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Treatment with high-dose methylprednisolone plus tocilizumab (Actemra, Genentech) as needed was associated with faster respiratory recovery, a lower likelihood of mechanical ventilation, and fewer in-hospital deaths compared with supportive care alone among people with COVID-19 experiencing a hyperinflammatory state known as a cytokine storm.

Compared with historic controls, participants in the treatment group were 79% more likely to achieve at least a two-stage improvement in respiratory status, for example.

“COVID-19-associated cytokine storm syndrome [CSS] is an important complication of severe acute respiratory syndrome coronavirus-2 infection in up to 25% of the patients,” lead author Sofia Ramiro, MD, PhD, said in an interview.

Furthermore, CSS often leads to death in this population, said Dr. Ramiro, a consultant rheumatologist and senior researcher at Leiden University Medical Center and Zuyderland Medical Center in Heerlen, the Netherlands.

Results of the COVID High-Intensity Immunosuppression in Cytokine Storm Syndrome (CHIC) study were published online July 20 in Annals of the Rheumatic Diseases.
 

Contrary to guidance?

The World Health Organization (WHO) cautions against administering corticosteroids to some critically ill patients with COVID-19. “WHO recommends against the routine use of systemic corticosteroids for treatment of viral pneumonia,” according to an interim guidance document on the clinical management of COVID-19 published May 27.

Dr. Ramiro and colleagues make a distinction, however, noting “the risk profile of such a short course of glucocorticoid for treatment of CSS needs to be separated from preexisting chronic use of glucocorticoid for conditions like rheumatic and musculoskeletal diseases.”

Participants in the current study tolerated immunosuppressive therapy well without evidence of impaired viral clearance or bacterial superinfection, they added.

Other experts disagree with recent recommendations to use corticosteroids to treat a hyperimmune response or suspected adrenal insufficiency in the setting of refractory shock in patients with COVID-19.

Information about immunosuppressive therapy and CSS linked to COVID-19 remains anecdotal, however, Dr. Ramiro and colleagues noted.

The researchers assessed outcomes of 86 individuals with COVID-19-associated CSS treated with high-dose methylprednisolone plus/minus tocilizumab, an anti-interleukin-6 receptor monoclonal antibody. They compared them with another 86 patients with COVID-19 treated with supportive care before initiation of the combination therapy protocol.

Participants with CSS had an oxygen saturation of 94% or lower at rest or tachypnea exceeding 30 breaths per minute.

They also had at least two of the following: C-reactive protein > 100 mg/L; serum ferritin > 900 mcg/L at one occasion or a twofold increase at admission within 48 hours; or D-dimer levels > 1,500 mcg/L.

The treatment group received methylprednisolone 250 mg intravenously on day 1, followed by 80 mg intravenously on days 2-5. Investigators permitted a 2-day extension if indicated.

Those who failed to clinically improve or experienced respiratory decline could also receive intravenous tocilizumab on day 2 or after. The agent was dosed at 8 mg/kg body weight during a single infusion from day 2-5 up to a maximum of 800 mg.

In all, 37 participants received tocilizumab, including two participants who received a second dose 5 days after initial treatment.  

Except for one patient in the treatment group, all participants also received antibiotic treatment and nearly 80% received chloroquine.
 

Mechanical ventilation and mortality

The primary outcome of at least a two-stage improvement in respiratory status on a WHO scale associated with treatment yielded a hazard ratio (HR) of 1.79. The treatment group achieved this improvement a median 7 days earlier than controls.

Mechanical ventilation to treat respiratory deterioration was 71% less likely for the treatment group versus controls (HR, 0.29).

The treatment group were also 65% less likely to die in hospital (HR, 0.35) than were controls.

The researchers also reported a significant difference in the number of deaths at day 14 in the treatment vs. control group, at 10 vs. 33 patients (P < .0001).
 

Glucocorticoid sufficient for many

In a sensitivity analysis excluding patients who received tocilizumab, the benefits of treatment remained statistically significant, “suggesting that a clinically relevant treatment effect can be reached by high-dose glucocorticoids alone,” the researchers noted.

This finding suggests “that the timely administration of high-dose glucocorticoids alone may provide significant benefit in more than half of the patients, and that tocilizumab is only needed in those cases that had insufficient clinical improvement on methylprednisolone alone,” they added.

“This is an important finding given the limited availability of tocilizumab in many countries and tocilizumab’s high costs.”

Complications were fairly balanced between groups. For example, bacterial infections during hospitalization were diagnosed in eight patients in the treatment group versus seven in the control group.

In addition, cardiac arrhythmias occurred in both groups, but slightly less frequently in the treatment group (P = .265), and there was a trend towards more pulmonary embolisms in the treatment group (P = .059).
 

Strengths and limitations

“A treatment with high-dose glucocorticoids is a convenient choice since glucocorticoids are safe, widely available, and inexpensive,” the researchers noted. “Longer follow-up, however, is needed to give final resolution about the safety and efficacy of the strategy.”

A strength of the study was “meticulous selection of those patients more likely to benefit from immunosuppressive treatment, namely patients with a CSS,” she added.

The study featured a prospective, observational design for the treatment group and retrospective analysis of the historic controls. “Methodologically, the main limitation of the study is not being a randomized controlled trial,” she noted.

“Ethically it has shown to be very rewarding to consciously decide against a randomized control trial, as we are talking about a disease that if only treated with supportive care can lead to mortality up to almost 50% from COVID-19-associated CSS,” Dr. Ramiro said.

Going forward, Dr. Ramiro plans to continue monitoring patients who experienced CSS to assess their outcome post-COVID-19 infection. “We want to focus on cardiorespiratory, functional, and quality of life outcomes,” she said. “We will also compare the outcomes between patients that have received immunosuppression with those that haven’t.”
 

‘Quite interesting’ results

“We desperately need better evidence to guide the management of patients hospitalized with COVID-19,” Nihar R. Desai, MD, MPH, who was not affiliated with the study, said in an interview.

“These data from the Netherlands are quite interesting and provide another signal to support the use of corticosteroids, with tocilizumab if needed, among hospitalized patients with COVID-19 to improve outcomes,” added Dr. Desai, associate professor of medicine and investigator at the Center for Outcomes Research and Evaluation, Yale University, New Haven, Conn.

“While these data are not randomized and have a relatively small sample size, we had recently seen the results of the RECOVERY trial, a UK-based randomized trial demonstrating the benefit of steroids in COVID-19,” he said.

“Taken together, these studies seem to suggest that there is a benefit with steroid therapy.” Further validation of these results is warranted, he added.
“While not a randomized clinical trial, and thus susceptible to unmeasured bias, the study adds to mounting evidence that supports targeting the excessive inflammation found in some patients with COVID-19,” Jared Radbel, MD, a pulmonologist, critical care specialist, and assistant professor of medicine at Rutgers Robert Wood Johnson Medical School, New Brunswick, N.J., said in an interview.

Dr. Radbel added that he is part of a multicenter group that has submitted a manuscript examining outcomes of critically ill patients with COVID-19 treated with tocilizumab.

Dr. Ramiro, Dr. Desai, and Dr. Radbel have disclosed no relevant financial relationships.
 

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

Treatment with high-dose methylprednisolone plus tocilizumab (Actemra, Genentech) as needed was associated with faster respiratory recovery, a lower likelihood of mechanical ventilation, and fewer in-hospital deaths compared with supportive care alone among people with COVID-19 experiencing a hyperinflammatory state known as a cytokine storm.

Compared with historic controls, participants in the treatment group were 79% more likely to achieve at least a two-stage improvement in respiratory status, for example.

“COVID-19-associated cytokine storm syndrome [CSS] is an important complication of severe acute respiratory syndrome coronavirus-2 infection in up to 25% of the patients,” lead author Sofia Ramiro, MD, PhD, said in an interview.

Furthermore, CSS often leads to death in this population, said Dr. Ramiro, a consultant rheumatologist and senior researcher at Leiden University Medical Center and Zuyderland Medical Center in Heerlen, the Netherlands.

Results of the COVID High-Intensity Immunosuppression in Cytokine Storm Syndrome (CHIC) study were published online July 20 in Annals of the Rheumatic Diseases.
 

Contrary to guidance?

The World Health Organization (WHO) cautions against administering corticosteroids to some critically ill patients with COVID-19. “WHO recommends against the routine use of systemic corticosteroids for treatment of viral pneumonia,” according to an interim guidance document on the clinical management of COVID-19 published May 27.

Dr. Ramiro and colleagues make a distinction, however, noting “the risk profile of such a short course of glucocorticoid for treatment of CSS needs to be separated from preexisting chronic use of glucocorticoid for conditions like rheumatic and musculoskeletal diseases.”

Participants in the current study tolerated immunosuppressive therapy well without evidence of impaired viral clearance or bacterial superinfection, they added.

Other experts disagree with recent recommendations to use corticosteroids to treat a hyperimmune response or suspected adrenal insufficiency in the setting of refractory shock in patients with COVID-19.

Information about immunosuppressive therapy and CSS linked to COVID-19 remains anecdotal, however, Dr. Ramiro and colleagues noted.

The researchers assessed outcomes of 86 individuals with COVID-19-associated CSS treated with high-dose methylprednisolone plus/minus tocilizumab, an anti-interleukin-6 receptor monoclonal antibody. They compared them with another 86 patients with COVID-19 treated with supportive care before initiation of the combination therapy protocol.

Participants with CSS had an oxygen saturation of 94% or lower at rest or tachypnea exceeding 30 breaths per minute.

They also had at least two of the following: C-reactive protein > 100 mg/L; serum ferritin > 900 mcg/L at one occasion or a twofold increase at admission within 48 hours; or D-dimer levels > 1,500 mcg/L.

The treatment group received methylprednisolone 250 mg intravenously on day 1, followed by 80 mg intravenously on days 2-5. Investigators permitted a 2-day extension if indicated.

Those who failed to clinically improve or experienced respiratory decline could also receive intravenous tocilizumab on day 2 or after. The agent was dosed at 8 mg/kg body weight during a single infusion from day 2-5 up to a maximum of 800 mg.

In all, 37 participants received tocilizumab, including two participants who received a second dose 5 days after initial treatment.  

Except for one patient in the treatment group, all participants also received antibiotic treatment and nearly 80% received chloroquine.
 

Mechanical ventilation and mortality

The primary outcome of at least a two-stage improvement in respiratory status on a WHO scale associated with treatment yielded a hazard ratio (HR) of 1.79. The treatment group achieved this improvement a median 7 days earlier than controls.

Mechanical ventilation to treat respiratory deterioration was 71% less likely for the treatment group versus controls (HR, 0.29).

The treatment group were also 65% less likely to die in hospital (HR, 0.35) than were controls.

The researchers also reported a significant difference in the number of deaths at day 14 in the treatment vs. control group, at 10 vs. 33 patients (P < .0001).
 

Glucocorticoid sufficient for many

In a sensitivity analysis excluding patients who received tocilizumab, the benefits of treatment remained statistically significant, “suggesting that a clinically relevant treatment effect can be reached by high-dose glucocorticoids alone,” the researchers noted.

This finding suggests “that the timely administration of high-dose glucocorticoids alone may provide significant benefit in more than half of the patients, and that tocilizumab is only needed in those cases that had insufficient clinical improvement on methylprednisolone alone,” they added.

“This is an important finding given the limited availability of tocilizumab in many countries and tocilizumab’s high costs.”

Complications were fairly balanced between groups. For example, bacterial infections during hospitalization were diagnosed in eight patients in the treatment group versus seven in the control group.

In addition, cardiac arrhythmias occurred in both groups, but slightly less frequently in the treatment group (P = .265), and there was a trend towards more pulmonary embolisms in the treatment group (P = .059).
 

Strengths and limitations

“A treatment with high-dose glucocorticoids is a convenient choice since glucocorticoids are safe, widely available, and inexpensive,” the researchers noted. “Longer follow-up, however, is needed to give final resolution about the safety and efficacy of the strategy.”

A strength of the study was “meticulous selection of those patients more likely to benefit from immunosuppressive treatment, namely patients with a CSS,” she added.

The study featured a prospective, observational design for the treatment group and retrospective analysis of the historic controls. “Methodologically, the main limitation of the study is not being a randomized controlled trial,” she noted.

“Ethically it has shown to be very rewarding to consciously decide against a randomized control trial, as we are talking about a disease that if only treated with supportive care can lead to mortality up to almost 50% from COVID-19-associated CSS,” Dr. Ramiro said.

Going forward, Dr. Ramiro plans to continue monitoring patients who experienced CSS to assess their outcome post-COVID-19 infection. “We want to focus on cardiorespiratory, functional, and quality of life outcomes,” she said. “We will also compare the outcomes between patients that have received immunosuppression with those that haven’t.”
 

‘Quite interesting’ results

“We desperately need better evidence to guide the management of patients hospitalized with COVID-19,” Nihar R. Desai, MD, MPH, who was not affiliated with the study, said in an interview.

“These data from the Netherlands are quite interesting and provide another signal to support the use of corticosteroids, with tocilizumab if needed, among hospitalized patients with COVID-19 to improve outcomes,” added Dr. Desai, associate professor of medicine and investigator at the Center for Outcomes Research and Evaluation, Yale University, New Haven, Conn.

“While these data are not randomized and have a relatively small sample size, we had recently seen the results of the RECOVERY trial, a UK-based randomized trial demonstrating the benefit of steroids in COVID-19,” he said.

