Last week, the World Health Organization (WHO) issued new guidelines on the use of corticosteroids for the treatment of novel coronavirus infection. Following the results of meta-analysis that pooled data from eight randomised clinical trials, the WHO has made two recommendations: that corticosteroid therapy be used for 7 to 10 days in patients with severe and critical Covid-19; that it not be used in patients with non-severe Covid-19.
What are corticosteroids?
Corticosteroids are low-cost anti-inflammatory drugs that closely mimic cortisol, the hormone naturally produced by the adrenal glands in humans. They are commonly used in treatment for rheumatological inflammatory conditions: inflammations of muscles, inflammation of blood vessels, chronic arthritis, and lupus. They are used in lung diseases, kidney inflammation, eye inflammation, and to reduce swelling associated with tumours of the brain and spine. Three commonly used corticosteroids are dexamethasone, hydrocortisone, and methylprednisolone.
Earlier, Oxford researchers leading the RECOVERY clinical trials in the UK had announced that dexamethasone reduced death by up to one-third in hospitalised Covid-19 patients who develop acute respiratory complications. Since then, dexamethasone has been part of standard clinical management protocol adopted by many countries.
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What is the newly published meta-analysis about?
The WHO Rapid Evidence Appraisal for Covid-19 Therapies (REACT) Working Group last week published a meta-analysis in JAMA on the association between the systemic administration of corticosteroids and mortality among critically ill patients with Covid-19. Seven trials were included in the final meta-analysis, with patients having been recruited from Australia, Brazil, Canada, China, Denmark, France, Ireland, the Netherlands, New Zealand, Spain, the UK, and the US. A total of 1,703 patients were randomised (678 to corticosteroids and 1025 to usual care or placebo).
The researchers classified trials based on low and high dose: dexamethasone at low and high doses, low-dose hydrocortisone, and high-dose methylprednisolone. The analysis sought to answer a key question: is the administration of corticosteroids associated with reduced 28-day mortality in critically ill patients?
What are the findings of the analysis?
The study reported 222 deaths among the 678 patients randomised to corticosteroids, and 425 deaths among the 1,025 randomised to usual care or placebo. “This corresponds to an absolute mortality risk of 32% with corticosteroids compared with an assumed mortality risk of 40% with usual care,” it said.
The analysis found that corticosteroids were associated with “lower mortality among critically ill patients who were and were not receiving invasive mechanical ventilation at randomization”. “… Trial results from diverse clinical and geographic settings suggest that in the absence of compelling contraindications, a corticosteroid regimen should be a component of standard care for critically ill patients with Covid-19,” it said.
“In this prospective meta-analysis of clinical trials of critically ill patients with Covid-19, administration of systemic corticosteroids, compared with usual care or placebo, was associated with lower 28-day all-cause mortality,” it said.
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What are the new WHO guidelines?
“We recommend systemic corticosteroids rather than no systemic corticosteroids for the treatment of patients with severe and critical COVID-19 (strong recommendation, based on moderate certainty evidence),” the WHO has said.
The WHO also highlighted that in contrast to other experimental treatment that is “expensive and “difficult” to obtain and require “advanced medical infrastructure”, corticosteroids are “low cost, easy to administer, and readily available globally”. “Accordingly, systemic corticosteroids are among a relatively small number of interventions for Covid-19 that have the potential to reduce inequities and improve equity in health. Those considerations influenced the strength of this recommendation,” it said.
“The ease of administration, the relatively short duration of a course of systemic corticosteroid therapy, and the generally benign safety profile of systemic corticosteroids administered for up to 7–10 days led the panel to conclude that the acceptability of this intervention was high,” it said.
Another recommendation said: “We suggest not to use corticosteroids in the treatment of patients with non-severe Covid-19 (conditional recommendation, based on low certainty evidence).”
The WHO said the second recommendation applies to patients with “non-severe disease regardless of their hospitalization status”. It pointed out specifically that patients hospitalised for isolation purpose, “should not be treated with systemic corticosteroids”.
“If the clinical condition of patients with non-severe Covid-19 worsens (i.e. increase in respiratory rate, signs of respiratory distress or hypoxemia) they should receive systemic corticosteroids,” the WHO said.
It recommended, however, that non-severe Covid-19 patients who are already being treated with systemic corticosteroids for other reasons chronic autoimmune disease and COPD —need not discontinue the course.
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What are the limitations of the study and the recommendation?
The findings of the meta-analysis are significant because it is on a relatively large number of critically ill patients with Covid-19 from geographically diverse sites. However, the study reported that optimal dose and duration of treatment could not be assessed in the analysis.
The WHO, for its part, has pointed out that the “long-term effect” of corticosteroids on mortality in Covid-19 survivors is unknown. Second, it says that clinical effects of corticosteroids in patients with non-severe Covid-19 — that is, pneumonia without hypoxemia — “remain unclear”. Third, the impact of corticosteroids on immunity and the risk of a subsequent infection, which may impact the risk of death after 28 days, is still uncertain.
What is India’s clinical management protocol on corticosteroids?
In June, the Indian government issued revised guidelines on clinical management of Covid-19 patients, where it recommended dexamethasone as an alternative to another steroid — methylprednisolone — for moderate to severe cases. In the most recently published FAQs on Covid-19 from AIIMS ICU, one the question is whether methylprednisole is better than dexamethasone. The answer: “Corticosteroids are currently indicated in moderate to severe Covid-19 patients. The recovery trial has used dexamethasone. However, both IV dexamethasone or methyl prednisolone may be used based on the availability.”
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