"My bet, assuming this can be confirmed, is that they may have just threaded the needle perfectly with a low dose at the right time in the infection."
— Carl June, MD (Interview - June 2020)
In light of the June 2020 publication of the interim findings of the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial, there is perhaps no more controversial area of COVID-19 related therapy at the moment than that of dexamethasone and the use of corticosteroids.
In approaching the issue, it seems pertinent to address several questions:
What is the Randomized Evaluation of COVID-19 Therapy (RECOVERY) Study?
The RECOVERY study is a large, on-going multi-center trial in the United Kingdom designed to assess the effects of several treatments, including dexamethasone, in patients hospitalized with COVID-19.
RECOVERY is the first randomized trial to evaluate an immunosuppressant for SARS-Co-V2. In the June preliminary report, which involved 6425 patients randomized to 6 mg/day of dexamethasone vs. usual care, dexamethasone was found to reduce deaths by one-third in patients on invasive mechanical ventilation (29.0% vs. 40.7%) and by one-fifth in patients receiving oxygen without invasive mechanical ventilation (21.5% vs. 25.0%).
Benefit was clearer in patients treated more than 7 days after onset of respiratory support (i.e., supplemental oxygen or mechanical ventilation) therapy. The drug did not reduce mortality in hospitalized patients not on respiratory support at randomization (17.0% vs. 13.2%).
Why was Dexamethasone studied in RECOVERY?
Dexamethasone works by suppressing inflammation and the immune system, both of which are activated in the course of COVID-19 infection. A generic glucocorticoid, it was one of several drugs studied in the RECOVERY trial (the others, hydroxychloroquine and lopinavir–ritonavir showed little promise and were abandoned).
Dexamethasone has the advantage of wide availability, a long track record of use (the drug was introduced in the 1950s) and can be administered in oral, injectable or infusible formats.
Given the well-known capacity of the immune system and inflammatory response to elicit lung tissue damage as a byproduct of its response to viral respiratory diseases, dexamethasone has been studied in influenza, severe acute respiratory syndrome (SARS) and Middle Eastern Respiratory Syndrome (MERS), and perhaps more importantly in the context of SARS-CoV-2, in acute respiratory distress syndrome (ARDS).
ARDS is the most common medical complication of SARS-CoV-2, resulting from secondary respiratory insults such as pneumonia, hypoxemia, widespread alveolar damage and immune system impairment.
Why is Dexamethasone Use in Respiratory Disease Controversial?
The use of the corticosteroids during a respiratory illness is controversial because while mounting an immune response to eliminate a viral infection, the body must not damage native lung tissue. An overactive immune response may result in harm to native lung tissue that is worse than damage from the original virus. Using corticosteroids to suppress an immune response may result in an uncontrolled viral infection. Identifying how and when corticosteroids can strike this equilibrium between benefit and harm is a substantial consideration.
Outside of patient factors, pathological characteristics and dosage issues, a key question when using the corticosteroids in respiratory illness is timing of administration. In bacterial or viral infection, symptoms generally appear within two days of initial exposure. The innate immune response and consequent inflammation follow within 4 to 7 days, with an antibody peak occurring at 7 to 10 days. The adaptive immune response then ramps up to stop and clear the infection at about 2 to 3 weeks.
Thus, hypothetically corticosteroids should be used early, on the heels of the innate response to reduce the ensuing inflammation. This timed approach has been supported by several well-designed clinical trials, all of which found an association between early corticosteroid use in patients with moderate-to-severe ARDS and therapeutic benefit (survival or reduction in need for respiratory therapy).
Why Is Timing an Issue for Dexamethasone Dosing in COVID-19?
If anything is clear, it’s that little in the trajectory of COVID-19 resembles that of previously described respiratory illnesses. Unlike MERS-CoV, for example, SARS-CoV-2 is seldom found in blood during symptomatic illness, even in people with severe disease. In influenza, viral clearance is usually associated with resolution of symptoms. In patients with COVID-19, however, hypoxemia can occur just as the viral load in the upper respiratory tract is disappearing.
As we have noted, in other respiratory diseases, ARDS tends to occur in the early days of the illness as the innate immune system responds to the infection and lung tissue inflammation begins to rise. In COVID-19, however, ARDS appears to occur much later, during the adaptive immune response to the infection, when a specific antibody against SARS-CoV-2 begins to appear.
In other words, by the time ARDS begins to occur in patients with COVID-19, the viral load has begun to wane, and patients are paradoxically requiring respiratory support (e.g., ventilator or supplemental oxygen).
This delayed ARDS phenomena is unique to SARS-CoV-2 and likely explains why patients in the RECOVERY trial treated early with dexamethasone (those not on respiratory therapy) did not benefit, while those treated later did.
The authors of RECOVERY note in their conclusion that peak viral shedding in COVID-19 appears to be higher early in the illness and declines thereafter. Thus, the early use of drugs such as corticosteroids that blunt the immune response in COVID-19 patients not yet seriously ill may be counterproductive, if not harmful.
Timing is Everything
In their summation, the RECOVERY authors expanded on the concept that timing is a vital element in dexamethasone therapy in COVID-19:
“It is likely that the beneficial effect of corticosteroids in severe viral respiratory infections is dependent on using the right dose, at the right time, in the right patient. High doses may be more harmful than helpful, as may corticosteroid treatment given at a time when control of viral replication is paramount and inflammation is minimal.”
Commenting at Penn Medicine's Cancer and COVID-19 virtual conference in late September 2020, NIAID Director Anthony Fauci, MD, observed that the lack of dexamethasone efficacy in early treated patients in the RECOVERY trial told us what we already know about the pathogenesis of COVID-19.
“Early on, you want to hit the virus and leave the immune response intact; whereas in later disease, what you want to do is dramatically diminish the hyperactive inflammatory response.”
Many thanks to Krisda H. Chaiyachati, MD, MPH, MSHP, who provided editorial guidance and reviewed medical content for this article.
Interviewed during the recent Cancer and COVID-19 Symposium at Penn Medicine, NIAID Director Anthony Fauci, MD, reflects in the video below on the RECOVERY trial and the scheduling of dexamethasone dosing in patients with COVID-19.