Guidelines should not pool evidence from uncomplicated and severe COVID-19

The WHO Global Development Group guidelines on COVID-19 therapeutics are meant to provide evidence-based advice to all countries on the medical management of patients with COVID-19.1, 2 The only small-molecule drug to show unequivocal benefit to date is dexamethasone. In the largest randomised controlled trial in patients who were admitted to hospital with COVID-19 (ie, the RECOVERY trial), dexamethasone at a low dose reduced mortality in the prospectively defined subgroups of patients requiring medical oxygen (rate ratio 0·82 [95% CI 0·72–0·94]) or being ventilated (0·64 [0·51–0·81]) but not in patients not receiving respiratory support at randomisation (1·19 [0·91–1·55]).³ The current WHO living guideline on COVID-19 therapeutics¹ recognises this important difference in therapeutic response in relation to stage of the disease by recommending use of corticosteroids in patients requiring respiratory support but conditionally recommending against their use in patients not requiring respiratory support. By stark contrast, largely on the basis of inpatient studies, the guideline has recommended strongly against hydroxychloroquine (87·4% [9549 of 10 921] of studied patients were inpatients¹) and lopinavir–ritonavir (all 7429 patients were inpatients¹) in patients with any disease severity. There is convincing evidence that these drugs do not benefit patients who are admitted to hospital and, outside hospitals, they should be used only in the context of clinical trials. However, on the basis of our current understanding of the evolution of COVID-19 (appendix), this broad generalisation from the treatment of severely ill patients who have been admitted to hospital to patients with uncomplicated COVID-19 in the community is not supported by current evidence. COVID-19 reflects a changing pathological process. Viral burden peaks early, around the time of first symptoms. This timepoint is when antiviral drugs are likely to be most beneficial. Thereafter, viral burden declines and inflammatory processes dominate in those patients who deteriorate and require admission to hospital, and ultimately respiratory support. Immune modulators and anti-inflammatories are more likely to be of benefit at this later stage but might be harmful if used earlier (ie, by enhancing viral replication).² Evidence reviews² and the guidelines that they generate¹ should recognise that, although SARS-CoV-2 is one virus, both the COVID-19 disease process and access to health care vary widely. The WHO Global Development Group “prioritized outcomes taking a patient perspective”.² They decided that mortality would be most important to patients, followed by need for and duration of mechanical ventilation. We argue that prevention of hospital admission is the therapeutic priority for low-resource settings, which usually have few facilities for intensive care. Efficacy assessments in prevention and in uncomplicated COVID-19 should not be pooled with results from severely ill patients who have been admitted to hospital.