So far, IL-6 on admission or before intubation generated an interest as a predictor of developing ARDS. For example, elevation of plasma IL-6 levels on admission has been related with the risk of requiring ICU management, MV, or ECMO in patients with COVID-19.23–28 Recently, Awasthi et al associated plasma level of IL-6 with the duration of ICU stay in COVID-19 patients.29 Moreover, an observational study reported that IL-6 level before intubation predicts requirement of invasive MV in COVID-19.30 The clinical utility of measuring IL-6 level after intubation and the development of ARDS, however, has not been elucidated. Additionally, although corticosteroid decreases plasma levels of IL-6,29 its clinical utility in the presence of steroid therapy remains elusive. We are the first to show that IL-6 levels serve as a predictive indicator of earlier invasive MV withdrawal in intubated patients with SARS-CoV-2-induced ARDS who received dexamethasone. IL-6 may be useful for predicting not only the risk of developing ARDS but also disease activity and responsiveness to steroid therapy of established severe ARDS. Our data extend the clinical utility of IL-6 in the management of patients with COVID-19.
A subset of survivors from established ARDS has been proven to develop irreversible fibrotic changes in disease lung, including fibroblast accumulation, deposition of collagen and other lung extracellular matrix components, which leads to high mortality.31 Thille et al demonstrated that the prevalence of fibrotic change in pulmonary origin is closely related with ARDS duration.32 Moreover, although the MV has facilitated the management of ARDS, ventilator-induced lung injury has been shown to be a predominant causative factor for lung fibrosis in ARDS patients.33 Thus, early withdrawal from MV is an important therapeutic strategy for established ARDS. Recently, efficacy of steroid administration on MV duration in established ARDS has been reported.10 Patients with severe ARDS have been shown to frequently require MV, with a mean duration of approximately 12 days, when they were treated with steroids.34 Consistently, a recent randomized controlled trial of COVID-19 in patients with ARDS showed that treatment with dexamethasone significantly shortens the duration of MV use (a mean duration of 12.5 vs. 13.9 days).35 Our data also supported this beneficial effect (a mean MV duration of 11.5 vs. 16.1 days). Interestingly, the present study demonstrated that among invasively ventilated patients with ARDS caused by SARS-CoV-2 who received dexamethasone, those with IL-6 levels below or above 20.6 pg/mL on day 7 after intubation are likely to withdraw from MV within 11 days or to require MV more persistently, respectively. Accordingly, measuring IL-6 level may facilitate steroid therapy and contribute to the improvement of short- and long-term outcomes by early withdrawal from MV and mitigation or prevention of lung fibrosis in patients with severe ARDS.
Capturing trends in IL-6 levels over time may be useful for understanding the clinical course in COVID-19. For example, elevation of consecutive IL-6 concentrations shows a predictive value for changes in disease severity from moderate to severe or critical. 36 Moreover, the re-elevation of IL-6 level after MV introduction or during treatment with steroid may be indicative of ventilator-induced lung injury and secondary bacterial infections, respectively.37–38 If so, neuromuscular blocking agents to suppress excessive spontaneous-breathing efforts or antibiotics for secondary pneumonia will be needed. Our data also associated changes in IL-6 levels after intubation with earlier withdrawal from invasive MV in SARS-CoV-2-induced ARDS. However, we could not confirm that the 2-day difference and percentage of change in IL-6 have better accuracy than the absolute level, because in the present study, some patients were started dexamethasone administration, which decreases baseline levels of IL-6, prior to admission to our institution. Analysis in a patient population with standardized steroid initiation times may improve their accuracies. Clinical utility of changes in IL-6 levels should also be investigated.
In the present data, absolute level and percentage of change in CRP were also associated with earlier withdrawal from invasive MV. Due to the small sample size, it was not possible to statistically compare the predicted values of CRP and IL-6. However, synthesis and release of CRP protein, which is widely used as a biomarker for inflammatory status, from liver and immune cells depends upon stimulation by IL-6.39–40 This supports the superiority of IL-6 in early predicting disease activity of established ARDS. Indeed, a previous study demonstrated that IL-6 level can earlier predict the requirement of MV in severe COVID-19 compared with CRP level.27
The present study has several strengths: First, the present results showed that IL-6 can predict not only the risk of developing ARDS, but also therapeutic response, such as early withdrawal from invasive MV, in established ARDS, which may suggest a potential utility as a determinant of therapeutic strategy, including continuation of treatment and the need for additional treatment. Second, it is easy to measure circulating IL-6 level over time in various clinical settings, as instruments for simple and rapid measurement are already widely available.41–42 Third, IL-6 has been widely recognized as a prognostic indicator of inflammatory diseases such as sepsis 43 and rheumatoid arthritis,44 making it easy for medical staff to interpret. Finally, IL-6 in plasma may be available in evaluating and monitoring the therapeutic effect of new drugs on inflammatory diseases including ARDS.
There are several limitations of this study. This was a retrospective study, so there were some missing values. Second, this study was conducted at a single institution, resulting in a biased patient selection. Third, our sample size is too small to evaluate optimal cutoffs of variables and to determine clinical utility of IL-6 in the treatment of ARDS and its superiority over other markers. Fourth, the cause of ARDS was limited to SARS-CoV-2 infection. Fifth, steroid therapy was not standardized in our study population. Thus, the applicability of IL-6 in clinical practice needs to be prospectively studied in multi-centers of strictly steroid-treated patients with ARDS derived from various etiologies.