An intense inflammatory response is often seen in patients with COVID-19 infection leading to multiorgan dysfunction, including lung injury and severe acute respiratory distress syndrome (ARDS). Complement pathways are activated, resulting in microvascular injury and a procoagulant state.1 The hyperinflammatory response in COVID-19 may resemble secondary hemophagocytic lymphohistiocytosis (sHLH), characterized by high levels of C-reactive protein, ferritin, and cytokines.2 In a retrospective study of 150 patients predictors of mortality included raised serum levels of ferritin and IL-6, suggesting that the SARS-COV-2- induced hyperinflammatory syndrome may be the trigger for poor outcomes.3 The hyperinflammatory syndrome that characterizes severe acute viral infections may lead to significant tissue injury that may be mitigated by corticosteroid administration.
When does the inflammatory reaction occur?
The early phase of COVID-19 occurs during viral entry and is characterized by mild symptoms, including fever, cough, and malaise. During the second stage of illness, viral replication and local inflammatory changes occur in the lung, which often results in significant arterial hypoxemia. At this stage, there may be a mild elevation in the level of inflammatory markers. The third stage typically results in a systemic hyperinflammatory response, often leading to respiratory failure, vasoplegia, and shock. During this stage of an overexuberant inflammatory response, corticosteroids and other immunomodulatory therapy may be beneficial.
Evidence from previous viral epidemics
The use of corticosteroids in viral pneumonia has been of ongoing interest. In a randomized controlled trial from 2004, intravenous hydrocortisone 100 mg 8 hourly was compared to placebo within the first 7 days of onset of Severe Acute Respiratory Syndrome (SARS). Intravenous methylprednisolone, 500 mg daily, was administered as rescue therapy in four of nine patients in the hydrocortisone group and six of seven patients in the control group. In the second and third week of illness, the plasma concentration of SARS-CoV RNA was significantly higher among patients who received intravenous hydrocortisone during the initial phase of the illness. This study suggested that early use of corticosteroids in SARS may lead to delayed viral clearance.4
A retrospective study of 401 patients with SARS included 152 who were critically ill. Corticosteroids were administered in 121 (79.6%) critically ill patients. On adjusted analysis, corticosteroid administration resulted in lower mortality and a shorter period of hospitalization. The incidence of infective or other complications was not increased with corticosteroid use.5
A retrospective cohort study was performed in ICU patients with Middle East Respiratory Syndrome (MERS) from 14 hospitals in Saudi Arabia. Of the 309 patients included in the study, 151(49%) patients received the equivalent of a median dose of 300 mg (IQR: 200–400) hydrocortisone per day. Corticosteroid-treated patients were more likely to require invasive ventilation and had a significantly higher 90-day mortality. Besides, corticosteroid administration was associated with delayed viral clearance.6
Corticosteroids in COVID-19
The Surviving Sepsis Guidelines had recommended against the use of corticosteroids in COVID-19 patients with respiratory failure who require mechanical ventilation at the beginning of the pandemic.7 In a retrospective observational study, 25 of 78 patients with COVID-19 received methylprednisolone based on clinician judgment. No delay in viral clearance was observed among patients who received corticosteroids in this study.8 In another study, methylprednisolone, 1–2 mg/kg, was administered intravenously in 26 of 46 patients with COVID-19 for 5–7 days. Compared to the control group, oxygenation saturation improved more rapidly in methylprednisolone-treated patients. Besides, the resolution of changes on CT imaging was more pronounced with the administration of methylprednisolone.9
Dexamethasone in COVID-19: The RECOVERY trial
The RECOVERY trial is a randomized clinical trial designed to evaluate several treatment modalities in patients with COVID-19 infection.10 The study included over 11,000 patients from 175 hospitals of the National Health Services. Hospitalized patients who had clinically suspected or laboratory-confirmed COVID-19 infection were eligible. Patients were assigned in a 2:1 ratio to receive usual care or, in addition, dexamethasone 6 mg once daily IV or orally for a maximum of 10 days using web-based randomization.11 Patients were excluded if dexamethasone was unavailable at the treating hospital or considered to be definitely indicated or contraindicated by the treating physician. The treating staff was not blinded to the study arm.
The sample size could not be estimated at the onset of the COVID-19 pandemic as clinical outcomes were unclear at that stage. During the course of the trial, the Steering Committee recommended that a sample size of 2000 patients in the intervention arm and 4000 patients in the control arm would provide the study with 90% power for a p-value of 0.11 to detect an absolute risk difference of 4% in the 28-day mortality. Hence, enrollment was ceased after 2104 patients were randomized to the dexamethasone and 4321 patients to the usual care arm. The mean age of patients was 66.1 years, and predominantly male (64%); 56% of patients had co-morbidities, including diabetes (24%), heart disease (27%), and chronic lung disease (21%). At baseline, 24% of all patients did not receive any respiratory support, 60% received oxygen alone or with non-invasive ventilatory support if required, and 16% received invasive mechanical ventilation or were on extracorporeal membrane oxygenation.
