Viral Respiratory Infections and Host Immune Dynamics in Diabetes: Clinical Outcomes in the Post-COVID Era

The introduction of respiratory multiplex PCR in the post-pandemic world has improved the detection of viral infections, whose clinical relevance is still being characterized. Patients with diabetes mellitus (DM) exhibit altered innate immune responses, yet the effect of concurrent viral infection on their inflammatory trajectory and clinical outcomes remains poorly characterized. This study examined whether diabetes is associated with a more pronounced inflammatory response, delayed resolution, and worse multi-organ outcomes during viral respiratory infections. A prospective, longitudinal cohort of 430 hospitalized adults (DM: n = 211; non-DM: n = 219) with PCR-confirmed viral respiratory infections was stratified into four groups by diabetes and co-infection status using a respiratory multiplex PCR panel. Serum IL-6, CRP, NLR, procalcitonin, and urea were measured at admission (Day 1) and at clinical stabilization (Day 6). All variables failed normality testing (Shapiro-Wilk p < 0.0001); non-parametric methods were applied. Receiver operating characteristic (ROC) analysis was used to identify candidate biomarker cutoffs for mortality prediction. SARS-CoV-2 was the predominant pathogen (29.1%). In an exploratory comparison limited by small subgroup sizes (n = 8 vs. n = 14), co-infected diabetic patients had higher baseline inflammatory markers than co-infected non-diabetic patients: median IL-6 32.87 vs. 6.20 pg/mL (Mann-Whitney p = 0.0006) and median CRP 103.83 vs. 23.03 mg/L (p = 0.0012). At the Day 6 checkpoint, co-infected diabetic survivors had higher IL-6 (12.01 vs. 6.13 pg/mL, p = 0.0183) and showed little within-group NLR change (Wilcoxon p = 0.2367); these Day 6 estimates are subject to survivor selection and should be interpreted accordingly. In-hospital mortality was 25.6% in diabetic vs. 3.7% in non-diabetic patients (p < 0.0001). Diabetic patients more frequently required orotracheal intubation (6.4% vs. 1.0%, p = 0.0207) and high-flow nasal oxygen (HFNO) support (7.9% vs. 1.8%, p = 0.0166). In an internal ROC analysis, baseline IL-6 showed the highest discriminatory performance for in-hospital mortality (AUC 0.812, 95% CI 0.772-0.848), with a candidate cutoff of > 55.78 pg/mL (sensitivity 71.0%, specificity 79.1%); IL-6 outperformed CRP (AUC 0.706, DeLong p = 0.0029) and NLR (AUC 0.656, DeLong p = 0.0001). As this cutoff was derived and evaluated in the same cohort, it is reported as exploratory and requires external validation. In this single-center cohort, diabetes was associated with a more pronounced baseline inflammatory profile, slower resolution of the neutrophil-to-lymphocyte ratio, and greater multi-organ involvement during viral respiratory infection, including in the small co-infected subgroup. In the full cohort, diabetes remained associated with higher mortality, IL-6, and CRP after adjustment for age, sex, and BMI; however, the small co-infected subgroups could not be adjusted, so those specific comparisons should be regarded as hypothesis-generating and need confirmation in larger, adequately powered multi-center cohorts.