“Taken together, these studies seem to suggest that there is a benefit with steroid therapy.” Further validation of these results is warranted, he added.
“While not a randomized clinical trial, and thus susceptible to unmeasured bias, the study adds to mounting evidence that supports targeting the excessive inflammation found in some patients with COVID-19,” Jared Radbel, MD, a pulmonologist, critical care specialist, and assistant professor of medicine at Rutgers Robert Wood Johnson Medical School, New Brunswick, N.J., said in an interview.

Dr. Radbel added that he is part of a multicenter group that has submitted a manuscript examining outcomes of critically ill patients with COVID-19 treated with tocilizumab.

Dr. Ramiro, Dr. Desai, and Dr. Radbel have disclosed no relevant financial relationships.
 

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

Treatment with high-dose methylprednisolone plus tocilizumab (Actemra, Genentech) as needed was associated with faster respiratory recovery, a lower likelihood of mechanical ventilation, and fewer in-hospital deaths compared with supportive care alone among people with COVID-19 experiencing a hyperinflammatory state known as a cytokine storm.

Compared with historic controls, participants in the treatment group were 79% more likely to achieve at least a two-stage improvement in respiratory status, for example.

“COVID-19-associated cytokine storm syndrome [CSS] is an important complication of severe acute respiratory syndrome coronavirus-2 infection in up to 25% of the patients,” lead author Sofia Ramiro, MD, PhD, said in an interview.

Furthermore, CSS often leads to death in this population, said Dr. Ramiro, a consultant rheumatologist and senior researcher at Leiden University Medical Center and Zuyderland Medical Center in Heerlen, the Netherlands.

Results of the COVID High-Intensity Immunosuppression in Cytokine Storm Syndrome (CHIC) study were published online July 20 in Annals of the Rheumatic Diseases.
 

Contrary to guidance?

The World Health Organization (WHO) cautions against administering corticosteroids to some critically ill patients with COVID-19. “WHO recommends against the routine use of systemic corticosteroids for treatment of viral pneumonia,” according to an interim guidance document on the clinical management of COVID-19 published May 27.

Dr. Ramiro and colleagues make a distinction, however, noting “the risk profile of such a short course of glucocorticoid for treatment of CSS needs to be separated from preexisting chronic use of glucocorticoid for conditions like rheumatic and musculoskeletal diseases.”

Participants in the current study tolerated immunosuppressive therapy well without evidence of impaired viral clearance or bacterial superinfection, they added.

Other experts disagree with recent recommendations to use corticosteroids to treat a hyperimmune response or suspected adrenal insufficiency in the setting of refractory shock in patients with COVID-19.

Information about immunosuppressive therapy and CSS linked to COVID-19 remains anecdotal, however, Dr. Ramiro and colleagues noted.

The researchers assessed outcomes of 86 individuals with COVID-19-associated CSS treated with high-dose methylprednisolone plus/minus tocilizumab, an anti-interleukin-6 receptor monoclonal antibody. They compared them with another 86 patients with COVID-19 treated with supportive care before initiation of the combination therapy protocol.

Participants with CSS had an oxygen saturation of 94% or lower at rest or tachypnea exceeding 30 breaths per minute.

They also had at least two of the following: C-reactive protein > 100 mg/L; serum ferritin > 900 mcg/L at one occasion or a twofold increase at admission within 48 hours; or D-dimer levels > 1,500 mcg/L.

The treatment group received methylprednisolone 250 mg intravenously on day 1, followed by 80 mg intravenously on days 2-5. Investigators permitted a 2-day extension if indicated.

Those who failed to clinically improve or experienced respiratory decline could also receive intravenous tocilizumab on day 2 or after. The agent was dosed at 8 mg/kg body weight during a single infusion from day 2-5 up to a maximum of 800 mg.

In all, 37 participants received tocilizumab, including two participants who received a second dose 5 days after initial treatment.  

Except for one patient in the treatment group, all participants also received antibiotic treatment and nearly 80% received chloroquine.
 

Mechanical ventilation and mortality

The primary outcome of at least a two-stage improvement in respiratory status on a WHO scale associated with treatment yielded a hazard ratio (HR) of 1.79. The treatment group achieved this improvement a median 7 days earlier than controls.

Mechanical ventilation to treat respiratory deterioration was 71% less likely for the treatment group versus controls (HR, 0.29).

The treatment group were also 65% less likely to die in hospital (HR, 0.35) than were controls.

The researchers also reported a significant difference in the number of deaths at day 14 in the treatment vs. control group, at 10 vs. 33 patients (P < .0001).
 

Glucocorticoid sufficient for many

In a sensitivity analysis excluding patients who received tocilizumab, the benefits of treatment remained statistically significant, “suggesting that a clinically relevant treatment effect can be reached by high-dose glucocorticoids alone,” the researchers noted.

This finding suggests “that the timely administration of high-dose glucocorticoids alone may provide significant benefit in more than half of the patients, and that tocilizumab is only needed in those cases that had insufficient clinical improvement on methylprednisolone alone,” they added.

“This is an important finding given the limited availability of tocilizumab in many countries and tocilizumab’s high costs.”

Complications were fairly balanced between groups. For example, bacterial infections during hospitalization were diagnosed in eight patients in the treatment group versus seven in the control group.

In addition, cardiac arrhythmias occurred in both groups, but slightly less frequently in the treatment group (P = .265), and there was a trend towards more pulmonary embolisms in the treatment group (P = .059).
 

Strengths and limitations

“A treatment with high-dose glucocorticoids is a convenient choice since glucocorticoids are safe, widely available, and inexpensive,” the researchers noted. “Longer follow-up, however, is needed to give final resolution about the safety and efficacy of the strategy.”

A strength of the study was “meticulous selection of those patients more likely to benefit from immunosuppressive treatment, namely patients with a CSS,” she added.

The study featured a prospective, observational design for the treatment group and retrospective analysis of the historic controls. “Methodologically, the main limitation of the study is not being a randomized controlled trial,” she noted.

“Ethically it has shown to be very rewarding to consciously decide against a randomized control trial, as we are talking about a disease that if only treated with supportive care can lead to mortality up to almost 50% from COVID-19-associated CSS,” Dr. Ramiro said.

Going forward, Dr. Ramiro plans to continue monitoring patients who experienced CSS to assess their outcome post-COVID-19 infection. “We want to focus on cardiorespiratory, functional, and quality of life outcomes,” she said. “We will also compare the outcomes between patients that have received immunosuppression with those that haven’t.”
 

‘Quite interesting’ results

“We desperately need better evidence to guide the management of patients hospitalized with COVID-19,” Nihar R. Desai, MD, MPH, who was not affiliated with the study, said in an interview.

“These data from the Netherlands are quite interesting and provide another signal to support the use of corticosteroids, with tocilizumab if needed, among hospitalized patients with COVID-19 to improve outcomes,” added Dr. Desai, associate professor of medicine and investigator at the Center for Outcomes Research and Evaluation, Yale University, New Haven, Conn.

“While these data are not randomized and have a relatively small sample size, we had recently seen the results of the RECOVERY trial, a UK-based randomized trial demonstrating the benefit of steroids in COVID-19,” he said.

“Taken together, these studies seem to suggest that there is a benefit with steroid therapy.” Further validation of these results is warranted, he added.
“While not a randomized clinical trial, and thus susceptible to unmeasured bias, the study adds to mounting evidence that supports targeting the excessive inflammation found in some patients with COVID-19,” Jared Radbel, MD, a pulmonologist, critical care specialist, and assistant professor of medicine at Rutgers Robert Wood Johnson Medical School, New Brunswick, N.J., said in an interview.

Dr. Radbel added that he is part of a multicenter group that has submitted a manuscript examining outcomes of critically ill patients with COVID-19 treated with tocilizumab.

Dr. Ramiro, Dr. Desai, and Dr. Radbel have disclosed no relevant financial relationships.
 

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

COVID-19 can mean weeks’ long illness, even in young adults and those without chronic conditions who have mild disease and are treated in outpatient settings, according to survey results in Morbidity and Mortality Weekly Report from the Centers for Disease Control and Prevention.

Mark W. Tenforde, MD, PhD, for the CDC-COVID-19 Response Team, and colleagues conducted a multistate telephone survey of symptomatic adults who tested positive for SARS-CoV-2. The researchers found that 35% had not returned to their usual state of wellness when they were interviewed 2-3 weeks after testing.

Among the 270 of 274 people interviewed for whom there were data on return to health, 175 (65%) reported that they had returned to baseline health an average of 7 days from the date of testing.

Among the 274 symptomatic outpatients, the median number of symptoms was seven. Fatigue (71%), cough (61%), and headache (61%) were the most commonly reported symptoms.

Prolonged illness is well described in adults hospitalized with severe COVID-19, especially among the older adult population, but little is known about other groups.

The proportion who had not returned to health differed by age: 26% of interviewees aged 18-34 years, 32% of those aged 35-49 years, and 47% of those at least 50 years old reported not having returned to their usual health (P = .010) within 14-21 days after receiving positive test results.

Among respondents aged 18-34 years who had no chronic medical condition, 19% (9 of 48) reported not having returned to their usual state of health during that time.

Public health messaging targeting younger adults, a group who might not be expected to be sick for weeks with mild disease, is particularly important, the authors wrote.

Kyle Annen, DO, medical director of transfusion services and patient blood management at Children’s Hospital Colorado and assistant professor of pathology at the University of Colorado, Denver, said in an interview that an important message is that delayed recovery (symptoms of fatigue, cough, and shortness of breath) was evident in nearly a quarter of 18- to 34-year-olds and in a third of 35- to 49-year-olds who were not sick enough to require hospitalization.

“This should impact the perception of this being a mild illness in the young adult population and encourage them to comply with recommendations of social distancing, masking, and hand washing,” she said.

Recovery time of more than 2 weeks will affect work and school performance, especially prolonged fatigue, she noted. This was one of the prominent symptoms that were reported to be slow to dissipate.

“I think the most interesting point in this study is that of underlying conditions; psychiatric conditions were significantly correlated with prolonged recovery. I don’t think that many people think of depression and anxiety as an underlying medical condition in regards to COVID-19 risk. This could potentially have an impact, as depression and anxiety rates will likely increase as COVID-19 continues,” she said.

Buddy Creech, MD, MPH, said in an interview that it is “important to realize that the spectrum of disease with COVID is wide, including mild disease, severe disease, and prolonged disease. This report helps us understand some of the risk factors for those with prolonged symptoms and may allow us to refine even more clearly how we prioritize treatment and vaccine administration, once available.

“It also highlights the challenge of dealing with this virus. Not only do the symptoms vary widely, but so do the incubation period, the duration of symptoms, and the residual symptoms that sometimes occur. Clearly, there is much we still need to understand about this virus,” he said.

The interviews were conducted from April 15 to June 25 with a random sample of adults at least 18 years old who had received a first positive test result for SARS-CoV-2 at an outpatient visit at one of 14 US academic healthcare systems in 13 states.
 

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

COVID-19 can mean weeks’ long illness, even in young adults and those without chronic conditions who have mild disease and are treated in outpatient settings, according to survey results in Morbidity and Mortality Weekly Report from the Centers for Disease Control and Prevention.

Mark W. Tenforde, MD, PhD, for the CDC-COVID-19 Response Team, and colleagues conducted a multistate telephone survey of symptomatic adults who tested positive for SARS-CoV-2. The researchers found that 35% had not returned to their usual state of wellness when they were interviewed 2-3 weeks after testing.

Among the 270 of 274 people interviewed for whom there were data on return to health, 175 (65%) reported that they had returned to baseline health an average of 7 days from the date of testing.

Among the 274 symptomatic outpatients, the median number of symptoms was seven. Fatigue (71%), cough (61%), and headache (61%) were the most commonly reported symptoms.

Prolonged illness is well described in adults hospitalized with severe COVID-19, especially among the older adult population, but little is known about other groups.

The proportion who had not returned to health differed by age: 26% of interviewees aged 18-34 years, 32% of those aged 35-49 years, and 47% of those at least 50 years old reported not having returned to their usual health (P = .010) within 14-21 days after receiving positive test results.

Among respondents aged 18-34 years who had no chronic medical condition, 19% (9 of 48) reported not having returned to their usual state of health during that time.

Public health messaging targeting younger adults, a group who might not be expected to be sick for weeks with mild disease, is particularly important, the authors wrote.

Kyle Annen, DO, medical director of transfusion services and patient blood management at Children’s Hospital Colorado and assistant professor of pathology at the University of Colorado, Denver, said in an interview that an important message is that delayed recovery (symptoms of fatigue, cough, and shortness of breath) was evident in nearly a quarter of 18- to 34-year-olds and in a third of 35- to 49-year-olds who were not sick enough to require hospitalization.

“This should impact the perception of this being a mild illness in the young adult population and encourage them to comply with recommendations of social distancing, masking, and hand washing,” she said.

Recovery time of more than 2 weeks will affect work and school performance, especially prolonged fatigue, she noted. This was one of the prominent symptoms that were reported to be slow to dissipate.

“I think the most interesting point in this study is that of underlying conditions; psychiatric conditions were significantly correlated with prolonged recovery. I don’t think that many people think of depression and anxiety as an underlying medical condition in regards to COVID-19 risk. This could potentially have an impact, as depression and anxiety rates will likely increase as COVID-19 continues,” she said.