The primary outcome was 28-day mortality. Overall, the 28-day mortality was significantly lower in patients who received dexamethasone compared to those who received standard care alone (21.6% vs. 24.6%; rate ratio: 0.83, CI: 0.74–0.92, P <0.001). The 28-day mortality was compared in pre-specified subgroups of patients receiving no respiratory support, requiring supplementary oxygen with or without non-invasive ventilation, and those who required invasive ventilation or extracorporeal membrane oxygenation. Overall, the 28-day mortality was highest among patients who received invasive mechanical ventilation (40.7%) compared to those who received oxygen alone (25%) and those who required no respiratory support (13.2%) at randomization. The greatest reduction in mortality was seen among patients who received invasive mechanical ventilation; dexamethasone administration resulted in a reduction in mortality by 35% in this subgroup (rate ratio 0.65; 95% CI: 0.51–0.82; p <0.001). A 20% reduction in mortality was observed among patients who received supplemental oxygen, with or without the use of non-invasive ventilation (rate ratio 0.80; 95% CI: 0.70–0.92; p = 0.002). However, there was no difference in 28-day mortality with dexamethasone in patients who did not require respiratory support.
Among the secondary outcomes, dexamethasone administration resulted in a statistically significant (though not clinically meaningful) reduction in the duration of hospitalization (median: 12 vs. 13 days) and a higher proportion of patients who were discharged within 28 days. Among patients who were not invasively ventilated at enrolment, significantly fewer patients progressed to the composite outcome of invasive ventilation or death in the dexamethasone arm.
The study does not provide details of ventilation parameters and the incidence and severity of organ failures in this preliminary online report. The study was unblinded, and hence may be subject to bias. Although pre-specified, the improved survival observed in patients receiving supplemental oxygen or invasive ventilation is based on subgroup analysis and can only be considered hypothesis-generating. The duration of hospital stay was less by a median of only 1 day, although this difference was statistically significant.
Conducted against the background of extremely challenging conditions, the RECOVERY trial provides robust evidence that dexamethasone reduces mortality in hospitalized patients with COVID-19. The effect on mortality appears to be highest among the sickest of patients who require respiratory support, including mechanical ventilation. In contrast, patients who are less severely ill do not seem to benefit.
- The use of corticosteroids in viral pneumonia has been shrouded in controversy, with previous studies suggesting delayed viral clearance and adverse impact on clinical outcomes
- The late stage of COVID-19 infection is characterized by an intense systemic hyperinflammatory response, often leading to respiratory failure, vasoplegia, and shock in severely ill patients
- Corticosteroids may alleviate the deleterious effects related to the hyperinflammatory phase
- The RECOVERY trial provides incontrovertible evidence that dexamethasone reduces 28-day mortality among patients who require respiratory support; the beneficial effects were not observed in patients who did not require supplemental oxygen at enrolment
- Future research needs to evaluate the type of steroid, the dose, and optimal duration of administration.
1. Magro C, Mulvey JJ, Berlin D, et al. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases. Transl Res. 2020;220:1-13. doi:10.1016/j.trsl.2020.04.007
2. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. The Lancet. 2020;395(10229):1033-1034. doi:10.1016/S0140-6736(20)30628-0
3. Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. Published online March 3, 2020:1-3. doi:10.1007/s00134-020-05991-x
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8. Fang X, Mei Q, Yang T, et al. Low-dose corticosteroid therapy does not delay viral clearance in patients with COVID-19. J Infect. 2020;81(1):147-178. doi:10.1016/j.jinf.2020.03.039
9. Wang Y, Jiang W, He Q, et al. Early, low-dose and short-term application of corticosteroid treatment in patients with severe COVID-19 pneumonia: single-center experience from Wuhan, China. medRxiv. Published online March 12, 2020:2020.03.06.20032342. doi:10.1101/2020.03.06.20032342
10. Randomised Evaluation of COVID-19 Therapy – Full Text View – ClinicalTrials.gov. Accessed June 29, 2020. https://clinicaltrials.gov/ct2/show/NCT04381936
11. Horby P, Lim WS, Emberson J, et al. Effect of Dexamethasone in Hospitalized Patients with COVID-19: Preliminary Report. Infectious Diseases (except HIV/AIDS); 2020. doi:10.1101/2020.06.22.20137273