Obesity, Inflammation, and Clinical Outcomes in COVID-19: A Multicenter Prospective Cohort Study

Abstract

Context: Obesity is a risk factor for coronavirus disease 2019 (COVID-19)-related outcomes; however, the mechanism remains unclear.

Objective: The objective of this analysis was to determine whether inflammation mediates the association between obesity and COVID-19 outcomes.

Methods: The International Study of Inflammation in COVID-19 (ISIC): A Prospective Multi-Center Observational Study Examining the Role of Biomarkers of Inflammation in Predicting Covid-19 Related Outcomes in Hospitalized Patients, was conducted at 10 hospitals in the United States and Europe. Participants were adults hospitalized specifically for COVID-19 between February 1, 2020, through October 19, 2022. Inflammatory biomarkers, including soluble urokinase plasminogen activator receptor (suPAR), were measured at admission. Associations were examined between body mass index (BMI, kg/m2) and a composite of death, need for mechanical ventilation, and renal replacement therapy, stratified by pre- and post-Omicron variants. The contribution of inflammation to the relationship between obesity and outcomes was assessed.

Results: Among 4644 participants (mean age 59.3, 45.6% male, 21.8% BMI ≥ 35), those with BMI > 40 (n = 485) had 55% higher odds of the composite outcome (95% CI, 1.21-1.98) compared with nonobese individuals (BMI < 30, n = 2358) in multivariable analysis. In multiple mediation analysis, only suPAR remained a significant mediator between BMI and composite outcome. Associations were amplified for participants younger than 65 years and with pre-Omicron variants.

Conclusion: Obesity is associated with worse outcomes in COVID-19, notably in younger participants and in the pre-Omicron era. Inflammation, as measured by suPAR, is a significant mediator of the association between obesity and COVID-19 outcomes.

Keywords: BMI; COVID-19; SARS-CoV-2; biomarkers; coronavirus; inflammation; obesity.

Figure 1.

Odds ratios for composite outcome by BMI categories. Bar graphs showing the odds ratios and 95% CI for the association of obesity with the composite outcome using nonobese (< 30 kg/m²) as reference vs Class I obese (30-34.9 kg/m²), Class II obese (35-39.9 kg/m²), and Class III obese (≥ 40 kg/m²) patients. Model 1 (blue): adjusted for age, sex, and race; Model 2 (orange): adjusted for Model 1 covariates plus history of smoking, eGFR at admission, hypertension, diabetes, coronary artery disease, and congestive heart failure; Model 3 (green): adjusted for Model 2 covariates plus suPAR. Abbreviations: BMI, body mass index; eGFR, estimated glomerular filtration rate; suPAR, soluble urokinase plasminogen activator receptor.

Figure 2.

Association of BMI with the composite outcome across subgroups. Forest plot showing the risk of composite outcome (mortality, need for mechanical ventilation, need for renal replacement therapy) for BMI > 35 kg/m² compared to < 35 kg/m² in specified subgroups. P value is for the interaction between BMI and each subgroup. The model with all patients is adjusted for age, sex, history of smoking, estimated GFR at admission, hypertension, diabetes, coronary artery disease, and coronary heart failure. All stratified models are adjusted by the same covariates, minus the stratification variable. Abbreviations: BMI, body mass index; CAD, coronary artery disease; CHF, congestive heart failure; eGFR, estimated glomerular filtration rate; OR, odds ratio.

Figure 3.

Associations of BMI categories with COVID-19 outcomes stratified by variant. Forest plot showing the risk of composite outcome, mortality, intubation, and dialysis by body mass index (BMI) categories, nonobese (< 30 kg/m²), Class I obese (30-34.9 kg/m²), Class II obese (35-39.9 kg/m²), and Class III obese (≥ 40 kg/m²) and stratified by Omicron status, defined as admission date before or after October 31, 2021. All models were adjusted for age, sex, history of smoking, estimated GFR at admission, hypertension, diabetes, coronary artery disease, and coronary heart failure.

Figure 4.

Beta coefficients for inflammatory biomarkers predicting BMI. Bar graph showing the beta coefficients and 95% CI for the association between inflammatory biomarkers (suPAR, CRP, IL-6, ferritin, D-Dimer, procalcitonin) and body mass index (BMI). Models are adjusted for age, sex, race, history of smoking, admission eGFR, hypertension, diabetes, coronary artery disease, and congestive heart failure. Abbreviations: CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; IL-6, interleukin-6; suPAR, soluble urokinase plasminogen activator receptor.