An additional 75,000 Americans could die by suicide, drugs, or alcohol abuse because of the COVID-19 pandemic, projections from a new national report released today suggest.

The number of “deaths of despair” could be even higher if the country fails to take bold action to address the mental health toll of unemployment, isolation, and uncertainty, according to the report from the Well Being Trust (WBT) and the Robert Graham Center for Policy Studies in Family Medicine and Primary Care.

“If nothing happens and nothing improves – ie, the worst-case scenario – we could be looking at an additional 150,000 people who died who didn’t have to,” Benjamin Miller, PsyD, WBT chief strategy officer, told Medscape Medical News.

“We can prevent these deaths. We know how and have a bevy of evidence-based solutions. We lack the resources to really stand this up in a way that can most positively impact communities,” Miller added.

Slow recovery, quick recovery scenarios

For the analysis, Miller and colleagues combined information on the number of deaths from suicide, alcohol, and drugs from 2018 as a baseline (n = 181,686). They projected levels of unemployment from 2020 to 2029 and then used economic modeling to estimate the additional annual number of deaths.

Across nine different scenarios, the number of additional deaths of despair range from 27,644 (quick recovery, smallest impact of unemployment on suicide, alcohol-, and drug-related deaths) to 154,037 (slow recovery, greatest impact of unemployment on these deaths), with 75,000 being the most likely.

The report offers several policy solutions to prevent a surge in “avoidable” deaths. They include finding ways to ameliorate the effects of unemployment and provide meaningful work to those who are out of work. Making access to care easier and fully integrating mental health and addiction care into primary and clinical care as well as community settings are also essential.

These solutions should also serve to prevent drug and alcohol misuse and suicide in normal times, the researchers say.

Miller believes it’s time for the federal government to fully support a framework of excellence in mental health and well-being and to invest in mental health now.

“In the short term, we need at least $48 billion to keep the lights on in the current system,” he said.

“This is because 92.6% of mental health organizations have had to reduce their operations in some capacity, 61.8% have had to completely close at least one program, and 31.0% have had to turn away patients. This scenario is not optimal for people who will need a system to help them right now during a crisis,” he added.

In the long term, $150 billion is needed for a “massive structural redesign” of the US mental health system, Miller said.

“This means bringing mental health fully into all facets of our healthcare system, of our community. It will take robust investment in creating new mechanisms for care ― those that are team-based, create a new type of workforce to deliver that care, and one that is seamless across clinical and community settings,” said Miller.

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

An additional 75,000 Americans could die by suicide, drugs, or alcohol abuse because of the COVID-19 pandemic, projections from a new national report released today suggest.

The number of “deaths of despair” could be even higher if the country fails to take bold action to address the mental health toll of unemployment, isolation, and uncertainty, according to the report from the Well Being Trust (WBT) and the Robert Graham Center for Policy Studies in Family Medicine and Primary Care.

“If nothing happens and nothing improves – ie, the worst-case scenario – we could be looking at an additional 150,000 people who died who didn’t have to,” Benjamin Miller, PsyD, WBT chief strategy officer, told Medscape Medical News.

“We can prevent these deaths. We know how and have a bevy of evidence-based solutions. We lack the resources to really stand this up in a way that can most positively impact communities,” Miller added.

Slow recovery, quick recovery scenarios

For the analysis, Miller and colleagues combined information on the number of deaths from suicide, alcohol, and drugs from 2018 as a baseline (n = 181,686). They projected levels of unemployment from 2020 to 2029 and then used economic modeling to estimate the additional annual number of deaths.

Across nine different scenarios, the number of additional deaths of despair range from 27,644 (quick recovery, smallest impact of unemployment on suicide, alcohol-, and drug-related deaths) to 154,037 (slow recovery, greatest impact of unemployment on these deaths), with 75,000 being the most likely.

The report offers several policy solutions to prevent a surge in “avoidable” deaths. They include finding ways to ameliorate the effects of unemployment and provide meaningful work to those who are out of work. Making access to care easier and fully integrating mental health and addiction care into primary and clinical care as well as community settings are also essential.

These solutions should also serve to prevent drug and alcohol misuse and suicide in normal times, the researchers say.

Miller believes it’s time for the federal government to fully support a framework of excellence in mental health and well-being and to invest in mental health now.

“In the short term, we need at least $48 billion to keep the lights on in the current system,” he said.

“This is because 92.6% of mental health organizations have had to reduce their operations in some capacity, 61.8% have had to completely close at least one program, and 31.0% have had to turn away patients. This scenario is not optimal for people who will need a system to help them right now during a crisis,” he added.

In the long term, $150 billion is needed for a “massive structural redesign” of the US mental health system, Miller said.

“This means bringing mental health fully into all facets of our healthcare system, of our community. It will take robust investment in creating new mechanisms for care ― those that are team-based, create a new type of workforce to deliver that care, and one that is seamless across clinical and community settings,” said Miller.

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

An additional 75,000 Americans could die by suicide, drugs, or alcohol abuse because of the COVID-19 pandemic, projections from a new national report released today suggest.

The number of “deaths of despair” could be even higher if the country fails to take bold action to address the mental health toll of unemployment, isolation, and uncertainty, according to the report from the Well Being Trust (WBT) and the Robert Graham Center for Policy Studies in Family Medicine and Primary Care.

“If nothing happens and nothing improves – ie, the worst-case scenario – we could be looking at an additional 150,000 people who died who didn’t have to,” Benjamin Miller, PsyD, WBT chief strategy officer, told Medscape Medical News.

“We can prevent these deaths. We know how and have a bevy of evidence-based solutions. We lack the resources to really stand this up in a way that can most positively impact communities,” Miller added.

Slow recovery, quick recovery scenarios

For the analysis, Miller and colleagues combined information on the number of deaths from suicide, alcohol, and drugs from 2018 as a baseline (n = 181,686). They projected levels of unemployment from 2020 to 2029 and then used economic modeling to estimate the additional annual number of deaths.

Across nine different scenarios, the number of additional deaths of despair range from 27,644 (quick recovery, smallest impact of unemployment on suicide, alcohol-, and drug-related deaths) to 154,037 (slow recovery, greatest impact of unemployment on these deaths), with 75,000 being the most likely.

The report offers several policy solutions to prevent a surge in “avoidable” deaths. They include finding ways to ameliorate the effects of unemployment and provide meaningful work to those who are out of work. Making access to care easier and fully integrating mental health and addiction care into primary and clinical care as well as community settings are also essential.

These solutions should also serve to prevent drug and alcohol misuse and suicide in normal times, the researchers say.

Miller believes it’s time for the federal government to fully support a framework of excellence in mental health and well-being and to invest in mental health now.

“In the short term, we need at least $48 billion to keep the lights on in the current system,” he said.

“This is because 92.6% of mental health organizations have had to reduce their operations in some capacity, 61.8% have had to completely close at least one program, and 31.0% have had to turn away patients. This scenario is not optimal for people who will need a system to help them right now during a crisis,” he added.

In the long term, $150 billion is needed for a “massive structural redesign” of the US mental health system, Miller said.

“This means bringing mental health fully into all facets of our healthcare system, of our community. It will take robust investment in creating new mechanisms for care ― those that are team-based, create a new type of workforce to deliver that care, and one that is seamless across clinical and community settings,” said Miller.

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

A second booster dose of the influenza vaccine in vaccine-naive children may significantly reduce their likelihood of getting the disease, new research suggests.

KatarzynaBialasiewicz/Thinkstock

Writing for JAMA Pediatrics, researchers reported on a case-control study of 7,533 children presenting to outpatient clinics – all in the U.S. Influenza Vaccine Effectiveness Network – with acute respiratory tract illnesses from 2014 to 2018. The study looked at the effectiveness of vaccination against laboratory-confirmed influenza.

Current U.S. guidelines recommend that children aged 6 months to 8 years receive two doses of the influenza vaccine initially – a priming dose and a booster dose – while those aged 9 years or older are considered to be ‘immunologically primed’ and therefore only require one annual dose.

The study found that 60% of the children had received two doses of the influenza vaccine during their first vaccination season, and 68% were first vaccinated before the current influenza season. Of those who had been vaccinated, 89% had received their first influenza vaccine dose when they were younger than 2 years.

Among the 2,140 children who were unvaccinated before the current influenza season, the 436 children who received two doses of the influenza vaccine had 43% lower odds of influenza compared with the 466 children who received one dose. The overall vaccine effectiveness among this vaccine-naive group aged under 2 years was 38%; for those who received two doses it was 53%, and for those who received one dose it was 23%.

“The higher risk of infection resulting from underdeveloped immune and respiratory tract systems provides a reason to identify vaccination strategies focusing on this vulnerable population of younger children,” wrote Jessie R. Chung, MPH, of the Influenza Division of the Centers for Disease Control and Prevention, and coauthors. “Promoting efforts to improve influenza vaccine coverage—particularly with 2 doses in the first vaccination season – may reduce the burden of influenza illness among young children, who are particularly vulnerable to complications and death from influenza infection.”

Overall 52% of children were unvaccinated for the current influenza season and 9% were partially vaccinated. Of those who were fully vaccinated for the current season, 83% had received one dose in the current season, and 17% had received two doses.

The authors found that full vaccination against any influenza was associated with a 22% lower odds of influenza compared with partial vaccination (95% confidence interval, 0.61-1.01), with partial vaccination defined as anything less than two doses of vaccine in the current season – at least 4 weeks apart – or two or more doses before the current season and one or more doses in the current season. However, even children who were only partially vaccinated still showed statistically significant vaccine effectiveness, except for those who received one dose of vaccine in the current season and were aged under 2 years.

“Compared with older children, young children, even if healthy, are at an elevated risk of influenza infection and influenza-associated complications, such as hospitalization,” the authors wrote. “One recent simulation study reported that even small improvements in either vaccine coverage or VE [vaccine effectiveness], and ideally both, may avert substantial amounts of influenza-associated illnesses, medical visits, and hospitalizations.”

The study also noted that children who had received only a single previous vaccine dose rarely received two doses in the current season.

In an accompanying editorial, Claire Abraham, MD, and Melissa S. Stockwell, MD, of Columbia University Medical Center, New York, wrote that modeling suggested that in the 2017-2018 influenza season, vaccination prevented 1.3 million cases of infection, 895,000 medical visits, 10,500 hospitalizations and 111 deaths in children aged under 5 years.

“This study highlights the importance of administering 2 doses of the influenza vaccine to children younger than 9 years for whom 2 doses are needed, and especially to vaccine naive children younger than 2 years,” they wrote.

But despite many studies showing the impact and importance of influenza vaccination, uptake of this vaccine remained lower than for other pediatric vaccines.

“This present study reemphasizes the need for further research exploring why families who are seemingly willing to vaccinate their children against influenza, as indicated by their receiving the first needed dose of influenza vaccine, find barriers to receiving all of the needed doses, placing their children at higher risk for contracting a potentially devastating virus.”

The U.S. Influenza Vaccine Effectiveness Network is funded by the CDC, and this project also received support from the National Institutes of Health. Eight authors declared grants from the CDC during the conduct of the study, and five declared grants and other funding from private industry outside the study.

SOURCE: Chung J et al. JAMA Pediatrics 2020 May 4. doi: 10.1001/jamapediatrics.2020.0372.

A second booster dose of the influenza vaccine in vaccine-naive children may significantly reduce their likelihood of getting the disease, new research suggests.

KatarzynaBialasiewicz/Thinkstock

Writing for JAMA Pediatrics, researchers reported on a case-control study of 7,533 children presenting to outpatient clinics – all in the U.S. Influenza Vaccine Effectiveness Network – with acute respiratory tract illnesses from 2014 to 2018. The study looked at the effectiveness of vaccination against laboratory-confirmed influenza.

Current U.S. guidelines recommend that children aged 6 months to 8 years receive two doses of the influenza vaccine initially – a priming dose and a booster dose – while those aged 9 years or older are considered to be ‘immunologically primed’ and therefore only require one annual dose.

The study found that 60% of the children had received two doses of the influenza vaccine during their first vaccination season, and 68% were first vaccinated before the current influenza season. Of those who had been vaccinated, 89% had received their first influenza vaccine dose when they were younger than 2 years.

Among the 2,140 children who were unvaccinated before the current influenza season, the 436 children who received two doses of the influenza vaccine had 43% lower odds of influenza compared with the 466 children who received one dose. The overall vaccine effectiveness among this vaccine-naive group aged under 2 years was 38%; for those who received two doses it was 53%, and for those who received one dose it was 23%.

“The higher risk of infection resulting from underdeveloped immune and respiratory tract systems provides a reason to identify vaccination strategies focusing on this vulnerable population of younger children,” wrote Jessie R. Chung, MPH, of the Influenza Division of the Centers for Disease Control and Prevention, and coauthors. “Promoting efforts to improve influenza vaccine coverage—particularly with 2 doses in the first vaccination season – may reduce the burden of influenza illness among young children, who are particularly vulnerable to complications and death from influenza infection.”

Overall 52% of children were unvaccinated for the current influenza season and 9% were partially vaccinated. Of those who were fully vaccinated for the current season, 83% had received one dose in the current season, and 17% had received two doses.

The authors found that full vaccination against any influenza was associated with a 22% lower odds of influenza compared with partial vaccination (95% confidence interval, 0.61-1.01), with partial vaccination defined as anything less than two doses of vaccine in the current season – at least 4 weeks apart – or two or more doses before the current season and one or more doses in the current season. However, even children who were only partially vaccinated still showed statistically significant vaccine effectiveness, except for those who received one dose of vaccine in the current season and were aged under 2 years.

“Compared with older children, young children, even if healthy, are at an elevated risk of influenza infection and influenza-associated complications, such as hospitalization,” the authors wrote. “One recent simulation study reported that even small improvements in either vaccine coverage or VE [vaccine effectiveness], and ideally both, may avert substantial amounts of influenza-associated illnesses, medical visits, and hospitalizations.”

The study also noted that children who had received only a single previous vaccine dose rarely received two doses in the current season.

In an accompanying editorial, Claire Abraham, MD, and Melissa S. Stockwell, MD, of Columbia University Medical Center, New York, wrote that modeling suggested that in the 2017-2018 influenza season, vaccination prevented 1.3 million cases of infection, 895,000 medical visits, 10,500 hospitalizations and 111 deaths in children aged under 5 years.

“This study highlights the importance of administering 2 doses of the influenza vaccine to children younger than 9 years for whom 2 doses are needed, and especially to vaccine naive children younger than 2 years,” they wrote.

But despite many studies showing the impact and importance of influenza vaccination, uptake of this vaccine remained lower than for other pediatric vaccines.

“This present study reemphasizes the need for further research exploring why families who are seemingly willing to vaccinate their children against influenza, as indicated by their receiving the first needed dose of influenza vaccine, find barriers to receiving all of the needed doses, placing their children at higher risk for contracting a potentially devastating virus.”

The U.S. Influenza Vaccine Effectiveness Network is funded by the CDC, and this project also received support from the National Institutes of Health. Eight authors declared grants from the CDC during the conduct of the study, and five declared grants and other funding from private industry outside the study.

SOURCE: Chung J et al. JAMA Pediatrics 2020 May 4. doi: 10.1001/jamapediatrics.2020.0372.

A second booster dose of the influenza vaccine in vaccine-naive children may significantly reduce their likelihood of getting the disease, new research suggests.

KatarzynaBialasiewicz/Thinkstock

Writing for JAMA Pediatrics, researchers reported on a case-control study of 7,533 children presenting to outpatient clinics – all in the U.S. Influenza Vaccine Effectiveness Network – with acute respiratory tract illnesses from 2014 to 2018. The study looked at the effectiveness of vaccination against laboratory-confirmed influenza.

Current U.S. guidelines recommend that children aged 6 months to 8 years receive two doses of the influenza vaccine initially – a priming dose and a booster dose – while those aged 9 years or older are considered to be ‘immunologically primed’ and therefore only require one annual dose.

The study found that 60% of the children had received two doses of the influenza vaccine during their first vaccination season, and 68% were first vaccinated before the current influenza season. Of those who had been vaccinated, 89% had received their first influenza vaccine dose when they were younger than 2 years.

Among the 2,140 children who were unvaccinated before the current influenza season, the 436 children who received two doses of the influenza vaccine had 43% lower odds of influenza compared with the 466 children who received one dose. The overall vaccine effectiveness among this vaccine-naive group aged under 2 years was 38%; for those who received two doses it was 53%, and for those who received one dose it was 23%.

“The higher risk of infection resulting from underdeveloped immune and respiratory tract systems provides a reason to identify vaccination strategies focusing on this vulnerable population of younger children,” wrote Jessie R. Chung, MPH, of the Influenza Division of the Centers for Disease Control and Prevention, and coauthors. “Promoting efforts to improve influenza vaccine coverage—particularly with 2 doses in the first vaccination season – may reduce the burden of influenza illness among young children, who are particularly vulnerable to complications and death from influenza infection.”

Overall 52% of children were unvaccinated for the current influenza season and 9% were partially vaccinated. Of those who were fully vaccinated for the current season, 83% had received one dose in the current season, and 17% had received two doses.

The authors found that full vaccination against any influenza was associated with a 22% lower odds of influenza compared with partial vaccination (95% confidence interval, 0.61-1.01), with partial vaccination defined as anything less than two doses of vaccine in the current season – at least 4 weeks apart – or two or more doses before the current season and one or more doses in the current season. However, even children who were only partially vaccinated still showed statistically significant vaccine effectiveness, except for those who received one dose of vaccine in the current season and were aged under 2 years.

“Compared with older children, young children, even if healthy, are at an elevated risk of influenza infection and influenza-associated complications, such as hospitalization,” the authors wrote. “One recent simulation study reported that even small improvements in either vaccine coverage or VE [vaccine effectiveness], and ideally both, may avert substantial amounts of influenza-associated illnesses, medical visits, and hospitalizations.”

The study also noted that children who had received only a single previous vaccine dose rarely received two doses in the current season.

In an accompanying editorial, Claire Abraham, MD, and Melissa S. Stockwell, MD, of Columbia University Medical Center, New York, wrote that modeling suggested that in the 2017-2018 influenza season, vaccination prevented 1.3 million cases of infection, 895,000 medical visits, 10,500 hospitalizations and 111 deaths in children aged under 5 years.

“This study highlights the importance of administering 2 doses of the influenza vaccine to children younger than 9 years for whom 2 doses are needed, and especially to vaccine naive children younger than 2 years,” they wrote.

But despite many studies showing the impact and importance of influenza vaccination, uptake of this vaccine remained lower than for other pediatric vaccines.

“This present study reemphasizes the need for further research exploring why families who are seemingly willing to vaccinate their children against influenza, as indicated by their receiving the first needed dose of influenza vaccine, find barriers to receiving all of the needed doses, placing their children at higher risk for contracting a potentially devastating virus.”

The U.S. Influenza Vaccine Effectiveness Network is funded by the CDC, and this project also received support from the National Institutes of Health. Eight authors declared grants from the CDC during the conduct of the study, and five declared grants and other funding from private industry outside the study.

SOURCE: Chung J et al. JAMA Pediatrics 2020 May 4. doi: 10.1001/jamapediatrics.2020.0372.

Background: Factor Xa inhibitors have become increasingly popular in the treatment and prevention of thrombotic events, but the lack of specific reversal agents in the event of life-threatening or uncontrolled bleeding may limit their use. Andexanet alfa is a new Food and Drug Administration–approved reversal agent which rapidly reduces anti–factor Xa activity, thereby reversing the anticoagulation effects of factor Xa inhibitors.

Limitations of the study include lack of a control group and absence of a significant relationship between a reduction in anti–factor Xa activity and hemostasis. The sponsor is planning to conduct a randomized trial with FDA guidance in the near future.

Bottom line: Andexanet alfa is an FDA-approved agent and appears effective in achieving hemostasis in patients with a factor Xa inhibitor–associated major acute bleeding.

Citation: Connolly SJ et al. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Eng J Med. 2019 Feb 7. doi: 10.1056/NEJMoa1814051.

Dr. Vedamurthy is a hospitalist at Massachusetts General Hospital.

Background: Factor Xa inhibitors have become increasingly popular in the treatment and prevention of thrombotic events, but the lack of specific reversal agents in the event of life-threatening or uncontrolled bleeding may limit their use. Andexanet alfa is a new Food and Drug Administration–approved reversal agent which rapidly reduces anti–factor Xa activity, thereby reversing the anticoagulation effects of factor Xa inhibitors.

Limitations of the study include lack of a control group and absence of a significant relationship between a reduction in anti–factor Xa activity and hemostasis. The sponsor is planning to conduct a randomized trial with FDA guidance in the near future.

Bottom line: Andexanet alfa is an FDA-approved agent and appears effective in achieving hemostasis in patients with a factor Xa inhibitor–associated major acute bleeding.

