Role of interleukin-6 levels in predicting COVID severity: A single-center experience

Abstract

The COVID-19 pandemic has changed the entire perspective of health-care scenario globally. Our fight against this virus is to enable ourselves to recognize early warning signs or biomarkers in those infected so that they can be allocated adequate health-care resources to decrease mortality and morbidity. It was for this reason that we analyzed the hematological parameter neutrophil-to-lymphocyte ratio (NLR) and inflammatory biomarker cytokine interleukin (IL)-6 to evaluate whether they can be used to predict the severity of COVID-19 infection and also to study if any significant association exist between the two. These parameters can be easily analyzed even in primary health-care setting to effectively triage patients requiring tertiary care/L-3 facilities. This study was conducted on 100 reverse transcription–polymerase chain reaction confirmed COVID-positive patients. The patients were then categorized into mild, moderate, and severe COVID at the time of admission according to the criteria laid down by symptoms and SpO2 levels at room air as defined by ICMR COVID guidelines by the Ministry of Health and Family Welfare[1] (MOHFW), Government of India, revised on January 14, 2022 – Mild disease – Upper respiratory tract symptoms and/or fever without shortness of breath or hypoxia Moderate disease – Any one of: Respiratory rate ≥24/min, SpO2: 90% to ≤93% on room air Severe disease – Any one of: Respiratory rate >30/min, SpO2 <90% on room air. For ease of comparison and to effectively evaluate high-risk patients, mild and moderate categories were clubbed together into nonsevere as they can be managed in L-2 facility. However, those falling in the severe category require L-3 facilities with advanced infrastructure and ICU facilities and are, therefore, categorized separately. Levels of IL-6 and NLR were compared between the two groups. NLR was derived by dividing the percentage of neutrophils to the percentage of lymphocytes after calculating differential leukocyte count taking the normal upper limit of NLR as 3.5, as identified by Forget et al.[2] for the adult nongeriatric population in good health.[2] The mean value of NLR in mild, moderate, and severe categories was 3.9, 3.1, and 6.7, respectively. On combining mild and moderate categories as nonsevere, the mean values of NLR obtained were 3.7, almost half of the NLR mean values observed in the severe category, i.e., 6.7. On applying the analysis of variance (ANOVA) t-test, a significant statistical correlation (P = 0.016) of NLR was found with clinical severity. Cytokine IL-6 is an inflammatory cytokine that has a role in different pathological conditions such as infections, inflammations, and in cancers. IL-6 is also considered the main culprit responsible for hyperinflammation, causing lung damage and eventually death in severe cases of COVID-19. The normal upper limit for IL-6 was set as 7 pg/ml. Out of 100 patients, those in the mild category had mean IL-6 levels of 30.8 pg/ml, moderate patients had a mean value of 47.1 pg/ml, and severe category had a mean value of 28.6 pg/ml. Clubbing mild and moderate categories together, mean IL-6 values were 35.6 pg/ml in the nonsevere category, while it was 28.6 pg/ml in the severe category [Table 1]. On applying ANOVA t-test for the strength of significance between groups, no significant association was found between IL-6 levels and clinical severity (P = 0.510).Table 1: Coronavirus disease 2019 severity and interleukin-6 levelsWith respect to IL-6, on comparing our results with other studies [Table 2], one Indian study undertaken by Bhandari et al.,[3] in which based on IL-6 levels participants (n = 132) were segregated into three groups and then correlated with the clinical condition of the patients. In their study, 88% of patients with raised IL-6 levels had clinically severe COVID; in our study, 75% had severe COVID, so the results are compatible. However, in nonsevere cases, 63.2% of patients in our study and 43.4% in their study had raised IL-6 levels highlighting the fact that a significant proportion of nonsevere patients who were asymptomatic or had mild-to-moderate symptoms had raised IL-6 levels. Similar picture was observed in the study conducted by Liu et al.,[4] in which almost 60% of patients with nonsevere COVID had raised IL-6 levels, clearly indicating that higher IL-6 serum levels failed to predict the severity of the disease.Table 2: Comparison of interleukin-6 with different studiesWe also analyzed normal NLR (<3.5) and raised NLR (≥3.5) with serum IL-6 levels and compared the results with the study conducted by Talwar et al. In their study, 60% of patients with normal IL-6 had normal NLR; in our study, it came to be 72.7%; our results are in concordance with Talwar et al.[5] in this category. In those having raised IL-6 levels, in the study done by Talwar et al., 85% had raised NLR also, whereas in our study, in those with raised IL-6 levels, only 45% of these patients had raised NLR. Hence, there was a disparity in this category as the majority of patients in our study had normal NLR despite raised IL-6 levels [Table 3].Table 3: Comparison between interleukin-6 and neutrophil-to-lymphocyte ratioOur study failed to show any correlation between raised IL-6 levels and NLR. It was also noticed that mean IL-6 levels were somehow higher in the nonsevere category (35.6 pg/ml) as compared to those having severe disease (28.6 pg/ml). Hence, to conclude, serum IL-6 levels done at the time of admission failed to predict severity in COVID patients. This finding supports the dubious nature of IL-6 receptor antagonists in treating moderate-to-severe COVID, as some of the studies done to assess the efficacy of IL-6 receptor antagonists to treat moderate-to-severe cases failed to show expected results. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.