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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 5  |  Issue : 1  |  Page : 2-8

Serial interleukin-6 titer monitoring in COVID-19 pneumonia: Valuable inflammatory marker in the assessment of severity, predicting ventilatory support requirement, and final radiological outcome – Prospective observational study in tertiary care setting in India


1 Department of Pulmonary Medicine, MIMSR Medical College, Latur, Maharashtra, India
2 Department of Pathology, MIMSR Medical College, Latur, Maharashtra, India
3 Department of Internal Medicine, MIMSR Medical College, Latur, Maharashtra, India

Date of Submission27-Mar-2022
Date of Decision24-Apr-2022
Date of Acceptance20-May-2022
Date of Web Publication12-Aug-2022

Correspondence Address:
Shital Patil
Department of Pulmonary Medicine, MIMSR Medical College, Latur, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/japt.japt_6_22

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  Abstract 


Introduction: Coronavirus disease 2019 (COVID-19) pneumonia is heterogeneous disease with variable effect on lung parenchyma, airways, and vasculature, leading to long-term effects on lung functions. Materials and Methods: Multicentric, prospective, observational, and interventional study included 1000 COVID-19 cases confirmed with reverse transcription-polymerase chain reaction. All cases were assessed with lung involvement documented and categorized on high-resolution computed tomography (CT) of the thorax, oxygen saturation, inflammatory marker as interleukin-6 (IL-6) at entry point and follow-up. Age, gender, comorbidity, and use bilevel positive airway pressure/noninvasive ventilation (BIPAP/NIV) and outcome as with or without lung fibrosis as per CT severity were key observations. Statistical analysis is performed using Chi-square test. Results: Age (<50 and > 50 years) and gender (male versus female) has significant association with IL-6 (P < 0.00001) and (P < 0.010], respectively. CT severity score at entry point has significant correlation with IL-6 level (P < 0.00001) IL-6 level has significant association with duration of illness (P < 0.00001). Comorbidity as diabetes mellitus, hypertension, chronic obstructive pulmonary disease, ischemic heart disease, and obesity has significant IL-6 level (P < 0.00001). IL-6 level has significant association with oxygen saturation (P < 0.00001). BIPAP/NIV requirement during course hospitalization has significant association with IL-6 level (P < 0.00001). Timing of BIPAP/NIV requirement during hospitalization has significant association with IL-6 level (P < 0.00001) Serial IL-6 titer during hospitalization as compared to entry point normal and abnormal IL-6 has significant association in post-COVID lung fibrosis (P < 0.00001). Conclusions: IL-6 is easily available, and universally acceptable inflammatory marker, documented crucial role in COVID-19 pneumonia in predicting the severity of illness, progression of illness including “cytokine storm” and assessing response to treatment during hospitalization.

Keywords: Coronavirus disease 2019 pneumonia, interleukin-6 inflammatory marker, oxygen saturation, post-coronavirus disease lung fibrosis


How to cite this article:
Patil S, Acharya A, Gondhali G, Narwade G. Serial interleukin-6 titer monitoring in COVID-19 pneumonia: Valuable inflammatory marker in the assessment of severity, predicting ventilatory support requirement, and final radiological outcome – Prospective observational study in tertiary care setting in India. J Assoc Pulmonologist Tamilnadu 2022;5:2-8

How to cite this URL:
Patil S, Acharya A, Gondhali G, Narwade G. Serial interleukin-6 titer monitoring in COVID-19 pneumonia: Valuable inflammatory marker in the assessment of severity, predicting ventilatory support requirement, and final radiological outcome – Prospective observational study in tertiary care setting in India. J Assoc Pulmonologist Tamilnadu [serial online] 2022 [cited 2022 Oct 3];5:2-8. Available from: http://www.japt.com/text.asp?2022/5/1/2/353745




  Introduction Top


The current pandemic of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2, originally emerged from China, has documented 274,628,461 confirmed cases and 5,358,978 deaths globally, and 34,752,164 confirmed cases 478,007 deaths in India.[1] The International Federation of Clinical Chemistry and Laboratory Medicine Task Force on COVID-19 has been established to synthesize up-to-date information on the epidemiology, pathogenesis, and laboratory diagnosis and monitoring of COVID-19, as well as to develop practical recommendations on the use of molecular, serological, and biochemical tests in disease diagnosis and management.[2],[3]

COVID-19 pneumonia is heterogeneous disease with variable effect on lung parenchyma, airways and vasculature, leading to long-term effects on lung functions. Although lung is the primary target organ involvement in COVID-19, many patients were shown pulmonary and extrapulmonary manifestations of diseases variably during first and second wave, which occurred as resultant pathophysiological effects of immune activation pathway and direct virus induced lung damage. In COVID-19 pneumonia, pathophysiology constitutes different pathways such as immune activation, inflammatory, thrombogenic, and direct viral affection to lungs and extrapulmonary tissues.

