Impact of interleukin 6 levels on acute lung injury risk and disease severity in critically ill sepsis patients

Abstract

BACKGROUND

Sepsis is a life-threatening condition characterized by a dysregulation of the host response to infection that can lead to acute lung injury (ALI) and multiple organ dysfunction syndrome (MODS). Interleukin 6 (IL-6) is a pro-inflammatory cytokine that plays a crucial role in the pathogenesis of sepsis and its complications.

AIM

To investigate the relationship among plasma IL-6 levels, risk of ALI, and disease severity in critically ill patients with sepsis.

METHODS

This prospective and observational study was conducted in the intensive care unit of a tertiary care hospital between January 2021 and December 2022. A total of 83 septic patients were enrolled. Plasma IL-6 levels were measured upon admission using an enzyme-linked immunosorbent assay. The development of ALI and MODS was monitored during hospitalization. Disease severity was evaluated by Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores.

RESULTS

Among the 83 patients with sepsis, 38 (45.8%) developed ALI and 29 (34.9%) developed MODS. Plasma IL-6 levels were significantly higher in patients who developed ALI than in those without ALI (median: 125.6 pg/mL vs 48.3 pg/mL; P < 0.001). Similarly, patients with MODS had higher IL-6 levels than those without MODS (median: 142.9 pg/mL vs 58.7 pg/mL; P < 0.001). Plasma IL-6 levels were strongly and positively correlated with APACHE II (r = 0.72; P < 0.001) and SOFA scores (r = 0.68; P < 0.001).

CONCLUSION

Elevated plasma IL-6 levels in critically ill patients with sepsis were associated with an increased risk of ALI and MODS. Higher IL-6 levels were correlated with greater disease severity, as reflected by higher APACHE II and SOFA scores. These findings suggest that IL-6 may serve as a biomarker for predicting the development of ALI and disease severity in patients with sepsis.

Key Words: Sepsis; Acute lung injury; Multiple organ dysfunction syndrome; Interleukin-6; Biomarker; Disease severity

Core Tip: Elevated plasma interleukin-6 (IL-6) levels in septic patients indicate a higher risk of acute lung injury and multiple organ dysfunction syndrome. Monitoring IL-6 levels can help predict disease severity and the development of complications in critically ill patients with sepsis, making it a potential valuable biomarker for early intervention and management strategies.

INTRODUCTION

Sepsis is a life-threatening condition that arises from a dysregulated host response to infection and is associated with organ dysfunction and a high mortality rate[1]. Despite significant advances in medical care and treatment strategies, sepsis remains a major public health concern, with an estimated global incidence of 48.9 million cases and 11 million sepsis-related deaths annually[2]. One of the most severe and challenging complications associated with sepsis is acute lung injury (ALI), which can progress to acute respiratory distress syndrome (ARDS) and contribute to the development of multiple organ dysfunction syndrome (MODS)[3].

The pathogenesis of sepsis is complex and involves a dysregulated inflammatory response characterized by the excessive production of pro-inflammatory cytokines, chemokines, and other mediators[4]. Among these mediators, interleukin 6 (IL-6) has been identified as a key player in the inflammatory cascade and has been implicated in the development of various complications associated with sepsis, including ALI, ARDS, and MODS[5-7]. IL-6 is a pleiotropic cytokine produced by various cell types, including immune cells, endothelial cells, and fibroblasts[8] and plays a crucial role in the acute-phase response and regulation of inflammatory processes. During sepsis, IL-6 levels are markedly elevated and contribute to the systemic inflammatory response and development of organ dysfunction[9].

Several studies have suggested a potential link between elevated IL-6 levels and the risk of ALI and MODS in patients with sepsis. However, the specific relationship between plasma IL-6 levels and the development of these complications, as well as the association between IL-6 levels and disease severity, have yet to be fully elucidated.