Buddy Creech, MD, MPH, said in an interview that it is “important to realize that the spectrum of disease with COVID is wide, including mild disease, severe disease, and prolonged disease. This report helps us understand some of the risk factors for those with prolonged symptoms and may allow us to refine even more clearly how we prioritize treatment and vaccine administration, once available.

“It also highlights the challenge of dealing with this virus. Not only do the symptoms vary widely, but so do the incubation period, the duration of symptoms, and the residual symptoms that sometimes occur. Clearly, there is much we still need to understand about this virus,” he said.

The interviews were conducted from April 15 to June 25 with a random sample of adults at least 18 years old who had received a first positive test result for SARS-CoV-2 at an outpatient visit at one of 14 US academic healthcare systems in 13 states.
 

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

COVID-19 can mean weeks’ long illness, even in young adults and those without chronic conditions who have mild disease and are treated in outpatient settings, according to survey results in Morbidity and Mortality Weekly Report from the Centers for Disease Control and Prevention.

Mark W. Tenforde, MD, PhD, for the CDC-COVID-19 Response Team, and colleagues conducted a multistate telephone survey of symptomatic adults who tested positive for SARS-CoV-2. The researchers found that 35% had not returned to their usual state of wellness when they were interviewed 2-3 weeks after testing.

Among the 270 of 274 people interviewed for whom there were data on return to health, 175 (65%) reported that they had returned to baseline health an average of 7 days from the date of testing.

Among the 274 symptomatic outpatients, the median number of symptoms was seven. Fatigue (71%), cough (61%), and headache (61%) were the most commonly reported symptoms.

Prolonged illness is well described in adults hospitalized with severe COVID-19, especially among the older adult population, but little is known about other groups.

The proportion who had not returned to health differed by age: 26% of interviewees aged 18-34 years, 32% of those aged 35-49 years, and 47% of those at least 50 years old reported not having returned to their usual health (P = .010) within 14-21 days after receiving positive test results.

Among respondents aged 18-34 years who had no chronic medical condition, 19% (9 of 48) reported not having returned to their usual state of health during that time.

Public health messaging targeting younger adults, a group who might not be expected to be sick for weeks with mild disease, is particularly important, the authors wrote.

Kyle Annen, DO, medical director of transfusion services and patient blood management at Children’s Hospital Colorado and assistant professor of pathology at the University of Colorado, Denver, said in an interview that an important message is that delayed recovery (symptoms of fatigue, cough, and shortness of breath) was evident in nearly a quarter of 18- to 34-year-olds and in a third of 35- to 49-year-olds who were not sick enough to require hospitalization.

“This should impact the perception of this being a mild illness in the young adult population and encourage them to comply with recommendations of social distancing, masking, and hand washing,” she said.

Recovery time of more than 2 weeks will affect work and school performance, especially prolonged fatigue, she noted. This was one of the prominent symptoms that were reported to be slow to dissipate.

“I think the most interesting point in this study is that of underlying conditions; psychiatric conditions were significantly correlated with prolonged recovery. I don’t think that many people think of depression and anxiety as an underlying medical condition in regards to COVID-19 risk. This could potentially have an impact, as depression and anxiety rates will likely increase as COVID-19 continues,” she said.

Buddy Creech, MD, MPH, said in an interview that it is “important to realize that the spectrum of disease with COVID is wide, including mild disease, severe disease, and prolonged disease. This report helps us understand some of the risk factors for those with prolonged symptoms and may allow us to refine even more clearly how we prioritize treatment and vaccine administration, once available.

“It also highlights the challenge of dealing with this virus. Not only do the symptoms vary widely, but so do the incubation period, the duration of symptoms, and the residual symptoms that sometimes occur. Clearly, there is much we still need to understand about this virus,” he said.

The interviews were conducted from April 15 to June 25 with a random sample of adults at least 18 years old who had received a first positive test result for SARS-CoV-2 at an outpatient visit at one of 14 US academic healthcare systems in 13 states.
 

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

An elderly, retired, married African American man sought psychiatric treatment for depression and suicidal thoughts. He had a detailed, lethal suicide plan, but he had not taken any steps to carry it out.

He met DSM-5 criteria for a major depressive episode, and he described a lifelong history of recurrent depressions as well as hypomanic episodes. He was diagnosed with bipolar II disorder, and he began weekly therapy, as well as medication. Despite several static and dynamic suicide risk factors, the psychiatrist also noted that he was help seeking and future oriented. He seemed transparent during his initial appointments. He did not have access to lethal means and welcomed the psychiatrist to communicate openly with his spouse.

The patient had never attempted suicide, there was no family history of suicide, and there was no psychosis or substance use disorder present. He was able to commit to reaching out to the psychiatrist, his spouse, or emergency personnel in the case of worsening suicidal thoughts or imminent suicidal action. He remained in the outpatient setting. His suicidal ideation faded and depression receded as psychotherapy and pharmacotherapy continued.

Discussion

Depression and suicidal ideation are ubiquitous in the practice of psychiatry. Psychiatrists draw from an array of assessment and management tools when this common clinical challenge arises. Among these tools is the no-suicide contract (NSC). The NSC goes by many names, including the no-harm contract and suicide prevention contract.¹ It is a promise, verbal or written, from the patient to not attempt suicide and to tell a loved one or psychiatric provider instead.² The verbal exchange between the patient and therapist described in the case fits the widely accepted clinical definition of an NSC. The contents and implementation of NSCs vary greatly; no standard approach is taught in psychiatric training.³ The American Psychiatric Association has warned against over-reliance on them, emphasizing that they have not been proven effective. It advises that NSCs should not be used independently of other tools or outside well-established patient-provider relationships.⁴ A 2007 review of the literature on NSCs concluded that there were no data to support their effectiveness and some data that they might even cause harm.⁵

The origin of the NSC

The NSC is fairly young and its foundation arguably weak. Its evolution has been traced back to a study published in 1973 by Robert C. Drye, MD, and associates on the effectiveness of a questionnaire for the assessment of suicide risk.⁶ The questionnaire centered on the patient’s reaction to the statement, “No matter what happens, I will not kill myself, accidently or on purpose, at any time.” The authors placed special emphasis on the words “I will,” which they felt to be a stronger indicator of commitment to safety than “I promise.” The authors thought the latter statement sounded like a child’s empty reply to a demanding parent. The authors reported a 100% success rate with “approximately 600 patients” across geographic regions and clinical settings.⁷ The study group is not further described, and that the authors contend that the intervention had “complete effectiveness in evaluating suicide risk” should give pause to anyone aiming to practice evidence-based psychiatry.

The theoretical basis of the NSC has been presumed by others to be based, in part, on the principles of transactional analysis. Specifically, the suicidal patient is seen as occupying the child ego state, and the NSC is seen as a means of moving the patient into the less problematic adult ego state. It has been argued, however, that an NSC can achieve exactly the opposite. The contract can pit the patient against the clinician, entrenching the patient deeper into the child ego and, therefore, suicidal state.⁸

Michael Craig Miller, MD, and associates proposed other psychological reasons why NSCs may be counterproductive. They write, “Psychological pitfalls abound, and any of them may contribute to a contract being thoughtless, unrealistic, irrelevant, cynical, punitive, or coercive.”⁹ They postulated that the NSC grew out of and assumes the same shared decision-making inherent in any therapeutic contract – and they argue that this assumption is flawed given the legal power clinicians have over suicidal patients. While acknowledging this problematic power differential, the authors go on to urge clinicians to aim for shared decision-making and a shared burden of risk when discussing treatment with suicidal patients.

Possible NSC common factors

Psychiatry, like the rest of medicine, is increasingly practiced in an evidence-based manner. The NSC should not be excluded from this movement. To this end, a recently published, randomized study of 97 active duty Army personnel seeking emergency behavioral health evaluation compared the effectiveness of NSCs and with an alternative intervention, the crisis response plan (CRP). The CRP was chosen because it had been suggested by the Joint Commision as an alternative to the NSC, although it also has little evidence supporting its use.¹⁰

The NSC and CRP interventions of the Army study were very similar. Both included suicide risk assessment, supportive listening, provision of crisis resources, and referral to treatment. In addition, the NSC intervention included asking whether the patients could keep themselves safe at home. The CRP intervention included collaboration with the patient to identify warning signs of crisis, self-management skills, and support persons. A seemingly small but interesting difference between the two interventions was which member of the dyad, patient or clinician, created a written record of the discussion. In the NSC group, the assessor did the writing, while in the CRP group, the patient controlled the pen.

The results of the study were intriguing. Suicidal ideation declined faster in the CRP arm. Participants in the CRP arm were 76% less likely to attempt suicide over 6 months, although this effect decreased and lost statistical significance when controlling for baseline severity of suicidal ideation. Despite those promising data, the only completed suicide was in the CRP arm.

The authors compared the makeup of the CRP intervention with key components of dialectical behavior therapy (DBT). They pointed to a 2015 study by Marsha Linehan, PhD, and associates that sought to identify the active ingredients of DBT. The Linehan study indicated that attending to warning signs and using self-management tools and social supports contributed more to the success of DBT than the individual therapy component. Interestingly, these were the same features that set the CRP intervention apart from the NSC in the Army study. Perhaps these are the common factors of effective counseling of suicidal patients.

Indeed, these factors seem to harken back to the NSC as originally envisioned by the late Dr. Drye – a patient-driven collaboration. Dr. Drye and associates wrote: “This approach developed out of our belief that the only therapeutic contracts likely to lead to change are those developed by the patient himself, for which he will assume responsibility.” While the data presented by Dr. Drye and associates were weak, the theory behind their NSC – patient commitment – seems solid. Commitment strategies, which grew out of social psychology, are effective and heavily used in DBT, including to decrease suicidal behaviors.¹¹

Conclusion

Suicidologist Shawn Christopher Shea, MD, argues that the answer to whether or not NSCs can work is conditional on the unique combination of patient, clinician, and therapeutic relationship at play. He considers the limited data available and has warned against resolutely assuming either a pro- or anti-NSC stance. He postulates that NSCs might have the best chance at saving a life in the context of ongoing therapy with a patient with mature defenses, while in other contexts, such as with a patient with borderline personality disorder, it might prove counterproductive. Importantly, he wrote, “there is not a shred of empirical evidence that safety contracting has not been a deterrent with specific clients in the hands of specific clinicians.”

Dr. Shea describes various ways of maximizing the utility of the NSC. First, he describes that NSCs may be more effective as safety assessment tools (paying attention to both verbal and nonverbal cues) than tools to directly deter attempts. Second, NSCs may have increased utility when repeated across time to provide an understanding for how the patient typically engages in contracting. Soliciting a patient’s reasons for living also can enhance a contract’s usefulness because patients with suicidal ideation weigh reasons for living against reasons for dying in their decision-making. Finally, the sound documentation of the process of contracting not only protects against subsequent legal action but also improves the quality of the clinical care, in part by entraining the psychiatrist to incorporate key elements into the contracting process.

Returning to the clinical case, the strengths and weakness of that NSC can now be evaluated. Looking at the NSC through the eyes of Dr. Shea, the young therapeutic relationship diminishes the value of the NSC, while the relationship’s ongoing basis and the patient’s mature defenses bolster it. Dr. Shea would encourage the psychiatrist to use the NSC as an assessment tool, including assessment of ambivalence. In this case, the patient’s ambivalence about suicide comes through, but it could have been explored and expanded through explicit discussion of reasons for living. Applying the lens of Dr. Linehan, the contract is strengthened by the attention paid to social supports, while it would have been improved by specific discussion about warning signs and self-management tools.

In line with Dr. Drye’s original vision of the NSC, the degree to which the patient owns the NSC seems to be particularly crucial. In this case, the patient’s ownership of the no-suicide decision was suggested by his transparency during interview and full engagement in contracting, including identification of crisis resources. Still, the patient could have been encouraged to take additional responsibility for the NSC. One means of transferring responsibility to the patient could have been giving the patient a pen to create a written record of the contract, mobilizing and symbolizing the patient’s greater control of the process and outcome. Finally, and of utmost importance, it should be reiterated that the NSC should be only part of the assessment and planning that a psychiatrist does with a suicidal patient. While there are circumstances and strategies that augment its utility, it should not be overly relied on.
 

References

1. Weiss A. Am J Psychother. 2001;55(3):414-9.

2. Kroll J. Am J Psychiatry. 2000;157(10):1684-6.

3. Shea SC. The Practical Art of Suicide Assessment: A Guide for Mental Health Professionals and Substance Abuse Counselors. Hoboken, N.J.: John Wiley & Sons, 2011.

4. Jacobs DG et al. Practice guideline for the assessment and treatment of patients with suicidal behavior. American Psychiatric Association, 2003 Nov.

5. Lewis LM. Suicide Life Threat Behav. 2007;37(1):50-7.

6. Goin M. Psychiatr News. 2003 Jul 18;38(14):3-38.

7. Drye RC et al. Am J Psychiatry. 1973;130(2):171-4.

8. Farrow TL. J Psychiatr Ment Health Nurs. 2003 Apr;10(2):199-202.

9. Miller MC et al. Harv Rev Psychiatry. 1998;6(2):78-87.

10. Bryan CJ et al. J Affect Disord. 2017 Apr;212:64-72.

11. Pederson LD. Dialectical Behavior Therapy: A Contemporary Guide for Practitioners. Hoboken, N.J.: John Wiley & Sons, 2015.
 

