August 9, 2020
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Dexamethasone in the treatment of covid-19

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  1. Raymond M Johnson, Associate Professor, Department of Medicine and Microbial Pathogenesis,
  2. Joseph M Vinetsprofessor of medicine
  1. Infectious Diseases Department, Internal Medicine Department, Yale School of Medicine, New Haven, Connecticut, USA
  1. Compliance: R M Johnson Raymond.Johnson {} on yale.edu

Preliminary test results are mostly good news, but time is everything.

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On June 16, a press release reported on investigators in Return 191, participants with severe Covid-19 (2104) who received 6 mg of dexamethasone once a day had a mortality rate of 8-26% lower than that of 4321 participants who received standard care. Changes to the treatment protocol for NHS Covid-19 were soon announced based on these results. The results are not reviewed or published, although the preprint is available. 2 In the context of an ongoing, geographically mobile, deadly pandemic in which few highly effective, not to mention affordable, treatments are available, the RECOVERY press release duly prepared a great deal of attention, including enthusiasm and care.

Before the release of RECOVERY, the only evidence-based treatment available was remdesivir, an RNA polymerase inhibitor that slightly reduced hospital discharge in patients with severe 193 but did not reduce the viral load on the airways. 45 RECOVERY is the first large randomized study check immunosuppression as a therapeutic option. It is important to note that the containment of a mature immune response to the SARS-CoV-2 virus is different from the presence of major immunosuppression during infection.

Disease trajectory

Covid-19 is a biphasic disease with an innate immune response that translates into a widely effective adaptive immune response, with the exception of a minority of people who develop a serious illness. The pathogenesis of SARS-CoV-2 is fundamentally different from its predecessors SARS-CoV-1 and MERS, in which poor results correlate with viremia and high viral loads in the lungs at the time of death.

The United States Centers for Disease Prevention and Control (CDC) Guidelines 9 recommend that you do not use corticosteroid therapy for coronavirus infections, since steroids “prolong the replication of the virus.” in patients with MER, although the time difference before virus clearance was not statistically significant in the primary data.610 Unlike the MERS coronavirus, SARS-CoV-2 is rarely found in the blood during the symptomatic phase of covid-19, even in people with severe illnesses . 11 In addition, hypoxemia can develop in the same way that a viral load in the upper respiratory tract decreases rapidly or becomes undetectable.

Patients admitted to the hospital with Covid-19 usually report onset of symptoms three to five days after exposure (fatigue, chills), progression to fever and dry cough after 48 hours. The transition to a serious illness with hypoxemia occurs within five to seven days with a symptomatic disease, approximately 8-14 days after the initial exposure. In the RECOVERY study, dexamethasone was useful for participants who received seven or more days in the symptomatic phase with the onset of hypoxemia. It is important to note that there was a slight tendency (P = 0.14) to possible harm affecting participants without hypoxemia and without mechanical ventilation. Thus, recovery results confirm the use of dexamethasone only for patients with hypoxemia, and not for patients with milder diseases. Data do not confirm the use of dexamethasone or other corticosteroids on an outpatient basis.

Timing is everything

Corticosteroids, such as dexamethasone, have a broad effect on innate and adaptive immunity. Adaptive immunity can be an integral part of covid-19 immunopathology, since the occurrence of acute respiratory distress syndrome temporarily correlates with the appearance of a specific antibody against SARS-CoV-2.14. In March 2020, a retrospective assessment of the clinical experience with covid-19 was conducted in China. reported that in the subgroup of patients with advanced ARDS, objectively more sick patients receiving methylprednisolone had lower mortality rates than patients not receiving methylprednisolone. Despite concerns about possible steroid-related complications, it would be unreasonable to defer the use of widely available treatments with the proven benefit of mortality.

Evidence Gaps

However, questions remain unresolved. RECOVERY researchers have not investigated the optimal type of corticosteroid, neither the time, nor the dose, nor the duration of this class of drugs. The dexamethasone dose used was about half the functional dose of the corticosteroid used to prevent treatment-induced acute respiratory distress syndrome in moderate or severe pneumocystis pneumonia. Although dexamethasone worked, it is unclear whether corticosteroids are the best option for all patients in the second phase of the disease or whether treatment may be less useful for some subgroups, such as people with diabetes. Ongoing immune modulation trials with calcineurin inhibitors may shed light on these issues.

Adults in need of ventilation were relatively young, with an average age of 59 years. In a subsequent analysis of the subsets, dexamethasone did not benefit the two older age groups, so the benefits and risks of dexamethasone for the elderly remain unclear. Virological indicators, such as viral load, have not been reported and will be useful in future studies because they may ultimately determine treatment decisions, including timing. Long-term follow-up of the baseline group will be critical in identifying the harm associated with corticosteroid use.

RECOVERY investigators and staff should be thanked for organizing and completing this test during a pandemic. The United Kingdom’s united healthcare system provides an opportunity for collaboration, and such research is difficult to conduct in a disparate academic medical environment, such as the United States and other countries. Perhaps less desirable is the current practice of disseminating early clinical trial data in press releases. Clinicians and politicians need access to detailed data and analyzes before making or making therapeutic decisions or recommendations.

This article is made freely available for use in accordance with the terms and conditions of the BMJ website for the period of the covid-19 pandemic or until the BMJ determines otherwise. You can use, download and print the article for any legal, non-commercial purposes (including extracting text and data), provided that all copyright and trademark notices are preserved.

https://bmj.com/coronavirus/usage

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