Citation: Connolly SJ et al. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Eng J Med. 2019 Feb 7. doi: 10.1056/NEJMoa1814051.

Dr. Vedamurthy is a hospitalist at Massachusetts General Hospital.

Background: Factor Xa inhibitors have become increasingly popular in the treatment and prevention of thrombotic events, but the lack of specific reversal agents in the event of life-threatening or uncontrolled bleeding may limit their use. Andexanet alfa is a new Food and Drug Administration–approved reversal agent which rapidly reduces anti–factor Xa activity, thereby reversing the anticoagulation effects of factor Xa inhibitors.

Limitations of the study include lack of a control group and absence of a significant relationship between a reduction in anti–factor Xa activity and hemostasis. The sponsor is planning to conduct a randomized trial with FDA guidance in the near future.

Bottom line: Andexanet alfa is an FDA-approved agent and appears effective in achieving hemostasis in patients with a factor Xa inhibitor–associated major acute bleeding.

Citation: Connolly SJ et al. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Eng J Med. 2019 Feb 7. doi: 10.1056/NEJMoa1814051.

Dr. Vedamurthy is a hospitalist at Massachusetts General Hospital.

Neoadjuvant nivolumab (Opdivo, Bristol-Myers Squibb) could improve outcomes for patients with high-risk resectable Merkel cell carcinoma (MCC), say researchers reporting the first trial in this patient population.

The results come from a cohort of 39 patients with stage IIA-IV disease, all of whom received nivolumab 240 mg intravenously on days 1 and 15, with surgery planned for day 29. About half achieved a pathologic complete response (pCR) and/or a radiographic response. Recurrence-free survival was also prolonged among responders, and no relapses were observed at a median follow-up of 19.3 months.

“Additional investigation of these promising findings is warranted,” say the investigators.

“To our knowledge, this is the first study to examine neoadjuvant anti-PD-1 therapy in MCC,” said lead author Suzanne Topalian, MD, professor of surgery at the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins Medicine, Baltimore, Maryland. “While the results seem encouraging, I think that clinical trial experience with a greater number of patients and follow-up for a longer time period will be needed to assess whether this treatment approach should become standard for high-risk resectable MCC.”

The study was published online April 23 in the Journal of Clinical Oncology.

Rare and Aggressive Skin Cancer

MCC is a rare and aggressive neuroendocrine skin cancer that is diagnosed in approximately 1600 people each year in the United States, note the authors.

The annual incidence of new MCC cases rose by 95% between 2000 and 2013, as previously reported by Medscape Medical News.

Although nearly two thirds of patients present with localized disease, regional and distant metastases often occur. Until recently, cytotoxic chemotherapy was the primary systemic therapy for advanced MCC. Although patients frequently respond to chemotherapy, the duration tends to be very limited, and 95% of patients experience disease progression within 1 year, the authors comment.

Growing evidence supports the hypothesis that MCC is an immunogenic cancer. Clinical trials of PD-L1 inhibitors have demonstrated increased progression-free and overall survival compared with chemotherapy when used either in the first-line or second-line setting, as reported by Medscape Medical News.

“Neoadjuvant anti-PD-1 cancer therapy is still early in development, and there are many aspects deserving careful consideration,” Topalian told Medscape Medical News. “They are centered on balancing patient risk and benefit, finding an optimal presurgical treatment interval, exploring treatment combinations, determining if anti-PD-1 therapy should be continued after surgery, and defining biomarkers to guide treatment strategies for individual patients.”

Study Details

Topian and colleagues investigated neoadjuvant use of nivolumab in the CheckMate 358 study, which involved 39 patients with stage IIA-IV MCC (of whom 36 went on to surgery).

The median age of the patients was 68 years, and at enrollment, most patients (66.7%) had stage III disease. For 35 patients, tumors were evaluable for MCPyV status; 22 (62.9%) were positive. Quantifiable tumor cell PD-L1 expression occurred in 27 patients; expression was 1% or higher for seven of those patients (25.9%).

The primary endpoint for the neoadjuvant cohort was safety and tolerability of nivolumab, as measured by treatment-related adverse events (TRAEs) and surgical delays, defined as the proportion of patients who experienced TRAE-related delays of more than 4 weeks from the planned surgery date.

Exploratory endpoints included pCR, radiographic response, recurrence-free survival, overall survival, association of tumor MCPyV status, and PD-L1 expression with efficacy.

The median follow-up was 20.3 months. TRAEs of any grade were reported in 18 patients (46.2%). Three (7.7%) experienced a grade 3/4 event. TRAEs with potential immunologic causes occurred in six (15.4%) patients (two TRAEs were of grade 3/4).

Among those who underwent surgery, 17 (47.2%) achieved a pCR. Among patients who were radiographically evaluable (n = 33), 29 (87.9%) achieved some degree of radiographic tumor reduction. Within this group, 18 (54.5%) experienced tumor reductions of 30% or greater (the median change in tumor burden from baseline was −32.8%). Responses were observed regardless of tumor MCPyV, PD-L1, or TMB status.

Survival Outcomes

The median relapse-free survival was not reached for any of the patients who underwent surgery. At 12 and 24 months postoperatively, rates were 77.5% and 68.5%, respectively.

Among patients with pCR, relapse-free survival at 12 months was 100.0%, compared with 59.6% among those without pCR. At 24 months, it was 88.9% for those with pCR, vs 52.2% for those without pCR (hazard ratio [HR], 0.12; 95% confidence interval [CI], 0.01 – 0.93]).

Relapse-free survival was also higher for patients with radiographic tumor reduction of ≥30% in comparison with those with reduction of <30% or progression. At 12 months, it was 100.0%, vs 56.5%; at 24 months, it was 90.9%, vs 48.5% (HR, 0.11; 95% CI, 0.01 – 0.87). No substantial difference was noted between patient subgroups with respect to tumor MCPyV status or PD-L1 expression.

Median overall survival was not reached in the entire cohort. At 12 and 24 months following the first dose of nivolumab, rates were 93.2% and 79.4%, respectively. For the patients who underwent surgery and were evaluable for pathologic response or radiographic response, 100.0% and 88.9% of patients with pCR and all patients with radiographic tumor reduction of ≥30% were alive at 12 and 24 months, respectively.

Overall survival rates among patients who underwent surgery were comparable in subgroups with regard to tumor MCPyV status and PD-L1 expression.

The study was supported by Bristol-Myers Squibb and Ono, the Mark Foundation for Cancer Research, and the National Cancer Institute. Topalian reports relationships with Aduro, Potenza, Five Prime, Tizona, DNAtrix, FLX Bio, WindMIL, Dragonfly, ERVAXX, Trieza, Amgen, MedImmune, Merck, Compugen, DNAtrix, FLX Bio, Dynavax, Immunomic, Janssen Oncology, Immunocore, Bristol-Myers Squibb, Compugen Arbor, and NexImmune. Several coauthors have also disclosed relationships with industry.

This article first appeared on Medscape.com.

Neoadjuvant nivolumab (Opdivo, Bristol-Myers Squibb) could improve outcomes for patients with high-risk resectable Merkel cell carcinoma (MCC), say researchers reporting the first trial in this patient population.

The results come from a cohort of 39 patients with stage IIA-IV disease, all of whom received nivolumab 240 mg intravenously on days 1 and 15, with surgery planned for day 29. About half achieved a pathologic complete response (pCR) and/or a radiographic response. Recurrence-free survival was also prolonged among responders, and no relapses were observed at a median follow-up of 19.3 months.

“Additional investigation of these promising findings is warranted,” say the investigators.

“To our knowledge, this is the first study to examine neoadjuvant anti-PD-1 therapy in MCC,” said lead author Suzanne Topalian, MD, professor of surgery at the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins Medicine, Baltimore, Maryland. “While the results seem encouraging, I think that clinical trial experience with a greater number of patients and follow-up for a longer time period will be needed to assess whether this treatment approach should become standard for high-risk resectable MCC.”

The study was published online April 23 in the Journal of Clinical Oncology.

Rare and Aggressive Skin Cancer

MCC is a rare and aggressive neuroendocrine skin cancer that is diagnosed in approximately 1600 people each year in the United States, note the authors.

The annual incidence of new MCC cases rose by 95% between 2000 and 2013, as previously reported by Medscape Medical News.

Although nearly two thirds of patients present with localized disease, regional and distant metastases often occur. Until recently, cytotoxic chemotherapy was the primary systemic therapy for advanced MCC. Although patients frequently respond to chemotherapy, the duration tends to be very limited, and 95% of patients experience disease progression within 1 year, the authors comment.

Growing evidence supports the hypothesis that MCC is an immunogenic cancer. Clinical trials of PD-L1 inhibitors have demonstrated increased progression-free and overall survival compared with chemotherapy when used either in the first-line or second-line setting, as reported by Medscape Medical News.

“Neoadjuvant anti-PD-1 cancer therapy is still early in development, and there are many aspects deserving careful consideration,” Topalian told Medscape Medical News. “They are centered on balancing patient risk and benefit, finding an optimal presurgical treatment interval, exploring treatment combinations, determining if anti-PD-1 therapy should be continued after surgery, and defining biomarkers to guide treatment strategies for individual patients.”

Study Details

Topian and colleagues investigated neoadjuvant use of nivolumab in the CheckMate 358 study, which involved 39 patients with stage IIA-IV MCC (of whom 36 went on to surgery).

The median age of the patients was 68 years, and at enrollment, most patients (66.7%) had stage III disease. For 35 patients, tumors were evaluable for MCPyV status; 22 (62.9%) were positive. Quantifiable tumor cell PD-L1 expression occurred in 27 patients; expression was 1% or higher for seven of those patients (25.9%).

The primary endpoint for the neoadjuvant cohort was safety and tolerability of nivolumab, as measured by treatment-related adverse events (TRAEs) and surgical delays, defined as the proportion of patients who experienced TRAE-related delays of more than 4 weeks from the planned surgery date.

Exploratory endpoints included pCR, radiographic response, recurrence-free survival, overall survival, association of tumor MCPyV status, and PD-L1 expression with efficacy.

The median follow-up was 20.3 months. TRAEs of any grade were reported in 18 patients (46.2%). Three (7.7%) experienced a grade 3/4 event. TRAEs with potential immunologic causes occurred in six (15.4%) patients (two TRAEs were of grade 3/4).

Among those who underwent surgery, 17 (47.2%) achieved a pCR. Among patients who were radiographically evaluable (n = 33), 29 (87.9%) achieved some degree of radiographic tumor reduction. Within this group, 18 (54.5%) experienced tumor reductions of 30% or greater (the median change in tumor burden from baseline was −32.8%). Responses were observed regardless of tumor MCPyV, PD-L1, or TMB status.

Survival Outcomes

The median relapse-free survival was not reached for any of the patients who underwent surgery. At 12 and 24 months postoperatively, rates were 77.5% and 68.5%, respectively.

Among patients with pCR, relapse-free survival at 12 months was 100.0%, compared with 59.6% among those without pCR. At 24 months, it was 88.9% for those with pCR, vs 52.2% for those without pCR (hazard ratio [HR], 0.12; 95% confidence interval [CI], 0.01 – 0.93]).

Relapse-free survival was also higher for patients with radiographic tumor reduction of ≥30% in comparison with those with reduction of <30% or progression. At 12 months, it was 100.0%, vs 56.5%; at 24 months, it was 90.9%, vs 48.5% (HR, 0.11; 95% CI, 0.01 – 0.87). No substantial difference was noted between patient subgroups with respect to tumor MCPyV status or PD-L1 expression.

Median overall survival was not reached in the entire cohort. At 12 and 24 months following the first dose of nivolumab, rates were 93.2% and 79.4%, respectively. For the patients who underwent surgery and were evaluable for pathologic response or radiographic response, 100.0% and 88.9% of patients with pCR and all patients with radiographic tumor reduction of ≥30% were alive at 12 and 24 months, respectively.

Overall survival rates among patients who underwent surgery were comparable in subgroups with regard to tumor MCPyV status and PD-L1 expression.

The study was supported by Bristol-Myers Squibb and Ono, the Mark Foundation for Cancer Research, and the National Cancer Institute. Topalian reports relationships with Aduro, Potenza, Five Prime, Tizona, DNAtrix, FLX Bio, WindMIL, Dragonfly, ERVAXX, Trieza, Amgen, MedImmune, Merck, Compugen, DNAtrix, FLX Bio, Dynavax, Immunomic, Janssen Oncology, Immunocore, Bristol-Myers Squibb, Compugen Arbor, and NexImmune. Several coauthors have also disclosed relationships with industry.

This article first appeared on Medscape.com.

Neoadjuvant nivolumab (Opdivo, Bristol-Myers Squibb) could improve outcomes for patients with high-risk resectable Merkel cell carcinoma (MCC), say researchers reporting the first trial in this patient population.

The results come from a cohort of 39 patients with stage IIA-IV disease, all of whom received nivolumab 240 mg intravenously on days 1 and 15, with surgery planned for day 29. About half achieved a pathologic complete response (pCR) and/or a radiographic response. Recurrence-free survival was also prolonged among responders, and no relapses were observed at a median follow-up of 19.3 months.

“Additional investigation of these promising findings is warranted,” say the investigators.

“To our knowledge, this is the first study to examine neoadjuvant anti-PD-1 therapy in MCC,” said lead author Suzanne Topalian, MD, professor of surgery at the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins Medicine, Baltimore, Maryland. “While the results seem encouraging, I think that clinical trial experience with a greater number of patients and follow-up for a longer time period will be needed to assess whether this treatment approach should become standard for high-risk resectable MCC.”

The study was published online April 23 in the Journal of Clinical Oncology.

Rare and Aggressive Skin Cancer

MCC is a rare and aggressive neuroendocrine skin cancer that is diagnosed in approximately 1600 people each year in the United States, note the authors.

The annual incidence of new MCC cases rose by 95% between 2000 and 2013, as previously reported by Medscape Medical News.

Although nearly two thirds of patients present with localized disease, regional and distant metastases often occur. Until recently, cytotoxic chemotherapy was the primary systemic therapy for advanced MCC. Although patients frequently respond to chemotherapy, the duration tends to be very limited, and 95% of patients experience disease progression within 1 year, the authors comment.

Growing evidence supports the hypothesis that MCC is an immunogenic cancer. Clinical trials of PD-L1 inhibitors have demonstrated increased progression-free and overall survival compared with chemotherapy when used either in the first-line or second-line setting, as reported by Medscape Medical News.

“Neoadjuvant anti-PD-1 cancer therapy is still early in development, and there are many aspects deserving careful consideration,” Topalian told Medscape Medical News. “They are centered on balancing patient risk and benefit, finding an optimal presurgical treatment interval, exploring treatment combinations, determining if anti-PD-1 therapy should be continued after surgery, and defining biomarkers to guide treatment strategies for individual patients.”

Study Details

Topian and colleagues investigated neoadjuvant use of nivolumab in the CheckMate 358 study, which involved 39 patients with stage IIA-IV MCC (of whom 36 went on to surgery).

The median age of the patients was 68 years, and at enrollment, most patients (66.7%) had stage III disease. For 35 patients, tumors were evaluable for MCPyV status; 22 (62.9%) were positive. Quantifiable tumor cell PD-L1 expression occurred in 27 patients; expression was 1% or higher for seven of those patients (25.9%).

The primary endpoint for the neoadjuvant cohort was safety and tolerability of nivolumab, as measured by treatment-related adverse events (TRAEs) and surgical delays, defined as the proportion of patients who experienced TRAE-related delays of more than 4 weeks from the planned surgery date.

Exploratory endpoints included pCR, radiographic response, recurrence-free survival, overall survival, association of tumor MCPyV status, and PD-L1 expression with efficacy.

The median follow-up was 20.3 months. TRAEs of any grade were reported in 18 patients (46.2%). Three (7.7%) experienced a grade 3/4 event. TRAEs with potential immunologic causes occurred in six (15.4%) patients (two TRAEs were of grade 3/4).

Among those who underwent surgery, 17 (47.2%) achieved a pCR. Among patients who were radiographically evaluable (n = 33), 29 (87.9%) achieved some degree of radiographic tumor reduction. Within this group, 18 (54.5%) experienced tumor reductions of 30% or greater (the median change in tumor burden from baseline was −32.8%). Responses were observed regardless of tumor MCPyV, PD-L1, or TMB status.

Survival Outcomes

The median relapse-free survival was not reached for any of the patients who underwent surgery. At 12 and 24 months postoperatively, rates were 77.5% and 68.5%, respectively.

Among patients with pCR, relapse-free survival at 12 months was 100.0%, compared with 59.6% among those without pCR. At 24 months, it was 88.9% for those with pCR, vs 52.2% for those without pCR (hazard ratio [HR], 0.12; 95% confidence interval [CI], 0.01 – 0.93]).

Relapse-free survival was also higher for patients with radiographic tumor reduction of ≥30% in comparison with those with reduction of <30% or progression. At 12 months, it was 100.0%, vs 56.5%; at 24 months, it was 90.9%, vs 48.5% (HR, 0.11; 95% CI, 0.01 – 0.87). No substantial difference was noted between patient subgroups with respect to tumor MCPyV status or PD-L1 expression.

Median overall survival was not reached in the entire cohort. At 12 and 24 months following the first dose of nivolumab, rates were 93.2% and 79.4%, respectively. For the patients who underwent surgery and were evaluable for pathologic response or radiographic response, 100.0% and 88.9% of patients with pCR and all patients with radiographic tumor reduction of ≥30% were alive at 12 and 24 months, respectively.

Overall survival rates among patients who underwent surgery were comparable in subgroups with regard to tumor MCPyV status and PD-L1 expression.

The study was supported by Bristol-Myers Squibb and Ono, the Mark Foundation for Cancer Research, and the National Cancer Institute. Topalian reports relationships with Aduro, Potenza, Five Prime, Tizona, DNAtrix, FLX Bio, WindMIL, Dragonfly, ERVAXX, Trieza, Amgen, MedImmune, Merck, Compugen, DNAtrix, FLX Bio, Dynavax, Immunomic, Janssen Oncology, Immunocore, Bristol-Myers Squibb, Compugen Arbor, and NexImmune. Several coauthors have also disclosed relationships with industry.

This article first appeared on Medscape.com.

Adults given propofol as part of an elective outpatient endoscopy procedure showed similar driving skills after postsedation recovery and prior to the procedure, based on simulation data from an open-label study of 41 patients.

Although current guidelines recommend that patients refrain from driving for 24 hours after propofol sedation and be accompanied by a responsible adult, data on the driving skills of patients after postsedation recovery are limited, Pooja Lal, MD, of the Cleveland Clinic Foundation and colleagues wrote in an abstract released as part of the annual Digestive Disease Week, which was canceled because of COVID-19.

“We assessed psychomotor recovery using a driving simulator which mimics real-life driving in outpatients undergoing gastrointestinal endoscopy with propofol,” they wrote.

The researchers enrolled 41 outpatients who were given propofol for various elective procedures at an endoscopy unit of a single center. Patients’ driving skills were tested at baseline and after postsedation recovery using a driving simulator. Postsedation recovery was defined as Aldrete score of 9 in the recovery room. Patients were excluded from the study if they demonstrated altered mental status of any type including dementia, delirium, and hepatic encephalopathy; if they were legally blind; or were currently inpatients.

Overall, driving skills were not significantly different between preprocedure and postsedation recovery on measures of number of times over the speed limit (3.2 vs. 3.4), number of times drivers went off the road (0.37 vs. 0.54), and total pedal reaction time (6.1 seconds vs. 7.6 seconds).

“The two variables including gas pedal reaction time and the total number of collisions did not follow normal distribution,” with medians of 0.70 for gas pedal reaction time in both groups and medians of 0 collisions for both groups, the investigators noted.

The study findings were limited by the small sample size and open-label design. However, the results suggest that driving skills were similar for patients at baseline and after achieving a postsedation Aldrete score of 9, the researchers wrote. Based on these findings, “current recommendations that patients should refrain from driving and unescorted use of public transport for 24 hours after sedation may need to be reconsidered in patients who receive propofol sedation.”

“With this study, we are aiming to identify the correct patient population who could potentially drive themselves home after their procedure rather than having to arrange for transportation,” Dr. Lal said in an interview.

“The significant cost associated with the daylong interruption of the activities of daily living, having a family member accompany them for their procedures, or not being able to use public transport unescorted may deter some patients from complying with colonoscopy screenings and other important endoscopic procedures,” she explained.

“There are patients who arrive for their procedure without any accompanying family members and we have to admit them to an observation unit overnight or reschedule their procedures. The expense and inconvenience associated with the extended recovery potentially could be an impediment to many important screening exams,” she noted. “In the setting of increased awareness regarding the need for these screening exams, this study is important to highlight these barriers and propose a solution for them.”

