key: cord-0869502-hwyrryxp
authors: sakai, k.; Nishii, M.; Saji, R.; Matsumura, R.; Ogawa, F.; Takeuchi, I.
title: Interleukin-6 as a predictor of early weaning from invasive mechanical ventilation in patients with acute respiratory distress syndrome
date: 2022-04-06
journal: nan
DOI: 10.1101/2022.04.04.22273418
sha: f45a5120b8a17371b573eeb2c459228667fe747e
doc_id: 869502
cord_uid: hwyrryxp

Background Therapeutic effects of steroids on acute respiratory distress syndrome (ARDS) requiring mechanical ventilation (MV) have been reported. However, predictive indicators of early weaning from MV post-treatment have not yet been defined, making treating established ARDS challenging. Interleukin (IL)-6 has been associated with the pathogenesis of ARDS. Objective Our aim was to clarify clinical utility of IL-6 level in ventilated patients with established ARDS. Methods Clinical, treatment, and outcome data were evaluated in 119 invasively ventilated patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-mediated ARDS. Plasma levels of IL-6 and C-reactive protein (CRP) were measured on days 1, 4, and 7 after intubation. Results Fifty-two patients were treated with dexamethasone (steroid group), while the remaining 67 patients were not (non-steroid group). Duration of MV use was significantly shorter in the steroid group compared to non-steroid group (11.5{+/-}0.6 vs. 16.1{+/-}1.0 days, P = 0.0005, respectively) along with significantly decreased levels of IL-6 and CRP. Even when restricted to the steroid group, among variables post-MV, IL-6 level on day 7 was most closely correlated with duration of MV use (Spearmans rank correlation coefficient [{rho}] = 0.73, P < 0.0001), followed by CRP level on day 7 and the percentage change in IL-6 or CRP levels between day 1 and day 7. Moreover, among these variables, IL-6 levels on day 7 showed the highest accuracy for withdrawal from MV within 11 days (AUC: 0.88), with optimal cutoff value of 20.6 pg/mL. Consistently, the rate of MV weaning increased significantly earlier in patients with low IL-6 (<= 20.6 pg/mL) than in those with high IL-6 (> 20.6 pg/mL) (log-rank test P < 0.0001). Conclusions In invasively ventilated patients with established ARDS due to SARS-CoV-2, plasma IL-6 levels served as a predictor of early withdrawal from MV after dexamethasone administration.

. CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 6, 2022. ; https://doi.org/10.1101/2022.04.04.22273418 doi: medRxiv preprint 3 1 In invasively ventilated patients with established ARDS due to SARS-CoV-2, plasma IL-6 levels served 2 as a predictor of early withdrawal from MV after dexamethasone administration.

3 Key Words 4 Acute respiratory distress syndrome, Interleukin-6, Dexamethasone, Invasive mechanical ventilator 5 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 6, 2022. ; https://doi.org/10.1101/2022.04.04.22273418 doi: medRxiv preprint Introduction 10 Acute respiratory distress syndrome (ARDS), characterized by acute diffuse inflammatory lung injury and 11 rapidly impaired oxygenation requiring mechanical ventilation (MV), represents a common pulmonary 12 disorder in intensive care unit (ICU). ARDS can be caused by many etiologies, such as trauma, 13 transfusion history, infection, sepsis, pneumonia, and even ventilator-induced lung injury. [1] [2] [3] Moreover, 14 in-hospital mortality remains high at approximately 40-50% in overall patients with ARDS, and further 15 increases along with severity of ARDS, from mild to severe. [4] [5] Against this background, development of 16 underlying therapies for ARDS is needed. So far, a number of randomized controlled studies have been 17 conducted to evaluate the efficacy of corticosteroids with the ability to modulate hyperinflammation on 18 ARDS. 6 -10 Based on these observations, the effectiveness of corticosteroids on ARDS is still controversial 19 8-9 yet early administration of dexamethasone is likely to reduce duration of MV use and mortality in 20 patients with moderate to severe ARDS. 10 Recently, at the end of 2019, COVID-19 outbreak 21 unexpectedly emerged from Wuhan, China, and quickly spread around the world. 11 Critically ill COVID-22 19 patients who required MV suffered from ARDS caused by severe acute respiratory syndrome 23 coronavirus 2 (SARS-CoV-2) and had a high in-hospital mortality. 12 Consistent with previous report, 10 24 early administration of dexamethasone as well as remdesivir, an antiviral agent was reported to reduce the 25 duration of MV use and in-hospital mortality in patients with ARDS caused by SARS-CoV-2. [13] [14] . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted April 6, 2022. ; https://doi.org/10.1101/2022.04.04.22273418 doi: medRxiv preprint 5 1 However, the treating ARDS with steroid therapy remains challenging, because the fundamental 2 indicators to predict early withdrawal from MV post-treatment have not yet been defined.