Dr. Roberts is a board-certified psychiatrist in Northern Virginia, working in both the partial hospital and outpatient settings. She has a special interest in working with patients with serious mental illness and believes in the recovery model of care, in which each patient’s life goals become the focal point of their treatment. Dr. Roberts completed her psychiatry residency at George Washington University, in Washington, where she also served as the 2018-2019 chief outpatient resident. She is a native of Minnesota and earned her medical degree from the University of Minnesota, Minneapolis, in 2015. Dr. Roberts has no disclosures.




 

An elderly, retired, married African American man sought psychiatric treatment for depression and suicidal thoughts. He had a detailed, lethal suicide plan, but he had not taken any steps to carry it out.

He met DSM-5 criteria for a major depressive episode, and he described a lifelong history of recurrent depressions as well as hypomanic episodes. He was diagnosed with bipolar II disorder, and he began weekly therapy, as well as medication. Despite several static and dynamic suicide risk factors, the psychiatrist also noted that he was help seeking and future oriented. He seemed transparent during his initial appointments. He did not have access to lethal means and welcomed the psychiatrist to communicate openly with his spouse.

The patient had never attempted suicide, there was no family history of suicide, and there was no psychosis or substance use disorder present. He was able to commit to reaching out to the psychiatrist, his spouse, or emergency personnel in the case of worsening suicidal thoughts or imminent suicidal action. He remained in the outpatient setting. His suicidal ideation faded and depression receded as psychotherapy and pharmacotherapy continued.

Discussion

Depression and suicidal ideation are ubiquitous in the practice of psychiatry. Psychiatrists draw from an array of assessment and management tools when this common clinical challenge arises. Among these tools is the no-suicide contract (NSC). The NSC goes by many names, including the no-harm contract and suicide prevention contract.¹ It is a promise, verbal or written, from the patient to not attempt suicide and to tell a loved one or psychiatric provider instead.² The verbal exchange between the patient and therapist described in the case fits the widely accepted clinical definition of an NSC. The contents and implementation of NSCs vary greatly; no standard approach is taught in psychiatric training.³ The American Psychiatric Association has warned against over-reliance on them, emphasizing that they have not been proven effective. It advises that NSCs should not be used independently of other tools or outside well-established patient-provider relationships.⁴ A 2007 review of the literature on NSCs concluded that there were no data to support their effectiveness and some data that they might even cause harm.⁵

The origin of the NSC

The NSC is fairly young and its foundation arguably weak. Its evolution has been traced back to a study published in 1973 by Robert C. Drye, MD, and associates on the effectiveness of a questionnaire for the assessment of suicide risk.⁶ The questionnaire centered on the patient’s reaction to the statement, “No matter what happens, I will not kill myself, accidently or on purpose, at any time.” The authors placed special emphasis on the words “I will,” which they felt to be a stronger indicator of commitment to safety than “I promise.” The authors thought the latter statement sounded like a child’s empty reply to a demanding parent. The authors reported a 100% success rate with “approximately 600 patients” across geographic regions and clinical settings.⁷ The study group is not further described, and that the authors contend that the intervention had “complete effectiveness in evaluating suicide risk” should give pause to anyone aiming to practice evidence-based psychiatry.

The theoretical basis of the NSC has been presumed by others to be based, in part, on the principles of transactional analysis. Specifically, the suicidal patient is seen as occupying the child ego state, and the NSC is seen as a means of moving the patient into the less problematic adult ego state. It has been argued, however, that an NSC can achieve exactly the opposite. The contract can pit the patient against the clinician, entrenching the patient deeper into the child ego and, therefore, suicidal state.⁸

Michael Craig Miller, MD, and associates proposed other psychological reasons why NSCs may be counterproductive. They write, “Psychological pitfalls abound, and any of them may contribute to a contract being thoughtless, unrealistic, irrelevant, cynical, punitive, or coercive.”⁹ They postulated that the NSC grew out of and assumes the same shared decision-making inherent in any therapeutic contract – and they argue that this assumption is flawed given the legal power clinicians have over suicidal patients. While acknowledging this problematic power differential, the authors go on to urge clinicians to aim for shared decision-making and a shared burden of risk when discussing treatment with suicidal patients.

Possible NSC common factors

Psychiatry, like the rest of medicine, is increasingly practiced in an evidence-based manner. The NSC should not be excluded from this movement. To this end, a recently published, randomized study of 97 active duty Army personnel seeking emergency behavioral health evaluation compared the effectiveness of NSCs and with an alternative intervention, the crisis response plan (CRP). The CRP was chosen because it had been suggested by the Joint Commision as an alternative to the NSC, although it also has little evidence supporting its use.¹⁰

The NSC and CRP interventions of the Army study were very similar. Both included suicide risk assessment, supportive listening, provision of crisis resources, and referral to treatment. In addition, the NSC intervention included asking whether the patients could keep themselves safe at home. The CRP intervention included collaboration with the patient to identify warning signs of crisis, self-management skills, and support persons. A seemingly small but interesting difference between the two interventions was which member of the dyad, patient or clinician, created a written record of the discussion. In the NSC group, the assessor did the writing, while in the CRP group, the patient controlled the pen.

The results of the study were intriguing. Suicidal ideation declined faster in the CRP arm. Participants in the CRP arm were 76% less likely to attempt suicide over 6 months, although this effect decreased and lost statistical significance when controlling for baseline severity of suicidal ideation. Despite those promising data, the only completed suicide was in the CRP arm.

The authors compared the makeup of the CRP intervention with key components of dialectical behavior therapy (DBT). They pointed to a 2015 study by Marsha Linehan, PhD, and associates that sought to identify the active ingredients of DBT. The Linehan study indicated that attending to warning signs and using self-management tools and social supports contributed more to the success of DBT than the individual therapy component. Interestingly, these were the same features that set the CRP intervention apart from the NSC in the Army study. Perhaps these are the common factors of effective counseling of suicidal patients.

Indeed, these factors seem to harken back to the NSC as originally envisioned by the late Dr. Drye – a patient-driven collaboration. Dr. Drye and associates wrote: “This approach developed out of our belief that the only therapeutic contracts likely to lead to change are those developed by the patient himself, for which he will assume responsibility.” While the data presented by Dr. Drye and associates were weak, the theory behind their NSC – patient commitment – seems solid. Commitment strategies, which grew out of social psychology, are effective and heavily used in DBT, including to decrease suicidal behaviors.¹¹

Conclusion

Suicidologist Shawn Christopher Shea, MD, argues that the answer to whether or not NSCs can work is conditional on the unique combination of patient, clinician, and therapeutic relationship at play. He considers the limited data available and has warned against resolutely assuming either a pro- or anti-NSC stance. He postulates that NSCs might have the best chance at saving a life in the context of ongoing therapy with a patient with mature defenses, while in other contexts, such as with a patient with borderline personality disorder, it might prove counterproductive. Importantly, he wrote, “there is not a shred of empirical evidence that safety contracting has not been a deterrent with specific clients in the hands of specific clinicians.”

Dr. Shea describes various ways of maximizing the utility of the NSC. First, he describes that NSCs may be more effective as safety assessment tools (paying attention to both verbal and nonverbal cues) than tools to directly deter attempts. Second, NSCs may have increased utility when repeated across time to provide an understanding for how the patient typically engages in contracting. Soliciting a patient’s reasons for living also can enhance a contract’s usefulness because patients with suicidal ideation weigh reasons for living against reasons for dying in their decision-making. Finally, the sound documentation of the process of contracting not only protects against subsequent legal action but also improves the quality of the clinical care, in part by entraining the psychiatrist to incorporate key elements into the contracting process.

Returning to the clinical case, the strengths and weakness of that NSC can now be evaluated. Looking at the NSC through the eyes of Dr. Shea, the young therapeutic relationship diminishes the value of the NSC, while the relationship’s ongoing basis and the patient’s mature defenses bolster it. Dr. Shea would encourage the psychiatrist to use the NSC as an assessment tool, including assessment of ambivalence. In this case, the patient’s ambivalence about suicide comes through, but it could have been explored and expanded through explicit discussion of reasons for living. Applying the lens of Dr. Linehan, the contract is strengthened by the attention paid to social supports, while it would have been improved by specific discussion about warning signs and self-management tools.

In line with Dr. Drye’s original vision of the NSC, the degree to which the patient owns the NSC seems to be particularly crucial. In this case, the patient’s ownership of the no-suicide decision was suggested by his transparency during interview and full engagement in contracting, including identification of crisis resources. Still, the patient could have been encouraged to take additional responsibility for the NSC. One means of transferring responsibility to the patient could have been giving the patient a pen to create a written record of the contract, mobilizing and symbolizing the patient’s greater control of the process and outcome. Finally, and of utmost importance, it should be reiterated that the NSC should be only part of the assessment and planning that a psychiatrist does with a suicidal patient. While there are circumstances and strategies that augment its utility, it should not be overly relied on.
 

References

1. Weiss A. Am J Psychother. 2001;55(3):414-9.

2. Kroll J. Am J Psychiatry. 2000;157(10):1684-6.

3. Shea SC. The Practical Art of Suicide Assessment: A Guide for Mental Health Professionals and Substance Abuse Counselors. Hoboken, N.J.: John Wiley & Sons, 2011.

4. Jacobs DG et al. Practice guideline for the assessment and treatment of patients with suicidal behavior. American Psychiatric Association, 2003 Nov.

5. Lewis LM. Suicide Life Threat Behav. 2007;37(1):50-7.

6. Goin M. Psychiatr News. 2003 Jul 18;38(14):3-38.

7. Drye RC et al. Am J Psychiatry. 1973;130(2):171-4.

8. Farrow TL. J Psychiatr Ment Health Nurs. 2003 Apr;10(2):199-202.

9. Miller MC et al. Harv Rev Psychiatry. 1998;6(2):78-87.

10. Bryan CJ et al. J Affect Disord. 2017 Apr;212:64-72.

11. Pederson LD. Dialectical Behavior Therapy: A Contemporary Guide for Practitioners. Hoboken, N.J.: John Wiley & Sons, 2015.
 

Dr. Roberts is a board-certified psychiatrist in Northern Virginia, working in both the partial hospital and outpatient settings. She has a special interest in working with patients with serious mental illness and believes in the recovery model of care, in which each patient’s life goals become the focal point of their treatment. Dr. Roberts completed her psychiatry residency at George Washington University, in Washington, where she also served as the 2018-2019 chief outpatient resident. She is a native of Minnesota and earned her medical degree from the University of Minnesota, Minneapolis, in 2015. Dr. Roberts has no disclosures.




 

An elderly, retired, married African American man sought psychiatric treatment for depression and suicidal thoughts. He had a detailed, lethal suicide plan, but he had not taken any steps to carry it out.

He met DSM-5 criteria for a major depressive episode, and he described a lifelong history of recurrent depressions as well as hypomanic episodes. He was diagnosed with bipolar II disorder, and he began weekly therapy, as well as medication. Despite several static and dynamic suicide risk factors, the psychiatrist also noted that he was help seeking and future oriented. He seemed transparent during his initial appointments. He did not have access to lethal means and welcomed the psychiatrist to communicate openly with his spouse.

The patient had never attempted suicide, there was no family history of suicide, and there was no psychosis or substance use disorder present. He was able to commit to reaching out to the psychiatrist, his spouse, or emergency personnel in the case of worsening suicidal thoughts or imminent suicidal action. He remained in the outpatient setting. His suicidal ideation faded and depression receded as psychotherapy and pharmacotherapy continued.

Discussion

Depression and suicidal ideation are ubiquitous in the practice of psychiatry. Psychiatrists draw from an array of assessment and management tools when this common clinical challenge arises. Among these tools is the no-suicide contract (NSC). The NSC goes by many names, including the no-harm contract and suicide prevention contract.¹ It is a promise, verbal or written, from the patient to not attempt suicide and to tell a loved one or psychiatric provider instead.² The verbal exchange between the patient and therapist described in the case fits the widely accepted clinical definition of an NSC. The contents and implementation of NSCs vary greatly; no standard approach is taught in psychiatric training.³ The American Psychiatric Association has warned against over-reliance on them, emphasizing that they have not been proven effective. It advises that NSCs should not be used independently of other tools or outside well-established patient-provider relationships.⁴ A 2007 review of the literature on NSCs concluded that there were no data to support their effectiveness and some data that they might even cause harm.⁵

The origin of the NSC

The NSC is fairly young and its foundation arguably weak. Its evolution has been traced back to a study published in 1973 by Robert C. Drye, MD, and associates on the effectiveness of a questionnaire for the assessment of suicide risk.⁶ The questionnaire centered on the patient’s reaction to the statement, “No matter what happens, I will not kill myself, accidently or on purpose, at any time.” The authors placed special emphasis on the words “I will,” which they felt to be a stronger indicator of commitment to safety than “I promise.” The authors thought the latter statement sounded like a child’s empty reply to a demanding parent. The authors reported a 100% success rate with “approximately 600 patients” across geographic regions and clinical settings.⁷ The study group is not further described, and that the authors contend that the intervention had “complete effectiveness in evaluating suicide risk” should give pause to anyone aiming to practice evidence-based psychiatry.

