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Clinical questionWhat is the role of drug interventions in the treatment and prevention of covid-19?RecommendationsThe first version on this living guidance focuses on corticosteroids. It contains a strong recommendation for systemic corticosteroids in patients with severe and critical covid-19, and a weak or conditional recommendation against systemic corticosteroids in patients with non-severe covid-19. Corticosteroids are inexpensive and are on the World Health Organisation list of essential medicines.Howthis guideline was created This guideline reflects an innovative collaboration between the WHO and the MAGIC Evidence Ecosystem Foundation, driven by an urgent need for global collaboration to provide trustworthy and living covid-19 guidance. A standing international panel of content experts, patients, clinicians, and methodologists, free from relevant conflicts of interest, produce recommendations for clinical practice. The panel follows standards, methods, processes, and platforms for trustworthy guideline development using the GRADE approach. We apply an individual patient perspective while considering contextual factors (that is, resources, feasibility, acceptability, equity) for countries and healthcare systems.The evidenceA living systematic review and network meta-analysis, supported by a prospective meta-analysis, with data from eight randomised trials (7184 participants) found that systemic corticosteroids probably reduce 28 day mortality in patients with critical covid-19 (moderate certainty evidence; 87 fewer deaths per 1000 patients (95% confidence interval 124 fewer to 41 fewer)), and also in those with severe disease (moderate certainty evidence; 67 fewer deaths per 1000 patients (100 fewer to 27 fewer)). In contrast, systemic corticosteroids may increase the risk of death in patients without severe covid-19 (low certainty evidence; absolute effect estimate 39 more per 1000 patients, (12 fewer to 107 more)). Systemic corticosteroids probably reduce the need for invasive mechanical ventilation, and harms are likely to be minor (indirect evidence).Understanding the recommendationsThe 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 may be harmed. Moreover, taking both a 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.UpdatesThis is a living guideline. Work is under way to evaluate other interventions. New recommendations will be published as updates to this guideline.Readers noteThis is version 1 of the living guideline, published on 4 September (BMJ 2020;370:m3379) version 1. Updates will be labelled as version 2, 3 etc. When citing this article, please cite the version number.SubmittedAugust 28AcceptedAugust 31

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The pathogenesis of pandemic coronavirus disease-2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) likely depends heavily on disruption of immune and inflammatory processes. Thus far, the precise immune mechanisms have not been fully elucidated or studied in detail. In this issue of EBioMedicine, Liu and colleagues [1] showed that patients with severe COVID-19 had lymphopenia and increased neutrophil counts along with high levels of circulating pro-inflammatory cytokines compared to patients with mild COVID-19 illness. The investigators used flow cytometry to investigate immune phenotype and function of peripheral blood mononuclear cells (PBMC), as well as quantified plasma cytokine levels, from 40 COVID-19 patients. In particular, substantial depletion of CD8+ T cells were associated with disease severity, and both the ratios of neutrophils to CD8+ T cells (N8R) and neutrophils to lymphocytes (NLR) were predictive of COVID-19 outcome. These data suggest that depletion of lymphocytes, particularly cytotoxic T lymphocytes that function by eliminating infected cells, coupled with neutrophils capable of mediating a proinflammatory "cytokine storm" may be key players in COVID-19 pathogenesis.While "cytokine storms" have long been associated with acute respiratory distress syndrome (ARDS) caused by SARS coronavirus (SARS-CoV) and MERS coronavirus (MERS-CoV) [2], pro-inflammatory cytokine dynamics in the context of cellular immune responses in COVID-19 have not been well-characterized. This study clearly demonstrates that severe COVID-19 is associated with significant increases in pro-inflammatory cytokines such as IL-6 as well as significant reductions in CD8+ T cells. Th1 antiviral responses appear to be suppressed, which is supported by increases in the Th2 cytokine IL-10. A recent study in 21 patients also demonstrated that COVID-19

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