Systemic inflammation mediates obesity-related severe COVID-19

Systemic inflammation plays a significant role in severe COVID-19 associated with obesity, particularly in patients aged <65 years, as captured by peak C-reactive protein (CRP) levels and erythrocyte sedimentation rate (ESR), a study has found.

“Stronger evidence of mediation in younger obese patients highlights clinical importance and potential therapeutic opportunity to target systemic inflammatory pathways and to monitor therapeutic interventions in high-risk, obese subgroups with elevated CRP levels,” the researchers said.

This observational study analysed a total of 3,828 patients with COVID-19 who were hospitalized between February and May 2020 at Massachusetts General Hospital (MGH; n=1,202) or Columbia University Irving Medical Center/New York Presbyterian Hospital (CUIMC/NYP; n=2,626).

The researchers performed mediation analyses to determine whether peak inflammatory biomarkers (CRP, ESR, D-dimer, ferritin, white blood cell count, and interleukin-6) were in the causal pathway between obesity (body mass index ≥30 kg/m²) and mechanical ventilation or death within 28 days of presentation to care.

In the MGH cohort, obese patients were more likely to use ventilation or die (odds ratio [OR], 1.73, 95 percent confidence interval [CI], 1.25‒2.41; p=0.001) and have higher peak CRP (p<0.001) than their nonobese counterparts. [J Clin Endocrinol Metab 2022;107:e698-e707]

The estimated proportion of the link between obesity and ventilation or death mediated by CRP was 0.49 (p<0.001). Evidence of mediation was more evident among patients <65 years of age (proportion mediated, 0.52 vs 0.44; p<0.001 vs p=0.180). These findings were modest but consistent for peak ESR.

Other inflammatory markers did not display a mediating role. Of note, these results were consistent with those observed in the CUIMC/NYP cohort.

“The highly consistent pattern for all biomarkers and by age strata in both MGH and CUIMC/NYP cohorts supports generalizability of a specific mediating role captured by peak CRP (and to a lesser extent ESR) levels in the pathways between obesity and severe disease,” the researchers said.

The present findings support those from previous studies. For instance, trials of systemic corticosteroids that succeeded in reducing all-cause mortality in patients with severe COVID-19 provides evidence of clinical benefits by targeting activation of innate immunity, captured by peak CRP levels. [N Engl J Med 2020;384:693-704; JAMA 2020;324:1330-1341; JAMA 2020;324:1317-1329]

“Indeed, there is an established link between corticosteroid benefit and reductions in CRP and ESR levels in non-COVID-19 inflammatory disorders,” the researchers said. “Whether reductions in CRP and ESR track with therapeutic benefit of corticosteroids in COVID-19 remains to be determined.” [Ann Rheum Dis 1999;58:49-54]

Elevated CRP levels may be used to stratify SARS-CoV-2‒infected patients into subgroups in clinical trials of anti-inflammatory strategies and to monitor therapeutic efficacy of novel interventions in COVID-19, they noted.

“Failure to design statistically powered COVID-19 clinical trials to target or detect effects in such subgroups may contribute to apparent lack of therapeutic efficacy and limit progress due to false negative trial data,” the researchers said. [Front Endocrinol (Lausanne) 2020;11:530]

Obesity is one of the most robust predictors of critical illness in SARS-CoV-2 infection, while dysregulation of innate and adaptive immunity is associated with poor COVID-19 outcomes. [Diabetologia 2020;63:1500-1515; Lancet Diabetes Endocrinol 2020;8:562-564; Cell 2020;182:1401-1418.e18; Immunology 2020;161:345-353]