Clinical Psychiatry News

Newly updated guidance on treating patients with the novel coronavirus (COVID-19) has been published by the World Health Organization.

While it can’t replace clinical judgment or specialist consultation, the new guidance may help strengthen the clinical management of patients when COVID-19 is suspected, according to its authors.

The guidance, adapted from an earlier edition focused on the management of suspected Middle East respiratory syndrome coronavirus (MERS-CoV), covers best practices for triage, infection prevention and control, and optimized supportive care for mild, severe, or critical coronavirus disease 2019 (COVID-19).

“This guidance should serve as a foundation for optimized supportive care to ensure the best possible chance for survival,” the authors wrote in the guidance.

Newly updated guidance on treating patients with the novel coronavirus (COVID-19) has been published by the World Health Organization.

While it can’t replace clinical judgment or specialist consultation, the new guidance may help strengthen the clinical management of patients when COVID-19 is suspected, according to its authors.

The guidance, adapted from an earlier edition focused on the management of suspected Middle East respiratory syndrome coronavirus (MERS-CoV), covers best practices for triage, infection prevention and control, and optimized supportive care for mild, severe, or critical coronavirus disease 2019 (COVID-19).

“This guidance should serve as a foundation for optimized supportive care to ensure the best possible chance for survival,” the authors wrote in the guidance.

Newly updated guidance on treating patients with the novel coronavirus (COVID-19) has been published by the World Health Organization.

While it can’t replace clinical judgment or specialist consultation, the new guidance may help strengthen the clinical management of patients when COVID-19 is suspected, according to its authors.

The guidance, adapted from an earlier edition focused on the management of suspected Middle East respiratory syndrome coronavirus (MERS-CoV), covers best practices for triage, infection prevention and control, and optimized supportive care for mild, severe, or critical coronavirus disease 2019 (COVID-19).

“This guidance should serve as a foundation for optimized supportive care to ensure the best possible chance for survival,” the authors wrote in the guidance.

No difference in the primary endpoint of the time to clinical improvement was seen in an open-label trial of the antiretroviral drug lopinavir-ritonavir versus standard of care in adult patients hospitalized with severe COVID-19.

The median time to clinical improvement – defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever was first – was 16 days in both groups (hazard ratio, 1.31; 95% confidence interval 0.95-1.85; P = .09).

Although a numerically lower number of deaths were recorded at 28 days (19.2% vs. 25%) with the antiretroviral treatment versus standard of care, a similar percentage of patients had detectable levels of viral RNA in throat swabs taken at various time points during the study, Chinese researchers reported in the New England Journal of Medicine.

Bai Cao, M.D, from the China-Japan Friendship Hospital and Chinese Academy of Medical Sciences, both in Beijing, and associates, performed a randomized, controlled, trial of 199 adult patients hospitalized at the Jin Yin-Tan Hospital in Wuhan in Hubei Province, China.

For inclusion, patients had to have laboratory confirmed infection with SARS-Cov-2, the virus that causes COVID-19; pneumonia confirmed by chest imaging; and severely reduced oxygen saturation (94% or less while breathing ambient air or a ratio of the partial pressure of oxygen to the fraction of inspired oxygen of less than 300 mm Hg).

Patients were randomized to receive either a combination of lopinavir (400 mg) and ritonavir (100 mg) twice a day on top of standard care (n = 99) or to standard care alone (n = 100) for 14 days. “Because of the emergency nature of the trial, placebos of lopinavir-ritonavir were not prepared,” Dr. Cao et al. explained, noting that standard care consisted of supplemental oxygen, ventilation, antibiotic treatment, vasopressor support, renal-replacement therapy, and extracorporeal membrane oxygenation.

While the trial did not meet its primary endpoint, Dr. Cao et al. reported that patients in the lopinavir-ritonavir group had a shorter stay in the intensive care unit than did those in the standard-care group, at a median of 6 versus 11 days. They also reported that the duration from randomization to hospital discharge was numerically shorter, at a median of 12 versus 14 days. Furthermore, there was a higher percentage of patients with clinical improvement at day 14 in the lopinavir-ritonavir group than in the standard-care group (45.5% vs. 30.0%)

“The trial was initiated in rapid response to the COVID-19 public health emergency, at which time there was very limited information about clinical outcomes in hospitalized patients with COVID-19,” the researchers observed. “The question of whether earlier lopinavir-ritonavir treatment in COVID-19 could have clinical benefit is an important one that requires further study,” they wrote.

Among the trial’s limitations are it was not blinded and the researchers do not have data on the lopinavir exposure levels in the trial participants.

“This was a heroic effort” in a “particularly challenging population,” Lindsey R. Baden, MD, and Eric J. Rubin, MD, stated in an editorial accompanying the article (Baden LR and Rubin EJ. New Engl J Med. March 18, 2020. doi: 10.1056/NEJMe2005477). “Unfortunately, the trial results were disappointing,” they noted.

“The secondary end points provide both reason for hope and reason for discouragement,” wrote Dr. Baden and Dr. Rubin. The lack of effect on viral shedding, however, “strongly [suggests] that it did not have the activity desired” they observed.

Dr. Baden and Dr. Rubin commented that one of the important takeaways from the trial is that “the investigators appropriately prioritized speed, designing a trial that could rapidly produce an answer.” They continued that the investigators had shown that “rapidly initiated, high-quality randomized clinical trials are possible in epidemic conditions” and that results of such trials, whether they are positive or negative, “will be central to clinical care as the dangerous coronavirus outbreak continues.”

As it stands, more than 100 trials are listed in the ClinicalTrials.gov database as testing a wide range of different treatment approaches for COVID-19. These include trials investigating if sarilumab, hydroxychloroquine, fingolimod, bevacizumab, and losartan might have a role to play. There are also trials looking at the potential of other antiviral agents, such as Gilead’s investigational drug remdesivir, which has shown to have in vitro and in vivo activity against many emerging viral pathogens that cause Ebola, Middle Eastern Respiratory Syndrome, and Severe Acute Respiratory Syndrome.

Dr. Cao’s trial was supported by grants from Major Projects of National Science and Technology on New Drug Creation and Development and from the Chinese Academy of Medical Sciences (CAMS) Emergency Project of Covid-19, and a National Science Grant for Distinguished Young Scholars.

All authors had no financial conflicts of interest to disclose.

Dr. Baden is the director of clinical research in the Division of Infectious Diseases at the Brigham and Women’s Hospital and the director of infectious diseases at the Dana-Farber Cancer Institute. He is a deputy editor of the New England Journal of Medicine and chair of the FDA’s Antimicrobial Drug Advisory Committee. He is involved in HIV vaccine clinical trials and has received research grants from the Ragon Institute, the National Institutes of Health/National Institute of Allergy and Infectious Diseases, and the Gates Foundation.

Dr. Rubin is employed by the New England Journal of Medicine as editor-in-chief. He is an associate physician at Brigham and Women’s Hospital and is chair and Irene Heinz Given Professor of Immunology and Infectious Diseases at the Harvard T.H. Chan School of Public Health.

SOURCE: Cao B et al. New Engl J Med. 2020 Mar 18. doi: 10.1056/NEJMoa2001282.

No difference in the primary endpoint of the time to clinical improvement was seen in an open-label trial of the antiretroviral drug lopinavir-ritonavir versus standard of care in adult patients hospitalized with severe COVID-19.

The median time to clinical improvement – defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever was first – was 16 days in both groups (hazard ratio, 1.31; 95% confidence interval 0.95-1.85; P = .09).

Although a numerically lower number of deaths were recorded at 28 days (19.2% vs. 25%) with the antiretroviral treatment versus standard of care, a similar percentage of patients had detectable levels of viral RNA in throat swabs taken at various time points during the study, Chinese researchers reported in the New England Journal of Medicine.

Bai Cao, M.D, from the China-Japan Friendship Hospital and Chinese Academy of Medical Sciences, both in Beijing, and associates, performed a randomized, controlled, trial of 199 adult patients hospitalized at the Jin Yin-Tan Hospital in Wuhan in Hubei Province, China.

For inclusion, patients had to have laboratory confirmed infection with SARS-Cov-2, the virus that causes COVID-19; pneumonia confirmed by chest imaging; and severely reduced oxygen saturation (94% or less while breathing ambient air or a ratio of the partial pressure of oxygen to the fraction of inspired oxygen of less than 300 mm Hg).

Patients were randomized to receive either a combination of lopinavir (400 mg) and ritonavir (100 mg) twice a day on top of standard care (n = 99) or to standard care alone (n = 100) for 14 days. “Because of the emergency nature of the trial, placebos of lopinavir-ritonavir were not prepared,” Dr. Cao et al. explained, noting that standard care consisted of supplemental oxygen, ventilation, antibiotic treatment, vasopressor support, renal-replacement therapy, and extracorporeal membrane oxygenation.

While the trial did not meet its primary endpoint, Dr. Cao et al. reported that patients in the lopinavir-ritonavir group had a shorter stay in the intensive care unit than did those in the standard-care group, at a median of 6 versus 11 days. They also reported that the duration from randomization to hospital discharge was numerically shorter, at a median of 12 versus 14 days. Furthermore, there was a higher percentage of patients with clinical improvement at day 14 in the lopinavir-ritonavir group than in the standard-care group (45.5% vs. 30.0%)

“The trial was initiated in rapid response to the COVID-19 public health emergency, at which time there was very limited information about clinical outcomes in hospitalized patients with COVID-19,” the researchers observed. “The question of whether earlier lopinavir-ritonavir treatment in COVID-19 could have clinical benefit is an important one that requires further study,” they wrote.

Among the trial’s limitations are it was not blinded and the researchers do not have data on the lopinavir exposure levels in the trial participants.

“This was a heroic effort” in a “particularly challenging population,” Lindsey R. Baden, MD, and Eric J. Rubin, MD, stated in an editorial accompanying the article (Baden LR and Rubin EJ. New Engl J Med. March 18, 2020. doi: 10.1056/NEJMe2005477). “Unfortunately, the trial results were disappointing,” they noted.

“The secondary end points provide both reason for hope and reason for discouragement,” wrote Dr. Baden and Dr. Rubin. The lack of effect on viral shedding, however, “strongly [suggests] that it did not have the activity desired” they observed.

Dr. Baden and Dr. Rubin commented that one of the important takeaways from the trial is that “the investigators appropriately prioritized speed, designing a trial that could rapidly produce an answer.” They continued that the investigators had shown that “rapidly initiated, high-quality randomized clinical trials are possible in epidemic conditions” and that results of such trials, whether they are positive or negative, “will be central to clinical care as the dangerous coronavirus outbreak continues.”

As it stands, more than 100 trials are listed in the ClinicalTrials.gov database as testing a wide range of different treatment approaches for COVID-19. These include trials investigating if sarilumab, hydroxychloroquine, fingolimod, bevacizumab, and losartan might have a role to play. There are also trials looking at the potential of other antiviral agents, such as Gilead’s investigational drug remdesivir, which has shown to have in vitro and in vivo activity against many emerging viral pathogens that cause Ebola, Middle Eastern Respiratory Syndrome, and Severe Acute Respiratory Syndrome.

Dr. Cao’s trial was supported by grants from Major Projects of National Science and Technology on New Drug Creation and Development and from the Chinese Academy of Medical Sciences (CAMS) Emergency Project of Covid-19, and a National Science Grant for Distinguished Young Scholars.

All authors had no financial conflicts of interest to disclose.

Dr. Baden is the director of clinical research in the Division of Infectious Diseases at the Brigham and Women’s Hospital and the director of infectious diseases at the Dana-Farber Cancer Institute. He is a deputy editor of the New England Journal of Medicine and chair of the FDA’s Antimicrobial Drug Advisory Committee. He is involved in HIV vaccine clinical trials and has received research grants from the Ragon Institute, the National Institutes of Health/National Institute of Allergy and Infectious Diseases, and the Gates Foundation.

Dr. Rubin is employed by the New England Journal of Medicine as editor-in-chief. He is an associate physician at Brigham and Women’s Hospital and is chair and Irene Heinz Given Professor of Immunology and Infectious Diseases at the Harvard T.H. Chan School of Public Health.

SOURCE: Cao B et al. New Engl J Med. 2020 Mar 18. doi: 10.1056/NEJMoa2001282.

No difference in the primary endpoint of the time to clinical improvement was seen in an open-label trial of the antiretroviral drug lopinavir-ritonavir versus standard of care in adult patients hospitalized with severe COVID-19.

The median time to clinical improvement – defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever was first – was 16 days in both groups (hazard ratio, 1.31; 95% confidence interval 0.95-1.85; P = .09).

Although a numerically lower number of deaths were recorded at 28 days (19.2% vs. 25%) with the antiretroviral treatment versus standard of care, a similar percentage of patients had detectable levels of viral RNA in throat swabs taken at various time points during the study, Chinese researchers reported in the New England Journal of Medicine.

Bai Cao, M.D, from the China-Japan Friendship Hospital and Chinese Academy of Medical Sciences, both in Beijing, and associates, performed a randomized, controlled, trial of 199 adult patients hospitalized at the Jin Yin-Tan Hospital in Wuhan in Hubei Province, China.

For inclusion, patients had to have laboratory confirmed infection with SARS-Cov-2, the virus that causes COVID-19; pneumonia confirmed by chest imaging; and severely reduced oxygen saturation (94% or less while breathing ambient air or a ratio of the partial pressure of oxygen to the fraction of inspired oxygen of less than 300 mm Hg).

Patients were randomized to receive either a combination of lopinavir (400 mg) and ritonavir (100 mg) twice a day on top of standard care (n = 99) or to standard care alone (n = 100) for 14 days. “Because of the emergency nature of the trial, placebos of lopinavir-ritonavir were not prepared,” Dr. Cao et al. explained, noting that standard care consisted of supplemental oxygen, ventilation, antibiotic treatment, vasopressor support, renal-replacement therapy, and extracorporeal membrane oxygenation.

While the trial did not meet its primary endpoint, Dr. Cao et al. reported that patients in the lopinavir-ritonavir group had a shorter stay in the intensive care unit than did those in the standard-care group, at a median of 6 versus 11 days. They also reported that the duration from randomization to hospital discharge was numerically shorter, at a median of 12 versus 14 days. Furthermore, there was a higher percentage of patients with clinical improvement at day 14 in the lopinavir-ritonavir group than in the standard-care group (45.5% vs. 30.0%)

“The trial was initiated in rapid response to the COVID-19 public health emergency, at which time there was very limited information about clinical outcomes in hospitalized patients with COVID-19,” the researchers observed. “The question of whether earlier lopinavir-ritonavir treatment in COVID-19 could have clinical benefit is an important one that requires further study,” they wrote.

Among the trial’s limitations are it was not blinded and the researchers do not have data on the lopinavir exposure levels in the trial participants.

“This was a heroic effort” in a “particularly challenging population,” Lindsey R. Baden, MD, and Eric J. Rubin, MD, stated in an editorial accompanying the article (Baden LR and Rubin EJ. New Engl J Med. March 18, 2020. doi: 10.1056/NEJMe2005477). “Unfortunately, the trial results were disappointing,” they noted.

“The secondary end points provide both reason for hope and reason for discouragement,” wrote Dr. Baden and Dr. Rubin. The lack of effect on viral shedding, however, “strongly [suggests] that it did not have the activity desired” they observed.

Dr. Baden and Dr. Rubin commented that one of the important takeaways from the trial is that “the investigators appropriately prioritized speed, designing a trial that could rapidly produce an answer.” They continued that the investigators had shown that “rapidly initiated, high-quality randomized clinical trials are possible in epidemic conditions” and that results of such trials, whether they are positive or negative, “will be central to clinical care as the dangerous coronavirus outbreak continues.”