3 Studies with experimental models of ARDS have demonstrated that that lung injury can be induced by 4 primed alveolar macrophages. 15-16 Consistently, the autopsy and pathological studies of SARS-CoV-2-5 induced ARDS patients suggested that over-activation of alveolar macrophages causes cytokine storm, 6 resulting in severe damage to lung tissue. 17 Interleukin (IL)-6, derived from inflammatory monocytes and 7 alveolar macrophage, may be responsible for severe lung inflammation and pulmonary function disability 8 in the pathophysiology of ARDS. It has been reported that in the bronchoalveolar lavage fluid (BALF) 9 from patients at risk for ARDS or with established ARDS, which mainly contains inflammatory 10 monocytes and alveolar macrophages, IL-6 levels were extremely increased and remained high 11 throughout the course of ARDS. 18-20 Moreover, detailed single-cell RNA sequencing data obtained from 12 BALF and peripheral blood mononuclear cells from patients with SARS-CoV-2-induced ARDS have 13 recently shown that IL-6 is released into the systemic circulation from SARS-CoV-2-affected lungs, 14 rather than from peripheral immune cells. 21 hospitalization, patients were provided negative and positive information regarding this study, including 21 the purpose and contribution of this study, the use of personal information, and complications associated 22 with blood collection, and were asked to participate in this study. Ultimately, we obtained written 23 informed consent for participation in the study and access to medical and laboratory records from 24 patients. Alternatively, we were unable to obtain written consent for participation from patients who died 25 without being weaned after being placed on a ventilator, which means that we used an opt-out method to 26 obtain consent for this study from them. The study had no risk/negative consequence on those who . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted April 6, 2022. ; https://doi.org/10.1101/2022.04.04.22273418 doi: medRxiv preprint 1 participated in the study. Medical record numbers were used for data collection and no personal 2 identifiers were collected or used in the research report. Data was accessed from February 16, 2020, to 3 October 30, 2021, and access to the collected information was limited to the principal investigator and 4 confidentiality was maintained throughout the project.

6 Clinical data and treatment and outcome data were obtained from electronic medical records. Two 7 researchers independently reviewed the data collection forms to double-check the collected data. 16 Differences between the different treatment groups were analyzed with Fisher's exact test (for categorical 17 data) or the Mann-Whitney U test (for continuous data). Logistic regression analysis was used for 18 univariate analysis of IL-6 and CRP levels. Correlations between variables were evaluated by the 19 Spearman's rank test. To evaluate the area under curves (AUCs) and cutoff values of parameters, the 20 receiver operator characteristic (ROC) curves were constructed. The optimal cutoff was defined as value 21 which had the best compromise between sensitivity and specificity for predicting withdrawal from MV on 22 ROC curve. Comparisons of ventilator weaning rates between subgroups were performed with the Log-23 rank test. Statistical significance was set at P < 0.05.

25 Baseline characteristics . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 6, 2022. ; https://doi.org/10.1101/2022.04.04.22273418 doi: medRxiv preprint 1 From February 2020 to July 2021, 268 patients with COVID-19 pneumonia were enrolled. Of those, 149 2 patients not using invasive MV or without complete data or consent for participation were excluded.

