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Table of Contents
ORIGINAL ARTICLE
Year : 2020  |  Volume : 11  |  Issue : 3  |  Page : 132-136

Evaluation of interleukin-6 and its association with the severity of disease in COVID-19 patients


1 Department of General Medicine, SMS Medical College and Attached Group of Hospital, Jaipur, Rajasthan, India
2 Department of Physiology, SMS Medical College and Attached Group of Hospital, Jaipur, Rajasthan, India

Date of Submission19-Jun-2020
Date of Acceptance19-Jul-2020
Date of Web Publication25-Aug-2020

Correspondence Address:
Dr. Govind Rankawat
Department of General Medicine, SMS Medical College and Attached Group of Hospital, Jaipur, Rajasthan
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/INJMS.INJMS_63_20

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  Abstract 


Background: The present study was undertaken to determine the levels of interleukin-6 (IL-6) and evaluate its association with clinical presentation, severity, radiological imaging, management, and outcome in coronavirus disease (COVID-19) infection. Methods: The present study included 132 admitted COVID-19 patients, categorized into three groups. Group 1 had IL-6 within the normal reference range, Group 2 had IL-6 raised up to ten times the upper normal limit (UNL), and Group 3 had IL-6 level raised > ten times the UNL. The patient's data concerning medical history, clinical manifestations, laboratory findings, radiological imaging, management, and outcome were extracted from their medical records for subsequent evaluation, interpretation, and association among the groups. Results: COVID-19 patients with raised IL-6 levels exhibited frequent symptomatic presentations, severity, and critical illness, especially with extremely high IL-6 levels (P < 0.001). Radiological findings in terms of a digital chest radiograph and high-resolution computed tomography (CT) chest indicated severe lung involvement in patients with extremely high IL-6 levels (P < 0.05). The majority of patients with extremely raised IL-6 levels were associated with the classic COVID-19 CT images (P = 0.014). Patients with extremely raised IL-6 levels required intensive treatment as compared to normal IL-6 group in terms of tocilizumab therapy (P = 0.008), noninvasive ventilation (P < 0.001), and intensive care unit care (P = 0.009) associated with higher mortality (P = 0.046). Conclusion: Raised IL-6 levels in COVID-19 patients should be considered a risk factor for the severity of the disease, inflammatory storm, and rapid pulmonary invasion. There is an urgent need for establishing a treatment protocol in patients with extremely raised IL-6 levels.

Keywords: Coronavirus disease-19, interleukin-6, management, severity of disease


How to cite this article:
Bhandari S, Rankawat G, Singh A, Wadhwani D, Patel B. Evaluation of interleukin-6 and its association with the severity of disease in COVID-19 patients. Indian J Med Spec 2020;11:132-6

How to cite this URL:
Bhandari S, Rankawat G, Singh A, Wadhwani D, Patel B. Evaluation of interleukin-6 and its association with the severity of disease in COVID-19 patients. Indian J Med Spec [serial online] 2020 [cited 2020 Sep 28];11:132-6. Available from: http://www.ijms.in/text.asp?2020/11/3/132/293324




  Introduction Top


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the pathogen behind coronavirus disease (COVID-19) that emerged from Wuhan in China and rapidly spread across most of the nations worldwide. The disease presentation may range from an asymptomatic state to severe pneumonia associated with acute respiratory failure.[1] COVID-19 incubation period may range from 2 to 14 days. The usual presentation in COVID-19 positive patients has been fever, cough, shortness of breath, fatigue, loss of appetite, sputum production, joint pain, nausea, vomiting, and diarrhea. Although a large number of patients may not exhibit noticeable symptoms. A severe disease could be associated with fatal complications such as pneumonia, acute respiratory distress syndrome (ARDS), multi-organ failure, septic shock, disseminated intravascular coagulation, and ultimately leading to death.[2],[3]

A large activation of T-lymphocytes and mononuclear macrophages occurs in COVID-19 patients, producing cytokines, especially the interleukin-6 (IL-6). Binding of this cytokine to its IL-6 receptor on the target cells is responsible for cytokine storm and severe inflammatory responses seen in the lungs and other tissues of COVID-19 patients. This process requires the binding of IL-6 with its soluble IL receptor (sIL-6R). The formed complex triggers signal transduction and the proinflammatory process through binding to gp130 present over the cell membrane.[4],[5],[6],[7] IL-6 is the most common cytokine reported in SARS-CoV-2 infection and is reflected in clinical manifestations, radiological features, management modalities, and outcomes. The present study was aimed to assess the IL-6 levels in COVID-19-infected patients and to evaluate its association with the severity of the disease, the requirement of additional management therapies, and outcomes.


