Cytokine and Endothelial Activation Patterns Related to Severe and Non-Severe Respiratory Viral Infections

Abstract

Respiratory viral infections (RVIs) are a major cause of global morbidity and mortality. Severe cases are driven by dysregulated inflammation, impaired interferon (IFN) responses, and thromboinflammation, yet the mechanisms underlying endothelial dysfunction remain poorly defined. We collected 234 leftover material samples from hospitalized patients with PCR-confirmed RVIs. Patients were stratified by viral etiology, differential involvement of the respiratory tract, age and possible co-infections. Cytokines (IL-6, IL-8, IL-1β, TNF-α), IFNs (α/β/γ), and endothelial markers (ICAM-1, VCAM-1) were quantified using microfluidic immunoassays. Routine coagulation parameters were measured in a subset of patients. Compared with controls, RVI patients exhibited significantly elevated systemic cytokines (p < 0.001). IL-6 and IL-8 were higher in patients with lower respiratory tract involvement, particularly in influenza cases. Elderly patients displayed reduced IFN-α/β responses but increased proinflammatory CRP levels. Infants and children had higher ICAM-1 but lower CRP levels. Patients with viral-bacterial co-infections showed amplified IFN-γ/IL-1β/ICAM-1 response. Older adults demonstrated prolonged prothrombin times and reduced fibrinogen, indicating coagulopathy. Severe RVIs are characterized by a triad of impaired antiviral IFN responses, hyperinflammation, and endothelial activation, culminating in thromboinflammation. Age, viral type and co-infections critically shape host responses, underscoring the need for biomarker-guided, personalized therapies.

Keywords: IL‐6; RSV; Respiratory viral infections; Rhinovirus; co‐infections; cytokine storm; endothelial dysfunction; influenza; interferon response; thrombosis.

Figure 1

(A–B) Plasma levels of IL‐6 and IL‐8 measured in the general population of patients with lower (LRT) and upper (URT) respiratory tract viral infections and in the control group (CTRL). (C) Plasma level of IL‐6 measured in patients with lower (LRT) and upper (URT) respiratory tract influenza virus infection and in control group (CTRL). Each dot represents a patient. The red lines represent the median and IQR. Statistical analysis: Quade′s non‐parametric ANCOVA. *= p < 0.05; **= p < 0.01; ***= p < 0.001.

Figure 2

Plasma levels of IFN‐α (A), ICAM‐1 (B), VCAM‐1 (C) and IFN‐β (D) measured in our patient cohort clustered by infecting virus. Each dot represents a patient. The red lines represent the median and IQR. Statistical analysis: Quade′s non‐parametric ANCOVA. *= p < 0.05; **= p < 0.01; ***= p < 0.001.

Figure 3

Plasma levels of IFN‐α (A), IFN‐β (B), IFN‐γ (C), TNF‐α (D) and ICAM‐1 (E) measured in our whole patient cohort, clustered by age range groups. Each dot represents a patient. The red lines represent the median and IQR. Statistical analysis: Kruskal‐Wallis test, followed by Dunn′s multiple comparison test. *= p < 0.05.

Figure 4

CRP (A), PT (B), P‐INR (C) and fibrinogen (D) measured in our general population of RV‐infected patients sorted by age range groups. Each dot represents a patient. For PT, P‐INR and fibrinogen we pooled all samples from patients younger than 18 years of age into a single group to ensure a comparable sample size across the different age groups. The red lines represent the median and IQR. Statistical analysis: Kruskal‐Wallis test, followed by Dunn′s multiple comparison test. *= p < 0.05; **= p < 0.01; ***= p < 0.001.

Figure 5

(A–E) Plasma levels of ICAM‐1 (A), IFN‐β (B), IFN‐γ (C) and IL‐1β (D) measured in patients with RV infection and bacterial coinfection compared to patients with only RV infection. (E–I) Plasma levels of IFN‐γ (E), IL‐8 (F), CRP (G), ICAM‐1 (H) and fibrinogen (I) measured in patients with RV infection and viral coinfection compared to patients with only RV infection. Each dot represents a patient. The red lines represent the median and IQR. Statistical analysis: Mann‐Whitney test. *= p < 0.05.

Figure 6

Plasma levels of IFN‐γ (A) and ICAM‐1 (B) measured in patients with RV infection and both bacterial and viral coinfection compared to patients with only RV infection. Each dot represents a patient. The red lines represent the median and IQR. Statistical analysis: Mann‐Whitney test. *= p < 0.05.