Role of IL-6 as ‘core inflammatory marker’ in assessment of severity, response to therapy and predicting outcome in COVID-19 pneumonia: A single center experience of 2400 cases in tertiary care setting in India

INTRODUCTION

Coronavirus disease-19 (COVID-19) is first coronavirus-related global pandemic caused by novel severe acute respiratory syndrome coronavirus-2, and rapid evolution of the pandemic has resulted in fast-track developments in antivirals, medical management, and vaccination for use to prevent morbidity and mortality. Although lung is the primary target organ involved in COVID-19, many patients were having pulmonary and extrapulmonary manifestations of diseases variably as resultant pathophysiological effects of the 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 infection to lungs, and extrapulmonary tissues.^[1]

Although the majority of published data has included, severe COVID-19 cases with critical illness hospitalized in indoor units and analyzed single time point interleukin-6 (IL-6) titer using cross-sectional studies rather than prospective and repeated or sequential titer measurement studies.^[2-4] This indicates a major gap in understanding the significant impact of these inflammatory markers in the overall assessment of COVID-19 pneumonia in those cases with clinical deterioration occurs, which can be earliest picked up by doing sequential IL-6 titers.^[5-7]

Importantly, different inflammatory biomarkers such as C-reactive protein (CRP), ferritin, lactate dehydrogenase (LDH), and D-dimer have documented important role in analyzing severity, predicting the need of interventions, targeting treatment options, and predicting the final outcome in COVID-19 pneumonia along with IL-6 titers.^[8-10] Authors have documented the important role of these inflammatory markers in overall predicting outcomes, and all these markers have been done in a quantified manner in hospitalized COVID-19 cases and followed cases till 3 months of discharge from the hospital.^[11-15]

As per published voidance, IL-6 is superior to CRP and other inflammatory markers in predicting ongoing inflammation and a better tool to predict cytokine storms and cases with impending respiratory failure. IL-6 is the most important driver of immune dysregulation, and its impact has been shown in acute respiratory distress syndrome (ARDS) and respiratory failure in COVID-19 disease.^[5-7]

In the present study, we have analyzed the role of IL-6 in COVID-19 pneumonia with special emphasis on the need for ventilatory support in correlation with IL-6 titer and the impact of these sequential titers of IL-6 in predicting final radiological outcomes.

MATERIAL AND METHODS

Methodology

A prospective and observational study, conducted during July 2020–June 2021, in MIMSR Medical College and Venkatesh Hospital Latur India, included that 2400 COVID-19 cases confirmed with reverse transcription-polymerase chain reaction (RT-PCR), to find out the role of IL-6 in predicting the severity of illness, assessing response to therapy and outcome as post-COVID fibrosis in diagnosed COVID-19 pneumonia cases admitted in the critical care unit. A total 2400 cases were enrolled in the study after written and informed consent was obtained from all individual participants admitted in indoor units after assessing overall status to give consent and whenever required, taken from attendants of critically ill admitted cases [Figure 1].

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Figure 1:

Flow of the study.

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RESULTS

DISCUSSION

We have observed that computed tomography (CT) severity can be considered as the best visual marker of the severity of COVID-19 pneumonia which can be correlated with inflammatory markers such as IL-6, ferritin, CRP, LDH, D-dimer and lymphopenia, and lymphocyte-platelet ratio. In the present study, CT severity score at the entry point with D-dimer level has a significant correlation in COVID-19 pneumonia cases. [(P < p<0.00001]). COVID-19 cases with CT severity score <8, 8-–15 and >15 documented normal and abnormal IL-6 level in 391/109, 236/564, and 363/737, respectively of a total of 2400 study cases. Various authors^[17-32] documented that IL-6 and other inflammatory markers such as CRP, ferritin, and LDH have been correlated with CT severity and cases from mild to moderate to severe were having increasing trends of inflammatory markers.

In the present study, IL-6 level has a significant association with Doi duration of illness in COVID-19 pneumonia cases. [(P < p<0.00001]). COVID-19 cases with Doi <7 days, 8-–15 days, and >15 days of onset of symptoms documented normal and abnormal IL-6 levels in 401/137, 209/742, and 338/573 cases, respectively. Rationale for the observation is not known; it may be that the inflammatory pattern is different during the first 1^st and third 3^rd weeks as compared to the second 2^nd weeks of illness. We have also correlated IL-6 patterns with other inflammatory markers such as ferritin, CRP, and LDH and documented that these markers raised parallel to IL-6. Raised IL-6 after the second 2^nd week illness may indicate worsening of COVID-19 pneumonia or secondary bacterial infection, which will guide the intensivist to screen for infection and formulate antibiotics policy accordingly. Thus, follow-up titers will guide indirectly in protocolized management in critical care settings.

