Interleukin-6-to-lymphocyte count ratio in the prognosis of moderate-to-severe acute respiratory distress syndrome supported by venovenous extracorporeal membrane oxygenation: a single-center retrospective study

Introduction

Acute respiratory distress syndrome (ARDS) (1,2) is a serious lung disease characterized by refractory hypoxemia and bilateral lung infiltrates, usually caused by direct or indirect lung injury. Despite advances in medical technology, the mortality of ARDS is still high, especially in moderate-to-severe cases, which affects approximately 200,000 individuals annually in the United States, resulting in nearly 75,000 deaths (3-5). Venovenous extracorporeal membrane oxygenation (VV ECMO), as an advanced life support technique, has been used to support moderate-to-severe ARDS patients to improve their survival (6-9). In 2021, Fisser’s et al. (10) reported that the main indication for VV ECMO was pneumonia, with an overall survival rate of 60%. They found that lower partial pressure of carbon dioxide (PaCO₂), higher pH, lower lactate (Lac), and less need for cardiopulmonary resuscitation (CPR) were observed among survivors. The best discrimination between survivors and non-survivors was observed with the PREdiction of Survival on ECMO Therapy (PRESET) score [area under the curve (AUC) 0.66, 95% confidence interval (CI): 0.60–0.72]. In 2024, Mazuru et al.’s (11) study about PRESET Score showed that Simplified Acute Physiology Score-II displayed the best prognostic value, with an AUC of 0.67 (95% CI: 0.57–0.76). Prediction performance was not good in all analyzed scores despite good calibration. However, the efficacy of prognostic prediction of these studies was not confirmed, and the search for effective prognostic assessment is vital in clinical practice. In recent years, the immune inflammatory response has been found to play an important role in the development of ARDS, especially, that an overactivated inflammatory response can exacerbate lung damage. Studies have shown that levels of certain cytokines, such as interleukin-6 (IL-6), are associated with disease severity and mortality (12). Immunosuppression is associated with a poor prognosis in patients with severe disease and a decrease in lymphocyte count (Lym) (13,14). The purpose of this study was to explore the potential of the IL-6/Lym index in the prognostic evaluation of patients with moderate to severe ARDS supported by VV ECMO. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1160/rc).

Methods

Study design and data source

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethical Committee of The People’s Hospital of Guangxi Zhuang Autonomous Region (approval No. KT-KJT-2022-161). The requirement for informed consent was waived in this retrospective study. The data were from a major referral center (The People’s Hospital of Guangxi Zhuang Autonomous Region) in Guangxi, China, collected from March 2022 to July 2024. All patient data were anonymized before being analyzed.

Eligible participants included adult inpatients diagnosed with moderate-to-severe ARDS who required VV ECMO support (ARDS was defined according to the Berlin criteria) (15).

• Criteria that apply to all ARDS categories:
  • Risk factors and origin of edema: precipitated by an acute predisposing risk factor such as pneumonia, non-pulmonary infection, trauma, transfusion, aspiration, or shock. Pulmonary edema is not exclusively or primarily attributable to cardiogenic pulmonary edema/fluid overload, and hypoxemia/gas exchange abnormalities are not primarily attributable to atelectasis. However, ARDS can be diagnosed in the presence of these conditions if a predisposing risk factor for ARDS is also present.
  • Timing: acute onset or worsening of hypoxemic respiratory failure within l week of the estimated onset of the predisposing risk factor or new or worsening respiratory symptoms.
  • Chest imaging: bilateral opacities on chest radiograph and computed tomography, or bilateral B lines and/or consolidations by ultrasound, not fully explained by effusions, atelectasis, or nodules/masses. Exclusion criteria: (a) patients under 18 years of age; (b) incomplete demographic or clinical data, i.e., date of birth, sex, and discharge diagnosis.
• All patients were intubated in our study. Criteria that apply to specific ARDS categories:
  • Moderate: 100< partial pressure of oxygen (PaO₂)/fraction of inspired oxygen (FiO₂) ≤200, or 148< saturation of peripheral oxygen (SpO₂)/FiO₂ ≤235 (if SpO₂ ≤97%).
  • Severe: PaO₂/FiO₂ ≤100 or SpO₂/FiO₂ ≤148 (if SpO₂ ≤97%).

