IL 33 Correlates With COVID-19 Severity, Radiographic and Clinical Finding

Abstract

Objective: The increased level of interleukin (IL)-33 is considered as a predictor of severe coronavirus disease 2019 (COVID-19) infection, but its role at different stages of the disease is still unclear. Our goal was to analyze the correlation of IL-33 and other innate immunity cytokines with disease severity. Methods: In this study, 220 patients with COVID-19 were included and divided into two groups, mild/moderate and severe/critical. The value of the cytokines, clinical, biochemical, radiographic data was collected and their correlation with disease severity was analyzed. Results: Most patients in the severe/critical group were male (81.8%) and older (over 64.5 years). We found a statistically significant difference (p < 0.05) in these two groups between clinical features (dyspnea, dry cough, fatigue, and auscultatory findings); laboratory [(neutrophil count, lymphocyte count, monocyte count, hemoglobin, plasma glucose, urea, creatinine, total bilirubin (TBIL), direct bilirubin (DBIL), aspartate aminotransferase (AST), albumin (ALB), lactate dehydrogenase (LDH), creatinine kinase (CK), D-dimer, C-reactive protein (CRP), procalcitonin (PCT), Fe, and Ferritin)], arterial blood gases (oxygen saturation-Sa0₂, partial pressure of oxygen -p0₂), and chest X-rays (CXR) lung findings (p = 0.000). We found a significantly higher serum concentration (p < 0.05) of TNF-α, IL-1β, IL-6, IL-12, IL-23, and IL-33 in patients with COVID-19 with severe disease. In the milder stage of COVID-19, a positive correlation was detected between IL-33 and IL-1β, IL-12 and IL-23, while a stronger positive correlation between the serum values of IL-33 and TNF-α, IL-1β, IL-6, and IL-12 and IL-23 was detected in patients with COVID-19 with severe disease. A weak negative correlation (p < 0.05) between pO₂ and serum IL-1β, IL-12, and IL-33 and between SaO₂ and serum IL-33 was noted. The positive relation (p < 0.05) between the serum values of IL-33 and IL-12, IL-33 and IL-6, and IL-6 and IL-12 is proven. Conclusion: In a more progressive stage of COVID-19, increased IL-33 facilitates lung inflammation by inducing the production of various innate proinflammatory cytokines (IL-1β, IL-6, TNF-α, IL-12, and IL-23) in several target cells leading to the most severe forms of the disease. IL-33 correlates with clinical parameters of COVID-19 and might represent a promising marker as well as a therapeutic target in COVID-19.

Keywords: COVID-19; IL 33; correlation; disease severity; proinflammatory innate immune response.

Figure 1

Systemic profile of innate immunity cytokines. According to the disease severity, all Coronavirus disease 2019 (COVID-19) patients were divided into two groups (I and II). The serum concentration of tumor necrosis factor α (TNFα), interleukin (IL)-1β, IL-6, IL-12, IL-23, and IL-33 were determined by ELISA. For statistical significance determination, Mann–Whitney Rank Sum test was used. *P < 0.05.

Figure 2

Ratio of IL-33 and proinflammatory cytokines. According to the disease severity, all COVID-19 patients were divided into two groups (I and II). The serum concentration of TNFα, IL-1β, IL-6, IL-12, IL-23, and IL-33 was determined by ELISA. The ratios of IL-33/TNF-α, IL-33/IL-1β, IL-33/IL-6, IL-33/IL-12, and IL-33/IL-23 were evaluated for each patient, separately. For statistical significance determination, Mann–Whitney Rank Sum test was used.

Figure 3

Level of serum IL-33 in patients sorted according to chest x-ray (CRX) findings. Using a digital portable anteroposterior (AP) technique, the chest X-ray findings were divided into five levels: (I) Normal finding (II) Interstitial thickening, {III) Focal consolidation, (IV) Multifocal consolidation (V) acute respiratory distress syndrome (ARDS). The serum concentration of IL-33 was determined by ELISA. For statistical significance determination, Mann–Whitney Rank Sum test was used. *P < 0.05.