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FDA okays emergency use for Impella RP in COVID-19 right heart failure
The Food and Drug Administration issued an emergency use authorization for use of the Impella RP heart pump system in COVID-19 patients with right heart failure or decompensation, Abiomed announced June 1.
“Based on extrapolation of data from the approved indication and reported clinical experience, FDA has concluded that the Impella RP may be effective at providing temporary right ventricular support for the treatment of acute right heart failure or decompensation caused by COVID-19 complications, including PE [pulmonary embolism],” the letter noted.
It cited, for example, use of the temporary heart pump in a 59-year-old woman suffering from COVID-19 who went into right ventricular failure and became hypotensive after an acute PE was removed. After placement of the device, the patient experienced a “dramatic and immediate” improvement in arterial pressure and the device was removed on the fifth day, according to Amir Kaki, MD, and Ted Schreiber, MD, of Ascension St. John Hospital, Detroit, whose review of the case has been posted online.
“Acute pulmonary embolism is clearly being recognized as a life-threatening manifestation of COVID-19. Impella RP is an important tool to help cardiologists save lives during this pandemic,” Dr. Kaki said in the letter. “As we have demonstrated in our series of patients, early recognition of right ventricular dysfunction and early placement of the Impella RP for patients who are hypotensive can be lifesaving.”
Other data cited in support of the Impella RP emergency use authorization (EUA) include a 2019 series of hemodynamically unstable patients with PE in Japan and a 2017 case report of a 47-year-old man with right ventricular failure, profound shock, and a massive PE.
The FDA granted premarket approval of the Impella RP system in 2017 to provide temporary right ventricular support for up to 14 days in patients with a body surface area of at least 1.5 m2 who develop acute right heart failure or decompensation following left ventricular assist device implantation, MI, heart transplant, or open-heart surgery.
The EUA indication for the Impella RP system is to provide temporary right ventricular support for up to 14 days in critical care patients with a body surface area of at least 1.5 m2 for the treatment of acute right heart failure or decompensation caused by complications related to COVID-19, including PE.
The Impella RP is authorized only for emergency use under the EUA and only for the duration of the circumstances justifying use of EUAs, the letter noted.
Last year, concerns were raised about off-indication use after interim results from a postapproval study suggested a higher risk for death than seen in premarket studies treated with the temporary heart pump.
A version of this article originally appeared on Medscape.com.
The Food and Drug Administration issued an emergency use authorization for use of the Impella RP heart pump system in COVID-19 patients with right heart failure or decompensation, Abiomed announced June 1.
“Based on extrapolation of data from the approved indication and reported clinical experience, FDA has concluded that the Impella RP may be effective at providing temporary right ventricular support for the treatment of acute right heart failure or decompensation caused by COVID-19 complications, including PE [pulmonary embolism],” the letter noted.
It cited, for example, use of the temporary heart pump in a 59-year-old woman suffering from COVID-19 who went into right ventricular failure and became hypotensive after an acute PE was removed. After placement of the device, the patient experienced a “dramatic and immediate” improvement in arterial pressure and the device was removed on the fifth day, according to Amir Kaki, MD, and Ted Schreiber, MD, of Ascension St. John Hospital, Detroit, whose review of the case has been posted online.
“Acute pulmonary embolism is clearly being recognized as a life-threatening manifestation of COVID-19. Impella RP is an important tool to help cardiologists save lives during this pandemic,” Dr. Kaki said in the letter. “As we have demonstrated in our series of patients, early recognition of right ventricular dysfunction and early placement of the Impella RP for patients who are hypotensive can be lifesaving.”
Other data cited in support of the Impella RP emergency use authorization (EUA) include a 2019 series of hemodynamically unstable patients with PE in Japan and a 2017 case report of a 47-year-old man with right ventricular failure, profound shock, and a massive PE.
The FDA granted premarket approval of the Impella RP system in 2017 to provide temporary right ventricular support for up to 14 days in patients with a body surface area of at least 1.5 m2 who develop acute right heart failure or decompensation following left ventricular assist device implantation, MI, heart transplant, or open-heart surgery.
The EUA indication for the Impella RP system is to provide temporary right ventricular support for up to 14 days in critical care patients with a body surface area of at least 1.5 m2 for the treatment of acute right heart failure or decompensation caused by complications related to COVID-19, including PE.
The Impella RP is authorized only for emergency use under the EUA and only for the duration of the circumstances justifying use of EUAs, the letter noted.
Last year, concerns were raised about off-indication use after interim results from a postapproval study suggested a higher risk for death than seen in premarket studies treated with the temporary heart pump.
A version of this article originally appeared on Medscape.com.
The Food and Drug Administration issued an emergency use authorization for use of the Impella RP heart pump system in COVID-19 patients with right heart failure or decompensation, Abiomed announced June 1.
“Based on extrapolation of data from the approved indication and reported clinical experience, FDA has concluded that the Impella RP may be effective at providing temporary right ventricular support for the treatment of acute right heart failure or decompensation caused by COVID-19 complications, including PE [pulmonary embolism],” the letter noted.
It cited, for example, use of the temporary heart pump in a 59-year-old woman suffering from COVID-19 who went into right ventricular failure and became hypotensive after an acute PE was removed. After placement of the device, the patient experienced a “dramatic and immediate” improvement in arterial pressure and the device was removed on the fifth day, according to Amir Kaki, MD, and Ted Schreiber, MD, of Ascension St. John Hospital, Detroit, whose review of the case has been posted online.
“Acute pulmonary embolism is clearly being recognized as a life-threatening manifestation of COVID-19. Impella RP is an important tool to help cardiologists save lives during this pandemic,” Dr. Kaki said in the letter. “As we have demonstrated in our series of patients, early recognition of right ventricular dysfunction and early placement of the Impella RP for patients who are hypotensive can be lifesaving.”
Other data cited in support of the Impella RP emergency use authorization (EUA) include a 2019 series of hemodynamically unstable patients with PE in Japan and a 2017 case report of a 47-year-old man with right ventricular failure, profound shock, and a massive PE.
The FDA granted premarket approval of the Impella RP system in 2017 to provide temporary right ventricular support for up to 14 days in patients with a body surface area of at least 1.5 m2 who develop acute right heart failure or decompensation following left ventricular assist device implantation, MI, heart transplant, or open-heart surgery.
The EUA indication for the Impella RP system is to provide temporary right ventricular support for up to 14 days in critical care patients with a body surface area of at least 1.5 m2 for the treatment of acute right heart failure or decompensation caused by complications related to COVID-19, including PE.
The Impella RP is authorized only for emergency use under the EUA and only for the duration of the circumstances justifying use of EUAs, the letter noted.
Last year, concerns were raised about off-indication use after interim results from a postapproval study suggested a higher risk for death than seen in premarket studies treated with the temporary heart pump.
A version of this article originally appeared on Medscape.com.
Smokers who are unmotivated to quit smoke more with e-cigarettes
Not only does the use of e-cigarettes not help cigarette smokers who are unmotivated to quit, it has the opposite effect, according to results from a new study.
“In our study, people vaping in addition to smoking actually started smoking more,” said study lead investigator Nancy Anoruo, MD, from the University of Massachusetts Medical School in Worcester.
This is “completely contradictory to what the e-cigarette manufacturers are telling us,” she told this news organization.
In their study, Dr. Anoruo and her colleagues looked at whether people were more likely to quit if they smoked e-cigarettes in addition to conventional cigarettes. The research is a substudy of the ongoing Take a Break project, funded by the National Institutes of Health, which is assessing whether a smoking-cessation motivation app helps smokers quit.
In a cohort of 405 smokers who were unmotivated to quit, 248 were defined as dual smokers after responding “yes” to “ever having used” e-cigarettes, and 157 were defined as traditional smokers who only smoked combustible cigarettes. The majority of participants, 82%, were white; 8.8% were black; and 49% were women.
More dual smokers than traditional smokers were younger than 40 years (27% vs. 16%; (P = .02), Dr. Anoruo reported during her virtual presentation at the American Thoracic Society 2020 International Conference.
The dual smokers reported smoking an average of 16 cigarettes a day, compared with 14 a day for the traditional smokers.
All the smokers were encouraged to consider a 3-week period of abstinence from combustible cigarettes. At the end of that period, the researchers compared outcomes reported by participants.
Abstinence challenge
Average abstinence intervals were shorter for dual smokers than for traditional smokers (0.93 vs. 1.8 days; P = .01). And dual smokers reported having a harder time quitting completely (6.3% vs. 13.0%; P = .02).
At 6-month follow-up, dual smokers were smoking more cigarettes than traditional smokers (daily average, 12.0 vs. 9.4; P = .04). And the reduction in cigarette use from baseline was smaller for dual smokers than for traditional smokers (21% vs. 33%; P = .04).
“E-cigarettes are not a special magic bullet to get people to quit smoking,” said Dr. Anoruo.
In this study, smoking cessation was defined as abstinence from combustible cigarettes, but that did not mean participants were abstinent from nicotine.
“If, at the end, they stopped smoking traditional cigarettes, we considered that successful smoking cessation,” Dr. Anoruo explained. This definition is in line with the school of thought that e-cigarettes are a harm-reduction tool.
“But we now know that e-cigarettes are not necessarily safe,” she added.
Still, it might be the lesser evil. “You end up taking in less dangerous chemicals, so we consider it quitting if you get off regular cigarettes,” she said.
“We would like to study the psychology of cigarette smokers to find out if they see e-cigarettes as a smoking-cessation aid,” Dr. Anoruo said, and to see if “their belief is driven by the advertising they see about e-cigarette use.”
A meager reduction
Similar results were shown last month in a study by Megan Piper, PhD, of University of Wisconsin–Madison and her colleagues, who reported that dual e-cigarette and combustible cigarette use “did not appear to be an effective path to cessation of combustible cigarettes.”
After 1 year, dual smokers smoked three cigarettes less each day than traditional smokers, which is “a meager reduction,” Dr. Piper said in a news release.
“Typically, you can’t have one foot in both camps. Most can’t be vaping and smoking and hope to quit smoking,” she added. “That sustained pattern is not going to help most people quit.”
A version of this article originally appeared on Medscape.com.
Not only does the use of e-cigarettes not help cigarette smokers who are unmotivated to quit, it has the opposite effect, according to results from a new study.
“In our study, people vaping in addition to smoking actually started smoking more,” said study lead investigator Nancy Anoruo, MD, from the University of Massachusetts Medical School in Worcester.
This is “completely contradictory to what the e-cigarette manufacturers are telling us,” she told this news organization.
In their study, Dr. Anoruo and her colleagues looked at whether people were more likely to quit if they smoked e-cigarettes in addition to conventional cigarettes. The research is a substudy of the ongoing Take a Break project, funded by the National Institutes of Health, which is assessing whether a smoking-cessation motivation app helps smokers quit.
In a cohort of 405 smokers who were unmotivated to quit, 248 were defined as dual smokers after responding “yes” to “ever having used” e-cigarettes, and 157 were defined as traditional smokers who only smoked combustible cigarettes. The majority of participants, 82%, were white; 8.8% were black; and 49% were women.
More dual smokers than traditional smokers were younger than 40 years (27% vs. 16%; (P = .02), Dr. Anoruo reported during her virtual presentation at the American Thoracic Society 2020 International Conference.
The dual smokers reported smoking an average of 16 cigarettes a day, compared with 14 a day for the traditional smokers.
All the smokers were encouraged to consider a 3-week period of abstinence from combustible cigarettes. At the end of that period, the researchers compared outcomes reported by participants.
Abstinence challenge
Average abstinence intervals were shorter for dual smokers than for traditional smokers (0.93 vs. 1.8 days; P = .01). And dual smokers reported having a harder time quitting completely (6.3% vs. 13.0%; P = .02).
At 6-month follow-up, dual smokers were smoking more cigarettes than traditional smokers (daily average, 12.0 vs. 9.4; P = .04). And the reduction in cigarette use from baseline was smaller for dual smokers than for traditional smokers (21% vs. 33%; P = .04).
“E-cigarettes are not a special magic bullet to get people to quit smoking,” said Dr. Anoruo.
In this study, smoking cessation was defined as abstinence from combustible cigarettes, but that did not mean participants were abstinent from nicotine.
“If, at the end, they stopped smoking traditional cigarettes, we considered that successful smoking cessation,” Dr. Anoruo explained. This definition is in line with the school of thought that e-cigarettes are a harm-reduction tool.
“But we now know that e-cigarettes are not necessarily safe,” she added.
Still, it might be the lesser evil. “You end up taking in less dangerous chemicals, so we consider it quitting if you get off regular cigarettes,” she said.
“We would like to study the psychology of cigarette smokers to find out if they see e-cigarettes as a smoking-cessation aid,” Dr. Anoruo said, and to see if “their belief is driven by the advertising they see about e-cigarette use.”
A meager reduction
Similar results were shown last month in a study by Megan Piper, PhD, of University of Wisconsin–Madison and her colleagues, who reported that dual e-cigarette and combustible cigarette use “did not appear to be an effective path to cessation of combustible cigarettes.”
After 1 year, dual smokers smoked three cigarettes less each day than traditional smokers, which is “a meager reduction,” Dr. Piper said in a news release.
“Typically, you can’t have one foot in both camps. Most can’t be vaping and smoking and hope to quit smoking,” she added. “That sustained pattern is not going to help most people quit.”
A version of this article originally appeared on Medscape.com.
Not only does the use of e-cigarettes not help cigarette smokers who are unmotivated to quit, it has the opposite effect, according to results from a new study.
“In our study, people vaping in addition to smoking actually started smoking more,” said study lead investigator Nancy Anoruo, MD, from the University of Massachusetts Medical School in Worcester.
This is “completely contradictory to what the e-cigarette manufacturers are telling us,” she told this news organization.
In their study, Dr. Anoruo and her colleagues looked at whether people were more likely to quit if they smoked e-cigarettes in addition to conventional cigarettes. The research is a substudy of the ongoing Take a Break project, funded by the National Institutes of Health, which is assessing whether a smoking-cessation motivation app helps smokers quit.
In a cohort of 405 smokers who were unmotivated to quit, 248 were defined as dual smokers after responding “yes” to “ever having used” e-cigarettes, and 157 were defined as traditional smokers who only smoked combustible cigarettes. The majority of participants, 82%, were white; 8.8% were black; and 49% were women.
More dual smokers than traditional smokers were younger than 40 years (27% vs. 16%; (P = .02), Dr. Anoruo reported during her virtual presentation at the American Thoracic Society 2020 International Conference.
The dual smokers reported smoking an average of 16 cigarettes a day, compared with 14 a day for the traditional smokers.
All the smokers were encouraged to consider a 3-week period of abstinence from combustible cigarettes. At the end of that period, the researchers compared outcomes reported by participants.
Abstinence challenge
Average abstinence intervals were shorter for dual smokers than for traditional smokers (0.93 vs. 1.8 days; P = .01). And dual smokers reported having a harder time quitting completely (6.3% vs. 13.0%; P = .02).
At 6-month follow-up, dual smokers were smoking more cigarettes than traditional smokers (daily average, 12.0 vs. 9.4; P = .04). And the reduction in cigarette use from baseline was smaller for dual smokers than for traditional smokers (21% vs. 33%; P = .04).
“E-cigarettes are not a special magic bullet to get people to quit smoking,” said Dr. Anoruo.
In this study, smoking cessation was defined as abstinence from combustible cigarettes, but that did not mean participants were abstinent from nicotine.
“If, at the end, they stopped smoking traditional cigarettes, we considered that successful smoking cessation,” Dr. Anoruo explained. This definition is in line with the school of thought that e-cigarettes are a harm-reduction tool.
“But we now know that e-cigarettes are not necessarily safe,” she added.
Still, it might be the lesser evil. “You end up taking in less dangerous chemicals, so we consider it quitting if you get off regular cigarettes,” she said.
“We would like to study the psychology of cigarette smokers to find out if they see e-cigarettes as a smoking-cessation aid,” Dr. Anoruo said, and to see if “their belief is driven by the advertising they see about e-cigarette use.”
A meager reduction
Similar results were shown last month in a study by Megan Piper, PhD, of University of Wisconsin–Madison and her colleagues, who reported that dual e-cigarette and combustible cigarette use “did not appear to be an effective path to cessation of combustible cigarettes.”
After 1 year, dual smokers smoked three cigarettes less each day than traditional smokers, which is “a meager reduction,” Dr. Piper said in a news release.
“Typically, you can’t have one foot in both camps. Most can’t be vaping and smoking and hope to quit smoking,” she added. “That sustained pattern is not going to help most people quit.”
A version of this article originally appeared on Medscape.com.
Short medication regimen noninferior to long regimen for rifampin-resistant TB
Background: Multidrug-resistant TB is more difficult to treat than is drug-susceptible TB. The 2011 World Health Organization (WHO) recommendations for the treatment of multidrug-resistant TB, based on very-low-quality and conditional evidence, consists of an intensive treatment phase of 8 months and total treatment duration of 20 months. Although cohort studies have shown promising cure rates among patients with multidrug-resistant TB who received existing drugs in regimens shorter than that recommended by the WHO, data from phase 3 randomized trials were lacking.
Study design: Randomized phase 3 noninferior trial.
Setting: Multisite, international; countries were selected based on background disease burden of TB, multidrug-resistant TB, and TB-HIV coinfection (Ethiopia, Mongolia, South Africa, Vietnam).
Synopsis: 424 patients were randomized to the short and long medication regimen groups with 369 included in the modified intention-to-treat analysis and 310 included in the final per protocol efficacy analysis. The short regimen included IV moxifloxacin, clofazimine, ethambutol, and pyrazinamide administered over a 40-week period, supplemented by kanamycin, isoniazid, and prothionamide in the first 16 weeks, compared with 8 months of intense treatment and total 20 months of treatment in the long regimen. At 132 weeks after randomization, cultures were negative for Mycobacterium tuberculosis in more than 78 % patients in both long- and short-regimen group. Unfavorable bacteriologic outcome (10.6%), cardiac conduction defects (9.9%), and hepatobiliary problems (8.9%) were more common in the short-regimen group whereas patients in long-regimen group were lost to follow-up more frequently (2.4%) and had more metabolic disorders (7.1%). More deaths were reported in the short-regimen group, especially in those with HIV coinfections (17.5%). Although the results of this trial are encouraging, further studies will be needed to find a short, simple regimen for multidrug-resistant tuberculosis with improved safety outcomes.
Bottom line: Short medication regimen (9-11 months) is noninferior to the traditional WHO-recommended long regimen (20 months) for treating rifampin-resistant tuberculosis.
Citation: Nunn AJ et al. A trial of a shorter regimen for rifampin-resistant tuberculosis. N Engl J Med. 2019 Mar 28; 380:1201-13.
Dr. Kamath is an assistant professor of medicine at Duke University.
Background: Multidrug-resistant TB is more difficult to treat than is drug-susceptible TB. The 2011 World Health Organization (WHO) recommendations for the treatment of multidrug-resistant TB, based on very-low-quality and conditional evidence, consists of an intensive treatment phase of 8 months and total treatment duration of 20 months. Although cohort studies have shown promising cure rates among patients with multidrug-resistant TB who received existing drugs in regimens shorter than that recommended by the WHO, data from phase 3 randomized trials were lacking.
Study design: Randomized phase 3 noninferior trial.
Setting: Multisite, international; countries were selected based on background disease burden of TB, multidrug-resistant TB, and TB-HIV coinfection (Ethiopia, Mongolia, South Africa, Vietnam).
Synopsis: 424 patients were randomized to the short and long medication regimen groups with 369 included in the modified intention-to-treat analysis and 310 included in the final per protocol efficacy analysis. The short regimen included IV moxifloxacin, clofazimine, ethambutol, and pyrazinamide administered over a 40-week period, supplemented by kanamycin, isoniazid, and prothionamide in the first 16 weeks, compared with 8 months of intense treatment and total 20 months of treatment in the long regimen. At 132 weeks after randomization, cultures were negative for Mycobacterium tuberculosis in more than 78 % patients in both long- and short-regimen group. Unfavorable bacteriologic outcome (10.6%), cardiac conduction defects (9.9%), and hepatobiliary problems (8.9%) were more common in the short-regimen group whereas patients in long-regimen group were lost to follow-up more frequently (2.4%) and had more metabolic disorders (7.1%). More deaths were reported in the short-regimen group, especially in those with HIV coinfections (17.5%). Although the results of this trial are encouraging, further studies will be needed to find a short, simple regimen for multidrug-resistant tuberculosis with improved safety outcomes.
Bottom line: Short medication regimen (9-11 months) is noninferior to the traditional WHO-recommended long regimen (20 months) for treating rifampin-resistant tuberculosis.
Citation: Nunn AJ et al. A trial of a shorter regimen for rifampin-resistant tuberculosis. N Engl J Med. 2019 Mar 28; 380:1201-13.
Dr. Kamath is an assistant professor of medicine at Duke University.
Background: Multidrug-resistant TB is more difficult to treat than is drug-susceptible TB. The 2011 World Health Organization (WHO) recommendations for the treatment of multidrug-resistant TB, based on very-low-quality and conditional evidence, consists of an intensive treatment phase of 8 months and total treatment duration of 20 months. Although cohort studies have shown promising cure rates among patients with multidrug-resistant TB who received existing drugs in regimens shorter than that recommended by the WHO, data from phase 3 randomized trials were lacking.
Study design: Randomized phase 3 noninferior trial.
Setting: Multisite, international; countries were selected based on background disease burden of TB, multidrug-resistant TB, and TB-HIV coinfection (Ethiopia, Mongolia, South Africa, Vietnam).
Synopsis: 424 patients were randomized to the short and long medication regimen groups with 369 included in the modified intention-to-treat analysis and 310 included in the final per protocol efficacy analysis. The short regimen included IV moxifloxacin, clofazimine, ethambutol, and pyrazinamide administered over a 40-week period, supplemented by kanamycin, isoniazid, and prothionamide in the first 16 weeks, compared with 8 months of intense treatment and total 20 months of treatment in the long regimen. At 132 weeks after randomization, cultures were negative for Mycobacterium tuberculosis in more than 78 % patients in both long- and short-regimen group. Unfavorable bacteriologic outcome (10.6%), cardiac conduction defects (9.9%), and hepatobiliary problems (8.9%) were more common in the short-regimen group whereas patients in long-regimen group were lost to follow-up more frequently (2.4%) and had more metabolic disorders (7.1%). More deaths were reported in the short-regimen group, especially in those with HIV coinfections (17.5%). Although the results of this trial are encouraging, further studies will be needed to find a short, simple regimen for multidrug-resistant tuberculosis with improved safety outcomes.