The potential costs of lost salaries is extremely high, she said. “If we assume that the 24-hour recovery period necessitates taking a day off from work, the value of lost salary per patient would be $183.68 as per the 2019 national hourly average wage. With an estimated 19 million colonoscopies performed annually in the United States, the aggregate cost of lost wages with the 24-hour guideline would be $3.5 billion. This amount does not account for the lost wages of the accompanying family member.”

Dr. Lal said she and her colleagues were not surprised by the findings. “The endoscopists in our endoscopy unit have noted that patients recover much more rapidly after sedation with propofol compared with other sedative agents. This observation led to the hypothesis that those patients receiving propofol should have a speedy psychomotor recovery and should be able to drive the same day. Our findings are in accordance with our observations.” However, “larger and preferably multicenter studies are needed to validate these findings and add to our knowledge about the postsedation psychomotor recovery,” said Dr. Lal. She added that the study is ongoing and the researchers have collected data from a total of 63 patients, which increases the power of the results.

The researchers had no financial conflicts to disclose.

*This story was updated on 5/8/2020.

SOURCE: Lal P et al. DDW 2020, Abstract 295.

Adults given propofol as part of an elective outpatient endoscopy procedure showed similar driving skills after postsedation recovery and prior to the procedure, based on simulation data from an open-label study of 41 patients.

Although current guidelines recommend that patients refrain from driving for 24 hours after propofol sedation and be accompanied by a responsible adult, data on the driving skills of patients after postsedation recovery are limited, Pooja Lal, MD, of the Cleveland Clinic Foundation and colleagues wrote in an abstract released as part of the annual Digestive Disease Week, which was canceled because of COVID-19.

“We assessed psychomotor recovery using a driving simulator which mimics real-life driving in outpatients undergoing gastrointestinal endoscopy with propofol,” they wrote.

The researchers enrolled 41 outpatients who were given propofol for various elective procedures at an endoscopy unit of a single center. Patients’ driving skills were tested at baseline and after postsedation recovery using a driving simulator. Postsedation recovery was defined as Aldrete score of 9 in the recovery room. Patients were excluded from the study if they demonstrated altered mental status of any type including dementia, delirium, and hepatic encephalopathy; if they were legally blind; or were currently inpatients.

Overall, driving skills were not significantly different between preprocedure and postsedation recovery on measures of number of times over the speed limit (3.2 vs. 3.4), number of times drivers went off the road (0.37 vs. 0.54), and total pedal reaction time (6.1 seconds vs. 7.6 seconds).

“The two variables including gas pedal reaction time and the total number of collisions did not follow normal distribution,” with medians of 0.70 for gas pedal reaction time in both groups and medians of 0 collisions for both groups, the investigators noted.

The study findings were limited by the small sample size and open-label design. However, the results suggest that driving skills were similar for patients at baseline and after achieving a postsedation Aldrete score of 9, the researchers wrote. Based on these findings, “current recommendations that patients should refrain from driving and unescorted use of public transport for 24 hours after sedation may need to be reconsidered in patients who receive propofol sedation.”

“With this study, we are aiming to identify the correct patient population who could potentially drive themselves home after their procedure rather than having to arrange for transportation,” Dr. Lal said in an interview.

“The significant cost associated with the daylong interruption of the activities of daily living, having a family member accompany them for their procedures, or not being able to use public transport unescorted may deter some patients from complying with colonoscopy screenings and other important endoscopic procedures,” she explained.

“There are patients who arrive for their procedure without any accompanying family members and we have to admit them to an observation unit overnight or reschedule their procedures. The expense and inconvenience associated with the extended recovery potentially could be an impediment to many important screening exams,” she noted. “In the setting of increased awareness regarding the need for these screening exams, this study is important to highlight these barriers and propose a solution for them.”

The potential costs of lost salaries is extremely high, she said. “If we assume that the 24-hour recovery period necessitates taking a day off from work, the value of lost salary per patient would be $183.68 as per the 2019 national hourly average wage. With an estimated 19 million colonoscopies performed annually in the United States, the aggregate cost of lost wages with the 24-hour guideline would be $3.5 billion. This amount does not account for the lost wages of the accompanying family member.”

Dr. Lal said she and her colleagues were not surprised by the findings. “The endoscopists in our endoscopy unit have noted that patients recover much more rapidly after sedation with propofol compared with other sedative agents. This observation led to the hypothesis that those patients receiving propofol should have a speedy psychomotor recovery and should be able to drive the same day. Our findings are in accordance with our observations.” However, “larger and preferably multicenter studies are needed to validate these findings and add to our knowledge about the postsedation psychomotor recovery,” said Dr. Lal. She added that the study is ongoing and the researchers have collected data from a total of 63 patients, which increases the power of the results.

The researchers had no financial conflicts to disclose.

*This story was updated on 5/8/2020.

SOURCE: Lal P et al. DDW 2020, Abstract 295.

Adults given propofol as part of an elective outpatient endoscopy procedure showed similar driving skills after postsedation recovery and prior to the procedure, based on simulation data from an open-label study of 41 patients.

Although current guidelines recommend that patients refrain from driving for 24 hours after propofol sedation and be accompanied by a responsible adult, data on the driving skills of patients after postsedation recovery are limited, Pooja Lal, MD, of the Cleveland Clinic Foundation and colleagues wrote in an abstract released as part of the annual Digestive Disease Week, which was canceled because of COVID-19.

“We assessed psychomotor recovery using a driving simulator which mimics real-life driving in outpatients undergoing gastrointestinal endoscopy with propofol,” they wrote.

The researchers enrolled 41 outpatients who were given propofol for various elective procedures at an endoscopy unit of a single center. Patients’ driving skills were tested at baseline and after postsedation recovery using a driving simulator. Postsedation recovery was defined as Aldrete score of 9 in the recovery room. Patients were excluded from the study if they demonstrated altered mental status of any type including dementia, delirium, and hepatic encephalopathy; if they were legally blind; or were currently inpatients.

Overall, driving skills were not significantly different between preprocedure and postsedation recovery on measures of number of times over the speed limit (3.2 vs. 3.4), number of times drivers went off the road (0.37 vs. 0.54), and total pedal reaction time (6.1 seconds vs. 7.6 seconds).

“The two variables including gas pedal reaction time and the total number of collisions did not follow normal distribution,” with medians of 0.70 for gas pedal reaction time in both groups and medians of 0 collisions for both groups, the investigators noted.

The study findings were limited by the small sample size and open-label design. However, the results suggest that driving skills were similar for patients at baseline and after achieving a postsedation Aldrete score of 9, the researchers wrote. Based on these findings, “current recommendations that patients should refrain from driving and unescorted use of public transport for 24 hours after sedation may need to be reconsidered in patients who receive propofol sedation.”

“With this study, we are aiming to identify the correct patient population who could potentially drive themselves home after their procedure rather than having to arrange for transportation,” Dr. Lal said in an interview.

“The significant cost associated with the daylong interruption of the activities of daily living, having a family member accompany them for their procedures, or not being able to use public transport unescorted may deter some patients from complying with colonoscopy screenings and other important endoscopic procedures,” she explained.

“There are patients who arrive for their procedure without any accompanying family members and we have to admit them to an observation unit overnight or reschedule their procedures. The expense and inconvenience associated with the extended recovery potentially could be an impediment to many important screening exams,” she noted. “In the setting of increased awareness regarding the need for these screening exams, this study is important to highlight these barriers and propose a solution for them.”

The potential costs of lost salaries is extremely high, she said. “If we assume that the 24-hour recovery period necessitates taking a day off from work, the value of lost salary per patient would be $183.68 as per the 2019 national hourly average wage. With an estimated 19 million colonoscopies performed annually in the United States, the aggregate cost of lost wages with the 24-hour guideline would be $3.5 billion. This amount does not account for the lost wages of the accompanying family member.”

Dr. Lal said she and her colleagues were not surprised by the findings. “The endoscopists in our endoscopy unit have noted that patients recover much more rapidly after sedation with propofol compared with other sedative agents. This observation led to the hypothesis that those patients receiving propofol should have a speedy psychomotor recovery and should be able to drive the same day. Our findings are in accordance with our observations.” However, “larger and preferably multicenter studies are needed to validate these findings and add to our knowledge about the postsedation psychomotor recovery,” said Dr. Lal. She added that the study is ongoing and the researchers have collected data from a total of 63 patients, which increases the power of the results.

The researchers had no financial conflicts to disclose.

*This story was updated on 5/8/2020.

SOURCE: Lal P et al. DDW 2020, Abstract 295.

Patients with an indication for an implantable cardiac defibrillator for primary prevention of sudden cardiac death and a sharply reduced left ventricular ejection fraction of 35% or less safely received treatment from a refined, subcutaneous device that produced one of the lowest rates of inappropriate cardiac shocks ever seen in a reported ICD study, in a single-arm trial with 1,111 patients followed for 18 months.

The results showed “high efficacy and safety with contemporary devices and programming” despite being “the ‘sickest’ cohort studied to date” for use of a subcutaneous ICD (S-ICD), Michael R. Gold, MD, said at the annual scientific sessions of the Heart Rhythm Society, held online because of COVID-19. The 3.1% 1-year rate of patients who received at least one inappropriate shock was “the lowest reported for the S-ICD, and lower than in many transvenous ICD device studies,” and was also “the lowest 1-year rate reported to date for a multicenter ICD trial,” said Dr. Gold, a cardiac electrophysiologist and professor of medicine at the Medical University of South Carolina, Charleston. The upshot is that these data may help convince clinicians to be more liberal about offering a S-ICD device to patients with left ventricular function in this low range who need an ICD and do not need pacing.

The study’s primary endpoint was the rate of freedom from inappropriate shocks during 18 months of follow-up, which happened in 95.9% of patients and was highly statistically significant for meeting the prespecified performance goal of 91.6% that had been set using “standard Food and Drug Administration benchmarks,” with particular reliance on the performance shown in the MADIT-RIT trial (N Engl J Med. 2012 Dec 13;367[24]:2275-83).
 

S-ICDs maintain ‘niche’ status despite advantages

The S-ICD first received Food and Drug Administration clearance for U.S. use in 2012, but despite not requiring placement of a transvenous lead and thus eliminating the possibility for lead complications and deterioration, it so far has had very modest penetration into American practice. Recently, roughly 4% of U.S. patients who’ve received an ICD have had a subcutaneous model placed, relegating the S-ICD to “niche device” status, noted Andrea M. Russo, MD, director of electrophysiology and arrhythmia services at Cooper University Health Care in Camden, N.J. A major limitation of S-ICD devices is that they cannot provide chronic pacing and so aren’t an option for the many patients who also need this function in addition to protection from life-threatening ventricular arrhythmias.

“We have had a bias for whom we place an S-ICD,” explained Dr. Gold. “They have mostly been used in younger patients with less heart disease,” but when used in the current study cohort with markedly depressed heart function, the results showed that “we didn’t appear to harm patients in any way,” including no episodes of syncope because of an arrhythmia. Compared with other S-ICD studies, the patients in the new study, UNTOUCHED, had “lower ejection fractions, more heart failure diagnoses, and a higher rate of ischemic etiology.”

The tested S-ICD device appears to have safety and efficacy that is “just as good, and perhaps better” than many ICDs that use transvenous leads, “which was very surprising to us,” said Dr. Gold during a press briefing. “I think it will change practice” for ICD placement in patients who do not need pacing. “We found the device works even in the sickest patients.”

“This was a classic ICD population, with a low ejection fraction, and the results showed that the device performed well,” commented Dr. Russo, who served on the steering committee for the study. “I agree that the results will help” increase use of this device, but she added that other factors in addition to concerns about the inappropriate shock rate and the lack of most pacing functions have hobbled uptake since the device came on the market. These notably include a somewhat different placement approach than operators need to learn. The device is not always offered as an option to patients by their clinicians “in part because of their lack of familiarity, and concern about inappropriate shocks,” she said in an interview. That’s despite the clear attractions of a leaderless device, which obviates issues of lead deterioration, lead placement complications like perforations and pneumothorax, and sizing issues that can come up for women with narrower veins, as well as cutting the risk both for infections overall and for infections that progress to bacteremia, noted Dr. Russo, who is president of the Heart Rhythm Society.
 

Device improvements boost performance

The low 1-year and 18-month rates of inappropriate shocks likely occurred because of new filtering and programming incorporated into the tested device. “By changing the filter, we could make it more like a transvenous device” that is not fooled by T wave over sensing. The programing also included a high beat threshold, with a conditional zone above 200 beats per minute and an “aggressive shock zone” of 250 bpm, Dr. Gold said. This helped make the tested S-ICD more immune to inappropriately shocking a supraventricular arrhythmia; the study recorded no inappropriate shocks of this type, he reported.

The UNTOUCHED study enrolled 1,116 patients at any of 110 sites in the United States and elsewhere who had a need for primary prevention of sudden cardiac death, a left ventricular ejection fraction of 35% or less, no need for pacing, and had successfully passed an S-ICD screening test. The investigators were able to include 1,111 of these patients in their endpoint analysis. Patients averaged 56 years of age, a quarter were women, and their average ejection fraction was 26%.

In addition to the primary endpoint and the 1-year inappropriate-shock rate, the results also showed an all-cause shock-free rate of 90.6% during 18-months’ follow-up, which significantly surpassed the prespecified performance goal for this metric of 85.8%. The tested device also appeared to successfully apply appropriate shocks when needed, delivering a total of 64 of these with just 1 shock failure, a case where the patient spontaneously reverted to normal rhythm. During the study period, 53 patients died (5%), including 3 arrhythmia-related deaths: 1 caused by asystole and 2 from pulseless electrical activity.

“The data show that in a standard ICD population, the device worked well, and was safe and effective,” Dr. Russo said. “These data say, at least consider this device along with a transvenous device” for appropriate patients. “It’s a great option for some patients. I’ve seen so may lead problems, and this avoids them.”

UNTOUCHED was sponsored by Boston Scientific, the company that markets the tested S-ICD. Dr. Gold has been a consultant to Boston Scientific and Medtronic and has been an investigator for trials sponsored by each of these companies. Dr. Russo served on the steering committee for UNTOUCHED but received no compensation and has no financial disclosures.

mzoler@mdedge.com

Patients with an indication for an implantable cardiac defibrillator for primary prevention of sudden cardiac death and a sharply reduced left ventricular ejection fraction of 35% or less safely received treatment from a refined, subcutaneous device that produced one of the lowest rates of inappropriate cardiac shocks ever seen in a reported ICD study, in a single-arm trial with 1,111 patients followed for 18 months.

The results showed “high efficacy and safety with contemporary devices and programming” despite being “the ‘sickest’ cohort studied to date” for use of a subcutaneous ICD (S-ICD), Michael R. Gold, MD, said at the annual scientific sessions of the Heart Rhythm Society, held online because of COVID-19. The 3.1% 1-year rate of patients who received at least one inappropriate shock was “the lowest reported for the S-ICD, and lower than in many transvenous ICD device studies,” and was also “the lowest 1-year rate reported to date for a multicenter ICD trial,” said Dr. Gold, a cardiac electrophysiologist and professor of medicine at the Medical University of South Carolina, Charleston. The upshot is that these data may help convince clinicians to be more liberal about offering a S-ICD device to patients with left ventricular function in this low range who need an ICD and do not need pacing.

The study’s primary endpoint was the rate of freedom from inappropriate shocks during 18 months of follow-up, which happened in 95.9% of patients and was highly statistically significant for meeting the prespecified performance goal of 91.6% that had been set using “standard Food and Drug Administration benchmarks,” with particular reliance on the performance shown in the MADIT-RIT trial (N Engl J Med. 2012 Dec 13;367[24]:2275-83).
 

S-ICDs maintain ‘niche’ status despite advantages

The S-ICD first received Food and Drug Administration clearance for U.S. use in 2012, but despite not requiring placement of a transvenous lead and thus eliminating the possibility for lead complications and deterioration, it so far has had very modest penetration into American practice. Recently, roughly 4% of U.S. patients who’ve received an ICD have had a subcutaneous model placed, relegating the S-ICD to “niche device” status, noted Andrea M. Russo, MD, director of electrophysiology and arrhythmia services at Cooper University Health Care in Camden, N.J. A major limitation of S-ICD devices is that they cannot provide chronic pacing and so aren’t an option for the many patients who also need this function in addition to protection from life-threatening ventricular arrhythmias.

“We have had a bias for whom we place an S-ICD,” explained Dr. Gold. “They have mostly been used in younger patients with less heart disease,” but when used in the current study cohort with markedly depressed heart function, the results showed that “we didn’t appear to harm patients in any way,” including no episodes of syncope because of an arrhythmia. Compared with other S-ICD studies, the patients in the new study, UNTOUCHED, had “lower ejection fractions, more heart failure diagnoses, and a higher rate of ischemic etiology.”

The tested S-ICD device appears to have safety and efficacy that is “just as good, and perhaps better” than many ICDs that use transvenous leads, “which was very surprising to us,” said Dr. Gold during a press briefing. “I think it will change practice” for ICD placement in patients who do not need pacing. “We found the device works even in the sickest patients.”

“This was a classic ICD population, with a low ejection fraction, and the results showed that the device performed well,” commented Dr. Russo, who served on the steering committee for the study. “I agree that the results will help” increase use of this device, but she added that other factors in addition to concerns about the inappropriate shock rate and the lack of most pacing functions have hobbled uptake since the device came on the market. These notably include a somewhat different placement approach than operators need to learn. The device is not always offered as an option to patients by their clinicians “in part because of their lack of familiarity, and concern about inappropriate shocks,” she said in an interview. That’s despite the clear attractions of a leaderless device, which obviates issues of lead deterioration, lead placement complications like perforations and pneumothorax, and sizing issues that can come up for women with narrower veins, as well as cutting the risk both for infections overall and for infections that progress to bacteremia, noted Dr. Russo, who is president of the Heart Rhythm Society.
 

Device improvements boost performance

The low 1-year and 18-month rates of inappropriate shocks likely occurred because of new filtering and programming incorporated into the tested device. “By changing the filter, we could make it more like a transvenous device” that is not fooled by T wave over sensing. The programing also included a high beat threshold, with a conditional zone above 200 beats per minute and an “aggressive shock zone” of 250 bpm, Dr. Gold said. This helped make the tested S-ICD more immune to inappropriately shocking a supraventricular arrhythmia; the study recorded no inappropriate shocks of this type, he reported.

The UNTOUCHED study enrolled 1,116 patients at any of 110 sites in the United States and elsewhere who had a need for primary prevention of sudden cardiac death, a left ventricular ejection fraction of 35% or less, no need for pacing, and had successfully passed an S-ICD screening test. The investigators were able to include 1,111 of these patients in their endpoint analysis. Patients averaged 56 years of age, a quarter were women, and their average ejection fraction was 26%.

In addition to the primary endpoint and the 1-year inappropriate-shock rate, the results also showed an all-cause shock-free rate of 90.6% during 18-months’ follow-up, which significantly surpassed the prespecified performance goal for this metric of 85.8%. The tested device also appeared to successfully apply appropriate shocks when needed, delivering a total of 64 of these with just 1 shock failure, a case where the patient spontaneously reverted to normal rhythm. During the study period, 53 patients died (5%), including 3 arrhythmia-related deaths: 1 caused by asystole and 2 from pulseless electrical activity.

“The data show that in a standard ICD population, the device worked well, and was safe and effective,” Dr. Russo said. “These data say, at least consider this device along with a transvenous device” for appropriate patients. “It’s a great option for some patients. I’ve seen so may lead problems, and this avoids them.”

UNTOUCHED was sponsored by Boston Scientific, the company that markets the tested S-ICD. Dr. Gold has been a consultant to Boston Scientific and Medtronic and has been an investigator for trials sponsored by each of these companies. Dr. Russo served on the steering committee for UNTOUCHED but received no compensation and has no financial disclosures.

mzoler@mdedge.com

Patients with an indication for an implantable cardiac defibrillator for primary prevention of sudden cardiac death and a sharply reduced left ventricular ejection fraction of 35% or less safely received treatment from a refined, subcutaneous device that produced one of the lowest rates of inappropriate cardiac shocks ever seen in a reported ICD study, in a single-arm trial with 1,111 patients followed for 18 months.

The results showed “high efficacy and safety with contemporary devices and programming” despite being “the ‘sickest’ cohort studied to date” for use of a subcutaneous ICD (S-ICD), Michael R. Gold, MD, said at the annual scientific sessions of the Heart Rhythm Society, held online because of COVID-19. The 3.1% 1-year rate of patients who received at least one inappropriate shock was “the lowest reported for the S-ICD, and lower than in many transvenous ICD device studies,” and was also “the lowest 1-year rate reported to date for a multicenter ICD trial,” said Dr. Gold, a cardiac electrophysiologist and professor of medicine at the Medical University of South Carolina, Charleston. The upshot is that these data may help convince clinicians to be more liberal about offering a S-ICD device to patients with left ventricular function in this low range who need an ICD and do not need pacing.