3 Ultimately, a total of 119 invasively ventilated patients with SARS-CoV-2-induced ARDS were evaluated 4 in this study (Fig. S1 ). Table 1 shows individual baseline clinical and outcome data in the present study 5 population. The age was 63.1±1.2 years. Of these patients, 96 (81%) were male and 23 (19%) were 6 female. The mean duration from symptom onset to intubation was 7.0 days. Approximately 20 to 30% 7 had comorbidity such as chronic kidney disease, diabetes mellitus, and hypertension. Among clinical and 8 laboratory data such as systolic blood pressure (SBP), platelet count, total bilirubin, and creatinine at 9 inclusion, creatinine levels were elevated in some cases. Thus, no high-risk patients with sequential organ 10 failure assessment scores of 5 or higher were identified in the study population. All patients received 11 anticoagulation therapy. Almost patients (83%) were treated with remdesivir. In 44% (n = 52), treatment 12 with dexamethasone (6 mg/day) was initiated before (n = 12) or on (n = 40) admission to YCUH and 13 continued at least during MV use. Duration of MV use in overall patients was 13 Clinical and laboratory data at inclusion . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 6, 2022. Table 2 ). There was fewer elderly male in the steroid group than in the non-steroid 10 group. Duration from symptom onset to intubation was significantly shorter in the steroid group than in 11 the non-steroid group. Regarding with comorbidity, diabetes mellitus was fewer in the steroid group.

12 Consideration of complications to steroids, including secondary infections and hyperglycemia, may have 13 influenced differences of age and comorbidity between the 2 groups. Among clinical and laboratory data 14 at inclusion, SBP was significantly lower in the steroid group than in the non-steroid group. However, no . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 6, 2022. ; https://doi.org/10.1101/2022.04.04.22273418 doi: medRxiv preprint 1 patients with SBP below 70 mmHg were identified in both groups. Platelet count, total bilirubin level, and 2 creatinine level were not significantly different between the 2 groups. Anti-viral agent use had no 3 significant difference between the 2 groups. Ultimately, combined event rate of ECMO use and in-4 hospital death was significantly lower in the steroid group than in the non-steroid group. Moreover, 5 duration of invasive MV use was significantly shorter in the steroid group than in the non-steroid group.

6 These results suggest that dexamethasone positively affects clinical outcomes in invasively ventilated 7 patients with established ARDS caused by SARS-CoV-2.

8 9 after MV introduction. As shown in Table 3 , levels of IL-6 and CRP were significantly lower in the 10 steroid group compared to the non-steroid group. Collectively, dexamethasone decreased circulating 11 levels of IL-6 as well as CRP in invasively ventilated patients with SARS-CoV-2-mediated ARDS.

12 Table 3 . is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 6, 2022. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 6, 2022. (Table 5 and Fig. 2) . The optimal cut-off value of IL-6 on 14 day 7 was 20.6 pg/mL, with sensitivity of 88% and specificity of 84% (Table 5 and Fig. 2 ). IL-6 was . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 6, 2022. ; https://doi.org/10.1101/2022.04.04.22273418 doi: medRxiv preprint 1 predictive of earlier withdrawal from invasive MV after steroid administration in intubated patients with 2 SARS-CoV-2-mediated ARDS. 10 12 AUC: area under the curve, CI: confidence interval, IL: interleukin, CRP: C-reactive protein, percentage 13 (%) of change in IL-6 or CRP between day 1 and day 7: (level on day 7 -level on day 1) / level on day 1×

14 100%. P-value for withdrawal from invasive MV within 11 days after intubation.

16 Moreover, Kaplan-Meier curves in the steroid group that were constructed according to above or below 17 optimal cutoffs demonstrated that the cumulative weaning rate from invasive MV increased significantly . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 6, 2022. ; https://doi.org/10.1101/2022.04.04.22273418 doi: medRxiv preprint 1 earlier in patients with low IL-6 (≤ 20.6 pg/mL, n = 19) compared to those with high IL-6 (> 20.6 pg/mL, 2 n = 21) (Fig. 3 ).

