Understanding the link between obesity and severe COVID-19 outcomes: Causal mediation by systemic inflammatory response.

BACKGROUND: Obesity is an established risk factor for severe COVID-19 outcomes. The mechanistic underpinnings of this association are not well-understood. OBJECTIVE: To evaluate the mediating role of systemic inflammation in obesity-associated COVID-19 outcomes. DESIGN: Hospital-based, observational. SETTING: Massachusetts General Hospital (MGH) or Columbia University Irving Medical Center/NewYork-Presbyterian Hospital (CUIMC/NYP). PATIENTS OR OTHER PARTICIPANTS: N=3828 SARS-CoV-2-infected patients hospitalized February to May 2020. MAIN OUTCOME MEASURES: Mediation analysis is used to evaluate whether peak inflammatory biomarkers [C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), D-dimer, ferritin, white blood cell count and interleukin-6] are in the causal pathway between obesity (BMI ≥ 30) and mechanical ventilation or death within 28 days of presentation to care. RESULTS: In the MGH cohort (n=1202), obesity was associated with greater likelihood of ventilation or death [OR=1.73, 95% CI=(1.25, 2.41), p=0.001] and higher peak CRP (p<0.001) compared to non-obese patients. The estimated proportion of the association between obesity and ventilation or death mediated by CRP was 0.49 (p<0.001). Evidence of mediation was more pronounced in patients <65 years [proportion mediated=0.52 (p<0.001) versus 0.44 (p=0.180)]. Findings were more moderate but consistent for peak ESR. Mediation by other inflammatory markers was not supported. Results were replicated in CUIMC/NYP cohort (n=2626). CONCLUSIONS: Findings support systemic inflammatory pathways in obesity-associated severe COVID-19 disease, particularly in patients <65 years, captured by CRP and ESR. Contextualized in clinical trials findings, these results reveal therapeutic opportunity to target systemic inflammatory pathways and monitor interventions in high-risk subgroups and particularly obese patients.