The study’s primary endpoint was the rate of freedom from inappropriate shocks during 18 months of follow-up, which happened in 95.9% of patients and was highly statistically significant for meeting the prespecified performance goal of 91.6% that had been set using “standard Food and Drug Administration benchmarks,” with particular reliance on the performance shown in the MADIT-RIT trial (N Engl J Med. 2012 Dec 13;367[24]:2275-83).
 

S-ICDs maintain ‘niche’ status despite advantages

The S-ICD first received Food and Drug Administration clearance for U.S. use in 2012, but despite not requiring placement of a transvenous lead and thus eliminating the possibility for lead complications and deterioration, it so far has had very modest penetration into American practice. Recently, roughly 4% of U.S. patients who’ve received an ICD have had a subcutaneous model placed, relegating the S-ICD to “niche device” status, noted Andrea M. Russo, MD, director of electrophysiology and arrhythmia services at Cooper University Health Care in Camden, N.J. A major limitation of S-ICD devices is that they cannot provide chronic pacing and so aren’t an option for the many patients who also need this function in addition to protection from life-threatening ventricular arrhythmias.

“We have had a bias for whom we place an S-ICD,” explained Dr. Gold. “They have mostly been used in younger patients with less heart disease,” but when used in the current study cohort with markedly depressed heart function, the results showed that “we didn’t appear to harm patients in any way,” including no episodes of syncope because of an arrhythmia. Compared with other S-ICD studies, the patients in the new study, UNTOUCHED, had “lower ejection fractions, more heart failure diagnoses, and a higher rate of ischemic etiology.”

The tested S-ICD device appears to have safety and efficacy that is “just as good, and perhaps better” than many ICDs that use transvenous leads, “which was very surprising to us,” said Dr. Gold during a press briefing. “I think it will change practice” for ICD placement in patients who do not need pacing. “We found the device works even in the sickest patients.”

“This was a classic ICD population, with a low ejection fraction, and the results showed that the device performed well,” commented Dr. Russo, who served on the steering committee for the study. “I agree that the results will help” increase use of this device, but she added that other factors in addition to concerns about the inappropriate shock rate and the lack of most pacing functions have hobbled uptake since the device came on the market. These notably include a somewhat different placement approach than operators need to learn. The device is not always offered as an option to patients by their clinicians “in part because of their lack of familiarity, and concern about inappropriate shocks,” she said in an interview. That’s despite the clear attractions of a leaderless device, which obviates issues of lead deterioration, lead placement complications like perforations and pneumothorax, and sizing issues that can come up for women with narrower veins, as well as cutting the risk both for infections overall and for infections that progress to bacteremia, noted Dr. Russo, who is president of the Heart Rhythm Society.
 

Device improvements boost performance

The low 1-year and 18-month rates of inappropriate shocks likely occurred because of new filtering and programming incorporated into the tested device. “By changing the filter, we could make it more like a transvenous device” that is not fooled by T wave over sensing. The programing also included a high beat threshold, with a conditional zone above 200 beats per minute and an “aggressive shock zone” of 250 bpm, Dr. Gold said. This helped make the tested S-ICD more immune to inappropriately shocking a supraventricular arrhythmia; the study recorded no inappropriate shocks of this type, he reported.

The UNTOUCHED study enrolled 1,116 patients at any of 110 sites in the United States and elsewhere who had a need for primary prevention of sudden cardiac death, a left ventricular ejection fraction of 35% or less, no need for pacing, and had successfully passed an S-ICD screening test. The investigators were able to include 1,111 of these patients in their endpoint analysis. Patients averaged 56 years of age, a quarter were women, and their average ejection fraction was 26%.

In addition to the primary endpoint and the 1-year inappropriate-shock rate, the results also showed an all-cause shock-free rate of 90.6% during 18-months’ follow-up, which significantly surpassed the prespecified performance goal for this metric of 85.8%. The tested device also appeared to successfully apply appropriate shocks when needed, delivering a total of 64 of these with just 1 shock failure, a case where the patient spontaneously reverted to normal rhythm. During the study period, 53 patients died (5%), including 3 arrhythmia-related deaths: 1 caused by asystole and 2 from pulseless electrical activity.

“The data show that in a standard ICD population, the device worked well, and was safe and effective,” Dr. Russo said. “These data say, at least consider this device along with a transvenous device” for appropriate patients. “It’s a great option for some patients. I’ve seen so may lead problems, and this avoids them.”

UNTOUCHED was sponsored by Boston Scientific, the company that markets the tested S-ICD. Dr. Gold has been a consultant to Boston Scientific and Medtronic and has been an investigator for trials sponsored by each of these companies. Dr. Russo served on the steering committee for UNTOUCHED but received no compensation and has no financial disclosures.

mzoler@mdedge.com

A novel clinical presentation in children involving symptoms seen with atypical Kawasaki disease and toxic shock syndrome may be linked to COVID-19 infection, according to reports from National Health Service England, The Lancet, and the New York City health department.

Courtesy NIAID-RML

Fifteen children in New York City hospitals have presented with the condition, provisionally called pediatric multisystem inflammatory syndrome, between April 17 and May 1, according to a health alert from New York City health department deputy commissioner Demetre C. Daskalakis, MD, MPH, on May 4. On May 5, the New York state department of health released a health advisory that 64 suspected cases had been reported in children in New York state hospitals, including New York City.

The New York City reports follow a case study published April 7 in Hospital Pediatrics about the presentation. There also was a statement from the U.K.’s Paediatric Intensive Care Society (PICS) on April 27 that noted “blood parameters consistent with severe COVID-19 in children” as well as abdominal pain, gastrointestinal symptoms, and cardiac inflammation.

“Whilst it is too early to say with confidence, features appear to include high CRP [C-reactive protein], high [erythrocyte sedimentation rate] and high ferritin,” the PICS release stated. The cardiac inflammation consists of “myocarditis with raised troponin and [prohormone brain natriuretic peptide],” according to the PICS statement. “Some have an appearance of their coronary arteries in keeping with Kawasaki disease.”

The initial 15 New York City patients reportedly all had “subjective or measured fever, and more than half reported rash, abdominal pain, vomiting, or diarrhea,” but fewer than half had respiratory symptoms.

The case study described a 6-month-old infant who was admitted and diagnosed with classic Kawasaki disease, who also tested positive for COVID-19 with fever and mild respiratory symptoms, reported Veena G. Jones, MD, a pediatric hospitalist in Palo Alto, Calif., and associates.

While many of the U.K. children presenting with the symptoms had a positive polymerase chain reaction tests for infection from SARS-CoV-2, some also had a negative test. Polymerase chain reaction testing in New York City was positive for 4 children and negative for 11 children, but 6 of the those who tested negative had positive serology tests, potentially pointing to postinfection sequelae.

At press time, more cases were reported from the United Kingdom in The Lancet. In London, eight children with hyperinflammatory shock, showing features similar to atypical Kawasaki disease, Kawasaki disease shock syndrome, or toxic shock syndrome, presented within 10 days to Evelina London Children’s Hospital Paediatric ICU, Shelley Riphagen, MBChB, and colleagues revealed.

Clinically, their presentations were similar, with persistent fever, rash, conjunctivitis, peripheral edema, extremity pain, and gastrointestinal symptoms. They all developed warm vasoplegic shock that did not respond to volume resuscitation; noradrenaline and milrinone were administered for hemodynamic support. Seven of the children needed mechanical ventilation for cardiovascular stabilization, although most of them had no significant respiratory involvement.

Of note was development of small pleural, pericardial, and ascitic effusion – “suggestive of a diffuse inflammatory process,” Dr. Riphagen and associates wrote. None of the children initially was positive for SARS-CoV-2; laboratory evidence of infection or inflammation included “elevated concentrations of CRP, procalcitonin, ferritin, triglycerides or d-dimers.”

“A common echocardiographic finding was echobright coronary vessels,” they wrote. “One child developed arrhythmia with refractory shock, requiring extracorporeal life support, and died from a large cerebrovascular infarct.”

As the article went to press, the doctors in that same ICU had seen more than 20 children with similar clinical presentations, Dr. Riphagen and associates reported, and the first 10 tested positive for SARS-CoV-2 antibody, including the 8 described above.

“Most of the children appear to have antibodies to the novel coronavirus, even when they do not have virus detectable in their nose,” said Audrey John, MD, PhD, chief of the division of pediatric infectious diseases at Children’s Hospital of Philadelphia, where clinicians have seen several cases similar to those described by NHS England and the New York City health department. “This suggests that these symptoms are ‘postinfectious,’ likely due to an abnormal immune response that happens after viral infection.”

She noted at the time of her interview, however, that fewer than 100 U.S. pediatric cases appear to have been reported.

“While our understanding is evolving, given the scope of the COVID-19 pandemic, this suggests that this kind of severe disease in children is very rare indeed,” Dr. John said. “Because this syndrome is so newly described, we have to continue to be cautious in attributing this syndrome to COVID-19, as there are many other diseases that look quite similar.”

She advised clinicians to be “wary of attributing fever/rash/shock to this syndrome, as the differential is broad, and we do not want to fail to recognize and treat true toxic shock or tick-borne disease.”

Dawn Nolt, MD, MPH, an associate professor of pediatrics in infectious diseases at Oregon Health & Science University’s Doernbecher Children’s Hospital, Portland, also underscored the need to avoid drawing conclusions too quickly.

“At this time, there is no causality established between SARS-COV-2 and these inflammatory syndromes other than a temporal association,” said Dr. Nolt, whose hospital has not yet seen any of these cases. “If there is a link, then the symptoms may be from a ‘direct hit’ of the virus on tissues, or from an overly exuberant immune response.”

None of the initial 15 New York City children died, although 5 needed mechanical ventilation and over half needed blood pressure support. The one child in London died from a large cerebrovascular infarct.

If the cases are connected to COVID-19, one explanation for the presentation may be related to the leading hypothesis “that SARS-CoV-2 may stimulate the immune system in such a way to promote vasculitis,” Dr. Nolt said in an interview.

“It is unusual that this particular constellation was not reported from the known pediatric cases out of China, where the COVID-19 pandemic originated,” Dr. Nolt said. “If there is a link between SARS-CoV-2 and these inflammatory syndromes, this may have resulted from genetic/host differences, changes in the SARS-CoV-2 virus, or other factors yet to be determined.”

The New York City bulletin recommended that clinicians immediately refer children presenting with the described symptoms to a specialist in pediatric infectious disease, rheumatology, or critical care.

“Early diagnosis and treatment of patients meeting full or partial criteria for Kawasaki disease is critical to preventing end-organ damage and other long-term complications,” the bulletin stated. It recommended aspirin and intravenous immunoglobulin for those who met Kawasaki criteria.

Dr. John said that children with the presentation appear to be responding well to intravenous immunoglobulin and/or steroids. She further emphasized that virtually all pediatric patients recover from COVID-19.

“Physicians should advise families to bring their children and teens back in for evaluation if they develop new fever, rash, or abdominal pain and diarrhea,” Dr. John said. “Families should not be afraid to seek care when their kids are sick. Our pediatric hospitals and EDs are open for business and working hard to protect staff and patients.”

A Kawasaki syndrome diagnosis requires at least 5 days of a fever at 101-104° F or higher along with four of the following five symptoms: rash over the torso; redness and swelling on palms and soles of the feet with later skin peeling; bloodshot, light-sensitive eyes; swollen lymph glands in the neck; and irritation and inflammation of the mouth, lips and throat, sometimes with “strawberry” tongue, according to the American Heart Association.

A press release from the AHA noted that Kawasaki disease is the most common cause of acquired heart disease in developed countries, but the condition remains rare.

Kawasaki disease’s etiology is unknown, but “some evidence suggests an infectious trigger, with winter-spring seasonality of the disease,” wrote the case study authors, noting that past research has linked Kawasaki disease with previous or concurrent infections of rhinovirus/enterovirus, parainfluenza, respiratory syncytial virus, influenza, adenovirus, and the four common human coronavirus strains.

“We have to remember that our experience with this pandemic is less than 12 months,” Dr. Nolt said. “We are still accumulating information, and any additional manifestations, particularly severe ones, adds to our ability to more quickly detect and treat children.”

Dr. Nolt and Dr. John had no disclosures.

SOURCES: Jones VG et al. Hosp Pediatr. 2020 Apr 7. doi: 10.1542/hpeds.2020-0123; Riphagen S et al. Lancet. 2020 May 6. doi: 10.1016/S0140-6736(20)31094-1.

A novel clinical presentation in children involving symptoms seen with atypical Kawasaki disease and toxic shock syndrome may be linked to COVID-19 infection, according to reports from National Health Service England, The Lancet, and the New York City health department.

Courtesy NIAID-RML

Fifteen children in New York City hospitals have presented with the condition, provisionally called pediatric multisystem inflammatory syndrome, between April 17 and May 1, according to a health alert from New York City health department deputy commissioner Demetre C. Daskalakis, MD, MPH, on May 4. On May 5, the New York state department of health released a health advisory that 64 suspected cases had been reported in children in New York state hospitals, including New York City.

The New York City reports follow a case study published April 7 in Hospital Pediatrics about the presentation. There also was a statement from the U.K.’s Paediatric Intensive Care Society (PICS) on April 27 that noted “blood parameters consistent with severe COVID-19 in children” as well as abdominal pain, gastrointestinal symptoms, and cardiac inflammation.

“Whilst it is too early to say with confidence, features appear to include high CRP [C-reactive protein], high [erythrocyte sedimentation rate] and high ferritin,” the PICS release stated. The cardiac inflammation consists of “myocarditis with raised troponin and [prohormone brain natriuretic peptide],” according to the PICS statement. “Some have an appearance of their coronary arteries in keeping with Kawasaki disease.”

The initial 15 New York City patients reportedly all had “subjective or measured fever, and more than half reported rash, abdominal pain, vomiting, or diarrhea,” but fewer than half had respiratory symptoms.

The case study described a 6-month-old infant who was admitted and diagnosed with classic Kawasaki disease, who also tested positive for COVID-19 with fever and mild respiratory symptoms, reported Veena G. Jones, MD, a pediatric hospitalist in Palo Alto, Calif., and associates.

While many of the U.K. children presenting with the symptoms had a positive polymerase chain reaction tests for infection from SARS-CoV-2, some also had a negative test. Polymerase chain reaction testing in New York City was positive for 4 children and negative for 11 children, but 6 of the those who tested negative had positive serology tests, potentially pointing to postinfection sequelae.

At press time, more cases were reported from the United Kingdom in The Lancet. In London, eight children with hyperinflammatory shock, showing features similar to atypical Kawasaki disease, Kawasaki disease shock syndrome, or toxic shock syndrome, presented within 10 days to Evelina London Children’s Hospital Paediatric ICU, Shelley Riphagen, MBChB, and colleagues revealed.

Clinically, their presentations were similar, with persistent fever, rash, conjunctivitis, peripheral edema, extremity pain, and gastrointestinal symptoms. They all developed warm vasoplegic shock that did not respond to volume resuscitation; noradrenaline and milrinone were administered for hemodynamic support. Seven of the children needed mechanical ventilation for cardiovascular stabilization, although most of them had no significant respiratory involvement.

Of note was development of small pleural, pericardial, and ascitic effusion – “suggestive of a diffuse inflammatory process,” Dr. Riphagen and associates wrote. None of the children initially was positive for SARS-CoV-2; laboratory evidence of infection or inflammation included “elevated concentrations of CRP, procalcitonin, ferritin, triglycerides or d-dimers.”

“A common echocardiographic finding was echobright coronary vessels,” they wrote. “One child developed arrhythmia with refractory shock, requiring extracorporeal life support, and died from a large cerebrovascular infarct.”

As the article went to press, the doctors in that same ICU had seen more than 20 children with similar clinical presentations, Dr. Riphagen and associates reported, and the first 10 tested positive for SARS-CoV-2 antibody, including the 8 described above.

“Most of the children appear to have antibodies to the novel coronavirus, even when they do not have virus detectable in their nose,” said Audrey John, MD, PhD, chief of the division of pediatric infectious diseases at Children’s Hospital of Philadelphia, where clinicians have seen several cases similar to those described by NHS England and the New York City health department. “This suggests that these symptoms are ‘postinfectious,’ likely due to an abnormal immune response that happens after viral infection.”

She noted at the time of her interview, however, that fewer than 100 U.S. pediatric cases appear to have been reported.

“While our understanding is evolving, given the scope of the COVID-19 pandemic, this suggests that this kind of severe disease in children is very rare indeed,” Dr. John said. “Because this syndrome is so newly described, we have to continue to be cautious in attributing this syndrome to COVID-19, as there are many other diseases that look quite similar.”

She advised clinicians to be “wary of attributing fever/rash/shock to this syndrome, as the differential is broad, and we do not want to fail to recognize and treat true toxic shock or tick-borne disease.”

Dawn Nolt, MD, MPH, an associate professor of pediatrics in infectious diseases at Oregon Health & Science University’s Doernbecher Children’s Hospital, Portland, also underscored the need to avoid drawing conclusions too quickly.

“At this time, there is no causality established between SARS-COV-2 and these inflammatory syndromes other than a temporal association,” said Dr. Nolt, whose hospital has not yet seen any of these cases. “If there is a link, then the symptoms may be from a ‘direct hit’ of the virus on tissues, or from an overly exuberant immune response.”

None of the initial 15 New York City children died, although 5 needed mechanical ventilation and over half needed blood pressure support. The one child in London died from a large cerebrovascular infarct.

If the cases are connected to COVID-19, one explanation for the presentation may be related to the leading hypothesis “that SARS-CoV-2 may stimulate the immune system in such a way to promote vasculitis,” Dr. Nolt said in an interview.

“It is unusual that this particular constellation was not reported from the known pediatric cases out of China, where the COVID-19 pandemic originated,” Dr. Nolt said. “If there is a link between SARS-CoV-2 and these inflammatory syndromes, this may have resulted from genetic/host differences, changes in the SARS-CoV-2 virus, or other factors yet to be determined.”

The New York City bulletin recommended that clinicians immediately refer children presenting with the described symptoms to a specialist in pediatric infectious disease, rheumatology, or critical care.

“Early diagnosis and treatment of patients meeting full or partial criteria for Kawasaki disease is critical to preventing end-organ damage and other long-term complications,” the bulletin stated. It recommended aspirin and intravenous immunoglobulin for those who met Kawasaki criteria.

Dr. John said that children with the presentation appear to be responding well to intravenous immunoglobulin and/or steroids. She further emphasized that virtually all pediatric patients recover from COVID-19.

“Physicians should advise families to bring their children and teens back in for evaluation if they develop new fever, rash, or abdominal pain and diarrhea,” Dr. John said. “Families should not be afraid to seek care when their kids are sick. Our pediatric hospitals and EDs are open for business and working hard to protect staff and patients.”

A Kawasaki syndrome diagnosis requires at least 5 days of a fever at 101-104° F or higher along with four of the following five symptoms: rash over the torso; redness and swelling on palms and soles of the feet with later skin peeling; bloodshot, light-sensitive eyes; swollen lymph glands in the neck; and irritation and inflammation of the mouth, lips and throat, sometimes with “strawberry” tongue, according to the American Heart Association.

A press release from the AHA noted that Kawasaki disease is the most common cause of acquired heart disease in developed countries, but the condition remains rare.

Kawasaki disease’s etiology is unknown, but “some evidence suggests an infectious trigger, with winter-spring seasonality of the disease,” wrote the case study authors, noting that past research has linked Kawasaki disease with previous or concurrent infections of rhinovirus/enterovirus, parainfluenza, respiratory syncytial virus, influenza, adenovirus, and the four common human coronavirus strains.

“We have to remember that our experience with this pandemic is less than 12 months,” Dr. Nolt said. “We are still accumulating information, and any additional manifestations, particularly severe ones, adds to our ability to more quickly detect and treat children.”

Dr. Nolt and Dr. John had no disclosures.

SOURCES: Jones VG et al. Hosp Pediatr. 2020 Apr 7. doi: 10.1542/hpeds.2020-0123; Riphagen S et al. Lancet. 2020 May 6. doi: 10.1016/S0140-6736(20)31094-1.

A novel clinical presentation in children involving symptoms seen with atypical Kawasaki disease and toxic shock syndrome may be linked to COVID-19 infection, according to reports from National Health Service England, The Lancet, and the New York City health department.