The theoretical basis of the NSC has been presumed by others to be based, in part, on the principles of transactional analysis. Specifically, the suicidal patient is seen as occupying the child ego state, and the NSC is seen as a means of moving the patient into the less problematic adult ego state. It has been argued, however, that an NSC can achieve exactly the opposite. The contract can pit the patient against the clinician, entrenching the patient deeper into the child ego and, therefore, suicidal state.⁸

Michael Craig Miller, MD, and associates proposed other psychological reasons why NSCs may be counterproductive. They write, “Psychological pitfalls abound, and any of them may contribute to a contract being thoughtless, unrealistic, irrelevant, cynical, punitive, or coercive.”⁹ They postulated that the NSC grew out of and assumes the same shared decision-making inherent in any therapeutic contract – and they argue that this assumption is flawed given the legal power clinicians have over suicidal patients. While acknowledging this problematic power differential, the authors go on to urge clinicians to aim for shared decision-making and a shared burden of risk when discussing treatment with suicidal patients.

Possible NSC common factors

Psychiatry, like the rest of medicine, is increasingly practiced in an evidence-based manner. The NSC should not be excluded from this movement. To this end, a recently published, randomized study of 97 active duty Army personnel seeking emergency behavioral health evaluation compared the effectiveness of NSCs and with an alternative intervention, the crisis response plan (CRP). The CRP was chosen because it had been suggested by the Joint Commision as an alternative to the NSC, although it also has little evidence supporting its use.¹⁰

The NSC and CRP interventions of the Army study were very similar. Both included suicide risk assessment, supportive listening, provision of crisis resources, and referral to treatment. In addition, the NSC intervention included asking whether the patients could keep themselves safe at home. The CRP intervention included collaboration with the patient to identify warning signs of crisis, self-management skills, and support persons. A seemingly small but interesting difference between the two interventions was which member of the dyad, patient or clinician, created a written record of the discussion. In the NSC group, the assessor did the writing, while in the CRP group, the patient controlled the pen.

The results of the study were intriguing. Suicidal ideation declined faster in the CRP arm. Participants in the CRP arm were 76% less likely to attempt suicide over 6 months, although this effect decreased and lost statistical significance when controlling for baseline severity of suicidal ideation. Despite those promising data, the only completed suicide was in the CRP arm.

The authors compared the makeup of the CRP intervention with key components of dialectical behavior therapy (DBT). They pointed to a 2015 study by Marsha Linehan, PhD, and associates that sought to identify the active ingredients of DBT. The Linehan study indicated that attending to warning signs and using self-management tools and social supports contributed more to the success of DBT than the individual therapy component. Interestingly, these were the same features that set the CRP intervention apart from the NSC in the Army study. Perhaps these are the common factors of effective counseling of suicidal patients.

Indeed, these factors seem to harken back to the NSC as originally envisioned by the late Dr. Drye – a patient-driven collaboration. Dr. Drye and associates wrote: “This approach developed out of our belief that the only therapeutic contracts likely to lead to change are those developed by the patient himself, for which he will assume responsibility.” While the data presented by Dr. Drye and associates were weak, the theory behind their NSC – patient commitment – seems solid. Commitment strategies, which grew out of social psychology, are effective and heavily used in DBT, including to decrease suicidal behaviors.¹¹

Conclusion

Suicidologist Shawn Christopher Shea, MD, argues that the answer to whether or not NSCs can work is conditional on the unique combination of patient, clinician, and therapeutic relationship at play. He considers the limited data available and has warned against resolutely assuming either a pro- or anti-NSC stance. He postulates that NSCs might have the best chance at saving a life in the context of ongoing therapy with a patient with mature defenses, while in other contexts, such as with a patient with borderline personality disorder, it might prove counterproductive. Importantly, he wrote, “there is not a shred of empirical evidence that safety contracting has not been a deterrent with specific clients in the hands of specific clinicians.”

Dr. Shea describes various ways of maximizing the utility of the NSC. First, he describes that NSCs may be more effective as safety assessment tools (paying attention to both verbal and nonverbal cues) than tools to directly deter attempts. Second, NSCs may have increased utility when repeated across time to provide an understanding for how the patient typically engages in contracting. Soliciting a patient’s reasons for living also can enhance a contract’s usefulness because patients with suicidal ideation weigh reasons for living against reasons for dying in their decision-making. Finally, the sound documentation of the process of contracting not only protects against subsequent legal action but also improves the quality of the clinical care, in part by entraining the psychiatrist to incorporate key elements into the contracting process.

Returning to the clinical case, the strengths and weakness of that NSC can now be evaluated. Looking at the NSC through the eyes of Dr. Shea, the young therapeutic relationship diminishes the value of the NSC, while the relationship’s ongoing basis and the patient’s mature defenses bolster it. Dr. Shea would encourage the psychiatrist to use the NSC as an assessment tool, including assessment of ambivalence. In this case, the patient’s ambivalence about suicide comes through, but it could have been explored and expanded through explicit discussion of reasons for living. Applying the lens of Dr. Linehan, the contract is strengthened by the attention paid to social supports, while it would have been improved by specific discussion about warning signs and self-management tools.

In line with Dr. Drye’s original vision of the NSC, the degree to which the patient owns the NSC seems to be particularly crucial. In this case, the patient’s ownership of the no-suicide decision was suggested by his transparency during interview and full engagement in contracting, including identification of crisis resources. Still, the patient could have been encouraged to take additional responsibility for the NSC. One means of transferring responsibility to the patient could have been giving the patient a pen to create a written record of the contract, mobilizing and symbolizing the patient’s greater control of the process and outcome. Finally, and of utmost importance, it should be reiterated that the NSC should be only part of the assessment and planning that a psychiatrist does with a suicidal patient. While there are circumstances and strategies that augment its utility, it should not be overly relied on.
 

References

1. Weiss A. Am J Psychother. 2001;55(3):414-9.

2. Kroll J. Am J Psychiatry. 2000;157(10):1684-6.

3. Shea SC. The Practical Art of Suicide Assessment: A Guide for Mental Health Professionals and Substance Abuse Counselors. Hoboken, N.J.: John Wiley & Sons, 2011.

4. Jacobs DG et al. Practice guideline for the assessment and treatment of patients with suicidal behavior. American Psychiatric Association, 2003 Nov.

5. Lewis LM. Suicide Life Threat Behav. 2007;37(1):50-7.

6. Goin M. Psychiatr News. 2003 Jul 18;38(14):3-38.

7. Drye RC et al. Am J Psychiatry. 1973;130(2):171-4.

8. Farrow TL. J Psychiatr Ment Health Nurs. 2003 Apr;10(2):199-202.

9. Miller MC et al. Harv Rev Psychiatry. 1998;6(2):78-87.

10. Bryan CJ et al. J Affect Disord. 2017 Apr;212:64-72.

11. Pederson LD. Dialectical Behavior Therapy: A Contemporary Guide for Practitioners. Hoboken, N.J.: John Wiley & Sons, 2015.
 

Dr. Roberts is a board-certified psychiatrist in Northern Virginia, working in both the partial hospital and outpatient settings. She has a special interest in working with patients with serious mental illness and believes in the recovery model of care, in which each patient’s life goals become the focal point of their treatment. Dr. Roberts completed her psychiatry residency at George Washington University, in Washington, where she also served as the 2018-2019 chief outpatient resident. She is a native of Minnesota and earned her medical degree from the University of Minnesota, Minneapolis, in 2015. Dr. Roberts has no disclosures.




 

The novel lysine-specific demethylase 1 inhibitor vafidemstat (ORY-2001, Oryzon Genomics) is effective for treating agitation and aggression across a number of psychiatric disorders, new research suggests.

The REIMAGINE trial included 30 patients with autism spectrum disorder (ASD), ADHD, or borderline personality disorder (BPD). Results showed significant improvements after 8 weeks in general functioning and agitation-aggression scores for all three disorders.

The study “supports vafidemstat as an emerging therapeutic option to treat aggression-agitation, as well as the nonaggression features of psychiatric diseases with high unmet medical need,” lead researcher Roger Bullock, MD, Oryzon Genomics, Corneliá De Llobregat, Spain, told Medscape Medical News.

“This is the first clinical demonstration of an epigenetic mode of action in psychiatry to date,” Bullock added.

However, another expert urged prudence when interpreting the findings.

“The study results must be viewed with caution, given the inherent limitations of an open-label trial, small sample size, and weak rationale for the sample selection,” said Nathan Kolla, MD, PhD, a psychiatrist at the University of Toronto, Canada, who was not involved with the research.

The findings were presented at the European Psychiatric Association (EPA) 2020 Congress, which was held online this year because of the COVID-19 pandemic.
 

Little evidence available

“Epigenetic mechanisms have been proposed in many psychiatric conditions, but so far, little clinical evidence is available,” Bullock said during his presentation.

In preclinical models, vafidemstat has been associated with a reduction in aggressive behavior “and the normal response to stress of immediate early genes in the prefrontal cortex” via the modification of gene transcription, noted Bullock.

“This new approach makes it a good candidate to look at aggression in multiple psychiatric and CNS conditions,” he added.

REIMAGINE was a phase 2a open-label trial that included 30 patients (53% women; mean age, 33.5 years; 87% White) with psychiatric disorders who had significant or persistent agitation or aggression that was disruptive of the patients› daily life.

Among the participants, 12 had BPD, 11 had ADHD, and seven had ASD. All were treated with vafidemstat 1.2 mg for 8 weeks.

In all, 23 patients completed all 8 weeks of treatment, including nine patients with BPD, eight with ADHD, and six with ASD.

Results showed that the study drug was well tolerated, with no serious adverse events reported and no patients withdrawing because of safety-related events.

The most common adverse events were headache (20%) and insomnia (10%), which resolved without intervention or treatment modification.
 

Significantly improved scores

Across the whole cohort, the drug was associated with significant reductions in scores over baseline on the Clinical Global Impression–Severity (CGI-S) and CGI-Improvement (CGI-I) scales. There were also significant improvements for Neuropsychiatric Inventory (NPI) total scores and agitation-aggression scores (P < .001 for comparisons).

Similar results were observed with respect to individual diagnoses, albeit at varying degrees of significance for each scale.

Patients with BPD experienced significant reductions in scores on the Borderline Personality Disorder Checklist (BPDCL) (P < .01). Patients with ADHD experienced reductions on the ADHD Rating Scale (P < .05).

Patients with BPD also experienced reductions in suicidal ideation, as measured with the Columbia Suicide Severity Rating Scale (P < .01). That is “the only cohort where this trait is relevant,” the researchers note.

In addition, significant correlations were shown between NPI total scores and scores on the BPDCL after treatment with vafidemstat (P = .015), as well as between NPI agitation-aggression scores and both CGI-I (P = .008) and CGI-S scores (P = .0001).

“This convergence of signals in scales of different nature and scope support the pharmacological role of vafidemstat in controlling aggression-agitation in different psychiatric conditions,” the investigators note.

Bullock added that further randomized placebo-controlled clinical trials “to confirm vafidemstat’s potential to treat aggression-agitation in psychiatric disorders are now planned.”

First up will be PORTICO, which is planned to start over the coming months in Spain and will include patients with BPD.
 

Several limitations

Commenting on the study for Medscape Medical News, Kolla, who is also a researcher at the Center for Addiction and Mental Health, noted that REIMAGINE was originally designed to test vafidemstat for the treatment of agitation and aggression in patients with Alzheimer’s disease (AD).

“It seems peculiar that the study investigators would choose to examine three additional psychiatric disorders that bear little resemblance to AD in terms of phenomenology. Additionally, the etiological underpinnings of the three disorders likely differ markedly from AD,” said Kolla, who was not involved with the research.

In addition, the “very small” sample size in each group makes it difficult to interpret the investigators’ conclusions, he noted.

There are also “many more sophisticated scales” to assess agitation and aggression than what were used in the study, he added.

Kolla also questioned the notion that a drug such as vafidemstat satisfies an unmet clinical need for the treatment of aggression and agitation.

Trials that “purport to reduce aggression in these populations often provide some level of global improvement in functioning that may appear as if they directly treat agitation or aggression,” he said. “However, no drug has ever been developed that directly reduces aggression and agitation.”

That means that, for now, there is insufficient evidence to “conclude that vafidemstat overcomes the unmet medical need of treating aggression/agitation,” he said.

For Kolla, the concept of a psychiatric drug that works by effecting epigenetic changes to the genome is also questionable, although such mechanisms may “play a role in the salubrious effects of certain mood stabilizers or antipsychotics for which better-defined mechanisms of action have been established.”

The study was funded by Oryzon Genomics. Bullock and the other investigators are employees of Oryzon Genomics.

This article first appeared on Medscape.com.

The novel lysine-specific demethylase 1 inhibitor vafidemstat (ORY-2001, Oryzon Genomics) is effective for treating agitation and aggression across a number of psychiatric disorders, new research suggests.

The REIMAGINE trial included 30 patients with autism spectrum disorder (ASD), ADHD, or borderline personality disorder (BPD). Results showed significant improvements after 8 weeks in general functioning and agitation-aggression scores for all three disorders.

The study “supports vafidemstat as an emerging therapeutic option to treat aggression-agitation, as well as the nonaggression features of psychiatric diseases with high unmet medical need,” lead researcher Roger Bullock, MD, Oryzon Genomics, Corneliá De Llobregat, Spain, told Medscape Medical News.

“This is the first clinical demonstration of an epigenetic mode of action in psychiatry to date,” Bullock added.

However, another expert urged prudence when interpreting the findings.

“The study results must be viewed with caution, given the inherent limitations of an open-label trial, small sample size, and weak rationale for the sample selection,” said Nathan Kolla, MD, PhD, a psychiatrist at the University of Toronto, Canada, who was not involved with the research.

The findings were presented at the European Psychiatric Association (EPA) 2020 Congress, which was held online this year because of the COVID-19 pandemic.
 

