Here’s another blog by Marissa Carter, PhD. Her background in epidemiology and data modeling help us interpret the tidal wave of information on COVID-19. We are all grateful for her insights.
Earlier this week while drinking my first coffee, I was astounded to read the press release on the RECOVERY trial regarding the low-dose (6 mg daily for 10 days) dexamethasone results. This is a British randomized controlled trial that has been running since March 2020 and has several arms besides usual standard of care, including Lopinavir-Ritonavir, low-dose corticosteroids, hydroxychloroquine, and azithromycin. In a factorial design, eligible patients are allocated simultaneously to no additional treatment vs convalescent plasma. The study allows a subsequent randomization for patients with progressive COVID-19 (evidence of hyper-inflammatory state): No additional treatment vs tocilizumab. The trial employs adaptive design and you can read the protocol online (it’s a well-designed trial in my opinion).
The results of dexamethasone among ventilated patients with COVID-19 are convincing:
Dexamethasone reduced deaths by one-third in ventilated patients (rate ratio 0.65 [95% confidence interval 0.48 to 0.88]; p=0.0003) and by one fifth in other patients receiving oxygen only (0.80 [0.67 to 0.96]; p=0.0021). There was no benefit among those patients who did not require respiratory support (1.22 [0.86 to 1.75; p=0.14).
So, why was I astounded?
Sepsis and Steroids
- Sepsis, as we all know, is a life-threatening organ dysfunction caused by a dysregulated host response to infection. A recent consensus document describes organ dysfunction as an acute increase in total Sequential Organ Failure Assessment (SOFA) score two points consequently to the infection.
- Treatment for sepsis has evolved over the years but mainly involves giving antibiotics, maintaining blood flow to organs, and treating the source of the infection. Steroids are frequently used in sepsis. However, high doses of steroids have been associated with poor outcomes.
- A very large ANZAC trial (the ADRENAL study) also showed that low doses of steroids did nothing to improve 90-day mortality. But, the same trial also showed that the median time to resolution of shock, median time to discharge from the ICU and the median time to cessation of mechanical ventilation were significantly shorter in the hydrocortisone group.
Viral Infections and Steroids
Steroids have also been used as a treatment for a variety of other viral infections. In the original SARS epidemic, various steroid regimens were used extensively.
After the epidemic abated, authors of this systematic review had the following to say about corticosteroid use in SARS patients:
“Corticosteroids were commonly prescribed to SARS patients with worsening pulmonary disease or progressing abnormalities on chest X-rays. Treatment regimens varied widely but can be classified into two groups, early treatment and rescue treatment given at a later stage of illness. It is difficult to make a clear recommendation about whether corticosteroids should be used to treat SARS-associated lung injury in any stage of illness, particularly as the drug is immunosuppressive and may delay viral clearance if given before viral replication is controlled. Of added concern are infectious complications, avascular necrosis, and steroid-induced psychosis—recognized adverse effects of corticosteroid use.”
My own review of steroid use in avian influenza was also very nuanced:
“The implication for treatment based upon the aforementioned discussion is for clinicians to proceed cautiously. In terms of practicalities, if adjunctive steroid therapy is decided upon, it should be at a low dose and administered for a sufficient time (7–10 days). There is no evidence that higher dosages are useful from both a theoretical or experimental point of view, and moreover, the side effects of high dosages can be substantial, even if the patient recovers from the infection.”
Kudos to the British researchers who took all lessons learned to heart by coming up with a dosage regimen of 6 mg daily for 10 days.
A key feature of many nasty viruses is the ability to induce hypercytokinemia (cytokine storms) in the cell. This is the deadly situation in which the virus induces excessive pro-inflammatory cytokine expressions while retarding the levels anti-inflammatory cytokines, thus upsetting the cell’s finely tuned immune response. In simple terms it would be like cutting a car’s brake fluid lines and gluing the accelerator pedal to the floorboard. The term originated from studies of H5N1 influenza in which researchers were trying to understand the lethality of the virus.
Cytokine storms induced by viruses are almost certainly different between species although they have some common features. At this point we do not know much about COVID-19 although there is some evidence that unrestrained activation of complement induced by the virus in the lungs and other organs plays a major role in acute and chronic inflammation, endothelial cell dysfunction, thrombus formation, and intravascular coagulation, and ultimately contributes to multiple organ failure and death. A slew of papers have also been deposited in various preprint archives this past week detailing some of the functions of the non-structural proteins that the virus produces but it will be several months before we have a clearer picture as to how these expressed proteins interfere with the boy’s normal response to a pathogen. How low-dose steroids are able to tweak a developing cytokine storm in seriously ill patients is also likely to be a hot topic of study this year.
The Path Forward
It will be some months before the British study undergoes formal review and is published. Given the recent debacle about studies published in the NEJM and The Lancet that were later retracted due to dodgy data, journal editors will likely take a bit more time. Nevertheless, the results to date of administering relatively low dose dexamethasone to intubated patients with COVID-19 are very promising and delightfully surprising. I urge clinicians who are involved in the treatment of COVID-19 patients to look at the data on dexamethazone.