Courtesy NIAID-RML

Fifteen children in New York City hospitals have presented with the condition, provisionally called pediatric multisystem inflammatory syndrome, between April 17 and May 1, according to a health alert from New York City health department deputy commissioner Demetre C. Daskalakis, MD, MPH, on May 4. On May 5, the New York state department of health released a health advisory that 64 suspected cases had been reported in children in New York state hospitals, including New York City.

The New York City reports follow a case study published April 7 in Hospital Pediatrics about the presentation. There also was a statement from the U.K.’s Paediatric Intensive Care Society (PICS) on April 27 that noted “blood parameters consistent with severe COVID-19 in children” as well as abdominal pain, gastrointestinal symptoms, and cardiac inflammation.

“Whilst it is too early to say with confidence, features appear to include high CRP [C-reactive protein], high [erythrocyte sedimentation rate] and high ferritin,” the PICS release stated. The cardiac inflammation consists of “myocarditis with raised troponin and [prohormone brain natriuretic peptide],” according to the PICS statement. “Some have an appearance of their coronary arteries in keeping with Kawasaki disease.”

The initial 15 New York City patients reportedly all had “subjective or measured fever, and more than half reported rash, abdominal pain, vomiting, or diarrhea,” but fewer than half had respiratory symptoms.

The case study described a 6-month-old infant who was admitted and diagnosed with classic Kawasaki disease, who also tested positive for COVID-19 with fever and mild respiratory symptoms, reported Veena G. Jones, MD, a pediatric hospitalist in Palo Alto, Calif., and associates.

While many of the U.K. children presenting with the symptoms had a positive polymerase chain reaction tests for infection from SARS-CoV-2, some also had a negative test. Polymerase chain reaction testing in New York City was positive for 4 children and negative for 11 children, but 6 of the those who tested negative had positive serology tests, potentially pointing to postinfection sequelae.

At press time, more cases were reported from the United Kingdom in The Lancet. In London, eight children with hyperinflammatory shock, showing features similar to atypical Kawasaki disease, Kawasaki disease shock syndrome, or toxic shock syndrome, presented within 10 days to Evelina London Children’s Hospital Paediatric ICU, Shelley Riphagen, MBChB, and colleagues revealed.

Clinically, their presentations were similar, with persistent fever, rash, conjunctivitis, peripheral edema, extremity pain, and gastrointestinal symptoms. They all developed warm vasoplegic shock that did not respond to volume resuscitation; noradrenaline and milrinone were administered for hemodynamic support. Seven of the children needed mechanical ventilation for cardiovascular stabilization, although most of them had no significant respiratory involvement.

Of note was development of small pleural, pericardial, and ascitic effusion – “suggestive of a diffuse inflammatory process,” Dr. Riphagen and associates wrote. None of the children initially was positive for SARS-CoV-2; laboratory evidence of infection or inflammation included “elevated concentrations of CRP, procalcitonin, ferritin, triglycerides or d-dimers.”

“A common echocardiographic finding was echobright coronary vessels,” they wrote. “One child developed arrhythmia with refractory shock, requiring extracorporeal life support, and died from a large cerebrovascular infarct.”

As the article went to press, the doctors in that same ICU had seen more than 20 children with similar clinical presentations, Dr. Riphagen and associates reported, and the first 10 tested positive for SARS-CoV-2 antibody, including the 8 described above.

“Most of the children appear to have antibodies to the novel coronavirus, even when they do not have virus detectable in their nose,” said Audrey John, MD, PhD, chief of the division of pediatric infectious diseases at Children’s Hospital of Philadelphia, where clinicians have seen several cases similar to those described by NHS England and the New York City health department. “This suggests that these symptoms are ‘postinfectious,’ likely due to an abnormal immune response that happens after viral infection.”

She noted at the time of her interview, however, that fewer than 100 U.S. pediatric cases appear to have been reported.

“While our understanding is evolving, given the scope of the COVID-19 pandemic, this suggests that this kind of severe disease in children is very rare indeed,” Dr. John said. “Because this syndrome is so newly described, we have to continue to be cautious in attributing this syndrome to COVID-19, as there are many other diseases that look quite similar.”

She advised clinicians to be “wary of attributing fever/rash/shock to this syndrome, as the differential is broad, and we do not want to fail to recognize and treat true toxic shock or tick-borne disease.”

Dawn Nolt, MD, MPH, an associate professor of pediatrics in infectious diseases at Oregon Health & Science University’s Doernbecher Children’s Hospital, Portland, also underscored the need to avoid drawing conclusions too quickly.

“At this time, there is no causality established between SARS-COV-2 and these inflammatory syndromes other than a temporal association,” said Dr. Nolt, whose hospital has not yet seen any of these cases. “If there is a link, then the symptoms may be from a ‘direct hit’ of the virus on tissues, or from an overly exuberant immune response.”

None of the initial 15 New York City children died, although 5 needed mechanical ventilation and over half needed blood pressure support. The one child in London died from a large cerebrovascular infarct.

If the cases are connected to COVID-19, one explanation for the presentation may be related to the leading hypothesis “that SARS-CoV-2 may stimulate the immune system in such a way to promote vasculitis,” Dr. Nolt said in an interview.

“It is unusual that this particular constellation was not reported from the known pediatric cases out of China, where the COVID-19 pandemic originated,” Dr. Nolt said. “If there is a link between SARS-CoV-2 and these inflammatory syndromes, this may have resulted from genetic/host differences, changes in the SARS-CoV-2 virus, or other factors yet to be determined.”

The New York City bulletin recommended that clinicians immediately refer children presenting with the described symptoms to a specialist in pediatric infectious disease, rheumatology, or critical care.

“Early diagnosis and treatment of patients meeting full or partial criteria for Kawasaki disease is critical to preventing end-organ damage and other long-term complications,” the bulletin stated. It recommended aspirin and intravenous immunoglobulin for those who met Kawasaki criteria.

Dr. John said that children with the presentation appear to be responding well to intravenous immunoglobulin and/or steroids. She further emphasized that virtually all pediatric patients recover from COVID-19.

“Physicians should advise families to bring their children and teens back in for evaluation if they develop new fever, rash, or abdominal pain and diarrhea,” Dr. John said. “Families should not be afraid to seek care when their kids are sick. Our pediatric hospitals and EDs are open for business and working hard to protect staff and patients.”

A Kawasaki syndrome diagnosis requires at least 5 days of a fever at 101-104° F or higher along with four of the following five symptoms: rash over the torso; redness and swelling on palms and soles of the feet with later skin peeling; bloodshot, light-sensitive eyes; swollen lymph glands in the neck; and irritation and inflammation of the mouth, lips and throat, sometimes with “strawberry” tongue, according to the American Heart Association.

A press release from the AHA noted that Kawasaki disease is the most common cause of acquired heart disease in developed countries, but the condition remains rare.

Kawasaki disease’s etiology is unknown, but “some evidence suggests an infectious trigger, with winter-spring seasonality of the disease,” wrote the case study authors, noting that past research has linked Kawasaki disease with previous or concurrent infections of rhinovirus/enterovirus, parainfluenza, respiratory syncytial virus, influenza, adenovirus, and the four common human coronavirus strains.

“We have to remember that our experience with this pandemic is less than 12 months,” Dr. Nolt said. “We are still accumulating information, and any additional manifestations, particularly severe ones, adds to our ability to more quickly detect and treat children.”

Dr. Nolt and Dr. John had no disclosures.

SOURCES: Jones VG et al. Hosp Pediatr. 2020 Apr 7. doi: 10.1542/hpeds.2020-0123; Riphagen S et al. Lancet. 2020 May 6. doi: 10.1016/S0140-6736(20)31094-1.

A couple of weeks ago, I posted a silly picture of myself with one N95 mask and asked the folks on Twitter what else I might need. In a matter of a few days, I had filled out a form online for volunteering through the Society of Critical Care Medicine, been assigned to work at a hospital in New York City, and booked a hotel and flight.

Courtesy Arghavan Salles, MD

I was going to volunteer, although I wasn’t sure of exactly what I would be doing. I’m trained as a bariatric surgeon – not obviously suited for critical care, but arguably even less suited for medicine wards.

I undoubtedly would have been less prepared if I hadn’t sought guidance on what to bring with me and generally what to expect. Less than a day after seeking advice, two local women physicians donated N95s, face shields, gowns, bouffants, and coveralls to me. I also received a laminated photo of myself to attach to my gown in the mail from a stranger I met online.

Others suggested I bring goggles, chocolate, protein bars, hand sanitizer, powdered laundry detergent, and alcohol wipes. After running around all over town, I was able find everything but the wipes.

Just as others helped me achieve my goal of volunteering, I hope I can guide those who would like to do similar work by sharing details about my experience and other information I have collected about volunteering.

Below I answer some questions that those considering volunteering might have, including why I went, who I contacted to set this up, who paid for my flight, and what I observed in the hospital.
 

Motivation and logistics

I am currently serving in a nonclinical role at my institution. So when the pandemic hit the United States, I felt an immense amount of guilt for not being on the front lines caring for patients. I offered my services to local hospitals and registered for the California Health Corps. I live in northern California, which was the first part of the country to shelter in place. Since my home was actually relatively spared, my services weren’t needed.

As the weeks passed, I was slowly getting more and more fit, exercising in my house since there was little else I could do, and the guilt became a cloud gathering over my head.

I decided to volunteer in a place where demands for help were higher – New York. I tried very hard to sign up to volunteer through the state’s registry for health care volunteers, but was unable to do so. Coincidentally, around that same time, I saw on Twitter that Josh Mugele, MD, emergency medicine physician and program director of the emergency medicine residency at Northeast Georgia Medical Center in Gainesville, was on his way to New York. He shared the Society of Critical Care Medicine’s form for volunteering with me, and in less than 48 hours, I was assigned to a hospital in New York City. Five days later I was on a plane from San Francisco to my destination on the opposite side of the country. The airline paid for my flight.

This is not the only path to volunteering. Another volunteer, Sara Pauk, MD, ob.gyn. at the University of Washington, Seattle, found her volunteer role through contacting the New York City Health and Hospitals system directly. Other who have volunteered told me they had contacted specific hospitals or worked with agencies that were placing physicians.
 

PPE

Courtesy Arghavan Salles. MD

The Brooklyn hospital where I volunteered provided me with two sets of scrubs and two N95s. Gowns were variably available on our unit, and there was no eye protection. As a colleague of mine, Ben Daxon, MD, anesthesia and critical care physician at the Mayo Clinic in Rochester, Minn., had suggested, anyone volunteering in this context should bring personal protective equipment (PPE) – That includes gowns, bouffants/scrub caps, eye protection, masks, and scrubs.

The “COVID corner”

Once I arrived in New York, I did not feel particularly safe in my hotel, so I moved to another the next day. Then I had to sort out how to keep the whole room from being contaminated. I created a “COVID corner” right by the door where I kept almost everything that had been outside the door.

Every time I walked in the door, I immediately took off my shoes and left them in that corner. I could not find alcohol wipes, even after looking around in the city, so I relied on time to kill the virus, which I presumed was on everything that came from outside.

Courtesy Arghavan Salles, MD

Groceries stayed by the door for 48-72 hours if possible. After that, I would move them to the “clean” parts of the room. I wore the same outfit to and from the hospital everyday, putting it on right before I left and taking it off immediately after walking into the room (and then proceeding directly to the shower). Those clothes – “my COVID outfit” – lived in the COVID corner. Anything else I wore, including exercise clothes and underwear, got washed right after I wore it.

At the hospital, I would change into scrubs and leave my COVID outfit in a plastic bag inside my handbag. Note: I fully accepted that my handbag was now a COVID handbag. I kept a pair of clogs in the hospital for daily wear. Without alcohol wipes, my room did not feel clean. But I did start to become at peace with my system, even though it was inferior to the system I use in my own home.

Meal time

In addition to bringing snacks from home, I gathered some meal items at a grocery store during my first day in New York. These included water, yogurt, a few protein drinks, fruit, and some mini chocolate croissants. It’s a pandemic – chocolate is encouraged, right?

Neither any of the volunteers I knew nor I had access to a kitchen, so this was about the best I could do.

My first week I worked nights and ate sporadically. A couple of days I bought bagel sandwiches on the way back to the hotel in the morning. Other times, I would eat yogurt or a protein bar.

I had trouble sleeping, so I would wake up early and either do yoga in my room or go for a run in a nearby park. Usually I didn’t plan well enough to eat before I went into the hospital, so I would take yogurt, some fruit, and a croissant with me as I headed out. It was hard eating on the run with a mask on my face.

When I switched to working days, I actually ordered proper dinners from local Thai, Mexican, and Indian restaurants. I paid around $20 a meal.

One night I even had dinner with a coworker who was staying at a hotel close to mine – what a luxury! Prior to all this I had been sheltering in place alone for weeks, so in that sense, this experience was a delight. I interacted with other people, in person, every day!
 

My commute

My hotel was about 20 minutes from the hospital. Well-meaning folks informed me that Hertz had free car rentals and Uber had discounts for health care workers. When I investigated these options, I found that only employees of certain hospitals were eligible. As a volunteer, I was not eligible.

Courtesy Arghavan Salles, MD

I ultimately took Uber back and forth, and I was lucky that a few friends had sent me Uber gift cards to defray the costs. Most days, I paid about $20 each way, although 1 day there actually was “surge pricing.” The grand total for the trip was close to $800.

Many of the Uber drivers had put up plastic partitions – reminiscent of the plastic Dexter would use to contain his crime scenes – to increase their separation from their passengers. It was a bit eerie, but also somewhat welcome.
 

New normal

The actual work at the hospital in Brooklyn where I volunteered was different from usual practice in numerous ways. One of the things I immediately noticed was how difficult it was to get chest x-rays. After placing an emergent chest tube for a tension pneumothorax, it took about 6 hours to get a chest x-ray to assess placement.

Because code medications were needed much more frequently than normal times, these medications were kept in an open supply closet for ease of access. Many of the ventilators looked like they were from the 1970s. (They had been borrowed from the Federal Emergency Management Agency.)

What was most distinct about this work was the sheer volume of deaths and dying patients -- at least one death on our unit occurred every day I was there -- and the way families communicated with their loved ones. Countless times I held my phone over the faces of my unconscious patients to let their family profess their love and beg them to fight. While I have had to deliver bad news over the phone many times in my career, I have never had to intrude on families’ last conversations with their dying loved ones or witness that conversation occurring via a tiny screen.
 

Reentry

In many ways, I am lucky that I do not do clinical work in my hometown. So while other volunteers were figuring out how many more vacation days they would have to use, or whether they would have to take unpaid leave, and when and how they would get tested, all I had to do was prepare to go back home and quarantine myself for a couple of weeks.

I used up 2 weeks of vacation to volunteer in New York, but luckily, I could resume my normal work the day after I returned home.

Obviously, living in the pandemic is unique to anything we have ever experienced. Recognizing that, I recorded video diaries the whole time I was in New York. I laughed (like when I tried to fit all of my PPE on my tiny head), and I cried – several times. I suppose 1 day I may actually watch them and be reminded of what it was like to have been able to serve in this historic moment. Until then, they will remain locked up on the same phone that served as the only communication vehicle between my patients and their loved ones.

Dr. Salles is a bariatric surgeon and is currently a Scholar in Residence at Stanford (Calif.) University.

A couple of weeks ago, I posted a silly picture of myself with one N95 mask and asked the folks on Twitter what else I might need. In a matter of a few days, I had filled out a form online for volunteering through the Society of Critical Care Medicine, been assigned to work at a hospital in New York City, and booked a hotel and flight.

Courtesy Arghavan Salles, MD

I was going to volunteer, although I wasn’t sure of exactly what I would be doing. I’m trained as a bariatric surgeon – not obviously suited for critical care, but arguably even less suited for medicine wards.

I undoubtedly would have been less prepared if I hadn’t sought guidance on what to bring with me and generally what to expect. Less than a day after seeking advice, two local women physicians donated N95s, face shields, gowns, bouffants, and coveralls to me. I also received a laminated photo of myself to attach to my gown in the mail from a stranger I met online.

Others suggested I bring goggles, chocolate, protein bars, hand sanitizer, powdered laundry detergent, and alcohol wipes. After running around all over town, I was able find everything but the wipes.

Just as others helped me achieve my goal of volunteering, I hope I can guide those who would like to do similar work by sharing details about my experience and other information I have collected about volunteering.

Below I answer some questions that those considering volunteering might have, including why I went, who I contacted to set this up, who paid for my flight, and what I observed in the hospital.
 

Motivation and logistics

I am currently serving in a nonclinical role at my institution. So when the pandemic hit the United States, I felt an immense amount of guilt for not being on the front lines caring for patients. I offered my services to local hospitals and registered for the California Health Corps. I live in northern California, which was the first part of the country to shelter in place. Since my home was actually relatively spared, my services weren’t needed.

As the weeks passed, I was slowly getting more and more fit, exercising in my house since there was little else I could do, and the guilt became a cloud gathering over my head.

I decided to volunteer in a place where demands for help were higher – New York. I tried very hard to sign up to volunteer through the state’s registry for health care volunteers, but was unable to do so. Coincidentally, around that same time, I saw on Twitter that Josh Mugele, MD, emergency medicine physician and program director of the emergency medicine residency at Northeast Georgia Medical Center in Gainesville, was on his way to New York. He shared the Society of Critical Care Medicine’s form for volunteering with me, and in less than 48 hours, I was assigned to a hospital in New York City. Five days later I was on a plane from San Francisco to my destination on the opposite side of the country. The airline paid for my flight.

This is not the only path to volunteering. Another volunteer, Sara Pauk, MD, ob.gyn. at the University of Washington, Seattle, found her volunteer role through contacting the New York City Health and Hospitals system directly. Other who have volunteered told me they had contacted specific hospitals or worked with agencies that were placing physicians.
 

PPE

Courtesy Arghavan Salles. MD

The Brooklyn hospital where I volunteered provided me with two sets of scrubs and two N95s. Gowns were variably available on our unit, and there was no eye protection. As a colleague of mine, Ben Daxon, MD, anesthesia and critical care physician at the Mayo Clinic in Rochester, Minn., had suggested, anyone volunteering in this context should bring personal protective equipment (PPE) – That includes gowns, bouffants/scrub caps, eye protection, masks, and scrubs.

The “COVID corner”

Once I arrived in New York, I did not feel particularly safe in my hotel, so I moved to another the next day. Then I had to sort out how to keep the whole room from being contaminated. I created a “COVID corner” right by the door where I kept almost everything that had been outside the door.

Every time I walked in the door, I immediately took off my shoes and left them in that corner. I could not find alcohol wipes, even after looking around in the city, so I relied on time to kill the virus, which I presumed was on everything that came from outside.

Courtesy Arghavan Salles, MD

Groceries stayed by the door for 48-72 hours if possible. After that, I would move them to the “clean” parts of the room. I wore the same outfit to and from the hospital everyday, putting it on right before I left and taking it off immediately after walking into the room (and then proceeding directly to the shower). Those clothes – “my COVID outfit” – lived in the COVID corner. Anything else I wore, including exercise clothes and underwear, got washed right after I wore it.

At the hospital, I would change into scrubs and leave my COVID outfit in a plastic bag inside my handbag. Note: I fully accepted that my handbag was now a COVID handbag. I kept a pair of clogs in the hospital for daily wear. Without alcohol wipes, my room did not feel clean. But I did start to become at peace with my system, even though it was inferior to the system I use in my own home.

Meal time

In addition to bringing snacks from home, I gathered some meal items at a grocery store during my first day in New York. These included water, yogurt, a few protein drinks, fruit, and some mini chocolate croissants. It’s a pandemic – chocolate is encouraged, right?

Neither any of the volunteers I knew nor I had access to a kitchen, so this was about the best I could do.

My first week I worked nights and ate sporadically. A couple of days I bought bagel sandwiches on the way back to the hotel in the morning. Other times, I would eat yogurt or a protein bar.

I had trouble sleeping, so I would wake up early and either do yoga in my room or go for a run in a nearby park. Usually I didn’t plan well enough to eat before I went into the hospital, so I would take yogurt, some fruit, and a croissant with me as I headed out. It was hard eating on the run with a mask on my face.

When I switched to working days, I actually ordered proper dinners from local Thai, Mexican, and Indian restaurants. I paid around $20 a meal.

One night I even had dinner with a coworker who was staying at a hotel close to mine – what a luxury! Prior to all this I had been sheltering in place alone for weeks, so in that sense, this experience was a delight. I interacted with other people, in person, every day!
 

My commute

My hotel was about 20 minutes from the hospital. Well-meaning folks informed me that Hertz had free car rentals and Uber had discounts for health care workers. When I investigated these options, I found that only employees of certain hospitals were eligible. As a volunteer, I was not eligible.