As it stands, more than 100 trials are listed in the ClinicalTrials.gov database as testing a wide range of different treatment approaches for COVID-19. These include trials investigating if sarilumab, hydroxychloroquine, fingolimod, bevacizumab, and losartan might have a role to play. There are also trials looking at the potential of other antiviral agents, such as Gilead’s investigational drug remdesivir, which has shown to have in vitro and in vivo activity against many emerging viral pathogens that cause Ebola, Middle Eastern Respiratory Syndrome, and Severe Acute Respiratory Syndrome.

Dr. Cao’s trial was supported by grants from Major Projects of National Science and Technology on New Drug Creation and Development and from the Chinese Academy of Medical Sciences (CAMS) Emergency Project of Covid-19, and a National Science Grant for Distinguished Young Scholars.

All authors had no financial conflicts of interest to disclose.

Dr. Baden is the director of clinical research in the Division of Infectious Diseases at the Brigham and Women’s Hospital and the director of infectious diseases at the Dana-Farber Cancer Institute. He is a deputy editor of the New England Journal of Medicine and chair of the FDA’s Antimicrobial Drug Advisory Committee. He is involved in HIV vaccine clinical trials and has received research grants from the Ragon Institute, the National Institutes of Health/National Institute of Allergy and Infectious Diseases, and the Gates Foundation.

Dr. Rubin is employed by the New England Journal of Medicine as editor-in-chief. He is an associate physician at Brigham and Women’s Hospital and is chair and Irene Heinz Given Professor of Immunology and Infectious Diseases at the Harvard T.H. Chan School of Public Health.

SOURCE: Cao B et al. New Engl J Med. 2020 Mar 18. doi: 10.1056/NEJMoa2001282.

Patients with COVID-19 may be at risk for liver injury, but mechanisms of damage remain unclear, according to investigators.

Proposed mechanisms include direct virus-induced effects, immune-induced damage due to excessive inflammatory responses, and drug-induced injury, reported lead author Ling Xu of Huazhong University of Science and Technology, Wuhan, China, and colleagues.

“From a clinical perspective, in addition to actively dealing with the primary disease caused by coronavirus infection, attention should also be paid to monitor the occurrence of liver injury, and to the application of drugs which may induce liver damage,” the investigators wrote in Liver International. “Patients with liver damage are advised to be treated with drugs that could both protect liver functions and inhibit inflammatory responses, such as ammonium glycyrrhizinate, which may, in turn, accelerate the process of disease recovery.”

The review of liver injury associated with major pathogenic coronaviruses included severe acute respiratory syndrome coronavirus (SARS-CoV), the Middle East respiratory syndrome coronavirus (MERS-CoV), and the newly emergent SARS-CoV-2, which causes COVID-19.

In cases of COVID-19, reported incidence of liver injury ranges from 15% to 53%, based on elevations of alanine transaminase (ALT) and aspartate aminotransferase (AST), along with slightly elevated bilirubin levels. In severe cases, albumin decreases have also been documented.

Liver injury appears to be significantly more common among those with severe infection. In one cohort of 82 patients who died from COVID-19, the incidence of liver injury was 78%, while another study of 36 nonsurvivors reported a rate of 58%.

According to the investigators, both bile duct epithelial cells and liver cells express angiotensin converting enzyme II (ACE2), which is an entry receptor for SARS-CoV-2; however, expression of ACE2 in bile duct cells is “much higher” than in liver cells, and comparable with alveolar type 2 cells in the lungs.

“Bile duct epithelial cells are known to play important roles in liver regeneration and immune response,” the investigators noted.

Beyond direct- and immune-induced effects of COVID-19, postmortem findings suggest that drug-induced liver injury may also be a possibility, with a number of theoretical culprits, including antibiotics, steroids, and antivirals. Although the investigators emphasized that data are insufficient to pinpoint an exact agent, they highlighted a recent preprint study, which reported a significantly higher rate of lopinavir/ritonavir administration among patients with abnormal liver function, compared with those who had normal liver function (56.1% vs. 25%; P = .009).

“Drug-induced liver injury during the treatment of coronavirus infection should not be ignored and needs to be carefully investigated,” the investigators concluded.

Fundamental Research Funds for the Central Universities supported the work. The investigators reported no conflicts of interest.

SOURCE: Xu L et al. Liver Int. 2020 Mar 14. doi: 10.1111/liv.14435.

Patients with COVID-19 may be at risk for liver injury, but mechanisms of damage remain unclear, according to investigators.

Proposed mechanisms include direct virus-induced effects, immune-induced damage due to excessive inflammatory responses, and drug-induced injury, reported lead author Ling Xu of Huazhong University of Science and Technology, Wuhan, China, and colleagues.

“From a clinical perspective, in addition to actively dealing with the primary disease caused by coronavirus infection, attention should also be paid to monitor the occurrence of liver injury, and to the application of drugs which may induce liver damage,” the investigators wrote in Liver International. “Patients with liver damage are advised to be treated with drugs that could both protect liver functions and inhibit inflammatory responses, such as ammonium glycyrrhizinate, which may, in turn, accelerate the process of disease recovery.”

The review of liver injury associated with major pathogenic coronaviruses included severe acute respiratory syndrome coronavirus (SARS-CoV), the Middle East respiratory syndrome coronavirus (MERS-CoV), and the newly emergent SARS-CoV-2, which causes COVID-19.

In cases of COVID-19, reported incidence of liver injury ranges from 15% to 53%, based on elevations of alanine transaminase (ALT) and aspartate aminotransferase (AST), along with slightly elevated bilirubin levels. In severe cases, albumin decreases have also been documented.

Liver injury appears to be significantly more common among those with severe infection. In one cohort of 82 patients who died from COVID-19, the incidence of liver injury was 78%, while another study of 36 nonsurvivors reported a rate of 58%.

According to the investigators, both bile duct epithelial cells and liver cells express angiotensin converting enzyme II (ACE2), which is an entry receptor for SARS-CoV-2; however, expression of ACE2 in bile duct cells is “much higher” than in liver cells, and comparable with alveolar type 2 cells in the lungs.

“Bile duct epithelial cells are known to play important roles in liver regeneration and immune response,” the investigators noted.

Beyond direct- and immune-induced effects of COVID-19, postmortem findings suggest that drug-induced liver injury may also be a possibility, with a number of theoretical culprits, including antibiotics, steroids, and antivirals. Although the investigators emphasized that data are insufficient to pinpoint an exact agent, they highlighted a recent preprint study, which reported a significantly higher rate of lopinavir/ritonavir administration among patients with abnormal liver function, compared with those who had normal liver function (56.1% vs. 25%; P = .009).

“Drug-induced liver injury during the treatment of coronavirus infection should not be ignored and needs to be carefully investigated,” the investigators concluded.

Fundamental Research Funds for the Central Universities supported the work. The investigators reported no conflicts of interest.

SOURCE: Xu L et al. Liver Int. 2020 Mar 14. doi: 10.1111/liv.14435.

Patients with COVID-19 may be at risk for liver injury, but mechanisms of damage remain unclear, according to investigators.

Proposed mechanisms include direct virus-induced effects, immune-induced damage due to excessive inflammatory responses, and drug-induced injury, reported lead author Ling Xu of Huazhong University of Science and Technology, Wuhan, China, and colleagues.

“From a clinical perspective, in addition to actively dealing with the primary disease caused by coronavirus infection, attention should also be paid to monitor the occurrence of liver injury, and to the application of drugs which may induce liver damage,” the investigators wrote in Liver International. “Patients with liver damage are advised to be treated with drugs that could both protect liver functions and inhibit inflammatory responses, such as ammonium glycyrrhizinate, which may, in turn, accelerate the process of disease recovery.”

The review of liver injury associated with major pathogenic coronaviruses included severe acute respiratory syndrome coronavirus (SARS-CoV), the Middle East respiratory syndrome coronavirus (MERS-CoV), and the newly emergent SARS-CoV-2, which causes COVID-19.

In cases of COVID-19, reported incidence of liver injury ranges from 15% to 53%, based on elevations of alanine transaminase (ALT) and aspartate aminotransferase (AST), along with slightly elevated bilirubin levels. In severe cases, albumin decreases have also been documented.

Liver injury appears to be significantly more common among those with severe infection. In one cohort of 82 patients who died from COVID-19, the incidence of liver injury was 78%, while another study of 36 nonsurvivors reported a rate of 58%.

According to the investigators, both bile duct epithelial cells and liver cells express angiotensin converting enzyme II (ACE2), which is an entry receptor for SARS-CoV-2; however, expression of ACE2 in bile duct cells is “much higher” than in liver cells, and comparable with alveolar type 2 cells in the lungs.

“Bile duct epithelial cells are known to play important roles in liver regeneration and immune response,” the investigators noted.

Beyond direct- and immune-induced effects of COVID-19, postmortem findings suggest that drug-induced liver injury may also be a possibility, with a number of theoretical culprits, including antibiotics, steroids, and antivirals. Although the investigators emphasized that data are insufficient to pinpoint an exact agent, they highlighted a recent preprint study, which reported a significantly higher rate of lopinavir/ritonavir administration among patients with abnormal liver function, compared with those who had normal liver function (56.1% vs. 25%; P = .009).

“Drug-induced liver injury during the treatment of coronavirus infection should not be ignored and needs to be carefully investigated,” the investigators concluded.

Fundamental Research Funds for the Central Universities supported the work. The investigators reported no conflicts of interest.

SOURCE: Xu L et al. Liver Int. 2020 Mar 14. doi: 10.1111/liv.14435.

In a JAMA Live Stream interview, Anthony S. Fauci, MD, a key member of the White House Coronavirus Task Force, urged resolve, rather than panic, as the coronavirus pandemic takes hold in the United States.

Dr. Fauci got into the details of what is known, what is unknown, what is being done in laboratories, and what clinical elements are still not understood about this disease.

The next several weeks, he said, are likely to tell the tale of whether our health care system is up to the challenge of care for the most ill among those who will be affected by COVID-19.

“It shouldn’t panic or frighten us, but we have to know we’re dealing with a very serious problem that we have to address, and we have to deal with it in a very bold way,” said Dr. Fauci, director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health.

Speaking in an interview with JAMA Editor in Chief Howard Bauchner, MD, Dr. Fauci said the situation favors action over fear. “Let’s apply that energy to doing the things that we know can mitigate this.”

He added that he heard the message loud and clear from health care leaders in Italy and France during a World Health Organization coronavirus call earlier in the day. Officials in those countries, he said, were “almost pleading with the rest of the world to please take this very seriously, because it happens all of a sudden – very abruptly. ... The best time to mitigate is before that happens, because if you wait until after it happens you’re playing catch-up.”

Dr. Bauchner, noting that strict social distancing has been underway in many parts of the United States for several days, posited that, by early April, “We’ll really have a sense if we can manage in terms of serious illness.” Seattle, New York, Boston, and the San Francisco Bay Area may experience demand that outstrips ICU capacity at that point, but the rest of the country, he said, “is doing relatively well.”
 

Stress test on the health care system

Dr. Fauci agreed with this statement and added: “We’re going to know – for better or worse – whether we have enough of what it takes to be able to practice the kind of medicine that we optimally would want to practice.

In the matter of a week or 2 ... I think we’ll get a feel for whether or not we really have enough of the supplies that it takes.”

The well-publicized regional shortages in personal protective equipment (PPE) are forcing tough choices in some areas. As expedited – and even drive-through – testing begins, some of the demand for testing-related PPE may abate, especially if protocols include self-administration of nasal swabs, he noted.

Dr. Fauci added that the strategic national stockpile of medical supplies and equipment has not yet been tapped, “but you need to backfill that as quickly as you can once you start drawing from the strategic national stockpile.”
 

Returning to work after COVID-19 infection

Regarding the thorny question of when health care workers should be permitted to return to work after coronavirus infection, “it’s an evolving story,” said Dr. Fauci. Current guidance advises that health care providers stay away from work until two negative tests after resolution of fever and improvement of respiratory symptoms, or 3 fever-free days.

“We are approaching a point where you’re going to get enough people who are getting infected that we aren’t going to be able to do that,” he said. Depending on the stress to the health care system in a given locality, he said that facilities are going to have to “decide with good judgment” when health care workers go back on the job after coronavirus infection.

Asked how soon an individual would reliably test positive for COVID-19 after exposure, Dr. Fauci said, “We don’t know the answer to that. ... We can surmise it ...” He noted that it’s a median of about 5 days with a range of 2 to 14 days, before an infected individual becomes symptomatic. “I can say it’s not going to happen immediately,” he added, noting that he wouldn’t expect to see a positive test until about 2 days after exposure at the earliest. “When you get to the point where you are symptomatic, you’re almost certainly going to be positive then. ... This is just an extrapolation,” rather than conclusions drawn from solid data, he emphasized.
 

Higher risk reported in cardiac patients

Dr. Bauchner, who was relaying questions sent in from physicians during the live-streamed interview, asked about a newly issued joint statement from the American Heart Association, American College of Cardiology, and the Heart Failure Society of America, which on March 17 affirmed that individuals on ACE inhibitors and angiotensin receptor blockers (ARBs) continue that therapy if they should become ill with COVID-19. The European Society of Cardiology issued a similar recommendation a few days prior.

Despite these societies’ statements, Dr. Fauci pointed to population-level data in Italy as suggesting that the case isn’t yet closed. “We really need to get data, and we need to get data fast. There’s a mechanistic rationale for the concern. It’s there, and it’s firm,” he said. The theoretical concern is that ACE inhibitors can upregulate expression of the ACE-2 protein on cell membranes, which is the entry point for SARS-Cov-2 to enter cells.

He added that he remains concerned about the number of coronavirus fatalities of patients in Italy who had hypertension as their only, or primary, underlying health problem.“That to me was a bit of a red flag,” he said. “Patients with hypertension almost certainly had a physician, and the physician almost certainly treated that person with medication. Why should someone who has hypertension that was well controlled have a much greater chance of dying?” he asked, noting that “I look at a person with well-controlled hypertension as a relatively healthy person. I don’t know what the answer is, but somebody has to look very carefully,” ideally by means of a natural history study that identifies medications used by those who died from coronavirus.
 

Potential therapies

Regarding potential therapies for COVID-19, Dr. Fauci acknowledged the social media buzz and flurry of medical letters and case reports about the use of hydroxychloroquine (Plaquenil) to treat active infection. He said that he and other researchers are “in active discussion” about how best to study the efficacy and safety of hydroxychloroquine, but he also acknowledged that many treating clinicians will use hydroxychloroquine empirically in the absence of other treatments with proven efficacy.

Clinical trials underway in China for antiviral medication are facing some enrollment challenges currently “because people want to get the drug,” said Dr. Fauci. “They don’t want to be in the trial; they just want to get the drug.” Though each of two trials has targeted approximately 500 participants as the number needed for sufficient statistical power, Dr. Fauci urged Chinese data safety monitoring boards to “take a close look” at the data already accrued for the several hundred patients who have already enrolled for the studies “to see if there’s any hint of efficacy.”

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In a JAMA Live Stream interview, Anthony S. Fauci, MD, a key member of the White House Coronavirus Task Force, urged resolve, rather than panic, as the coronavirus pandemic takes hold in the United States.

Dr. Fauci got into the details of what is known, what is unknown, what is being done in laboratories, and what clinical elements are still not understood about this disease.

The next several weeks, he said, are likely to tell the tale of whether our health care system is up to the challenge of care for the most ill among those who will be affected by COVID-19.

“It shouldn’t panic or frighten us, but we have to know we’re dealing with a very serious problem that we have to address, and we have to deal with it in a very bold way,” said Dr. Fauci, director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health.