Bottom line: Short medication regimen (9-11 months) is noninferior to the traditional WHO-recommended long regimen (20 months) for treating rifampin-resistant tuberculosis.
Citation: Nunn AJ et al. A trial of a shorter regimen for rifampin-resistant tuberculosis. N Engl J Med. 2019 Mar 28; 380:1201-13.
Dr. Kamath is an assistant professor of medicine at Duke University.
Despite guidelines, controversy remains over corticosteroids in COVID-19
Three main reasons have been put forth for using corticosteroids in critically ill patients with COVID-19, but only one – the hope of preventing lung fibrosis in patients with unresolved acute respiratory distress syndrome – is reasonable to employ now outside of formal randomized trials, Peter Pickkers, MD, PhD, asserted at a webinar on COVID-19 sponsored by the European Society of Intensive Care Medicine.
The most commonly invoked rationale for giving steroids in patients with severe COVID-19 is to modulate the destructive inflammatory immune response that occurs with advancing disease. Another justification cited for giving steroids is to treat suspected adrenal insufficiency in those with refractory shock. Of note, both practices are endorsed in the recent Surviving Sepsis Campaign guidelines on management of critically ill patients with COVID-19 (Intensive Care Med. 2020 May;46[5]:854-87).
But those recommendations – numbers 22 and 42 out of a total of 50 recommendations included in the guidelines – should never have been made, according to Dr. Pickkers, professor of experimental intensive care medicine at Radboud University Medical Center in Nijmegen, the Netherlands.
Dueling guidelines
The Surviving Sepsis Campaign guidelines, which were developed by a panel comprising 36 experts in 12 countries, are quite frank in conceding that the guidance in favor of corticosteroids are weak recommendations based on low-quality evidence.
The guidelines recommend against using corticosteroids to try to modulate the immune system in mechanically ventilated COVID-19 patients without acute respiratory distress syndrome (ARDS), but do recommend steroids in those with COVID-19 and ARDS. However, the guidelines also note that, because of the very low quality of the evidence, some experts on the panel preferred not to issue a pro-steroids recommendation at all until higher-quality evidence becomes available. Dr. Pickkers said he believes that the minority view should have prevailed. Moreover, current COVID-19 guidance from the World Health Organization is at odds with the Surviving Sepsis Campaign recommendations; the WHO advises against corticosteroids unless the treatment is indicated for a reason other than immunomodulation, he noted.
The evidence in favor of steroids in an effort to blunt the immune response in COVID patients with ARDS is based largely upon a single small, retrospective, non–peer-reviewed report that 5-7 days of treatment with 1-2 mg/kg per day of methylprednisolone was associated with shortened fever duration and need for supplemental oxygen.
The evidence against steroids for immunomodulation comes mainly from earlier studies of the SARS and MERS novel coronaviruses. For example, in a multicenter study of 309 patients with the MERS (Middle East respiratory syndrome) virus, those who received corticosteroids received no benefit and experienced delayed viral clearance (Am J Respir Crit Care Med. 2018 Mar 15;197[6]:757-67).
“The thing is, virtually all COVID-19 patients in the ICU fulfill the criteria for ARDS, so following the Surviving Sepsis Campaign guidelines would have far-reaching consequences,” Dr. Pickkers said.
Those consequences include a theoretic potential for serious harm arising from dampening the immune response at a point in the course of COVID-19 when the virus is still present, which could result in slowed viral clearance and prolonged viral shedding. Moreover so far no one has been able to identify a sweet spot in the disease course where the viral load has waned and the immune response is sufficiently early that intervention with corticosteroids might have an optimal benefit/risk ratio, he continued.
“My opinion is that at this moment there is no benefit at all for corticosteroids for immunomodulation in patients with COVID-19,” Dr. Pickkers said. “My personal recommendation, in contrast to the Surviving Sepsis Campaign recommendation, is not to use this therapy outside of a study.”
He added that randomized, controlled trials of corticosteroid therapy in critically ill patients with COVID-19 are ongoing in Europe and the United States, including the large RECOVERY study of dexamethasone in the United Kingdom.
As for the Surviving Sepsis Campaign recommendation to use corticosteroids to treat refractory shock in COVID-19, Dr. Pickkers dismissed this guidance as largely irrelevant. That’s because few patients with COVID-19 who need mechanical ventilation have refractory shock as evidenced by the need for a high infusion rate of norepinephrine. Anyway, he noted, that Surviving Sepsis recommendation is based upon extrapolation from evidence of benefit in bacterial septic shock patients, which he deemed to be of questionable relevance to the COVID-19 pandemic.
Attacking the fibroproliferative phase of ARDS
First off, Dr. Pickkers conceded, there is no evidence that treatment with corticosteroids to prevent lung fibrosis in COVID-19 patients with nonresolving ARDS is an effective strategy; the pandemic is simply too new at this point for the appropriate studies to have been done. But this much is known: Postmortem pathologic studies show fibroplastic proliferation is present in the lungs of COVID-19 patients, as in those who die of ARDS of other causes. Also, COVID-19 patients typically aren’t admitted to the ICU until day 11 or 12 after developing their first symptoms, so by the time they display indications that their ARDS is not resolving, the virus has typically left the scene; thus, there is little risk at that point that corticosteroids will promote viral proliferation. Additionally, studies in critically ill patients with nonresolving ARDS of other causes show clinically meaningful benefits for corticosteroid therapy.
Dr. Pickkers cited as “must reading” an analysis of five randomized trials of corticosteroid therapy in a total of 518 patients with acute lung injury ARDS of non–COVID-19 origin. The analysis by investigators at the University of Tennessee, Memphis, concluded that treatment resulted in clinically meaningful reductions in duration of mechanical ventilation and ICU length of stay. Moreover, in the 400 patients whose steroid therapy commenced before day 14 of ARDS, there was a statistically significant 22% reduction in risk of death, compared with patients in whom corticosteroids were started later (Intensive Care Med. 2008 Jan;34[1]:61-9).
Session cochair Jan De Waele, MD, PhD, struck a cautious note, remarking, “It’s my perception that we’re using the evidence that we’ve gathered in other conditions and are now trying to apply it in COVID-19. But quality data on patients with COVID-19 itself is pretty scare, and it’s really hard to say whether this disease behaves similarly to bacterial septic shock or to other viral infections.”
“We need more information about the use of corticosteroids in COVID-19, although I think a lot of people are using it at this moment,” added Dr. De Waele, a surgical intensivist at Ghent (Belgium) University.
That being said, he asked Dr. Pickkers when he considers using corticosteroids to prevent pulmonary fibrosis.
Dr. Pickkers said that when he notices that a COVID-19 patient’s lung compliance is worsening, that stiff lung is a clue that fibrosis is occurring and is having clinical consequences. “We also measure blood procollagen, a not very sensitive but moderately specific marker of fibroproliferation. If we see an increase in this biomarker and the lung mechanics are changing, then we do treat these patients with corticosteroids,” Dr. Pickkers replied.
He and his colleagues try to start steroids before day 14 of ARDS, and they continue treatment for longer than 7 days in order to prevent a rebound inflammatory response upon treatment discontinuation. They also avoid using neuromuscular agents and engage in meticulous infection surveillance in order to minimize potential complications of corticosteroid therapy in the ICU.
Dr. Pickkers reported having no financial conflicts regarding his presentation.
Three main reasons have been put forth for using corticosteroids in critically ill patients with COVID-19, but only one – the hope of preventing lung fibrosis in patients with unresolved acute respiratory distress syndrome – is reasonable to employ now outside of formal randomized trials, Peter Pickkers, MD, PhD, asserted at a webinar on COVID-19 sponsored by the European Society of Intensive Care Medicine.
The most commonly invoked rationale for giving steroids in patients with severe COVID-19 is to modulate the destructive inflammatory immune response that occurs with advancing disease. Another justification cited for giving steroids is to treat suspected adrenal insufficiency in those with refractory shock. Of note, both practices are endorsed in the recent Surviving Sepsis Campaign guidelines on management of critically ill patients with COVID-19 (Intensive Care Med. 2020 May;46[5]:854-87).
But those recommendations – numbers 22 and 42 out of a total of 50 recommendations included in the guidelines – should never have been made, according to Dr. Pickkers, professor of experimental intensive care medicine at Radboud University Medical Center in Nijmegen, the Netherlands.
Dueling guidelines
The Surviving Sepsis Campaign guidelines, which were developed by a panel comprising 36 experts in 12 countries, are quite frank in conceding that the guidance in favor of corticosteroids are weak recommendations based on low-quality evidence.
The guidelines recommend against using corticosteroids to try to modulate the immune system in mechanically ventilated COVID-19 patients without acute respiratory distress syndrome (ARDS), but do recommend steroids in those with COVID-19 and ARDS. However, the guidelines also note that, because of the very low quality of the evidence, some experts on the panel preferred not to issue a pro-steroids recommendation at all until higher-quality evidence becomes available. Dr. Pickkers said he believes that the minority view should have prevailed. Moreover, current COVID-19 guidance from the World Health Organization is at odds with the Surviving Sepsis Campaign recommendations; the WHO advises against corticosteroids unless the treatment is indicated for a reason other than immunomodulation, he noted.
The evidence in favor of steroids in an effort to blunt the immune response in COVID patients with ARDS is based largely upon a single small, retrospective, non–peer-reviewed report that 5-7 days of treatment with 1-2 mg/kg per day of methylprednisolone was associated with shortened fever duration and need for supplemental oxygen.
The evidence against steroids for immunomodulation comes mainly from earlier studies of the SARS and MERS novel coronaviruses. For example, in a multicenter study of 309 patients with the MERS (Middle East respiratory syndrome) virus, those who received corticosteroids received no benefit and experienced delayed viral clearance (Am J Respir Crit Care Med. 2018 Mar 15;197[6]:757-67).
“The thing is, virtually all COVID-19 patients in the ICU fulfill the criteria for ARDS, so following the Surviving Sepsis Campaign guidelines would have far-reaching consequences,” Dr. Pickkers said.
Those consequences include a theoretic potential for serious harm arising from dampening the immune response at a point in the course of COVID-19 when the virus is still present, which could result in slowed viral clearance and prolonged viral shedding. Moreover so far no one has been able to identify a sweet spot in the disease course where the viral load has waned and the immune response is sufficiently early that intervention with corticosteroids might have an optimal benefit/risk ratio, he continued.
“My opinion is that at this moment there is no benefit at all for corticosteroids for immunomodulation in patients with COVID-19,” Dr. Pickkers said. “My personal recommendation, in contrast to the Surviving Sepsis Campaign recommendation, is not to use this therapy outside of a study.”
He added that randomized, controlled trials of corticosteroid therapy in critically ill patients with COVID-19 are ongoing in Europe and the United States, including the large RECOVERY study of dexamethasone in the United Kingdom.
As for the Surviving Sepsis Campaign recommendation to use corticosteroids to treat refractory shock in COVID-19, Dr. Pickkers dismissed this guidance as largely irrelevant. That’s because few patients with COVID-19 who need mechanical ventilation have refractory shock as evidenced by the need for a high infusion rate of norepinephrine. Anyway, he noted, that Surviving Sepsis recommendation is based upon extrapolation from evidence of benefit in bacterial septic shock patients, which he deemed to be of questionable relevance to the COVID-19 pandemic.
Attacking the fibroproliferative phase of ARDS
First off, Dr. Pickkers conceded, there is no evidence that treatment with corticosteroids to prevent lung fibrosis in COVID-19 patients with nonresolving ARDS is an effective strategy; the pandemic is simply too new at this point for the appropriate studies to have been done. But this much is known: Postmortem pathologic studies show fibroplastic proliferation is present in the lungs of COVID-19 patients, as in those who die of ARDS of other causes. Also, COVID-19 patients typically aren’t admitted to the ICU until day 11 or 12 after developing their first symptoms, so by the time they display indications that their ARDS is not resolving, the virus has typically left the scene; thus, there is little risk at that point that corticosteroids will promote viral proliferation. Additionally, studies in critically ill patients with nonresolving ARDS of other causes show clinically meaningful benefits for corticosteroid therapy.
Dr. Pickkers cited as “must reading” an analysis of five randomized trials of corticosteroid therapy in a total of 518 patients with acute lung injury ARDS of non–COVID-19 origin. The analysis by investigators at the University of Tennessee, Memphis, concluded that treatment resulted in clinically meaningful reductions in duration of mechanical ventilation and ICU length of stay. Moreover, in the 400 patients whose steroid therapy commenced before day 14 of ARDS, there was a statistically significant 22% reduction in risk of death, compared with patients in whom corticosteroids were started later (Intensive Care Med. 2008 Jan;34[1]:61-9).
Session cochair Jan De Waele, MD, PhD, struck a cautious note, remarking, “It’s my perception that we’re using the evidence that we’ve gathered in other conditions and are now trying to apply it in COVID-19. But quality data on patients with COVID-19 itself is pretty scare, and it’s really hard to say whether this disease behaves similarly to bacterial septic shock or to other viral infections.”
“We need more information about the use of corticosteroids in COVID-19, although I think a lot of people are using it at this moment,” added Dr. De Waele, a surgical intensivist at Ghent (Belgium) University.
That being said, he asked Dr. Pickkers when he considers using corticosteroids to prevent pulmonary fibrosis.
Dr. Pickkers said that when he notices that a COVID-19 patient’s lung compliance is worsening, that stiff lung is a clue that fibrosis is occurring and is having clinical consequences. “We also measure blood procollagen, a not very sensitive but moderately specific marker of fibroproliferation. If we see an increase in this biomarker and the lung mechanics are changing, then we do treat these patients with corticosteroids,” Dr. Pickkers replied.
He and his colleagues try to start steroids before day 14 of ARDS, and they continue treatment for longer than 7 days in order to prevent a rebound inflammatory response upon treatment discontinuation. They also avoid using neuromuscular agents and engage in meticulous infection surveillance in order to minimize potential complications of corticosteroid therapy in the ICU.
Dr. Pickkers reported having no financial conflicts regarding his presentation.
Three main reasons have been put forth for using corticosteroids in critically ill patients with COVID-19, but only one – the hope of preventing lung fibrosis in patients with unresolved acute respiratory distress syndrome – is reasonable to employ now outside of formal randomized trials, Peter Pickkers, MD, PhD, asserted at a webinar on COVID-19 sponsored by the European Society of Intensive Care Medicine.
The most commonly invoked rationale for giving steroids in patients with severe COVID-19 is to modulate the destructive inflammatory immune response that occurs with advancing disease. Another justification cited for giving steroids is to treat suspected adrenal insufficiency in those with refractory shock. Of note, both practices are endorsed in the recent Surviving Sepsis Campaign guidelines on management of critically ill patients with COVID-19 (Intensive Care Med. 2020 May;46[5]:854-87).
But those recommendations – numbers 22 and 42 out of a total of 50 recommendations included in the guidelines – should never have been made, according to Dr. Pickkers, professor of experimental intensive care medicine at Radboud University Medical Center in Nijmegen, the Netherlands.
Dueling guidelines
The Surviving Sepsis Campaign guidelines, which were developed by a panel comprising 36 experts in 12 countries, are quite frank in conceding that the guidance in favor of corticosteroids are weak recommendations based on low-quality evidence.
The guidelines recommend against using corticosteroids to try to modulate the immune system in mechanically ventilated COVID-19 patients without acute respiratory distress syndrome (ARDS), but do recommend steroids in those with COVID-19 and ARDS. However, the guidelines also note that, because of the very low quality of the evidence, some experts on the panel preferred not to issue a pro-steroids recommendation at all until higher-quality evidence becomes available. Dr. Pickkers said he believes that the minority view should have prevailed. Moreover, current COVID-19 guidance from the World Health Organization is at odds with the Surviving Sepsis Campaign recommendations; the WHO advises against corticosteroids unless the treatment is indicated for a reason other than immunomodulation, he noted.
The evidence in favor of steroids in an effort to blunt the immune response in COVID patients with ARDS is based largely upon a single small, retrospective, non–peer-reviewed report that 5-7 days of treatment with 1-2 mg/kg per day of methylprednisolone was associated with shortened fever duration and need for supplemental oxygen.
The evidence against steroids for immunomodulation comes mainly from earlier studies of the SARS and MERS novel coronaviruses. For example, in a multicenter study of 309 patients with the MERS (Middle East respiratory syndrome) virus, those who received corticosteroids received no benefit and experienced delayed viral clearance (Am J Respir Crit Care Med. 2018 Mar 15;197[6]:757-67).
“The thing is, virtually all COVID-19 patients in the ICU fulfill the criteria for ARDS, so following the Surviving Sepsis Campaign guidelines would have far-reaching consequences,” Dr. Pickkers said.
Those consequences include a theoretic potential for serious harm arising from dampening the immune response at a point in the course of COVID-19 when the virus is still present, which could result in slowed viral clearance and prolonged viral shedding. Moreover so far no one has been able to identify a sweet spot in the disease course where the viral load has waned and the immune response is sufficiently early that intervention with corticosteroids might have an optimal benefit/risk ratio, he continued.
“My opinion is that at this moment there is no benefit at all for corticosteroids for immunomodulation in patients with COVID-19,” Dr. Pickkers said. “My personal recommendation, in contrast to the Surviving Sepsis Campaign recommendation, is not to use this therapy outside of a study.”
He added that randomized, controlled trials of corticosteroid therapy in critically ill patients with COVID-19 are ongoing in Europe and the United States, including the large RECOVERY study of dexamethasone in the United Kingdom.
As for the Surviving Sepsis Campaign recommendation to use corticosteroids to treat refractory shock in COVID-19, Dr. Pickkers dismissed this guidance as largely irrelevant. That’s because few patients with COVID-19 who need mechanical ventilation have refractory shock as evidenced by the need for a high infusion rate of norepinephrine. Anyway, he noted, that Surviving Sepsis recommendation is based upon extrapolation from evidence of benefit in bacterial septic shock patients, which he deemed to be of questionable relevance to the COVID-19 pandemic.
Attacking the fibroproliferative phase of ARDS
First off, Dr. Pickkers conceded, there is no evidence that treatment with corticosteroids to prevent lung fibrosis in COVID-19 patients with nonresolving ARDS is an effective strategy; the pandemic is simply too new at this point for the appropriate studies to have been done. But this much is known: Postmortem pathologic studies show fibroplastic proliferation is present in the lungs of COVID-19 patients, as in those who die of ARDS of other causes. Also, COVID-19 patients typically aren’t admitted to the ICU until day 11 or 12 after developing their first symptoms, so by the time they display indications that their ARDS is not resolving, the virus has typically left the scene; thus, there is little risk at that point that corticosteroids will promote viral proliferation. Additionally, studies in critically ill patients with nonresolving ARDS of other causes show clinically meaningful benefits for corticosteroid therapy.
Dr. Pickkers cited as “must reading” an analysis of five randomized trials of corticosteroid therapy in a total of 518 patients with acute lung injury ARDS of non–COVID-19 origin. The analysis by investigators at the University of Tennessee, Memphis, concluded that treatment resulted in clinically meaningful reductions in duration of mechanical ventilation and ICU length of stay. Moreover, in the 400 patients whose steroid therapy commenced before day 14 of ARDS, there was a statistically significant 22% reduction in risk of death, compared with patients in whom corticosteroids were started later (Intensive Care Med. 2008 Jan;34[1]:61-9).
Session cochair Jan De Waele, MD, PhD, struck a cautious note, remarking, “It’s my perception that we’re using the evidence that we’ve gathered in other conditions and are now trying to apply it in COVID-19. But quality data on patients with COVID-19 itself is pretty scare, and it’s really hard to say whether this disease behaves similarly to bacterial septic shock or to other viral infections.”
“We need more information about the use of corticosteroids in COVID-19, although I think a lot of people are using it at this moment,” added Dr. De Waele, a surgical intensivist at Ghent (Belgium) University.
That being said, he asked Dr. Pickkers when he considers using corticosteroids to prevent pulmonary fibrosis.
Dr. Pickkers said that when he notices that a COVID-19 patient’s lung compliance is worsening, that stiff lung is a clue that fibrosis is occurring and is having clinical consequences. “We also measure blood procollagen, a not very sensitive but moderately specific marker of fibroproliferation. If we see an increase in this biomarker and the lung mechanics are changing, then we do treat these patients with corticosteroids,” Dr. Pickkers replied.
He and his colleagues try to start steroids before day 14 of ARDS, and they continue treatment for longer than 7 days in order to prevent a rebound inflammatory response upon treatment discontinuation. They also avoid using neuromuscular agents and engage in meticulous infection surveillance in order to minimize potential complications of corticosteroid therapy in the ICU.
Dr. Pickkers reported having no financial conflicts regarding his presentation.
Testing the limits of medical technology
On March 9 my team was given a directive by the chief medical officer of our health system. It seemed like an impossible task, involving the mobilization of people, processes, and technology at a scale and speed we had never before achieved. It turned out getting this done was impossible. In spite of our best efforts, we failed to meet the deadline – it actually took us 3 days. Still, by March 12, we had opened the doors on the first community testing site in our area and gained the attention of local and national news outlets for our accomplishment.
Now more than 2 months later, I’m quite proud of what our team was able to achieve for the health system, but I’m still quite frustrated at the state of COVID-19 testing nationwide – there’s simply not enough available, and there is tremendous variability in the reliability of the tests. In this column, we’d like to highlight some of the challenges we’ve faced and reflect on how the shortcomings of modern technology have once again proven that medicine is both a science and an art.
Our dangerous lack of preparation
Prior to the coronavirus pandemic, I had never considered surgical masks, face shields, and nasal swabs to be critical components of medical technology. My opinion quickly changed after opening our drive-through COVID-19 site. I now have a much greater appreciation for the importance of personal protective equipment and basic testing supplies.
I was shocked by how difficult obtaining it has been during the past few months. It seems that no one anticipated the possibility of a pandemic on this grand a scale, so stockpiles of equipment were depleted quickly and couldn’t be replenished. Also, most manufacturing occurs outside the United States, which creates additional barriers to controlling the supply chain. One need not look far to find stories of widespread price-gouging, black market racketeering, and even hijackings that have stood in the way of accessing the necessary supplies. Sadly, the lack of equipment is far from the only challenge we’ve faced. In some cases, it has been a mistrust of results that has prevented widespread testing and mitigation.
