Understanding the Link Between Obesity and Severe COVID-19 Outcomes

Causal Mediation by Systemic Inflammatory Response

Andrea S. Foulkes; Caitlin Selvaggi; Daniel Shinnick; Heidi Lumish; Eunyoung Kim; Tingyi Cao; Tanayott Thaweethai; Jing Qian; Frances Lu; Joyce Yan; David Cheng; Wei He; Kevin J. Clerkin; Mahesh V. Madhavan; James B. Meigs; Virginia A. Triant; Steven A. Lubitz; Aakriti Gupta; Ingrid V. Bassett; Muredach P. Reilly


J Clin Endocrinol Metab. 2022;107(2):e698-e707. 

In This Article

Abstract and Introduction


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.


Obesity is one of the strongest risk factors for critical illness among severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals.[1–4] Moreover, emerging evidence suggests that obesity-associated severe disease is more pronounced in younger populations compared with older populations.[5–8] At the same time, studies of multiple biomarkers of pathophysiological processes reveal elevated levels of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), D-dimer, ferritin, interleukin-6 (IL-6) and white blood cell count (WBC) and its fractions contribute to severe COVID-19 outcomes.[4,9] Indeed, emerging immunophenotyping data suggest that a marked dysregulation of innate and adaptive immunity is a hallmark of poor outcomes in COVID-19.[10–12]

As the relationship between obesity and inflammatory markers is well-established in population and clinical based epidemiologic studies of non-SARS-CoV-2-infected individuals,[13–15] several commentaries have postulated on complex mechanisms linking obesity, inflammatory pathways, age, and race/ethnicity to severe disease in COVID-19.[16,17] However, the specific role of inflammation in the causal pathways between obesity and severe COVID-19 outcomes remains unknown and the translational clinical utility of disease biomarkers in COVID-19 remains to be fully developed and exploited. In this work, we hypothesize that biomarkers of obesity-associated systemic inflammation are mediators of severe outcomes in COVID-19. Through a rigorous investigation of causal mediation by systemic inflammatory responses in the link between obesity and severe COVID-19 outcomes, this research is designed to advance clinical translational opportunities for targeted interventions.