Speaking in an interview with JAMA Editor in Chief Howard Bauchner, MD, Dr. Fauci said the situation favors action over fear. “Let’s apply that energy to doing the things that we know can mitigate this.”

He added that he heard the message loud and clear from health care leaders in Italy and France during a World Health Organization coronavirus call earlier in the day. Officials in those countries, he said, were “almost pleading with the rest of the world to please take this very seriously, because it happens all of a sudden – very abruptly. ... The best time to mitigate is before that happens, because if you wait until after it happens you’re playing catch-up.”

Dr. Bauchner, noting that strict social distancing has been underway in many parts of the United States for several days, posited that, by early April, “We’ll really have a sense if we can manage in terms of serious illness.” Seattle, New York, Boston, and the San Francisco Bay Area may experience demand that outstrips ICU capacity at that point, but the rest of the country, he said, “is doing relatively well.”
 

Stress test on the health care system

Dr. Fauci agreed with this statement and added: “We’re going to know – for better or worse – whether we have enough of what it takes to be able to practice the kind of medicine that we optimally would want to practice.

In the matter of a week or 2 ... I think we’ll get a feel for whether or not we really have enough of the supplies that it takes.”

The well-publicized regional shortages in personal protective equipment (PPE) are forcing tough choices in some areas. As expedited – and even drive-through – testing begins, some of the demand for testing-related PPE may abate, especially if protocols include self-administration of nasal swabs, he noted.

Dr. Fauci added that the strategic national stockpile of medical supplies and equipment has not yet been tapped, “but you need to backfill that as quickly as you can once you start drawing from the strategic national stockpile.”
 

Returning to work after COVID-19 infection

Regarding the thorny question of when health care workers should be permitted to return to work after coronavirus infection, “it’s an evolving story,” said Dr. Fauci. Current guidance advises that health care providers stay away from work until two negative tests after resolution of fever and improvement of respiratory symptoms, or 3 fever-free days.

“We are approaching a point where you’re going to get enough people who are getting infected that we aren’t going to be able to do that,” he said. Depending on the stress to the health care system in a given locality, he said that facilities are going to have to “decide with good judgment” when health care workers go back on the job after coronavirus infection.

Asked how soon an individual would reliably test positive for COVID-19 after exposure, Dr. Fauci said, “We don’t know the answer to that. ... We can surmise it ...” He noted that it’s a median of about 5 days with a range of 2 to 14 days, before an infected individual becomes symptomatic. “I can say it’s not going to happen immediately,” he added, noting that he wouldn’t expect to see a positive test until about 2 days after exposure at the earliest. “When you get to the point where you are symptomatic, you’re almost certainly going to be positive then. ... This is just an extrapolation,” rather than conclusions drawn from solid data, he emphasized.
 

Higher risk reported in cardiac patients

Dr. Bauchner, who was relaying questions sent in from physicians during the live-streamed interview, asked about a newly issued joint statement from the American Heart Association, American College of Cardiology, and the Heart Failure Society of America, which on March 17 affirmed that individuals on ACE inhibitors and angiotensin receptor blockers (ARBs) continue that therapy if they should become ill with COVID-19. The European Society of Cardiology issued a similar recommendation a few days prior.

Despite these societies’ statements, Dr. Fauci pointed to population-level data in Italy as suggesting that the case isn’t yet closed. “We really need to get data, and we need to get data fast. There’s a mechanistic rationale for the concern. It’s there, and it’s firm,” he said. The theoretical concern is that ACE inhibitors can upregulate expression of the ACE-2 protein on cell membranes, which is the entry point for SARS-Cov-2 to enter cells.

He added that he remains concerned about the number of coronavirus fatalities of patients in Italy who had hypertension as their only, or primary, underlying health problem.“That to me was a bit of a red flag,” he said. “Patients with hypertension almost certainly had a physician, and the physician almost certainly treated that person with medication. Why should someone who has hypertension that was well controlled have a much greater chance of dying?” he asked, noting that “I look at a person with well-controlled hypertension as a relatively healthy person. I don’t know what the answer is, but somebody has to look very carefully,” ideally by means of a natural history study that identifies medications used by those who died from coronavirus.
 

Potential therapies

Regarding potential therapies for COVID-19, Dr. Fauci acknowledged the social media buzz and flurry of medical letters and case reports about the use of hydroxychloroquine (Plaquenil) to treat active infection. He said that he and other researchers are “in active discussion” about how best to study the efficacy and safety of hydroxychloroquine, but he also acknowledged that many treating clinicians will use hydroxychloroquine empirically in the absence of other treatments with proven efficacy.

Clinical trials underway in China for antiviral medication are facing some enrollment challenges currently “because people want to get the drug,” said Dr. Fauci. “They don’t want to be in the trial; they just want to get the drug.” Though each of two trials has targeted approximately 500 participants as the number needed for sufficient statistical power, Dr. Fauci urged Chinese data safety monitoring boards to “take a close look” at the data already accrued for the several hundred patients who have already enrolled for the studies “to see if there’s any hint of efficacy.”

[email protected]

In a JAMA Live Stream interview, Anthony S. Fauci, MD, a key member of the White House Coronavirus Task Force, urged resolve, rather than panic, as the coronavirus pandemic takes hold in the United States.

Dr. Fauci got into the details of what is known, what is unknown, what is being done in laboratories, and what clinical elements are still not understood about this disease.

The next several weeks, he said, are likely to tell the tale of whether our health care system is up to the challenge of care for the most ill among those who will be affected by COVID-19.

“It shouldn’t panic or frighten us, but we have to know we’re dealing with a very serious problem that we have to address, and we have to deal with it in a very bold way,” said Dr. Fauci, director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health.

Speaking in an interview with JAMA Editor in Chief Howard Bauchner, MD, Dr. Fauci said the situation favors action over fear. “Let’s apply that energy to doing the things that we know can mitigate this.”

He added that he heard the message loud and clear from health care leaders in Italy and France during a World Health Organization coronavirus call earlier in the day. Officials in those countries, he said, were “almost pleading with the rest of the world to please take this very seriously, because it happens all of a sudden – very abruptly. ... The best time to mitigate is before that happens, because if you wait until after it happens you’re playing catch-up.”

Dr. Bauchner, noting that strict social distancing has been underway in many parts of the United States for several days, posited that, by early April, “We’ll really have a sense if we can manage in terms of serious illness.” Seattle, New York, Boston, and the San Francisco Bay Area may experience demand that outstrips ICU capacity at that point, but the rest of the country, he said, “is doing relatively well.”
 

Stress test on the health care system

Dr. Fauci agreed with this statement and added: “We’re going to know – for better or worse – whether we have enough of what it takes to be able to practice the kind of medicine that we optimally would want to practice.

In the matter of a week or 2 ... I think we’ll get a feel for whether or not we really have enough of the supplies that it takes.”

The well-publicized regional shortages in personal protective equipment (PPE) are forcing tough choices in some areas. As expedited – and even drive-through – testing begins, some of the demand for testing-related PPE may abate, especially if protocols include self-administration of nasal swabs, he noted.

Dr. Fauci added that the strategic national stockpile of medical supplies and equipment has not yet been tapped, “but you need to backfill that as quickly as you can once you start drawing from the strategic national stockpile.”
 

Returning to work after COVID-19 infection

Regarding the thorny question of when health care workers should be permitted to return to work after coronavirus infection, “it’s an evolving story,” said Dr. Fauci. Current guidance advises that health care providers stay away from work until two negative tests after resolution of fever and improvement of respiratory symptoms, or 3 fever-free days.

“We are approaching a point where you’re going to get enough people who are getting infected that we aren’t going to be able to do that,” he said. Depending on the stress to the health care system in a given locality, he said that facilities are going to have to “decide with good judgment” when health care workers go back on the job after coronavirus infection.

Asked how soon an individual would reliably test positive for COVID-19 after exposure, Dr. Fauci said, “We don’t know the answer to that. ... We can surmise it ...” He noted that it’s a median of about 5 days with a range of 2 to 14 days, before an infected individual becomes symptomatic. “I can say it’s not going to happen immediately,” he added, noting that he wouldn’t expect to see a positive test until about 2 days after exposure at the earliest. “When you get to the point where you are symptomatic, you’re almost certainly going to be positive then. ... This is just an extrapolation,” rather than conclusions drawn from solid data, he emphasized.
 

Higher risk reported in cardiac patients

Dr. Bauchner, who was relaying questions sent in from physicians during the live-streamed interview, asked about a newly issued joint statement from the American Heart Association, American College of Cardiology, and the Heart Failure Society of America, which on March 17 affirmed that individuals on ACE inhibitors and angiotensin receptor blockers (ARBs) continue that therapy if they should become ill with COVID-19. The European Society of Cardiology issued a similar recommendation a few days prior.

Despite these societies’ statements, Dr. Fauci pointed to population-level data in Italy as suggesting that the case isn’t yet closed. “We really need to get data, and we need to get data fast. There’s a mechanistic rationale for the concern. It’s there, and it’s firm,” he said. The theoretical concern is that ACE inhibitors can upregulate expression of the ACE-2 protein on cell membranes, which is the entry point for SARS-Cov-2 to enter cells.

He added that he remains concerned about the number of coronavirus fatalities of patients in Italy who had hypertension as their only, or primary, underlying health problem.“That to me was a bit of a red flag,” he said. “Patients with hypertension almost certainly had a physician, and the physician almost certainly treated that person with medication. Why should someone who has hypertension that was well controlled have a much greater chance of dying?” he asked, noting that “I look at a person with well-controlled hypertension as a relatively healthy person. I don’t know what the answer is, but somebody has to look very carefully,” ideally by means of a natural history study that identifies medications used by those who died from coronavirus.
 

Potential therapies

Regarding potential therapies for COVID-19, Dr. Fauci acknowledged the social media buzz and flurry of medical letters and case reports about the use of hydroxychloroquine (Plaquenil) to treat active infection. He said that he and other researchers are “in active discussion” about how best to study the efficacy and safety of hydroxychloroquine, but he also acknowledged that many treating clinicians will use hydroxychloroquine empirically in the absence of other treatments with proven efficacy.

Clinical trials underway in China for antiviral medication are facing some enrollment challenges currently “because people want to get the drug,” said Dr. Fauci. “They don’t want to be in the trial; they just want to get the drug.” Though each of two trials has targeted approximately 500 participants as the number needed for sufficient statistical power, Dr. Fauci urged Chinese data safety monitoring boards to “take a close look” at the data already accrued for the several hundred patients who have already enrolled for the studies “to see if there’s any hint of efficacy.”

[email protected]

Clinical manifestations of COVID-19 infection among children in mainland China generally have been less severe than those among adults, but children of all ages – and infants in particular – are vulnerable to infection, according to a review of 2,143 cases.

CDC/ Dr. Fred Murphy; Sylvia Whitfield

Further, infection patterns in the nationwide series of all pediatric patients reported to the Chinese Center for Disease Control and Prevention from Jan. 16 to Feb. 8, 2020, provide strong evidence of human-to-human transmission, Yuanyuan Dong, MPH, a research assistant at Shanghai Children’s Medical Center, Shanghai Jiao Tong University, China, and colleagues reported in Pediatrics.

Of the 2,143 patients included in the review, 57% were boys and the median age was 7 years; 34% had laboratory-confirmed infection and 67% had suspected infection. More than 90% had asymptomatic, mild, or moderate disease (4%, 51%, and 39%, respectively), and 46% were from Hubei Province, where the first cases were reported, the investigators found.

The median time from illness onset to diagnosis was 2 days, and there was a trend of rapid increase of disease at the early stage of the epidemic – with rapid spread from Hubei Province to surrounding provinces – followed by a gradual and steady decrease, they noted.

“The total number of pediatric patients increased remarkably between mid-January and early February, peaked around February 1, and then declined since early February 2020,” they wrote. The proportion of severe and critical cases was 11% for infants under 1 year of age, compared with 7% for those aged 1-5 years; 4% for those aged 6-10 years; 4% for those 11-15 years; and 3% for those 16 years and older.

As of Feb. 8, 2020, only one child in this group of study patients died and most cases of COVID-19 symptoms were mild. There were many fewer severe and critical cases among the children (6%), compared with those reported in adult patients in other studies (19%). “It suggests that, compared with adult patients, clinical manifestations of children’s COVID-19 may be less severe,” the investigators suggested.

“As most of these children were likely to expose themselves to family members and/or other children with COVID-19, it clearly indicates person-to-person transmission ” of novel coronavirus 2019, they said, adding that similar evidence of such transmission also has been reported from studies of adult patients.

The reasons for reduced severity in children versus adults remain unclear, but may be related to both exposure and host factors, Ms. Dong and associates said. “Children were usually well cared for at home and might have relatively [fewer] opportunities to expose themselves to pathogens and/or sick patients.”

The findings demonstrate a pediatric distribution that varied across time and space, with most cases concentrated in the Hubei province and surrounding areas. No significant gender-related difference in infection rates was observed, and although the median patient age was 7 years, the range was 1 day to 18 years, suggesting that “all ages at childhood were susceptible” to the virus, they added.

The declining number of cases over time further suggests that disease control measures implemented by the government were effective, and that cases will “continue to decline, and finally stop in the near future unless sustained human-to-human transmissions occur,” Ms. Dong and associates concluded.

In an accompanying editorial, Andrea T. Cruz, MD, of Baylor College of Medicine, Houston, and Steven L. Zeichner, MD, PhD, of the University of Virginia, Charlottesville, said the findings regarding reduced severity among children versus adults with novel coronavirus 2019 infection are consistent with data on non-COVID-19 coronavirus.

They pointed out that Ms. Dong and associates did find that 13% of virologically-confirmed cases had asymptomatic infection, “a rate that almost certainly understates the true rate of asymptomatic infection, since many asymptomatic children are unlikely to be tested.”

Of the symptomatic children, “5% had dyspnea or hypoxemia (a substantially lower percentage than what has been reported for adults) and 0.6% progressed to acute respiratory distress syndrome (ARDS) or multiorgan system dysfunction”; this also is at a lower rate than seen in adults, they said.

Very young children –infants or children in preschool – were more likely to have severe clinical manifestations than children who were older.

Thus, it appears that certain subpopulations of children are at increased risk for more significant COVID-19 illness: “younger age, underlying pulmonary pathology, and immunocompromising conditions,” Dr. Cruz and Dr. Zeichner suggested.

The two editorialists said the findings suggest children “may play a major role in community-based viral transmission.” Evidence suggests that children may have more upper respiratory tract involvement and that fecal shedding may occur for several weeks after diagnosis; this raises concerns about fecal-oral transmission, particularly for infants and children, and about viral replication in the gastrointestinal tract, they said. This has substantial implications for community spread in day care centers, schools, and in the home.

A great deal has been learned about COVID-19 in a short time, but there still is much to learn about the effect of the virus on children, the impact of children on viral spread, and about possible vertical transmission, they said.

“Widespread availability of testing will allow for us to more accurately describe the spectrum of illness and may result in adjustment of the apparent morbidity and mortality rate as fewer ill individuals are diagnosed,” Dr. Cruz and Dr. Zeichner wrote, adding that “rigorously gauging the impact of COVID-19 on children will be important to accurately model the pandemic and to ensure that appropriate resources are allocated to children requiring care.”

They noted that understanding differences in children versus adults with COVID-19 “can yield important insights into disease pathogenesis, informing management and the development of therapeutics.”

This study was partially supported by the Science and Technology Commission of Shanghai Municipality. The authors reported having no disclosures. Dr. Cruz and Dr. Zeichner are associate editors for Pediatrics. Dr. Cruz reported having no disclosures. Dr. Zeichner is an inventor of new technologies for the rapid production of vaccines, for which the University of Virginia has filed patent applications.

