Inflammatory and endothelial host responses in community-acquired pneumonia: exploring the relationships with HbA1c, admission plasma glucose, and glycaemic gap-a cross-sectional study

Abstract

Introduction: Diabetes is associated with dysregulated immune function and impaired cytokine release, while transient acute hyperglycaemia has been shown to enhance inflammatory cytokine release in preclinical studies. Although diabetes and acute hyperglycaemia are common among patients with community-acquired pneumonia (CAP), the impact of chronic, acute, and acute-on-chronic hyperglycaemia on the host response within this population remains poorly understood. This study investigated whether chronic, acute, and acute-on- chronic hyperglycaemia are associated with distinct mediators of inflammatory, endothelial, and angiogenic host response pathways in patients with CAP.

Methods: In a cross-sectional study of 555 patients with CAP, HbA1c, admission plasma (p)-glucose, and the glycaemic gap (admission p-glucose minus HbA1c- derived average p-glucose) were employed as measures of chronic, acute, and acute-on-chronic hyperglycaemia, respectively. Linear regression was used to model the associations between the hyperglycaemia measures and 47 proteins involved in inflammation, endothelial activation, and angiogenesis measured at admission. The models were adjusted for age, sex, CAP severity, pathogen, immunosuppression, comorbidity, and body mass index. Adjustments for multiple testing were performed with a false discovery rate threshold of less than 0.05.

Results: The analyses showed that HbA1c levels were positively associated with IL-8, IL-15, IL-17A/F, IL-1RA, sFlt-1, and VEGF-C. Admission plasma glucose was also positively associated with these proteins and GM-CSF. The glycaemic gap was positively associated with IL-8, IL-15, IL-17A/F, IL-2, and VEGF-C.

Conclusion: In conclusion, chronic, acute, and acute-on-chronic hyperglycaemia were positively associated with similar host response mediators. Furthermore, acute and acute-on-chronic hyperglycaemia had unique associations with the inflammatory pathways involving GM-CSF and IL-2, respectively.

Keywords: admission p-glucose; community-acquired pneumonia; glycaemic gap; glycated haemoglobin (HbA1c); host response mediators; hyperglycaemia.

Figure 1

Flowchart of study enrolment. COVID-19, coronavirus disease 2019.

Figure 2

Forest plots illustrating the associations in base and adjusted models. (A) Base models with HbA1c as the predictor. (B) Adjusted models with HbA1c as the predictor. (C) Base models with admission p-glucose as the predictor. (D) Adjusted models with admission p-glucose as the predictor. (E) Base models with the glycaemic gap as the predictor. (F) Adjusted models with the glycaemic gap as the predictor. The x-axis shows the fold change in protein concentration for each 1 unit increase in HbA1c (mmol/mol), admission p-glucose (mmol/L), or glycaemic gap (mmol/L), with the corresponding 95% confidence intervals. Only proteins with statistically significant false discovery rate-adjusted p-values are included.