Courtesy Arghavan Salles, MD

I ultimately took Uber back and forth, and I was lucky that a few friends had sent me Uber gift cards to defray the costs. Most days, I paid about $20 each way, although 1 day there actually was “surge pricing.” The grand total for the trip was close to $800.

Many of the Uber drivers had put up plastic partitions – reminiscent of the plastic Dexter would use to contain his crime scenes – to increase their separation from their passengers. It was a bit eerie, but also somewhat welcome.
 

New normal

The actual work at the hospital in Brooklyn where I volunteered was different from usual practice in numerous ways. One of the things I immediately noticed was how difficult it was to get chest x-rays. After placing an emergent chest tube for a tension pneumothorax, it took about 6 hours to get a chest x-ray to assess placement.

Because code medications were needed much more frequently than normal times, these medications were kept in an open supply closet for ease of access. Many of the ventilators looked like they were from the 1970s. (They had been borrowed from the Federal Emergency Management Agency.)

What was most distinct about this work was the sheer volume of deaths and dying patients -- at least one death on our unit occurred every day I was there -- and the way families communicated with their loved ones. Countless times I held my phone over the faces of my unconscious patients to let their family profess their love and beg them to fight. While I have had to deliver bad news over the phone many times in my career, I have never had to intrude on families’ last conversations with their dying loved ones or witness that conversation occurring via a tiny screen.
 

Reentry

In many ways, I am lucky that I do not do clinical work in my hometown. So while other volunteers were figuring out how many more vacation days they would have to use, or whether they would have to take unpaid leave, and when and how they would get tested, all I had to do was prepare to go back home and quarantine myself for a couple of weeks.

I used up 2 weeks of vacation to volunteer in New York, but luckily, I could resume my normal work the day after I returned home.

Obviously, living in the pandemic is unique to anything we have ever experienced. Recognizing that, I recorded video diaries the whole time I was in New York. I laughed (like when I tried to fit all of my PPE on my tiny head), and I cried – several times. I suppose 1 day I may actually watch them and be reminded of what it was like to have been able to serve in this historic moment. Until then, they will remain locked up on the same phone that served as the only communication vehicle between my patients and their loved ones.

Dr. Salles is a bariatric surgeon and is currently a Scholar in Residence at Stanford (Calif.) University.

A couple of weeks ago, I posted a silly picture of myself with one N95 mask and asked the folks on Twitter what else I might need. In a matter of a few days, I had filled out a form online for volunteering through the Society of Critical Care Medicine, been assigned to work at a hospital in New York City, and booked a hotel and flight.

Courtesy Arghavan Salles, MD

I was going to volunteer, although I wasn’t sure of exactly what I would be doing. I’m trained as a bariatric surgeon – not obviously suited for critical care, but arguably even less suited for medicine wards.

I undoubtedly would have been less prepared if I hadn’t sought guidance on what to bring with me and generally what to expect. Less than a day after seeking advice, two local women physicians donated N95s, face shields, gowns, bouffants, and coveralls to me. I also received a laminated photo of myself to attach to my gown in the mail from a stranger I met online.

Others suggested I bring goggles, chocolate, protein bars, hand sanitizer, powdered laundry detergent, and alcohol wipes. After running around all over town, I was able find everything but the wipes.

Just as others helped me achieve my goal of volunteering, I hope I can guide those who would like to do similar work by sharing details about my experience and other information I have collected about volunteering.

Below I answer some questions that those considering volunteering might have, including why I went, who I contacted to set this up, who paid for my flight, and what I observed in the hospital.
 

Motivation and logistics

I am currently serving in a nonclinical role at my institution. So when the pandemic hit the United States, I felt an immense amount of guilt for not being on the front lines caring for patients. I offered my services to local hospitals and registered for the California Health Corps. I live in northern California, which was the first part of the country to shelter in place. Since my home was actually relatively spared, my services weren’t needed.

As the weeks passed, I was slowly getting more and more fit, exercising in my house since there was little else I could do, and the guilt became a cloud gathering over my head.

I decided to volunteer in a place where demands for help were higher – New York. I tried very hard to sign up to volunteer through the state’s registry for health care volunteers, but was unable to do so. Coincidentally, around that same time, I saw on Twitter that Josh Mugele, MD, emergency medicine physician and program director of the emergency medicine residency at Northeast Georgia Medical Center in Gainesville, was on his way to New York. He shared the Society of Critical Care Medicine’s form for volunteering with me, and in less than 48 hours, I was assigned to a hospital in New York City. Five days later I was on a plane from San Francisco to my destination on the opposite side of the country. The airline paid for my flight.

This is not the only path to volunteering. Another volunteer, Sara Pauk, MD, ob.gyn. at the University of Washington, Seattle, found her volunteer role through contacting the New York City Health and Hospitals system directly. Other who have volunteered told me they had contacted specific hospitals or worked with agencies that were placing physicians.
 

PPE

Courtesy Arghavan Salles. MD

The Brooklyn hospital where I volunteered provided me with two sets of scrubs and two N95s. Gowns were variably available on our unit, and there was no eye protection. As a colleague of mine, Ben Daxon, MD, anesthesia and critical care physician at the Mayo Clinic in Rochester, Minn., had suggested, anyone volunteering in this context should bring personal protective equipment (PPE) – That includes gowns, bouffants/scrub caps, eye protection, masks, and scrubs.

The “COVID corner”

Once I arrived in New York, I did not feel particularly safe in my hotel, so I moved to another the next day. Then I had to sort out how to keep the whole room from being contaminated. I created a “COVID corner” right by the door where I kept almost everything that had been outside the door.

Every time I walked in the door, I immediately took off my shoes and left them in that corner. I could not find alcohol wipes, even after looking around in the city, so I relied on time to kill the virus, which I presumed was on everything that came from outside.

Courtesy Arghavan Salles, MD

Groceries stayed by the door for 48-72 hours if possible. After that, I would move them to the “clean” parts of the room. I wore the same outfit to and from the hospital everyday, putting it on right before I left and taking it off immediately after walking into the room (and then proceeding directly to the shower). Those clothes – “my COVID outfit” – lived in the COVID corner. Anything else I wore, including exercise clothes and underwear, got washed right after I wore it.

At the hospital, I would change into scrubs and leave my COVID outfit in a plastic bag inside my handbag. Note: I fully accepted that my handbag was now a COVID handbag. I kept a pair of clogs in the hospital for daily wear. Without alcohol wipes, my room did not feel clean. But I did start to become at peace with my system, even though it was inferior to the system I use in my own home.

Meal time

In addition to bringing snacks from home, I gathered some meal items at a grocery store during my first day in New York. These included water, yogurt, a few protein drinks, fruit, and some mini chocolate croissants. It’s a pandemic – chocolate is encouraged, right?

Neither any of the volunteers I knew nor I had access to a kitchen, so this was about the best I could do.

My first week I worked nights and ate sporadically. A couple of days I bought bagel sandwiches on the way back to the hotel in the morning. Other times, I would eat yogurt or a protein bar.

I had trouble sleeping, so I would wake up early and either do yoga in my room or go for a run in a nearby park. Usually I didn’t plan well enough to eat before I went into the hospital, so I would take yogurt, some fruit, and a croissant with me as I headed out. It was hard eating on the run with a mask on my face.

When I switched to working days, I actually ordered proper dinners from local Thai, Mexican, and Indian restaurants. I paid around $20 a meal.

One night I even had dinner with a coworker who was staying at a hotel close to mine – what a luxury! Prior to all this I had been sheltering in place alone for weeks, so in that sense, this experience was a delight. I interacted with other people, in person, every day!
 

My commute

My hotel was about 20 minutes from the hospital. Well-meaning folks informed me that Hertz had free car rentals and Uber had discounts for health care workers. When I investigated these options, I found that only employees of certain hospitals were eligible. As a volunteer, I was not eligible.

Courtesy Arghavan Salles, MD

I ultimately took Uber back and forth, and I was lucky that a few friends had sent me Uber gift cards to defray the costs. Most days, I paid about $20 each way, although 1 day there actually was “surge pricing.” The grand total for the trip was close to $800.

Many of the Uber drivers had put up plastic partitions – reminiscent of the plastic Dexter would use to contain his crime scenes – to increase their separation from their passengers. It was a bit eerie, but also somewhat welcome.
 

New normal

The actual work at the hospital in Brooklyn where I volunteered was different from usual practice in numerous ways. One of the things I immediately noticed was how difficult it was to get chest x-rays. After placing an emergent chest tube for a tension pneumothorax, it took about 6 hours to get a chest x-ray to assess placement.

Because code medications were needed much more frequently than normal times, these medications were kept in an open supply closet for ease of access. Many of the ventilators looked like they were from the 1970s. (They had been borrowed from the Federal Emergency Management Agency.)

What was most distinct about this work was the sheer volume of deaths and dying patients -- at least one death on our unit occurred every day I was there -- and the way families communicated with their loved ones. Countless times I held my phone over the faces of my unconscious patients to let their family profess their love and beg them to fight. While I have had to deliver bad news over the phone many times in my career, I have never had to intrude on families’ last conversations with their dying loved ones or witness that conversation occurring via a tiny screen.
 

Reentry

In many ways, I am lucky that I do not do clinical work in my hometown. So while other volunteers were figuring out how many more vacation days they would have to use, or whether they would have to take unpaid leave, and when and how they would get tested, all I had to do was prepare to go back home and quarantine myself for a couple of weeks.

I used up 2 weeks of vacation to volunteer in New York, but luckily, I could resume my normal work the day after I returned home.

Obviously, living in the pandemic is unique to anything we have ever experienced. Recognizing that, I recorded video diaries the whole time I was in New York. I laughed (like when I tried to fit all of my PPE on my tiny head), and I cried – several times. I suppose 1 day I may actually watch them and be reminded of what it was like to have been able to serve in this historic moment. Until then, they will remain locked up on the same phone that served as the only communication vehicle between my patients and their loved ones.

Dr. Salles is a bariatric surgeon and is currently a Scholar in Residence at Stanford (Calif.) University.

As the COVID-19 pandemic has swept across the world, a striking difference has been seen between the sexes. But why are men so much more susceptible to severe outcomes from COVID-19 than women?

Suspicions naturally turn to the sex hormones, and there have been suggestions that estrogen may be protective against COVID-19 in females and/or that androgens worsen COVID-19 outcomes in males.

New data supporting the androgen theory come from a study in Italy.

These researchers found that patients with prostate cancer being treated with androgen deprivation therapy (ADT) were less likely to become infected with COVID-19 and die from the disease than other groups, including other patients with cancer.

The findings suggest that androgens somehow make the virus more virulent and that this exacerbates the severity of disease in men, they say. They also speculate that ADT may be protective against COVID-19.

The study was published online May 7 in Annals of Oncology.

The team analyzed data from 68 hospitals in the Veneto region, one of the areas in Italy most severely affected by the COVID-19 pandemic.

They found data on 9280 patients with laboratory-confirmed SARS-CoV-2 infection — of whom 4532 were males.

Women in the region were actually slightly more likely to be infected with COVID-19 than men, 56% vs 44%, the researchers point out.

However, men were more prone to develop more severe forms of the disease: 60% of men vs 40% of women required hospitalization, rising to 78% of men vs 22% of women who required intensive care. Also, more men died than women (62% vs 38%).

The team then turned their focus onto patients with cancer.

Of the entire male population of Veneto, those with cancer had an almost twofold higher risk of becoming infected with COVID-19 than men without cancer (P < .0001).

However, when the team looked specifically at men with prostate cancer in the region, they found “strikingly, only 4 out of 5273 patients receiving ADT developed SARS-CoV-2 infection and none of these patients died.”

This compared to 37,161 men with prostate cancer who were not receiving ADT, among whom 114 men developed COVID-19 and 18 died.

Among another 79,661 patients in the Veneto region with cancer other than prostate cancer, 312 developed COVID-19 and 57 died.

“This is the first paper to suggest a link between ADT and COVID-19,” commented lead author Andrea Alimonti, MD, PhD, Università della Svizzera Italiana in Lugano, Switzerland.

“Patients with prostate cancer receiving ADT had a significant fourfold reduced risk of COVID-19 infections compared to patients who did not receive ADT. An even greater difference (fivefold reduction in risk) was found when we compared prostate cancer patients receiving ADT to patients with any other type of cancer,” he said.

The finding raises “the hypothesis that androgen levels can facilitate coronavirus infections and increase the severity of symptoms, as has been seen in male patients,” he said.

“These data are very interesting and raise a fascinating hypothesis,” said Richard Martin, PhD, professor of clinical epidemiology at the University of Bristol, UK, commenting about the study. “But they do need independent validation in other large population-wide datasets...with appropriate statistical analysis including adjustment for important risk factors for SARS-CoV-2.”

He noted that the Italian study results were not adjusted for potential confounders, for example, age, body mass index, and cardiometabolic comorbidities, that are strong risk factors for SARS-CoV-2. In addition, men taking ADT may have been more likely to self-isolate and so be at reduced risk of getting the infection, he suggested.
 

How Do Androgens Interact With the Virus?

Alimonti and colleagues offer a mechanistic explanation of how androgens interact with the virus.

Coronavirus gains entry into the human cell by binding its viral spike (S) proteins to ACE2 and on S protein priming by TMPRSS2. TMPRSS2 is a member of a family of proteins called type II transmembrane serine proteases, which are involved in a number of processes including cancer and viral infections, they explain.

“Intriguingly, TMPRSS2 is an androgen-regulated gene that is upregulated in prostate cancer where it supports tumor progression,” they point out.

There is also evidence that the same androgen receptor regulates TMPRSS2 expression in nonprostatic tissues, including the lungs.

“[This] may explain the increased susceptibility of men to develop SARS-CoV-2 severe infections when compared to women,” the authors speculate.

Because ADT is known to decrease TMPRSS2 levels, they suggest that androgen receptor antagonists “could be used to block or decrease the severity of SARS-CoV-2 infection in male patients.”

They go even further and suggest that men without prostate cancer at high risk for COVID-19 could take ADT to prevent infection.

For men who do become infected with COVID-19, ADT might also help reduce symptom severity, they add.

Given that the effects of androgen receptor antagonists are reversible, “they could be used transiently (eg, 1 month) in patients affected by SARS-CoV-2, thereby reducing the risk of side effects due to long-term administration,” the authors suggest.
 

Another Theory: Is Estrogen Protective?

Another theory to explain the male/female difference for severe COVID-19 is that the female hormone estrogen may be protective.

“People have to stop putting estrogen in that ‘female hormone box’ because it’s a molecule that we all use as humans, it’s just not women,” Sharon Nachman, MD, told Medscape Medical News.

“Looking at estrogen as having potentially important immune effects is part of thinking outside the box,” she said.

Nachman is associate dean for research at the Renaissance School of Medicine, Stony Brook University in New York, and is working together with Antonios Gasparis, MD, professor of surgery at the same center.

They are exploring the use of a transdermal estrogen patch in patients with COVID-19 in a randomized trial with a placebo-controlled arm. They are recruiting patients who present to their emergency department with signs and symptoms of COVID-19, and enroll them into the trial if they are interested.

“We are testing everyone as well, but we are starting patients on the medication at the time of entry as opposed to waiting until we have a test result back,” Nachman explained.

The primary objective of the study is to evaluate whether the transdermal patch, applied to the skin for 7 days, might reduce the need for intubation in men and women infected with COVID-19 versus standard of care.

The product is the same single-use transdermal estradiol patch (Climara, 25 cm², Bayer) prescribed for postmenopausal women and will be used at the same dose, which is known to be safe.

After the patch is removed, patients will be carefully tracked for symptoms over the next 45 days to see if the patch reduced symptom severity, and if so, in which patients.

Nachman would have preferred to enroll patients before they had overt symptoms, but this simply isn’t possible in a medical center where symptomatic patients present, she told Medscape Medical News.

However, she does know that even at their own medical center, the odds are stacked against male COVID-19 patients — and something is needed to mitigate its severity in this patient group.

As they were developing the protocol for the current study, the team decided to see who was in their ICU during a single study day.

The answer: mostly males. Intubation and death rates in men in their ICU for that single day was approximately 80% compared with only 20% among women.

“We have a new horrific pathogen that is pandemic and we’re all probably going to get it, it’s just a question of when and how sick we’ll be from it,” Nachman said.

Alimonti and coauthors have reported no relevant financial relationships, as did Goulder and Nachman.

This article first appeared on Medscape.com.

As the COVID-19 pandemic has swept across the world, a striking difference has been seen between the sexes. But why are men so much more susceptible to severe outcomes from COVID-19 than women?

Suspicions naturally turn to the sex hormones, and there have been suggestions that estrogen may be protective against COVID-19 in females and/or that androgens worsen COVID-19 outcomes in males.

New data supporting the androgen theory come from a study in Italy.

These researchers found that patients with prostate cancer being treated with androgen deprivation therapy (ADT) were less likely to become infected with COVID-19 and die from the disease than other groups, including other patients with cancer.

The findings suggest that androgens somehow make the virus more virulent and that this exacerbates the severity of disease in men, they say. They also speculate that ADT may be protective against COVID-19.

The study was published online May 7 in Annals of Oncology.

The team analyzed data from 68 hospitals in the Veneto region, one of the areas in Italy most severely affected by the COVID-19 pandemic.

They found data on 9280 patients with laboratory-confirmed SARS-CoV-2 infection — of whom 4532 were males.

Women in the region were actually slightly more likely to be infected with COVID-19 than men, 56% vs 44%, the researchers point out.

However, men were more prone to develop more severe forms of the disease: 60% of men vs 40% of women required hospitalization, rising to 78% of men vs 22% of women who required intensive care. Also, more men died than women (62% vs 38%).

The team then turned their focus onto patients with cancer.

Of the entire male population of Veneto, those with cancer had an almost twofold higher risk of becoming infected with COVID-19 than men without cancer (P < .0001).

However, when the team looked specifically at men with prostate cancer in the region, they found “strikingly, only 4 out of 5273 patients receiving ADT developed SARS-CoV-2 infection and none of these patients died.”

This compared to 37,161 men with prostate cancer who were not receiving ADT, among whom 114 men developed COVID-19 and 18 died.

Among another 79,661 patients in the Veneto region with cancer other than prostate cancer, 312 developed COVID-19 and 57 died.

“This is the first paper to suggest a link between ADT and COVID-19,” commented lead author Andrea Alimonti, MD, PhD, Università della Svizzera Italiana in Lugano, Switzerland.

“Patients with prostate cancer receiving ADT had a significant fourfold reduced risk of COVID-19 infections compared to patients who did not receive ADT. An even greater difference (fivefold reduction in risk) was found when we compared prostate cancer patients receiving ADT to patients with any other type of cancer,” he said.

The finding raises “the hypothesis that androgen levels can facilitate coronavirus infections and increase the severity of symptoms, as has been seen in male patients,” he said.

“These data are very interesting and raise a fascinating hypothesis,” said Richard Martin, PhD, professor of clinical epidemiology at the University of Bristol, UK, commenting about the study. “But they do need independent validation in other large population-wide datasets...with appropriate statistical analysis including adjustment for important risk factors for SARS-CoV-2.”

He noted that the Italian study results were not adjusted for potential confounders, for example, age, body mass index, and cardiometabolic comorbidities, that are strong risk factors for SARS-CoV-2. In addition, men taking ADT may have been more likely to self-isolate and so be at reduced risk of getting the infection, he suggested.
 

How Do Androgens Interact With the Virus?

Alimonti and colleagues offer a mechanistic explanation of how androgens interact with the virus.

Coronavirus gains entry into the human cell by binding its viral spike (S) proteins to ACE2 and on S protein priming by TMPRSS2. TMPRSS2 is a member of a family of proteins called type II transmembrane serine proteases, which are involved in a number of processes including cancer and viral infections, they explain.

“Intriguingly, TMPRSS2 is an androgen-regulated gene that is upregulated in prostate cancer where it supports tumor progression,” they point out.

There is also evidence that the same androgen receptor regulates TMPRSS2 expression in nonprostatic tissues, including the lungs.

“[This] may explain the increased susceptibility of men to develop SARS-CoV-2 severe infections when compared to women,” the authors speculate.

Because ADT is known to decrease TMPRSS2 levels, they suggest that androgen receptor antagonists “could be used to block or decrease the severity of SARS-CoV-2 infection in male patients.”

They go even further and suggest that men without prostate cancer at high risk for COVID-19 could take ADT to prevent infection.

For men who do become infected with COVID-19, ADT might also help reduce symptom severity, they add.

Given that the effects of androgen receptor antagonists are reversible, “they could be used transiently (eg, 1 month) in patients affected by SARS-CoV-2, thereby reducing the risk of side effects due to long-term administration,” the authors suggest.
 

Another Theory: Is Estrogen Protective?

Another theory to explain the male/female difference for severe COVID-19 is that the female hormone estrogen may be protective.