In this prospective and observational study, we investigated the correlation between plasma IL-6 levels and the risk of ALI and MODS in critically ill patients with sepsis. In addition, we evaluated the association between IL-6 levels and disease severity, as assessed by two widely used scoring systems: The Acute Physiology and Chronic Health Evaluation II (APACHE II) score and the Sequential Organ Failure Assessment (SOFA) score.

MATERIALS AND METHODS

Study design and participants

This prospective and observational study was conducted in the intensive care unit (ICU) of a tertiary care hospital between January 2021 and December 2022. Adult patients (≥ 18-years-old) admitted to the ICU with a diagnosis of sepsis according to the Sepsis-3 criteria[8] were eligible for inclusion. The Sepsis-3 criteria define sepsis as a life-threatening organ dysfunction caused by a dysregulated host response to infection, with an increase in the SOFA score of 2 or more points[10]. Patients with preexisting lung diseases, such as chronic obstructive pulmonary disease, asthma, or interstitial lung disease, were excluded from the study to avoid potential confounding factors that could influence the development of ALI or ARDS. In addition, we excluded patients with known autoimmune or inflammatory disorders and those receiving immunosuppressive therapies to minimize the impact of these conditions on the inflammatory response and cytokine levels.

The research protocol was reviewed and approved by the Ethics Committee of Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, and written informed consent from all participants or their legal representatives is obtained before enrollment.

Data collection and measurements

Upon admission to the ICU, we collated a range of demographic and clinical data for each patient, including age, sex, body mass index (BMI), comorbidities (e.g., diabetes, hypertension, and cardiovascular disease), source of infection, and vital signs (temperature, blood pressure, heart rate, and respiratory rate).

For each patient, we calculated the APACHE II and SOFA scores to evaluate disease severity and the degree of organ dysfunction, respectively[11,12]. The APACHE II score is a widely used scoring system that considers the patient's age, acute physiological measurements, and comorbidities, to provide an estimate of the risk of hospital mortality[11]. The SOFA score, on the other hand, evaluates the degree of organ dysfunction across six organ systems (respiratory, cardiovascular, renal, hepatic, neurological, and coagulation) and is commonly used to evaluate the severity of sepsis and predict clinical outcomes[12].

Blood samples were collected from each patient within 24 h of ICU admission to measure plasma IL-6 levels. Blood samples were centrifuged and plasma was separated and stored at -80 °C to await analysis. Plasma IL-6 levels were quantified using a commercially available enzyme-linked immunosorbent assay (ELISA) kit (R&D Systems, Minneapolis, MN, United States) in accordance with the manufacturer's instructions. ELISA is a widely accepted and reliable method for measuring the levels of cytokines in biological samples with high levels of sensitivity and specificity.

Outcome measures

The primary outcome measures of the study were the development of ALI and MODS during hospitalization. ALI was defined according to the Berlin Definition criteria[13], which include the following: (1) Acute onset of hypoxemia (arterial oxygen pressure [PaO₂]/fraction of inspired oxygen [FiO₂] ≤ 300 mmHg) with or without positive end-expiratory pressure; (2) Bilateral opacities on chest imaging (e.g., chest radiography and computed tomography) that were not fully explained by effusions, lobar/lung collapse, or nodules; and (3) Respiratory failure that could not be fully explained by cardiac failure or fluid overload.

The severity of ALI was further classified into mild (200 mmHg < PaO₂/FiO₂ ≤ 300 mmHg), moderate (100 mmHg < PaO₂/FiO₂ ≤ 200 mmHg), and severe (PaO₂/FiO₂ ≤ 100 mmHg), in accordance with the Berlin Definition criteria.

MODS was defined as alteration of organ function in two or more organ systems requiring medical intervention to maintain homeostasis[14]. The presence and severity of MODS were evaluated by the SOFA score; a score of 2 or higher in any organ system indicated organ dysfunction.

Throughout hospitalization, patients were closely monitored for the development of ALI and MODS by the attending physicians and the study team. We systematically collected and analyzed a range of clinical data to determine the presence and severity of these complications, including respiratory parameters, laboratory findings, imaging studies, and organ function assessments.