Interleukin-6 (IL)-6 was found in 1973 as a soluble factor that is secreted by T-cells and is important for antibody production by B-cells.[5] Since its discovery, role of IL-6 in immune regulation and dysregulation in many diseases has been studied in the past 50 years. Before COVID-19, this molecule has been studied in various inflammatory and rheumatological conditions with or without systemic manifestations.[4] Robust data are available regarding its abnormally elevated levels of IL-6 in local tissue and serum of these cases due to dysregulated immune function, and targeted therapy against this novel molecule is now considered as best disease modifying approach in these cases rather than conventional steroids.[6],[7],[8]

Role of IL-6 as marker of dysregulated immune system is earliest reports from China in initial period of COVID-19 pandemic by Huang et al.,[9] they also mentioned that IL-6 is can be used with other inflammatory markers such as CRP and Ferritin. Leisman et al.[10] documented that IL-6 is raised in COVID-19, but its level not as high as documented in sepsis. Chen et al.[11] documented that, 1000-fold increase in IL-6 level in COVID-19 pneumonia cases requiring intensive care unit hospitalization. U. S. FDA[12] had approved IL-6 analysis during workup of COVID-19 pneumonia in June 2020, since then many laboratory companies came up with their methodology of IL-6 assay in COVID-19 pandemic. Hypercytokinemic immune dysregulation in COVID-19 is also known as cytokine storm syndrome. IL-6 levels ≥80 pg/mL predict an increased risk of respiratory failure and death, and immunomodulatory therapy is an area of urgent investigation.[11]

In the present study, we have utilized IL-6 as basic marker in laboratory panel workup in all COVID patients and analyzed its role in predicting cytokine storm, response to therapy, and earliest predictor of post-COVID fibrosis in tertiary care setting.


  Materials and Methods Top


Multicentric, prospective, observational, and interventional study, conducted during July 2020 to May 2021, in MIMSR Medical College and Venkatesh Hospital Latur India, included 1000 COVID-19 cases confirmed with the reverse transcription-polymerase chain reaction (RT PCR), to find out role of IL-6 in predicting severity of illness, assessing response to therapy and outcome as post-COVID fibrosis in diagnosed COVID-19 pneumonia cases admitted in critical care unit. A total of 1000 cases were enrolled in the study after IRB approval and written informed consent of patient.

Inclusion criteria

COVID-19 patients, confirmed with RT-PCR, above the age of 18 years, hospitalized in the study centers, including those with comorbidities and irrespective of severity and oxygen saturation were included in the study

Exclusion criteria

Those not willing to give consent, not able to perform IL-6 and not willing to remain in follow-up were excluded

All study cases were undergone following assessment before enrolling in the study

  1. COVID-19 RT PCR test performed in all cases, if first test results were negative and radiological features clearly documenting pneumonia, we have repeated RT PCR test and enrolled all cases with positive COVID-19 RT-PCR test
  2. High-resolution computed tomography (HRCT) of the thorax to assess severity of lung involvement, and categorized as mild if score <7, moderated if score 8–15, and severe if score >15 or 15–25
  3. Clinical assessment as – vital parameters such as heart rate, oxygen saturation, respiratory rate, blood pressure, and documentation of respiratory adventitious sounds
  4. Laboratory parameters – hemoglobin, renal functions, blood sugar level, liver functions, ECG
  5. Viral inflammatory markers such as IL-6, CRP, ferritin assessed at entry point and repeated whenever required during course of illness. Normal and abnormal parameter readings were considered as per pathological laboratory standard
  6. Entry point IL-6 titer was utilized as assessment tool of the severity of illness with clinical parameters
  7. If IL-6 analysis was normal at entry point, then IL-6 titer was repeated on day of discharge from hospital or done during hospitalization if clinical course deteriorates
  8. If IL-6 analysis was abnormal at entry point, we repeated on every 72 h as follow-up to assess severity, progression of illness and also titer level utilized to assess response to medical treatment
  9. Follow-up HRCT of the thorax at 12 weeks for the assessment of post-COVID lung fibrosis, and compared with entry point HRCT thorax severity
  10. Follow-up HRCT of the thorax was done after 12 weeks or 3 months of discharge from hospital for analysis of post-COVID lung fibrosis in selected cases with abnormal IL-6 level at discharge and required bilevel positive airway pressure/noninvasive ventilation (BIPAP/NIV) during hospitalization and cases required oxygen supplementation at home.