Little evidence available

“Epigenetic mechanisms have been proposed in many psychiatric conditions, but so far, little clinical evidence is available,” Bullock said during his presentation.

In preclinical models, vafidemstat has been associated with a reduction in aggressive behavior “and the normal response to stress of immediate early genes in the prefrontal cortex” via the modification of gene transcription, noted Bullock.

“This new approach makes it a good candidate to look at aggression in multiple psychiatric and CNS conditions,” he added.

REIMAGINE was a phase 2a open-label trial that included 30 patients (53% women; mean age, 33.5 years; 87% White) with psychiatric disorders who had significant or persistent agitation or aggression that was disruptive of the patients› daily life.

Among the participants, 12 had BPD, 11 had ADHD, and seven had ASD. All were treated with vafidemstat 1.2 mg for 8 weeks.

In all, 23 patients completed all 8 weeks of treatment, including nine patients with BPD, eight with ADHD, and six with ASD.

Results showed that the study drug was well tolerated, with no serious adverse events reported and no patients withdrawing because of safety-related events.

The most common adverse events were headache (20%) and insomnia (10%), which resolved without intervention or treatment modification.
 

Significantly improved scores

Across the whole cohort, the drug was associated with significant reductions in scores over baseline on the Clinical Global Impression–Severity (CGI-S) and CGI-Improvement (CGI-I) scales. There were also significant improvements for Neuropsychiatric Inventory (NPI) total scores and agitation-aggression scores (P < .001 for comparisons).

Similar results were observed with respect to individual diagnoses, albeit at varying degrees of significance for each scale.

Patients with BPD experienced significant reductions in scores on the Borderline Personality Disorder Checklist (BPDCL) (P < .01). Patients with ADHD experienced reductions on the ADHD Rating Scale (P < .05).

Patients with BPD also experienced reductions in suicidal ideation, as measured with the Columbia Suicide Severity Rating Scale (P < .01). That is “the only cohort where this trait is relevant,” the researchers note.

In addition, significant correlations were shown between NPI total scores and scores on the BPDCL after treatment with vafidemstat (P = .015), as well as between NPI agitation-aggression scores and both CGI-I (P = .008) and CGI-S scores (P = .0001).

“This convergence of signals in scales of different nature and scope support the pharmacological role of vafidemstat in controlling aggression-agitation in different psychiatric conditions,” the investigators note.

Bullock added that further randomized placebo-controlled clinical trials “to confirm vafidemstat’s potential to treat aggression-agitation in psychiatric disorders are now planned.”

First up will be PORTICO, which is planned to start over the coming months in Spain and will include patients with BPD.
 

Several limitations

Commenting on the study for Medscape Medical News, Kolla, who is also a researcher at the Center for Addiction and Mental Health, noted that REIMAGINE was originally designed to test vafidemstat for the treatment of agitation and aggression in patients with Alzheimer’s disease (AD).

“It seems peculiar that the study investigators would choose to examine three additional psychiatric disorders that bear little resemblance to AD in terms of phenomenology. Additionally, the etiological underpinnings of the three disorders likely differ markedly from AD,” said Kolla, who was not involved with the research.

In addition, the “very small” sample size in each group makes it difficult to interpret the investigators’ conclusions, he noted.

There are also “many more sophisticated scales” to assess agitation and aggression than what were used in the study, he added.

Kolla also questioned the notion that a drug such as vafidemstat satisfies an unmet clinical need for the treatment of aggression and agitation.

Trials that “purport to reduce aggression in these populations often provide some level of global improvement in functioning that may appear as if they directly treat agitation or aggression,” he said. “However, no drug has ever been developed that directly reduces aggression and agitation.”

That means that, for now, there is insufficient evidence to “conclude that vafidemstat overcomes the unmet medical need of treating aggression/agitation,” he said.

For Kolla, the concept of a psychiatric drug that works by effecting epigenetic changes to the genome is also questionable, although such mechanisms may “play a role in the salubrious effects of certain mood stabilizers or antipsychotics for which better-defined mechanisms of action have been established.”

The study was funded by Oryzon Genomics. Bullock and the other investigators are employees of Oryzon Genomics.

This article first appeared on Medscape.com.

The novel lysine-specific demethylase 1 inhibitor vafidemstat (ORY-2001, Oryzon Genomics) is effective for treating agitation and aggression across a number of psychiatric disorders, new research suggests.

The REIMAGINE trial included 30 patients with autism spectrum disorder (ASD), ADHD, or borderline personality disorder (BPD). Results showed significant improvements after 8 weeks in general functioning and agitation-aggression scores for all three disorders.

The study “supports vafidemstat as an emerging therapeutic option to treat aggression-agitation, as well as the nonaggression features of psychiatric diseases with high unmet medical need,” lead researcher Roger Bullock, MD, Oryzon Genomics, Corneliá De Llobregat, Spain, told Medscape Medical News.

“This is the first clinical demonstration of an epigenetic mode of action in psychiatry to date,” Bullock added.

However, another expert urged prudence when interpreting the findings.

“The study results must be viewed with caution, given the inherent limitations of an open-label trial, small sample size, and weak rationale for the sample selection,” said Nathan Kolla, MD, PhD, a psychiatrist at the University of Toronto, Canada, who was not involved with the research.

The findings were presented at the European Psychiatric Association (EPA) 2020 Congress, which was held online this year because of the COVID-19 pandemic.
 

Little evidence available

“Epigenetic mechanisms have been proposed in many psychiatric conditions, but so far, little clinical evidence is available,” Bullock said during his presentation.

In preclinical models, vafidemstat has been associated with a reduction in aggressive behavior “and the normal response to stress of immediate early genes in the prefrontal cortex” via the modification of gene transcription, noted Bullock.

“This new approach makes it a good candidate to look at aggression in multiple psychiatric and CNS conditions,” he added.

REIMAGINE was a phase 2a open-label trial that included 30 patients (53% women; mean age, 33.5 years; 87% White) with psychiatric disorders who had significant or persistent agitation or aggression that was disruptive of the patients› daily life.

Among the participants, 12 had BPD, 11 had ADHD, and seven had ASD. All were treated with vafidemstat 1.2 mg for 8 weeks.

In all, 23 patients completed all 8 weeks of treatment, including nine patients with BPD, eight with ADHD, and six with ASD.

Results showed that the study drug was well tolerated, with no serious adverse events reported and no patients withdrawing because of safety-related events.

The most common adverse events were headache (20%) and insomnia (10%), which resolved without intervention or treatment modification.
 

Significantly improved scores

Across the whole cohort, the drug was associated with significant reductions in scores over baseline on the Clinical Global Impression–Severity (CGI-S) and CGI-Improvement (CGI-I) scales. There were also significant improvements for Neuropsychiatric Inventory (NPI) total scores and agitation-aggression scores (P < .001 for comparisons).

Similar results were observed with respect to individual diagnoses, albeit at varying degrees of significance for each scale.

Patients with BPD experienced significant reductions in scores on the Borderline Personality Disorder Checklist (BPDCL) (P < .01). Patients with ADHD experienced reductions on the ADHD Rating Scale (P < .05).

Patients with BPD also experienced reductions in suicidal ideation, as measured with the Columbia Suicide Severity Rating Scale (P < .01). That is “the only cohort where this trait is relevant,” the researchers note.

In addition, significant correlations were shown between NPI total scores and scores on the BPDCL after treatment with vafidemstat (P = .015), as well as between NPI agitation-aggression scores and both CGI-I (P = .008) and CGI-S scores (P = .0001).

“This convergence of signals in scales of different nature and scope support the pharmacological role of vafidemstat in controlling aggression-agitation in different psychiatric conditions,” the investigators note.

Bullock added that further randomized placebo-controlled clinical trials “to confirm vafidemstat’s potential to treat aggression-agitation in psychiatric disorders are now planned.”

First up will be PORTICO, which is planned to start over the coming months in Spain and will include patients with BPD.
 

Several limitations

Commenting on the study for Medscape Medical News, Kolla, who is also a researcher at the Center for Addiction and Mental Health, noted that REIMAGINE was originally designed to test vafidemstat for the treatment of agitation and aggression in patients with Alzheimer’s disease (AD).

“It seems peculiar that the study investigators would choose to examine three additional psychiatric disorders that bear little resemblance to AD in terms of phenomenology. Additionally, the etiological underpinnings of the three disorders likely differ markedly from AD,” said Kolla, who was not involved with the research.

In addition, the “very small” sample size in each group makes it difficult to interpret the investigators’ conclusions, he noted.

There are also “many more sophisticated scales” to assess agitation and aggression than what were used in the study, he added.

Kolla also questioned the notion that a drug such as vafidemstat satisfies an unmet clinical need for the treatment of aggression and agitation.

Trials that “purport to reduce aggression in these populations often provide some level of global improvement in functioning that may appear as if they directly treat agitation or aggression,” he said. “However, no drug has ever been developed that directly reduces aggression and agitation.”

That means that, for now, there is insufficient evidence to “conclude that vafidemstat overcomes the unmet medical need of treating aggression/agitation,” he said.

For Kolla, the concept of a psychiatric drug that works by effecting epigenetic changes to the genome is also questionable, although such mechanisms may “play a role in the salubrious effects of certain mood stabilizers or antipsychotics for which better-defined mechanisms of action have been established.”

The study was funded by Oryzon Genomics. Bullock and the other investigators are employees of Oryzon Genomics.

This article first appeared on Medscape.com.

New guidelines from the Centers for Disease Control and Prevention outline a “test and treat” strategy for health care personnel (HCP) with potential occupational exposure to hepatitis C virus (HCV).

The new guidance was developed in part as a result of an increase in the incidence of acute HCV infection in the United States, which increases the risk for occupational exposure among HCP. “[I]n certain health care settings, HCP might be exposed to source patients with early HCV infection before those patients develop serologic evidence of infection or symptoms indicative of viral hepatitis,” wrote the authors of the report, published online July 24 in the CDC’s Morbidity and Mortality Weekly Report.

The guidelines, which no longer recommend waiting for spontaneous resolution upon initial diagnosis, include recommendations and algorithms for baseline and follow-up testing, appropriate test type, and recommendations for clinical management. The recommendations were developed on the basis of a current literature review, expert opinion from subject matter experts, and recent guidance from the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America.
 

Baseline testing ASAP

Baseline testing of the source patient and the HCP should be performed as soon as possible, preferably within 48 hours of exposure. The source patient should be tested for HCV RNA using a nucleic acid test. Alternatively, screening anti-HCV serology can be performed in patients at low risk for HCV and a nucleic acid test performed if serology is positive.

Baseline testing for the HCP should include anti-HCV testing and, if positive, HCV RNA testing is recommended. HCPs who test positive for HCV RNA at baseline are considered to have a preexisting HCV infection and should be referred for treatment.
 

Follow-up testing

For HCPs with exposure to blood or body fluids from a patient who is anti-HCV positive but HCV RNA negative, follow-up testing is not required.

If the source patient is HCV RNA positive, or if status of the source patient is unknown, the authors recommend that exposed HCPs have HCV RNA follow-up testing at 3-6 weeks post exposure, in addition to baseline testing. A final anti-HCV test is recommended at 4-6 months post exposure as there can be potential periods of aviremia during acute HCV infection.

Exposed HCPs who develop signs of illness indicative of HCV infection at any time should be tested for HCV RNA.

HCPs with positive HCV RNA test results should be referred for care and curative antiviral therapy.
 

Postexposure prophylaxis is not recommended

Recent data have shown that the risk for HCV infection from percutaneous exposure is 0.2% and from mucocutaneous exposure is 0%. On the basis of this information, the CDC guidelines no longer recommend routine postexposure prophylaxis for HCPs with occupational exposure to HCV. Rather, curative antiviral regimens should be reserved for instances of documented HCV transmission.

The authors disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

New guidelines from the Centers for Disease Control and Prevention outline a “test and treat” strategy for health care personnel (HCP) with potential occupational exposure to hepatitis C virus (HCV).

The new guidance was developed in part as a result of an increase in the incidence of acute HCV infection in the United States, which increases the risk for occupational exposure among HCP. “[I]n certain health care settings, HCP might be exposed to source patients with early HCV infection before those patients develop serologic evidence of infection or symptoms indicative of viral hepatitis,” wrote the authors of the report, published online July 24 in the CDC’s Morbidity and Mortality Weekly Report.

The guidelines, which no longer recommend waiting for spontaneous resolution upon initial diagnosis, include recommendations and algorithms for baseline and follow-up testing, appropriate test type, and recommendations for clinical management. The recommendations were developed on the basis of a current literature review, expert opinion from subject matter experts, and recent guidance from the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America.
 

Baseline testing ASAP

Baseline testing of the source patient and the HCP should be performed as soon as possible, preferably within 48 hours of exposure. The source patient should be tested for HCV RNA using a nucleic acid test. Alternatively, screening anti-HCV serology can be performed in patients at low risk for HCV and a nucleic acid test performed if serology is positive.

Baseline testing for the HCP should include anti-HCV testing and, if positive, HCV RNA testing is recommended. HCPs who test positive for HCV RNA at baseline are considered to have a preexisting HCV infection and should be referred for treatment.
 

Follow-up testing

For HCPs with exposure to blood or body fluids from a patient who is anti-HCV positive but HCV RNA negative, follow-up testing is not required.

If the source patient is HCV RNA positive, or if status of the source patient is unknown, the authors recommend that exposed HCPs have HCV RNA follow-up testing at 3-6 weeks post exposure, in addition to baseline testing. A final anti-HCV test is recommended at 4-6 months post exposure as there can be potential periods of aviremia during acute HCV infection.

