 5-year OS).

The final model was validated in the test group and then replicated in the non–screen-detected patients with adenocarcinoma patients. Since the disease stage differed significantly across the risk groups, the model was stratified by stage and the authors found “compelling” results among early-stage patients, who generally have good outcomes. In this subset, the high-risk group was associated with a worse overall survival (HR, 2.63; 56% 2.5-year and 42% 5-year OS) vs. the low-risk group (HR, 1.00; 75% 2.5-year and 75% 5-year OS).

“We have ongoing studies to determine if these results are consistent in the real-world setting of lung cancer screening across multiple centers,” said Dr. Schabath. “If the NELSON, LUSI, or MILD trial data become publicly available, we will certainly pursue validating our results in those clinical trials.”

The study was funded by the National Cancer Institute. Dr. Schabath and Dr. Madabhushi have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.