  Methods Top


Study design

The present descriptive observational study was conducted on 132 COVID-19 patients at S.M.S. Medical College and attached hospitals, Jaipur, India, admitted between May 1 and May 30, 2020. The study participants were reverse transcriptase-polymerase chain reaction positive for SARS-CoV-2, with known IL-6 levels. This study was approved by the Institutional Ethics Committee. Based on the IL-6 levels, the participants were categorized into three groups. (I) Group 1 had patients of COVID-19, who had IL-6 within the normal range (0–5.9 pg/mL), (II) Group 2 had patients of COVID-19, who had raised IL-6 up to ten times of the upper normal limit (UNL) (6.0–60.0 pg/mL), and (III) Group 3 had patients of COVID-19, who had extremely raised IL-6 > ten times of UNL (>60.0 pg/mL).

Data collection

COVID-19 was diagnosed based on the World Health Organization interim guidance.[1] The patient information regarding demographic data, medical history, clinical manifestation, general physical examination, laboratory findings, chest radiograph (CXR) findings, high-resolution computed tomography (HRCT) scans of the chest, treatment, and outcome data were extracted from the medical records for data analysis. For clinical correlation, the study participants were segregated into four categories based on the level of disease severity, viz. asymptomatic, mildly ill, severely ill and critically ill as per the Indian Council of Medical Research (ICMR) guidelines. The mild illness group constituted COVID-19-positive patients with symptoms of upper respiratory tract infection including fever, cough, sore throat, headache, shortness of breath, myalgia, joint pain, etc. without evidence of viral pneumonia or hypoxia. The severely ill category had COVID-19-positive patients with clinical signs of pneumonia (fever, cough, shortness of breath, fast breathing) with respiratory distress and SpO2 >90% on room air. The critically ill category had COVID-19-positive patients with clinical signs of severe pneumonia and radiological evidence of bilateral opacities in the chest with respiratory failure and COVID-19-related complication such as ARDS, sepsis, and septic shock after exclusion of other causes. Radiological findings were inferred using digital CXR evaluated for average visual score (scored 0–4 through visual assessment of involved lung area),[8] HRCT chest evaluated for computed tomography (CT) severity score (assigned out of 25 based on the percentage area involved in each of the 5 lobes)[9] and proportion of patients who had classic COVID-19 CT images. A classic COVID-19 CT showed typical images of diffuse, bilateral, peripheral ground glass opacities (GGOs) with or without consolidation or crazy paving, found frequently and specifically in COVID-19 pneumonia or indeterminate images of multifocal, diffuse, perihilar, or unilateral GGOs.[10] Data concerning specific pharmacological treatment against IL-6, such as tocilizumab therapy and supportive measures such as intensive care unit (ICU) care and noninvasive ventilation (NIV) was also collected. The adverse outcome of COVID-19 patients was estimated by the number of mortalities reported during treatment. The data was compiled, tabulated, interpreted, and correlated in all the groups to establish differences in COVID-19 manifestation with serum levels of IL-6.

Statistical analysis

Quantitative data were expressed as mean and standard deviation. Pearson correlation coefficient (r) was used to determine the correlation among the variables. Qualitative data were expressed as proportions, and the level of significance was inferred using the Chi-square test. The level of significance was assigned at P < 0.05. Statistical Package for the Social Sciences (IBM SPSS statistics for windows, [IBM Corp, Amonk, N.Y., USA]) and R program was used for the statistical analysis.


  Results Top


A total of 132 COVID-19 patients were included in this study, of which 60 patients (45.45%) fell into Group 1 with serum IL-6 levels within the normal reference range (0–5.9 pg/mL). Forty-eight patients (36.36%) had raised serum level of IL-6 (6.0–60.0 pg/mL) up to ten times of UNL, and belonged to Group 2, whereas 24 patients (18.18%) had extremely raised serum level of IL-6 (>60 pg/mL) >ten times of UNL, and belonged to Group 3.