Exposed HCPs who develop signs of illness indicative of HCV infection at any time should be tested for HCV RNA.

HCPs with positive HCV RNA test results should be referred for care and curative antiviral therapy.
 

Postexposure prophylaxis is not recommended

Recent data have shown that the risk for HCV infection from percutaneous exposure is 0.2% and from mucocutaneous exposure is 0%. On the basis of this information, the CDC guidelines no longer recommend routine postexposure prophylaxis for HCPs with occupational exposure to HCV. Rather, curative antiviral regimens should be reserved for instances of documented HCV transmission.

The authors disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

New guidelines from the Centers for Disease Control and Prevention outline a “test and treat” strategy for health care personnel (HCP) with potential occupational exposure to hepatitis C virus (HCV).

The new guidance was developed in part as a result of an increase in the incidence of acute HCV infection in the United States, which increases the risk for occupational exposure among HCP. “[I]n certain health care settings, HCP might be exposed to source patients with early HCV infection before those patients develop serologic evidence of infection or symptoms indicative of viral hepatitis,” wrote the authors of the report, published online July 24 in the CDC’s Morbidity and Mortality Weekly Report.

The guidelines, which no longer recommend waiting for spontaneous resolution upon initial diagnosis, include recommendations and algorithms for baseline and follow-up testing, appropriate test type, and recommendations for clinical management. The recommendations were developed on the basis of a current literature review, expert opinion from subject matter experts, and recent guidance from the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America.
 

Baseline testing ASAP

Baseline testing of the source patient and the HCP should be performed as soon as possible, preferably within 48 hours of exposure. The source patient should be tested for HCV RNA using a nucleic acid test. Alternatively, screening anti-HCV serology can be performed in patients at low risk for HCV and a nucleic acid test performed if serology is positive.

Baseline testing for the HCP should include anti-HCV testing and, if positive, HCV RNA testing is recommended. HCPs who test positive for HCV RNA at baseline are considered to have a preexisting HCV infection and should be referred for treatment.
 

Follow-up testing

For HCPs with exposure to blood or body fluids from a patient who is anti-HCV positive but HCV RNA negative, follow-up testing is not required.

If the source patient is HCV RNA positive, or if status of the source patient is unknown, the authors recommend that exposed HCPs have HCV RNA follow-up testing at 3-6 weeks post exposure, in addition to baseline testing. A final anti-HCV test is recommended at 4-6 months post exposure as there can be potential periods of aviremia during acute HCV infection.

Exposed HCPs who develop signs of illness indicative of HCV infection at any time should be tested for HCV RNA.

HCPs with positive HCV RNA test results should be referred for care and curative antiviral therapy.
 

Postexposure prophylaxis is not recommended

Recent data have shown that the risk for HCV infection from percutaneous exposure is 0.2% and from mucocutaneous exposure is 0%. On the basis of this information, the CDC guidelines no longer recommend routine postexposure prophylaxis for HCPs with occupational exposure to HCV. Rather, curative antiviral regimens should be reserved for instances of documented HCV transmission.

The authors disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Antibody levels in patients with mild COVID-19, the level of disease most people have, appear to drop by half within 36 days, new research suggests. The research was conducted by F. Javier Ibarrondo, PhD, and colleagues and was published online on July 21 in a letter to the editor of the New England Journal of Medicine. Ibarrondo is associate researcher at the University of California, Los Angeles. (The original letter incorrectly calculated the half-life at 73 days.)

Coauthor Otto Yang, MD, professor of medicine in the division of infectious diseases at UCLA, told Medscape Medical News that the rapidity in the antibody drop at 5 weeks “is striking compared to other infections.”

The phenomenon has been suspected and has been observed before but had not been quantified.

“Our paper is the first to put firm numbers on the dropping of antibodies after early infection,” he said.

The researchers evaluated 34 people (average age, 43 years) who had recovered from mild COVID-19 and had referred themselves to UCLA for observational research.
 

Previous report also found a quick fade

As Medscape Medical News reported, a previous study from China that was published in Nature Medicine also found that the antibodies fade quickly.

Interpreting the meaning of the current research comes with a few caveats, Dr. Yang said.

“One is that we don’t know for sure that antibodies are what protect people from getting infected,” he said. Although it’s a reasonable assumption, he said, that’s not always the case.

Another caveat is that even if antibodies do protect, the tests being used to measure them – including the test that was used in this study – may not measure them the right way, and it is not yet known how many antibodies are needed for protection, he explained.

The UCLA researchers used an enzyme-linked immunosorbent assay to detect anti–SARS-CoV-2 spike receptor–binding domain immunoglobulin G concentrations.
 

“No reason for anybody to be getting an antibody test medically”

The study provides further proof that “[t]here’s no reason for anybody to be getting an antibody test medically right now,” Dr. Yang said.

Additionally, “FDA-approved tests are not approved for quantitative measures, only qualitative,” he continued. He noted that the findings may have implications with respect to herd immunity.

“Herd immunity depends on a lot of people having immunity to the infection all at the same time. If infection is followed by only brief protection from infection, the natural infection is not going to reach herd immunity,” he explained.

Buddy Creech, MD, MPH, associate professor of pediatrics and director of the Vanderbilt Vaccine Research Program in Nashville, Tenn., pointed out that antibodies “are just part of the story.”

“When we make an immune response to any germ,” he said, “we not only make an immune response for the time being but for the future. The next time we’re exposed, we can call into action B cells and T cells who have been there and done that.”

So even though the antibodies fade over time, other arms of the immune system are being trained for future action, he said.

Herd immunity does not require that populations have a huge level of antibodies that remains forever, he explained.

“It requires that in general, we’re not going to get infected as easily, and we’re not going to have disease as easily, and we’re not going to transmit the virus for as long,” he said.

Dr. Creech said he and others researching COVID-19 find that studies that show that antibodies fade quickly provide more proof “that this coronavirus is going to be here to stay unless we can take care of it through very effective treatments to take it from potentially fatal disease to one that is nothing more than a cold” or until a vaccine is developed.

He noted there are four other coronaviruses in widespread circulation every year that “amount to about 25% of the common cold.”

This study may help narrow the window as to when convalescent plasma – plasma that is taken from people who have recovered from COVID-19 and that is used to help people who are acutely ill with the disease – will be most effective, Dr. Creech explained. He said the results suggest that it is important that plasma be collected within the first couple of months after recovery so as to capture the most antibodies.

This study is important as another snapshot “so we understand the differences between severe and mild disease, so we can study it over time, so we have all the tools we need as we start these pivotal vaccine studies to make sure we’re making the right immune response for the right duration of time so we can put an end to this pandemic,” Dr. Creech concluded.

The study was supported by grants from the AIDS Healthcare Foundation, the Doris Duke Charitable Foundation, the National Institutes of Health, the James B. Pendleton Charitable Trust, and the McCarthy Family Foundation. A coauthor reports receiving grants from Gilead outside the submitted work. Dr. Creech has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Antibody levels in patients with mild COVID-19, the level of disease most people have, appear to drop by half within 36 days, new research suggests. The research was conducted by F. Javier Ibarrondo, PhD, and colleagues and was published online on July 21 in a letter to the editor of the New England Journal of Medicine. Ibarrondo is associate researcher at the University of California, Los Angeles. (The original letter incorrectly calculated the half-life at 73 days.)

Coauthor Otto Yang, MD, professor of medicine in the division of infectious diseases at UCLA, told Medscape Medical News that the rapidity in the antibody drop at 5 weeks “is striking compared to other infections.”

The phenomenon has been suspected and has been observed before but had not been quantified.

“Our paper is the first to put firm numbers on the dropping of antibodies after early infection,” he said.

The researchers evaluated 34 people (average age, 43 years) who had recovered from mild COVID-19 and had referred themselves to UCLA for observational research.
 

Previous report also found a quick fade

As Medscape Medical News reported, a previous study from China that was published in Nature Medicine also found that the antibodies fade quickly.

Interpreting the meaning of the current research comes with a few caveats, Dr. Yang said.

“One is that we don’t know for sure that antibodies are what protect people from getting infected,” he said. Although it’s a reasonable assumption, he said, that’s not always the case.

Another caveat is that even if antibodies do protect, the tests being used to measure them – including the test that was used in this study – may not measure them the right way, and it is not yet known how many antibodies are needed for protection, he explained.

The UCLA researchers used an enzyme-linked immunosorbent assay to detect anti–SARS-CoV-2 spike receptor–binding domain immunoglobulin G concentrations.
 

“No reason for anybody to be getting an antibody test medically”

The study provides further proof that “[t]here’s no reason for anybody to be getting an antibody test medically right now,” Dr. Yang said.

Additionally, “FDA-approved tests are not approved for quantitative measures, only qualitative,” he continued. He noted that the findings may have implications with respect to herd immunity.

“Herd immunity depends on a lot of people having immunity to the infection all at the same time. If infection is followed by only brief protection from infection, the natural infection is not going to reach herd immunity,” he explained.

Buddy Creech, MD, MPH, associate professor of pediatrics and director of the Vanderbilt Vaccine Research Program in Nashville, Tenn., pointed out that antibodies “are just part of the story.”

“When we make an immune response to any germ,” he said, “we not only make an immune response for the time being but for the future. The next time we’re exposed, we can call into action B cells and T cells who have been there and done that.”

So even though the antibodies fade over time, other arms of the immune system are being trained for future action, he said.

Herd immunity does not require that populations have a huge level of antibodies that remains forever, he explained.

“It requires that in general, we’re not going to get infected as easily, and we’re not going to have disease as easily, and we’re not going to transmit the virus for as long,” he said.

Dr. Creech said he and others researching COVID-19 find that studies that show that antibodies fade quickly provide more proof “that this coronavirus is going to be here to stay unless we can take care of it through very effective treatments to take it from potentially fatal disease to one that is nothing more than a cold” or until a vaccine is developed.

He noted there are four other coronaviruses in widespread circulation every year that “amount to about 25% of the common cold.”

This study may help narrow the window as to when convalescent plasma – plasma that is taken from people who have recovered from COVID-19 and that is used to help people who are acutely ill with the disease – will be most effective, Dr. Creech explained. He said the results suggest that it is important that plasma be collected within the first couple of months after recovery so as to capture the most antibodies.

This study is important as another snapshot “so we understand the differences between severe and mild disease, so we can study it over time, so we have all the tools we need as we start these pivotal vaccine studies to make sure we’re making the right immune response for the right duration of time so we can put an end to this pandemic,” Dr. Creech concluded.

The study was supported by grants from the AIDS Healthcare Foundation, the Doris Duke Charitable Foundation, the National Institutes of Health, the James B. Pendleton Charitable Trust, and the McCarthy Family Foundation. A coauthor reports receiving grants from Gilead outside the submitted work. Dr. Creech has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Antibody levels in patients with mild COVID-19, the level of disease most people have, appear to drop by half within 36 days, new research suggests. The research was conducted by F. Javier Ibarrondo, PhD, and colleagues and was published online on July 21 in a letter to the editor of the New England Journal of Medicine. Ibarrondo is associate researcher at the University of California, Los Angeles. (The original letter incorrectly calculated the half-life at 73 days.)

Coauthor Otto Yang, MD, professor of medicine in the division of infectious diseases at UCLA, told Medscape Medical News that the rapidity in the antibody drop at 5 weeks “is striking compared to other infections.”

The phenomenon has been suspected and has been observed before but had not been quantified.

“Our paper is the first to put firm numbers on the dropping of antibodies after early infection,” he said.

The researchers evaluated 34 people (average age, 43 years) who had recovered from mild COVID-19 and had referred themselves to UCLA for observational research.
 

Previous report also found a quick fade

As Medscape Medical News reported, a previous study from China that was published in Nature Medicine also found that the antibodies fade quickly.

Interpreting the meaning of the current research comes with a few caveats, Dr. Yang said.

“One is that we don’t know for sure that antibodies are what protect people from getting infected,” he said. Although it’s a reasonable assumption, he said, that’s not always the case.

Another caveat is that even if antibodies do protect, the tests being used to measure them – including the test that was used in this study – may not measure them the right way, and it is not yet known how many antibodies are needed for protection, he explained.

The UCLA researchers used an enzyme-linked immunosorbent assay to detect anti–SARS-CoV-2 spike receptor–binding domain immunoglobulin G concentrations.
 

“No reason for anybody to be getting an antibody test medically”

The study provides further proof that “[t]here’s no reason for anybody to be getting an antibody test medically right now,” Dr. Yang said.

Additionally, “FDA-approved tests are not approved for quantitative measures, only qualitative,” he continued. He noted that the findings may have implications with respect to herd immunity.

“Herd immunity depends on a lot of people having immunity to the infection all at the same time. If infection is followed by only brief protection from infection, the natural infection is not going to reach herd immunity,” he explained.

Buddy Creech, MD, MPH, associate professor of pediatrics and director of the Vanderbilt Vaccine Research Program in Nashville, Tenn., pointed out that antibodies “are just part of the story.”

“When we make an immune response to any germ,” he said, “we not only make an immune response for the time being but for the future. The next time we’re exposed, we can call into action B cells and T cells who have been there and done that.”

So even though the antibodies fade over time, other arms of the immune system are being trained for future action, he said.

Herd immunity does not require that populations have a huge level of antibodies that remains forever, he explained.

