Demographic characteristics, main comorbidities, clinical manifestations, medications, and vital signs on presentation are shown in Table 1. Twenty-one consecutive participants (mean age 49 ± 22; 9 m, 12 f) presented to the emergency department with one or more of the following chief complaints (in descending order of frequency): fever, dry cough, sore throat, rhinorrhea, fatigue, headache, diarrhea, anosmia, productive cough, dyspnea, ear pain, ageusia, anorexia, abdominal pain, nausea, emesis, seizure, syncope, myalgia, rash, and no symptoms. Fever and dry cough were the principal manifestations in all patients, whereas other symptoms varied among severity groups. Among the patients, comorbidities were as follows: hypertension, diabetes mellitus, dyslipidemia, coronary artery disease, congestive heart failure, atrial fibrillation, chronic obstructive pulmonary disease, cerebrovascular disease, leukemia in remission, colorectal cancer in remission, post-renal transplant, Hodgkin’s lymphoma in remission, and hypothyroidism.

To compare cytokine expression levels between COVID-19 patients and controls, plasma cytokine levels were measured using Luminex in 4 patient groups: severe COVID-19 (n = 6), moderate COVID-19 (n = 9), Mild COVID-19 (n = 6), and controls (n = 4). Leukocyte profile, CRP, Ferritin and Beta 2 microglobulin were also measured (figure 1). Beta-2 microglobulin was elevated in severe patients, compared to moderate, mild and controls (P <0.001) Figure 2. IP-10 level was significantly elevated in severe COVID-19 patients, in comparison to controls, mild and moderate (P< 0.0103), (P< 0.0188), (P< 0.0448) respectively. IL-1RA was also significant elevated in severe patients in comparison with other groups (figure 3). TNFA was significantly elevated in the severe COVID-19 patients’ group, compared to controls, mild, and moderate groups (P< 0.001) (Figure 4). Those biomarkers were obtained before the clinical deterioration and development of cytokine storm and ARDS, which indicate that those cytokines may play a role in early detection and recognition of severe COVID-19 disease and risk of development of cytokine storm.

In this study, we found that the early production of inhibitory mediators such as IL-1RA, IP-10 and MCP-1 were significantly associated with severe disease. This shows similarity to influenza virus infections, where similar associations with disease severity were also observed in both pandemic (pdm2009) H1N1 and avian H5N1 infections 21222324. The IL-1RA is an early inhibitory cytokine that suppresses proinflammatory cytokines and T lymphocyte responses. IL-1RA is a cytokine that controls inflammatory responses during early stages of immune activation 25. Early IL-1RA production could affect induction of proinflammatory and antiviral cytokines during the early phase of COVID-19 infection. In mild cases, the inhibitory role of elevated IL-1RA may be overridden by the robust adaptive immune responses to the virus. However, in the severe cases, much higher levels of IL-1RA were observed in comparison with mild cases, suggestive of an overactive immune response, which may contribute to the switch from controlled and protective immune environment to inflammation-induced tissue damage. Serum levels of IL-1RA, MCP-1 and IP-10 were found to be elevated before the clinical deterioration, indicating that these cytokines may play a role in early detection of disease severity especially in the pre-storm phase. Medications that target cytokines may prevent the development of an overt cytokine storm.

Given the obvious limitations of a single-center study and the small sample size, larger cohorts, preferably in areas of the world other than the Arabian Peninsula, are needed to definitively assess the value of IL-1RA, IP-10 and MCP-1 levels as independent biomarkers of disease severity and predictors of outcomes with the advantage of having less fluctuations or extraneous influences than other parameters, such as iron stores for ferritin, coagulopathies for D-dimers and secondary bacterial infections for CRP.