Diabetes predicts severity of COVID‐19 infection in a retrospective cohort: A mediatory role of the inflammatory biomarker C‐reactive protein

Abstract

Diabetes is a risk factor for developing severe COVID-19, but the pathogenesis remains unclear. We investigated if the association of diabetes and COVID-19 severity may be mediated by inflammation. We also hypothesized that this increased risk may extend to prediabetes. Hospitalized patients in Singapore with COVID-19 were subdivided into three groups in a retrospective cohort: normoglycemia (HbA1c: ≤5.6%), prediabetes (HbA1c: 5.7%-6.4%) and diabetes (HbA1c: ≥6.5%). The primary outcome of severe COVID-19 was defined by respiratory rate ≥30, SpO2 ≤93% or intensive care unit admission. The association between clinical factors on severe COVID-19 outcome was analyzed by cox regression. Adjusted mediation analysis of C-reactive protein (CRP) on the relationship between diabetes and severe COVID-19 was performed. Of 1042 hospitalized patients, mean age 39 ± 11 years, 13% had diabetes, 9% prediabetes and 78% normoglycemia. Severe COVID-19 occurred in 4.9% of subjects. Compared to normoglycemia, diabetes was significantly associated with severe COVID-19 on both univariate (hazard ratio [HR]: 9.94; 95% confidence interval [CI]: 5.54-17.84; p < .001) and multivariate analysis (HR: 3.99; 95% CI: 1.92-8.31; p < .001), while prediabetes was not a risk factor (HR: 0.94; 95% CI: 0.22-4.03; p = .929). CRP, a biomarker of inflammation, mediated 32.7% of the total association between diabetes and severe COVID-19 outcome. In conclusion, CRP is a partial mediator of the association between diabetes and severe COVID-19 infection, confirming that inflammation is important in the pathogenesis of severe COVID-19 in diabetes.

Inflammation, Hyperglycemia, and Adverse Outcomes in Individuals With Diabetes Mellitus Hospitalized for COVID-19

“…Our mediation analysis supports this finding in that we found that suPAR levels accounted for 84.2% of the effect of DM on the outcomes. Conversely, another study found that CRP accounted for only 32.7% (12). SuPAR is an immune-derived signaling glycoprotein, which is notorious for its role in kidney disease (25)(26)(27), cardiovascular disease (28)(29)(30), and most recently, COVID-19 (13,31).…”

“…Hyperglycemia further upregulates inflammatory and oxidative stress markers in a vicious cycle (10,11). The interplay between inflammatory cytokines and hyperglycemia may be a major factor in the development of multiorgan damage and mortality in individuals admitted for COVID-19 (12). Understanding the relationship among DM, inflammation, and hyperglycemia in individuals hospitalized for COVID-19 is instrumental in devising targeted strategies for improving outcomes in this high-risk patient population.…”

Interleukin-37: A Link Between COVID-19, Diabetes, and the Black Fungus

“…People with diabetes and COVID-19 should be monitored for inflammatory and prothrombotic markers ( Gianchandani et al, 2020 ). CRP is a good inflammatory marker revealing the association between diabetes and adverse COVID-19 outcomes, including the need for ICU admission, dyspnea, and length of stay ( Koh et al, 2021 ), whereas fibrinogen for coagulation dysfunction ( Varikasuvu et al, 2021 ). The use of corticosteroids can modulate the risk when used prudently.…”

Association of serum C-reactive protein (CRP) and D-dimer concentration on the severity of COVID-19 cases with or without diabetes: a systematic review and meta-analysis

“…In the present study, we observed that male diabetic patients were more infected with COVID-19 diseases than the female patients (OR = 2.48; 95% Cl: 1.70–3.61, p < 0.00001). Almost seven studies [ 37 , 39 , 44 , 46 , 49 , 52 , 65 ] reported that the COVID-19 severity was significantly higher in male diabetic patients where patients were classified into two groups: male and female. A study conducted in Bangladesh reported that males were more susceptible to COVID-19 than the female and developed severe symptoms (OR = 2.41, p < 0.00001) [ 81 ].…”