The risks of flying blind
When President Trump touted the introduction of a rapid COVID-19 test at the end of March, many people were excited. Promising positive results in as few as 5 minutes, the assay was granted an Emergency Use Authorization (EUA) by the Food and Drug Administration in order to expedite its availability in the market. According to the FDA’s website, an EUA allows “unapproved medical products or unapproved uses of approved medical products to be used in an emergency to diagnose, treat, or prevent serious or life-threatening diseases or conditions.” This rapid (though untested) approval was all that many health care providers needed to hear – immediately hospitals and physicians scrambled to get their hands on the testing devices. Unfortunately, on May 14th, the FDA issued a press release that raised concerns about that same test because it seemed to be reporting a high number of false-negative results. Just as quickly as the devices had been adopted, health care providers began backing away from them in favor of other assays, and a serious truth about COVID-19 testing was revealed: In many ways, we’re flying blind.
Laboratory manufacturers have been working overtime to create assays for SARS-CoV-2 (the coronavirus that causes COVID-19) and have used different technologies for detection. The most commonly used are polymerase chain reaction (PCR) tests. In these assays, viral RNA is converted to DNA by reverse transcriptase, then amplified through the addition of primers that enable detection. PCR technology has been available for years and is a reliable method for identifying DNA and RNA, but the required heating and cooling process takes time and results can take several hours to return. To address this and expedite testing, other methods of detection have been tried, such as the loop-mediated isothermal amplification (LAMP) technique employed by the rapid assay mentioned above. Regardless of methodology, all laboratory tests have one thing in common: None of them is perfect.
Every assay has a different level of reliability. When screening for a disease such as COVID-19, we are particularly interested in a test’s sensitivity (that is, it’s ability to detect disease); we’d love such a screening test to be 100% sensitive and thereby not miss a single case. In truth, no test’s sensitivity is 100%, and in this particular case even the best assays only score around 98%. This means that out of every 100 patients with COVID-19 who are evaluated, two might test negative for the virus. In a pandemic this can have dire consequences, so health care providers – unable to fully trust their instruments – must employ clinical acumen and years of experience to navigate these cloudy skies. We are hopeful that additional tools will complement our current methods, but with new assays also come new questions.
Is anyone safe?
We receive regular questions from physicians about the value of antibody testing, but it’s not yet clear how best to respond. While the assays seem to be reliable, the utility of the results are still ill defined. Antibodies to SARS-CoV-2 (both IgG and IgM) appear to peak about 2-3 weeks after symptom onset, but we don’t yet know if the presence of those antibodies confers long-term immunity. Therefore, patients should not use the information to change their masking or social-distancing practices, nor should they presume that they are safe from becoming reinfected with COVID-19. While new research looks promising, there are still too many unknowns to be able to confidently reassure providers or patients of the true value of antibody testing. This underscores our final point: Medicine remains an art.
As we are regularly reminded, we’ll never fully anticipate the challenges or barriers to success, and technology will never replace the value of clinical judgment and human experience. While the situation is unsettling in many ways, we are reassured and encouraged by the role we still get to play in keeping our patients healthy in this health care crisis, and we’ll continue to do so through whatever the future holds.
Dr. Notte is a family physician and chief medical officer of Abington Lansdale (Pa.) Hospital - Jefferson Health. Follow him on Twitter (@doctornotte). Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Philadelphia, and associate director of the family medicine residency program at Abington (Pa.) Hospital–Jefferson Health. They have no conflicts related to the content of this piece.
On March 9 my team was given a directive by the chief medical officer of our health system. It seemed like an impossible task, involving the mobilization of people, processes, and technology at a scale and speed we had never before achieved. It turned out getting this done was impossible. In spite of our best efforts, we failed to meet the deadline – it actually took us 3 days. Still, by March 12, we had opened the doors on the first community testing site in our area and gained the attention of local and national news outlets for our accomplishment.
Now more than 2 months later, I’m quite proud of what our team was able to achieve for the health system, but I’m still quite frustrated at the state of COVID-19 testing nationwide – there’s simply not enough available, and there is tremendous variability in the reliability of the tests. In this column, we’d like to highlight some of the challenges we’ve faced and reflect on how the shortcomings of modern technology have once again proven that medicine is both a science and an art.
Our dangerous lack of preparation
Prior to the coronavirus pandemic, I had never considered surgical masks, face shields, and nasal swabs to be critical components of medical technology. My opinion quickly changed after opening our drive-through COVID-19 site. I now have a much greater appreciation for the importance of personal protective equipment and basic testing supplies.
I was shocked by how difficult obtaining it has been during the past few months. It seems that no one anticipated the possibility of a pandemic on this grand a scale, so stockpiles of equipment were depleted quickly and couldn’t be replenished. Also, most manufacturing occurs outside the United States, which creates additional barriers to controlling the supply chain. One need not look far to find stories of widespread price-gouging, black market racketeering, and even hijackings that have stood in the way of accessing the necessary supplies. Sadly, the lack of equipment is far from the only challenge we’ve faced. In some cases, it has been a mistrust of results that has prevented widespread testing and mitigation.
The risks of flying blind
When President Trump touted the introduction of a rapid COVID-19 test at the end of March, many people were excited. Promising positive results in as few as 5 minutes, the assay was granted an Emergency Use Authorization (EUA) by the Food and Drug Administration in order to expedite its availability in the market. According to the FDA’s website, an EUA allows “unapproved medical products or unapproved uses of approved medical products to be used in an emergency to diagnose, treat, or prevent serious or life-threatening diseases or conditions.” This rapid (though untested) approval was all that many health care providers needed to hear – immediately hospitals and physicians scrambled to get their hands on the testing devices. Unfortunately, on May 14th, the FDA issued a press release that raised concerns about that same test because it seemed to be reporting a high number of false-negative results. Just as quickly as the devices had been adopted, health care providers began backing away from them in favor of other assays, and a serious truth about COVID-19 testing was revealed: In many ways, we’re flying blind.
Laboratory manufacturers have been working overtime to create assays for SARS-CoV-2 (the coronavirus that causes COVID-19) and have used different technologies for detection. The most commonly used are polymerase chain reaction (PCR) tests. In these assays, viral RNA is converted to DNA by reverse transcriptase, then amplified through the addition of primers that enable detection. PCR technology has been available for years and is a reliable method for identifying DNA and RNA, but the required heating and cooling process takes time and results can take several hours to return. To address this and expedite testing, other methods of detection have been tried, such as the loop-mediated isothermal amplification (LAMP) technique employed by the rapid assay mentioned above. Regardless of methodology, all laboratory tests have one thing in common: None of them is perfect.
Every assay has a different level of reliability. When screening for a disease such as COVID-19, we are particularly interested in a test’s sensitivity (that is, it’s ability to detect disease); we’d love such a screening test to be 100% sensitive and thereby not miss a single case. In truth, no test’s sensitivity is 100%, and in this particular case even the best assays only score around 98%. This means that out of every 100 patients with COVID-19 who are evaluated, two might test negative for the virus. In a pandemic this can have dire consequences, so health care providers – unable to fully trust their instruments – must employ clinical acumen and years of experience to navigate these cloudy skies. We are hopeful that additional tools will complement our current methods, but with new assays also come new questions.
Is anyone safe?
We receive regular questions from physicians about the value of antibody testing, but it’s not yet clear how best to respond. While the assays seem to be reliable, the utility of the results are still ill defined. Antibodies to SARS-CoV-2 (both IgG and IgM) appear to peak about 2-3 weeks after symptom onset, but we don’t yet know if the presence of those antibodies confers long-term immunity. Therefore, patients should not use the information to change their masking or social-distancing practices, nor should they presume that they are safe from becoming reinfected with COVID-19. While new research looks promising, there are still too many unknowns to be able to confidently reassure providers or patients of the true value of antibody testing. This underscores our final point: Medicine remains an art.
As we are regularly reminded, we’ll never fully anticipate the challenges or barriers to success, and technology will never replace the value of clinical judgment and human experience. While the situation is unsettling in many ways, we are reassured and encouraged by the role we still get to play in keeping our patients healthy in this health care crisis, and we’ll continue to do so through whatever the future holds.
Dr. Notte is a family physician and chief medical officer of Abington Lansdale (Pa.) Hospital - Jefferson Health. Follow him on Twitter (@doctornotte). Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Philadelphia, and associate director of the family medicine residency program at Abington (Pa.) Hospital–Jefferson Health. They have no conflicts related to the content of this piece.
On March 9 my team was given a directive by the chief medical officer of our health system. It seemed like an impossible task, involving the mobilization of people, processes, and technology at a scale and speed we had never before achieved. It turned out getting this done was impossible. In spite of our best efforts, we failed to meet the deadline – it actually took us 3 days. Still, by March 12, we had opened the doors on the first community testing site in our area and gained the attention of local and national news outlets for our accomplishment.
Now more than 2 months later, I’m quite proud of what our team was able to achieve for the health system, but I’m still quite frustrated at the state of COVID-19 testing nationwide – there’s simply not enough available, and there is tremendous variability in the reliability of the tests. In this column, we’d like to highlight some of the challenges we’ve faced and reflect on how the shortcomings of modern technology have once again proven that medicine is both a science and an art.
Our dangerous lack of preparation
Prior to the coronavirus pandemic, I had never considered surgical masks, face shields, and nasal swabs to be critical components of medical technology. My opinion quickly changed after opening our drive-through COVID-19 site. I now have a much greater appreciation for the importance of personal protective equipment and basic testing supplies.
I was shocked by how difficult obtaining it has been during the past few months. It seems that no one anticipated the possibility of a pandemic on this grand a scale, so stockpiles of equipment were depleted quickly and couldn’t be replenished. Also, most manufacturing occurs outside the United States, which creates additional barriers to controlling the supply chain. One need not look far to find stories of widespread price-gouging, black market racketeering, and even hijackings that have stood in the way of accessing the necessary supplies. Sadly, the lack of equipment is far from the only challenge we’ve faced. In some cases, it has been a mistrust of results that has prevented widespread testing and mitigation.
The risks of flying blind
When President Trump touted the introduction of a rapid COVID-19 test at the end of March, many people were excited. Promising positive results in as few as 5 minutes, the assay was granted an Emergency Use Authorization (EUA) by the Food and Drug Administration in order to expedite its availability in the market. According to the FDA’s website, an EUA allows “unapproved medical products or unapproved uses of approved medical products to be used in an emergency to diagnose, treat, or prevent serious or life-threatening diseases or conditions.” This rapid (though untested) approval was all that many health care providers needed to hear – immediately hospitals and physicians scrambled to get their hands on the testing devices. Unfortunately, on May 14th, the FDA issued a press release that raised concerns about that same test because it seemed to be reporting a high number of false-negative results. Just as quickly as the devices had been adopted, health care providers began backing away from them in favor of other assays, and a serious truth about COVID-19 testing was revealed: In many ways, we’re flying blind.
Laboratory manufacturers have been working overtime to create assays for SARS-CoV-2 (the coronavirus that causes COVID-19) and have used different technologies for detection. The most commonly used are polymerase chain reaction (PCR) tests. In these assays, viral RNA is converted to DNA by reverse transcriptase, then amplified through the addition of primers that enable detection. PCR technology has been available for years and is a reliable method for identifying DNA and RNA, but the required heating and cooling process takes time and results can take several hours to return. To address this and expedite testing, other methods of detection have been tried, such as the loop-mediated isothermal amplification (LAMP) technique employed by the rapid assay mentioned above. Regardless of methodology, all laboratory tests have one thing in common: None of them is perfect.
Every assay has a different level of reliability. When screening for a disease such as COVID-19, we are particularly interested in a test’s sensitivity (that is, it’s ability to detect disease); we’d love such a screening test to be 100% sensitive and thereby not miss a single case. In truth, no test’s sensitivity is 100%, and in this particular case even the best assays only score around 98%. This means that out of every 100 patients with COVID-19 who are evaluated, two might test negative for the virus. In a pandemic this can have dire consequences, so health care providers – unable to fully trust their instruments – must employ clinical acumen and years of experience to navigate these cloudy skies. We are hopeful that additional tools will complement our current methods, but with new assays also come new questions.
Is anyone safe?
We receive regular questions from physicians about the value of antibody testing, but it’s not yet clear how best to respond. While the assays seem to be reliable, the utility of the results are still ill defined. Antibodies to SARS-CoV-2 (both IgG and IgM) appear to peak about 2-3 weeks after symptom onset, but we don’t yet know if the presence of those antibodies confers long-term immunity. Therefore, patients should not use the information to change their masking or social-distancing practices, nor should they presume that they are safe from becoming reinfected with COVID-19. While new research looks promising, there are still too many unknowns to be able to confidently reassure providers or patients of the true value of antibody testing. This underscores our final point: Medicine remains an art.
As we are regularly reminded, we’ll never fully anticipate the challenges or barriers to success, and technology will never replace the value of clinical judgment and human experience. While the situation is unsettling in many ways, we are reassured and encouraged by the role we still get to play in keeping our patients healthy in this health care crisis, and we’ll continue to do so through whatever the future holds.
Dr. Notte is a family physician and chief medical officer of Abington Lansdale (Pa.) Hospital - Jefferson Health. Follow him on Twitter (@doctornotte). Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Philadelphia, and associate director of the family medicine residency program at Abington (Pa.) Hospital–Jefferson Health. They have no conflicts related to the content of this piece.
Scientific doubt tempers COVID-19 vaccine optimism
US government and industry projections that a COVID-19 vaccine will be ready by this fall or even January would take compressing what usually takes at least a decade into months, with little room for error or safety surprises.
“If all the cards fall into the right place and all the stars are aligned, you definitely could get a vaccine by December or January,” Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, said last week.
But Fauci said a more realistic timeline is still 12 to 18 months, and experts interviewed by Medscape Medical News agree. They say that although recent developments are encouraging, history and scientific reason say the day when a COVID-19 vaccine is widely available will not come this year and may not come by the end of 2021.
The encouraging signals come primarily from two recent announcements: the $1.2 billion United States backing last week of one vaccine platform and the announcement on May 18 that the first human trials of another have produced some positive phase 1 results.
Recent developments
On May 21, the US Department of Health and Human Services (HHS) under “Operation Warp Speed” announced that the US will give AstraZeneca $1.2 billion “to make available at least 300 million doses of a coronavirus vaccine called AZD1222, with the first doses delivered as early as October 2020.”
On May 18, the Massachusetts-based biotechnology company Moderna announced that phase 1 clinical results showed that its vaccine candidate, which uses a new messenger RNA (mRNA) technology, appeared safe. Eight participants in the human trials were able to produce neutralizing antibodies that researchers believe are important in developing protection from the virus.
Moderna Chief Medical Officer Tal Zaks, MD, PhD told CNN that if the vaccine candidate does well in phase 2, “it could be ready by January 2021.”
The two candidates are among 10 in clinical trials for the SARS-CoV-2 virus, according to the World Health Organization (WHO). The AstraZeneca/ AZD1222 candidate (also called ChAdOx1 nCoV-19, in collaboration with the University of Oxford) has entered phase 2/3.
Moderna’s candidate and another being developed in Beijing, China, are in phase 2, WHO reports. As of yesterday, 115 other candidates are in preclinical evaluation.
Maria Elena Bottazzi, PhD, associate dean of the National School of Tropical Medicine at Baylor College of Medicine in Houston, Texas, told Medscape Medical News it’s important to realize that, in the case of the $1.2 billion US investment, “what they’re talking about is manufacturing.”
The idea, she said, is to pay AstraZeneca up front so that manufacturing can start before it is known whether the vaccine candidate is safe or effective, the reverse of how the clinical trial process usually works.
That way, if the candidate is deemed safe and effective, time is not lost by then deciding how to make it and distribute it.
By the end of this year, she said, “Maybe we will have many vaccines made and stored in a refrigerator somewhere. But between now and December, there’s absolutely no way you can show efficacy of the vaccine at the same time you confirm that it’s safe.”
“Take these things with a grain of salt”
Animal testing for the AstraZeneca candidate, made in partnership with the University of Oxford in the United Kingdom, has yielded lackluster results, according to results on the preprint server BioRxiv, which have not been peer-reviewed.
“The results were not bad, but they were not gangbusters,” Bottazzi said. The results show the vaccine offered only partial protection.
“Partial protection is better than no protection,” she noted. “You have to take these things with a grain of salt. We don’t know what’s going to happen in humans.”
As for the Moderna candidate, Bottazzi said, “the good news is they found an appropriate safety profile. But from an eight-person group to make the extrapolation that they have efficacy — it’s unrealistic.”
Nicole Lurie, MD, MSPH, is senior adviser to the CEO for the Coalition for Epidemic Preparedness Innovation (CEPI), a nongovernmental organization funded by the Wellcome Trust, the Bill and Melinda Gates Foundation, the European Commission, and eight countries (Australia, Belgium, Canada, Ethiopia, Germany, Japan, Norway, and the United Kingdom) charged with supporting development of vaccines for pathogens on WHO’s priority list.
She and her colleagues write in a paper published online in the New England Journal of Medicine on March 30 that “it typically takes multiple candidates and many years to produce a licensed vaccine.”
The fastest time for developing a vaccine to date is 4 years, for the mumps vaccine, licensed in 1967.
As to whether she would expect a rollout of any vaccine by the end of the year, Lurie told Medscape Medical News, “If everything goes according to plan in every way, shape or form, well then maybe you can get there. But I wouldn’t hold my breath.”
Lurie and her colleagues write that “it’s far from certain that these new platforms will be scalable or that existing capacity can provide sufficient quantities of vaccine fast enough.”
On a call with reporters today, leaders of some of the words largest pharmaceutical companies said that one of the key bottlenecks is the sheer number of vials needed in order to distribute billions of doses of a successful vaccine.
Pfizer CEO Albert Bourla, DVM, PhD, said, “Typically we are producing vaccines in single-dose vials. We are exploring with governments right now if it would be more convenient if there were 5-dose vials or 10-dose vials. I think we can resolve a significant part of the bottleneck.”
Despite the challenges, experts interviewed for this article agree that it will be possible to make a vaccine for COVID-19. They don’t expect attempts to meet the same complications that HIV researchers have seen over decades as the virus continues to confound with mutations.
Fred Ledley, MD, director of the Center for Integration of Science and Industry at Bentley University in Waltham, Massachusetts, told Medscape Medical News, “There doesn’t appear to be anything terribly diabolical about this virus. The mutation rate doesn’t appear to be anything like HIV. It appears to have some big, ugly proteins on the surface, which is good for vaccines — proteins with a lot of physical features look distinguishable from healthy cells. Signs all point to that it should be possible to make a vaccine.”
History raises safety concerns
However, Ledley said, “The idea of doing it in 6 months is largely unrealistic.”
He says 18 months is more realistic, primarily because of the sheer number of people that would have to be enrolled in a phase 3 study to truly test whether the endpoints are being met.
Vaccines are given to healthy volunteers. If safety signals arise, they may not be apparent until massive numbers of people are tested in phase 3.
“You’re never going to see the rates cut to 0%, but to see the difference between 10 people getting sick and seven people getting sick, takes very, very large numbers,” Ledley said. “There’s no way that can be done in 6 months. You’re talking about tens of thousands of people enrolled.”
He notes at this point it’s unclear what the endpoints will be and what the safety thresholds will be after consideration of risks and benefit.
Another big question for Ledley: “We don’t know what type of immunity we need to protect us against the virus. Do you just need the antibodies in your blood or do you need cells that are primed to attack the virus? Is it more of a chemical clearance or do the cells need to physically go in and digest the virus?”
History also points to the need for rigorous safety precautions that scientists fear could be compromised as trial phases overlap and processes are run in parallel instead of one step at a time.
An early batch of the Salk vaccine for polio in 1955, for example, turned out to be contaminated and caused paralysis in some children and 10 deaths, he points out.
CEPI’s Lurie adds that early candidates for another coronavirus, severe acute respiratory syndrome (SARS), “caused a reaction in the lungs that was very dangerous” before development was halted.
She also pointed to previous findings that a vaccine for dengue fever could worsen the disease in some people through a phenomenon called antibody-dependent enhancement.
Lurie and colleagues write in their paper that “it’s critical that vaccines also be developed using the tried-and-true methods, even if they may take longer to enter clinical trials or to result in large numbers of doses.”
Live attenuated vaccine
Raul Andino, PhD, a virologist at the University of California San Francisco, is among the scientists working with a tried-and-true method — a live attenuated vaccine — and he told Medscape Medical News he’s predicting it will take 2 years to develop.
He said it is cheaper to produce because scientists just have to learn how to grow the virus. Because the technology is already proven, a live attenuated vaccine could be rapidly produced on a worldwide scale.
The hope is also that a live attenuated vaccine would be given once in a lifetime and therefore be more affordable, especially in poorer countries.
“While a Moderna vaccine might be good for Europe and the United States,” he said, “It’s not going to be good for Africa, India, Brazil.”
Andino said, “I would bet money” that the front-runner vaccines so far will not be one-time vaccines.
He points out that most of the vaccine candidates are trying to protect people from disease. While there’s nothing wrong with that, he said, “In my opinion that is the lower-hanging fruit.”
“In my mind we need something that interrupts the chain of transmission and induces protection,” Andino said, important for developing herd immunity.
The reason this type of approach takes longer is because you are introducing a weakened form of the virus to the body and you have to make sure it doesn’t cause disease, not just in a small test population, but in populations who may be more susceptible to the disease, Andino said.
A call for unified strategies
Universities, countries, international consortiums, and public-private partnerships are all racing to find several safe and effective vaccines as no one entity will likely be able to provide the global solution.
Some of the efforts involve overlap of entities but with different focuses.
Along with “Operation Warp Speed” and CEPI, other collaborations include Gavi the Vaccine Alliance, whose core partners include WHO, UNICEF, the World Bank, and the Gates Foundation; and “Accelerating Therapeutic Interventions and Vaccines (ACTIV) partnership,” led by the National Institutes of Health.
Industry partners in ACTIV (18 biopharmaceutical companies), according to a May 18 article published online in the Journal of the American Medical Association, have said they will contribute their respective clinical trial capacities, regardless of which agent is studied.
Some, however, have called for more streamlining of efforts.
