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Table of Content Volume 17 Issue 3 - March 2021

 

Study of interleukin-6 and its association with the severity of COVID-19 disease at a tertiary hospital

 

Gautam Kalita1, L T Rawat2*

 

1Associate Professor, 2Ex Professor, Department of Medicine, Terna Medical College, Nerul Navi Mumbai Maharashtra, INDIA.

Email: drgautam11@gmail.com , laxmandasrawat@gmail.com

 

Abstract              Background: It is increasingly recognized that excessive, malfunctional host immune response may play an important role in the development and maintenance of critical stages of COVID-19. A higher neutrophil count and elevated C-reactive protein may predict this subgroup of patients and interleukin-6 (IL-6) is a key cytokine in the cytokine storm. Severity prediction will also improve the prognosis by reducing the mortality rate. Present study was aimed to study interleukin-6 and its association with the severity of COVID-19 disease at a tertiary hospital. Material and Methods: Present study was a prospective observational study, conducted in patients with reverse transcriptasepolymerase chain reaction positive (RT-PCR) for SARSCoV2, underwent IL-6 level estimation at time of admission. Results: In present study total 216 patients were included. Age and gender distribution was comparable in all three groups and no significant difference was noted amongst them. Male patients were more than female, male: female ratio was 1.18:1. Co-morbidities such as hypertension, age > 65 years, diabetes, COPD and ischemic heart disease were noted in study patients. Severity of disease (mild and very mild cases, moderate cases and severe cases) was positively corelated with IL-6 levels. Highly significant levels of IL-6 were noted with chest radiograph visual score, CT severity score and CT severity score >12/25. Management modalities (non-invasive ventilation, ICU care, tocilizumab therapy) and mortality was significantly higher in patients with extremely raised IL-6 levels. Conclusion: We conclude that high IL-6 levels at admission are at increased risk of developing a severe form of the disease, poor radiological score, requiring ICU care and mortality.

Keywords: interleukin-6, severity of COVID-19, ICU care, CT score.

 

INTRODUCTION

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), COVID-19 infection has a variable clinical presentation from asymptomatic to milder symptoms, including fever, dry cough, dyspnea, myalgia, sore throat and headache, to more severe and emergent manifestation including confusion, chest pain, hypoxemia, pneumonia and other complications requiring intensive care unit (ICU) admission and mechanical ventilation. It is increasingly recognized that excessive, malfunctional host immune response may play an important role in the development and maintenance of critical stages of COVID-19. A subgroup of patients with COVID-19 develop severe cytokine activation and secondary hemophagocytic lymphohistiocytosis (HLH), leading to rapid-onset hypoxemia, shock and multiorgan dysfunction.2 A higher neutrophil count and elevated C-reactive protein may predict this subgroup of patients and interleukin-6 (IL-6) is a key cytokine in the cytokine storm.3,4 Ruan et al. suggest that virally driven hyper-inflammation could also be a possible predictor of fatality due to elevated levels of ferritin and IL-6 observed at 150 confirmed COVID-19 cases.4 Mehta et al. impose the beneficial effect of earlier identifying and treating hyper-inflammation on reducing the overall mortality.5  To avoid the unnecessary or inappropriate utilization of the healthcare resources, early prediction of the severity of COVID-19 will be helpful. Severity prediction will also improve the prognosis by reducing the mortality rate. Present study was aimed to study interleukin-6 and its association with the severity of COVID-19 disease at a tertiary hospital.

 

MATERIAL AND METHODS

Present study was a prospective observational study, conducted in COVID wards at XXX Medical College and hospital, XXX. Study duration was of 3 months, from July 1 to September 30, 2020. Present study was approved by the Institutional Ethics Committee. The study participants were reverse transcriptasepolymerase chain reaction positive (RT-PCR) for SARSCoV2, underwent IL-6 level estimation at time of admission. The patient information regarding demographic data, clinical features, medical history, general physical examination, laboratory findings, chest radiograph (CXR) findings, highresolution computed tomography (HRCT) scans of the chest, treatment details and outcome data were collected from the medical records. For clinical correlation, the study participants were segregated into 3 categories based on the level of disease severity, as per the Indian Council of Medical Research (ICMR) guidelines (Mild and very mild cases, moderate cases and severe cases).


 

 

Table 1: ICMR severity of disease6

Disease severity

Clinical criteria:

Mild and very mild cases

Cases presenting with fever and/or upper respiratory tract illness (Influenza Like Illness, ILI).

Moderate cases

Pneumonia with no signs of severe disease (Respiratory Rate 15 to 30/minute, SpO2 90%-94%).

