Understanding the Link Between Obesity and Severe COVID-19 Outcomes: Causal Mediation by Systemic Inflammatory Response

Abstract

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.

Methods: This hospital-based, observational study included 3828 SARS-CoV-2-infected patients who were hospitalized February to May 2020 at Massachusetts General Hospital (MGH) or Columbia University Irving Medical Center/New York Presbyterian Hospital (CUIMC/NYP). We use mediation analysis 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 with nonobese 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] vs 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).

Conclusion: 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 trial findings, these results reveal therapeutic opportunity to target systemic inflammatory pathways and monitor interventions in high-risk subgroups and particularly obese patients.

Keywords: COVID-19; SARS-CoV-2; biomarkers; inflammation; obesity; severe disease.

Figure 1.

Causal mediation model. The aim of this study is to evaluate the extent to which the association between obesity (BMI ≥30) and severe disease (mechanical ventilation or death) among confirmed SARS-CoV-2-infected PCR-positive hospitalized patients was mediated by an increase in inflammation, as measured by CRP level, prior to mechanical ventilation, discharge, or death. Potential confounders accounted for in the primary analysis included age, sex, race/ethnicity, and number of CRP measurements. Fully adjusted models also included history of type 2 diabetes mellitus, hypertension, dyslipidemia, and pulmonary disease. The proportion mediated is given by the Natural Indirect Effect (NIE) divided by the Total Effect = NIE + Natural Direct Effect (NDE).

Figure 2.

CRP trajectory over time by obesity status for MGH cohort. Subject level CRP trajectories are plotted against the number of days before and after the corresponding individual’s peak value (day = 0) for obese (left-hand panel) and nonobese (right-hand panel) patients. Patients who died or were mechanically ventilated within 28 days of PTC are represented by gold lines, and those patients who survived and were not mechanically ventilated are represented by blue lines. Larger filled circles represent medians at the corresponding day from peak within patients who died or were mechanically ventilated (gold) or survived and were not mechanically ventilated (blue). The primary causal mediation analysis included the subset of CRP values up to and including the day of mechanical ventilation, death, or discharge.