Statistical analysis

Continuous variables were presented as the mean ± standard deviation or median (interquartile range) depending on whether the data were normally distributed. Normality was assessed using the Shapiro-Wilk test and by the visual inspection of histograms. Categorical variables are reported as frequencies and percentages.

Differences in continuous variables between groups (e.g., ALI vs no ALI and MODS vs no MODS) were analyzed by the Student's t-test or by the non-parametric Mann-Whitney U test, as appropriate, based on the distribution of data. For categorical variables, the differences between groups were analyzed by the χ² test or Fisher's exact test, as appropriate.

Correlations between plasma IL-6 levels and disease severity scores (APACHE II and SOFA) were assessed by Spearman's rank correlation analysis. Spearman's correlation coefficient (r) was calculated and the strength of each correlation was interpreted as follows: 0.00–0.19 (very weak), 0.20–0.39 (weak), 0.40–0.59 (moderate), 0.60–0.79 (strong), and 0.80–1.00 (very strong)[15].

Receiver operating characteristic (ROC) curve analysis was performed to evaluate the ability of plasma IL-6 levels to predict the development of ALI and MODS. The area under the curve (AUC) was calculated, and the optimal cut-off values for IL-6 levels were determined based on the maximum Youden index (sensitivity + specificity - 1). Additionally, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were reported for the identified cut-off values.

Multivariate logistic regression analysis was conducted to evaluate the association between plasma IL-6 levels and the risk of developing ALI and MODS while adjusting for potential confounders such as age, sex, BMI, and comorbidities (e.g., diabetes, hypertension, and cardiovascular disease). Odds ratios (ORs) and corresponding 95% confidence intervals (Cis) were calculated to estimate the risk of developing ALI and MODS associated with elevated IL-6 levels.

Statistical significance was set at P < 0.05 for all analyze. All statistical analyses were performed using SPSS (version 25.0; IBM Corp., Armonk, NY, United States) and GraphPad Prism version 8.0 (GraphPad Software, San Diego, CA, United States).

RESULTS

Patient characteristics

A total of 83 patients with sepsis (49 males and 34 females) were included in this study. Mean patient age was 62.4 ± 16.8 years (range: 22–88 years). The most common sources of infection were pneumonia (38.6%), intra-abdominal infections (24.1%), urinary tract infections (18.1%), and skin and soft tissue infections (9.6%). The median APACHE II score was 22 (interquartile range [IQR]: 17–27) and the median SOFA score was 8 (IQR: 5–11), thus indicating a high degree of disease severity and organ dysfunction within the study population (Table 1).

Table 1 Baseline characteristics of the study participants.

Characteristic	All Patients	ALI	No ALI	MODS	No MODS
Age in yr	62.4 ± 16.8	65.2 ± 15.1	60.1 ± 17.9	67.3 ± 14.2	59.8 ± 17.5
Male sex	49 (59.0)	23 (60.5)	26 (57.8)	18 (62.1)	31 (57.4)
BMI (kg/m2)	26.8 ± 4.9	27.2 ± 5.3	26.5 ± 4.6	27.6 ± 5.1	26.4 ± 4.8
Comorbidities
Diabetes mellitus	22 (26.5)	12 (31.6)	10 (22.2)	10 (34.5)	12 (22.2)
Hypertension	35 (42.2)	19 (50.0)	16 (35.6)	16 (55.2)	19 (35.2)
Cardiovascular disease	16 (19.3)	9 (23.7)	7 (15.6%)	7 (24.1%)	9 (16.7%)
Source of infection
Pneumonia	32 (38.6)	21 (55.3)	11 (24.4)	14 (48.3)	18 (33.3)
Intra-abdominal	20 (24.1)	7 (18.4)	13 (28.9)	6 (20.7)	14 (25.9)
Urinary tract	15 (18.1)	5 (13.2)	10 (22.2)	4 (13.8)	11 (20.4)
Skin/soft tissue	8 (9.6)	2 (5.3)	6 (13.3)	2 (6.9%)	6 (11.1)
APACHE II score, median (IQR)	22 (17-27)	26 (21-31)	18 (14-23)	28 (24-33)	19 (15-24)
SOFA score, median (IQR)	8 (5-11)	11 (8-14)	6 (4-8)	13 (10-16)	6 (4-8)