Severe cases

Severe Pneumonia (with respiratory rate ≥30/minute and/or SpO2 < 90% in room air) or ARDS or Septic shock


Radiological findings were inferred using digital CXR evaluated for average visual score (scored 0–4 through visual assessment of involved lung area)7, 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)8 and proportion of patients who had classic COVID19 CT images. Serum concentrations of IL-6 were measured in all patients using enzyme-linked immunosorbent assay (ELISA) according to the manufacturer’s instructions (PeproTech, USA) Based on the IL6 levels, COVID19 patients were categorized into three groups.

  1. Group 1 had patients of who had IL6 within the normal range (0–5.9 pg/mL),
  2. Group 2 had patients of COVID19, who had raised IL6 up to ten times of the upper normal limit (UNL) (6.0–60.0 pg/mL), and
  3. Group 3 had patients of COVID19, who had extremely raised IL6 > ten times of UNL (>60.0 pg/mL).

Data concerning specific pharmacological treatment against IL6, such as tocilizumab therapy and supportive measures such as intensive care unit (ICU) care and noninvasive ventilation (NIV) was also collected.

Statistical Package for the Social Sciences 21 and R program was used for the 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 Chisquare test. P value less than 0.05 was significant and less than 0.001 was highly significant.


 

RESULTS

In present study total 216 patients were included. Age and gender distribution was comparable in all three groups and no significant difference was noted amongst them. Male patients were more than female, male: female ratio was 1.18:1. Co-morbidities such as hypertension, age > 65 years, diabetes, COPD and ischemic heart disease were noted in study patients. Severity of disease (mild and very mild cases, moderate cases and severe cases) was positively corelated with IL-6 levels. Highly significant levels of IL-6 were noted with chest radiograph visual score, CT severity score and CT severity score >12/25.

 

 

 

 

Table 1: Distribution of demographic, clinical and radiological characteristics according to IL-6 levels

 

Group I

(normal IL6) (n=121) (%)

Group II

(Raised IL6)

(n=56) (%)

Group III

(extremely Raised)

IL6 (n=39) (%)

Total

(n=24) (%)

p value

Age (in years) (Mean ± SD)

52.18 ± 8.59

47.23 ± 7.25

55.18 ± 4.66

51.13 ± 5.59

P = 0.34

Gender

 

 

 

 

P = 0.13

Male

62 (54%)

32 (57%)

23 (59%)

117 (54%)

 

Female

59 (49%)

24 (43%)

16 (41%)

99 (46%)

 

Co-morbidities

 

 

 

 

 

Hypertension

24 (20%)

14 (25%)

12 (31%)

50 (23%)

 

Age > 65 years

11 (9%)

14 (25%)

14 (36%)

39 (18%)

 

Diabetes

9 (7%)

12 (21%)

15 (38%)

36 (17%)

 

COPD

2 (2%)

6 (11%)

13 (33%)

21 (10%)

 

Ischemic heart disease

7 (6%)

3 (5%)

4 (10%)

14 (6%)

 

Disease severity

 

 

 

 

P<0.001

Mild and very mild

99 (82%)

14 (25%)

2 (5%)

115 (53%)

 

Moderate

18 (15%)

31 (55%)

5 (13%)

54 (25%)

 

Severe

4 (3%)

11 (20%)

32 (82%)

47 (22%)

 

Radiological

 

 

 

 

 

Chest radiograph visual score

0.08 ± 0.15

1.71 ± 1.55

2.88±1.18

1.53 ± 1.21

P<0.001

CT severity score

2.97 ± 2.88

6.24 ± 5.42

17.27 ± 3.89

7.01 ± 5.93

P<0.001

CT severity score >12/25

16 (13%)

19 (34%)

33 (85%)

68 (31%)

P<0.001

(P value less than 0.05 was significant and less than 0.001 was highly significant)

Management modalities (non-invasive ventilation, ICU care, tocilizumab therapy) and mortality was significantly higher in patients with extremely raised IL-6 levels.

 

Table 2: Distribution according to management

Management

Group I

(normal IL6) (n=121) (%)

Group II

(Raised IL6)

(n=56) (%)

Group III

(extremely Raised)

IL6 (n=39) (%)

Total (%)

p value

Non-Invasive Ventilation

3 (2%)

8 (14%)

21 (54%)

32 (15%)

P<0.001

ICU care

25 (21%)

21 (38%)

31 (179%)

77 (36%)

P<0.001

Tocilizumab therapy

1 (1%)

6 (11%)

23 (59%)

30 (14%)

P<0.001

Mortality

1 (1%)

4 (7%)

7 (18%)

12 (6%)

P=0.021

(P value less than 0.05 was significant and less than 0.001 was highly significant)

 


