Guidelines should not pool evidence from uncomplicated and severe COVID-19
Authors: Nicholas J White, Nathalie Strub-Wourgaft, Abul Faiz, Philippe J Guerin
Journal: The Lancet (2021)

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-19.1WHOTherapeutics and COVID-19: living guideline.https://www.who.int/publications/i/item/therapeutics-and-covid-19-living-guidelineDate: Dec 17, 2020Date accessed: February 14, 2021Google Scholar, 2Siemieniuk R Rochwerg B Agoritsas T et al.A living WHO guideline on drugs for COVID-19.BMJ. 2020; 371m4475PubMed Google Scholar 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]).3The RECOVERY Collaborative GroupDexamethasone in hospitalized patients with COVID-19—preliminary report.N Engl J Med. 2020; (published online July 17.)https://doi.org/10.1056/NEJMoa2021436Crossref Scopus (6947) Google Scholar The current WHO living guideline on COVID-19 therapeutics1WHOTherapeutics and COVID-19: living guideline.https://www.who.int/publications/i/item/therapeutics-and-covid-19-living-guidelineDate: Dec 17, 2020Date accessed: February 14, 2021Google Scholar 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 inpatients1WHOTherapeutics and COVID-19: living guideline.https://www.who.int/publications/i/item/therapeutics-and-covid-19-living-guidelineDate: Dec 17, 2020Date accessed: February 14, 2021Google Scholar) and lopinavir–ritonavir (all 7429 patients were inpatients1WHOTherapeutics and COVID-19: living guideline.https://www.who.int/publications/i/item/therapeutics-and-covid-19-living-guidelineDate: Dec 17, 2020Date accessed: February 14, 2021Google Scholar) 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).2Siemieniuk R Rochwerg B Agoritsas T et al.A living WHO guideline on drugs for COVID-19.BMJ. 2020; 371m4475PubMed Google Scholar Evidence reviews2Siemieniuk R Rochwerg B Agoritsas T et al.A living WHO guideline on drugs for COVID-19.BMJ. 2020; 371m4475PubMed Google Scholar and the guidelines that they generate1WHOTherapeutics and COVID-19: living guideline.https://www.who.int/publications/i/item/therapeutics-and-covid-19-living-guidelineDate: Dec 17, 2020Date accessed: February 14, 2021Google Scholar 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".2Siemieniuk R Rochwerg B Agoritsas T et al.A living WHO guideline on drugs for COVID-19.BMJ. 2020; 371m4475PubMed Google Scholar 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. We declare no competing interests. Download .pdf (.25 MB) Help with pdf files Supplementary appendix WHO COVID-19 therapeutic guidelines – Authors' replyWe thank Bram Rochwerg and colleagues for information on the WHO therapeutic guideline development process. Unfortunately, they do not address our main concern: the unjustified extrapolation of evidence from randomised controlled trials in severe COVID-19 to therapeutic guidelines for uncomplicated illness.1 Pooling summary data from studies with different severity definitions, deciding on inappropriate primary outcomes, and extrapolating from results in hospitalised patients to ambulant individuals with mild infections suggests a worrying lack of clinical judgement. Full-Text PDF WHO COVID-19 therapeutic guidelinesIn response to Nicholas White and colleagues,1 we offer these clarifications. WHO guideline development methods are prespecified,2 abiding by principles for producing trustworthy guidelines. The WHO COVID-19 Therapeutics Guideline Development Group (GDG) is composed of external experts, with geographical representation and gender balance, including COVID-19 survivors, ethicists, and methodologists who are vetted for potential conflicts of interest. The GDG prioritises outcomes and identifies subgroups to be considered for each recommendation, always including age and disease severity (using WHO COVID-19 definitions of non-severe, severe, and critical). Full-Text PDF