COVID-19 Infection—Preventing Clinical Deterioration | Critical Care Medicine | JAMA | JAMA Network
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Editor's Note
November 12, 2020

COVID-19 Infection—Preventing Clinical Deterioration

Author Affiliations
  • 1Associate Editor, JAMA
  • 2Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
  • 3Editor, JAMA
  • 4Deputy Editor, JAMA
JAMA. 2020;324(22):2300. doi:10.1001/jama.2020.21720

More than 38 million individuals worldwide have been infected with severe acute respiratory syndrome coronavirus 2, the virus causing coronavirus disease 2019 (COVID-19). For primary prevention, traditional public health approaches include wearing masks, physical distancing, contact tracing, and quarantine. These steps are the current standard of care as the world awaits the results of randomized trials of vaccines and monoclonal antibodies. For the treatment of patients with serious illness in the hospital, corticosteroids have emerged as the standard of care.1,2

But what about treatments for patients with COVID-19 who are neither hospitalized nor severely ill? The pilot study by Lenze and colleagues3 addresses a critically important question during the pandemic of how to prevent individuals who acquire COVID-19 from deteriorating to serious illness.4 If an effective treatment is found for this key gap in treatment, it will affect the health of millions of people worldwide. This study has important limitations, and the findings should be interpreted as only hypothesis generating; they should not be used as the basis for current treatment decisions. Despite this representing preliminary evidence, there were 2 reasons the editors decided to publish it in JAMA.

First, JAMA has received more than 10 000 COVID-19 submissions since February 2020, many proposing potential therapeutic approaches and studies describing the outcomes of various treatments for COVID-19, the vast majority of which used an observational design. As such, these reports had important limitations, such as susceptibility to selection bias, immortal time bias, and measurement bias, all of which can affect the magnitude of observed effects as well as the underlying validity of the findings. The World Health Organization, the US Centers for Disease Control and Prevention, and the broader medical community have called for more randomized clinical trials.5,6 This study by Lenze and colleagues3 presents only preliminary information, and requires confirmation in larger trials. But at the same time, it is a double-blind, placebo-controlled, randomized clinical trial, which is generally considered a design that minimizes bias and can support causal inference.

Second, the conduct of clinical trials is always difficult, but even more so during a pandemic. The study that Lenze and colleagues3 conducted is a remote trial, including no direct contact with self-quarantined participants, and has features that the editors believe are worth highlighting. The researchers delivered the study drug, supplies, and oxygen saturation monitoring devices to participants, conducted remote screening, and most often obtained virtual informed consent. They also collected the data via patient self-report and phone interviews. Although these individual components are part of other trials, in the current trial3 they are combined into a contactless design to protect both participants and researchers during a pandemic.

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Article Information

Published Online: November 12, 2020. doi:10.1001/jama.2020.21720

Corresponding Author: Christopher W. Seymour, MD, MSc, Department of Critical Care Medicine, University of Pittsburgh, Keystone Building, 3520 Fifth Ave, Ste 100, Pittsburgh, PA 15261 (

Conflict of Interest Disclosures: Dr Seymour reported receiving grants from the National Institutes of Health and receiving personal fees from Beckman Coulter and Edwards Lifesciences Inc. No other disclosures were reported.

Prescott  HC, Rice  TW.  Corticosteroids in COVID-19 ARDS.   JAMA. 2020;324(13):1292-1295. PubMedGoogle ScholarCrossref
Sterne  JAC, Murthy  S, Diaz  JV,  et al.  Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19.   JAMA. 2020;324(13):1330-1341. PubMedGoogle ScholarCrossref
Lenze  EJ, Mattar  C, Zorumski  CF,  et al.  Fluvoxamine vs placebo and clinical deterioration in outpatients with symptomatic COVID-19: a randomized clinical trial.   JAMA. Published online November 12, 2020. doi:10.1001/jama.2020.22760 Google Scholar
Kim  PS, Read  SW, Fauci  AS.  Therapy for early COVID-19: a critical need.   JAMA. Published online November 11, 2020. doi:10.1001/jama.2020.22813 Google Scholar
Kalil  AC.  Treating COVID-19—off-label drug use, compassionate use, and randomized clinical trials during pandemics.   JAMA. 2020;323(19):1897-1898. PubMedGoogle ScholarCrossref
Califf  RM, Hernandez  AF, Landray  M.  Weighing the benefits and risks of proliferating observational treatment assessments.   JAMA. 2020;324(7):625-626. PubMedGoogle ScholarCrossref
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    1 Comment for this article
    Consider All Evidence in Clinical Decisions
    Steve Kirsch, Executive Director | COVID-19 Early Treatment Fund (CETF)
    I read with concern this editorial on the phase II trial of fluvoxamine for COVID19 that my foundation, the COVID-19 Early Treatment Fund (CETF), sponsored.

    The study showed that fluvoxamine, with a long track record of clinical safety, has the potential to reduce clinical deterioration by an absolute 8.7% based on 0 events in the intervention and 6 events in the placebo group.

    The editors advise that this study should "not be used as the basis for current treatment decisions."

    We believe doctors should consider all available evidence in their clinical decisions, especially in a
    pandemic where the need to reduce the hospitalization rate is now critical.

    While it is true that a full phase III trial will be required for adding COVID19 as an FDA-approved indication for fluvoxamine, the editors should realize that for many patients, the results of such a phase III trial will come too late. Given the strong phase II data combined with the long safety record of fluvoxamine, the decision to prescribe fluvoxamine should be an option, left to the best judgment of the individual physician, balancing the likelihood of potential harm versus benefit.

    In a preprint, a large multi-center French observational study reported a protective effect of drugs that activate the sigma1 receptor [1]. Fluvoxamine is a stronger activator of sigma1 than the drugs included in that study, so we were not surprised that the protective effect was superior to that observed in the French study. Francis Collins recently wrote about the importance of the Sigma-1 receptor in protecting patients from deterioration [2].

    While the general sentiments of the JAMA editors are laudable, it reflects a pre-COVID19 mindset that ignores the grim reality of >5,000 people dying of COVID19 worldwide of COVID19 on a daily basis.


    [1] Association between SSRI Antidepressant Use and Reduced Risk of Intubation or Death
    in Hospitalized Patients with Coronavirus Disease 2019: a Multicenter Retrospective
    Observational Study, medRxiv preprint doi:; August 7, 2020

    [2] Protein Mapping Study Reveals Valuable Clues for COVID-19 Drug Development,
    CONFLICT OF INTEREST: We were a primary sponsor the fluvoxamine trial