[email protected]

SOURCE: Dong Y et al. Pediatrics. 2020 Mar 16. doi: 10.1542/peds.2020-0702; Cruz A and Zeichner S. Pediatrics. 2020 Mar 16. doi: 10.1542/peds.2020-0834.

Clinical manifestations of COVID-19 infection among children in mainland China generally have been less severe than those among adults, but children of all ages – and infants in particular – are vulnerable to infection, according to a review of 2,143 cases.

CDC/ Dr. Fred Murphy; Sylvia Whitfield

Further, infection patterns in the nationwide series of all pediatric patients reported to the Chinese Center for Disease Control and Prevention from Jan. 16 to Feb. 8, 2020, provide strong evidence of human-to-human transmission, Yuanyuan Dong, MPH, a research assistant at Shanghai Children’s Medical Center, Shanghai Jiao Tong University, China, and colleagues reported in Pediatrics.

Of the 2,143 patients included in the review, 57% were boys and the median age was 7 years; 34% had laboratory-confirmed infection and 67% had suspected infection. More than 90% had asymptomatic, mild, or moderate disease (4%, 51%, and 39%, respectively), and 46% were from Hubei Province, where the first cases were reported, the investigators found.

The median time from illness onset to diagnosis was 2 days, and there was a trend of rapid increase of disease at the early stage of the epidemic – with rapid spread from Hubei Province to surrounding provinces – followed by a gradual and steady decrease, they noted.

“The total number of pediatric patients increased remarkably between mid-January and early February, peaked around February 1, and then declined since early February 2020,” they wrote. The proportion of severe and critical cases was 11% for infants under 1 year of age, compared with 7% for those aged 1-5 years; 4% for those aged 6-10 years; 4% for those 11-15 years; and 3% for those 16 years and older.

As of Feb. 8, 2020, only one child in this group of study patients died and most cases of COVID-19 symptoms were mild. There were many fewer severe and critical cases among the children (6%), compared with those reported in adult patients in other studies (19%). “It suggests that, compared with adult patients, clinical manifestations of children’s COVID-19 may be less severe,” the investigators suggested.

“As most of these children were likely to expose themselves to family members and/or other children with COVID-19, it clearly indicates person-to-person transmission ” of novel coronavirus 2019, they said, adding that similar evidence of such transmission also has been reported from studies of adult patients.

The reasons for reduced severity in children versus adults remain unclear, but may be related to both exposure and host factors, Ms. Dong and associates said. “Children were usually well cared for at home and might have relatively [fewer] opportunities to expose themselves to pathogens and/or sick patients.”

The findings demonstrate a pediatric distribution that varied across time and space, with most cases concentrated in the Hubei province and surrounding areas. No significant gender-related difference in infection rates was observed, and although the median patient age was 7 years, the range was 1 day to 18 years, suggesting that “all ages at childhood were susceptible” to the virus, they added.

The declining number of cases over time further suggests that disease control measures implemented by the government were effective, and that cases will “continue to decline, and finally stop in the near future unless sustained human-to-human transmissions occur,” Ms. Dong and associates concluded.

In an accompanying editorial, Andrea T. Cruz, MD, of Baylor College of Medicine, Houston, and Steven L. Zeichner, MD, PhD, of the University of Virginia, Charlottesville, said the findings regarding reduced severity among children versus adults with novel coronavirus 2019 infection are consistent with data on non-COVID-19 coronavirus.

They pointed out that Ms. Dong and associates did find that 13% of virologically-confirmed cases had asymptomatic infection, “a rate that almost certainly understates the true rate of asymptomatic infection, since many asymptomatic children are unlikely to be tested.”

Of the symptomatic children, “5% had dyspnea or hypoxemia (a substantially lower percentage than what has been reported for adults) and 0.6% progressed to acute respiratory distress syndrome (ARDS) or multiorgan system dysfunction”; this also is at a lower rate than seen in adults, they said.

Very young children –infants or children in preschool – were more likely to have severe clinical manifestations than children who were older.

Thus, it appears that certain subpopulations of children are at increased risk for more significant COVID-19 illness: “younger age, underlying pulmonary pathology, and immunocompromising conditions,” Dr. Cruz and Dr. Zeichner suggested.

The two editorialists said the findings suggest children “may play a major role in community-based viral transmission.” Evidence suggests that children may have more upper respiratory tract involvement and that fecal shedding may occur for several weeks after diagnosis; this raises concerns about fecal-oral transmission, particularly for infants and children, and about viral replication in the gastrointestinal tract, they said. This has substantial implications for community spread in day care centers, schools, and in the home.

A great deal has been learned about COVID-19 in a short time, but there still is much to learn about the effect of the virus on children, the impact of children on viral spread, and about possible vertical transmission, they said.

“Widespread availability of testing will allow for us to more accurately describe the spectrum of illness and may result in adjustment of the apparent morbidity and mortality rate as fewer ill individuals are diagnosed,” Dr. Cruz and Dr. Zeichner wrote, adding that “rigorously gauging the impact of COVID-19 on children will be important to accurately model the pandemic and to ensure that appropriate resources are allocated to children requiring care.”

They noted that understanding differences in children versus adults with COVID-19 “can yield important insights into disease pathogenesis, informing management and the development of therapeutics.”

This study was partially supported by the Science and Technology Commission of Shanghai Municipality. The authors reported having no disclosures. Dr. Cruz and Dr. Zeichner are associate editors for Pediatrics. Dr. Cruz reported having no disclosures. Dr. Zeichner is an inventor of new technologies for the rapid production of vaccines, for which the University of Virginia has filed patent applications.

[email protected]

SOURCE: Dong Y et al. Pediatrics. 2020 Mar 16. doi: 10.1542/peds.2020-0702; Cruz A and Zeichner S. Pediatrics. 2020 Mar 16. doi: 10.1542/peds.2020-0834.

Clinical manifestations of COVID-19 infection among children in mainland China generally have been less severe than those among adults, but children of all ages – and infants in particular – are vulnerable to infection, according to a review of 2,143 cases.

CDC/ Dr. Fred Murphy; Sylvia Whitfield

Further, infection patterns in the nationwide series of all pediatric patients reported to the Chinese Center for Disease Control and Prevention from Jan. 16 to Feb. 8, 2020, provide strong evidence of human-to-human transmission, Yuanyuan Dong, MPH, a research assistant at Shanghai Children’s Medical Center, Shanghai Jiao Tong University, China, and colleagues reported in Pediatrics.

Of the 2,143 patients included in the review, 57% were boys and the median age was 7 years; 34% had laboratory-confirmed infection and 67% had suspected infection. More than 90% had asymptomatic, mild, or moderate disease (4%, 51%, and 39%, respectively), and 46% were from Hubei Province, where the first cases were reported, the investigators found.

The median time from illness onset to diagnosis was 2 days, and there was a trend of rapid increase of disease at the early stage of the epidemic – with rapid spread from Hubei Province to surrounding provinces – followed by a gradual and steady decrease, they noted.

“The total number of pediatric patients increased remarkably between mid-January and early February, peaked around February 1, and then declined since early February 2020,” they wrote. The proportion of severe and critical cases was 11% for infants under 1 year of age, compared with 7% for those aged 1-5 years; 4% for those aged 6-10 years; 4% for those 11-15 years; and 3% for those 16 years and older.

As of Feb. 8, 2020, only one child in this group of study patients died and most cases of COVID-19 symptoms were mild. There were many fewer severe and critical cases among the children (6%), compared with those reported in adult patients in other studies (19%). “It suggests that, compared with adult patients, clinical manifestations of children’s COVID-19 may be less severe,” the investigators suggested.

“As most of these children were likely to expose themselves to family members and/or other children with COVID-19, it clearly indicates person-to-person transmission ” of novel coronavirus 2019, they said, adding that similar evidence of such transmission also has been reported from studies of adult patients.

The reasons for reduced severity in children versus adults remain unclear, but may be related to both exposure and host factors, Ms. Dong and associates said. “Children were usually well cared for at home and might have relatively [fewer] opportunities to expose themselves to pathogens and/or sick patients.”

The findings demonstrate a pediatric distribution that varied across time and space, with most cases concentrated in the Hubei province and surrounding areas. No significant gender-related difference in infection rates was observed, and although the median patient age was 7 years, the range was 1 day to 18 years, suggesting that “all ages at childhood were susceptible” to the virus, they added.

The declining number of cases over time further suggests that disease control measures implemented by the government were effective, and that cases will “continue to decline, and finally stop in the near future unless sustained human-to-human transmissions occur,” Ms. Dong and associates concluded.

In an accompanying editorial, Andrea T. Cruz, MD, of Baylor College of Medicine, Houston, and Steven L. Zeichner, MD, PhD, of the University of Virginia, Charlottesville, said the findings regarding reduced severity among children versus adults with novel coronavirus 2019 infection are consistent with data on non-COVID-19 coronavirus.

They pointed out that Ms. Dong and associates did find that 13% of virologically-confirmed cases had asymptomatic infection, “a rate that almost certainly understates the true rate of asymptomatic infection, since many asymptomatic children are unlikely to be tested.”

Of the symptomatic children, “5% had dyspnea or hypoxemia (a substantially lower percentage than what has been reported for adults) and 0.6% progressed to acute respiratory distress syndrome (ARDS) or multiorgan system dysfunction”; this also is at a lower rate than seen in adults, they said.

Very young children –infants or children in preschool – were more likely to have severe clinical manifestations than children who were older.

Thus, it appears that certain subpopulations of children are at increased risk for more significant COVID-19 illness: “younger age, underlying pulmonary pathology, and immunocompromising conditions,” Dr. Cruz and Dr. Zeichner suggested.

The two editorialists said the findings suggest children “may play a major role in community-based viral transmission.” Evidence suggests that children may have more upper respiratory tract involvement and that fecal shedding may occur for several weeks after diagnosis; this raises concerns about fecal-oral transmission, particularly for infants and children, and about viral replication in the gastrointestinal tract, they said. This has substantial implications for community spread in day care centers, schools, and in the home.

A great deal has been learned about COVID-19 in a short time, but there still is much to learn about the effect of the virus on children, the impact of children on viral spread, and about possible vertical transmission, they said.

“Widespread availability of testing will allow for us to more accurately describe the spectrum of illness and may result in adjustment of the apparent morbidity and mortality rate as fewer ill individuals are diagnosed,” Dr. Cruz and Dr. Zeichner wrote, adding that “rigorously gauging the impact of COVID-19 on children will be important to accurately model the pandemic and to ensure that appropriate resources are allocated to children requiring care.”

They noted that understanding differences in children versus adults with COVID-19 “can yield important insights into disease pathogenesis, informing management and the development of therapeutics.”

This study was partially supported by the Science and Technology Commission of Shanghai Municipality. The authors reported having no disclosures. Dr. Cruz and Dr. Zeichner are associate editors for Pediatrics. Dr. Cruz reported having no disclosures. Dr. Zeichner is an inventor of new technologies for the rapid production of vaccines, for which the University of Virginia has filed patent applications.

[email protected]

SOURCE: Dong Y et al. Pediatrics. 2020 Mar 16. doi: 10.1542/peds.2020-0702; Cruz A and Zeichner S. Pediatrics. 2020 Mar 16. doi: 10.1542/peds.2020-0834.

The American College of Physicians has published tips for medical practices related to billing and coding for telehealth, and for handling clinician and staff absences due to illness or quarantine during the COVID-19 pandemic.

It strongly encourages practices to use telehealth, whenever possible, to mitigate exposure of patients who are sick or at risk because of other underlying conditions and to protect health care workers and the community from the spread of the disease.

The national organization of internists also recommends in the guidance that practices establish protocols and procedures for use by clinicians and all other staff in light of the pandemic.

The billing and coding tips are being offered to help practices deal with the rapidly changing situation surrounding the COVID-19 emergency, according to a statement from the ACP.

The coding-related guidance incorporates changes to a number of telehealth rules for Medicare beneficiaries, announced by the Centers for Medicare and Medicaid Services on March 17.

“Now in a full state of emergency, many Medicare restrictions related to telehealth have been lifted. Patients can be at home, and non-HIPAA compliant technology is allowed. There is no cost sharing for COVID-19 testing. In addition, to encourage use by patients, Medicare is allowing practices to waive cost sharing (copays and deductibles) for all telehealth services,” the organization said in the guidance. It notes, however, that the CMS does not currently reimburse for telephone calls.

The guidance includes details of the new ICD-10 codes, and stresses the importance of using the appropriate codes, given that some service cost-sharing has been waived for COVID-19 testing and treatment.

There is detailed coding guidance for virtual check-in, online evaluation and management, remote monitoring, originating site, and allowed technology and services.

In regard to clinician and staff absence due to illness or quarantine, the ACP says “practices may need to review emergency plans related to telework and to employee and clinician absence.” Among its recommendations are that practices and employers consider temporary adjustments to compensation formulas to accommodate those clinicians who experience a loss of income because they are paid based on production.

The organization emphasizes that, given the rapidly changing availability of testing for COVID-19, practices should contact their local health departments, hospitals, reference labs, or state health authorities to determine the status of their access to testing.

The full list of the ACP’s tips are available here.

Any new guidance for physicians will be posted on the ACP’s COVID-19 resource page.

[email protected]

The American College of Physicians has published tips for medical practices related to billing and coding for telehealth, and for handling clinician and staff absences due to illness or quarantine during the COVID-19 pandemic.

It strongly encourages practices to use telehealth, whenever possible, to mitigate exposure of patients who are sick or at risk because of other underlying conditions and to protect health care workers and the community from the spread of the disease.

The national organization of internists also recommends in the guidance that practices establish protocols and procedures for use by clinicians and all other staff in light of the pandemic.

The billing and coding tips are being offered to help practices deal with the rapidly changing situation surrounding the COVID-19 emergency, according to a statement from the ACP.

The coding-related guidance incorporates changes to a number of telehealth rules for Medicare beneficiaries, announced by the Centers for Medicare and Medicaid Services on March 17.

“Now in a full state of emergency, many Medicare restrictions related to telehealth have been lifted. Patients can be at home, and non-HIPAA compliant technology is allowed. There is no cost sharing for COVID-19 testing. In addition, to encourage use by patients, Medicare is allowing practices to waive cost sharing (copays and deductibles) for all telehealth services,” the organization said in the guidance. It notes, however, that the CMS does not currently reimburse for telephone calls.

The guidance includes details of the new ICD-10 codes, and stresses the importance of using the appropriate codes, given that some service cost-sharing has been waived for COVID-19 testing and treatment.

There is detailed coding guidance for virtual check-in, online evaluation and management, remote monitoring, originating site, and allowed technology and services.

In regard to clinician and staff absence due to illness or quarantine, the ACP says “practices may need to review emergency plans related to telework and to employee and clinician absence.” Among its recommendations are that practices and employers consider temporary adjustments to compensation formulas to accommodate those clinicians who experience a loss of income because they are paid based on production.

The organization emphasizes that, given the rapidly changing availability of testing for COVID-19, practices should contact their local health departments, hospitals, reference labs, or state health authorities to determine the status of their access to testing.

The full list of the ACP’s tips are available here.

Any new guidance for physicians will be posted on the ACP’s COVID-19 resource page.

[email protected]

The American College of Physicians has published tips for medical practices related to billing and coding for telehealth, and for handling clinician and staff absences due to illness or quarantine during the COVID-19 pandemic.

It strongly encourages practices to use telehealth, whenever possible, to mitigate exposure of patients who are sick or at risk because of other underlying conditions and to protect health care workers and the community from the spread of the disease.