Indications by the Extracorporeal Life Support Organization (ELSO) (16) on the start of VV ECMO support in adult patients—

Assessment conditions of these criteria:

• FiO₂ 0.8, positive end-expiratory pressure (PEEP) ≥10 cm H₂O.
• Respiratory rate (RR), 35 rpm.
• P_plate ≤32 cm H₂O, tidal volume (TV) of 6 mL/kg of ideal weight.
• Recommendation on the use of neuromuscular block, and prone positioning maneuver.

Hypercapnia:

• PaO₂/FiO₂ <150 mmHg with an FiO₂ of 0.9 for over 9 hours.
• PaO₂/FiO₂ <100 mmHg with an FiO₂ of 0.9 for over 6 hours.
• PaCO₂ >60 mmHg, and for over 6 hours.

Collected data included demographic information (i.e., age, sex, height, and weight), comorbidities [e.g., hypertension, diabetes, heart failure, chronic obstructive pulmonary disease (COPD), renal failure, neurological diseases, and malignancy], and clinical outcomes [length of ECMO support, ECMO weaning, length of intensive care unit (ICU) stay, length of hospital stay]. The severity of illness was assessed using the Acute Physiological and Chronic Health Evaluation II (APACHE II) score. In contrast, sepsis severity was evaluated using the Sequential Organ Failure Assessment (SOFA) score and norepinephrine (NE) dose. Baseline vital signs included temperature (T), heart rate (HR), RR, systolic blood pressure (SBP), diastolic blood pressure (DBP), and SPO₂. The initial ECMO parameters related to respiratory parameters included peak airway pressure (P_peak), VT, mean airway pressure (P_mean), and static lung compliance (C_stat). The initial ECMO parameters included ECMO oxygen, ECMO revolutions, ECMO blood flow, or ECMO gas. Laboratory test results at baseline ECMO initiation included P/F, Lac, white blood cells (WBC), neutrophils (NEU), lymphocytes (Lym), platelets (PLT), and IL-6.

Statistical analysis

Data were managed using Microsoft Excel (Microsoft Corp., Redmond, WA, USA) and analyzed with SPSS 26.0 (IBM Corp., Armonk, NY, USA). Continuous variables were expressed as medians with interquartile ranges (IQR) and compared using the Mann-Whitney U test. Categorical variables were presented as counts and percentages, with comparisons performed using chi-square or Fisher’s exact tests. Univariate and multivariate Cox proportional hazard regression analyses were performed to assess the association between prognostic factors, and the potential prognostic factors were evaluated and compared according to receiver operating characteristic (ROC) curve analysis. Kaplan-Meier survival curves were generated to compare the mortality, with log-rank tests analyzing differences.

Results

Participants

A total of 117 patients with moderate-to-severe ARDS with VV ECMO support were included in the analysis and divided into two groups based on whether they survived for 28 days after admission to the ICU (the flowchart of patient inclusion is shown in Figure 1).

Figure 1 Flowchart. ARDS, acute respiratory distress syndrome; ICU, intensive care unit; VV ECMO, venovenous extracorporeal membrane oxygenation.