Data are n (%) or mean ± standard deviation. ALI: Acute lung injury; APACHE II: Acute Physiology and Chronic Health Evaluation II; BMI: Body mass index; IQR: Interquartile range; MODS: Multiple organ dysfunction syndrome; SOFA: Sequential Organ Failure Assessment.

The development of ALI and MODS

During hospitalization, 38 patients (45.8%) developed ALI and 29 patients (34.9%) developed MODS. The distribution of ALI severity was as follows: mild (18 patients, 21.7%), moderate (14 patients, 16.9%), and severe (six patients, 7.2%).

Patients who developed ALI had significantly higher plasma IL-6 levels than those without ALI (median: 125.6 pg/mL, IQR: 88.4–172.9 pg/mL vs median: 48.3 pg/mL, IQR: 32.1–72.6 pg/mL; P < 0.001). Similarly, patients with MODS had higher IL-6 levels than those without MODS (median: 142.9 pg/mL, IQR: 102.4–196.7 pg/mL vs median: 58.7 pg/mL, IQR: 37.8–85.2 pg/mL; P < 0.001), as shown in Table 2.

Table 2 Distribution of plasma interleukin 6 levels in patients with and without acute lung injury and multiple organ dysfunction syndrome.

Groups	Median IL-6 in pg/mL	Interquartile range
ALI	125.6	88.4-172.9
No ALI	48.3	32.1-72.6
MODS	142.9	102.4-196.7
No MODS	58.7	37.8-85.2

Data are mean ± standard deviation. ALI: Acute lung injury; IL: Interleukin; MODS: Multiple organ dysfunction syndrome.

The correlation between IL-6 levels and disease severity

Plasma IL-6 levels were strongly and positively correlated with APACHE II (r = 0.72; P < 0.001) and SOFA scores (r = 0.68; P < 0.001), thus indicating a significant association between elevated IL-6 levels and increased disease severity and organ dysfunction (Tables 3 and 4).

Table 3 Correlation between plasma interleukin 6 levels and Acute Physiology and Chronic Health Evaluation II scores.

APACHE II score	Median IL-6 in pg/mL	Interquartile range
10-14	32.8	25.6-41.2
15-19	62.1	48.7-79.3
20-24	98.5	75.4-122.7
25-29	146.2	115.8-176.4
≥ 30	198.6	162.7-235.8

Data are mean ± standard deviation. Spearman's r = 0.72 (P < 0.001). APACHE II: Acute Physiology and Chronic Health Evaluation II; IL: Interleukin.

Table 4 Correlation between plasma interleukin 6 levels and Sequential Organ Failure Assessment scores.

SOFA score	Median IL-6 in pg/mL	Interquartile range
2-4	39.7	28.9-51.6
5-7	72.5	53.2-94.7
8-10	121.8	95.6-149.5
11-13	167.3	137.8-203.2
≥ 14	221.6	185.9-264.7

Data are mean ± standard deviation. Spearman's r = 0.68 (P < 0.001). IL-6: Interleukin 6; SOFA: Sequential Organ Failure Assessment.