In the present study, BIPAP/NIV requirement during the course of COVID-19 pneumonia in a critical care setting has a significant association with IL-6 level. [(P < p<0.00001]). COVID-19 cases received BIPAP/NIV during hospitalization were documented with normal and abnormal IL-6 levels in 398/980 and 592/430 cases, respectively. We have also documented that IL-6 level has a positive correlation with the requirement of BIPAP/NIV, high-flow nasal cannula (HFNC) oxygen supplementation, and invasive mechanical ventilation in critical care settings. Studies by various authors^[21-39] have documented that high IL-6 is a predictor of critical illness requiring intensive care unit treatment, including non-invasive and invasive ventilatory support as compared to cases with normal IL-6 levels.

In the present study, IL-6 level has a significant association with SpO₂ oxygen saturation in COVID-19 pneumonia cases. [(P < p<0.00001]). COVID-19 cases with SpO₂ oxygen saturation >90%, 75-–90%, and <75% were observed as normal and abnormal IL-6 levels in 429/87, 209/763, and 274/638 cases, respectively. We have also documented that hypoxia at the entry point during hospitalization has a positive correlation with abnormal IL-6 levels. Numerous authors^[23-37] have documented that a higher IL-6 level is associated with hypoxemia, also mentioned that higher IL-6 level is an indicator of an advanced pneumonia process and progressed lung parenchymal inflammatory injury or necrosis resulting in failure of oxygenation.

In the present study, timing of BIPAP/NIV requirements during the course of COVID-19 pneumonia in a critical care setting has a significant association with IL-6 level. [(P < p<0.00001]). COVID-19 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 levels in 452/140, 181/251, and 154/200 cases, respectively. We have also observed that early initiation of BIPAP/NIV in COVID-19 pneumonia cases meeting the criteria of oxygen supplementation, that is, SpO₂ oxygen saturation <89% at room air during hospitalization were having a beneficial effect in controlling systemic immune inflammatory syndrome, which can be measured by IL-6 level in follow-up. Rationality for similar observations may be due to improvement in oxygenation and lung compliance after the use of BIPAP/NIV in these cases. The plausible mechanism is that hypoxia is an important trigger for the rise in inflammatory markers by means of a rise in hypoxia inducible transcription factors. Previously published studies by various authors^[37-41] have documented similar observations to our study and noted higher levels of IL-6 titer in those cases that required ventilatory support during hospitalization in intensive care units.

In the present study, we have observed that entry point normal and abnormal IL-6 titer has a significant association with cytokine storm [(P < p<0.00001]). Total COVID-19 cases with cytokine storm (498/2400) have normal 98/498 and abnormal 400/498 IL-6 titer. Total COVID-19 cases without cytokine storm (1902/2400) have 892/1902 and 1010/1902 have entry point abnormal IL-6 titer. We have also documented that ‘Cytokine storm’ is an independent predictor of poor outcome, and many of these cases represent rapidly evolving COVID-19 pneumonia progressing to ARDS and requiring ventilatory support. We have followed all these cases with cytokine storm and observed that a proportionately large number of these cases were required high-flow oxygen supplementation for a longer duration during hospitalization, and a few cases required oxygen supplementation at home for 3 months after discharge from the critical care setting. Numerous authors^[18-31] have documented similar observations to our study. 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 titer, ventilatory support requirement in the majority of cases, and mortality benefit in few cases. Thus, timely IL-6 inhibitor or tocilizumab has outcome a modifying role in intensive care units in cases with acute lung injury (ALI)/ ARDS with IL-6 level above 100 pg/mL. Various authors^[31-46] have documented similar to our findings in their studies and mentioned that IL-6 targeted treatment will help in disease progression and good treatment outcomes.