Patient characteristics

The characteristics of the two groups of Nonsurvivors and Survivors are summarized in Table 1. There were no significant differences between the groups in terms of demographic characteristics or common comorbidities. The ICU admission scores in the nonsurvivors and SOFA scores were higher than those of the survivors (12.0±3.3 vs. 10.6±2.7, P=0.02), but the APACHE II scores showed no significant differences between the groups. There was no statistically significant difference in vital signs at ECMO initiation, such as RR, SBP, DBP, and SpO₂, between the two groups. All of the parameters related to respiratory mechanics were higher in the Survivors group, except for P_peak, which was higher in the nonsurvivors group (nonsurvivors vs. survivors: 27.5±6.3 vs. 25.0±6.4, P=0.04). Regarding the initial ECMO parameters, ECMO oxygen was higher in the nonsurvivors group (nonsurvivors vs. survivors: 100%±0% vs. 94.3%±13.6%, P=0.001). Meanwhile, no significant difference was found in ECMO revolutions, ECMO blood flow, or ECMO gas. Similarly, the results of some laboratory were significant, including Lym [nonsurvivors vs. survivors: 0.4 (0.3–0.7) vs. 0.6 (0.5–1.2), P=0.03] and IL-6 [nonsurvivors vs. survivors: 356.9 (85.2–858.0) vs. 81.5 (17.9–232.4), P<0.001], yet others such as the PaO₂/FiO₂ ratio, Lac, WBC, NEU, and PLT showed no significant difference. In terms of outcomes, nonsurvivors ECMO weaning was less (P<0.001), and both ICU duration but also hospital duration was shorter (P<0.001).

The AUROC curve analysis for the prognosis of ICU 28-day mortality

The AUROC curve analyses are summarized in Table 2. The best discrimination between survivors and non-survivors was observed with the IL-6/Lym [AUC of 0.80 (95% CI: 0.69–0.88), Youden index 0.55, cut-off 138.0, sensitivity 0.86, specificity 0.68] (Figure 2).

Figure 2 The AUROC curve analysis for the prognosis of ICU 28-day mortality. AUC, area under the curve; AUROC, area under the receiver operating characteristic curve; C_stat, static lung compliance; ICU, intensive care unit; IL-6, interleukin-6; Lac, lactate; Lym, lymphocyte; ROC, receiver operating characteristic; SOFA, Sequential Organ Failure Assessment; WBC, white blood cell.

The ROC curve analysis for the prognosis of ICU 28-day mortality with a 10-fold cross-validation

A 10-fold cross-validation procedure was employed to assess AUROC for predicting 28-day mortality in the ICU using various clinical indicators. The entire dataset was randomly partitioned into 10 mutually exclusive subsets of approximately equal size (folds). For each of the 10 iterations, a single fold was retained as the validation test set. The remaining nine folds were combined to form the training set. A logistic regression model was trained on the training dataset. The trained model was applied to the test set to generate probability estimates, from which the AUC was computed.

The final result also confirmed our previous conclusion: the mean AUC of IL-6/Lym was 0.82 (95% CI: 0.80–0.83), which had a good predictive ability for the prognosis of patients with moderate to severe ARDS who require VV ECMO support, and the statistical analysis results (Table 3).

Cox proportional hazards regression analysis

According to univariable Cox analysis (Table 4), baseline SOFA score [hazard ratio (HR) 1.09, 95% CI: 1.02–1.18; P=0.02], baseline vasoactive-inotropic score (VIS) (HR 2.13, 95% CI: 1.30–3.48; P=0.003), baseline Lac (HR 1.13, 95% CI: 1.07–1.19; P<0.001), and baseline C_stat (HR 0.97, 95% CI: 0.95–1.00; P=0.03), and baseline IL-6/Lym >138.0 (HR 4.85, 95% CI: 2.37–9.91; P<0.001), baseline Lac (HR 1.09, 95% CI: 1.03–1.15; P=0.003), and baseline IL-6/Lym >138.0 (HR 4.73, 95% CI: 2.83–8.00; P<0.001) were independent prognostic factors for ICU 28-day mortality in patients according to multivariate Cox analysis (Figure 3).

Figure 3 Kaplan-Meier curve for ICU 28-day mortality of IL-6/Lym. CI, confidence interval; HR, hazard ratio; ICU, intensive care unit; IL-6, interleukin-6; Lym, lymphocyte.