The national organization of internists also recommends in the guidance that practices establish protocols and procedures for use by clinicians and all other staff in light of the pandemic.

The billing and coding tips are being offered to help practices deal with the rapidly changing situation surrounding the COVID-19 emergency, according to a statement from the ACP.

The coding-related guidance incorporates changes to a number of telehealth rules for Medicare beneficiaries, announced by the Centers for Medicare and Medicaid Services on March 17.

“Now in a full state of emergency, many Medicare restrictions related to telehealth have been lifted. Patients can be at home, and non-HIPAA compliant technology is allowed. There is no cost sharing for COVID-19 testing. In addition, to encourage use by patients, Medicare is allowing practices to waive cost sharing (copays and deductibles) for all telehealth services,” the organization said in the guidance. It notes, however, that the CMS does not currently reimburse for telephone calls.

The guidance includes details of the new ICD-10 codes, and stresses the importance of using the appropriate codes, given that some service cost-sharing has been waived for COVID-19 testing and treatment.

There is detailed coding guidance for virtual check-in, online evaluation and management, remote monitoring, originating site, and allowed technology and services.

In regard to clinician and staff absence due to illness or quarantine, the ACP says “practices may need to review emergency plans related to telework and to employee and clinician absence.” Among its recommendations are that practices and employers consider temporary adjustments to compensation formulas to accommodate those clinicians who experience a loss of income because they are paid based on production.

The organization emphasizes that, given the rapidly changing availability of testing for COVID-19, practices should contact their local health departments, hospitals, reference labs, or state health authorities to determine the status of their access to testing.

The full list of the ACP’s tips are available here.

Any new guidance for physicians will be posted on the ACP’s COVID-19 resource page.

[email protected]

Clinicians across the United States are petitioning the federal government to follow the lead of South Korea, China, and other nations by imposing an immediate nationwide quarantine to slow the inevitable spread of COVID-19. Without federal action, the creators say, their lives and the lives of their colleagues, patients, and families are being put at increased risk.

In addition to the quarantine, the petition, posted on the website Change.org, calls on U.S. leaders to institute emergency production and distribution of personal protective equipment for healthcare workers and to rapidly increase access to testing.

The petition – which garnered more than 40,000 signatures in just 12 hours and as of this writing was approaching 94,000 – was started by an apolitical Facebook group to focus attention on what members see as the most critical issues for clinicians: slowing the spread of the virus through a coast-to-coast quarantine, protection of medical personnel with adequate supplies of essential equipment, and widespread testing.

“We started this group last Friday out of the realization that clinicians needed information about the outbreak and weren’t getting it,” said coadministrator Jessica McIntyre, MD, a pediatric hospitalist at Elliot Hospital in Manchester, N.H.

“We wanted to get ahead of it and connect with people before we were in the trenches experiencing it and to see what other programs were doing. From a local perspective, it has been really hard to see what people are doing in other states, especially when the protocols in our own states are changing every single day as we collect more information,” she said in an interview.
 

The Horse Has Bolted

A family medicine physician in Illinois helped launch the Facebook group. She asked that her name not be used but said in an interview that earlier actions may have prevented or at least delayed the need for the more draconian measures that her group is recommending.

“Clearly South Korea is one of the superstars as far as response has gone, but the concern we have in the United States is that we’re well beyond that point – we needed to be testing people over a month ago, in the hope of preventing a quarantine,” she said in an interview.

According to National Public Radio, as of March 13, South Korea had conducted 3,600 tests per million population, compared with five per million in the United States.

“I think the most concerning part is to see where Italy is now and where we are in comparison. Our ICUs have not yet overflowed, but I think we’re definitely looking at that in the next few weeks – hopefully longer, but I suspect that it will happen shortly,” she continued.

She cited work by Harvard University biostatistician Xihong Lin, PhD, that shows that when health authorities in Wuhan, China – widely cited as the epicenter of the global pandemic – cordoned off the city, the infection rate dropped from one person infecting 3.8 others to one infecting 1.25, thereby significantly slowing the rate of transmission.

“This is absolutely what we need to be doing,” she said.
 

Real News

Within 3 days of its creation, the online group had accrued more than 80,000 members with advanced medical training, including MDs, DOs, physician assistants, nurse practitioners, and certified registered nurse anesthetists.

“A lot of us were already very busy with our day-to-day work outside of COVID-19, and I think a lot of us felt unsure about where to get the best information,” said coadministrator David Janssen, MD, a family medicine physician in group practice in Sioux Center, Iowa,

“If you turn on the TV, there’s a lot of politicizing of the issue, and there’s a lot of good information, but also a lot of bad information. When health care providers talk to other health care providers, that’s often how we get our information and how we learn,” he said in an interview.

The COVID-19 U.S. Physicians/APP Facebook group includes 20 volunteer moderators who handle hundreds of posts per hour from persons seeking information on the novel coronavirus, what to tell patients, and how to protect themselves.

“It’s been wonderful to see how providers have been helping other providers sort through issues. Teaching hospitals have their hands on the latest research, but a lot of people like myself are at small community hospitals, critical-access hospitals, where we may have a lot of questions but don’t necessarily have the answers readily available to us,” Dr. Janssen said.

Dr. Janssen said that his community of about 8,000 residents initially had only four COVID-19 testing kits, or one for every 2,000 people. The situation has since improved, and more tests are now available, he added.

Dr. McIntyre, Dr. Janssen, and the Illinois family physician have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Clinicians across the United States are petitioning the federal government to follow the lead of South Korea, China, and other nations by imposing an immediate nationwide quarantine to slow the inevitable spread of COVID-19. Without federal action, the creators say, their lives and the lives of their colleagues, patients, and families are being put at increased risk.

In addition to the quarantine, the petition, posted on the website Change.org, calls on U.S. leaders to institute emergency production and distribution of personal protective equipment for healthcare workers and to rapidly increase access to testing.

The petition – which garnered more than 40,000 signatures in just 12 hours and as of this writing was approaching 94,000 – was started by an apolitical Facebook group to focus attention on what members see as the most critical issues for clinicians: slowing the spread of the virus through a coast-to-coast quarantine, protection of medical personnel with adequate supplies of essential equipment, and widespread testing.

“We started this group last Friday out of the realization that clinicians needed information about the outbreak and weren’t getting it,” said coadministrator Jessica McIntyre, MD, a pediatric hospitalist at Elliot Hospital in Manchester, N.H.

“We wanted to get ahead of it and connect with people before we were in the trenches experiencing it and to see what other programs were doing. From a local perspective, it has been really hard to see what people are doing in other states, especially when the protocols in our own states are changing every single day as we collect more information,” she said in an interview.
 

The Horse Has Bolted

A family medicine physician in Illinois helped launch the Facebook group. She asked that her name not be used but said in an interview that earlier actions may have prevented or at least delayed the need for the more draconian measures that her group is recommending.

“Clearly South Korea is one of the superstars as far as response has gone, but the concern we have in the United States is that we’re well beyond that point – we needed to be testing people over a month ago, in the hope of preventing a quarantine,” she said in an interview.

According to National Public Radio, as of March 13, South Korea had conducted 3,600 tests per million population, compared with five per million in the United States.

“I think the most concerning part is to see where Italy is now and where we are in comparison. Our ICUs have not yet overflowed, but I think we’re definitely looking at that in the next few weeks – hopefully longer, but I suspect that it will happen shortly,” she continued.

She cited work by Harvard University biostatistician Xihong Lin, PhD, that shows that when health authorities in Wuhan, China – widely cited as the epicenter of the global pandemic – cordoned off the city, the infection rate dropped from one person infecting 3.8 others to one infecting 1.25, thereby significantly slowing the rate of transmission.

“This is absolutely what we need to be doing,” she said.
 

Real News

Within 3 days of its creation, the online group had accrued more than 80,000 members with advanced medical training, including MDs, DOs, physician assistants, nurse practitioners, and certified registered nurse anesthetists.

“A lot of us were already very busy with our day-to-day work outside of COVID-19, and I think a lot of us felt unsure about where to get the best information,” said coadministrator David Janssen, MD, a family medicine physician in group practice in Sioux Center, Iowa,

“If you turn on the TV, there’s a lot of politicizing of the issue, and there’s a lot of good information, but also a lot of bad information. When health care providers talk to other health care providers, that’s often how we get our information and how we learn,” he said in an interview.

The COVID-19 U.S. Physicians/APP Facebook group includes 20 volunteer moderators who handle hundreds of posts per hour from persons seeking information on the novel coronavirus, what to tell patients, and how to protect themselves.

“It’s been wonderful to see how providers have been helping other providers sort through issues. Teaching hospitals have their hands on the latest research, but a lot of people like myself are at small community hospitals, critical-access hospitals, where we may have a lot of questions but don’t necessarily have the answers readily available to us,” Dr. Janssen said.

Dr. Janssen said that his community of about 8,000 residents initially had only four COVID-19 testing kits, or one for every 2,000 people. The situation has since improved, and more tests are now available, he added.

Dr. McIntyre, Dr. Janssen, and the Illinois family physician have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Clinicians across the United States are petitioning the federal government to follow the lead of South Korea, China, and other nations by imposing an immediate nationwide quarantine to slow the inevitable spread of COVID-19. Without federal action, the creators say, their lives and the lives of their colleagues, patients, and families are being put at increased risk.

In addition to the quarantine, the petition, posted on the website Change.org, calls on U.S. leaders to institute emergency production and distribution of personal protective equipment for healthcare workers and to rapidly increase access to testing.

The petition – which garnered more than 40,000 signatures in just 12 hours and as of this writing was approaching 94,000 – was started by an apolitical Facebook group to focus attention on what members see as the most critical issues for clinicians: slowing the spread of the virus through a coast-to-coast quarantine, protection of medical personnel with adequate supplies of essential equipment, and widespread testing.

“We started this group last Friday out of the realization that clinicians needed information about the outbreak and weren’t getting it,” said coadministrator Jessica McIntyre, MD, a pediatric hospitalist at Elliot Hospital in Manchester, N.H.

“We wanted to get ahead of it and connect with people before we were in the trenches experiencing it and to see what other programs were doing. From a local perspective, it has been really hard to see what people are doing in other states, especially when the protocols in our own states are changing every single day as we collect more information,” she said in an interview.
 

The Horse Has Bolted

A family medicine physician in Illinois helped launch the Facebook group. She asked that her name not be used but said in an interview that earlier actions may have prevented or at least delayed the need for the more draconian measures that her group is recommending.

“Clearly South Korea is one of the superstars as far as response has gone, but the concern we have in the United States is that we’re well beyond that point – we needed to be testing people over a month ago, in the hope of preventing a quarantine,” she said in an interview.

According to National Public Radio, as of March 13, South Korea had conducted 3,600 tests per million population, compared with five per million in the United States.

“I think the most concerning part is to see where Italy is now and where we are in comparison. Our ICUs have not yet overflowed, but I think we’re definitely looking at that in the next few weeks – hopefully longer, but I suspect that it will happen shortly,” she continued.

She cited work by Harvard University biostatistician Xihong Lin, PhD, that shows that when health authorities in Wuhan, China – widely cited as the epicenter of the global pandemic – cordoned off the city, the infection rate dropped from one person infecting 3.8 others to one infecting 1.25, thereby significantly slowing the rate of transmission.

“This is absolutely what we need to be doing,” she said.
 

Real News

Within 3 days of its creation, the online group had accrued more than 80,000 members with advanced medical training, including MDs, DOs, physician assistants, nurse practitioners, and certified registered nurse anesthetists.

“A lot of us were already very busy with our day-to-day work outside of COVID-19, and I think a lot of us felt unsure about where to get the best information,” said coadministrator David Janssen, MD, a family medicine physician in group practice in Sioux Center, Iowa,

“If you turn on the TV, there’s a lot of politicizing of the issue, and there’s a lot of good information, but also a lot of bad information. When health care providers talk to other health care providers, that’s often how we get our information and how we learn,” he said in an interview.

The COVID-19 U.S. Physicians/APP Facebook group includes 20 volunteer moderators who handle hundreds of posts per hour from persons seeking information on the novel coronavirus, what to tell patients, and how to protect themselves.

“It’s been wonderful to see how providers have been helping other providers sort through issues. Teaching hospitals have their hands on the latest research, but a lot of people like myself are at small community hospitals, critical-access hospitals, where we may have a lot of questions but don’t necessarily have the answers readily available to us,” Dr. Janssen said.

Dr. Janssen said that his community of about 8,000 residents initially had only four COVID-19 testing kits, or one for every 2,000 people. The situation has since improved, and more tests are now available, he added.

Dr. McIntyre, Dr. Janssen, and the Illinois family physician have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Microdiscectomy could significantly reduce pain intensity at 6 months in people with chronic sciatica caused by lumbar disc herniation, a randomized controlled trial has found.

Catherine Yeulet/Thinkstock

Researchers reported the outcomes of a single-center trial in the New England Journal of Medicine in which 128 patients with chronic sciatica resulting from lumbar disc herniation were randomized either to microdiscectomy or 6 months of standardized nonoperative care, followed by surgery if required.

Chris S. Bailey, MD, of the Schulich School of Medicine and Dentistry at Western University in Toronto, Ontario, and coauthors wrote that, while the majority of patients with sciatica from acute herniation of the lumbar disc improve with conservative care, there is little study comparing surgery with conservative care in patients whose symptoms have lasted longer than 3 months.

In this study, all patients had experienced unilateral radiculopathy for 4-12 months. Those randomized to surgery were operated on a median of 3.1 weeks after enrollment, while those randomized to nonsurgical treatment received education on exercise, functioning, and the use of oral analgesics, as well as active physiotherapy and epidural glucocorticoid injections if needed.

At 6 months, the surgical group showed significantly lower visual analog scale scores for leg-pain intensity, compared with the nonsurgical group (2.8 vs. 5.2; 95% confidence interval, 1.4-3.4; P < .001) and the difference persisted at 1 year (2.6 vs. 4.7).

In an editorial accompanying the study, Andrew J. Schoenfeld, MD, and James D. Kang, MD, of the department of orthopedic surgery at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, described the results in this group of patients with persistent sciatica as “encouraging,” and suggested the improvement may be because the surgery achieves more rapid decompression of the compressed nerve.

“Patients in the current trial who were assigned to undergo surgery received the intervention relatively quickly, at a median of 3 weeks, and it is reasonable to conclude that expeditious removal of the nerve compression minimized the potential for long-term persistence of pain,” they wrote.

Among the 64 patients who were randomized to nonsurgical treatment, 22 (34%) crossed over to undergo surgery at a median of 11 months after enrollment in the study. These patients tended to be younger at baseline, and less likely to have an asymmetrical decrease in reflexes.

The intention-to-treat analysis found a similar rate of surgical adverse events in the group initially randomized to surgery and the group who crossed over to have surgery (6% vs. 8%). Two patients in the surgical group and one in the crossover group experienced superficial wound infections, while two patients in the crossover group and one in the surgical group experienced new-onset postoperative neuropathic pain. Two patients in the surgical group also had a recurrence of their herniation; one underwent further surgery for it 250 days after the initial procedure, and the other did not.

The secondary outcomes of the study were disability score, physical health, mental health, back pain intensity, satisfaction with treatment, and employment status. All these showed differences that favored the surgical intervention, but “the absence of a prespecified plan for adjustment for multiple comparisons does not allow for clinical inferences from secondary outcomes.”

The authors noted that some previous randomized trials have shown that surgery was better than conservative care among patients with lumbar disc herniation for the first 6 months, but those trials largely focused on patients who had had symptoms for less than 4 months at the time of the intervention. The results of these trials had also been mixed; some trials in patients with shorter duration of symptoms found little or no benefit of surgery over conservative care.