“Ideally we’d be working together,” Lurie told Medscape Medical News.
“I’m hopeful we will find ways to collaborate scientifically,” she said. “The US government’s responsibility is to make doses for the US. CEPI’s responsibility is to make doses for the world. A big focus of CEPI is to make sure we have manufacturing capacity outside of the US so those doses can be available to the world and they don’t get seized by wealthy countries.”
Bottazzi, Ledley, Lurie, and Andino report no relevant financial relationships.
This article first appeared on Medscape.com.
US government and industry projections that a COVID-19 vaccine will be ready by this fall or even January would take compressing what usually takes at least a decade into months, with little room for error or safety surprises.
“If all the cards fall into the right place and all the stars are aligned, you definitely could get a vaccine by December or January,” Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, said last week.
But Fauci said a more realistic timeline is still 12 to 18 months, and experts interviewed by Medscape Medical News agree. They say that although recent developments are encouraging, history and scientific reason say the day when a COVID-19 vaccine is widely available will not come this year and may not come by the end of 2021.
The encouraging signals come primarily from two recent announcements: the $1.2 billion United States backing last week of one vaccine platform and the announcement on May 18 that the first human trials of another have produced some positive phase 1 results.
Recent developments
On May 21, the US Department of Health and Human Services (HHS) under “Operation Warp Speed” announced that the US will give AstraZeneca $1.2 billion “to make available at least 300 million doses of a coronavirus vaccine called AZD1222, with the first doses delivered as early as October 2020.”
On May 18, the Massachusetts-based biotechnology company Moderna announced that phase 1 clinical results showed that its vaccine candidate, which uses a new messenger RNA (mRNA) technology, appeared safe. Eight participants in the human trials were able to produce neutralizing antibodies that researchers believe are important in developing protection from the virus.
Moderna Chief Medical Officer Tal Zaks, MD, PhD told CNN that if the vaccine candidate does well in phase 2, “it could be ready by January 2021.”
The two candidates are among 10 in clinical trials for the SARS-CoV-2 virus, according to the World Health Organization (WHO). The AstraZeneca/ AZD1222 candidate (also called ChAdOx1 nCoV-19, in collaboration with the University of Oxford) has entered phase 2/3.
Moderna’s candidate and another being developed in Beijing, China, are in phase 2, WHO reports. As of yesterday, 115 other candidates are in preclinical evaluation.
Maria Elena Bottazzi, PhD, associate dean of the National School of Tropical Medicine at Baylor College of Medicine in Houston, Texas, told Medscape Medical News it’s important to realize that, in the case of the $1.2 billion US investment, “what they’re talking about is manufacturing.”
The idea, she said, is to pay AstraZeneca up front so that manufacturing can start before it is known whether the vaccine candidate is safe or effective, the reverse of how the clinical trial process usually works.
That way, if the candidate is deemed safe and effective, time is not lost by then deciding how to make it and distribute it.
By the end of this year, she said, “Maybe we will have many vaccines made and stored in a refrigerator somewhere. But between now and December, there’s absolutely no way you can show efficacy of the vaccine at the same time you confirm that it’s safe.”
“Take these things with a grain of salt”
Animal testing for the AstraZeneca candidate, made in partnership with the University of Oxford in the United Kingdom, has yielded lackluster results, according to results on the preprint server BioRxiv, which have not been peer-reviewed.
“The results were not bad, but they were not gangbusters,” Bottazzi said. The results show the vaccine offered only partial protection.
“Partial protection is better than no protection,” she noted. “You have to take these things with a grain of salt. We don’t know what’s going to happen in humans.”
As for the Moderna candidate, Bottazzi said, “the good news is they found an appropriate safety profile. But from an eight-person group to make the extrapolation that they have efficacy — it’s unrealistic.”
Nicole Lurie, MD, MSPH, is senior adviser to the CEO for the Coalition for Epidemic Preparedness Innovation (CEPI), a nongovernmental organization funded by the Wellcome Trust, the Bill and Melinda Gates Foundation, the European Commission, and eight countries (Australia, Belgium, Canada, Ethiopia, Germany, Japan, Norway, and the United Kingdom) charged with supporting development of vaccines for pathogens on WHO’s priority list.
She and her colleagues write in a paper published online in the New England Journal of Medicine on March 30 that “it typically takes multiple candidates and many years to produce a licensed vaccine.”
The fastest time for developing a vaccine to date is 4 years, for the mumps vaccine, licensed in 1967.
As to whether she would expect a rollout of any vaccine by the end of the year, Lurie told Medscape Medical News, “If everything goes according to plan in every way, shape or form, well then maybe you can get there. But I wouldn’t hold my breath.”
Lurie and her colleagues write that “it’s far from certain that these new platforms will be scalable or that existing capacity can provide sufficient quantities of vaccine fast enough.”
On a call with reporters today, leaders of some of the words largest pharmaceutical companies said that one of the key bottlenecks is the sheer number of vials needed in order to distribute billions of doses of a successful vaccine.
Pfizer CEO Albert Bourla, DVM, PhD, said, “Typically we are producing vaccines in single-dose vials. We are exploring with governments right now if it would be more convenient if there were 5-dose vials or 10-dose vials. I think we can resolve a significant part of the bottleneck.”
Despite the challenges, experts interviewed for this article agree that it will be possible to make a vaccine for COVID-19. They don’t expect attempts to meet the same complications that HIV researchers have seen over decades as the virus continues to confound with mutations.
Fred Ledley, MD, director of the Center for Integration of Science and Industry at Bentley University in Waltham, Massachusetts, told Medscape Medical News, “There doesn’t appear to be anything terribly diabolical about this virus. The mutation rate doesn’t appear to be anything like HIV. It appears to have some big, ugly proteins on the surface, which is good for vaccines — proteins with a lot of physical features look distinguishable from healthy cells. Signs all point to that it should be possible to make a vaccine.”
History raises safety concerns
However, Ledley said, “The idea of doing it in 6 months is largely unrealistic.”
He says 18 months is more realistic, primarily because of the sheer number of people that would have to be enrolled in a phase 3 study to truly test whether the endpoints are being met.
Vaccines are given to healthy volunteers. If safety signals arise, they may not be apparent until massive numbers of people are tested in phase 3.
“You’re never going to see the rates cut to 0%, but to see the difference between 10 people getting sick and seven people getting sick, takes very, very large numbers,” Ledley said. “There’s no way that can be done in 6 months. You’re talking about tens of thousands of people enrolled.”
He notes at this point it’s unclear what the endpoints will be and what the safety thresholds will be after consideration of risks and benefit.
Another big question for Ledley: “We don’t know what type of immunity we need to protect us against the virus. Do you just need the antibodies in your blood or do you need cells that are primed to attack the virus? Is it more of a chemical clearance or do the cells need to physically go in and digest the virus?”
History also points to the need for rigorous safety precautions that scientists fear could be compromised as trial phases overlap and processes are run in parallel instead of one step at a time.
An early batch of the Salk vaccine for polio in 1955, for example, turned out to be contaminated and caused paralysis in some children and 10 deaths, he points out.
CEPI’s Lurie adds that early candidates for another coronavirus, severe acute respiratory syndrome (SARS), “caused a reaction in the lungs that was very dangerous” before development was halted.
She also pointed to previous findings that a vaccine for dengue fever could worsen the disease in some people through a phenomenon called antibody-dependent enhancement.
Lurie and colleagues write in their paper that “it’s critical that vaccines also be developed using the tried-and-true methods, even if they may take longer to enter clinical trials or to result in large numbers of doses.”
Live attenuated vaccine
Raul Andino, PhD, a virologist at the University of California San Francisco, is among the scientists working with a tried-and-true method — a live attenuated vaccine — and he told Medscape Medical News he’s predicting it will take 2 years to develop.
He said it is cheaper to produce because scientists just have to learn how to grow the virus. Because the technology is already proven, a live attenuated vaccine could be rapidly produced on a worldwide scale.
The hope is also that a live attenuated vaccine would be given once in a lifetime and therefore be more affordable, especially in poorer countries.
“While a Moderna vaccine might be good for Europe and the United States,” he said, “It’s not going to be good for Africa, India, Brazil.”
Andino said, “I would bet money” that the front-runner vaccines so far will not be one-time vaccines.
He points out that most of the vaccine candidates are trying to protect people from disease. While there’s nothing wrong with that, he said, “In my opinion that is the lower-hanging fruit.”
“In my mind we need something that interrupts the chain of transmission and induces protection,” Andino said, important for developing herd immunity.
The reason this type of approach takes longer is because you are introducing a weakened form of the virus to the body and you have to make sure it doesn’t cause disease, not just in a small test population, but in populations who may be more susceptible to the disease, Andino said.
A call for unified strategies
Universities, countries, international consortiums, and public-private partnerships are all racing to find several safe and effective vaccines as no one entity will likely be able to provide the global solution.
Some of the efforts involve overlap of entities but with different focuses.
Along with “Operation Warp Speed” and CEPI, other collaborations include Gavi the Vaccine Alliance, whose core partners include WHO, UNICEF, the World Bank, and the Gates Foundation; and “Accelerating Therapeutic Interventions and Vaccines (ACTIV) partnership,” led by the National Institutes of Health.
Industry partners in ACTIV (18 biopharmaceutical companies), according to a May 18 article published online in the Journal of the American Medical Association, have said they will contribute their respective clinical trial capacities, regardless of which agent is studied.
Some, however, have called for more streamlining of efforts.
“Ideally we’d be working together,” Lurie told Medscape Medical News.
“I’m hopeful we will find ways to collaborate scientifically,” she said. “The US government’s responsibility is to make doses for the US. CEPI’s responsibility is to make doses for the world. A big focus of CEPI is to make sure we have manufacturing capacity outside of the US so those doses can be available to the world and they don’t get seized by wealthy countries.”
Bottazzi, Ledley, Lurie, and Andino report no relevant financial relationships.
This article first appeared on Medscape.com.
US government and industry projections that a COVID-19 vaccine will be ready by this fall or even January would take compressing what usually takes at least a decade into months, with little room for error or safety surprises.
“If all the cards fall into the right place and all the stars are aligned, you definitely could get a vaccine by December or January,” Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, said last week.
But Fauci said a more realistic timeline is still 12 to 18 months, and experts interviewed by Medscape Medical News agree. They say that although recent developments are encouraging, history and scientific reason say the day when a COVID-19 vaccine is widely available will not come this year and may not come by the end of 2021.
The encouraging signals come primarily from two recent announcements: the $1.2 billion United States backing last week of one vaccine platform and the announcement on May 18 that the first human trials of another have produced some positive phase 1 results.
Recent developments
On May 21, the US Department of Health and Human Services (HHS) under “Operation Warp Speed” announced that the US will give AstraZeneca $1.2 billion “to make available at least 300 million doses of a coronavirus vaccine called AZD1222, with the first doses delivered as early as October 2020.”
On May 18, the Massachusetts-based biotechnology company Moderna announced that phase 1 clinical results showed that its vaccine candidate, which uses a new messenger RNA (mRNA) technology, appeared safe. Eight participants in the human trials were able to produce neutralizing antibodies that researchers believe are important in developing protection from the virus.
Moderna Chief Medical Officer Tal Zaks, MD, PhD told CNN that if the vaccine candidate does well in phase 2, “it could be ready by January 2021.”
The two candidates are among 10 in clinical trials for the SARS-CoV-2 virus, according to the World Health Organization (WHO). The AstraZeneca/ AZD1222 candidate (also called ChAdOx1 nCoV-19, in collaboration with the University of Oxford) has entered phase 2/3.
Moderna’s candidate and another being developed in Beijing, China, are in phase 2, WHO reports. As of yesterday, 115 other candidates are in preclinical evaluation.
Maria Elena Bottazzi, PhD, associate dean of the National School of Tropical Medicine at Baylor College of Medicine in Houston, Texas, told Medscape Medical News it’s important to realize that, in the case of the $1.2 billion US investment, “what they’re talking about is manufacturing.”
The idea, she said, is to pay AstraZeneca up front so that manufacturing can start before it is known whether the vaccine candidate is safe or effective, the reverse of how the clinical trial process usually works.
That way, if the candidate is deemed safe and effective, time is not lost by then deciding how to make it and distribute it.
By the end of this year, she said, “Maybe we will have many vaccines made and stored in a refrigerator somewhere. But between now and December, there’s absolutely no way you can show efficacy of the vaccine at the same time you confirm that it’s safe.”
“Take these things with a grain of salt”
Animal testing for the AstraZeneca candidate, made in partnership with the University of Oxford in the United Kingdom, has yielded lackluster results, according to results on the preprint server BioRxiv, which have not been peer-reviewed.
“The results were not bad, but they were not gangbusters,” Bottazzi said. The results show the vaccine offered only partial protection.
“Partial protection is better than no protection,” she noted. “You have to take these things with a grain of salt. We don’t know what’s going to happen in humans.”
As for the Moderna candidate, Bottazzi said, “the good news is they found an appropriate safety profile. But from an eight-person group to make the extrapolation that they have efficacy — it’s unrealistic.”
Nicole Lurie, MD, MSPH, is senior adviser to the CEO for the Coalition for Epidemic Preparedness Innovation (CEPI), a nongovernmental organization funded by the Wellcome Trust, the Bill and Melinda Gates Foundation, the European Commission, and eight countries (Australia, Belgium, Canada, Ethiopia, Germany, Japan, Norway, and the United Kingdom) charged with supporting development of vaccines for pathogens on WHO’s priority list.
She and her colleagues write in a paper published online in the New England Journal of Medicine on March 30 that “it typically takes multiple candidates and many years to produce a licensed vaccine.”
The fastest time for developing a vaccine to date is 4 years, for the mumps vaccine, licensed in 1967.
As to whether she would expect a rollout of any vaccine by the end of the year, Lurie told Medscape Medical News, “If everything goes according to plan in every way, shape or form, well then maybe you can get there. But I wouldn’t hold my breath.”
Lurie and her colleagues write that “it’s far from certain that these new platforms will be scalable or that existing capacity can provide sufficient quantities of vaccine fast enough.”
On a call with reporters today, leaders of some of the words largest pharmaceutical companies said that one of the key bottlenecks is the sheer number of vials needed in order to distribute billions of doses of a successful vaccine.
Pfizer CEO Albert Bourla, DVM, PhD, said, “Typically we are producing vaccines in single-dose vials. We are exploring with governments right now if it would be more convenient if there were 5-dose vials or 10-dose vials. I think we can resolve a significant part of the bottleneck.”
Despite the challenges, experts interviewed for this article agree that it will be possible to make a vaccine for COVID-19. They don’t expect attempts to meet the same complications that HIV researchers have seen over decades as the virus continues to confound with mutations.
Fred Ledley, MD, director of the Center for Integration of Science and Industry at Bentley University in Waltham, Massachusetts, told Medscape Medical News, “There doesn’t appear to be anything terribly diabolical about this virus. The mutation rate doesn’t appear to be anything like HIV. It appears to have some big, ugly proteins on the surface, which is good for vaccines — proteins with a lot of physical features look distinguishable from healthy cells. Signs all point to that it should be possible to make a vaccine.”
History raises safety concerns
However, Ledley said, “The idea of doing it in 6 months is largely unrealistic.”
He says 18 months is more realistic, primarily because of the sheer number of people that would have to be enrolled in a phase 3 study to truly test whether the endpoints are being met.
Vaccines are given to healthy volunteers. If safety signals arise, they may not be apparent until massive numbers of people are tested in phase 3.
“You’re never going to see the rates cut to 0%, but to see the difference between 10 people getting sick and seven people getting sick, takes very, very large numbers,” Ledley said. “There’s no way that can be done in 6 months. You’re talking about tens of thousands of people enrolled.”
He notes at this point it’s unclear what the endpoints will be and what the safety thresholds will be after consideration of risks and benefit.
Another big question for Ledley: “We don’t know what type of immunity we need to protect us against the virus. Do you just need the antibodies in your blood or do you need cells that are primed to attack the virus? Is it more of a chemical clearance or do the cells need to physically go in and digest the virus?”
History also points to the need for rigorous safety precautions that scientists fear could be compromised as trial phases overlap and processes are run in parallel instead of one step at a time.
An early batch of the Salk vaccine for polio in 1955, for example, turned out to be contaminated and caused paralysis in some children and 10 deaths, he points out.
CEPI’s Lurie adds that early candidates for another coronavirus, severe acute respiratory syndrome (SARS), “caused a reaction in the lungs that was very dangerous” before development was halted.
She also pointed to previous findings that a vaccine for dengue fever could worsen the disease in some people through a phenomenon called antibody-dependent enhancement.
Lurie and colleagues write in their paper that “it’s critical that vaccines also be developed using the tried-and-true methods, even if they may take longer to enter clinical trials or to result in large numbers of doses.”
Live attenuated vaccine
Raul Andino, PhD, a virologist at the University of California San Francisco, is among the scientists working with a tried-and-true method — a live attenuated vaccine — and he told Medscape Medical News he’s predicting it will take 2 years to develop.
He said it is cheaper to produce because scientists just have to learn how to grow the virus. Because the technology is already proven, a live attenuated vaccine could be rapidly produced on a worldwide scale.
The hope is also that a live attenuated vaccine would be given once in a lifetime and therefore be more affordable, especially in poorer countries.
“While a Moderna vaccine might be good for Europe and the United States,” he said, “It’s not going to be good for Africa, India, Brazil.”
Andino said, “I would bet money” that the front-runner vaccines so far will not be one-time vaccines.
He points out that most of the vaccine candidates are trying to protect people from disease. While there’s nothing wrong with that, he said, “In my opinion that is the lower-hanging fruit.”
“In my mind we need something that interrupts the chain of transmission and induces protection,” Andino said, important for developing herd immunity.
The reason this type of approach takes longer is because you are introducing a weakened form of the virus to the body and you have to make sure it doesn’t cause disease, not just in a small test population, but in populations who may be more susceptible to the disease, Andino said.
A call for unified strategies
Universities, countries, international consortiums, and public-private partnerships are all racing to find several safe and effective vaccines as no one entity will likely be able to provide the global solution.
Some of the efforts involve overlap of entities but with different focuses.
Along with “Operation Warp Speed” and CEPI, other collaborations include Gavi the Vaccine Alliance, whose core partners include WHO, UNICEF, the World Bank, and the Gates Foundation; and “Accelerating Therapeutic Interventions and Vaccines (ACTIV) partnership,” led by the National Institutes of Health.
Industry partners in ACTIV (18 biopharmaceutical companies), according to a May 18 article published online in the Journal of the American Medical Association, have said they will contribute their respective clinical trial capacities, regardless of which agent is studied.
Some, however, have called for more streamlining of efforts.
“Ideally we’d be working together,” Lurie told Medscape Medical News.
“I’m hopeful we will find ways to collaborate scientifically,” she said. “The US government’s responsibility is to make doses for the US. CEPI’s responsibility is to make doses for the world. A big focus of CEPI is to make sure we have manufacturing capacity outside of the US so those doses can be available to the world and they don’t get seized by wealthy countries.”
Bottazzi, Ledley, Lurie, and Andino report no relevant financial relationships.
This article first appeared on Medscape.com.
New York City inpatient detox unit keeps running: Here’s how
Substance use disorder and its daily consequences take no breaks even during a pandemic. The stressors created by COVID-19, including deaths of loved ones and the disruptions to normal life from policies aimed at flattening the curve, seem to have increased substance use.
I practice as a hospitalist with an internal medicine background and specialty in addiction medicine at BronxCare Health System’s inpatient detoxification unit, a 24/7, 20-bed medically-supervised unit in South Bronx in New York City. It is one of the comprehensive services provided by the BronxCare’s life recovery center and addiction services, which also includes an outpatient clinic, opioid treatment program, inpatient rehab, and a half-way house. Inpatient detoxification units like ours are designed to treat serious addictions and chemical dependency and prevent and treat life-threatening withdrawal symptoms and signs or complications. Our patients come from all over the city and its adjoining suburbs, including from emergency room referrals, referral clinics, courts and the justice system, walk-ins, and self-referrals.
At a time when many inpatient detoxification units within the city were temporarily closed due to fear of inpatient spread of the virus or to provide extra COVID beds in anticipation for the peak surge, we have been able to provide a needed service. In fact, several other inpatient detoxification programs within the city have been able to refer their patients to our facility.
Individuals with substance use disorder have historically been a vulnerable and underserved population and possess high risk for multiple health problems as well as preexisting conditions. Many have limited life options financially, educationally, and with housing, and encounter barriers to accessing primary health care services, including preventive services. The introduction of the COVID-19 pandemic into these patients’ precarious health situations only made things worse as many of the limited resources for patients with substance use disorder were diverted to battling the pandemic. Numerous inpatient and outpatient addiction services, for example, were temporarily shut down. This has led to an increase in domestic violence, and psychiatric decompensation, including psychosis, suicidal attempts, and worsening of medical comorbidities in these patients.
Our wake-up call came when the first case of COVID-19 was confirmed in New York in early March. Within a short period of time the state became the epicenter for COVID-19. With the projection of millions of cases being positive and the number of new cases doubling every third day at the onset in New York City, we knew we had a battle brewing and needed to radically transform our mode of operation fast.
Our first task was to ensure the safety of our patients and the dedicated health workers attending to them. We streamlined the patient point of entry through one screening site, while also brushing up on our history-taking to intently screen for COVID-19. This included not just focusing on travels from China, but from Europe and other parts of the world.
Yes, we did ask patients about cough, fever, shortness of breath or difficulty breathing, feeling fatigued, severe body ache, and possible contact with someone who is sick or has traveled overseas. But we were also attuned to the increased rate of community spread and the presentation of other symptoms, such as loss of taste and smell, early in the process. Hence we were able to triage patients with suspected cases to the appropriate sections of the hospital for further screening, testing, and evaluation, instead of having those patients admitted to the detox unit.
Early in the process a huddle team was instituted with daily briefing of staff lasting 30 minutes or less. This team consists of physicians, nurses, a physician assistant, a social worker, and a counselor. In addition to discussing treatment plans for the patient, they deliberate on the public health information from the hospital’s COVID-19 command center, New York State Department of Health, the Office of Mental Health, and the Centers for Disease Control and Prevention concerning the latest evidence-based information. These discussions have helped us modify our policies and practices.