Discussion

VV ECMO is increasingly being employed in the management of severe ARDS (17). Identifying risk factors associated with poor outcomes remains essential for optimizing patient selection and prognostic evaluation. In the present study, univariable and multivariate Cox regression analyses identified a baseline IL-6/Lym greater than 138.0 as an independent predictor of 28-day ICU mortality (adjusted HR =4.73, 95% CI: 2.83–8.00; P<0.001). Moreover, the IL-6/Lym ratio exhibited strong discriminative performance for 28-day ICU survival, yielding an AUC of 0.80 (95% CI: 0.69–0.88).

With respect to mortality, existing literature has reported rates between 45% and 50%, a range that aligns closely with the 28-day ICU mortality rate of 52.8% observed in our cohort (17-19). Zayat et al.’s study (18) also identified significantly elevated IL-6 levels in non-survivors compared to survivors on univariate analysis, and further established IL-6 as an independent prognostic marker for mortality (HR =1.07, 95% CI: 1.00–1.14; P=0.05). Their model, based on IL-6, demonstrated high predictive accuracy with an AUC of 0.87, sensitivity of 87.5%, and specificity of 77.8%. It is noteworthy, however, that their study cohort predominantly comprised coronavirus disease of 2019 (COVID-19)-related ARDS patients and was limited by a small sample size (n=17). These factors may affect the generalizability of the reported associations.

A prospective, multicenter, observational study conducted across 133 centers in 21 countries is scheduled for publication in 2025 (20). This investigation included 1,215 adult COVID-19 patients who received VV ECMO support during the pandemic, among whom 613 survived to hospital discharge and 602 died. The study identified age, duration from endotracheal intubation to ECMO initiation, pre-existing chronic renal failure, and the use of vasoactive agents and neuromuscular blocking agents as independent risk factors for in-hospital mortality. Although these findings provide valuable insights, it is important to note that the study population consisted exclusively of COVID-19-associated ARDS patients. In the post-pandemic context, VV ECMO is increasingly used in non-COVID ARDS, underscoring the need for continued prognostic evaluation in this population. Furthermore, certain risk factors—such as age—are non-modifiable, and clinical consensus remains lacking regarding the optimal timing of ECMO initiation following intubation, as well as standardized use of vasoactive and neuromuscular blocking drugs in these critically ill patients.

Given these constraints, our study emphasizes the role of inflammatory and immune status during ECMO support. By focusing on modifiable aspects of the immune response and systemic inflammation, we aim to improve patient management and outcomes. We further propose that future prospective interventional studies target immunomodulatory strategies to optimize clinical outcomes in patients receiving VV ECMO.

In a 2024 study based on ELSO registration (21), a pooled analysis of 27,811 patients from 144 centers who received VV ECMO for ARDS demonstrated a significant association between advanced age and increased hospital mortality and post-ECMO complications. These differences became apparent as early as 30 years of age and were consistently observed in both COVID-19 and non-COVID-19 ARDS subgroups. Although these findings underscore the importance of considering age as a prognostic factor in the selection of COVID-19 patients for VV ECMO, it should be emphasized that due to the multifactorial nature of outcomes, treatment decisions based solely on age are not appropriate.