“The decision about whether to recommend discectomy or nonsurgical treatment in this population is controversial because a longer duration of symptoms has been correlated with a poorer outcome associated with lumbar discectomy in some studies,” they wrote. “However, patients may prefer to avoid surgery if they think that nonsurgical treatment could be successful or if they anticipate a risk from surgery.”

There was the risk for selection bias in the study, the authors said, because both surgeons and patients might have been less inclined to go with nonsurgical care in cases of more severe sciatic pain. However they said patients did not have the option of choosing to have surgery at the center outside the trial, which should have minimized that risk.

The authors of the editorial noted that while the study limited itself to patients who had had symptoms for 4-12 months, it didn’t account for other clinical factors that might impact the outcome of discectomy, such as the size of disc herniation or extent of nerve compression.

They also pointed out that questions still remained about which patients were more likely to benefit from immediate surgical intervention and how long nonsurgical care should be trialed before recommending surgery.

The study was supported by a grant from the Physicians’ Services Incorporated Foundation. None of the study authors reported conflicts of interest. Dr. Kang reported grants from Pfizer, personal fees from DePuy (Johnson & Johnson), nonfinancial support from Stryker, owning stock in ALung and Cardiorobotics, and serving on a scientific advisory board for OnPoint Surgical, outside the submitted work. Dr. Schoenfeld reported grants from the National Institute for Arthritis and Musculoskeletal and Skin Diseases, the Orthopaedic Research and Education Foundation, and the U.S. Department of Defense, outside the submitted work.

SOURCE: Bailey C et al. N Engl J Med. 2020;382:1093-102.

Microdiscectomy could significantly reduce pain intensity at 6 months in people with chronic sciatica caused by lumbar disc herniation, a randomized controlled trial has found.

Catherine Yeulet/Thinkstock

Researchers reported the outcomes of a single-center trial in the New England Journal of Medicine in which 128 patients with chronic sciatica resulting from lumbar disc herniation were randomized either to microdiscectomy or 6 months of standardized nonoperative care, followed by surgery if required.

Chris S. Bailey, MD, of the Schulich School of Medicine and Dentistry at Western University in Toronto, Ontario, and coauthors wrote that, while the majority of patients with sciatica from acute herniation of the lumbar disc improve with conservative care, there is little study comparing surgery with conservative care in patients whose symptoms have lasted longer than 3 months.

In this study, all patients had experienced unilateral radiculopathy for 4-12 months. Those randomized to surgery were operated on a median of 3.1 weeks after enrollment, while those randomized to nonsurgical treatment received education on exercise, functioning, and the use of oral analgesics, as well as active physiotherapy and epidural glucocorticoid injections if needed.

At 6 months, the surgical group showed significantly lower visual analog scale scores for leg-pain intensity, compared with the nonsurgical group (2.8 vs. 5.2; 95% confidence interval, 1.4-3.4; P < .001) and the difference persisted at 1 year (2.6 vs. 4.7).

In an editorial accompanying the study, Andrew J. Schoenfeld, MD, and James D. Kang, MD, of the department of orthopedic surgery at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, described the results in this group of patients with persistent sciatica as “encouraging,” and suggested the improvement may be because the surgery achieves more rapid decompression of the compressed nerve.

“Patients in the current trial who were assigned to undergo surgery received the intervention relatively quickly, at a median of 3 weeks, and it is reasonable to conclude that expeditious removal of the nerve compression minimized the potential for long-term persistence of pain,” they wrote.

Among the 64 patients who were randomized to nonsurgical treatment, 22 (34%) crossed over to undergo surgery at a median of 11 months after enrollment in the study. These patients tended to be younger at baseline, and less likely to have an asymmetrical decrease in reflexes.

The intention-to-treat analysis found a similar rate of surgical adverse events in the group initially randomized to surgery and the group who crossed over to have surgery (6% vs. 8%). Two patients in the surgical group and one in the crossover group experienced superficial wound infections, while two patients in the crossover group and one in the surgical group experienced new-onset postoperative neuropathic pain. Two patients in the surgical group also had a recurrence of their herniation; one underwent further surgery for it 250 days after the initial procedure, and the other did not.

The secondary outcomes of the study were disability score, physical health, mental health, back pain intensity, satisfaction with treatment, and employment status. All these showed differences that favored the surgical intervention, but “the absence of a prespecified plan for adjustment for multiple comparisons does not allow for clinical inferences from secondary outcomes.”

The authors noted that some previous randomized trials have shown that surgery was better than conservative care among patients with lumbar disc herniation for the first 6 months, but those trials largely focused on patients who had had symptoms for less than 4 months at the time of the intervention. The results of these trials had also been mixed; some trials in patients with shorter duration of symptoms found little or no benefit of surgery over conservative care.

“The decision about whether to recommend discectomy or nonsurgical treatment in this population is controversial because a longer duration of symptoms has been correlated with a poorer outcome associated with lumbar discectomy in some studies,” they wrote. “However, patients may prefer to avoid surgery if they think that nonsurgical treatment could be successful or if they anticipate a risk from surgery.”

There was the risk for selection bias in the study, the authors said, because both surgeons and patients might have been less inclined to go with nonsurgical care in cases of more severe sciatic pain. However they said patients did not have the option of choosing to have surgery at the center outside the trial, which should have minimized that risk.

The authors of the editorial noted that while the study limited itself to patients who had had symptoms for 4-12 months, it didn’t account for other clinical factors that might impact the outcome of discectomy, such as the size of disc herniation or extent of nerve compression.

They also pointed out that questions still remained about which patients were more likely to benefit from immediate surgical intervention and how long nonsurgical care should be trialed before recommending surgery.

The study was supported by a grant from the Physicians’ Services Incorporated Foundation. None of the study authors reported conflicts of interest. Dr. Kang reported grants from Pfizer, personal fees from DePuy (Johnson & Johnson), nonfinancial support from Stryker, owning stock in ALung and Cardiorobotics, and serving on a scientific advisory board for OnPoint Surgical, outside the submitted work. Dr. Schoenfeld reported grants from the National Institute for Arthritis and Musculoskeletal and Skin Diseases, the Orthopaedic Research and Education Foundation, and the U.S. Department of Defense, outside the submitted work.

SOURCE: Bailey C et al. N Engl J Med. 2020;382:1093-102.

Microdiscectomy could significantly reduce pain intensity at 6 months in people with chronic sciatica caused by lumbar disc herniation, a randomized controlled trial has found.

Catherine Yeulet/Thinkstock

Researchers reported the outcomes of a single-center trial in the New England Journal of Medicine in which 128 patients with chronic sciatica resulting from lumbar disc herniation were randomized either to microdiscectomy or 6 months of standardized nonoperative care, followed by surgery if required.

Chris S. Bailey, MD, of the Schulich School of Medicine and Dentistry at Western University in Toronto, Ontario, and coauthors wrote that, while the majority of patients with sciatica from acute herniation of the lumbar disc improve with conservative care, there is little study comparing surgery with conservative care in patients whose symptoms have lasted longer than 3 months.

In this study, all patients had experienced unilateral radiculopathy for 4-12 months. Those randomized to surgery were operated on a median of 3.1 weeks after enrollment, while those randomized to nonsurgical treatment received education on exercise, functioning, and the use of oral analgesics, as well as active physiotherapy and epidural glucocorticoid injections if needed.

At 6 months, the surgical group showed significantly lower visual analog scale scores for leg-pain intensity, compared with the nonsurgical group (2.8 vs. 5.2; 95% confidence interval, 1.4-3.4; P < .001) and the difference persisted at 1 year (2.6 vs. 4.7).

In an editorial accompanying the study, Andrew J. Schoenfeld, MD, and James D. Kang, MD, of the department of orthopedic surgery at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, described the results in this group of patients with persistent sciatica as “encouraging,” and suggested the improvement may be because the surgery achieves more rapid decompression of the compressed nerve.

“Patients in the current trial who were assigned to undergo surgery received the intervention relatively quickly, at a median of 3 weeks, and it is reasonable to conclude that expeditious removal of the nerve compression minimized the potential for long-term persistence of pain,” they wrote.

Among the 64 patients who were randomized to nonsurgical treatment, 22 (34%) crossed over to undergo surgery at a median of 11 months after enrollment in the study. These patients tended to be younger at baseline, and less likely to have an asymmetrical decrease in reflexes.

The intention-to-treat analysis found a similar rate of surgical adverse events in the group initially randomized to surgery and the group who crossed over to have surgery (6% vs. 8%). Two patients in the surgical group and one in the crossover group experienced superficial wound infections, while two patients in the crossover group and one in the surgical group experienced new-onset postoperative neuropathic pain. Two patients in the surgical group also had a recurrence of their herniation; one underwent further surgery for it 250 days after the initial procedure, and the other did not.

The secondary outcomes of the study were disability score, physical health, mental health, back pain intensity, satisfaction with treatment, and employment status. All these showed differences that favored the surgical intervention, but “the absence of a prespecified plan for adjustment for multiple comparisons does not allow for clinical inferences from secondary outcomes.”

The authors noted that some previous randomized trials have shown that surgery was better than conservative care among patients with lumbar disc herniation for the first 6 months, but those trials largely focused on patients who had had symptoms for less than 4 months at the time of the intervention. The results of these trials had also been mixed; some trials in patients with shorter duration of symptoms found little or no benefit of surgery over conservative care.

“The decision about whether to recommend discectomy or nonsurgical treatment in this population is controversial because a longer duration of symptoms has been correlated with a poorer outcome associated with lumbar discectomy in some studies,” they wrote. “However, patients may prefer to avoid surgery if they think that nonsurgical treatment could be successful or if they anticipate a risk from surgery.”

There was the risk for selection bias in the study, the authors said, because both surgeons and patients might have been less inclined to go with nonsurgical care in cases of more severe sciatic pain. However they said patients did not have the option of choosing to have surgery at the center outside the trial, which should have minimized that risk.

The authors of the editorial noted that while the study limited itself to patients who had had symptoms for 4-12 months, it didn’t account for other clinical factors that might impact the outcome of discectomy, such as the size of disc herniation or extent of nerve compression.

They also pointed out that questions still remained about which patients were more likely to benefit from immediate surgical intervention and how long nonsurgical care should be trialed before recommending surgery.

The study was supported by a grant from the Physicians’ Services Incorporated Foundation. None of the study authors reported conflicts of interest. Dr. Kang reported grants from Pfizer, personal fees from DePuy (Johnson & Johnson), nonfinancial support from Stryker, owning stock in ALung and Cardiorobotics, and serving on a scientific advisory board for OnPoint Surgical, outside the submitted work. Dr. Schoenfeld reported grants from the National Institute for Arthritis and Musculoskeletal and Skin Diseases, the Orthopaedic Research and Education Foundation, and the U.S. Department of Defense, outside the submitted work.

SOURCE: Bailey C et al. N Engl J Med. 2020;382:1093-102.

Controversy continued over the potential effect of drugs that interfere with the renin-angiotensin-aldosterone system via the angiotensin-converting enzymes (ACE) may have on exacerbating infection with the SARS-CoV-2 virus that causes COVID-19.

A joint statement from the American Heart Association, American College of Cardiology, and the Heart Failure Society of America on March 17 gave full, unqualified support to maintaining patients on drugs that work this way, specifically the ACE inhibitors and angiotensin-receptor blockers (ARBs), which together form a long-standing cornerstone of treatment for hypertension, heart failure, and ischemic heart disease.

The three societies “recommend continuation” of ACE inhibitors or ARBs “for all patients already prescribed.” The statement went on to say that patients already diagnosed with a COVID-19 infection “should be fully evaluated before adding or removing any treatments, and any changes to their treatment should be based on the latest scientific evidence and shared decision making with their physician and health care team.”

“We understand the concern – as it has become clear that people with cardiovascular disease are at much higher risk of serious complications including death from COVID-19. However, we have reviewed the latest research – the evidence does not confirm the need to discontinue ACE inhibitors or ARBs, and we strongly recommend all physicians to consider the individual needs of each patient before making any changes to ACE-inhibitor or ARB treatment regimens,” said Robert A. Harrington, MD, president of the American Heart Association and professor and chair of medicine at Stanford (Calif.) University, in the statement.

“There are no experimental or clinical data demonstrating beneficial or adverse outcomes among COVID-19 patients using ACE-inhibitor or ARB medications,” added Richard J. Kovacs, MD, president of the American College of Cardiology and professor of cardiology at Indiana University in Indianapolis.

The “latest research” referred to in the statement likely focuses on a report that had appeared less than a week earlier in a British journal that hypothesized a possible increase in the susceptibility of human epithelial cells of the lungs, intestine, kidneys, and blood vessels exposed to these or certain other drugs, like the thiazolidinedione oral diabetes drugs or ibuprofen, because they cause up-regulation of the ACE2 protein in cell membranes, and ACE2 is the primary cell-surface receptor that allows the SARS-CoV-2 virus to enter.

“We therefore hypothesize that diabetes and hypertension treatment with ACE2-stimulating drugs increases the risk of developing severe and fatal COVID-19,” wrote Michael Roth, MD, and his associates in their recent article (Lancet Resp Med. 2020 Mar 11. doi: 10.1016/S2213-2600[20]30116-8). While the potential clinical impact of an increase in the number of ACE2 molecules in a cell’s surface membrane remains uninvestigated, the risk this phenomenon poses should mean that patients taking these drugs should receive heightened monitoring for COVID-19 disease, suggested Dr. Roth, a professor of biomedicine who specializes in studying inflammatory lung diseases including asthma, and associates.

However, others who have considered the impact that ACE inhibitors and ARBs might have on ACE2 and COVID-19 infections have noted that the picture is not simple. “Higher ACE2 expression following chronically medicating SARS‐CoV‐2 infected patients with AT1R [angiotensin receptor 1] blockers, while seemingly paradoxical, may protect them against acute lung injury rather than putting them at higher risk to develop SARS. This may be accounted for by two complementary mechanisms: blocking the excessive angiotensin‐mediated AT1R activation caused by the viral infection, as well as up-regulating ACE2, thereby reducing angiotensin production by ACE and increasing the production” of a vasodilating form of angiotensin, wrote David Gurwitz, PhD, in a recently published editorial (Drug Dev Res. 2020 Mar 4. doi: 10.1002/ddr.21656). A data-mining approach may allow researchers to determine whether patients who received drugs that interfere with angiotensin 1 function prior to being diagnosed with a COVID-19 infection had a better disease outcome, suggested Dr. Gurwitz, a molecular geneticist at Tel Aviv University in Jerusalem.

The statement from the three U.S. cardiology societies came a few days following a similar statement of support for ongoing use of ACE inhibitors and ARBs from the European Society of Cardiology’s Council on Hypertension.

Dr. Harrington, Dr. Kovacs, Dr. Roth, and Dr. Gurwitz had no relevant disclosures.

[email protected]

Controversy continued over the potential effect of drugs that interfere with the renin-angiotensin-aldosterone system via the angiotensin-converting enzymes (ACE) may have on exacerbating infection with the SARS-CoV-2 virus that causes COVID-19.

A joint statement from the American Heart Association, American College of Cardiology, and the Heart Failure Society of America on March 17 gave full, unqualified support to maintaining patients on drugs that work this way, specifically the ACE inhibitors and angiotensin-receptor blockers (ARBs), which together form a long-standing cornerstone of treatment for hypertension, heart failure, and ischemic heart disease.

The three societies “recommend continuation” of ACE inhibitors or ARBs “for all patients already prescribed.” The statement went on to say that patients already diagnosed with a COVID-19 infection “should be fully evaluated before adding or removing any treatments, and any changes to their treatment should be based on the latest scientific evidence and shared decision making with their physician and health care team.”