We instituted a no visiting rule during a short hospital stay of 5-7 days, and this was initiated weeks in advance of many institutions, including nursing homes with vulnerable populations. Our admitting criteria was reviewed to allow for admission of only those patients who absolutely needed inpatient substance use disorder treatment, including patients with severe withdrawal symptoms and signs, comorbidities, or neuropsychiatric manifestations that made them unsafe for outpatient or home detoxification. Others were triaged to the outpatient services which was amply supported with telemedicine. Rooms and designated areas of the building were earmarked as places for isolation/quarantine if suspected COVID-19 cases were identified pending testing. To assess patients’ risk of COVID-19, we do point-of-care nasopharyngeal swab testing with polymerase chain reaction.
Regarding face masks, patients and staff were fitted with ones early in the process. Additionally, staff were trained on the importance of face mask use and how to ensure you have a tight seal around the mouth and nose and were provided with other appropriate personal protective equipment. Concerning social distancing, we reduced the patient population capacity for the unit down to 50% and offered only single room admissions. Social distancing was encouraged in the unit, including in the television and recreation room and dining room, and during small treatment groups of less than six individuals. Daily temperature checks with noncontact handheld thermometers were enforced for staff and anyone coming into the life recovery center.
Patients are continuously being educated on the presentations of COVID-19 and encouraged to report any symptoms. Any staff feeling sick or having symptoms are encouraged to stay home. Rigorous and continuous cleaning of surfaces, especially of areas subjected to common use, is done frequently by the hospital housekeeping and environmental crew and is the order of the day.
Dr. Fagbemi is a hospitalist at BronxCare Health System, a not-for-profit health and teaching hospital system serving South and Central Bronx in New York. He has no conflicts of interest to disclose.
Substance use disorder and its daily consequences take no breaks even during a pandemic. The stressors created by COVID-19, including deaths of loved ones and the disruptions to normal life from policies aimed at flattening the curve, seem to have increased substance use.
I practice as a hospitalist with an internal medicine background and specialty in addiction medicine at BronxCare Health System’s inpatient detoxification unit, a 24/7, 20-bed medically-supervised unit in South Bronx in New York City. It is one of the comprehensive services provided by the BronxCare’s life recovery center and addiction services, which also includes an outpatient clinic, opioid treatment program, inpatient rehab, and a half-way house. Inpatient detoxification units like ours are designed to treat serious addictions and chemical dependency and prevent and treat life-threatening withdrawal symptoms and signs or complications. Our patients come from all over the city and its adjoining suburbs, including from emergency room referrals, referral clinics, courts and the justice system, walk-ins, and self-referrals.
At a time when many inpatient detoxification units within the city were temporarily closed due to fear of inpatient spread of the virus or to provide extra COVID beds in anticipation for the peak surge, we have been able to provide a needed service. In fact, several other inpatient detoxification programs within the city have been able to refer their patients to our facility.
Individuals with substance use disorder have historically been a vulnerable and underserved population and possess high risk for multiple health problems as well as preexisting conditions. Many have limited life options financially, educationally, and with housing, and encounter barriers to accessing primary health care services, including preventive services. The introduction of the COVID-19 pandemic into these patients’ precarious health situations only made things worse as many of the limited resources for patients with substance use disorder were diverted to battling the pandemic. Numerous inpatient and outpatient addiction services, for example, were temporarily shut down. This has led to an increase in domestic violence, and psychiatric decompensation, including psychosis, suicidal attempts, and worsening of medical comorbidities in these patients.
Our wake-up call came when the first case of COVID-19 was confirmed in New York in early March. Within a short period of time the state became the epicenter for COVID-19. With the projection of millions of cases being positive and the number of new cases doubling every third day at the onset in New York City, we knew we had a battle brewing and needed to radically transform our mode of operation fast.
Our first task was to ensure the safety of our patients and the dedicated health workers attending to them. We streamlined the patient point of entry through one screening site, while also brushing up on our history-taking to intently screen for COVID-19. This included not just focusing on travels from China, but from Europe and other parts of the world.
Yes, we did ask patients about cough, fever, shortness of breath or difficulty breathing, feeling fatigued, severe body ache, and possible contact with someone who is sick or has traveled overseas. But we were also attuned to the increased rate of community spread and the presentation of other symptoms, such as loss of taste and smell, early in the process. Hence we were able to triage patients with suspected cases to the appropriate sections of the hospital for further screening, testing, and evaluation, instead of having those patients admitted to the detox unit.
Early in the process a huddle team was instituted with daily briefing of staff lasting 30 minutes or less. This team consists of physicians, nurses, a physician assistant, a social worker, and a counselor. In addition to discussing treatment plans for the patient, they deliberate on the public health information from the hospital’s COVID-19 command center, New York State Department of Health, the Office of Mental Health, and the Centers for Disease Control and Prevention concerning the latest evidence-based information. These discussions have helped us modify our policies and practices.
We instituted a no visiting rule during a short hospital stay of 5-7 days, and this was initiated weeks in advance of many institutions, including nursing homes with vulnerable populations. Our admitting criteria was reviewed to allow for admission of only those patients who absolutely needed inpatient substance use disorder treatment, including patients with severe withdrawal symptoms and signs, comorbidities, or neuropsychiatric manifestations that made them unsafe for outpatient or home detoxification. Others were triaged to the outpatient services which was amply supported with telemedicine. Rooms and designated areas of the building were earmarked as places for isolation/quarantine if suspected COVID-19 cases were identified pending testing. To assess patients’ risk of COVID-19, we do point-of-care nasopharyngeal swab testing with polymerase chain reaction.
Regarding face masks, patients and staff were fitted with ones early in the process. Additionally, staff were trained on the importance of face mask use and how to ensure you have a tight seal around the mouth and nose and were provided with other appropriate personal protective equipment. Concerning social distancing, we reduced the patient population capacity for the unit down to 50% and offered only single room admissions. Social distancing was encouraged in the unit, including in the television and recreation room and dining room, and during small treatment groups of less than six individuals. Daily temperature checks with noncontact handheld thermometers were enforced for staff and anyone coming into the life recovery center.
Patients are continuously being educated on the presentations of COVID-19 and encouraged to report any symptoms. Any staff feeling sick or having symptoms are encouraged to stay home. Rigorous and continuous cleaning of surfaces, especially of areas subjected to common use, is done frequently by the hospital housekeeping and environmental crew and is the order of the day.
Dr. Fagbemi is a hospitalist at BronxCare Health System, a not-for-profit health and teaching hospital system serving South and Central Bronx in New York. He has no conflicts of interest to disclose.
Substance use disorder and its daily consequences take no breaks even during a pandemic. The stressors created by COVID-19, including deaths of loved ones and the disruptions to normal life from policies aimed at flattening the curve, seem to have increased substance use.
I practice as a hospitalist with an internal medicine background and specialty in addiction medicine at BronxCare Health System’s inpatient detoxification unit, a 24/7, 20-bed medically-supervised unit in South Bronx in New York City. It is one of the comprehensive services provided by the BronxCare’s life recovery center and addiction services, which also includes an outpatient clinic, opioid treatment program, inpatient rehab, and a half-way house. Inpatient detoxification units like ours are designed to treat serious addictions and chemical dependency and prevent and treat life-threatening withdrawal symptoms and signs or complications. Our patients come from all over the city and its adjoining suburbs, including from emergency room referrals, referral clinics, courts and the justice system, walk-ins, and self-referrals.
At a time when many inpatient detoxification units within the city were temporarily closed due to fear of inpatient spread of the virus or to provide extra COVID beds in anticipation for the peak surge, we have been able to provide a needed service. In fact, several other inpatient detoxification programs within the city have been able to refer their patients to our facility.
Individuals with substance use disorder have historically been a vulnerable and underserved population and possess high risk for multiple health problems as well as preexisting conditions. Many have limited life options financially, educationally, and with housing, and encounter barriers to accessing primary health care services, including preventive services. The introduction of the COVID-19 pandemic into these patients’ precarious health situations only made things worse as many of the limited resources for patients with substance use disorder were diverted to battling the pandemic. Numerous inpatient and outpatient addiction services, for example, were temporarily shut down. This has led to an increase in domestic violence, and psychiatric decompensation, including psychosis, suicidal attempts, and worsening of medical comorbidities in these patients.
Our wake-up call came when the first case of COVID-19 was confirmed in New York in early March. Within a short period of time the state became the epicenter for COVID-19. With the projection of millions of cases being positive and the number of new cases doubling every third day at the onset in New York City, we knew we had a battle brewing and needed to radically transform our mode of operation fast.
Our first task was to ensure the safety of our patients and the dedicated health workers attending to them. We streamlined the patient point of entry through one screening site, while also brushing up on our history-taking to intently screen for COVID-19. This included not just focusing on travels from China, but from Europe and other parts of the world.
Yes, we did ask patients about cough, fever, shortness of breath or difficulty breathing, feeling fatigued, severe body ache, and possible contact with someone who is sick or has traveled overseas. But we were also attuned to the increased rate of community spread and the presentation of other symptoms, such as loss of taste and smell, early in the process. Hence we were able to triage patients with suspected cases to the appropriate sections of the hospital for further screening, testing, and evaluation, instead of having those patients admitted to the detox unit.
Early in the process a huddle team was instituted with daily briefing of staff lasting 30 minutes or less. This team consists of physicians, nurses, a physician assistant, a social worker, and a counselor. In addition to discussing treatment plans for the patient, they deliberate on the public health information from the hospital’s COVID-19 command center, New York State Department of Health, the Office of Mental Health, and the Centers for Disease Control and Prevention concerning the latest evidence-based information. These discussions have helped us modify our policies and practices.
We instituted a no visiting rule during a short hospital stay of 5-7 days, and this was initiated weeks in advance of many institutions, including nursing homes with vulnerable populations. Our admitting criteria was reviewed to allow for admission of only those patients who absolutely needed inpatient substance use disorder treatment, including patients with severe withdrawal symptoms and signs, comorbidities, or neuropsychiatric manifestations that made them unsafe for outpatient or home detoxification. Others were triaged to the outpatient services which was amply supported with telemedicine. Rooms and designated areas of the building were earmarked as places for isolation/quarantine if suspected COVID-19 cases were identified pending testing. To assess patients’ risk of COVID-19, we do point-of-care nasopharyngeal swab testing with polymerase chain reaction.
Regarding face masks, patients and staff were fitted with ones early in the process. Additionally, staff were trained on the importance of face mask use and how to ensure you have a tight seal around the mouth and nose and were provided with other appropriate personal protective equipment. Concerning social distancing, we reduced the patient population capacity for the unit down to 50% and offered only single room admissions. Social distancing was encouraged in the unit, including in the television and recreation room and dining room, and during small treatment groups of less than six individuals. Daily temperature checks with noncontact handheld thermometers were enforced for staff and anyone coming into the life recovery center.
Patients are continuously being educated on the presentations of COVID-19 and encouraged to report any symptoms. Any staff feeling sick or having symptoms are encouraged to stay home. Rigorous and continuous cleaning of surfaces, especially of areas subjected to common use, is done frequently by the hospital housekeeping and environmental crew and is the order of the day.
Dr. Fagbemi is a hospitalist at BronxCare Health System, a not-for-profit health and teaching hospital system serving South and Central Bronx in New York. He has no conflicts of interest to disclose.
A long road to recovery: Lung rehab needed after COVID-19
If one word describes Eladio (“Lad”) Braganza, age 77, it’s “tenacious.” For 28 days, he clung to life on a ventilator in a Seattle ICU. Now – after a 46-day hospitalization for SARS-CoV-2 infection – he’s making progress in inpatient rehab, determined to regain function.
“We were not sure if he was going to make it through his first night in the hospital, and for a while after that. We were really prepared that he would not survive his ventilator time,” his daughter, Maria Braganza, said in an interview just 5 days after her father had been transferred to inpatient rehab.
In many ways, Mr. Braganza’s experience is typical of seriously ill COVID-19 patients. Many go from walking and talking to being on a ventilator within 10 hours or less. Mr. Braganza was admitted to the hospital on March 21 and was intubated that day. To keep him on the ventilator, he was heavily sedated and unconscious at times. In the ICU, he experienced bouts of low blood pressure, a pattern of shock that occurs in COVID-19 patients and that does not always respond to fluids.
Doctors have quickly learned to treat these patients aggressively. Many patients in the ICU with COVID-19 develop an inflamed, atypical form of acute respiratory distress syndrome (ARDS), in which the lung’s compliance, or stiffness, does not match the severity of hypoxia. These patients require high levels of oxygen and high ventilator settings. Many develop pneumothorax, or collapsed lungs, because of the high pressures needed to deliver oxygen and the prolonged time on ventilation.
“The vast majority of COVID patients in the ICU have lung disease that is quite severe, much more severe than I have seen in my 20 years of doing this,” said critical care specialist Anna Nolan, MD, of the department of medicine at New York University.
After about 2 weeks, some of these patients can come off the ventilator, or they may undergo a tracheostomy, a hole in the neck through which a tube is placed to deliver oxygen. By this time, many have developed ICU-acquired weakness and muscle wasting. Some may be so debilitated that they cannot walk. Even the respiratory muscles that help them breathe may have weakened as a result of the ventilator doing the work for them.
These patients “get sick very fast, and it takes a long time for them to heal. What’s not really well appreciated is how much rehab and how much recovery time these patients are going to need,” said David Chong, MD. He is medical director of the ICU at New York–Presbyterian Hospital/Columbia University Medical Center, and he has been on the front lines during the COVID-19 surge in New York City.
The road to recovery
Regardless of the cause, many people who have a prolonged stint in the ICU face an even longer convalescence. Still-unanswered questions concern whether recovery time will be longer for those with COVID-19, compared with other illnesses, and whether some of the damage may be permanent. A number of small studies in Hong Kong and China, as well as studies of severe acute respiratory syndrome patients’ recoveries, have promoted speculation about possible long-lasting damage to lungs and other organs from COVID-19.
Yet some of these reports have left out important details about ARDS in COVID-19 patients who also may be most at risk for long-lasting damage. To clear up some of the confusion, the Pulmonary Fibrosis Foundation said on April 6 that some but not all of COVID-19 patients who develop ARDS may go on to develop lung fibrosis – scarring of the lungs – which may be permanent.
“Post-ARDS fibrosis typically is not progressive, but nonetheless can be severe and limiting. The recovery period for post-ARDS fibrosis is approximately 1 year and the residual deficits persist, but generally do not progress,” the foundation noted.
Emerging research on lung damage in COVID-19
Because the pandemic is only a few months in, it’s unclear as yet what the long-term consequences of severe COVID-19 may be. But emerging data are enabling researchers to venture an educated guess about what may happen in the months and years ahead.
The key to understanding the data is knowing that ARDS is a syndrome – the end product of a variety of diseases or insults to the lung. Under the microscope, lung damage from ARDS associated with COVID-19 is indistinguishable from lung damage resulting from other causes, such as vaping, sepsis, or shock caused by a motor vehicle accident, said Sanjay Mukhopadhyay, MD, director of pulmonary pathology at Cleveland Clinic.
Dr. Mukhopadhyay, who specializes in lung pathology, performed one of the first complete autopsies of a COVID-19 patient in the United States. In most autopsy series published to date, he said, the most common lung finding in patients who have died from COVID-19 is diffuse alveolar damage (DAD), a pattern of lung injury seen in ARDS from many other causes.
In DAD, the walls of the alveoli – thinly lined air sacs that facilitate gas exchange in the lung – develop a pink, hyaline membrane composed of damaged cells and plasma proteins that leak from capillaries in the wall of the alveolus. This hyaline membrane gets plastered against the wall of the alveolus and interferes with diffusion of oxygen into the body.
“We know what happens in ARDS from other causes. If you follow people who have been on a ventilator long term, some of their respiratory function goes back to normal,” Dr. Mukhopadhyay said. “But there are other people in whom some degree of respiratory impairment lingers. In these patients, we think the DAD progresses to an organizing stage.”
Organizing pneumonia refers to a family of diseases in which fibroblasts (cells involved in wound healing) arrive and form scar tissue that forms hyaline membranes and fibrin balls (tough proteins) that fill up the alveoli, making gas exchange very difficult.
Also called BOOP (bronchiolitis obliterans organizing pneumonia), this condition is sensitive to steroids. Early aggressive steroid treatment can prevent long-term lung damage. Without steroids, damage can become permanent. A variant of this condition is termed acute fibrinous and organizing pneumonia (AFOP), which is also sensitive to steroids. A report from France demonstrates AFOP in some patients who have died from COVID-19.
The trick is identifying who is developing BOOP and who is not, and beyond that, who might be most amenable to treatment. Use of steroids for patients with certain other problems, such as a bacterial infection on top of COVID-19, could be harmful. David H. Chong, MD, and colleagues at Columbia University Irving Medical Center, New York, are investigating this to determine which COVID-19 patients may benefit from early steroid therapy.
“It’s not clear if there is a predominant histologic type or if we are catching people at different phases of their disease, and therefore we’re seeing different lung pathology,” Dr. Chong said.
He thinks that many patients with severe COVID-19 probably will not develop this pattern of lung scarring. “We’re speculating that lung damage from severe COVID-19 is probably going to behave more like lung damage from regular ARDS, which is often reversible. We think the vast majority of these patients probably have DAD that is similar to most patients with ARDS from other etiologies,” Dr. Chong said.
That would be consistent with information from China. In an April interview with Chinese domestic media, Zhong Nanshan, MD, a pulmonologist at the head of China’s COVID-19 task force, stated that he expects that the lungs in most patients with COVID-19 will gradually recover. He was responding to a widely publicized small study that found evidence of residual lung abnormalities at hospital discharge in most patients (94%, 66/70) who suffered from COVID-19 pneumonia in Wuhan, China, from January to February 2020.
Tough research conditions
Experts say that follow-up in this Chinese study and others to date has not been nearly long enough to allow predictions about lasting lung damage in COVID-19.
They also highlight the tough conditions in which researchers are working. Few autopsies have been performed so far – autopsies take time, extra precautions must be taken to avoid spread of COVID-19, and many patients and families do not consent to an autopsy. Furthermore, autopsy data from patients who died of COVID-19 may not extrapolate to survivors.
“I would not hang my hat on any of the limited data I have seen on autopsies,” said Lina Miyakawa, MD, a critical care and pulmonary medicine specialist at Mount Sinai Hospital in New York City.
“Even though we have answers about how the lungs are damaged at the end stage, this does not elucidate any answers about the earlier lung damage from this disease,” she continued. “It would be informative to have pathological data from the early or transitional phase, to see if that may translate into a treatment modality for COVID-19 patients.”
The problem is that these patients often experience a large amount of sloughing of airway cells, along with mucous plugging (collections of mucous that can block airflow and collapse alveoli). Bronchoscopy, which is used to view the inside of the lungs and sometimes to retrieve biopsy specimens for microscopic evaluation, is too risky for many COVID-19 patients.
In addition, few CT data exist for severely ill COVID-19 patients, who can be so unstable that to transport them to undergo a CT scan can be dangerous, not to mention the concern regarding infection control.
Even if sufficient data did exist, findings from chest x-rays, CTs, pathology studies, and lung function tests do not always match up. A patient who has lung abnormalities on CT may not necessarily have clinically impaired lung function or abnormal pathologic findings, according to Ali Gholamrezanezhad, MD, an emergency radiologist who is with the department of clinical radiology at the University of Southern California, Los Angeles.
Together with colleagues at USC, Dr. Gholamrezanezhad has started a long-term study of patients who were hospitalized with COVID-19. The researchers will follow patients for at least 1 year and will use chest x-ray, chest CT, and exercise testing to evaluate lung recovery over time.
“In the acute phase, we have acute inflammation called ground glass opacities, which usually happen bilaterally in COVID-19. That is totally reversible damage that can return to normal with no scarring,” Dr. Gholamrezanezhad said.
On the basis of data from survivors of other severe pneumonias, such as Middle East respiratory syndrome, SARS-CoV-1 infection, and H1N1 influenza, Gholamrezanezhad thinks that most survivors of COVID-19 will be able to return to work and normal life, although some may show residual lung dysfunction. Age, underlying medical conditions, smoking, length of hospital stay, severity of illness, and quality of treatment may all play a role in how well these people recover.
The lung has a remarkable capacity to recover, he added. Critical illness can destroy type one pneumocytes — the cells that line the alveoli in the lung — but over time, these cells grow back and reline the lungs. When they do, they can also help repair the lungs.
On top of that, the lung has a large functional reserve, and when one section becomes damaged, the rest of the lung can compensate.
However, for some people, total maximum exercise capacity may be affected, he commented.
Mukhopadhyay said: “My feeling is you will get reversal to normal in some patients and you will get long-term fibrosis from ARDS in some survivors. The question is, how many will have complete resolution and how many will have fibrosis? To know the answer, we will need a lot more data than we have now.”
Convalescence of COVID-19 Patients
Like many who become seriously ill with COVID-19, Braganza had underlying medical problems. Before becoming ill, he had had a heart attack and stroke. He walked with a walker and had some age-related memory problems.
Five days after transfer to inpatient rehab, Braganza was walking up and down the hallway using a walker. He was still shaking off the effects of being heavily sedated for so long, and he experienced periods of confusion. When he first came off the ventilator, he mixed up days and nights. Sometimes he did not remember being so sick. A former software engineer, Braganza usually had no problem using technology, but he has had to relearn how to use his phone and connect his iPad to Wi-Fi.
“He is still struggling quite a bit with remembering how to do basic things,” Maria Braganza said. “He has times of being really depressed because he feels like he’s not making progress.”
Doctors are taking note and starting to think about what lies ahead for ICU survivors of COVID-19. They worry about the potential for disease recurrence as well as readmission for other problems, such as other infections and hip fractures.
“As COVID-19 survivors begin to recover, there will be a large burden of chronic critical illness. We expect a significant need for rehabilitation in most ICU survivors of COVID-19,” said Steve Lubinsky, MD, medical director of respiratory care at New York University Langone Tisch Hospital.
Thinking about her father, Maria Braganza brings an extra dimension to these concerns. She thinks about depression, loneliness, and social isolation among older survivors of COVID-19. These problems existed long before the pandemic, but COVID-19 has magnified them.
The rehab staff estimates that Mr. Braganza will spend 10-14 days in their program, but discharge home creates a conundrum. Before becoming ill, Mr. Braganza lived in an independent senior living facility. Now, because of social distancing, he will no longer be able to hang out and have meals with his friends.