Methodology of interleukin-6 titer assessment: Immunoturbidimetry[4]

Normal values[4]

Normal values up to <7 pg/mL.

Interpretation of results[4]

  1. Negative: Value up to <7 pg/mL
  2. Positive: Value above <7 pg/mL
  3. Significant: Four-fold raised IL-6 vale, i.e., >28 pg/mL
  4. Highly significant: Sixteen-fold raised values, i.e., 98 pg/mL, i.e., level considered as required for labeled as cytokine storm
  5. Follow-up significance: Values raised or decreased in two-to-four-fold change.


The statistical analysis was performed using Chi-squared test. Significant values of Chi-squared were seen from probability table for different degree of freedom required. P value was considered statistically significant if it was below 0.05 and highly significant in case if it was <0.001.

Observations and analysis

In the present study, 1000 COVID-19 pneumonia cases confirmed by COVID-19 RT PCR, males were 650/1000 and females were 350/1000, age >50 were 600 cases and age <50 were 400 cases.

Computed tomography (CT) severity score at entry point with IL-6 level has significant correlation in COVID-19 pneumonia cases (P < 0.00001) [Table 1].
Table 1: Correlation of computed tomography severity (at entry point) and interleukin-6 in coronavirus disease 2019 cases (n=1000)

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IL-6 level has significant association with duration of illness in COVID1-19 pneumonia cases (P < 0.00001) [Table 2].
Table 2: Duration of illness at entry point during hospitalization and interleukin-6 level in coronavirus disease 2019 pneumonia cases (n=1000)

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Significant association in IL-6 and COVID-19 pneumonia has been documented with variables such as age, gender, diabetes mellitus, ischemic heart disease (IHD), hypertension, chronic obstructive pulmonary disease (COPD), obesity (P < 0.00001) [Table 3].
Table 3: Other variables and interleukin-6 level in coronavirus disease 2019 pneumonia cases (n=1000)

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IL-6 level has significant association with oxygen saturation in COVID-19 pneumonia cases (P < 0.00001) [Table 4].
Table 4: Oxygen saturation at the entry point and interleukin-6 level in coronavirus disease 2019 pneumonia cases (n=1000)

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BIPAP/NIV requirement during course of COVID-19 pneumonia in critical care setting has significant association with IL-6 level (P < 0.00001) [Table 5].
Table 5: Correlation of bilevel positive airway pressure use with the interleukin-6 level in coronavirus disease 2019 pneumonia cases (n=1000)

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Timing of BIPAP/NIV requirement during course of COVID-19 pneumonia in critical care setting has significant association with IL-6 level (P < 0.00001) [Table 6].
Table 6: Bi-level positive airway pressure/noninvasive ventilation initiation time at entry point and interleukin-6 level coronavirus disease 2019 pneumonia cases (n=600)

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Follow-up IL-6 titer during hospitalization as compared to entry point abnormal IL-6 has a significant association in post-COVID lung fibrosis (P < 0.00001) [Table 7].
Table 7: Abnormal interleukin-6 level at entry point (n=680) and follow-up and its correlation with post-COVID lung fibrosis (n=210)

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Follow-up IL-6 titer during hospitalization as compared to entry point normal IL-6 has a significant association in post-COVID lung fibrosis (P < 0.00001) [Table 8].
Table 8: Normal interleukin-6 level (n=320) at entry point and follow-up and its correlation with post-COVID lung fibrosis (n=40)

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Follow-up IL-6 titer during hospitalization as compared to entry point abnormal IL-6 has a significant association in predicting cytokine storm irrespective of normal or abnormal of IL-6 at the entry point (P < 0.0001) [Table 9].
Table 9: Normal interleukin-6 level (n=320) and abnormal interleukin-6 level at entry point (n=680) and its correlation with follow-up titer with cytokine storm (n=190)

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  Discussion Top


Correlation of computed tomography severity (at entry point) and interleukin-6 in COVID-19 cases

In the present study, CT severity score at the entry point with IL-6 level has a significant correlation in COVID-19 pneumonia cases, score <8, 8–15, and >15 documented normal and abnormal IL-6 levels as in 190/110, 90/210, and 40/360, respectively, of total 1000 study cases. (P < 0.00001) We have observed that CT severity is the best visual assessment and indirect marker of inflammation which can be collaborated with IL-6, a classical marker of inflammation. Numerous authors[9],[13],[14],[15],[16] have mentioned similar observation in their study. We have documented that as CT severity increases, i.e., lung involvement due to pneumonia process increases, IL-6 level increases and this finding can be correlated with other inflammatory markers such as CRP, LDH, and D-dimer, similarly in studies by various authors.[17],[18],[19],[20],[21],[22],[23],[24],[25],[26]