The mean age of SARS-CoV-2 infected patients tested for IL-6 was 50.08 years (95% confidence interval: 50.08 ± 3.59, standard deviation = 16.39). Mean ages in Group 1, 2, and 3 were found to be 51 ± 17.25 years, 46.94 ± 13.15 years, and 50.84 ± 17.35 years, respectively, and did not differ significantly (P = 0.538) [Table 1]. A male preponderance was observed in Group 3 as compared to other groups, although gender distribution did not differ significantly (P = 0.915).
Table 1: Association of interleukin-6 level with severity of the disease, radiological changes and impact on management in coronavirus disease-19 infected patients

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Clinical presentation and interleukin-6

Sixty-eight patients (51.52%) had the asymptomatic presentation, 31 patients (23.48%) had mild disease, 18 patients (13.64%) had severe disease, and 15 (11.36%) had critical disease. In Group 1, 80.00% of patients were found asymptomatic, 13.33% of patients mildly ill, 5.00% severely ill, and 1.67% critically ill. In Group 2, 37.50% of patients had asymptomatic presentation, 43.75% of patients had mild disease, 10.42% of patients had severe disease and 8.33% of patients had critical disease. In Group 3, 41.67% of patients were critically ill, another 41.67% patients severely ill, 8.33% patients mildly ill, and the remaining 8.33% of patients asymptomatic. There was a significant association between the level of IL-6 and the severity of clinical manifestation (P < 0.001). Forty-two patients (31.82%) patients had underlying comorbid diseases. Comorbidities were significantly higher (54.17%) in patients of extremely raised IL-6 as compared to patients (26.67%) of normal IL-6 level (P = 0.0341).

Radiological findings and interleukin-6

Lung involvement was assessed by CXR and HRCT chest in all patients. The visual score on CXR was 1.28 ± 1.47 out of 4. The average CT severity score was 6.89 ± 6.06 out of 25 with CT severity score >10/25 in 28 patients (21.21%) and classic for COVID-19 CT images in 52 patients (39.39%).

Radiological findings among Groups 1, 2, and 3 were observed as follows: CXR average visual score was found 0.06 ± 0.23, 1.66 ± 1.31, and 2.88 ± 1.18 in Groups 1, 2, and 3, respectively, with a significant difference (P < 0.001). Average CT severity score was significantly higher (P < 0.001) in Group 3 (15.72 ± 4.62) as compared to Group 1 (3.76 ± 3.18).

The percentage of patients with CT severity score >10/25 was significantly higher (P < 0.001) in Group 3 (62.50%) as compared to Group 1 (8.33%). The percentage of patients with the classic COVID CT images was significantly higher (P = 0.0141) in patients of extremely raised IL-6 (58.33%) as compared to patients with normal IL-6 levels (26.67%).

Treatment and outcome

In our study population, all patients were treated with standard of care as per ICMR guidelines. Treatment was also influenced by severity and complication of COVID-19 infection, which required special pharmacological and supportive treatment in terms of anti-IL6 therapy tocilizumab, supportive therapy like ICU care, NIV, etc., In the present study, 29 patients (21.97%) needed ICU care, 14 patients (10.61%) needed NIV, and eight patients (6.06%) needed tocilizumab therapy. The percentage of patients requiring ICU care was significantly higher (P = 0.009) in patients of Group 3 (50%) as compared to Group 1 (13.33%). The need of NIV therapy was significantly higher (P < 0.001) in patients of Group 3 (37.50%) as compared to Group 1 (1.67%). A higher percentage (P = 0.008) of patients from Group 3 (25.00%) required tocilizumab therapy as compared to Group 1 (4.17%). A total of five patients (3.79%) succumbed to COVID-19 with three patients from Group 3 and one patient each from Group 1 and 2. The percentage of mortality was significantly higher (P = 0.046) in patients of extremely raised IL-6 group (12.50%) as compared to the normal IL-6 group (1.67%).