This study has several limitations. First, as a single-center retrospective analysis, the generalizability of our findings may be limited despite the relatively large sample size. Future multicenter, nationwide studies are warranted to validate these results. Second, the potential influence of concomitant therapies—such as corticosteroids—was not systematically compared between groups, highlighting a need for further investigation in prospective settings. Additionally, the type of respiratory support provided prior to ECMO was found to substantially affect patient prognosis, suggesting that pre-ECMO management should be considered carefully in future prognostic models. The Grotberg et al. (22) identified the risk of death associated with the number of days of high-flow nasal oxygen (HFNO), non-invasive ventilation (NIV), and invasive mechanical ventilation (IMV) before ECMO. The odds of right ventricular failure [odds ratio (OR): 1.07, 95% CI: 1.00–1.14] and in-hospital mortality (OR: 1.17, 95% CI: 1.08–1.27) increased for each additional day of pre-ECMO advanced respiratory support. In Giani et al.’s study (23), it was confirmed that the use of bilevel positive airway pressure (BiPAP) before intubation and the time from admission to intubation were independently associated with increased in-hospital mortality (OR, daily increase of 1.32, 95% CI: 1.08–1.61 and 1.03, 1.00–1.06). The impact of pre-ECMO respiratory support on the prognosis of patients is also very important, and in this center, there are fewer respiratory supports using HFNO and NIV before invasive ventilator assistance. Lastly, although we observed differences in outcomes between the two groups, the underlying mechanisms remain unclear and require further investigation.

Conclusions

This study’s results demonstrate that IL-6/Lym may be an independent protective factor for predicting ICU 28-day mortality in patients with moderate-to-severe ARDS supported with VV ECMO. The conclusions of the study need to be further confirmed by a multicenter prospective study.

Acknowledgments

The authors thank The People’s Hospital of Guangxi Zhuang Autonomous Region for the data supply that made the study possible. We extend our gratitude to all data collectors for their cooperation and efforts during the data collection.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1160/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1160/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1160/prf