Duration of illness at entry point during hospitalization and interleukin-6 level in COVID-19 pneumonia cases (n = 1000)

In the present study, IL-6 level has a significant association with duration of illness in COVID-19 pneumonia cases, Doi <7 days, 8–15 days, and >15 days of onset of symptoms documented normal and abnormal IL-6 levels in 30/310, 160/300, and 130/70 cases, respectively (P < 0.00001). Although IL-6 is raised in COVID-19 pneumonia, we have documented that the proportionate number of cases with a duration of illness <1 week or 7 days and many cases with a duration of illness >2 weeks or 15 days had normal IL-6 levels, while pneumonia cases between 7 and 14 days of illness had abnormal or raised IL-6 level. The rational for observation is not known, maybe inflammatory response pattern is different, and we have correlated the IL-6 pattern with other inflammatory markers such as IL-6 and IL-6 and documented that these two markers raised parallel to IL-6. Raised IL-6 after 2nd week of illness may indicate worsening of COVID-19 pneumonia or secondary bacterial infection which will help the clinician to formulate antibiotics policy accordingly and indirectly guiding in the management of these cases by assessing follow-up titers.

Correlation of bilevel positive airway pressure/noninvasive ventilation use with interleukin-6 level in COVID-19 pneumonia cases (n = 1000)

In the present study, BIPAP/NIV requirement during the course of COVID-19 pneumonia in critical care setting has a significant association with IL-6 levels; cases received BIPAP/NIV during hospitalization were documented normal and abnormal IL-6 levels in 155/445, 165/235 cases respectively. (P < 0.00001) IL-6 level has very well correlation with the requirement of BIPAP/NIV, high flow nasal canula oxygen supplementation, and invasive mechanical ventilation in COVID-19 pneumonia cases. Various authors[9],[18],[21],[27] have documented similar observation. We have observed that IL-6 can be used as core marker of inflammation and in clinical scenarios with worsened hypoxia and increased inflammatory markers like CRP and IL-6 will help guiding BIPAP/NIV therapy; in addition, it will also help in assessing response to therapy by doing follow-up titers with clinical assessment.

Correlation of oxygen saturation at entry point and interleukin-6 level in COVID-19 pneumonia cases (n = 1000)

In the present study, D-Dimer level has a significant association with oxygen saturation in COVID-19 pneumonia cases; cases with oxygen saturation >90%, 75%–90%, and <75% were observed as normal and abnormal D-Dimer levels in 110/100, 150/340, and 60/240 cases, respectively (P < 0.00001) We have documented positive correlation with hypoxia at entry point during hospitalization and abnormal IL-6 level. Various studies[9],[13],[14],[15],[27],[28] have documented similar observation. We have documented, that IL-6 level could be an independent biomarker for poor outcomes as with oxygenation status and the need for aggressive ICU interventions and our findings are in collaborating with studies by various authors.[17],[22],[23],[24],[25],[26]


  Correlation of bilevel positive airway pressure/noninvasive ventilation initiation time at entry point and interleukin-6 level COVID-19 pneumonia cases (n = 600) Top


In the present study, the timing of BIPAP/NIV requirement during the course of COVID-19 pneumonia in critical care setting has a significant association with IL-6 level; cases received BIPAP/NIV at entry point <1 day, 3–7 days, and after 7 days of hospitalization were documented significance in four-fold raised IL-6 level in 110/70, 150/160, and 30/80 cases, respectively (P < 0.00001) We observed that early initiation of BIPAP/NIV those meeting criteria of oxygenation, i. e., oxygen saturation <89% at room air during hospitalization had a beneficial effect in controlling systemic immune-inflammatory syndrome which can be measured by IL-6 level in follow-up. This may be because of improvement in oxygenation and lung compliance after use of BIPAP/NIV and as hypoxia is important trigger for rise in inflammatory burden secondary to hypoxia-inducible transcription factor. A similar observation has been documented in various studies.[19],[20]

Normal interleukin-6 level (n = 320) and abnormal interleukin-6 level at entry point (n = 680) and its correlation with follow up titer with cytokine storm (n = 190)

Follow-up IL-6 titer during hospitalization as compared to entry point abnormal IL-6 has a significant association in predicting cytokine storm irrespective normal or abnormal of IL-6 at entry point (P < 0.0001) “cytokine storm” is independent predictor of poor outcome and many of these cases represent rapidly evolving COVID-19 pneumonia progressing to ARDS and required ventilatory support and proportionately majority required high flow oxygen supplementation during hospitalization and few cases require oxygen backup at home after discharge form-critical care setting. Various authors[29],[30],[31],[32],[33],[34],[35] have documented similar observations in their studies.