“People have to stop putting estrogen in that ‘female hormone box’ because it’s a molecule that we all use as humans, it’s just not women,” Sharon Nachman, MD, told Medscape Medical News.

“Looking at estrogen as having potentially important immune effects is part of thinking outside the box,” she said.

Nachman is associate dean for research at the Renaissance School of Medicine, Stony Brook University in New York, and is working together with Antonios Gasparis, MD, professor of surgery at the same center.

They are exploring the use of a transdermal estrogen patch in patients with COVID-19 in a randomized trial with a placebo-controlled arm. They are recruiting patients who present to their emergency department with signs and symptoms of COVID-19, and enroll them into the trial if they are interested.

“We are testing everyone as well, but we are starting patients on the medication at the time of entry as opposed to waiting until we have a test result back,” Nachman explained.

The primary objective of the study is to evaluate whether the transdermal patch, applied to the skin for 7 days, might reduce the need for intubation in men and women infected with COVID-19 versus standard of care.

The product is the same single-use transdermal estradiol patch (Climara, 25 cm², Bayer) prescribed for postmenopausal women and will be used at the same dose, which is known to be safe.

After the patch is removed, patients will be carefully tracked for symptoms over the next 45 days to see if the patch reduced symptom severity, and if so, in which patients.

Nachman would have preferred to enroll patients before they had overt symptoms, but this simply isn’t possible in a medical center where symptomatic patients present, she told Medscape Medical News.

However, she does know that even at their own medical center, the odds are stacked against male COVID-19 patients — and something is needed to mitigate its severity in this patient group.

As they were developing the protocol for the current study, the team decided to see who was in their ICU during a single study day.

The answer: mostly males. Intubation and death rates in men in their ICU for that single day was approximately 80% compared with only 20% among women.

“We have a new horrific pathogen that is pandemic and we’re all probably going to get it, it’s just a question of when and how sick we’ll be from it,” Nachman said.

Alimonti and coauthors have reported no relevant financial relationships, as did Goulder and Nachman.

This article first appeared on Medscape.com.

As the COVID-19 pandemic has swept across the world, a striking difference has been seen between the sexes. But why are men so much more susceptible to severe outcomes from COVID-19 than women?

Suspicions naturally turn to the sex hormones, and there have been suggestions that estrogen may be protective against COVID-19 in females and/or that androgens worsen COVID-19 outcomes in males.

New data supporting the androgen theory come from a study in Italy.

These researchers found that patients with prostate cancer being treated with androgen deprivation therapy (ADT) were less likely to become infected with COVID-19 and die from the disease than other groups, including other patients with cancer.

The findings suggest that androgens somehow make the virus more virulent and that this exacerbates the severity of disease in men, they say. They also speculate that ADT may be protective against COVID-19.

The study was published online May 7 in Annals of Oncology.

The team analyzed data from 68 hospitals in the Veneto region, one of the areas in Italy most severely affected by the COVID-19 pandemic.

They found data on 9280 patients with laboratory-confirmed SARS-CoV-2 infection — of whom 4532 were males.

Women in the region were actually slightly more likely to be infected with COVID-19 than men, 56% vs 44%, the researchers point out.

However, men were more prone to develop more severe forms of the disease: 60% of men vs 40% of women required hospitalization, rising to 78% of men vs 22% of women who required intensive care. Also, more men died than women (62% vs 38%).

The team then turned their focus onto patients with cancer.

Of the entire male population of Veneto, those with cancer had an almost twofold higher risk of becoming infected with COVID-19 than men without cancer (P < .0001).

However, when the team looked specifically at men with prostate cancer in the region, they found “strikingly, only 4 out of 5273 patients receiving ADT developed SARS-CoV-2 infection and none of these patients died.”

This compared to 37,161 men with prostate cancer who were not receiving ADT, among whom 114 men developed COVID-19 and 18 died.

Among another 79,661 patients in the Veneto region with cancer other than prostate cancer, 312 developed COVID-19 and 57 died.

“This is the first paper to suggest a link between ADT and COVID-19,” commented lead author Andrea Alimonti, MD, PhD, Università della Svizzera Italiana in Lugano, Switzerland.

“Patients with prostate cancer receiving ADT had a significant fourfold reduced risk of COVID-19 infections compared to patients who did not receive ADT. An even greater difference (fivefold reduction in risk) was found when we compared prostate cancer patients receiving ADT to patients with any other type of cancer,” he said.

The finding raises “the hypothesis that androgen levels can facilitate coronavirus infections and increase the severity of symptoms, as has been seen in male patients,” he said.

“These data are very interesting and raise a fascinating hypothesis,” said Richard Martin, PhD, professor of clinical epidemiology at the University of Bristol, UK, commenting about the study. “But they do need independent validation in other large population-wide datasets...with appropriate statistical analysis including adjustment for important risk factors for SARS-CoV-2.”

He noted that the Italian study results were not adjusted for potential confounders, for example, age, body mass index, and cardiometabolic comorbidities, that are strong risk factors for SARS-CoV-2. In addition, men taking ADT may have been more likely to self-isolate and so be at reduced risk of getting the infection, he suggested.
 

How Do Androgens Interact With the Virus?

Alimonti and colleagues offer a mechanistic explanation of how androgens interact with the virus.

Coronavirus gains entry into the human cell by binding its viral spike (S) proteins to ACE2 and on S protein priming by TMPRSS2. TMPRSS2 is a member of a family of proteins called type II transmembrane serine proteases, which are involved in a number of processes including cancer and viral infections, they explain.

“Intriguingly, TMPRSS2 is an androgen-regulated gene that is upregulated in prostate cancer where it supports tumor progression,” they point out.

There is also evidence that the same androgen receptor regulates TMPRSS2 expression in nonprostatic tissues, including the lungs.

“[This] may explain the increased susceptibility of men to develop SARS-CoV-2 severe infections when compared to women,” the authors speculate.

Because ADT is known to decrease TMPRSS2 levels, they suggest that androgen receptor antagonists “could be used to block or decrease the severity of SARS-CoV-2 infection in male patients.”

They go even further and suggest that men without prostate cancer at high risk for COVID-19 could take ADT to prevent infection.

For men who do become infected with COVID-19, ADT might also help reduce symptom severity, they add.

Given that the effects of androgen receptor antagonists are reversible, “they could be used transiently (eg, 1 month) in patients affected by SARS-CoV-2, thereby reducing the risk of side effects due to long-term administration,” the authors suggest.
 

Another Theory: Is Estrogen Protective?

Another theory to explain the male/female difference for severe COVID-19 is that the female hormone estrogen may be protective.

“People have to stop putting estrogen in that ‘female hormone box’ because it’s a molecule that we all use as humans, it’s just not women,” Sharon Nachman, MD, told Medscape Medical News.

“Looking at estrogen as having potentially important immune effects is part of thinking outside the box,” she said.

Nachman is associate dean for research at the Renaissance School of Medicine, Stony Brook University in New York, and is working together with Antonios Gasparis, MD, professor of surgery at the same center.

They are exploring the use of a transdermal estrogen patch in patients with COVID-19 in a randomized trial with a placebo-controlled arm. They are recruiting patients who present to their emergency department with signs and symptoms of COVID-19, and enroll them into the trial if they are interested.

“We are testing everyone as well, but we are starting patients on the medication at the time of entry as opposed to waiting until we have a test result back,” Nachman explained.

The primary objective of the study is to evaluate whether the transdermal patch, applied to the skin for 7 days, might reduce the need for intubation in men and women infected with COVID-19 versus standard of care.

The product is the same single-use transdermal estradiol patch (Climara, 25 cm², Bayer) prescribed for postmenopausal women and will be used at the same dose, which is known to be safe.

After the patch is removed, patients will be carefully tracked for symptoms over the next 45 days to see if the patch reduced symptom severity, and if so, in which patients.

Nachman would have preferred to enroll patients before they had overt symptoms, but this simply isn’t possible in a medical center where symptomatic patients present, she told Medscape Medical News.

However, she does know that even at their own medical center, the odds are stacked against male COVID-19 patients — and something is needed to mitigate its severity in this patient group.

As they were developing the protocol for the current study, the team decided to see who was in their ICU during a single study day.

The answer: mostly males. Intubation and death rates in men in their ICU for that single day was approximately 80% compared with only 20% among women.

“We have a new horrific pathogen that is pandemic and we’re all probably going to get it, it’s just a question of when and how sick we’ll be from it,” Nachman said.

Alimonti and coauthors have reported no relevant financial relationships, as did Goulder and Nachman.

This article first appeared on Medscape.com.

Introduction

Since reported in late 2019 in Wuhan China, the disease named “novel coronavirus disease 2019” (COVID-19), caused by the virus referred to as Severe Acute Respiratory Syndrome-causing Coronavirus-2 (SARS-CoV-2) has spread widely to many parts of the world. As of April 13, 2020, a total of 210 countries reported more than 1.9 million cases, resulting in more than 119,000 deaths.¹ All 50 states have reported cases of COVID-19 to the Centers for Disease Control and Prevention (CDC), and most US states are reporting community spread. While levels of COVID-19 activity vary by region, the CDC has reported that the US remains in the acceleration phase of the pandemic, and that widespread transmission is expected.

On March 18, the Centers for Medicare & Medicaid Services (CMS) advised² that all elective surgeries and nonessential medical, surgical, and dental procedures should be delayed to promote physical distancing, preserve personal protective equipment (PPE), and enable health-care workers (HCW) to redirect work to high-need areas. California was the first to issue a statewide shelter-in-place order on March 19, and by April, leaders in 42 states, the District of Columbia, and Puerto Rico issued similar stay-at-home orders. The White House has announced that physical distancing should continue until at least April 30. With the potential for an explosion of new cases that could overwhelm health-care resources, “business as usual” ceased to exist practically overnight.

The speed with which these events transpired, the demand to tailor response within days or even hours, the lack of robust data to support decision-making, the possibility of spread by asymptomatic carriers, and the potential risk for airborne, as well as droplet and fecal-oral spread, caused sleep medicine clinicians to rely on expert consensus and clinical judgment. The goal of such guidance has been to optimize care to patients with sleep disorders, while protecting the health and safety of all. Sleep medicine practices have had to balance efforts to reduce viral exposure and transmission, the need to triage health-care resources and personnel, and maintain access to care.
 

General clinical measures

From the outset, in areas of community spread, sleep medicine practices were called to adapt to now-standard measures, such as provider self-quarantine if ill or exposed, in-person clinic triage strategies for patients and staff prior to entrance to facilities to rapidly identify people with respiratory illness (eg, temperature monitoring), elimination of nonessential visitors, and infection control measures such as vigilant cleaning and appropriate use of personal protective equipment (PPE) during patient interactions. Typical issues facing sleep medicine practices include the need to prioritize urgent or emergency care, track canceled or postponed visits, and maintain access to communication with patients, the health-care team, payors, and employers.

Infection mitigation recommendations: sleep laboratories and ambulatory practices

Diagnostic testing

By mid-March, relatively early in the course of the outbreak in the US, the American Academy of Sleep Medicine (AASM) released recommendations for sleep clinics and laboratories regarding continuation of in-lab diagnostic, split-night, and titration studies, as well as clinical interactions and telemedicine, taking into account the CDC mitigation strategies³ which vary according to level of community transmission or impact of COVID-19.

This advisory was updated repeatedly over the ensuing weeks, most recently on April 8, as community-based spread increased. The AASM now strongly urges all sleep clinicians to postpone in-laboratory polysomnography (PSG) for adults and children, both diagnostic and positive airway pressure (PAP) titrations, except in emergencies. Data regarding adherence with these recommendations are lacking; anecdotal reports suggest that sleep medicine communities most heavily affected by the community spread are indeed following this practice.

The AASM guidance also advises use of home sleep apnea testing (HSAT) with consideration of single-use components or devices, use of mail-in recorders, and/or removal of reusable devices from service for 72 hours between patients.
 

Positive airway pressure (PAP) therapy

The potential for PAP devices to promote the aerosolization of viral particles, which could increase transmission to others on shared ventilation networks in homes and health-care settings, requires careful attention.

Generally, exhaled particle size depends on multiple characteristics, including the force and pressure at generation and environmental conditions (eg, temperature, relative humidity, and air flow). Large-size particles remain suspended in the air only briefly and settle within 1 meter from the source; these are usually mediated by breathing zones of individuals.⁴ However, smaller particles can travel farther, with distance governed by airflow that is driven by many variables, including ventilation, human movement, and temperature gradients. While droplets tend to evaporate rapidly, dry residues can remain suspended in the air.⁵ Infectious respiratory aerosols can occur as droplets >5 mcm diameter, or droplet nuclei (<5 mcm diameter).⁶ Present evidence indicates that SARS-CoV-2 transmission occurs primarily through droplet spread in settings with normal breathing. However, the World Health Organization (WHO) advises more stringent, airborne precautions for aerosol-generating procedures with COVID-19. Such procedures include intubation, extubation, noninvasive ventilation, high-flow nasal cannula, and cardiopulmonary resuscitation before intubation.⁷ Some evidence indicates that SARS-CoV-2 can linger in aerosol form for hours,⁸ and aerosol transmission is therefore plausible. Non-peer reviewed data in real-world settings indicates the presence of SARS-CoV-2 in air samples from hallways outside and in rooms adjacent to COVID-19-containing patients.⁹

These findings raised some concerns about use of PAP in medical and home environments, leading to the recommendation that the decision to continue or withhold PAP temporarily be made based on a risk-benefit evaluation. Scant data hint that PAP therapy may be safe to use in rooms that support appropriate ventilation (eg, negative pressure rooms). Regarding mask type, recently, a group reported the possibility that oronasal masks have a better aerosol dispersal profile.5 However, this conclusion was based on a single study of a specific model of oronasal mask, which demonstrated an absence of ability to measure a dispersion air jet, because the exhalation ports on the mask caused diffuse rather than directed dispersion of air.¹⁰ The same study found, that when the jet could be measured (with nasal pillows or with leak from any interface), greater dispersion was indeed evident. While anecdotal practical methods to filter exhaled air from PAP devices to reduce aerosol transmission have been proposed, data regarding successful reduction in transmission are still lacking, and such methods are not endorsed by mask manufacturers.



Ambulatory clinics: role of telemedicine

As the spread of COVID-19 disease accelerated, the AASM recommended that sleep medicine practices postpone and reschedule all nonemergency, in-person appointments, and conduct as many visits as possible by telemedicine.

This rapid transition posed many layers of logistical complexity, including how to quickly initiate or scale up an often fledging telemedicine presence; scheduling and instructing patients for telemedicine encounters; problem-solving in situations with limited device and Internet availability; triaging patients based on risk; and tracking postponed appointments. Administrators, medical assistants, nurses, advanced practitioners, respiratory therapists, technologists, and physicians have learned new ways of doing things, and laboratory personnel have undergone training and transitioned to new roles and responsibilities during postponement of lab studies. Training programs, in particular, have had to be nimble in finding ways to meet the educational needs of sleep medicine fellows that leveraged telemedicine opportunities.
 

Economic implications of transformed sleep medicine practices

While deploying such systematic change costs both time and money, sleep practices are also confronted with questions around lost revenue from drops in laboratory and clinic volumes. Many additional questions around reimbursement and revenue shortfalls are present, and short-term, furloughed employees may not be able to sustain income loss, which could result in difficulty in resuming services when the COVID-19 threat has been reduced.

Helpfully, during this public health emergency, CMS has expanded coverage for telemedicine services and waived requirements for face-to-face or in-person encounters,¹¹ and some private payers have followed. Additionally, for the duration of the public health emergency, Medicare will cover PAP devices based on the clinician’s assessment of the patient without requiring PSG or a home sleep apnea test (HSAT). However, CMS has not clarified what follow-up testing, if any, may be required after this public health emergency is over. The duration of these new payment models remains uncertain.
 

Recommendations for PAP users

Patients and families, practitioners, and group living facilities have all expressed concerns about use of PAP during the epidemic given presumed increased risk of viral spread. In many hospital protocols, the use of PAP is restricted or disallowed for patients with suspected or confirmed COVID-19. Guidance regarding out-of-hospital use of PAP has been sparse.

AASM has recommended avoidance of PAP or noninvasive ventilation (NIV) for those with presumed or confirmed COVID-19 who cannot self-isolate according to CDC guidance. Risk-benefit assessment is recommended for those who perform safety-sensitive activities or have higher-risk medical conditions. During the period that PAP is withheld, alternative or modifying therapies can be considered, such as positional therapy or oral appliance.

Cleaning device components and washing and replacing filters as recommended by the manufacturer, as well as simple but important interventions like handwashing before and after touching the face or airway gear is thought to be especially important during this time.
 

Conclusions

The COVID-19 pandemic has fueled unprecedented, rapid changes in the way sleep medicine practices deliver care to millions of patients. These changes have been propelled by practitioners and staff who have embraced adaptability, creativity, resourcefulness, and attention to safety and effectiveness. Widespread use of telemedicine services, greater reliance on ambulatory testing, ongoing risk-benefit stratification, leveraging technology and teamwork, and sharing knowledge as it becomes available has resulted in care that is more accessible and convenient for some vulnerable patients, and, yet, challenges persist in accessing needed care. Necessity has been the mother of invention, and we expect the field will need to continue to rebalance as the situation evolves. The ultimate test of these rapid innovations will be how sleep medicine patients fare in the long run, in terms of their health, safety, mortality, and overall quality of life. Future research must address these questions, and the resulting information may yet inform the way sleep medicine is practiced in the years to come.

Dr. Shannon is Medical Director, EVAL Research Institute, Palo Alto, CA; Dr. Gurubhagavatula is Associate Professor, Perelman School of Medicine, University of Pennsylvania, and with Crescenz VA Medical Center, Philadelphia, PA.

1. Worldometer. COVID-19 coronavirus pandemic.

2. Centers for Medicare & Medicaid Services. CMS releases recommendations on adult elective surgeries, non-essential medical, surgical, and dental procedures during COVID-19 response. 2020 Mar 18.

3. Centers for Medicare & Medicaid Services. Implementation of mitigation strategies for communities with local COVID-19 transmission.

4. Tang JW et al. Factors involved in the aerosol transmission of infection and control of ventilation in healthcare premises. J Hosp Infect. 2006;64(2):100-14.

5. Martina Ferioli et al. Protecting healthcare workers from SARS-CoV-2 infection: practical indications. European Respiratory Review 2020;29:200068. doi: 10.1183/16000617.0068-2020.

6. World Health Organization. 2014 Apr. Infection prevention and control of epidemic and pandemic-prone acute respiratory infections in health care.

7. World Health Organization. 2020 Feb 27. Rational use of personal protective equipment for coronavirus disease 2019 (COVID-19) Interim guidance.

8. Van Doremalen N et al. Aerosol and surface stability of SARS-CoV-2 as compared with SARS-CoV-1. N Engl J Med. 2020 Apr 16;382(16):1564-7. doi: 10.1056/NEJMc2004973.

9. Joshua L Santarpia et al. Transmission potential of SARS-CoV-2 in viral shedding observed at the University of Nebraska Medical Center. MedRxiv. 2020 Mar 26. doi: 10.1101/2020.03.23.20039446.

10. David S. Hui et al. Exhaled air dispersion during high-flow nasal cannula therapy versus CPAP via different masks. Eur Respir J. 2019 Apr 11.53(4):pii: 1802339. doi: 10.1183/13993003.02339-2018.

11. Worldometer. COVID-19 coronavirus pandemic.
 

Introduction

Since reported in late 2019 in Wuhan China, the disease named “novel coronavirus disease 2019” (COVID-19), caused by the virus referred to as Severe Acute Respiratory Syndrome-causing Coronavirus-2 (SARS-CoV-2) has spread widely to many parts of the world. As of April 13, 2020, a total of 210 countries reported more than 1.9 million cases, resulting in more than 119,000 deaths.¹ All 50 states have reported cases of COVID-19 to the Centers for Disease Control and Prevention (CDC), and most US states are reporting community spread. While levels of COVID-19 activity vary by region, the CDC has reported that the US remains in the acceleration phase of the pandemic, and that widespread transmission is expected.

On March 18, the Centers for Medicare & Medicaid Services (CMS) advised² that all elective surgeries and nonessential medical, surgical, and dental procedures should be delayed to promote physical distancing, preserve personal protective equipment (PPE), and enable health-care workers (HCW) to redirect work to high-need areas. California was the first to issue a statewide shelter-in-place order on March 19, and by April, leaders in 42 states, the District of Columbia, and Puerto Rico issued similar stay-at-home orders. The White House has announced that physical distancing should continue until at least April 30. With the potential for an explosion of new cases that could overwhelm health-care resources, “business as usual” ceased to exist practically overnight.