DISCUSSION

IL-6 is a pleiotropic cytokine with different physiological activities including regulation of inflammatory processes, metabolism of bone, and immune response. However, overproduction of IL-6 may contribute to systemic inflammatory processes and induce cytokines production.9,10 Patients with severe COVID-19 disease manifest immune system dysregulation, which is believed to be triggered by a particular mode of programmed cell death called pyroptosis. This form of cell death induces several proinflammatory cytokines and chemokines such as IL-1b, IL-2, IL-6, tumour necrosis factor a (TNF-a), and monocyte chemoattractant protein 1 (MCP1) and lymphopenia with attrition of both CD4þ and CD8þ T cells and natural killer T cells.2 IL-6 and IL-1 production promote neutrophil and cytotoxic T cell recruitment to the affected tissues, both of which contribute to tissue damage resulting in acute lung injury through production of oxygen free radicals and inflammatory mediators such as leukotrienes.2 The majority of the cases develop lymphopenia and pneumonia with the characterizing feature of pulmonary ground-glass opacity on chest computed tomography (CT) scan, high levels of pro-inflammatory cytokines are evident mostly in the severe to critical patients.11 A classic COVID19 CT showed typical images of diffuse, bilateral, peripheral ground glass opacities (GGOs) with or without consolidation or crazy paving, found frequently and specifically in COVID19 pneumonia or indeterminate images of multifocal, diffuse, perihilar, or unilateral GGOs.12 Chen X et al.,13 elevated blood levels of IL-6 have been shown to correlate with COVID-19 disease severity and SARS-CoV-2 RNA blood levels in COVID-19 patients and is also associated with a worse prognosis. Similar findings were noted in other studies. 14,15,16 In a similar study Bhandari S et al.,17 noted that COVID19 patients with raised IL6 levels exhibited frequent symptomatic presentations, severity, and critical illness, especially with extremely high IL6 levels. Radiological findings in terms of a digital chest radiograph and highresolution computed tomography (CT) chest indicated severe lung involvement in patients with extremely high IL6 levels. The majority of patients with extremely raised IL6 levels were associated with the classic COVID19 CT images. Patients with extremely raised IL6 levels required intensive treatment as compared to normal IL6 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). They concluded that raised IL6 levels in COVID19 patients should be considered a risk factor for the severity of the disease, inflammatory storm, and rapid pulmonary invasion.17 Similar findings were noted in present study. Among hospitalized patients with COVID-19, patients with high IL-6 levels at admission are at increased risk of developing a severe form of the disease, requiring mechanical ventilation and ICU, and progressing to respiratory distress syndrome and multiorgan failure. Mojtabavi H et al.,18 conducted a meta-analysis of eleven studies with moderate to the high quality of evidence and confirmed that patients with severe COVID-19 have higher concentrations of IL-6 than patients with non-severe COVID-19. This relationship seems to exist, independent of age and sex. Yong et al. identified the cut-off value of 24.3 pg/ml of IL-6 combining with D-Dimer for early detection of severe cases in a cohort of 43 cases.19 Giofoni et al. identified a cut-off value of 25 pg/ml of serum IL-6 as an independent risk factor of progression for severe COVID-19 and/or in-hospital mortality in a cohort of 77 patients.20 In another cohort in Munich, elevated IL-6 (> 80 pg/ml) was strongly associated with a 22 times higher need for mechanical ventilation compared with patients with lower IL-6 levels in a cohort involving 40 patients, suggesting that high IL-6 level might predict the critical illness.15 One challenge in halting this pandemic is the absence of evidence demonstrating effective pharmacologic interventions to prevent COVID-19. Tocilizumab and sarilumab are humanized monoclonal antibodies that target soluble and membrane-bound IL-6 receptors and inhibit downstream IL-6 effects.21 IL-6 inhibitors (IL6ri) have been approved by the US Food and Drug Administration for the treatment of CRS (Cytokine release syndrome) in patients undergoing chimeric antigen receptor T-cell therapy. More recent larger observational studies have further confirmed the benefits of IL6ri therapy in patients with COVID-19.22,23 The levels of IL-6 should be measured dynamically, as the maximal level of blood IL-6 above a certain threshold may predict a fatal outcome. The dynamic detection of plasma IL-6 is critical for determining the intervention time of an anti-IL-6 receptor antibody. Despite high levels in blood, use of isolated IL-6 measurement as a COVID-19 prognostic tool, or as a means of evaluating clinical response to treatment, is hindered by several factors. First, IL-6 levels within the same patient vary significantly over the course of any given day, the most conspicuous effect being a trough in the morning.23 Second, the magnitude of the IL-6 response to infection is, in absolute terms, also variable between patients.24 Furthermore, the presence of immune-metabolic comorbidities such as obesity can also influence circulating IL-6 levels and IL-6 release.25 Clinicians should always consider other clinical factors while corelating disease severity with raised IL-6 levels.

 

CONCLUSION

Early detection and treatment for severe and critically ill patients are crucial issues requiring urgent investigation. We conclude that high IL-6 levels at admission are at increased risk of developing a severe form of the disease, poor radiological score, requiring ICU care and mortality.

 

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