4 Kaplan-Meier curves showing the cumulative weaning rate from invasive MV in SARS-CoV-2-mediated 5 ARDS patients who were treated with dexamethasone according to IL-6 levels above or below the 6 optimal cutoffs (20.6 pg/mL) on day 7 after intubation. 25 In the present data, absolute levels and percentage of change in CRP were also associated with earlier 26 withdrawal from invasive MV. Due to the small sample size, it was not possible to statistically compare . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 6, 2022. ; https://doi.org/10.1101/2022.04.04.22273418 doi: medRxiv preprint 1 the predicted values of CRP and IL-6. However, synthesis and release of CRP protein, which is widely 2 used as a biomarker for inflammatory status, from liver and immune cells depends upon stimulation by 3 IL-6. 41-42 This supports the superiority of IL-6 in early predicting disease activity of established ARDS.

4 Indeed, a previous study demonstrated that IL-6 level can earlier predict the requirement of MV in severe 5 COVID-19 compared with CRP level. 29 6 The present study has several strengths: First, the present results showed that IL-6 can predict not only the 7 risk of developing ARDS, but also therapeutic response, such as early withdrawal from invasive MV, in 8 established ARDS, which may suggest a potential utility as a determinant of therapeutic strategy, 15 There are several limitations of this study. The data set of this study was a backward-looking study, so 16 there were some missing values. Second, this study was conducted at a single institution, resulting in a 17 biased patient population. Third, our sample size is too small to evaluate optimal cutoffs of variables and 18 to determine clinical utility of IL-6 in the treatment of ARDS and its superiority over other markers.

19 Fourth, the cause of ARDS was limited to SARS-CoV-2 infection. Fifth, steroid therapy was not 20 standardized in our study population. Thus, the applicability of IL-6 in clinical practice needs to be 21 prospectively studied in large cohorts of strictly steroid-treated patients with ARDS derived from various 22 etiologies.

24 We are the first to present data illustrating that IL-6 in plasma is a promising indicator for predicting 25 earlier withdrawal from invasive MV after dexamethasone administration in intubated patients with . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted April 6, 2022. ; https://doi.org/10.1101/2022.04.04.22273418 doi: medRxiv preprint 1 SARS-CoV-2-mediated ARDS. This suggests that measuring IL-6 may allow monitoring responsiveness 2 to dexamethasone and help determine therapeutic strategy in established ARDS. Our data provide the first 3 evidence suggesting the importance of measuring IL-6 level after intubation and in patients with 4 established ARDS. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted April 6, 2022. ; https://doi.org/10.1101/2022.04.04.22273418 doi: medRxiv preprint . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted April 6, 2022. ; https://doi.org/10.1101/2022.04.04.22273418 doi: medRxiv preprint

Consistently, a recent randomized controlled trial of COVID-19 in patients with ARDS showed that 2 treatment with dexamethasone significantly shortens the duration of MV use (a mean duration of 12

37 Our data also supported this beneficial effect (a mean MV duration of 11

Importantly, we 5 are the first to show that IL-6 levels serve as a predictive indictor of earlier MV withdrawal after 6 dexamethasone administration in invasively ventilated patients with SARS-CoV-2-induced ARDS, and 7 that patients with IL-6 levels below or above 20.6 pg/mL on day 7 after intubation are likely to withdraw 8 from MV within 11 days or to require MV more persistently

may help monitoring therapeutic efficacy and facilitate steroid therapy in invasively ventilated patients 10 with established ARDS and contribute to the improvement of short-and long-term outcomes by early 11 withdrawal from MV and mitigation or prevention of lung fibrosis. Moreover, these observations also 12 provide a warrant for further investigation of the potential IL-6-guided therapy for established ARDS

For example, elevation of consecutive IL-6 concentrations shows a predictive value for changes in 15 disease severity from moderate to severe or critical. 38 Moreover, the re-elevation of IL-6 level after MV 16 introduction or during treatment with steroid may be indicative of ventilator-induced lung injury and 17 secondary bacterial infections, respectively. 39-40 If so, neuromuscular blocking agents to suppress 18 excessive spontaneous-breathing efforts or antibiotics for secondary pneumonia will be needed. Our data 19 also associated changes in IL-6 levels after intubation with earlier withdrawal from invasive MV in 20 SARS-CoV-2-induced ARDS. However

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