Funding: This work was supported by the Guangxi Clinical Research Center Construction Project for Critical Treatment of Major Communicable Diseases (No. AD22035101, to B.X.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1160/coif). B.X. reports receiving funding from Guangxi Clinical Research Center Construction Project for Critical Treatment of Major Communicable Diseases (Grant No. AD22035101). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethical Committee of The People’s Hospital of Guangxi Zhuang Autonomous Region (approval No. KT-KJT-2022-161). Informed consent was waived in this retrospective study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Calfee CS, Janz DR, Bernard GR, et al. Distinct molecular phenotypes of direct vs indirect ARDS in single-center and multicenter studies. Chest 2015;147:1539-48. [Crossref] [PubMed]
2. Luo L, Shaver CM, Zhao Z, et al. Clinical Predictors of Hospital Mortality Differ Between Direct and Indirect ARDS. Chest 2017;151:755-63. [Crossref] [PubMed]
3. Meyer NJ, Gattinoni L, Calfee CS. Acute respiratory distress syndrome. Lancet 2021;398:622-37. [Crossref] [PubMed]
4. Fan E, Brodie D, Slutsky AS. Acute Respiratory Distress Syndrome: Advances in Diagnosis and Treatment. JAMA 2018;319:698-710. [Crossref] [PubMed]
5. Bellani G, Laffey JG, Pham T, et al. Epidemiology, Patterns of Care, and Mortality for Patients With Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries. JAMA 2016;315:788-800. [Crossref] [PubMed]
6. Barbaro RP, MacLaren G, Boonstra PS, et al. Extracorporeal membrane oxygenation support in COVID-19: an international cohort study of the Extracorporeal Life Support Organization registry. Lancet 2020;396:1071-8. [Crossref] [PubMed]
7. Ramanathan K, Antognini D, Combes A, et al. Planning and provision of ECMO services for severe ARDS during the COVID-19 pandemic and other outbreaks of emerging infectious diseases. Lancet Respir Med 2020;8:518-26. [Crossref] [PubMed]
8. Schmidt M, Hajage D, Lebreton G, et al. Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome associated with COVID-19: a retrospective cohort study. Lancet Respir Med 2020;8:1121-31. [Crossref] [PubMed]
9. Qadir N, Sahetya S, Munshi L, et al. An Update on Management of Adult Patients with Acute Respiratory Distress Syndrome: An Official American Thoracic Society Clinical Practice Guideline. Am J Respir Crit Care Med 2024;209:24-36. [Crossref] [PubMed]
10. Fisser C, Rincon-Gutierrez LA, Enger TB, et al. Validation of Prognostic Scores in Extracorporeal Life Support: A Multi-Centric Retrospective Study. Membranes (Basel) 2021;11:84. [Crossref] [PubMed]
11. Mazuru V, Mang S, Ajouri J, et al. External Validation of the PREdiction of Survival on Extracorporeal Membrane Oxygenation Therapy (PRESET) Score: A Single-Center Cohort Experience. ASAIO J 2024;70:1001-7. [Crossref] [PubMed]
12. Sinha P, Churpek MM, Calfee CS. Machine Learning Classifier Models Can Identify Acute Respiratory Distress Syndrome Phenotypes Using Readily Available Clinical Data. Am J Respir Crit Care Med 2020;202:996-1004. [Crossref] [PubMed]
13. Adrie C, Lugosi M, Sonneville R, et al. Persistent lymphopenia is a risk factor for ICU-acquired infections and for death in ICU patients with sustained hypotension at admission. Ann Intensive Care 2017;7:30. [Crossref] [PubMed]
14. Hao T, Jin C, Hu D, et al. Dynamic decline of lymphocytes predicts extracorporeal membrane oxygenation-related infections: a retrospective observational study. J Thorac Dis 2024;16:4429-39. [Crossref] [PubMed]
15. Matthay MA, Arabi Y, Arroliga AC, et al. A New Global Definition of Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med 2024;209:37-47. [Crossref] [PubMed]
16. Tonna JE, Abrams D, Brodie D, et al. Management of Adult Patients Supported with Venovenous Extracorporeal Membrane Oxygenation (VV ECMO): Guideline from the Extracorporeal Life Support Organization (ELSO). ASAIO J 2021;67:601-10. [Crossref] [PubMed]
17. Erlebach R, Wild LC, Seeliger B, et al. Outcomes of patients with acute respiratory failure on veno-venous extracorporeal membrane oxygenation requiring additional circulatory support by veno-venoarterial extracorporeal membrane oxygenation. Front Med (Lausanne) 2022;9:1000084. [Crossref] [PubMed]
18. Zayat R, Kalverkamp S, Grottke O, et al. Role of extracorporeal membrane oxygenation in critically Ill COVID-19 patients and predictors of mortality. Artif Organs 2021;45:E158-70. [Crossref] [PubMed]
19. Schopka S, Philipp A, Müller T, et al. The impact of interleukin serum levels on the prognosis of patients undergoing venoarterial extracorporeal membrane oxygenation. Artif Organs 2020;44:837-45. [Crossref] [PubMed]
20. De Piero ME, Mariani S, van Bussel BCT, et al. In-hospital outcomes and 6-month follow-up results of patients supported with extracorporeal membrane oxygenation for COVID-19 from the second wave to the end of the pandemic (EuroECMO-COVID): a prospective, international, multicentre, observational study. Lancet Respir Med 2025;13:307-17. [Crossref] [PubMed]
21. Fernando SM, Brodie D, Barbaro RP, et al. Age and associated outcomes among patients receiving venovenous extracorporeal membrane oxygenation for acute respiratory failure: analysis of the Extracorporeal Life Support Organization registry. Intensive Care Med 2024;50:395-405. [Crossref] [PubMed]
22. Grotberg JC, Kraft BD, Sullivan M, et al. Advanced Respiratory Support Days as a Novel Marker of Mortality in COVID-19 Acute Respiratory Distress Syndrome Requiring Extracorporeal Membrane Oxygenation. ASAIO J 2024;70:427-35. [Crossref] [PubMed]
23. Giani M, Rezoagli E, Barbaro RP, et al. Noninvasive Ventilation Before Intubation and Mortality in Patients Receiving Extracorporeal Membrane Oxygenation for COVID-19: An Analysis of the Extracorporeal Life Support Organization Registry. ASAIO J 2024;70:633-9. [Crossref] [PubMed]