We have documented the significant role of tocilizumab in curtailing “cytokine storm” with severe COVID-19 pneumonia cases requiring ventilatory support and it will show improvement in oxygenation, inflammatory markers, ventilatory requirement in the majority of cases and mortality benefit in few cases. Thus, timely IL-6 inhibitor or tocilizumab has outcome defining role in intensive care units in cases with ALI/ARDS with IL-6 level above 98 pg/ml, and our findings are very well collaborated with results documented by author[15],[23],[28],[36],[37],[38],[39] in respective studies.

Other important observations in this study

Correlation of abnormal interleukin-6 level at entry point (n = 680) and follow-up (serial titers) and its correlation with post-COVID lung fibrosis

In the present study, follow-up IL-6 titer during hospitalization as compared to entry point abnormal IL-6 has a significant association in post-COVID lung fibrosis (P < 0.00001) i.e., IL-6 at the entry point to four-fold raised cases in the presence or absence of pulmonary fibrosis were 40/170 and 360/110 cases, respectively. We have documented that serial measurement of IL-6 during hospitalization irrespective of entry point level has a very well correlation with outcome and requirement of interventions in the intensive care setting, which will indirectly help in predicting future risk of the development of post-COVID lung fibrosis in majority of cases required aggressive interventions such as high-flow nasal canula, BIPAP/NIV, ECMO, Invasive mechanical ventilation irrespective of IL-6 level reaching to cytokine storm. Serial measurements also predict the chances of lung fibrosis in these patients as cytokine-induced lung damage resulted in lung necrosis and resultant lung fibrosis. Similar observations have been documented in studies by various authors[38],[39],[40],[41] and the results were collaborating with our study.

Correlation of normal interleukin-6 level (n = 320) at entry point and follow-up (serial titers) and its correlation with post-COVID lung fibrosis

In the present study, Follow-up IL-6 titer during hospitalization as compared to entry point normal IL-6 has a significant association in post-COVID lung fibrosis (P < 0.00001), i.e., IL-6 at the entry point to four-fold raised cases in the presence or absence of pulmonary fibrosis were 5/35 and 115/165 cases respectively. We have documented that normal IL-6 is predictor of good clinical and radiological outcomes in COVID-19 pneumonia. Serial measurement of IL-6 during hospitalization irrespective of entry point level has very well correlation with underlying lung pathology and rising trends will help in defining underlying lung parenchymal damage secondary to cytokine-induced lung necrosis and cytokine-induced ALI/ARDS. These may be considered early marker of future lung fibrosis, being the requirement of interventions required for satisfactory outcomes of these patients including ventilatory support. Similar observations have been documented in studies by authors[14],[21],[37],[40],[41] and mentioned facts collaborating with our results.

Correlation of other variables and interleukin-6 level in COVID-19 pneumonia cases

In the present study, age (<50 and >50 years) and gender (male versus female) has significant association with IL-6 (P < 0.00001) and (P < 0.010], respectively. Numerous authors[9],[13],[14],[16],[17],[24],[27],[29] have documented similar observation in their studies.

In the present study, comorbidity as diabetes mellitus, COPD, hypertension, IHD and obesity has significant association in COVID-19 cases with normal and abnormal D-Dimer level (P < 0.00001). Studies by various authors[9],[13],[14],[16],[17],[24],[27],[29],[37] documented similar observation.


  Conclusions Top


IL-6 is an easily available, and universally acceptable inflammatory marker, documented crucial role in COVID-19 pneumonia in predicting the severity of illness, progression of illness including “cytokine storm” and assessing response to treatment during hospitalization. IL-6 has an important role during management, as serial or follow-up titers have a significant role in step-up or step-down interventions in critical care settings. Correlating IL-6 with variables such as duration of illness, oxygenation status, and timing of BIPAP/NIV at the entry point is important to have a satisfactory treatment outcome.

IL-6 titer has significant associations with predicting progression of pneumonia, as the proportionate number of pneumonia cases with mild variety on CT of the thorax and normal initial IL-6 has progressed to the critical course and we have documented follow-up titers have played a crucial role with other inflammatory markers CRP, LDH, and D-Dimer, and many times in the 2nd week of illness rising titers of IL-6 indicates nosocomial bacterial infection and target therapy accordingly. Serial or follow-up IL-6 titer can help in predicting the progression of COVID-19 pneumonia, and assessing the risk of post-COVID lung fibrosis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9]



 

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