“We understand the concern – as it has become clear that people with cardiovascular disease are at much higher risk of serious complications including death from COVID-19. However, we have reviewed the latest research – the evidence does not confirm the need to discontinue ACE inhibitors or ARBs, and we strongly recommend all physicians to consider the individual needs of each patient before making any changes to ACE-inhibitor or ARB treatment regimens,” said Robert A. Harrington, MD, president of the American Heart Association and professor and chair of medicine at Stanford (Calif.) University, in the statement.

“There are no experimental or clinical data demonstrating beneficial or adverse outcomes among COVID-19 patients using ACE-inhibitor or ARB medications,” added Richard J. Kovacs, MD, president of the American College of Cardiology and professor of cardiology at Indiana University in Indianapolis.

The “latest research” referred to in the statement likely focuses on a report that had appeared less than a week earlier in a British journal that hypothesized a possible increase in the susceptibility of human epithelial cells of the lungs, intestine, kidneys, and blood vessels exposed to these or certain other drugs, like the thiazolidinedione oral diabetes drugs or ibuprofen, because they cause up-regulation of the ACE2 protein in cell membranes, and ACE2 is the primary cell-surface receptor that allows the SARS-CoV-2 virus to enter.

“We therefore hypothesize that diabetes and hypertension treatment with ACE2-stimulating drugs increases the risk of developing severe and fatal COVID-19,” wrote Michael Roth, MD, and his associates in their recent article (Lancet Resp Med. 2020 Mar 11. doi: 10.1016/S2213-2600[20]30116-8). While the potential clinical impact of an increase in the number of ACE2 molecules in a cell’s surface membrane remains uninvestigated, the risk this phenomenon poses should mean that patients taking these drugs should receive heightened monitoring for COVID-19 disease, suggested Dr. Roth, a professor of biomedicine who specializes in studying inflammatory lung diseases including asthma, and associates.

However, others who have considered the impact that ACE inhibitors and ARBs might have on ACE2 and COVID-19 infections have noted that the picture is not simple. “Higher ACE2 expression following chronically medicating SARS‐CoV‐2 infected patients with AT1R [angiotensin receptor 1] blockers, while seemingly paradoxical, may protect them against acute lung injury rather than putting them at higher risk to develop SARS. This may be accounted for by two complementary mechanisms: blocking the excessive angiotensin‐mediated AT1R activation caused by the viral infection, as well as up-regulating ACE2, thereby reducing angiotensin production by ACE and increasing the production” of a vasodilating form of angiotensin, wrote David Gurwitz, PhD, in a recently published editorial (Drug Dev Res. 2020 Mar 4. doi: 10.1002/ddr.21656). A data-mining approach may allow researchers to determine whether patients who received drugs that interfere with angiotensin 1 function prior to being diagnosed with a COVID-19 infection had a better disease outcome, suggested Dr. Gurwitz, a molecular geneticist at Tel Aviv University in Jerusalem.

The statement from the three U.S. cardiology societies came a few days following a similar statement of support for ongoing use of ACE inhibitors and ARBs from the European Society of Cardiology’s Council on Hypertension.

Dr. Harrington, Dr. Kovacs, Dr. Roth, and Dr. Gurwitz had no relevant disclosures.

[email protected]

Controversy continued over the potential effect of drugs that interfere with the renin-angiotensin-aldosterone system via the angiotensin-converting enzymes (ACE) may have on exacerbating infection with the SARS-CoV-2 virus that causes COVID-19.

A joint statement from the American Heart Association, American College of Cardiology, and the Heart Failure Society of America on March 17 gave full, unqualified support to maintaining patients on drugs that work this way, specifically the ACE inhibitors and angiotensin-receptor blockers (ARBs), which together form a long-standing cornerstone of treatment for hypertension, heart failure, and ischemic heart disease.

The three societies “recommend continuation” of ACE inhibitors or ARBs “for all patients already prescribed.” The statement went on to say that patients already diagnosed with a COVID-19 infection “should be fully evaluated before adding or removing any treatments, and any changes to their treatment should be based on the latest scientific evidence and shared decision making with their physician and health care team.”

“We understand the concern – as it has become clear that people with cardiovascular disease are at much higher risk of serious complications including death from COVID-19. However, we have reviewed the latest research – the evidence does not confirm the need to discontinue ACE inhibitors or ARBs, and we strongly recommend all physicians to consider the individual needs of each patient before making any changes to ACE-inhibitor or ARB treatment regimens,” said Robert A. Harrington, MD, president of the American Heart Association and professor and chair of medicine at Stanford (Calif.) University, in the statement.

“There are no experimental or clinical data demonstrating beneficial or adverse outcomes among COVID-19 patients using ACE-inhibitor or ARB medications,” added Richard J. Kovacs, MD, president of the American College of Cardiology and professor of cardiology at Indiana University in Indianapolis.

The “latest research” referred to in the statement likely focuses on a report that had appeared less than a week earlier in a British journal that hypothesized a possible increase in the susceptibility of human epithelial cells of the lungs, intestine, kidneys, and blood vessels exposed to these or certain other drugs, like the thiazolidinedione oral diabetes drugs or ibuprofen, because they cause up-regulation of the ACE2 protein in cell membranes, and ACE2 is the primary cell-surface receptor that allows the SARS-CoV-2 virus to enter.

“We therefore hypothesize that diabetes and hypertension treatment with ACE2-stimulating drugs increases the risk of developing severe and fatal COVID-19,” wrote Michael Roth, MD, and his associates in their recent article (Lancet Resp Med. 2020 Mar 11. doi: 10.1016/S2213-2600[20]30116-8). While the potential clinical impact of an increase in the number of ACE2 molecules in a cell’s surface membrane remains uninvestigated, the risk this phenomenon poses should mean that patients taking these drugs should receive heightened monitoring for COVID-19 disease, suggested Dr. Roth, a professor of biomedicine who specializes in studying inflammatory lung diseases including asthma, and associates.

However, others who have considered the impact that ACE inhibitors and ARBs might have on ACE2 and COVID-19 infections have noted that the picture is not simple. “Higher ACE2 expression following chronically medicating SARS‐CoV‐2 infected patients with AT1R [angiotensin receptor 1] blockers, while seemingly paradoxical, may protect them against acute lung injury rather than putting them at higher risk to develop SARS. This may be accounted for by two complementary mechanisms: blocking the excessive angiotensin‐mediated AT1R activation caused by the viral infection, as well as up-regulating ACE2, thereby reducing angiotensin production by ACE and increasing the production” of a vasodilating form of angiotensin, wrote David Gurwitz, PhD, in a recently published editorial (Drug Dev Res. 2020 Mar 4. doi: 10.1002/ddr.21656). A data-mining approach may allow researchers to determine whether patients who received drugs that interfere with angiotensin 1 function prior to being diagnosed with a COVID-19 infection had a better disease outcome, suggested Dr. Gurwitz, a molecular geneticist at Tel Aviv University in Jerusalem.

The statement from the three U.S. cardiology societies came a few days following a similar statement of support for ongoing use of ACE inhibitors and ARBs from the European Society of Cardiology’s Council on Hypertension.

Dr. Harrington, Dr. Kovacs, Dr. Roth, and Dr. Gurwitz had no relevant disclosures.

[email protected]

A new article in the Journal of the Neurological Sciences provides an impressive review of research on the complex impairments produced by a wide range of drugs of abuse with a close look at physicians and other health care professionals.¹

This review breaks new ground in outlining fitness for duty as an important outcome of the state physician health programs (PHPs). In addition, the review and case report by Alexandria G. Polles, MD, and colleagues are a response to the growing call for the state PHP system of care management to explicitly endorse the use of medication-assisted treatment, specifically the use of buprenorphine and methadone, in the treatment of physicians diagnosed with opioid use disorder (OUD). The article usefully situates the controversy in the context of other safety-sensitive jobs, including commercial pilots, truck drivers, and police, because of the elevated rate of substance use disorders among physicians and the safety-sensitive nature of the practice of medicine.

Medication-assisted treatment (MAT)² for opioid use disorders now dominates the field of treatment in terms of prescribing and also funding to address the opioid overdose crisis. MAT generally includes naltrexone and injectable naltrexone, though those antagonist medications have been used successfully for many decades by PHPs.³ However, to understand the controversy over the use of MAT in the care management of physicians first requires an understanding of state PHPs and how those programs oversee the care of physicians diagnosed with substance use disorders (SUDs), including OUDs.

A national blueprint study of PHPs showed that care begins with a formal diagnostic evaluation.⁴ Only when a diagnosis of an SUD is established is a physician referred to the attention of a state PHP, and a monitoring contract is signed. PHPs typically do not offer any direct treatment; instead, they manage the care of physician participants in programs in which the PHPs have confidence. Formal addiction treatment most often is 30 days of residential treatment, but many physicians receive intensive outpatient treatment.

After completing an episode of formal treatment, physicians are closely monitored, usually for 5 years, through random drug and alcohol tests, and work site monitors. They are required to engage in intensive recovery support, typically 12-step fellowships but also other alternative recovery support programs. Comorbid conditions, including mental health disorders, are also treated. Managing PHPs have no sanctions for noncompliance; however, importantly, they do offer a safe haven from state medical licensing boards for physicians who are compliant with their recommendations and who remain abstinent from any use of alcohol, marijuana, illicit drugs, or other nonmedical drug use.

The national blueprint study included 16 state PHPs and reviewed single episodes of PHP care for 908 physicians. Complete abstinence from any use of alcohol, marijuana, or other drugs was required of all physicians for monitoring periods of at least 5 years. During the extended period, 78% of the physicians did not have a single positive or missed test. Two-thirds of physicians who had one positive or missed test did not have a second. About a dozen publications have resulted from this national study, including an analysis of the roughly one-third of the physicians who were diagnosed with OUD.⁵

A sample of 702 PHP participants was grouped based on primary drug at intake: alcohol only, any opioid with or without alcohol, and nonopioid drugs. No significant differences were found among these groups in the percentage who completed PHP contracts, failed to complete their contract, or extended their contract and continued to be monitored. Only one physician received methadone to treat chronic pain. None received opioid agonists to treat their opioid use disorder. Opioid antagonist medication (naltrexone) was used for 40 physicians, or 5.7% of the total sample: 2 physicians (1%) from the alcohol-only group; 35 physicians (10.3%) from the any opioid group, and 3 physicians (1.9%) from nonopioid group.

The second fact that needs to be understood is that medical practice in relationship to SUDs is treated by state licensing boards as a safety-sensitive job, analogous to commercial airline pilots who have the Human Intervention Motivation Study (HIMS),⁶ which is their own care management program analogous to that of PHPs. A similar program exists for attorneys known as Commission on Lawyer Assistance Programs (CoLAP).⁷ Fitness for duty and prevention of harm are major concerns in occupations such as those of physicians, commercial truck drivers, and people working in the nuclear power industry, all of whom have similar safety protections requiring no drug use.

A third fact that deserves special attention is that the unique system of care management for physicians began in the early 1970s. It grew out of employee assistance programs, led then and often now by physicians who are themselves in recovery from SUDs. Many of the successful addiction treatment tools used today come from extensive research of their use in PHPs. Contingency management, 12 steps, caduceus recovery, cognitive-behavioral therapy, and treatment outcomes defined in years are examples in which PHP research helped change treatment and long-term management of SUDs in non-PHP populations.

Dr. Polles and colleagues provide an impressive and comprehensive summary of the issues involved in the new interest in providing the physicians with OUD under PHP care management the option of using buprenorphine or methadone. Such a model within an abstinence-based framework is now being pioneered by a variety of programs, from COAT⁸ at West Virginia University, Morgantown, to the Hazelden Betty Ford Foundation.⁹ In those programs, patients with OUD are offered the option of using buprenorphine, methadone, or naltrexone as well as the option of using none of those medications in an extended abstinence-based intensive treatment. The authors impressively and fairly summarize the evidence on whether there are cognitive or behavioral deficits associated with the therapeutic use of either buprenorphine or methadone, which might make them unacceptable for physicians. The strongest evidence that these medicines are not necessary in the treatment of OUDs in PHPs is the outstanding outcomes PHPs produce without use of these two medications. If skeptical of the use of medications for OUD treatment in PHP care management, Dr. Polles and colleagues are open to experiments to test the effects of this option just as Florida PHP programs pioneered contracts that included mandatory naltrexone.¹⁰ West Virginia University, the Hazelden Betty Ford Foundation, and other programs should be tested to evaluate just how safe, effective, and attractive such an option would be to physicians.

Many, if not most, SUD treatment programs that use MAT are not associated with the intensive psychological treatment or extended participation in recovery support, such as the 12-step fellowships. MAT is viewed as a harm reduction strategy rather than conceptualized as an abstinence-oriented treatment. For example, there is seldom a “sobriety date” among individuals in MAT, i.e., the last day the individual used any substance of abuse, including alcohol and marijuana. These are, however, central features of PHP care, and they are features of the Hazelden Betty Ford Foundation’s definition of recovery¹¹ and use of MAT.

Dr. Polles and colleagues call attention to the unique care management of the PHP for all SUDs, not just for OUDs, because the PHPs set the standard for returning physicians to work who have the fitness and cognitive skills to first do no harm. They emphasize the importance of making sustained recovery the expected outcome of SUD treatment. There is a robust literature on the ways in which this distinctive system of care management shows the path forward for addiction treatment generally to regularly achieve 5-year recovery.¹² The current controversy over the potential use of buprenorphine and buprenorphine plus naloxone in PHPs is a useful entry into this far larger issue of the potential for PHPs to show the path forward for the addiction treatment field.
 

Dr. DuPont, the first director of the National Institute on Drug Abuse (NIDA), is president of the Institute for Behavior and Health Inc., a nonprofit drug-policy research organization in Rockville, Md. He has no disclosures. Dr. Gold is professor of psychiatry (adjunct) at Washington University in St. Louis. He is also the 17th Distinguished Alumni Professor at the University of Florida Gainesville. He has no disclosures.

References

1. Polles AG et al. J Neurol Sci. 2020 Jan 30;411:116714.

2. Oesterle TS et al. Mayo Clin Proc. 2019 Oct;94(10):2072-86.

3. Srivastava AB and Gold MS. Cerebrum. 2018 Sep-Oct; cer-13-8.

4. DuPont RL et al. J Subst Abuse Treat. 2009 Mar 1;36(2):159-71.

5. Merlo LJ et al. J Subst Abuse Treat. 2016 May 1;64:47-54.

6. Human Intervention Motivation Study (HIMS): An Occupational Substance Abuse Treatment Program.

7. Commission on Lawyer Assistance Programs (CoLAP).

8. Lander LR et al. J Neurol Sci. 2020;411:116712-8.

9. Klein AA et al. J Subst Abuse Treat. 2019;104:51-63.

10. Merlo LJ et al. J Addict Med. 2012;5(4):279-83.

11. Betty Ford Consensus Panel. J Subst Abuse Treat. 2007 Oct;33(3):221-8.

12. Carr GD et al. “Physician health programs: The U.S. model.” In KJ Brower and MB Riba, (eds.) Physician Mental Health and Well-Being (pp. 265-94). Cham, Switzerland: Springer International Publishing, 2017.

A new article in the Journal of the Neurological Sciences provides an impressive review of research on the complex impairments produced by a wide range of drugs of abuse with a close look at physicians and other health care professionals.¹

This review breaks new ground in outlining fitness for duty as an important outcome of the state physician health programs (PHPs). In addition, the review and case report by Alexandria G. Polles, MD, and colleagues are a response to the growing call for the state PHP system of care management to explicitly endorse the use of medication-assisted treatment, specifically the use of buprenorphine and methadone, in the treatment of physicians diagnosed with opioid use disorder (OUD). The article usefully situates the controversy in the context of other safety-sensitive jobs, including commercial pilots, truck drivers, and police, because of the elevated rate of substance use disorders among physicians and the safety-sensitive nature of the practice of medicine.