“Dad’s already feeling really lonely in the hospital. If we stay on a semipermanent lockdown, will he be able to see the people he loves?” Maria Braganza said. “Even though somebody is older, they have a lot to give and a lot of experience. They just need a little extra to be able to have that life.”
Dr. Nolan, Dr. Chong, Dr. Mukhopadhyay, Dr. Miyakawa, Dr. Gholamrezanezhad, and Dr. Lubinsky report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
If one word describes Eladio (“Lad”) Braganza, age 77, it’s “tenacious.” For 28 days, he clung to life on a ventilator in a Seattle ICU. Now – after a 46-day hospitalization for SARS-CoV-2 infection – he’s making progress in inpatient rehab, determined to regain function.
“We were not sure if he was going to make it through his first night in the hospital, and for a while after that. We were really prepared that he would not survive his ventilator time,” his daughter, Maria Braganza, said in an interview just 5 days after her father had been transferred to inpatient rehab.
In many ways, Mr. Braganza’s experience is typical of seriously ill COVID-19 patients. Many go from walking and talking to being on a ventilator within 10 hours or less. Mr. Braganza was admitted to the hospital on March 21 and was intubated that day. To keep him on the ventilator, he was heavily sedated and unconscious at times. In the ICU, he experienced bouts of low blood pressure, a pattern of shock that occurs in COVID-19 patients and that does not always respond to fluids.
Doctors have quickly learned to treat these patients aggressively. Many patients in the ICU with COVID-19 develop an inflamed, atypical form of acute respiratory distress syndrome (ARDS), in which the lung’s compliance, or stiffness, does not match the severity of hypoxia. These patients require high levels of oxygen and high ventilator settings. Many develop pneumothorax, or collapsed lungs, because of the high pressures needed to deliver oxygen and the prolonged time on ventilation.
“The vast majority of COVID patients in the ICU have lung disease that is quite severe, much more severe than I have seen in my 20 years of doing this,” said critical care specialist Anna Nolan, MD, of the department of medicine at New York University.
After about 2 weeks, some of these patients can come off the ventilator, or they may undergo a tracheostomy, a hole in the neck through which a tube is placed to deliver oxygen. By this time, many have developed ICU-acquired weakness and muscle wasting. Some may be so debilitated that they cannot walk. Even the respiratory muscles that help them breathe may have weakened as a result of the ventilator doing the work for them.
These patients “get sick very fast, and it takes a long time for them to heal. What’s not really well appreciated is how much rehab and how much recovery time these patients are going to need,” said David Chong, MD. He is medical director of the ICU at New York–Presbyterian Hospital/Columbia University Medical Center, and he has been on the front lines during the COVID-19 surge in New York City.
The road to recovery
Regardless of the cause, many people who have a prolonged stint in the ICU face an even longer convalescence. Still-unanswered questions concern whether recovery time will be longer for those with COVID-19, compared with other illnesses, and whether some of the damage may be permanent. A number of small studies in Hong Kong and China, as well as studies of severe acute respiratory syndrome patients’ recoveries, have promoted speculation about possible long-lasting damage to lungs and other organs from COVID-19.
Yet some of these reports have left out important details about ARDS in COVID-19 patients who also may be most at risk for long-lasting damage. To clear up some of the confusion, the Pulmonary Fibrosis Foundation said on April 6 that some but not all of COVID-19 patients who develop ARDS may go on to develop lung fibrosis – scarring of the lungs – which may be permanent.
“Post-ARDS fibrosis typically is not progressive, but nonetheless can be severe and limiting. The recovery period for post-ARDS fibrosis is approximately 1 year and the residual deficits persist, but generally do not progress,” the foundation noted.
Emerging research on lung damage in COVID-19
Because the pandemic is only a few months in, it’s unclear as yet what the long-term consequences of severe COVID-19 may be. But emerging data are enabling researchers to venture an educated guess about what may happen in the months and years ahead.
The key to understanding the data is knowing that ARDS is a syndrome – the end product of a variety of diseases or insults to the lung. Under the microscope, lung damage from ARDS associated with COVID-19 is indistinguishable from lung damage resulting from other causes, such as vaping, sepsis, or shock caused by a motor vehicle accident, said Sanjay Mukhopadhyay, MD, director of pulmonary pathology at Cleveland Clinic.
Dr. Mukhopadhyay, who specializes in lung pathology, performed one of the first complete autopsies of a COVID-19 patient in the United States. In most autopsy series published to date, he said, the most common lung finding in patients who have died from COVID-19 is diffuse alveolar damage (DAD), a pattern of lung injury seen in ARDS from many other causes.
In DAD, the walls of the alveoli – thinly lined air sacs that facilitate gas exchange in the lung – develop a pink, hyaline membrane composed of damaged cells and plasma proteins that leak from capillaries in the wall of the alveolus. This hyaline membrane gets plastered against the wall of the alveolus and interferes with diffusion of oxygen into the body.
“We know what happens in ARDS from other causes. If you follow people who have been on a ventilator long term, some of their respiratory function goes back to normal,” Dr. Mukhopadhyay said. “But there are other people in whom some degree of respiratory impairment lingers. In these patients, we think the DAD progresses to an organizing stage.”
Organizing pneumonia refers to a family of diseases in which fibroblasts (cells involved in wound healing) arrive and form scar tissue that forms hyaline membranes and fibrin balls (tough proteins) that fill up the alveoli, making gas exchange very difficult.
Also called BOOP (bronchiolitis obliterans organizing pneumonia), this condition is sensitive to steroids. Early aggressive steroid treatment can prevent long-term lung damage. Without steroids, damage can become permanent. A variant of this condition is termed acute fibrinous and organizing pneumonia (AFOP), which is also sensitive to steroids. A report from France demonstrates AFOP in some patients who have died from COVID-19.
The trick is identifying who is developing BOOP and who is not, and beyond that, who might be most amenable to treatment. Use of steroids for patients with certain other problems, such as a bacterial infection on top of COVID-19, could be harmful. David H. Chong, MD, and colleagues at Columbia University Irving Medical Center, New York, are investigating this to determine which COVID-19 patients may benefit from early steroid therapy.
“It’s not clear if there is a predominant histologic type or if we are catching people at different phases of their disease, and therefore we’re seeing different lung pathology,” Dr. Chong said.
He thinks that many patients with severe COVID-19 probably will not develop this pattern of lung scarring. “We’re speculating that lung damage from severe COVID-19 is probably going to behave more like lung damage from regular ARDS, which is often reversible. We think the vast majority of these patients probably have DAD that is similar to most patients with ARDS from other etiologies,” Dr. Chong said.
That would be consistent with information from China. In an April interview with Chinese domestic media, Zhong Nanshan, MD, a pulmonologist at the head of China’s COVID-19 task force, stated that he expects that the lungs in most patients with COVID-19 will gradually recover. He was responding to a widely publicized small study that found evidence of residual lung abnormalities at hospital discharge in most patients (94%, 66/70) who suffered from COVID-19 pneumonia in Wuhan, China, from January to February 2020.
Tough research conditions
Experts say that follow-up in this Chinese study and others to date has not been nearly long enough to allow predictions about lasting lung damage in COVID-19.
They also highlight the tough conditions in which researchers are working. Few autopsies have been performed so far – autopsies take time, extra precautions must be taken to avoid spread of COVID-19, and many patients and families do not consent to an autopsy. Furthermore, autopsy data from patients who died of COVID-19 may not extrapolate to survivors.
“I would not hang my hat on any of the limited data I have seen on autopsies,” said Lina Miyakawa, MD, a critical care and pulmonary medicine specialist at Mount Sinai Hospital in New York City.
“Even though we have answers about how the lungs are damaged at the end stage, this does not elucidate any answers about the earlier lung damage from this disease,” she continued. “It would be informative to have pathological data from the early or transitional phase, to see if that may translate into a treatment modality for COVID-19 patients.”
The problem is that these patients often experience a large amount of sloughing of airway cells, along with mucous plugging (collections of mucous that can block airflow and collapse alveoli). Bronchoscopy, which is used to view the inside of the lungs and sometimes to retrieve biopsy specimens for microscopic evaluation, is too risky for many COVID-19 patients.
In addition, few CT data exist for severely ill COVID-19 patients, who can be so unstable that to transport them to undergo a CT scan can be dangerous, not to mention the concern regarding infection control.
Even if sufficient data did exist, findings from chest x-rays, CTs, pathology studies, and lung function tests do not always match up. A patient who has lung abnormalities on CT may not necessarily have clinically impaired lung function or abnormal pathologic findings, according to Ali Gholamrezanezhad, MD, an emergency radiologist who is with the department of clinical radiology at the University of Southern California, Los Angeles.
Together with colleagues at USC, Dr. Gholamrezanezhad has started a long-term study of patients who were hospitalized with COVID-19. The researchers will follow patients for at least 1 year and will use chest x-ray, chest CT, and exercise testing to evaluate lung recovery over time.
“In the acute phase, we have acute inflammation called ground glass opacities, which usually happen bilaterally in COVID-19. That is totally reversible damage that can return to normal with no scarring,” Dr. Gholamrezanezhad said.
On the basis of data from survivors of other severe pneumonias, such as Middle East respiratory syndrome, SARS-CoV-1 infection, and H1N1 influenza, Gholamrezanezhad thinks that most survivors of COVID-19 will be able to return to work and normal life, although some may show residual lung dysfunction. Age, underlying medical conditions, smoking, length of hospital stay, severity of illness, and quality of treatment may all play a role in how well these people recover.
The lung has a remarkable capacity to recover, he added. Critical illness can destroy type one pneumocytes — the cells that line the alveoli in the lung — but over time, these cells grow back and reline the lungs. When they do, they can also help repair the lungs.
On top of that, the lung has a large functional reserve, and when one section becomes damaged, the rest of the lung can compensate.
However, for some people, total maximum exercise capacity may be affected, he commented.
Mukhopadhyay said: “My feeling is you will get reversal to normal in some patients and you will get long-term fibrosis from ARDS in some survivors. The question is, how many will have complete resolution and how many will have fibrosis? To know the answer, we will need a lot more data than we have now.”
Convalescence of COVID-19 Patients
Like many who become seriously ill with COVID-19, Braganza had underlying medical problems. Before becoming ill, he had had a heart attack and stroke. He walked with a walker and had some age-related memory problems.
Five days after transfer to inpatient rehab, Braganza was walking up and down the hallway using a walker. He was still shaking off the effects of being heavily sedated for so long, and he experienced periods of confusion. When he first came off the ventilator, he mixed up days and nights. Sometimes he did not remember being so sick. A former software engineer, Braganza usually had no problem using technology, but he has had to relearn how to use his phone and connect his iPad to Wi-Fi.
“He is still struggling quite a bit with remembering how to do basic things,” Maria Braganza said. “He has times of being really depressed because he feels like he’s not making progress.”
Doctors are taking note and starting to think about what lies ahead for ICU survivors of COVID-19. They worry about the potential for disease recurrence as well as readmission for other problems, such as other infections and hip fractures.
“As COVID-19 survivors begin to recover, there will be a large burden of chronic critical illness. We expect a significant need for rehabilitation in most ICU survivors of COVID-19,” said Steve Lubinsky, MD, medical director of respiratory care at New York University Langone Tisch Hospital.
Thinking about her father, Maria Braganza brings an extra dimension to these concerns. She thinks about depression, loneliness, and social isolation among older survivors of COVID-19. These problems existed long before the pandemic, but COVID-19 has magnified them.
The rehab staff estimates that Mr. Braganza will spend 10-14 days in their program, but discharge home creates a conundrum. Before becoming ill, Mr. Braganza lived in an independent senior living facility. Now, because of social distancing, he will no longer be able to hang out and have meals with his friends.
“Dad’s already feeling really lonely in the hospital. If we stay on a semipermanent lockdown, will he be able to see the people he loves?” Maria Braganza said. “Even though somebody is older, they have a lot to give and a lot of experience. They just need a little extra to be able to have that life.”
Dr. Nolan, Dr. Chong, Dr. Mukhopadhyay, Dr. Miyakawa, Dr. Gholamrezanezhad, and Dr. Lubinsky report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
If one word describes Eladio (“Lad”) Braganza, age 77, it’s “tenacious.” For 28 days, he clung to life on a ventilator in a Seattle ICU. Now – after a 46-day hospitalization for SARS-CoV-2 infection – he’s making progress in inpatient rehab, determined to regain function.
“We were not sure if he was going to make it through his first night in the hospital, and for a while after that. We were really prepared that he would not survive his ventilator time,” his daughter, Maria Braganza, said in an interview just 5 days after her father had been transferred to inpatient rehab.
In many ways, Mr. Braganza’s experience is typical of seriously ill COVID-19 patients. Many go from walking and talking to being on a ventilator within 10 hours or less. Mr. Braganza was admitted to the hospital on March 21 and was intubated that day. To keep him on the ventilator, he was heavily sedated and unconscious at times. In the ICU, he experienced bouts of low blood pressure, a pattern of shock that occurs in COVID-19 patients and that does not always respond to fluids.
Doctors have quickly learned to treat these patients aggressively. Many patients in the ICU with COVID-19 develop an inflamed, atypical form of acute respiratory distress syndrome (ARDS), in which the lung’s compliance, or stiffness, does not match the severity of hypoxia. These patients require high levels of oxygen and high ventilator settings. Many develop pneumothorax, or collapsed lungs, because of the high pressures needed to deliver oxygen and the prolonged time on ventilation.
“The vast majority of COVID patients in the ICU have lung disease that is quite severe, much more severe than I have seen in my 20 years of doing this,” said critical care specialist Anna Nolan, MD, of the department of medicine at New York University.
After about 2 weeks, some of these patients can come off the ventilator, or they may undergo a tracheostomy, a hole in the neck through which a tube is placed to deliver oxygen. By this time, many have developed ICU-acquired weakness and muscle wasting. Some may be so debilitated that they cannot walk. Even the respiratory muscles that help them breathe may have weakened as a result of the ventilator doing the work for them.
These patients “get sick very fast, and it takes a long time for them to heal. What’s not really well appreciated is how much rehab and how much recovery time these patients are going to need,” said David Chong, MD. He is medical director of the ICU at New York–Presbyterian Hospital/Columbia University Medical Center, and he has been on the front lines during the COVID-19 surge in New York City.
The road to recovery
Regardless of the cause, many people who have a prolonged stint in the ICU face an even longer convalescence. Still-unanswered questions concern whether recovery time will be longer for those with COVID-19, compared with other illnesses, and whether some of the damage may be permanent. A number of small studies in Hong Kong and China, as well as studies of severe acute respiratory syndrome patients’ recoveries, have promoted speculation about possible long-lasting damage to lungs and other organs from COVID-19.
Yet some of these reports have left out important details about ARDS in COVID-19 patients who also may be most at risk for long-lasting damage. To clear up some of the confusion, the Pulmonary Fibrosis Foundation said on April 6 that some but not all of COVID-19 patients who develop ARDS may go on to develop lung fibrosis – scarring of the lungs – which may be permanent.
“Post-ARDS fibrosis typically is not progressive, but nonetheless can be severe and limiting. The recovery period for post-ARDS fibrosis is approximately 1 year and the residual deficits persist, but generally do not progress,” the foundation noted.
Emerging research on lung damage in COVID-19
Because the pandemic is only a few months in, it’s unclear as yet what the long-term consequences of severe COVID-19 may be. But emerging data are enabling researchers to venture an educated guess about what may happen in the months and years ahead.
The key to understanding the data is knowing that ARDS is a syndrome – the end product of a variety of diseases or insults to the lung. Under the microscope, lung damage from ARDS associated with COVID-19 is indistinguishable from lung damage resulting from other causes, such as vaping, sepsis, or shock caused by a motor vehicle accident, said Sanjay Mukhopadhyay, MD, director of pulmonary pathology at Cleveland Clinic.
Dr. Mukhopadhyay, who specializes in lung pathology, performed one of the first complete autopsies of a COVID-19 patient in the United States. In most autopsy series published to date, he said, the most common lung finding in patients who have died from COVID-19 is diffuse alveolar damage (DAD), a pattern of lung injury seen in ARDS from many other causes.
In DAD, the walls of the alveoli – thinly lined air sacs that facilitate gas exchange in the lung – develop a pink, hyaline membrane composed of damaged cells and plasma proteins that leak from capillaries in the wall of the alveolus. This hyaline membrane gets plastered against the wall of the alveolus and interferes with diffusion of oxygen into the body.
“We know what happens in ARDS from other causes. If you follow people who have been on a ventilator long term, some of their respiratory function goes back to normal,” Dr. Mukhopadhyay said. “But there are other people in whom some degree of respiratory impairment lingers. In these patients, we think the DAD progresses to an organizing stage.”
Organizing pneumonia refers to a family of diseases in which fibroblasts (cells involved in wound healing) arrive and form scar tissue that forms hyaline membranes and fibrin balls (tough proteins) that fill up the alveoli, making gas exchange very difficult.
Also called BOOP (bronchiolitis obliterans organizing pneumonia), this condition is sensitive to steroids. Early aggressive steroid treatment can prevent long-term lung damage. Without steroids, damage can become permanent. A variant of this condition is termed acute fibrinous and organizing pneumonia (AFOP), which is also sensitive to steroids. A report from France demonstrates AFOP in some patients who have died from COVID-19.
The trick is identifying who is developing BOOP and who is not, and beyond that, who might be most amenable to treatment. Use of steroids for patients with certain other problems, such as a bacterial infection on top of COVID-19, could be harmful. David H. Chong, MD, and colleagues at Columbia University Irving Medical Center, New York, are investigating this to determine which COVID-19 patients may benefit from early steroid therapy.
“It’s not clear if there is a predominant histologic type or if we are catching people at different phases of their disease, and therefore we’re seeing different lung pathology,” Dr. Chong said.
He thinks that many patients with severe COVID-19 probably will not develop this pattern of lung scarring. “We’re speculating that lung damage from severe COVID-19 is probably going to behave more like lung damage from regular ARDS, which is often reversible. We think the vast majority of these patients probably have DAD that is similar to most patients with ARDS from other etiologies,” Dr. Chong said.
That would be consistent with information from China. In an April interview with Chinese domestic media, Zhong Nanshan, MD, a pulmonologist at the head of China’s COVID-19 task force, stated that he expects that the lungs in most patients with COVID-19 will gradually recover. He was responding to a widely publicized small study that found evidence of residual lung abnormalities at hospital discharge in most patients (94%, 66/70) who suffered from COVID-19 pneumonia in Wuhan, China, from January to February 2020.
Tough research conditions
Experts say that follow-up in this Chinese study and others to date has not been nearly long enough to allow predictions about lasting lung damage in COVID-19.
They also highlight the tough conditions in which researchers are working. Few autopsies have been performed so far – autopsies take time, extra precautions must be taken to avoid spread of COVID-19, and many patients and families do not consent to an autopsy. Furthermore, autopsy data from patients who died of COVID-19 may not extrapolate to survivors.
“I would not hang my hat on any of the limited data I have seen on autopsies,” said Lina Miyakawa, MD, a critical care and pulmonary medicine specialist at Mount Sinai Hospital in New York City.
“Even though we have answers about how the lungs are damaged at the end stage, this does not elucidate any answers about the earlier lung damage from this disease,” she continued. “It would be informative to have pathological data from the early or transitional phase, to see if that may translate into a treatment modality for COVID-19 patients.”
The problem is that these patients often experience a large amount of sloughing of airway cells, along with mucous plugging (collections of mucous that can block airflow and collapse alveoli). Bronchoscopy, which is used to view the inside of the lungs and sometimes to retrieve biopsy specimens for microscopic evaluation, is too risky for many COVID-19 patients.
In addition, few CT data exist for severely ill COVID-19 patients, who can be so unstable that to transport them to undergo a CT scan can be dangerous, not to mention the concern regarding infection control.
Even if sufficient data did exist, findings from chest x-rays, CTs, pathology studies, and lung function tests do not always match up. A patient who has lung abnormalities on CT may not necessarily have clinically impaired lung function or abnormal pathologic findings, according to Ali Gholamrezanezhad, MD, an emergency radiologist who is with the department of clinical radiology at the University of Southern California, Los Angeles.
Together with colleagues at USC, Dr. Gholamrezanezhad has started a long-term study of patients who were hospitalized with COVID-19. The researchers will follow patients for at least 1 year and will use chest x-ray, chest CT, and exercise testing to evaluate lung recovery over time.
“In the acute phase, we have acute inflammation called ground glass opacities, which usually happen bilaterally in COVID-19. That is totally reversible damage that can return to normal with no scarring,” Dr. Gholamrezanezhad said.
On the basis of data from survivors of other severe pneumonias, such as Middle East respiratory syndrome, SARS-CoV-1 infection, and H1N1 influenza, Gholamrezanezhad thinks that most survivors of COVID-19 will be able to return to work and normal life, although some may show residual lung dysfunction. Age, underlying medical conditions, smoking, length of hospital stay, severity of illness, and quality of treatment may all play a role in how well these people recover.
The lung has a remarkable capacity to recover, he added. Critical illness can destroy type one pneumocytes — the cells that line the alveoli in the lung — but over time, these cells grow back and reline the lungs. When they do, they can also help repair the lungs.
On top of that, the lung has a large functional reserve, and when one section becomes damaged, the rest of the lung can compensate.
However, for some people, total maximum exercise capacity may be affected, he commented.
Mukhopadhyay said: “My feeling is you will get reversal to normal in some patients and you will get long-term fibrosis from ARDS in some survivors. The question is, how many will have complete resolution and how many will have fibrosis? To know the answer, we will need a lot more data than we have now.”
Convalescence of COVID-19 Patients
Like many who become seriously ill with COVID-19, Braganza had underlying medical problems. Before becoming ill, he had had a heart attack and stroke. He walked with a walker and had some age-related memory problems.
Five days after transfer to inpatient rehab, Braganza was walking up and down the hallway using a walker. He was still shaking off the effects of being heavily sedated for so long, and he experienced periods of confusion. When he first came off the ventilator, he mixed up days and nights. Sometimes he did not remember being so sick. A former software engineer, Braganza usually had no problem using technology, but he has had to relearn how to use his phone and connect his iPad to Wi-Fi.
“He is still struggling quite a bit with remembering how to do basic things,” Maria Braganza said. “He has times of being really depressed because he feels like he’s not making progress.”