In the present study, radiological outcome as post-COVID lung fibrosis has a significant association with a fourfold rise in follow-up IL-6 titer during hospitalization in cases with abnormal IL-6 titer at the entry point. (P < 0.00001). In post-COVID-19 lung fibrosis cases with abnormal IL-6 (560/1410) at the entry point, 114/560 and 386/560 cases had abnormal and four-fold rises in IL-6 titer, respectively. In COVID-19 cases without radiological sequel (850/1410) and abnormal IL-6 at the entry point, 576/850 and 334/850 cases had an abnormal and four-fold rises in IL-6 titer, respectively. We have also documented that serial measurement of IL-6 during hospitalization irrespective of the entry point abnormal level has very well correlation with the requirement of interventions in indoor and intensive care units such as high flow nasal cannula (HFNC), BIPAP/NIV (bilevel positive airway pressure/Noninvasive ventilation), and invasive mechanical ventilation. Cases with cytokine storm were picked up earlier by serial IL-6 level, and a proportionately large number will have post-COVID lung fibrosis. Thus, IL-6 will indirectly help in predicting the future risk of the development of post-COVID lung fibrosis. Authors^[34-42] have observed similar findings in their respective studies and reported rising titers of IL-6 which is a marker of exaggerated lung inflammation and necrosis, which will result in lung fibrosis.

In the present study, radiological outcome as post-COVID lung fibrosis has a significant association with four-fold rise in follow-up IL-6 titer during hospitalization in cases with normal or less than four-fold IL-6 titer at the entry point. (P < 0.00001). In post-COVID-19 lung fibrosis cases with abnormal IL-6 (191/990) at the entry point, 29/191 and 162/191 cases had normal or less than four-fold IL-6 titer at the entry point and a sequential four-fold rise in IL-6 titer, respectively. In COVID-19 cases without radiological sequel (799/990) and abnormal IL-6 at the entry point, 665/799 and 134/799 cases had normal or less than four-fold IL-6 titer at the entry point and a serial four-fold rise in IL-6 titer, respectively. We have also documented that normal IL-6 is a predictor of good clinical and radiological outcomes, and serial measurement of IL-6 during hospitalization, irrespective of entry point level, has a very good correlation with underlying lung pathology. We have observed that IL-6 rising trends would help in predicting exaggerated underlying lung parenchymal damage secondary to cytokine induced lung necrosis and cytokine induced ALI (Acute lung injury)/ARDS (acute respiratory distress syndrome). These insults such as necrosis or ALI/ARDS are considered as early markers of future lung fibrosis. Authors^{[23-31, 37-46]} documented similar observations and mentioned the importance of serial IL-6 titers in assessing high-risk cases for respiratory failure. They have observed the role of follow-up IL-6 titers in assessing critical COVD-19 cases and the crucial role in de-escalating interventions in the intensive care units along with clinical assessment. Authors have documented rising trends of IL-6 as a marker of post-COVID lung fibrosis.

We have documented that the age and gender of included cases have a significant association with IL-6 level. Studies by various authors^{[23-31,37-46]} also documented similar observations. In the present study, comorbidity as diabetes mellitus, COPD, hypertension, IHD, and obesity has significant association IL-6 level [(P < p<0.00001].). Studies by various authors^{[23-31,37-46]} also documented similar observations in IL-6 level and its correlation with underlying comorbidities.

CONCLUSION

IL-6 is an easily available and sensitive marker of inflammation and has a documented ‘“game changer’ changer” role in COVID-19 pneumonia. IL-6 titer assessment at the entry point has documented a crucial role in the initial assessment of the severity of COVID-19 illness and guided in triaging the case to admission in different utilities from the indoor unit to the critical care unit. Thus, IL-6 titer has been observed to play an important role in predicting the need for ventilatory support and also guided positive outcomes through early use of these interventions in critical care units. IL-6 titer at the entry point has indirectly helped in predicting the final outcome because the majority of patients presenting with normal or abnormal titers have behaved differently and, in these scenarios, sequential titers have played a crucial role. IL-6 follow titer analysis has shown a significant impact in predicting real time course during hospitalization than entry point titer. Sequential IL-6 titer has also guided the exact risk of ‘cytokine storm’ than entry point titer as the majority of entry point normal titer has progressed to advanced disease in a short time, and these cases were easily picked up by easily available follow titer. Sequential titer is the best predictor of final radiological outcome as the majority of cases with increased follow-up titers were having post-COVID lung fibrosis than entry point normal IL-6 titer. Thus, we recommend follow-up titer assessment in all cases to have a successful treatment outcome by means of timely honoring these cases with interventions and preventing poor clinical and radiological outcomes.