Medication-assisted treatment (MAT)² for opioid use disorders now dominates the field of treatment in terms of prescribing and also funding to address the opioid overdose crisis. MAT generally includes naltrexone and injectable naltrexone, though those antagonist medications have been used successfully for many decades by PHPs.³ However, to understand the controversy over the use of MAT in the care management of physicians first requires an understanding of state PHPs and how those programs oversee the care of physicians diagnosed with substance use disorders (SUDs), including OUDs.

A national blueprint study of PHPs showed that care begins with a formal diagnostic evaluation.⁴ Only when a diagnosis of an SUD is established is a physician referred to the attention of a state PHP, and a monitoring contract is signed. PHPs typically do not offer any direct treatment; instead, they manage the care of physician participants in programs in which the PHPs have confidence. Formal addiction treatment most often is 30 days of residential treatment, but many physicians receive intensive outpatient treatment.

After completing an episode of formal treatment, physicians are closely monitored, usually for 5 years, through random drug and alcohol tests, and work site monitors. They are required to engage in intensive recovery support, typically 12-step fellowships but also other alternative recovery support programs. Comorbid conditions, including mental health disorders, are also treated. Managing PHPs have no sanctions for noncompliance; however, importantly, they do offer a safe haven from state medical licensing boards for physicians who are compliant with their recommendations and who remain abstinent from any use of alcohol, marijuana, illicit drugs, or other nonmedical drug use.

The national blueprint study included 16 state PHPs and reviewed single episodes of PHP care for 908 physicians. Complete abstinence from any use of alcohol, marijuana, or other drugs was required of all physicians for monitoring periods of at least 5 years. During the extended period, 78% of the physicians did not have a single positive or missed test. Two-thirds of physicians who had one positive or missed test did not have a second. About a dozen publications have resulted from this national study, including an analysis of the roughly one-third of the physicians who were diagnosed with OUD.⁵

A sample of 702 PHP participants was grouped based on primary drug at intake: alcohol only, any opioid with or without alcohol, and nonopioid drugs. No significant differences were found among these groups in the percentage who completed PHP contracts, failed to complete their contract, or extended their contract and continued to be monitored. Only one physician received methadone to treat chronic pain. None received opioid agonists to treat their opioid use disorder. Opioid antagonist medication (naltrexone) was used for 40 physicians, or 5.7% of the total sample: 2 physicians (1%) from the alcohol-only group; 35 physicians (10.3%) from the any opioid group, and 3 physicians (1.9%) from nonopioid group.

The second fact that needs to be understood is that medical practice in relationship to SUDs is treated by state licensing boards as a safety-sensitive job, analogous to commercial airline pilots who have the Human Intervention Motivation Study (HIMS),⁶ which is their own care management program analogous to that of PHPs. A similar program exists for attorneys known as Commission on Lawyer Assistance Programs (CoLAP).⁷ Fitness for duty and prevention of harm are major concerns in occupations such as those of physicians, commercial truck drivers, and people working in the nuclear power industry, all of whom have similar safety protections requiring no drug use.

A third fact that deserves special attention is that the unique system of care management for physicians began in the early 1970s. It grew out of employee assistance programs, led then and often now by physicians who are themselves in recovery from SUDs. Many of the successful addiction treatment tools used today come from extensive research of their use in PHPs. Contingency management, 12 steps, caduceus recovery, cognitive-behavioral therapy, and treatment outcomes defined in years are examples in which PHP research helped change treatment and long-term management of SUDs in non-PHP populations.

Dr. Polles and colleagues provide an impressive and comprehensive summary of the issues involved in the new interest in providing the physicians with OUD under PHP care management the option of using buprenorphine or methadone. Such a model within an abstinence-based framework is now being pioneered by a variety of programs, from COAT⁸ at West Virginia University, Morgantown, to the Hazelden Betty Ford Foundation.⁹ In those programs, patients with OUD are offered the option of using buprenorphine, methadone, or naltrexone as well as the option of using none of those medications in an extended abstinence-based intensive treatment. The authors impressively and fairly summarize the evidence on whether there are cognitive or behavioral deficits associated with the therapeutic use of either buprenorphine or methadone, which might make them unacceptable for physicians. The strongest evidence that these medicines are not necessary in the treatment of OUDs in PHPs is the outstanding outcomes PHPs produce without use of these two medications. If skeptical of the use of medications for OUD treatment in PHP care management, Dr. Polles and colleagues are open to experiments to test the effects of this option just as Florida PHP programs pioneered contracts that included mandatory naltrexone.¹⁰ West Virginia University, the Hazelden Betty Ford Foundation, and other programs should be tested to evaluate just how safe, effective, and attractive such an option would be to physicians.

Many, if not most, SUD treatment programs that use MAT are not associated with the intensive psychological treatment or extended participation in recovery support, such as the 12-step fellowships. MAT is viewed as a harm reduction strategy rather than conceptualized as an abstinence-oriented treatment. For example, there is seldom a “sobriety date” among individuals in MAT, i.e., the last day the individual used any substance of abuse, including alcohol and marijuana. These are, however, central features of PHP care, and they are features of the Hazelden Betty Ford Foundation’s definition of recovery¹¹ and use of MAT.

Dr. Polles and colleagues call attention to the unique care management of the PHP for all SUDs, not just for OUDs, because the PHPs set the standard for returning physicians to work who have the fitness and cognitive skills to first do no harm. They emphasize the importance of making sustained recovery the expected outcome of SUD treatment. There is a robust literature on the ways in which this distinctive system of care management shows the path forward for addiction treatment generally to regularly achieve 5-year recovery.¹² The current controversy over the potential use of buprenorphine and buprenorphine plus naloxone in PHPs is a useful entry into this far larger issue of the potential for PHPs to show the path forward for the addiction treatment field.
 

Dr. DuPont, the first director of the National Institute on Drug Abuse (NIDA), is president of the Institute for Behavior and Health Inc., a nonprofit drug-policy research organization in Rockville, Md. He has no disclosures. Dr. Gold is professor of psychiatry (adjunct) at Washington University in St. Louis. He is also the 17th Distinguished Alumni Professor at the University of Florida Gainesville. He has no disclosures.

References

1. Polles AG et al. J Neurol Sci. 2020 Jan 30;411:116714.

2. Oesterle TS et al. Mayo Clin Proc. 2019 Oct;94(10):2072-86.

3. Srivastava AB and Gold MS. Cerebrum. 2018 Sep-Oct; cer-13-8.

4. DuPont RL et al. J Subst Abuse Treat. 2009 Mar 1;36(2):159-71.

5. Merlo LJ et al. J Subst Abuse Treat. 2016 May 1;64:47-54.

6. Human Intervention Motivation Study (HIMS): An Occupational Substance Abuse Treatment Program.

7. Commission on Lawyer Assistance Programs (CoLAP).

8. Lander LR et al. J Neurol Sci. 2020;411:116712-8.

9. Klein AA et al. J Subst Abuse Treat. 2019;104:51-63.

10. Merlo LJ et al. J Addict Med. 2012;5(4):279-83.

11. Betty Ford Consensus Panel. J Subst Abuse Treat. 2007 Oct;33(3):221-8.

12. Carr GD et al. “Physician health programs: The U.S. model.” In KJ Brower and MB Riba, (eds.) Physician Mental Health and Well-Being (pp. 265-94). Cham, Switzerland: Springer International Publishing, 2017.

A new article in the Journal of the Neurological Sciences provides an impressive review of research on the complex impairments produced by a wide range of drugs of abuse with a close look at physicians and other health care professionals.¹

This review breaks new ground in outlining fitness for duty as an important outcome of the state physician health programs (PHPs). In addition, the review and case report by Alexandria G. Polles, MD, and colleagues are a response to the growing call for the state PHP system of care management to explicitly endorse the use of medication-assisted treatment, specifically the use of buprenorphine and methadone, in the treatment of physicians diagnosed with opioid use disorder (OUD). The article usefully situates the controversy in the context of other safety-sensitive jobs, including commercial pilots, truck drivers, and police, because of the elevated rate of substance use disorders among physicians and the safety-sensitive nature of the practice of medicine.

Medication-assisted treatment (MAT)² for opioid use disorders now dominates the field of treatment in terms of prescribing and also funding to address the opioid overdose crisis. MAT generally includes naltrexone and injectable naltrexone, though those antagonist medications have been used successfully for many decades by PHPs.³ However, to understand the controversy over the use of MAT in the care management of physicians first requires an understanding of state PHPs and how those programs oversee the care of physicians diagnosed with substance use disorders (SUDs), including OUDs.

A national blueprint study of PHPs showed that care begins with a formal diagnostic evaluation.⁴ Only when a diagnosis of an SUD is established is a physician referred to the attention of a state PHP, and a monitoring contract is signed. PHPs typically do not offer any direct treatment; instead, they manage the care of physician participants in programs in which the PHPs have confidence. Formal addiction treatment most often is 30 days of residential treatment, but many physicians receive intensive outpatient treatment.

After completing an episode of formal treatment, physicians are closely monitored, usually for 5 years, through random drug and alcohol tests, and work site monitors. They are required to engage in intensive recovery support, typically 12-step fellowships but also other alternative recovery support programs. Comorbid conditions, including mental health disorders, are also treated. Managing PHPs have no sanctions for noncompliance; however, importantly, they do offer a safe haven from state medical licensing boards for physicians who are compliant with their recommendations and who remain abstinent from any use of alcohol, marijuana, illicit drugs, or other nonmedical drug use.

The national blueprint study included 16 state PHPs and reviewed single episodes of PHP care for 908 physicians. Complete abstinence from any use of alcohol, marijuana, or other drugs was required of all physicians for monitoring periods of at least 5 years. During the extended period, 78% of the physicians did not have a single positive or missed test. Two-thirds of physicians who had one positive or missed test did not have a second. About a dozen publications have resulted from this national study, including an analysis of the roughly one-third of the physicians who were diagnosed with OUD.⁵

A sample of 702 PHP participants was grouped based on primary drug at intake: alcohol only, any opioid with or without alcohol, and nonopioid drugs. No significant differences were found among these groups in the percentage who completed PHP contracts, failed to complete their contract, or extended their contract and continued to be monitored. Only one physician received methadone to treat chronic pain. None received opioid agonists to treat their opioid use disorder. Opioid antagonist medication (naltrexone) was used for 40 physicians, or 5.7% of the total sample: 2 physicians (1%) from the alcohol-only group; 35 physicians (10.3%) from the any opioid group, and 3 physicians (1.9%) from nonopioid group.

The second fact that needs to be understood is that medical practice in relationship to SUDs is treated by state licensing boards as a safety-sensitive job, analogous to commercial airline pilots who have the Human Intervention Motivation Study (HIMS),⁶ which is their own care management program analogous to that of PHPs. A similar program exists for attorneys known as Commission on Lawyer Assistance Programs (CoLAP).⁷ Fitness for duty and prevention of harm are major concerns in occupations such as those of physicians, commercial truck drivers, and people working in the nuclear power industry, all of whom have similar safety protections requiring no drug use.

A third fact that deserves special attention is that the unique system of care management for physicians began in the early 1970s. It grew out of employee assistance programs, led then and often now by physicians who are themselves in recovery from SUDs. Many of the successful addiction treatment tools used today come from extensive research of their use in PHPs. Contingency management, 12 steps, caduceus recovery, cognitive-behavioral therapy, and treatment outcomes defined in years are examples in which PHP research helped change treatment and long-term management of SUDs in non-PHP populations.

Dr. Polles and colleagues provide an impressive and comprehensive summary of the issues involved in the new interest in providing the physicians with OUD under PHP care management the option of using buprenorphine or methadone. Such a model within an abstinence-based framework is now being pioneered by a variety of programs, from COAT⁸ at West Virginia University, Morgantown, to the Hazelden Betty Ford Foundation.⁹ In those programs, patients with OUD are offered the option of using buprenorphine, methadone, or naltrexone as well as the option of using none of those medications in an extended abstinence-based intensive treatment. The authors impressively and fairly summarize the evidence on whether there are cognitive or behavioral deficits associated with the therapeutic use of either buprenorphine or methadone, which might make them unacceptable for physicians. The strongest evidence that these medicines are not necessary in the treatment of OUDs in PHPs is the outstanding outcomes PHPs produce without use of these two medications. If skeptical of the use of medications for OUD treatment in PHP care management, Dr. Polles and colleagues are open to experiments to test the effects of this option just as Florida PHP programs pioneered contracts that included mandatory naltrexone.¹⁰ West Virginia University, the Hazelden Betty Ford Foundation, and other programs should be tested to evaluate just how safe, effective, and attractive such an option would be to physicians.

Many, if not most, SUD treatment programs that use MAT are not associated with the intensive psychological treatment or extended participation in recovery support, such as the 12-step fellowships. MAT is viewed as a harm reduction strategy rather than conceptualized as an abstinence-oriented treatment. For example, there is seldom a “sobriety date” among individuals in MAT, i.e., the last day the individual used any substance of abuse, including alcohol and marijuana. These are, however, central features of PHP care, and they are features of the Hazelden Betty Ford Foundation’s definition of recovery¹¹ and use of MAT.

Dr. Polles and colleagues call attention to the unique care management of the PHP for all SUDs, not just for OUDs, because the PHPs set the standard for returning physicians to work who have the fitness and cognitive skills to first do no harm. They emphasize the importance of making sustained recovery the expected outcome of SUD treatment. There is a robust literature on the ways in which this distinctive system of care management shows the path forward for addiction treatment generally to regularly achieve 5-year recovery.¹² The current controversy over the potential use of buprenorphine and buprenorphine plus naloxone in PHPs is a useful entry into this far larger issue of the potential for PHPs to show the path forward for the addiction treatment field.
 

Dr. DuPont, the first director of the National Institute on Drug Abuse (NIDA), is president of the Institute for Behavior and Health Inc., a nonprofit drug-policy research organization in Rockville, Md. He has no disclosures. Dr. Gold is professor of psychiatry (adjunct) at Washington University in St. Louis. He is also the 17th Distinguished Alumni Professor at the University of Florida Gainesville. He has no disclosures.

References

1. Polles AG et al. J Neurol Sci. 2020 Jan 30;411:116714.

2. Oesterle TS et al. Mayo Clin Proc. 2019 Oct;94(10):2072-86.

3. Srivastava AB and Gold MS. Cerebrum. 2018 Sep-Oct; cer-13-8.

4. DuPont RL et al. J Subst Abuse Treat. 2009 Mar 1;36(2):159-71.

5. Merlo LJ et al. J Subst Abuse Treat. 2016 May 1;64:47-54.

6. Human Intervention Motivation Study (HIMS): An Occupational Substance Abuse Treatment Program.

7. Commission on Lawyer Assistance Programs (CoLAP).

8. Lander LR et al. J Neurol Sci. 2020;411:116712-8.

9. Klein AA et al. J Subst Abuse Treat. 2019;104:51-63.

10. Merlo LJ et al. J Addict Med. 2012;5(4):279-83.

11. Betty Ford Consensus Panel. J Subst Abuse Treat. 2007 Oct;33(3):221-8.

12. Carr GD et al. “Physician health programs: The U.S. model.” In KJ Brower and MB Riba, (eds.) Physician Mental Health and Well-Being (pp. 265-94). Cham, Switzerland: Springer International Publishing, 2017.