Doctors are taking note and starting to think about what lies ahead for ICU survivors of COVID-19. They worry about the potential for disease recurrence as well as readmission for other problems, such as other infections and hip fractures.
“As COVID-19 survivors begin to recover, there will be a large burden of chronic critical illness. We expect a significant need for rehabilitation in most ICU survivors of COVID-19,” said Steve Lubinsky, MD, medical director of respiratory care at New York University Langone Tisch Hospital.
Thinking about her father, Maria Braganza brings an extra dimension to these concerns. She thinks about depression, loneliness, and social isolation among older survivors of COVID-19. These problems existed long before the pandemic, but COVID-19 has magnified them.
The rehab staff estimates that Mr. Braganza will spend 10-14 days in their program, but discharge home creates a conundrum. Before becoming ill, Mr. Braganza lived in an independent senior living facility. Now, because of social distancing, he will no longer be able to hang out and have meals with his friends.
“Dad’s already feeling really lonely in the hospital. If we stay on a semipermanent lockdown, will he be able to see the people he loves?” Maria Braganza said. “Even though somebody is older, they have a lot to give and a lot of experience. They just need a little extra to be able to have that life.”
Dr. Nolan, Dr. Chong, Dr. Mukhopadhyay, Dr. Miyakawa, Dr. Gholamrezanezhad, and Dr. Lubinsky report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
‘The story unfolding is worrisome’ for diabetes and COVID-19
The American Diabetes Association has dedicated a whole section of its journal, Diabetes Care, to the topic of “Diabetes and COVID-19,” publishing a range of articles with new data to help guide physicians in caring for patients.
“Certain groups are more vulnerable to COVID-19, notably older people and those with underlying medical conditions. Because diabetes is one of the conditions associated with high risk, the diabetes community urgently needs to know more about COVID-19 and its effects on people with diabetes,” an introductory commentary noted.
Entitled “COVID-19 in people with diabetes: Urgently needed lessons from early reports,” the commentary is penned by the journal’s editor-in-chief, Matthew Riddle, MD, of Oregon Health & Science University, Portland, and colleagues.
Also writing in the same issue, William T. Cefalu, MD, and colleagues from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) noted it is known that the SARS-CoV-2 virus enters cells via the angiotensin-converting enzyme 2 (ACE-2) receptor. The ACE-2 receptor is known to be in the lungs and upper respiratory tract, “but we also know that it is expressed in other tissues such as heart, small and large intestines, and pancreas,” they wrote, and also “in the kidney.”
Hence, there are emerging reports of acute kidney injury resulting from COVID-19, as well as the impact on many other endocrine/metabolic and gastrointestinal outcomes.
“Pilot clinical studies (observational and interventional) are needed that will support the understanding or treatment of COVID-19–related diseases within the mission of the NIDDK,” they stated.
Although rapidly collected, data “offer important clues”
Some of the new ground covered in the journal articles includes an analysis of COVID-19 outcomes by type of glucose-lowering medication; remote glucose monitoring in hospitalized patients with COVID-19; a suggested approach to cardiovascular risk management in the COVID-19 era, as already reported by Medscape Medical News; and the diagnosis and management of gestational diabetes during the pandemic.
Other articles provide new data for previously reported phenomena, including obesity as a risk factor for worse COVID-19 outcomes and the role of inpatient glycemic control on COVID-19 outcomes.
“The data reported in these articles were rapidly collected and analyzed, in most cases under urgent and stressful conditions,” Dr. Riddle and colleagues cautioned. “Thus, some of the analyses are understandably limited due to missing data, incomplete follow-up, and inability to identify infected but asymptomatic patients.”
Even so, they wrote, some points are clear. “The consistency of findings in these rapidly published reports is reassuring in terms of scientific validity, but the story unfolding is worrisome.”
Specifically, while diabetes does not appear to increase the likelihood of SARS-CoV-2 infection, progression to severe illness is more likely in people with diabetes and COVID-19: They are two to three times as likely to require intensive care, and to die, compared with those infected but without diabetes.
“Neither the mechanisms underlying the increased risk nor the best interventions to limit it have yet been defined, but the studies in this collection of articles offer important clues,” Dr. Riddle and colleagues wrote.
Existing insulin use linked to COVID-19 death risk
One of the articles is a retrospective study of 904 hospitalized COVID-19 patients by Yuchen Chen, MD, of the Huazhong University of Science and Technology, Wuhan, China, and colleagues.
Among the 136 patients with diabetes, risk factors for mortality included older age (adjusted odds ratio, 1.09 per year increase; P = .001) elevated C-reactive protein (aOR, 1.12; P = .043), and insulin use (aOR, 3.58; P = .009).
“Attention needs to be paid to patients with diabetes and COVID-19 who use insulin,” the Chinese authors wrote. “Whether this was due to effects of insulin itself or to characteristics of the patients for whom it was prescribed is not clear,” Dr. Riddle and colleagues noted.
Dr. Chen and colleagues also found no difference in clinical outcomes between those diabetes patients with COVID-19 who were taking an ACE inhibitor or angiotensin II type I receptor blocker, compared with those who did not, which supports existing recommendations to continue use of this type of medication.
Remote glucose monitoring a novel tool for COVID-19 isolation
Another publication, by Gilat Shehav-Zaltzman of Sheba Medical Center, Tel Hashomer, Israel, and colleagues, describes the use of remote continuous glucose monitoring (CGM) in two hospitalized COVID-19 patients who were in isolation – one with type 1 diabetes and the other with type 2 diabetes – treated with basal-bolus insulin.
Using Medtronic CGM systems, the hospital staff was able to view patients’ real-time data uploaded to the Web from computer terminals in virus-free areas outside the patients’ rooms. The hospital’s endocrinology team had trained the intensive care staff on how to replace the sensors weekly and calibrate them twice daily.
“Converting a personal CGM system originally designed for diabetes self-management to team-based, real-time remote glucose monitoring offers a novel tool for inpatient diabetes control in COVID-19 isolation facilities,” the authors wrote.
“Such a solution in addition to ongoing remotely monitored clinical parameters (such as pulse rate, electrocardiogram, and oxygen saturation) adds to quality of diabetes care while minimizing risk of staff exposure and burden,” they observed.
Dr. Riddle and colleagues concurred: “Newer methods of remotely monitoring glucose patterns could be uniquely helpful.”
Key question: Does glycemic management make a difference?
With regard to the important issue of in-hospital control of glucose, Celestino Sardu, MD, PhD, of the University of Campania Luigi Vanvitelli, Naples, Italy, and colleagues reported on 59 patients hospitalized with confirmed COVID-19 and moderately severe pneumonia.
They were categorized as normoglycemic (n = 34) or hyperglycemic (n = 25), as well as with or without diabetes, on the basis of a diagnosis preceding the current illness. Of the 25 patients with hyperglycemia, 15 patients were treated with insulin infusion and 10 patients were not.
In a risk-adjusted analysis, both patients with hyperglycemia and patients with diabetes had a higher risk of severe disease than did those without diabetes and with normoglycemia. Patients with hyperglycemia treated with insulin infusion had a lower risk of severe disease than did patients who didn’t receive an insulin infusion.
And although they noted limitations, the authors wrote, “Our data evidenced that optimal glucose control in the immediate postadmission period for almost 18 days was associated with a significant reduction of inflammatory cytokines and procoagulative status.”
Dr. Riddle and colleagues wrote that the findings of this unrandomized comparison were interpreted “as suggesting that insulin infusion may improve outcomes.”
“If the benefits of seeking excellent glycemic control by this means are confirmed, close monitoring of glucose levels will be essential.”
More on obesity and COVID-19, this time from China
Because it has become increasingly clear that obesity is a risk factor for severe COVID-19, new data from China – where this was less apparent initially – support observations in Europe and the United States.
An article by Qingxian Cai, PhD, of Southern University of Science and Technology, Shenzhen, Guangdong, China, and colleagues looks at this. They found that, among 383 hospitalized patients with COVID-19, the 41 patients with obesity (defined as a body mass index ≥ 28 kg/m2) were significantly more likely to progress to severe disease compared with the 203 patients classified as having normal weight (BMI, 18.5-23.9), with an odds ratio of 3.4.
A similar finding comes from Feng Gao, MD, PhD, of the First Affiliated Hospital of Wenzhou (China) Medical University and colleagues, who studied 75 patients hospitalized with confirmed COVID-19 and obesity (defined as a BMI > 25 in this Asian population) to 75 patients without obesity matched by age and sex. After adjustment for clinical characteristics including the presence of diabetes, those with obesity had a threefold greater risk of progression to severe or critical COVID-19 status, with a nearly linear relationship.
Emerging from the crisis: Protect the vulnerable, increase knowledge base
As the research community emerges from the crisis, “there should be renewed efforts for multidisciplinary research ... aimed at greatly increasing the knowledge base to understand how ... the current COVID-19 threat” affects “both healthy people and people with chronic diseases and conditions,” Dr. Cefalu and colleagues concluded in their commentary.
Dr. Riddle and coauthors agreed: “We will enter a longer interval in which we must continue to support the most vulnerable populations – especially older people, those with diabetes or obesity, and those who lack the resources to limit day-to-day exposure to infection. We hope a growing sense of community will help in this task.”
Dr. Riddle has reported receiving research grant support through Oregon Health & Science University from AstraZeneca, Eli Lilly, and Novo Nordisk, and honoraria for consulting from Adocia, AstraZeneca, Eli Lilly, GlaxoSmithKline, Novo Nordisk, Sanofi, and Theracos. Dr. Cefalu has reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
The American Diabetes Association has dedicated a whole section of its journal, Diabetes Care, to the topic of “Diabetes and COVID-19,” publishing a range of articles with new data to help guide physicians in caring for patients.
“Certain groups are more vulnerable to COVID-19, notably older people and those with underlying medical conditions. Because diabetes is one of the conditions associated with high risk, the diabetes community urgently needs to know more about COVID-19 and its effects on people with diabetes,” an introductory commentary noted.
Entitled “COVID-19 in people with diabetes: Urgently needed lessons from early reports,” the commentary is penned by the journal’s editor-in-chief, Matthew Riddle, MD, of Oregon Health & Science University, Portland, and colleagues.
Also writing in the same issue, William T. Cefalu, MD, and colleagues from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) noted it is known that the SARS-CoV-2 virus enters cells via the angiotensin-converting enzyme 2 (ACE-2) receptor. The ACE-2 receptor is known to be in the lungs and upper respiratory tract, “but we also know that it is expressed in other tissues such as heart, small and large intestines, and pancreas,” they wrote, and also “in the kidney.”
Hence, there are emerging reports of acute kidney injury resulting from COVID-19, as well as the impact on many other endocrine/metabolic and gastrointestinal outcomes.
“Pilot clinical studies (observational and interventional) are needed that will support the understanding or treatment of COVID-19–related diseases within the mission of the NIDDK,” they stated.
Although rapidly collected, data “offer important clues”
Some of the new ground covered in the journal articles includes an analysis of COVID-19 outcomes by type of glucose-lowering medication; remote glucose monitoring in hospitalized patients with COVID-19; a suggested approach to cardiovascular risk management in the COVID-19 era, as already reported by Medscape Medical News; and the diagnosis and management of gestational diabetes during the pandemic.
Other articles provide new data for previously reported phenomena, including obesity as a risk factor for worse COVID-19 outcomes and the role of inpatient glycemic control on COVID-19 outcomes.
“The data reported in these articles were rapidly collected and analyzed, in most cases under urgent and stressful conditions,” Dr. Riddle and colleagues cautioned. “Thus, some of the analyses are understandably limited due to missing data, incomplete follow-up, and inability to identify infected but asymptomatic patients.”
Even so, they wrote, some points are clear. “The consistency of findings in these rapidly published reports is reassuring in terms of scientific validity, but the story unfolding is worrisome.”
Specifically, while diabetes does not appear to increase the likelihood of SARS-CoV-2 infection, progression to severe illness is more likely in people with diabetes and COVID-19: They are two to three times as likely to require intensive care, and to die, compared with those infected but without diabetes.
“Neither the mechanisms underlying the increased risk nor the best interventions to limit it have yet been defined, but the studies in this collection of articles offer important clues,” Dr. Riddle and colleagues wrote.
Existing insulin use linked to COVID-19 death risk
One of the articles is a retrospective study of 904 hospitalized COVID-19 patients by Yuchen Chen, MD, of the Huazhong University of Science and Technology, Wuhan, China, and colleagues.
Among the 136 patients with diabetes, risk factors for mortality included older age (adjusted odds ratio, 1.09 per year increase; P = .001) elevated C-reactive protein (aOR, 1.12; P = .043), and insulin use (aOR, 3.58; P = .009).
“Attention needs to be paid to patients with diabetes and COVID-19 who use insulin,” the Chinese authors wrote. “Whether this was due to effects of insulin itself or to characteristics of the patients for whom it was prescribed is not clear,” Dr. Riddle and colleagues noted.
Dr. Chen and colleagues also found no difference in clinical outcomes between those diabetes patients with COVID-19 who were taking an ACE inhibitor or angiotensin II type I receptor blocker, compared with those who did not, which supports existing recommendations to continue use of this type of medication.
Remote glucose monitoring a novel tool for COVID-19 isolation
Another publication, by Gilat Shehav-Zaltzman of Sheba Medical Center, Tel Hashomer, Israel, and colleagues, describes the use of remote continuous glucose monitoring (CGM) in two hospitalized COVID-19 patients who were in isolation – one with type 1 diabetes and the other with type 2 diabetes – treated with basal-bolus insulin.
Using Medtronic CGM systems, the hospital staff was able to view patients’ real-time data uploaded to the Web from computer terminals in virus-free areas outside the patients’ rooms. The hospital’s endocrinology team had trained the intensive care staff on how to replace the sensors weekly and calibrate them twice daily.
“Converting a personal CGM system originally designed for diabetes self-management to team-based, real-time remote glucose monitoring offers a novel tool for inpatient diabetes control in COVID-19 isolation facilities,” the authors wrote.
“Such a solution in addition to ongoing remotely monitored clinical parameters (such as pulse rate, electrocardiogram, and oxygen saturation) adds to quality of diabetes care while minimizing risk of staff exposure and burden,” they observed.
Dr. Riddle and colleagues concurred: “Newer methods of remotely monitoring glucose patterns could be uniquely helpful.”
Key question: Does glycemic management make a difference?
With regard to the important issue of in-hospital control of glucose, Celestino Sardu, MD, PhD, of the University of Campania Luigi Vanvitelli, Naples, Italy, and colleagues reported on 59 patients hospitalized with confirmed COVID-19 and moderately severe pneumonia.
They were categorized as normoglycemic (n = 34) or hyperglycemic (n = 25), as well as with or without diabetes, on the basis of a diagnosis preceding the current illness. Of the 25 patients with hyperglycemia, 15 patients were treated with insulin infusion and 10 patients were not.
In a risk-adjusted analysis, both patients with hyperglycemia and patients with diabetes had a higher risk of severe disease than did those without diabetes and with normoglycemia. Patients with hyperglycemia treated with insulin infusion had a lower risk of severe disease than did patients who didn’t receive an insulin infusion.
And although they noted limitations, the authors wrote, “Our data evidenced that optimal glucose control in the immediate postadmission period for almost 18 days was associated with a significant reduction of inflammatory cytokines and procoagulative status.”
Dr. Riddle and colleagues wrote that the findings of this unrandomized comparison were interpreted “as suggesting that insulin infusion may improve outcomes.”
“If the benefits of seeking excellent glycemic control by this means are confirmed, close monitoring of glucose levels will be essential.”
More on obesity and COVID-19, this time from China
Because it has become increasingly clear that obesity is a risk factor for severe COVID-19, new data from China – where this was less apparent initially – support observations in Europe and the United States.
An article by Qingxian Cai, PhD, of Southern University of Science and Technology, Shenzhen, Guangdong, China, and colleagues looks at this. They found that, among 383 hospitalized patients with COVID-19, the 41 patients with obesity (defined as a body mass index ≥ 28 kg/m2) were significantly more likely to progress to severe disease compared with the 203 patients classified as having normal weight (BMI, 18.5-23.9), with an odds ratio of 3.4.
A similar finding comes from Feng Gao, MD, PhD, of the First Affiliated Hospital of Wenzhou (China) Medical University and colleagues, who studied 75 patients hospitalized with confirmed COVID-19 and obesity (defined as a BMI > 25 in this Asian population) to 75 patients without obesity matched by age and sex. After adjustment for clinical characteristics including the presence of diabetes, those with obesity had a threefold greater risk of progression to severe or critical COVID-19 status, with a nearly linear relationship.
Emerging from the crisis: Protect the vulnerable, increase knowledge base
As the research community emerges from the crisis, “there should be renewed efforts for multidisciplinary research ... aimed at greatly increasing the knowledge base to understand how ... the current COVID-19 threat” affects “both healthy people and people with chronic diseases and conditions,” Dr. Cefalu and colleagues concluded in their commentary.
Dr. Riddle and coauthors agreed: “We will enter a longer interval in which we must continue to support the most vulnerable populations – especially older people, those with diabetes or obesity, and those who lack the resources to limit day-to-day exposure to infection. We hope a growing sense of community will help in this task.”
Dr. Riddle has reported receiving research grant support through Oregon Health & Science University from AstraZeneca, Eli Lilly, and Novo Nordisk, and honoraria for consulting from Adocia, AstraZeneca, Eli Lilly, GlaxoSmithKline, Novo Nordisk, Sanofi, and Theracos. Dr. Cefalu has reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
The American Diabetes Association has dedicated a whole section of its journal, Diabetes Care, to the topic of “Diabetes and COVID-19,” publishing a range of articles with new data to help guide physicians in caring for patients.
“Certain groups are more vulnerable to COVID-19, notably older people and those with underlying medical conditions. Because diabetes is one of the conditions associated with high risk, the diabetes community urgently needs to know more about COVID-19 and its effects on people with diabetes,” an introductory commentary noted.
Entitled “COVID-19 in people with diabetes: Urgently needed lessons from early reports,” the commentary is penned by the journal’s editor-in-chief, Matthew Riddle, MD, of Oregon Health & Science University, Portland, and colleagues.
Also writing in the same issue, William T. Cefalu, MD, and colleagues from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) noted it is known that the SARS-CoV-2 virus enters cells via the angiotensin-converting enzyme 2 (ACE-2) receptor. The ACE-2 receptor is known to be in the lungs and upper respiratory tract, “but we also know that it is expressed in other tissues such as heart, small and large intestines, and pancreas,” they wrote, and also “in the kidney.”
Hence, there are emerging reports of acute kidney injury resulting from COVID-19, as well as the impact on many other endocrine/metabolic and gastrointestinal outcomes.
“Pilot clinical studies (observational and interventional) are needed that will support the understanding or treatment of COVID-19–related diseases within the mission of the NIDDK,” they stated.
Although rapidly collected, data “offer important clues”
Some of the new ground covered in the journal articles includes an analysis of COVID-19 outcomes by type of glucose-lowering medication; remote glucose monitoring in hospitalized patients with COVID-19; a suggested approach to cardiovascular risk management in the COVID-19 era, as already reported by Medscape Medical News; and the diagnosis and management of gestational diabetes during the pandemic.
Other articles provide new data for previously reported phenomena, including obesity as a risk factor for worse COVID-19 outcomes and the role of inpatient glycemic control on COVID-19 outcomes.
“The data reported in these articles were rapidly collected and analyzed, in most cases under urgent and stressful conditions,” Dr. Riddle and colleagues cautioned. “Thus, some of the analyses are understandably limited due to missing data, incomplete follow-up, and inability to identify infected but asymptomatic patients.”
Even so, they wrote, some points are clear. “The consistency of findings in these rapidly published reports is reassuring in terms of scientific validity, but the story unfolding is worrisome.”
Specifically, while diabetes does not appear to increase the likelihood of SARS-CoV-2 infection, progression to severe illness is more likely in people with diabetes and COVID-19: They are two to three times as likely to require intensive care, and to die, compared with those infected but without diabetes.
“Neither the mechanisms underlying the increased risk nor the best interventions to limit it have yet been defined, but the studies in this collection of articles offer important clues,” Dr. Riddle and colleagues wrote.
Existing insulin use linked to COVID-19 death risk
One of the articles is a retrospective study of 904 hospitalized COVID-19 patients by Yuchen Chen, MD, of the Huazhong University of Science and Technology, Wuhan, China, and colleagues.
Among the 136 patients with diabetes, risk factors for mortality included older age (adjusted odds ratio, 1.09 per year increase; P = .001) elevated C-reactive protein (aOR, 1.12; P = .043), and insulin use (aOR, 3.58; P = .009).
“Attention needs to be paid to patients with diabetes and COVID-19 who use insulin,” the Chinese authors wrote. “Whether this was due to effects of insulin itself or to characteristics of the patients for whom it was prescribed is not clear,” Dr. Riddle and colleagues noted.
Dr. Chen and colleagues also found no difference in clinical outcomes between those diabetes patients with COVID-19 who were taking an ACE inhibitor or angiotensin II type I receptor blocker, compared with those who did not, which supports existing recommendations to continue use of this type of medication.
Remote glucose monitoring a novel tool for COVID-19 isolation
Another publication, by Gilat Shehav-Zaltzman of Sheba Medical Center, Tel Hashomer, Israel, and colleagues, describes the use of remote continuous glucose monitoring (CGM) in two hospitalized COVID-19 patients who were in isolation – one with type 1 diabetes and the other with type 2 diabetes – treated with basal-bolus insulin.
Using Medtronic CGM systems, the hospital staff was able to view patients’ real-time data uploaded to the Web from computer terminals in virus-free areas outside the patients’ rooms. The hospital’s endocrinology team had trained the intensive care staff on how to replace the sensors weekly and calibrate them twice daily.
“Converting a personal CGM system originally designed for diabetes self-management to team-based, real-time remote glucose monitoring offers a novel tool for inpatient diabetes control in COVID-19 isolation facilities,” the authors wrote.
“Such a solution in addition to ongoing remotely monitored clinical parameters (such as pulse rate, electrocardiogram, and oxygen saturation) adds to quality of diabetes care while minimizing risk of staff exposure and burden,” they observed.
Dr. Riddle and colleagues concurred: “Newer methods of remotely monitoring glucose patterns could be uniquely helpful.”
Key question: Does glycemic management make a difference?
