A living WHO guideline on drugs for COVID-19 released

A standing international panel of content experts, patients, clinicians, and methodologists, free from relevant conflicts of interest, produce recommendations for clinical practice and they conducted a systematic review to conclude that systemic corticosteroids reduce the need for invasive mechanical ventilation and its harms are likely to be minor.

A living systematic review and network meta-analysis, supported by a prospective meta-analysis, with data from eight randomized trials (7184 participants) was carried out and they found that systemic corticosteroids probably reduce 28-day mortality in patients with critical COVID-19 and also in those with severe disease. In contrast, systemic corticosteroids may increase the risk of death in patients without severe COVID-19.

The panel made a strong recommendation for use of corticosteroids in severe and critical COVID-19 because there is a lower risk of death among people treated with systemic corticosteroids (moderate certainty evidence), and they believe that all or almost all fully informed patients with severe and critical COVID-19 would choose this treatment. In contrast, the panel concluded that patients with non-severe COVID-19 would decline this treatment because they would be unlikely to benefit and maybe harmed.

Recommendation 1

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).

This recommendation applies to patients with severe and critical covid-19. The panel judged that all or almost all fully informed patients with severe covid-19 would choose to take systemic corticosteroids. The recommendation should apply to patients with severe and critical covid-19 even if they cannot be hospitalised or receive oxygen because of resource limitations.

Recommendation 2

We suggest not to use corticosteroids in the treatment of patients with non-severe covid-19 (weak or conditional recommendation based on low certainty evidence).

This recommendation applies to patients with non-severe disease regardless of their hospitalisation status. The panel noted that patients with non-severe covid-19 would not normally require acute care in hospital or respiratory support, but in some jurisdictions these patients may be hospitalised for isolation purposes only, in which case they should not be treated with systemic corticosteroids. Several specific circumstances were considered.

Systemic corticosteroids should not be stopped for patients with non-severe covid-19 who are already treated with systemic corticosteroids for other reasons (such as patients with chronic obstructive pulmonary disease or chronic autoimmune disease).

If the clinical condition of patients with non-severe covid-19 worsens (that is, increase in respiratory rate, signs of respiratory distress or hypoxaemia) they should receive systemic corticosteroids (see recommendation 1).

Pregnancy: antenatal corticosteroid therapy may be administered for pregnant women at risk of preterm birth from 24 to 34 weeks' gestation when there is no clinical evidence of maternal infection, and adequate childbirth and newborn care is available. In cases where the woman presents with mild or moderate covid-19, the clinical benefits of antenatal corticosteroid might outweigh the risks of potential harm to the mother. In this situation, the balance of benefits and harms for the woman and the preterm newborn should be discussed with the woman to ensure an informed decision, as this assessment may vary depending on the woman's clinical condition, her wishes and that of her family, and available healthcare resources.

Endemic infections that may worsen with corticosteroids should be considered. For example, for Strongyloides stercoralis hyperinfection associated with corticosteroid therapy, diagnosis or empiric treatment may be considered in endemic areas if steroids are used.

Practical considerations for steroid treatment-

Route—Systemic corticosteroids may be administered both orally and intravenously. Of note, while the bioavailability of dexamethasone is very high (that is, similar concentrations are achieved in plasma after oral and intravenous intake), critically ill patients may be unable to absorb any nutrients or medications due to intestinal dysfunction. Clinicians therefore may consider administering systemic corticosteroids intravenously rather than orally if intestinal dysfunction is suspected.

Duration—While more patients received corticosteroids in the form of dexamethasone 6 mg daily for up to 10 days, the total duration of regimens evaluated in the seven trials varied between five and 14 days, and treatment was generally discontinued at hospital discharge (that is, the duration of treatment could be less than the duration stipulated in the protocols).

Dose—The once daily dexamethasone formulation may increase adherence. A dose of 6 mg of dexamethasone is equivalent (in terms of glucocorticoid effect) to 150 mg of hydrocortisone (that is, 50 mg every 8 hours), 40 mg of prednisone, or 32 mg of methylprednisolone (8 mg every 6 hours or 16 mg every 12 hours).

Monitoring—It would be prudent to monitor glucose levels in patients with severe and critical covid-19, regardless of whether the patient is known to have diabetes.

Timing—The timing of therapy from onset of symptoms was discussed by the panel. The RECOVERY investigators reported a subgroup analysis suggesting that the initiation of therapy seven days or more after symptom onset may be more beneficial than treatment initiated within seven days of symptom onset. A post hoc subgroup analysis within the prospective meta-analysis did not support this hypothesis. While some panel members believed that postponing systemic corticosteroids until after viral replication is contained by the immune system may be reasonable, many noted that, in practice, it is often impossible to ascertain symptom onset and that signs of severity often appear late (that is, denote a co-linearity between severity and timing). The panel concluded that, given the evidence, it was preferable to err on the side of administering corticosteroids when treating patients with severe or critical covid-19 (even if within 7 days of symptoms onset) and to err on the side of not giving corticosteroids when treating patients with non-severe disease (even if after 7 days of symptoms onset)."

Uncertainty-

The following uncertainties remain.

Long term effect of systemic corticosteroids on mortality and functional outcomes in covid-19 survivors are unknown and will be the subject of future analyses of the evidence considered by the panel.

The clinical effects of systemic corticosteroids in patients with non-severe covid-19 (that is, pneumonia without hypoxaemia) remain unclear and may be studied further.

As additional therapies emerge for covid-19, notably novel immunomodulators, it will become increasingly important to ascertain how these interact with systemic corticosteroids. All investigational therapies for severe and critical covid-19 (including remdesivir) should be compared with systemic corticosteroids or evaluated in combination with systemic corticosteroids versus systemic corticosteroids alone.

Other uncertainties include:

The impact of systemic corticosteroids on immunity and the risk of a subsequent infection, which may affect the risk of death after 28 days.

Steroid preparation, dosing, and optimal timing of drug initiation.

Generalisability of study results to populations that were underrepresented in the trials considered by the panel (such as children, immunocompromised patients, patients with tuberculosis).

Generalisability in resource-limited settings (that is, low and middle income countries).

Effect on viral replication.

Taking both public health and a patient perspective, the panel warned that indiscriminate use of any therapy for COVID-19 would potentially rapidly deplete global resources and deprive patients who may benefit from it most as potentially lifesaving therapy.

For the full article Click on the link: https://doi.org/10.1136/bmj.m3379