The speed with which these events transpired, the demand to tailor response within days or even hours, the lack of robust data to support decision-making, the possibility of spread by asymptomatic carriers, and the potential risk for airborne, as well as droplet and fecal-oral spread, caused sleep medicine clinicians to rely on expert consensus and clinical judgment. The goal of such guidance has been to optimize care to patients with sleep disorders, while protecting the health and safety of all. Sleep medicine practices have had to balance efforts to reduce viral exposure and transmission, the need to triage health-care resources and personnel, and maintain access to care.
 

General clinical measures

From the outset, in areas of community spread, sleep medicine practices were called to adapt to now-standard measures, such as provider self-quarantine if ill or exposed, in-person clinic triage strategies for patients and staff prior to entrance to facilities to rapidly identify people with respiratory illness (eg, temperature monitoring), elimination of nonessential visitors, and infection control measures such as vigilant cleaning and appropriate use of personal protective equipment (PPE) during patient interactions. Typical issues facing sleep medicine practices include the need to prioritize urgent or emergency care, track canceled or postponed visits, and maintain access to communication with patients, the health-care team, payors, and employers.

Infection mitigation recommendations: sleep laboratories and ambulatory practices

Diagnostic testing

By mid-March, relatively early in the course of the outbreak in the US, the American Academy of Sleep Medicine (AASM) released recommendations for sleep clinics and laboratories regarding continuation of in-lab diagnostic, split-night, and titration studies, as well as clinical interactions and telemedicine, taking into account the CDC mitigation strategies³ which vary according to level of community transmission or impact of COVID-19.

This advisory was updated repeatedly over the ensuing weeks, most recently on April 8, as community-based spread increased. The AASM now strongly urges all sleep clinicians to postpone in-laboratory polysomnography (PSG) for adults and children, both diagnostic and positive airway pressure (PAP) titrations, except in emergencies. Data regarding adherence with these recommendations are lacking; anecdotal reports suggest that sleep medicine communities most heavily affected by the community spread are indeed following this practice.

The AASM guidance also advises use of home sleep apnea testing (HSAT) with consideration of single-use components or devices, use of mail-in recorders, and/or removal of reusable devices from service for 72 hours between patients.
 

Positive airway pressure (PAP) therapy

The potential for PAP devices to promote the aerosolization of viral particles, which could increase transmission to others on shared ventilation networks in homes and health-care settings, requires careful attention.

Generally, exhaled particle size depends on multiple characteristics, including the force and pressure at generation and environmental conditions (eg, temperature, relative humidity, and air flow). Large-size particles remain suspended in the air only briefly and settle within 1 meter from the source; these are usually mediated by breathing zones of individuals.⁴ However, smaller particles can travel farther, with distance governed by airflow that is driven by many variables, including ventilation, human movement, and temperature gradients. While droplets tend to evaporate rapidly, dry residues can remain suspended in the air.⁵ Infectious respiratory aerosols can occur as droplets >5 mcm diameter, or droplet nuclei (<5 mcm diameter).⁶ Present evidence indicates that SARS-CoV-2 transmission occurs primarily through droplet spread in settings with normal breathing. However, the World Health Organization (WHO) advises more stringent, airborne precautions for aerosol-generating procedures with COVID-19. Such procedures include intubation, extubation, noninvasive ventilation, high-flow nasal cannula, and cardiopulmonary resuscitation before intubation.⁷ Some evidence indicates that SARS-CoV-2 can linger in aerosol form for hours,⁸ and aerosol transmission is therefore plausible. Non-peer reviewed data in real-world settings indicates the presence of SARS-CoV-2 in air samples from hallways outside and in rooms adjacent to COVID-19-containing patients.⁹

These findings raised some concerns about use of PAP in medical and home environments, leading to the recommendation that the decision to continue or withhold PAP temporarily be made based on a risk-benefit evaluation. Scant data hint that PAP therapy may be safe to use in rooms that support appropriate ventilation (eg, negative pressure rooms). Regarding mask type, recently, a group reported the possibility that oronasal masks have a better aerosol dispersal profile.5 However, this conclusion was based on a single study of a specific model of oronasal mask, which demonstrated an absence of ability to measure a dispersion air jet, because the exhalation ports on the mask caused diffuse rather than directed dispersion of air.¹⁰ The same study found, that when the jet could be measured (with nasal pillows or with leak from any interface), greater dispersion was indeed evident. While anecdotal practical methods to filter exhaled air from PAP devices to reduce aerosol transmission have been proposed, data regarding successful reduction in transmission are still lacking, and such methods are not endorsed by mask manufacturers.



Ambulatory clinics: role of telemedicine

As the spread of COVID-19 disease accelerated, the AASM recommended that sleep medicine practices postpone and reschedule all nonemergency, in-person appointments, and conduct as many visits as possible by telemedicine.

This rapid transition posed many layers of logistical complexity, including how to quickly initiate or scale up an often fledging telemedicine presence; scheduling and instructing patients for telemedicine encounters; problem-solving in situations with limited device and Internet availability; triaging patients based on risk; and tracking postponed appointments. Administrators, medical assistants, nurses, advanced practitioners, respiratory therapists, technologists, and physicians have learned new ways of doing things, and laboratory personnel have undergone training and transitioned to new roles and responsibilities during postponement of lab studies. Training programs, in particular, have had to be nimble in finding ways to meet the educational needs of sleep medicine fellows that leveraged telemedicine opportunities.
 

Economic implications of transformed sleep medicine practices

While deploying such systematic change costs both time and money, sleep practices are also confronted with questions around lost revenue from drops in laboratory and clinic volumes. Many additional questions around reimbursement and revenue shortfalls are present, and short-term, furloughed employees may not be able to sustain income loss, which could result in difficulty in resuming services when the COVID-19 threat has been reduced.

Helpfully, during this public health emergency, CMS has expanded coverage for telemedicine services and waived requirements for face-to-face or in-person encounters,¹¹ and some private payers have followed. Additionally, for the duration of the public health emergency, Medicare will cover PAP devices based on the clinician’s assessment of the patient without requiring PSG or a home sleep apnea test (HSAT). However, CMS has not clarified what follow-up testing, if any, may be required after this public health emergency is over. The duration of these new payment models remains uncertain.
 

Recommendations for PAP users

Patients and families, practitioners, and group living facilities have all expressed concerns about use of PAP during the epidemic given presumed increased risk of viral spread. In many hospital protocols, the use of PAP is restricted or disallowed for patients with suspected or confirmed COVID-19. Guidance regarding out-of-hospital use of PAP has been sparse.

AASM has recommended avoidance of PAP or noninvasive ventilation (NIV) for those with presumed or confirmed COVID-19 who cannot self-isolate according to CDC guidance. Risk-benefit assessment is recommended for those who perform safety-sensitive activities or have higher-risk medical conditions. During the period that PAP is withheld, alternative or modifying therapies can be considered, such as positional therapy or oral appliance.

Cleaning device components and washing and replacing filters as recommended by the manufacturer, as well as simple but important interventions like handwashing before and after touching the face or airway gear is thought to be especially important during this time.
 

Conclusions

The COVID-19 pandemic has fueled unprecedented, rapid changes in the way sleep medicine practices deliver care to millions of patients. These changes have been propelled by practitioners and staff who have embraced adaptability, creativity, resourcefulness, and attention to safety and effectiveness. Widespread use of telemedicine services, greater reliance on ambulatory testing, ongoing risk-benefit stratification, leveraging technology and teamwork, and sharing knowledge as it becomes available has resulted in care that is more accessible and convenient for some vulnerable patients, and, yet, challenges persist in accessing needed care. Necessity has been the mother of invention, and we expect the field will need to continue to rebalance as the situation evolves. The ultimate test of these rapid innovations will be how sleep medicine patients fare in the long run, in terms of their health, safety, mortality, and overall quality of life. Future research must address these questions, and the resulting information may yet inform the way sleep medicine is practiced in the years to come.

Dr. Shannon is Medical Director, EVAL Research Institute, Palo Alto, CA; Dr. Gurubhagavatula is Associate Professor, Perelman School of Medicine, University of Pennsylvania, and with Crescenz VA Medical Center, Philadelphia, PA.

1. Worldometer. COVID-19 coronavirus pandemic.

2. Centers for Medicare & Medicaid Services. CMS releases recommendations on adult elective surgeries, non-essential medical, surgical, and dental procedures during COVID-19 response. 2020 Mar 18.

3. Centers for Medicare & Medicaid Services. Implementation of mitigation strategies for communities with local COVID-19 transmission.

4. Tang JW et al. Factors involved in the aerosol transmission of infection and control of ventilation in healthcare premises. J Hosp Infect. 2006;64(2):100-14.

5. Martina Ferioli et al. Protecting healthcare workers from SARS-CoV-2 infection: practical indications. European Respiratory Review 2020;29:200068. doi: 10.1183/16000617.0068-2020.

6. World Health Organization. 2014 Apr. Infection prevention and control of epidemic and pandemic-prone acute respiratory infections in health care.

7. World Health Organization. 2020 Feb 27. Rational use of personal protective equipment for coronavirus disease 2019 (COVID-19) Interim guidance.

8. Van Doremalen N et al. Aerosol and surface stability of SARS-CoV-2 as compared with SARS-CoV-1. N Engl J Med. 2020 Apr 16;382(16):1564-7. doi: 10.1056/NEJMc2004973.

9. Joshua L Santarpia et al. Transmission potential of SARS-CoV-2 in viral shedding observed at the University of Nebraska Medical Center. MedRxiv. 2020 Mar 26. doi: 10.1101/2020.03.23.20039446.

10. David S. Hui et al. Exhaled air dispersion during high-flow nasal cannula therapy versus CPAP via different masks. Eur Respir J. 2019 Apr 11.53(4):pii: 1802339. doi: 10.1183/13993003.02339-2018.

11. Worldometer. COVID-19 coronavirus pandemic.
 

Introduction

Since reported in late 2019 in Wuhan China, the disease named “novel coronavirus disease 2019” (COVID-19), caused by the virus referred to as Severe Acute Respiratory Syndrome-causing Coronavirus-2 (SARS-CoV-2) has spread widely to many parts of the world. As of April 13, 2020, a total of 210 countries reported more than 1.9 million cases, resulting in more than 119,000 deaths.¹ All 50 states have reported cases of COVID-19 to the Centers for Disease Control and Prevention (CDC), and most US states are reporting community spread. While levels of COVID-19 activity vary by region, the CDC has reported that the US remains in the acceleration phase of the pandemic, and that widespread transmission is expected.

On March 18, the Centers for Medicare & Medicaid Services (CMS) advised² that all elective surgeries and nonessential medical, surgical, and dental procedures should be delayed to promote physical distancing, preserve personal protective equipment (PPE), and enable health-care workers (HCW) to redirect work to high-need areas. California was the first to issue a statewide shelter-in-place order on March 19, and by April, leaders in 42 states, the District of Columbia, and Puerto Rico issued similar stay-at-home orders. The White House has announced that physical distancing should continue until at least April 30. With the potential for an explosion of new cases that could overwhelm health-care resources, “business as usual” ceased to exist practically overnight.

The speed with which these events transpired, the demand to tailor response within days or even hours, the lack of robust data to support decision-making, the possibility of spread by asymptomatic carriers, and the potential risk for airborne, as well as droplet and fecal-oral spread, caused sleep medicine clinicians to rely on expert consensus and clinical judgment. The goal of such guidance has been to optimize care to patients with sleep disorders, while protecting the health and safety of all. Sleep medicine practices have had to balance efforts to reduce viral exposure and transmission, the need to triage health-care resources and personnel, and maintain access to care.
 

General clinical measures

From the outset, in areas of community spread, sleep medicine practices were called to adapt to now-standard measures, such as provider self-quarantine if ill or exposed, in-person clinic triage strategies for patients and staff prior to entrance to facilities to rapidly identify people with respiratory illness (eg, temperature monitoring), elimination of nonessential visitors, and infection control measures such as vigilant cleaning and appropriate use of personal protective equipment (PPE) during patient interactions. Typical issues facing sleep medicine practices include the need to prioritize urgent or emergency care, track canceled or postponed visits, and maintain access to communication with patients, the health-care team, payors, and employers.

Infection mitigation recommendations: sleep laboratories and ambulatory practices

Diagnostic testing

By mid-March, relatively early in the course of the outbreak in the US, the American Academy of Sleep Medicine (AASM) released recommendations for sleep clinics and laboratories regarding continuation of in-lab diagnostic, split-night, and titration studies, as well as clinical interactions and telemedicine, taking into account the CDC mitigation strategies³ which vary according to level of community transmission or impact of COVID-19.

This advisory was updated repeatedly over the ensuing weeks, most recently on April 8, as community-based spread increased. The AASM now strongly urges all sleep clinicians to postpone in-laboratory polysomnography (PSG) for adults and children, both diagnostic and positive airway pressure (PAP) titrations, except in emergencies. Data regarding adherence with these recommendations are lacking; anecdotal reports suggest that sleep medicine communities most heavily affected by the community spread are indeed following this practice.

The AASM guidance also advises use of home sleep apnea testing (HSAT) with consideration of single-use components or devices, use of mail-in recorders, and/or removal of reusable devices from service for 72 hours between patients.
 

Positive airway pressure (PAP) therapy

The potential for PAP devices to promote the aerosolization of viral particles, which could increase transmission to others on shared ventilation networks in homes and health-care settings, requires careful attention.

Generally, exhaled particle size depends on multiple characteristics, including the force and pressure at generation and environmental conditions (eg, temperature, relative humidity, and air flow). Large-size particles remain suspended in the air only briefly and settle within 1 meter from the source; these are usually mediated by breathing zones of individuals.⁴ However, smaller particles can travel farther, with distance governed by airflow that is driven by many variables, including ventilation, human movement, and temperature gradients. While droplets tend to evaporate rapidly, dry residues can remain suspended in the air.⁵ Infectious respiratory aerosols can occur as droplets >5 mcm diameter, or droplet nuclei (<5 mcm diameter).⁶ Present evidence indicates that SARS-CoV-2 transmission occurs primarily through droplet spread in settings with normal breathing. However, the World Health Organization (WHO) advises more stringent, airborne precautions for aerosol-generating procedures with COVID-19. Such procedures include intubation, extubation, noninvasive ventilation, high-flow nasal cannula, and cardiopulmonary resuscitation before intubation.⁷ Some evidence indicates that SARS-CoV-2 can linger in aerosol form for hours,⁸ and aerosol transmission is therefore plausible. Non-peer reviewed data in real-world settings indicates the presence of SARS-CoV-2 in air samples from hallways outside and in rooms adjacent to COVID-19-containing patients.⁹

These findings raised some concerns about use of PAP in medical and home environments, leading to the recommendation that the decision to continue or withhold PAP temporarily be made based on a risk-benefit evaluation. Scant data hint that PAP therapy may be safe to use in rooms that support appropriate ventilation (eg, negative pressure rooms). Regarding mask type, recently, a group reported the possibility that oronasal masks have a better aerosol dispersal profile.5 However, this conclusion was based on a single study of a specific model of oronasal mask, which demonstrated an absence of ability to measure a dispersion air jet, because the exhalation ports on the mask caused diffuse rather than directed dispersion of air.¹⁰ The same study found, that when the jet could be measured (with nasal pillows or with leak from any interface), greater dispersion was indeed evident. While anecdotal practical methods to filter exhaled air from PAP devices to reduce aerosol transmission have been proposed, data regarding successful reduction in transmission are still lacking, and such methods are not endorsed by mask manufacturers.



Ambulatory clinics: role of telemedicine

As the spread of COVID-19 disease accelerated, the AASM recommended that sleep medicine practices postpone and reschedule all nonemergency, in-person appointments, and conduct as many visits as possible by telemedicine.

This rapid transition posed many layers of logistical complexity, including how to quickly initiate or scale up an often fledging telemedicine presence; scheduling and instructing patients for telemedicine encounters; problem-solving in situations with limited device and Internet availability; triaging patients based on risk; and tracking postponed appointments. Administrators, medical assistants, nurses, advanced practitioners, respiratory therapists, technologists, and physicians have learned new ways of doing things, and laboratory personnel have undergone training and transitioned to new roles and responsibilities during postponement of lab studies. Training programs, in particular, have had to be nimble in finding ways to meet the educational needs of sleep medicine fellows that leveraged telemedicine opportunities.
 

Economic implications of transformed sleep medicine practices

While deploying such systematic change costs both time and money, sleep practices are also confronted with questions around lost revenue from drops in laboratory and clinic volumes. Many additional questions around reimbursement and revenue shortfalls are present, and short-term, furloughed employees may not be able to sustain income loss, which could result in difficulty in resuming services when the COVID-19 threat has been reduced.

Helpfully, during this public health emergency, CMS has expanded coverage for telemedicine services and waived requirements for face-to-face or in-person encounters,¹¹ and some private payers have followed. Additionally, for the duration of the public health emergency, Medicare will cover PAP devices based on the clinician’s assessment of the patient without requiring PSG or a home sleep apnea test (HSAT). However, CMS has not clarified what follow-up testing, if any, may be required after this public health emergency is over. The duration of these new payment models remains uncertain.
 

Recommendations for PAP users

Patients and families, practitioners, and group living facilities have all expressed concerns about use of PAP during the epidemic given presumed increased risk of viral spread. In many hospital protocols, the use of PAP is restricted or disallowed for patients with suspected or confirmed COVID-19. Guidance regarding out-of-hospital use of PAP has been sparse.

AASM has recommended avoidance of PAP or noninvasive ventilation (NIV) for those with presumed or confirmed COVID-19 who cannot self-isolate according to CDC guidance. Risk-benefit assessment is recommended for those who perform safety-sensitive activities or have higher-risk medical conditions. During the period that PAP is withheld, alternative or modifying therapies can be considered, such as positional therapy or oral appliance.

Cleaning device components and washing and replacing filters as recommended by the manufacturer, as well as simple but important interventions like handwashing before and after touching the face or airway gear is thought to be especially important during this time.
 

Conclusions

The COVID-19 pandemic has fueled unprecedented, rapid changes in the way sleep medicine practices deliver care to millions of patients. These changes have been propelled by practitioners and staff who have embraced adaptability, creativity, resourcefulness, and attention to safety and effectiveness. Widespread use of telemedicine services, greater reliance on ambulatory testing, ongoing risk-benefit stratification, leveraging technology and teamwork, and sharing knowledge as it becomes available has resulted in care that is more accessible and convenient for some vulnerable patients, and, yet, challenges persist in accessing needed care. Necessity has been the mother of invention, and we expect the field will need to continue to rebalance as the situation evolves. The ultimate test of these rapid innovations will be how sleep medicine patients fare in the long run, in terms of their health, safety, mortality, and overall quality of life. Future research must address these questions, and the resulting information may yet inform the way sleep medicine is practiced in the years to come.

Dr. Shannon is Medical Director, EVAL Research Institute, Palo Alto, CA; Dr. Gurubhagavatula is Associate Professor, Perelman School of Medicine, University of Pennsylvania, and with Crescenz VA Medical Center, Philadelphia, PA.

1. Worldometer. COVID-19 coronavirus pandemic.

2. Centers for Medicare & Medicaid Services. CMS releases recommendations on adult elective surgeries, non-essential medical, surgical, and dental procedures during COVID-19 response. 2020 Mar 18.

3. Centers for Medicare & Medicaid Services. Implementation of mitigation strategies for communities with local COVID-19 transmission.

4. Tang JW et al. Factors involved in the aerosol transmission of infection and control of ventilation in healthcare premises. J Hosp Infect. 2006;64(2):100-14.

5. Martina Ferioli et al. Protecting healthcare workers from SARS-CoV-2 infection: practical indications. European Respiratory Review 2020;29:200068. doi: 10.1183/16000617.0068-2020.

6. World Health Organization. 2014 Apr. Infection prevention and control of epidemic and pandemic-prone acute respiratory infections in health care.

7. World Health Organization. 2020 Feb 27. Rational use of personal protective equipment for coronavirus disease 2019 (COVID-19) Interim guidance.

8. Van Doremalen N et al. Aerosol and surface stability of SARS-CoV-2 as compared with SARS-CoV-1. N Engl J Med. 2020 Apr 16;382(16):1564-7. doi: 10.1056/NEJMc2004973.

9. Joshua L Santarpia et al. Transmission potential of SARS-CoV-2 in viral shedding observed at the University of Nebraska Medical Center. MedRxiv. 2020 Mar 26. doi: 10.1101/2020.03.23.20039446.

10. David S. Hui et al. Exhaled air dispersion during high-flow nasal cannula therapy versus CPAP via different masks. Eur Respir J. 2019 Apr 11.53(4):pii: 1802339. doi: 10.1183/13993003.02339-2018.

11. Worldometer. COVID-19 coronavirus pandemic.