Adiposity and Mortality among Patients Severely Ill with COVID-19 and non-COVID-19 Respiratory Conditions: A Cross-Context Comparison Study in the UK

Objective To assess the causality of adiposity for mortality among patients severely ill with COVID-19 and non-COVID-19 respiratory conditions by examining the consistency of associations across temporal and geographical contexts where biases vary Design Prospective cohort study Setting 297 intensive care units (ICUs) in England, Wales, and Northern Ireland monitored by the Intensive Care National Audit and Research Centre Case Mix Programme Participants Patients aged ≥16 years admitted to ICU with COVID-19 (N=33,352; Feb 2020-Aug 2021) and non-COVID-19 respiratory conditions (N=24,739; Feb 2018-Aug 2019) Main outcome measure 30-day mortality post ICU admission Results Compared with non-COVID-19 respiratory patients, COVID-19 patients were younger, less often of a white ethnic group, and more often with extreme obesity (body mass index (BMI) ≥ 40kg/m2). COVID-19 patients had fewer comorbidities but higher mortality (35% vs. 23% mortality in non-COVID-19). Socio-demographic and comorbidity factors and their associations with BMI and mortality varied more by date than geographical region of ICU admission, particularly among COVID-19 patients. Among COVID-19 patients, higher BMI was associated with a small excess mortality (hazard ratio (HR) per standard deviation (SD)=1.05; 95% CI=1.03, 1.08), driven by extreme obesity (HR per SD=1.21; 95% CI=1.13, 1.31 vs. normal-weight). Extreme obesity was strongly associated with higher mortality only during Feb-April 2020 (HR=1.49, 95% CI=1.27, 1.73 vs. normal-weight); this association weakened thereafter (BMI-date interaction P=0.03). Among non-COVID-19 respiratory patients, higher BMI was associated with lower mortality (HR per SD=0.84; 95% CI=0.82, 0.87), seen across all overweight/obesity groups. These negative obesity-mortality associations were similar across most admission dates and regions. Conclusions Obesity is associated with higher mortality among COVID-19 patients, but lower mortality among non-COVID respiratory patients. These associations appear vulnerable to confounding/selection bias in both patient groups, questioning the existence or stability of causal effects. Among COVID-19 patients, unfavourable obesity-mortality associations differ by admission date. Among non-COVID-19 respiratory patients, favourable obesity-mortality associations may reflect comorbidity-induced weight loss. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement JAB, DC, and AH are supported by the Elizabeth Blackwell Institute for Health Research and the Development and Alumni Relations Office, University of Bristol. JAB, DC, AH, KT, and GDS work in a unit funded by the UK MRC (MC\_UU\_00011/1; MC\_UU\_00011/3) and the University of Bristol. This publication is the work of the authors and JAB is the guarantor for its contents. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Approval for the collection and use of patient-identifiable data without consent in the Case Mix Programme was obtained from the Confidentiality Advisory Group of the Health Research Authority under Section 251 of the NHS Act 2006 (approval number PIAG2-10[f]/2005). All data were pseudonymised (patient identifiers removed) prior to extraction for this research. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Individual-level data are available via application to ICNARC (managed access).