“It requires that in general, we’re not going to get infected as easily, and we’re not going to have disease as easily, and we’re not going to transmit the virus for as long,” he said.

Dr. Creech said he and others researching COVID-19 find that studies that show that antibodies fade quickly provide more proof “that this coronavirus is going to be here to stay unless we can take care of it through very effective treatments to take it from potentially fatal disease to one that is nothing more than a cold” or until a vaccine is developed.

He noted there are four other coronaviruses in widespread circulation every year that “amount to about 25% of the common cold.”

This study may help narrow the window as to when convalescent plasma – plasma that is taken from people who have recovered from COVID-19 and that is used to help people who are acutely ill with the disease – will be most effective, Dr. Creech explained. He said the results suggest that it is important that plasma be collected within the first couple of months after recovery so as to capture the most antibodies.

This study is important as another snapshot “so we understand the differences between severe and mild disease, so we can study it over time, so we have all the tools we need as we start these pivotal vaccine studies to make sure we’re making the right immune response for the right duration of time so we can put an end to this pandemic,” Dr. Creech concluded.

The study was supported by grants from the AIDS Healthcare Foundation, the Doris Duke Charitable Foundation, the National Institutes of Health, the James B. Pendleton Charitable Trust, and the McCarthy Family Foundation. A coauthor reports receiving grants from Gilead outside the submitted work. Dr. Creech has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

A study that observed oral petechial lesions in a small number of COVID-19 patients with skin rash fortifies growing evidence that the virus has dermatologic manifestations. Larger studies should explore and confirm this association, the study’s authors and other experts suggested.

Dermatologists are already aware of the connection between enanthem and viral etiology. “As seen with other viral infections, we wondered if COVID-19 could produce enanthem in addition to skin rash exanthem,” one of the study author’s, Juan Jiménez-Cauhe, MD, a dermatologist with Hospital Universitario Ramon y Cajal, Madrid, said in an interview. He and his colleagues summarized their findings in a research letter in JAMA Dermatology.

They examined the oral cavity of 21 COVID-19 patients at a tertiary care hospital who also had a skin rash from March 30 to April 8. They classified enanthems into four categories: petechial, macular, macular with petechiae, or erythematovesicular. Six of the patients presented with oral lesions, all of them located in the palate; in one patient, the enanthem was macular, it was petechial in two patients and was macular with petechiae in three patients. The six patients ranged between the ages of 40 and 69 years; four were women.

Petechial or vesicular patterns are often associated with viral infections. In this particular study, the investigators did not observe vesicular lesions.

On average, mucocutaneous lesions appeared about 12 days after the onset of COVID-19 symptoms. “Interestingly, this latency was shorter in patients with petechial enanthem, compared with those with a macular lesion with petechiae appearance,” the authors wrote.

This shorter time might suggest an association for SARS-CoV-2, said Dr. Jiménez-Cauhe. Strong cough may have also caused petechial lesions on the palate, but it’s unlikely, as they appeared close in time to COVID-19 symptoms. It’s also unlikely that any drugs caused the lesions, as drug rashes can take 2-3 weeks to appear.

This fits in line with other evidence of broader skin manifestations appearing at the same time or after COVID-19, Esther Freeman, MD, said in an interview. Dr. Freeman, director of global health dermatology at Massachusetts General Hospital, Boston, is the principal investigator of the COVID-19 Dermatology Registry, a collaboration of the American Academy of Dermatology and International League of Dermatological Societies.

The study’s small cohort made it difficult to establish a solid association between the oral lesions and SARS-CoV-2. “However, the presence of enanthem in a patient with a skin rash is a useful finding that suggests a viral etiology rather than a drug reaction. This is particularly useful in COVID-19 patients, who were receiving many drugs as part of the treatment,” Dr. Jimenez-Cauhe said. Future studies should assess whether the presence of enanthem and exanthem lead physicians to consider SARS-CoV-2 as possible agents, ruling out infection with a blood or nasopharyngeal test.

This study adds to the growing body of knowledge on cutaneous and mucocutaneous findings associated with SARS-CoV-2 infection, Jules Lipoff, MD, of the department of dermatology, University of Pennsylvania, Philadelphia, said in an interview. “One challenge in evaluating these findings is that these findings are nonspecific, and medication reactions can often cause similar rashes, such as morbilliform eruptions that can be associated with both viruses and medications.”

Enanthems, as the study authors noted, are more specific to viral infections and are less commonly associated with medication reactions. “So, even though this is a small case series with significant limitations, it does add more evidence that COVID-19 is directly responsible for findings in the skin and mucous membranes,” said Dr. Lipoff.

Dr. Freeman noted that the study may also encourage clinicians to look in a patient’s mouth when assessing for SARS-CoV-2. Additional research should examine these data in a larger population.

Several studies by Dr. Freeman, Dr. Lipoff, and others strongly suggest that SARS-CoV-2 has a spectrum of associated dermatologic manifestations. One evaluated perniolike skin lesions (J Am Acad Dermatol. 2020 Aug; 83[2]:486-92). The other was a case series from the COVID-19 registry that examined 716 cases of new-onset dermatologic symptoms in patients from 31 countries with confirmed/suspected SARS-CoV-2 (J Am Acad Dermatol. 2020 Jul 2;S0190-9622[20]32126-5.).

The authors of the report had no disclosures.

SOURCE: Jimenez-Cauhe J et al. JAMA Dermatol. 2020 Jul 15. doi: 10.1001/jamadermatol.2020.2550.

A study that observed oral petechial lesions in a small number of COVID-19 patients with skin rash fortifies growing evidence that the virus has dermatologic manifestations. Larger studies should explore and confirm this association, the study’s authors and other experts suggested.

Dermatologists are already aware of the connection between enanthem and viral etiology. “As seen with other viral infections, we wondered if COVID-19 could produce enanthem in addition to skin rash exanthem,” one of the study author’s, Juan Jiménez-Cauhe, MD, a dermatologist with Hospital Universitario Ramon y Cajal, Madrid, said in an interview. He and his colleagues summarized their findings in a research letter in JAMA Dermatology.

They examined the oral cavity of 21 COVID-19 patients at a tertiary care hospital who also had a skin rash from March 30 to April 8. They classified enanthems into four categories: petechial, macular, macular with petechiae, or erythematovesicular. Six of the patients presented with oral lesions, all of them located in the palate; in one patient, the enanthem was macular, it was petechial in two patients and was macular with petechiae in three patients. The six patients ranged between the ages of 40 and 69 years; four were women.

Petechial or vesicular patterns are often associated with viral infections. In this particular study, the investigators did not observe vesicular lesions.

On average, mucocutaneous lesions appeared about 12 days after the onset of COVID-19 symptoms. “Interestingly, this latency was shorter in patients with petechial enanthem, compared with those with a macular lesion with petechiae appearance,” the authors wrote.

This shorter time might suggest an association for SARS-CoV-2, said Dr. Jiménez-Cauhe. Strong cough may have also caused petechial lesions on the palate, but it’s unlikely, as they appeared close in time to COVID-19 symptoms. It’s also unlikely that any drugs caused the lesions, as drug rashes can take 2-3 weeks to appear.

This fits in line with other evidence of broader skin manifestations appearing at the same time or after COVID-19, Esther Freeman, MD, said in an interview. Dr. Freeman, director of global health dermatology at Massachusetts General Hospital, Boston, is the principal investigator of the COVID-19 Dermatology Registry, a collaboration of the American Academy of Dermatology and International League of Dermatological Societies.

The study’s small cohort made it difficult to establish a solid association between the oral lesions and SARS-CoV-2. “However, the presence of enanthem in a patient with a skin rash is a useful finding that suggests a viral etiology rather than a drug reaction. This is particularly useful in COVID-19 patients, who were receiving many drugs as part of the treatment,” Dr. Jimenez-Cauhe said. Future studies should assess whether the presence of enanthem and exanthem lead physicians to consider SARS-CoV-2 as possible agents, ruling out infection with a blood or nasopharyngeal test.

This study adds to the growing body of knowledge on cutaneous and mucocutaneous findings associated with SARS-CoV-2 infection, Jules Lipoff, MD, of the department of dermatology, University of Pennsylvania, Philadelphia, said in an interview. “One challenge in evaluating these findings is that these findings are nonspecific, and medication reactions can often cause similar rashes, such as morbilliform eruptions that can be associated with both viruses and medications.”

Enanthems, as the study authors noted, are more specific to viral infections and are less commonly associated with medication reactions. “So, even though this is a small case series with significant limitations, it does add more evidence that COVID-19 is directly responsible for findings in the skin and mucous membranes,” said Dr. Lipoff.

Dr. Freeman noted that the study may also encourage clinicians to look in a patient’s mouth when assessing for SARS-CoV-2. Additional research should examine these data in a larger population.

Several studies by Dr. Freeman, Dr. Lipoff, and others strongly suggest that SARS-CoV-2 has a spectrum of associated dermatologic manifestations. One evaluated perniolike skin lesions (J Am Acad Dermatol. 2020 Aug; 83[2]:486-92). The other was a case series from the COVID-19 registry that examined 716 cases of new-onset dermatologic symptoms in patients from 31 countries with confirmed/suspected SARS-CoV-2 (J Am Acad Dermatol. 2020 Jul 2;S0190-9622[20]32126-5.).

The authors of the report had no disclosures.

SOURCE: Jimenez-Cauhe J et al. JAMA Dermatol. 2020 Jul 15. doi: 10.1001/jamadermatol.2020.2550.

A study that observed oral petechial lesions in a small number of COVID-19 patients with skin rash fortifies growing evidence that the virus has dermatologic manifestations. Larger studies should explore and confirm this association, the study’s authors and other experts suggested.

Dermatologists are already aware of the connection between enanthem and viral etiology. “As seen with other viral infections, we wondered if COVID-19 could produce enanthem in addition to skin rash exanthem,” one of the study author’s, Juan Jiménez-Cauhe, MD, a dermatologist with Hospital Universitario Ramon y Cajal, Madrid, said in an interview. He and his colleagues summarized their findings in a research letter in JAMA Dermatology.

They examined the oral cavity of 21 COVID-19 patients at a tertiary care hospital who also had a skin rash from March 30 to April 8. They classified enanthems into four categories: petechial, macular, macular with petechiae, or erythematovesicular. Six of the patients presented with oral lesions, all of them located in the palate; in one patient, the enanthem was macular, it was petechial in two patients and was macular with petechiae in three patients. The six patients ranged between the ages of 40 and 69 years; four were women.

Petechial or vesicular patterns are often associated with viral infections. In this particular study, the investigators did not observe vesicular lesions.

On average, mucocutaneous lesions appeared about 12 days after the onset of COVID-19 symptoms. “Interestingly, this latency was shorter in patients with petechial enanthem, compared with those with a macular lesion with petechiae appearance,” the authors wrote.

This shorter time might suggest an association for SARS-CoV-2, said Dr. Jiménez-Cauhe. Strong cough may have also caused petechial lesions on the palate, but it’s unlikely, as they appeared close in time to COVID-19 symptoms. It’s also unlikely that any drugs caused the lesions, as drug rashes can take 2-3 weeks to appear.

This fits in line with other evidence of broader skin manifestations appearing at the same time or after COVID-19, Esther Freeman, MD, said in an interview. Dr. Freeman, director of global health dermatology at Massachusetts General Hospital, Boston, is the principal investigator of the COVID-19 Dermatology Registry, a collaboration of the American Academy of Dermatology and International League of Dermatological Societies.

The study’s small cohort made it difficult to establish a solid association between the oral lesions and SARS-CoV-2. “However, the presence of enanthem in a patient with a skin rash is a useful finding that suggests a viral etiology rather than a drug reaction. This is particularly useful in COVID-19 patients, who were receiving many drugs as part of the treatment,” Dr. Jimenez-Cauhe said. Future studies should assess whether the presence of enanthem and exanthem lead physicians to consider SARS-CoV-2 as possible agents, ruling out infection with a blood or nasopharyngeal test.

This study adds to the growing body of knowledge on cutaneous and mucocutaneous findings associated with SARS-CoV-2 infection, Jules Lipoff, MD, of the department of dermatology, University of Pennsylvania, Philadelphia, said in an interview. “One challenge in evaluating these findings is that these findings are nonspecific, and medication reactions can often cause similar rashes, such as morbilliform eruptions that can be associated with both viruses and medications.”

Enanthems, as the study authors noted, are more specific to viral infections and are less commonly associated with medication reactions. “So, even though this is a small case series with significant limitations, it does add more evidence that COVID-19 is directly responsible for findings in the skin and mucous membranes,” said Dr. Lipoff.

Dr. Freeman noted that the study may also encourage clinicians to look in a patient’s mouth when assessing for SARS-CoV-2. Additional research should examine these data in a larger population.

Several studies by Dr. Freeman, Dr. Lipoff, and others strongly suggest that SARS-CoV-2 has a spectrum of associated dermatologic manifestations. One evaluated perniolike skin lesions (J Am Acad Dermatol. 2020 Aug; 83[2]:486-92). The other was a case series from the COVID-19 registry that examined 716 cases of new-onset dermatologic symptoms in patients from 31 countries with confirmed/suspected SARS-CoV-2 (J Am Acad Dermatol. 2020 Jul 2;S0190-9622[20]32126-5.).

The authors of the report had no disclosures.

SOURCE: Jimenez-Cauhe J et al. JAMA Dermatol. 2020 Jul 15. doi: 10.1001/jamadermatol.2020.2550.