  Discussion Top


In the present study, an association between IL-6 levels and severity of COVID-19 was observed. Chen et al. reported a similar finding with significant elevation in the level of inflammatory cytokine IL-6 in critically ill COVID-19 patients. The raised IL-6 levels were closely correlated with the incidence of RNAaemia and COVID-19-related mortality.[11] IL-6 is an important pro-inflammatory factor in the disease process of SARS-CoV-2. It contributes to COVID-19-associated cytokine storms, largely enhancing vascular permeability and impairing the organ function. The SARS-CoV-2 virus replicates rapidly, triggering a storm characterized by increased levels of cytokines such as IL-6. Such an inflammatory response causes inflammation of the respiratory system and other bodily systems, with subsequent occurrence of ARDS or respiratory failure. The estimation of IL-6 levels could be an important tool to assess disease severity in COVID-19 patients. This IL-6 level might be an important tool to detect the severity of COVID-19 infection and further to decide treatment protocol. Moreover, the treatment strategy of using antivirals alone in COVID-19 may not be sufficient to reverse such deteriorating effects of IL-6.

In our study, no significant variations were found in age and gender distribution for IL-6. Symptomatic clinical presentation was more prevalent in an extremely raised IL-6 group as compared to the normal IL-6 group. Most of the patients with normal IL-6 levels had asymptomatic presentation except a few patients that had severe or critical disease. Patients with extremely raised IL-6 were susceptible to develop the severe and critical diseases. Raised cytokines levels are a part of the inflammatory process adversely affecting the COVID-19 patients. The patients with severe illness also had extremely raised IL-6 levels in the majority of patients, while the majority of asymptomatic patients had IL-6 within the normal reference range. Extremely raised IL-6 level was frequently associated with some comorbid conditions, whereas, a lesser number of patients had underlying comorbidities among normal IL-6 groups. Moreover, patients with underlying comorbidities were more susceptible to develop severe disease secondary to extremely high IL-6 levels.

Radiological findings provide a rapid and documented tool for assessing prognosis of COVID-19 infection and might be beneficial in categorizing the severity of disease. Patients with raised IL-6 levels exhibited a higher overall CXR visual score. Radiographic severity of COVID-19 disease directly correlated with IL-6 levels. HRCT chest could provide a precise detection of the extent of lung involvement in COVID-19 patients. This was evident by higher CT severity score associated with extremely raised IL-6 levels, whereas low CT severity score with normal IL-6 levels. Moreover, classic COVID-19 CT image that is peculiar to differentiate SARS-CoV-2 infection from other pulmonary disease was frequently reported in patients with extremely raised IL-6 levels. As the inflammatory process progressed raised IL-6 levels corroborated with the severity of the disease as reflected by early and extensive involvement of lung documented by HRCT chest.

The COVID-19 patients of this study were treated with standard care as per ICMR guidelines. The treatment line was also influenced by severity and complication of COVID-19 infection, which required additional pharmacological and supportive treatment in terms of anti-IL-6 therapy tocilizumab, supportive therapy like ICU care, and NIV. IL-6 monoclonal antibody (Tocilizumab)-directed COVID-19 therapy, after its use in clinical trials has recently been incorporated into COVID-19 management guidelines. Tocilizumab can specifically bind to sIL-6R and mIL-6R and inhibit signal transduction. This drug was already being used for rheumatoid arthritis.[7] Additional pharmacological treatment was given in the form of injectable tocilizumab in standard therapy. Tocilizumab, a recombinant humanized anti-human IL-6 receptor monoclonal antibody, is an injectable preparation designed for COVID-19 patients, especially with extremely raised IL-6. Supportive therapy in the form of NIV and ICU care was frequently needed in patients with extremely raised IL-6 level, while only a few patients with normal IL-6 levels required ICU care. Higher mortality was associated with extremely raised IL-6 levels. The aforementioned evidence of the present study signifies the role of Il-6 levels in estimating the disease severity.


  Conclusion Top


COVID-19-infected patients with extremely high IL-6 levels are definitely at high risk of severe and fatal infection, due to the increased inflammatory drive, induced by cytokines storm, leading to higher mortality. SARS-CoV-2-infected patients with extremely elevated IL-6 levels are susceptible to develop severe and critical disease requiring intensive pharmacological as well as supportive treatment. IL-6 levels might be a predictive marker of the disease severity in COVID-19 patients and also for standard clinical measures to predict impending adverse outcomes with high accuracy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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