With regard to the important issue of in-hospital control of glucose, Celestino Sardu, MD, PhD, of the University of Campania Luigi Vanvitelli, Naples, Italy, and colleagues reported on 59 patients hospitalized with confirmed COVID-19 and moderately severe pneumonia.
They were categorized as normoglycemic (n = 34) or hyperglycemic (n = 25), as well as with or without diabetes, on the basis of a diagnosis preceding the current illness. Of the 25 patients with hyperglycemia, 15 patients were treated with insulin infusion and 10 patients were not.
In a risk-adjusted analysis, both patients with hyperglycemia and patients with diabetes had a higher risk of severe disease than did those without diabetes and with normoglycemia. Patients with hyperglycemia treated with insulin infusion had a lower risk of severe disease than did patients who didn’t receive an insulin infusion.
And although they noted limitations, the authors wrote, “Our data evidenced that optimal glucose control in the immediate postadmission period for almost 18 days was associated with a significant reduction of inflammatory cytokines and procoagulative status.”
Dr. Riddle and colleagues wrote that the findings of this unrandomized comparison were interpreted “as suggesting that insulin infusion may improve outcomes.”
“If the benefits of seeking excellent glycemic control by this means are confirmed, close monitoring of glucose levels will be essential.”
More on obesity and COVID-19, this time from China
Because it has become increasingly clear that obesity is a risk factor for severe COVID-19, new data from China – where this was less apparent initially – support observations in Europe and the United States.
An article by Qingxian Cai, PhD, of Southern University of Science and Technology, Shenzhen, Guangdong, China, and colleagues looks at this. They found that, among 383 hospitalized patients with COVID-19, the 41 patients with obesity (defined as a body mass index ≥ 28 kg/m2) were significantly more likely to progress to severe disease compared with the 203 patients classified as having normal weight (BMI, 18.5-23.9), with an odds ratio of 3.4.
A similar finding comes from Feng Gao, MD, PhD, of the First Affiliated Hospital of Wenzhou (China) Medical University and colleagues, who studied 75 patients hospitalized with confirmed COVID-19 and obesity (defined as a BMI > 25 in this Asian population) to 75 patients without obesity matched by age and sex. After adjustment for clinical characteristics including the presence of diabetes, those with obesity had a threefold greater risk of progression to severe or critical COVID-19 status, with a nearly linear relationship.
Emerging from the crisis: Protect the vulnerable, increase knowledge base
As the research community emerges from the crisis, “there should be renewed efforts for multidisciplinary research ... aimed at greatly increasing the knowledge base to understand how ... the current COVID-19 threat” affects “both healthy people and people with chronic diseases and conditions,” Dr. Cefalu and colleagues concluded in their commentary.
Dr. Riddle and coauthors agreed: “We will enter a longer interval in which we must continue to support the most vulnerable populations – especially older people, those with diabetes or obesity, and those who lack the resources to limit day-to-day exposure to infection. We hope a growing sense of community will help in this task.”
Dr. Riddle has reported receiving research grant support through Oregon Health & Science University from AstraZeneca, Eli Lilly, and Novo Nordisk, and honoraria for consulting from Adocia, AstraZeneca, Eli Lilly, GlaxoSmithKline, Novo Nordisk, Sanofi, and Theracos. Dr. Cefalu has reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Can you catch COVID-19 through your eyes?
You can catch COVID-19 if an infected person coughs or sneezes and contagious droplets enter your nose or mouth. But can you become ill if the virus lands in your eyes?
Virologist Joseph Fair, PhD, an NBC News contributor, raised that concern when he became critically ill with COVID-19, the disease caused by the coronavirus. From a hospital bed in his hometown of New Orleans, he told the network that he had flown on a crowded plane where flight attendants weren’t wearing masks. He wore a mask and gloves, but no eye protection.
“My best guess,” he told the interviewer, “was that it came through the eye route.”
Asked if people should start wearing eye protection, Dr. Fair replied, “In my opinion, yes.”
While Dr. Fair is convinced that eye protection helps, other experts aren’t sure. So much remains unknown about the new coronavirus, SARS-CoV-2, that researchers are still trying to establish whether infection can actually happen through the eyes.
“I don’t think we can answer that question with 100% confidence at this time,” said H. Nida Sen, MD, director of the uveitis clinic at the National Eye Institute in Bethesda, Md., and a clinical investigator who is studying the effects of COVID-19 on the eye. But, she says, “I think it is biologically plausible.”
Some research has begun pointing in that direction, according to Elia Duh, MD, a researcher and professor of ophthalmology at Johns Hopkins University in Baltimore.
The clear tissue that covers the white of the eye and lines the inside of the eyelid, known as the conjunctiva, “can be infected by other viruses, such as adenoviruses associated with the common cold and the herpes simplex virus,” he said.
There’s the same chance of infection with SARS-CoV-2, said Dr. Duh. “ just like the nasal passages are exposed. In addition, people rub and touch their eyes a lot. So there’s certainly already the vulnerability.”
To study whether SARS-CoV-2 could infect the eyes, Dr. Duh and fellow researchers at Johns Hopkins looked at whether the eye’s surface cells possess key factors that make the virus more likely to enter and infect them.
In their study (BioRxiv. 2020 May 9. doi: 10.1101/2020.05.09.086165), which is now being peer-reviewed, the team examined 10 postmortem eyes and five surgical samples of conjunctiva from patients who did not have the coronavirus. They wanted to see whether the eyes’ surface cells produced the key receptor for coronavirus, the ACE2 receptor.
For SARS-CoV-2 to enter a cell, “the cell has to have ACE2 on its surface so that the coronavirus can latch onto it and gain entry into the cell,” Dr. Duh said.
Not much research existed on ACE2 and the eye’s surface cells, he said. “We were really struck that ACE2 was clearly present in the surface cells of all of the specimens.” In addition, the researchers found that the eye’s surface cells also produce TMPRSS2, an enzyme that helps the virus enter the cell.
More research is needed for a definitive answer, Dr. Duh said. But “all of this evidence together seems to suggest that there’s a good likelihood that the ocular surface cells are susceptible to infection by coronavirus.”
If that’s the case, the virus then could be transmitted through the tear ducts that connect the eyes to the nasal cavity and subsequently infect the respiratory cells, he said.
Edward E. Manche, MD, professor of ophthalmology at Stanford (Calif.) University, said that while doctors don’t know for sure, many think eye infection can happen. “I think it’s widely believed now that you can acquire it through the eye. The way the virus works, it’s most commonly transmitted through the mouth and nasal passages. We have mucosal tissues where it can get in.”
Dr. Manche said the eyes would be “the least common mode of transmission.”
Besides looking at the eyes as an entryway, researchers are exploring whether people with SARS-CoV-2 in their eyes could infect others through their tears or eye secretions.
“The virus has been detected in tears and conjunctival swab specimens from individuals with COVID-19,” Dr. Duh said. “If someone rubs their eyes and then touches someone else or touches a surface, that kind of transmission mechanism could occur.
“It again highlights how contagious the coronavirus is and how stealthy it can be in its contagiousness,” he said.
If it turns out that the coronavirus can infect the eyes, the virus could persist there as a source of contagion, Dr. Duh said. “The eyes and tears could serve as a source of infection to others for longer.” He noted a case of a COVID-infected woman with conjunctivitis who still had detectable virus in her eyes 3 weeks after her symptoms started.
Conjunctivitis, commonly called pink eye, could be a symptom of COVID-19, said Dr. Sen, who is an ophthalmologist. She recommends that people get tested for COVID-19 if they have this condition, which is marked by redness, itchiness, tearing, discharge, and a gritty sensation in the eye.
Dr. Fair, the virologist, was released from the hospital to recover at home and continued to urge eye protection. “People like to call people like me fearmongers ... but the reality is, we’re just trying to keep them safe,” he told NBC News.
The CDC hasn’t issued such advice. In an email, the agency said it “does not have specific recommendations for the public regarding eye protection. However, in health care settings, the CDC does recommend eye protection for health care workers to prevent transmission via droplets.”
Dr. Sen agrees. “For the general public, I don’t think we have enough data to suggest that they should be covering the eyes in some form,” she said.
When she goes to the grocery store, she doesn’t wear eye protection. “I am only wearing goggles when I’m seeing ophthalmology patients up close, basically because I’m 4 or 5 inches away from them.”
But fuller protection – a mask, gloves, and even eye protection, such as goggles – might help those taking care of a COVID-19 patient at home, Dr. Manche said. “If you’re caring for somebody, that’s a much higher risk because they’re shedding viral load. You lessen the chance of transmission.”
For the public, Dr. Sen stresses the continued importance of hand hygiene. “In an abundance of caution, I would still encourage handwashing and not touching the eye for many reasons, not just COVID. You can transmit simple infections to your eye. We have other viruses and bacteria that are circulating in the environment and in our bodies elsewhere, so we can easily carry those to the eyes.”
Switching from contact lenses to eyeglasses could help cut down on touching the eyes, she says. Eyeglasses can also be a “mechanical barrier” to keep hands away.
Eyeglasses might block some droplets if someone nearby sneezes or coughs, Dr. Manche said, although they “aren’t sealed around the edges. They’re not like true medical goggles that are going to keep out the virus.”
Dr. Duh agrees that health care workers must don eye protection, but he said the public doesn’t need to start wearing goggles, face shields, or other eye protection. “I still think the major mode of transmission is through the nasal passages and the respiratory system,” he said.
It’s unclear whether eye protection is warranted for airplane passengers, Dr. Manche said. “It probably wouldn’t hurt, but I think the more important thing would be to take precautions: wearing a face mask, washing your hands, cleaning the seats and tray tables in front of you, and not touching things and touching your face and eyes.”
A version of this article originally appeared on WebMD.com.
You can catch COVID-19 if an infected person coughs or sneezes and contagious droplets enter your nose or mouth. But can you become ill if the virus lands in your eyes?
Virologist Joseph Fair, PhD, an NBC News contributor, raised that concern when he became critically ill with COVID-19, the disease caused by the coronavirus. From a hospital bed in his hometown of New Orleans, he told the network that he had flown on a crowded plane where flight attendants weren’t wearing masks. He wore a mask and gloves, but no eye protection.
“My best guess,” he told the interviewer, “was that it came through the eye route.”
Asked if people should start wearing eye protection, Dr. Fair replied, “In my opinion, yes.”
While Dr. Fair is convinced that eye protection helps, other experts aren’t sure. So much remains unknown about the new coronavirus, SARS-CoV-2, that researchers are still trying to establish whether infection can actually happen through the eyes.
“I don’t think we can answer that question with 100% confidence at this time,” said H. Nida Sen, MD, director of the uveitis clinic at the National Eye Institute in Bethesda, Md., and a clinical investigator who is studying the effects of COVID-19 on the eye. But, she says, “I think it is biologically plausible.”
Some research has begun pointing in that direction, according to Elia Duh, MD, a researcher and professor of ophthalmology at Johns Hopkins University in Baltimore.
The clear tissue that covers the white of the eye and lines the inside of the eyelid, known as the conjunctiva, “can be infected by other viruses, such as adenoviruses associated with the common cold and the herpes simplex virus,” he said.
There’s the same chance of infection with SARS-CoV-2, said Dr. Duh. “ just like the nasal passages are exposed. In addition, people rub and touch their eyes a lot. So there’s certainly already the vulnerability.”
To study whether SARS-CoV-2 could infect the eyes, Dr. Duh and fellow researchers at Johns Hopkins looked at whether the eye’s surface cells possess key factors that make the virus more likely to enter and infect them.
In their study (BioRxiv. 2020 May 9. doi: 10.1101/2020.05.09.086165), which is now being peer-reviewed, the team examined 10 postmortem eyes and five surgical samples of conjunctiva from patients who did not have the coronavirus. They wanted to see whether the eyes’ surface cells produced the key receptor for coronavirus, the ACE2 receptor.
For SARS-CoV-2 to enter a cell, “the cell has to have ACE2 on its surface so that the coronavirus can latch onto it and gain entry into the cell,” Dr. Duh said.
Not much research existed on ACE2 and the eye’s surface cells, he said. “We were really struck that ACE2 was clearly present in the surface cells of all of the specimens.” In addition, the researchers found that the eye’s surface cells also produce TMPRSS2, an enzyme that helps the virus enter the cell.
More research is needed for a definitive answer, Dr. Duh said. But “all of this evidence together seems to suggest that there’s a good likelihood that the ocular surface cells are susceptible to infection by coronavirus.”
If that’s the case, the virus then could be transmitted through the tear ducts that connect the eyes to the nasal cavity and subsequently infect the respiratory cells, he said.
Edward E. Manche, MD, professor of ophthalmology at Stanford (Calif.) University, said that while doctors don’t know for sure, many think eye infection can happen. “I think it’s widely believed now that you can acquire it through the eye. The way the virus works, it’s most commonly transmitted through the mouth and nasal passages. We have mucosal tissues where it can get in.”
Dr. Manche said the eyes would be “the least common mode of transmission.”
Besides looking at the eyes as an entryway, researchers are exploring whether people with SARS-CoV-2 in their eyes could infect others through their tears or eye secretions.
“The virus has been detected in tears and conjunctival swab specimens from individuals with COVID-19,” Dr. Duh said. “If someone rubs their eyes and then touches someone else or touches a surface, that kind of transmission mechanism could occur.
“It again highlights how contagious the coronavirus is and how stealthy it can be in its contagiousness,” he said.
If it turns out that the coronavirus can infect the eyes, the virus could persist there as a source of contagion, Dr. Duh said. “The eyes and tears could serve as a source of infection to others for longer.” He noted a case of a COVID-infected woman with conjunctivitis who still had detectable virus in her eyes 3 weeks after her symptoms started.
Conjunctivitis, commonly called pink eye, could be a symptom of COVID-19, said Dr. Sen, who is an ophthalmologist. She recommends that people get tested for COVID-19 if they have this condition, which is marked by redness, itchiness, tearing, discharge, and a gritty sensation in the eye.
Dr. Fair, the virologist, was released from the hospital to recover at home and continued to urge eye protection. “People like to call people like me fearmongers ... but the reality is, we’re just trying to keep them safe,” he told NBC News.
The CDC hasn’t issued such advice. In an email, the agency said it “does not have specific recommendations for the public regarding eye protection. However, in health care settings, the CDC does recommend eye protection for health care workers to prevent transmission via droplets.”
Dr. Sen agrees. “For the general public, I don’t think we have enough data to suggest that they should be covering the eyes in some form,” she said.
When she goes to the grocery store, she doesn’t wear eye protection. “I am only wearing goggles when I’m seeing ophthalmology patients up close, basically because I’m 4 or 5 inches away from them.”
But fuller protection – a mask, gloves, and even eye protection, such as goggles – might help those taking care of a COVID-19 patient at home, Dr. Manche said. “If you’re caring for somebody, that’s a much higher risk because they’re shedding viral load. You lessen the chance of transmission.”
For the public, Dr. Sen stresses the continued importance of hand hygiene. “In an abundance of caution, I would still encourage handwashing and not touching the eye for many reasons, not just COVID. You can transmit simple infections to your eye. We have other viruses and bacteria that are circulating in the environment and in our bodies elsewhere, so we can easily carry those to the eyes.”
Switching from contact lenses to eyeglasses could help cut down on touching the eyes, she says. Eyeglasses can also be a “mechanical barrier” to keep hands away.
Eyeglasses might block some droplets if someone nearby sneezes or coughs, Dr. Manche said, although they “aren’t sealed around the edges. They’re not like true medical goggles that are going to keep out the virus.”
Dr. Duh agrees that health care workers must don eye protection, but he said the public doesn’t need to start wearing goggles, face shields, or other eye protection. “I still think the major mode of transmission is through the nasal passages and the respiratory system,” he said.
It’s unclear whether eye protection is warranted for airplane passengers, Dr. Manche said. “It probably wouldn’t hurt, but I think the more important thing would be to take precautions: wearing a face mask, washing your hands, cleaning the seats and tray tables in front of you, and not touching things and touching your face and eyes.”
A version of this article originally appeared on WebMD.com.
You can catch COVID-19 if an infected person coughs or sneezes and contagious droplets enter your nose or mouth. But can you become ill if the virus lands in your eyes?
Virologist Joseph Fair, PhD, an NBC News contributor, raised that concern when he became critically ill with COVID-19, the disease caused by the coronavirus. From a hospital bed in his hometown of New Orleans, he told the network that he had flown on a crowded plane where flight attendants weren’t wearing masks. He wore a mask and gloves, but no eye protection.
“My best guess,” he told the interviewer, “was that it came through the eye route.”
Asked if people should start wearing eye protection, Dr. Fair replied, “In my opinion, yes.”
While Dr. Fair is convinced that eye protection helps, other experts aren’t sure. So much remains unknown about the new coronavirus, SARS-CoV-2, that researchers are still trying to establish whether infection can actually happen through the eyes.
“I don’t think we can answer that question with 100% confidence at this time,” said H. Nida Sen, MD, director of the uveitis clinic at the National Eye Institute in Bethesda, Md., and a clinical investigator who is studying the effects of COVID-19 on the eye. But, she says, “I think it is biologically plausible.”
Some research has begun pointing in that direction, according to Elia Duh, MD, a researcher and professor of ophthalmology at Johns Hopkins University in Baltimore.
The clear tissue that covers the white of the eye and lines the inside of the eyelid, known as the conjunctiva, “can be infected by other viruses, such as adenoviruses associated with the common cold and the herpes simplex virus,” he said.
There’s the same chance of infection with SARS-CoV-2, said Dr. Duh. “ just like the nasal passages are exposed. In addition, people rub and touch their eyes a lot. So there’s certainly already the vulnerability.”
To study whether SARS-CoV-2 could infect the eyes, Dr. Duh and fellow researchers at Johns Hopkins looked at whether the eye’s surface cells possess key factors that make the virus more likely to enter and infect them.
In their study (BioRxiv. 2020 May 9. doi: 10.1101/2020.05.09.086165), which is now being peer-reviewed, the team examined 10 postmortem eyes and five surgical samples of conjunctiva from patients who did not have the coronavirus. They wanted to see whether the eyes’ surface cells produced the key receptor for coronavirus, the ACE2 receptor.
For SARS-CoV-2 to enter a cell, “the cell has to have ACE2 on its surface so that the coronavirus can latch onto it and gain entry into the cell,” Dr. Duh said.
Not much research existed on ACE2 and the eye’s surface cells, he said. “We were really struck that ACE2 was clearly present in the surface cells of all of the specimens.” In addition, the researchers found that the eye’s surface cells also produce TMPRSS2, an enzyme that helps the virus enter the cell.
More research is needed for a definitive answer, Dr. Duh said. But “all of this evidence together seems to suggest that there’s a good likelihood that the ocular surface cells are susceptible to infection by coronavirus.”
If that’s the case, the virus then could be transmitted through the tear ducts that connect the eyes to the nasal cavity and subsequently infect the respiratory cells, he said.
Edward E. Manche, MD, professor of ophthalmology at Stanford (Calif.) University, said that while doctors don’t know for sure, many think eye infection can happen. “I think it’s widely believed now that you can acquire it through the eye. The way the virus works, it’s most commonly transmitted through the mouth and nasal passages. We have mucosal tissues where it can get in.”
Dr. Manche said the eyes would be “the least common mode of transmission.”
Besides looking at the eyes as an entryway, researchers are exploring whether people with SARS-CoV-2 in their eyes could infect others through their tears or eye secretions.
“The virus has been detected in tears and conjunctival swab specimens from individuals with COVID-19,” Dr. Duh said. “If someone rubs their eyes and then touches someone else or touches a surface, that kind of transmission mechanism could occur.
“It again highlights how contagious the coronavirus is and how stealthy it can be in its contagiousness,” he said.
If it turns out that the coronavirus can infect the eyes, the virus could persist there as a source of contagion, Dr. Duh said. “The eyes and tears could serve as a source of infection to others for longer.” He noted a case of a COVID-infected woman with conjunctivitis who still had detectable virus in her eyes 3 weeks after her symptoms started.
Conjunctivitis, commonly called pink eye, could be a symptom of COVID-19, said Dr. Sen, who is an ophthalmologist. She recommends that people get tested for COVID-19 if they have this condition, which is marked by redness, itchiness, tearing, discharge, and a gritty sensation in the eye.
Dr. Fair, the virologist, was released from the hospital to recover at home and continued to urge eye protection. “People like to call people like me fearmongers ... but the reality is, we’re just trying to keep them safe,” he told NBC News.
The CDC hasn’t issued such advice. In an email, the agency said it “does not have specific recommendations for the public regarding eye protection. However, in health care settings, the CDC does recommend eye protection for health care workers to prevent transmission via droplets.”
Dr. Sen agrees. “For the general public, I don’t think we have enough data to suggest that they should be covering the eyes in some form,” she said.
When she goes to the grocery store, she doesn’t wear eye protection. “I am only wearing goggles when I’m seeing ophthalmology patients up close, basically because I’m 4 or 5 inches away from them.”
But fuller protection – a mask, gloves, and even eye protection, such as goggles – might help those taking care of a COVID-19 patient at home, Dr. Manche said. “If you’re caring for somebody, that’s a much higher risk because they’re shedding viral load. You lessen the chance of transmission.”
For the public, Dr. Sen stresses the continued importance of hand hygiene. “In an abundance of caution, I would still encourage handwashing and not touching the eye for many reasons, not just COVID. You can transmit simple infections to your eye. We have other viruses and bacteria that are circulating in the environment and in our bodies elsewhere, so we can easily carry those to the eyes.”
Switching from contact lenses to eyeglasses could help cut down on touching the eyes, she says. Eyeglasses can also be a “mechanical barrier” to keep hands away.
Eyeglasses might block some droplets if someone nearby sneezes or coughs, Dr. Manche said, although they “aren’t sealed around the edges. They’re not like true medical goggles that are going to keep out the virus.”
Dr. Duh agrees that health care workers must don eye protection, but he said the public doesn’t need to start wearing goggles, face shields, or other eye protection. “I still think the major mode of transmission is through the nasal passages and the respiratory system,” he said.
It’s unclear whether eye protection is warranted for airplane passengers, Dr. Manche said. “It probably wouldn’t hurt, but I think the more important thing would be to take precautions: wearing a face mask, washing your hands, cleaning the seats and tray tables in front of you, and not touching things and touching your face and eyes.”
A version of this article originally appeared on WebMD.com.