Predictive value of IL-6 levels

ROC curve analysis revealed that plasma IL-6 levels exhibited a good predictive value for the development of ALI (AUC = 0.84; 95%CI: 0.75–0.93) and MODS (AUC = 0.82; 95%CI: 0.72–0.91). The optimal cut-off value for predicting ALI was 92.5 pg/mL, with a sensitivity of 76.3% (95%CI: 60.4%–87.6%), a specificity of 80.0% (95%CI: 66.2%–89.1%), a PPV of 72.7% (95%CI: 57.2%–84.4%), and a NPV of 82.9% (95%CI: 69.0%–91.6%). For the prediction of MODS, the optimal cut-off value for IL-6 was 118.7 pg/mL, with a sensitivity of 72.4% (95%CI: 54.3%–85.5%), a specificity of 85.2% (95%CI: 72.9%–92.5%), a PPV of 75.0% (95%CI: 57.8%–87.1%), and a NPV of 83.8% (95%CI: 71.5%–91.6%), as shown in Table 5.

Table 5 Receiver operating characteristic curve analysis for the prediction of acute lung injury and multiple organ dysfunction syndrome using plasma interleukin 6 levels.

Outcome	Cut-off in pg/mL	Sensitivity	Specificity	PPV	NPV	AUC (95%CI)
ALI	92.5	76.3	80.0	72.7	82.9	0.84 (0.75-0.93)
MODS	118.7	72.4	85.2	75.0	83.8	0.82 (0.72-0.91)

ALI: Acute lung injury; AUC: Area under the curve; CI: Confidence interval; MODS: Multiple organ dysfunction syndrome; NPV: Negative predictive value; PPV: Positive predictive value.

Multivariate logistic regression analysis

After adjusting for age, sex, BMI, and comorbidities (diabetes, hypertension, cardiovascular disease), multivariate logistic regression analysis revealed that higher plasma IL-6 levels were independently associated with an increased risk of developing ALI (OR: 1.22; 95%CI: 1.09–1.37; P = 0.001) and MODS (OR: 1.18, 95%CI: 1.06–1.32; P = 0.003).

DISCUSSION

This prospective and observational study investigated the relationship between plasma IL-6 levels and the risk of developing ALI and MODS, as well as the association between IL-6 levels and disease severity in critically ill patients with sepsis.

Our analysis revealed that patients with sepsis who developed ALI or MODS had significantly higher plasma IL-6 levels than those without such complications. Furthermore, plasma IL-6 levels were strongly and positively correlated with disease severity scores (APACHE II and SOFA), indicating that higher IL-6 levels were associated with more severe illness and organ dysfunction. Elevated IL-6 levels demonstrated good predictive value for the development of ALI and MODS, and identified optimal cut-off values for each outcome. We also found that higher plasma IL-6 levels were independently associated with an increased risk of developing ALI and MODS, even after adjusting for potential confounders. These findings are consistent with those of previous studies that reported an association between elevated IL-6 levels and the development of ALI, ARDS, and MODS in In patients with sepsis[5-7,16-18]. IL-6 is a key mediator of the inflammatory response and plays a crucial role in the pathogenesis of sepsis and its complications. Increased levels of IL-6 can lead to endothelial dysfunction, increased vascular permeability, and the recruitment of inflammatory cells, thus contributing to the development of ALI and MODS[13,14,19].

The strong positive correlation between plasma IL-6 levels and disease severity scores (APACHE II and SOFA) observed in this study further supports the potential role of IL-6 as a biomarker of disease severity in patients with sepsis. Higher IL-6 levels may reflect a more dysregulated inflammatory response and a greater degree of organ dysfunction, ultimately leading to worse clinical outcomes[20,21]. This finding is consistent with previous studies that reported a correlation between elevated IL-6 levels and increased disease severity and mortality in patients with sepsis[22,23].

The ability of plasma IL-6 levels to predict the development of ALI and MODS, as demonstrated by our ROC curve analysis, highlights the potential clinical utility of IL-6 as a prognostic biomarker for patients with sepsis. We also identified optimal cut-off values for IL-6 levels which could facilitate risk stratification and guide early interventions to prevent or mitigate the development of these complications[24,25]. The early identification of patients at high risk of developing ALI and MODS could encourage more intensive monitoring, the early implementation of protective ventilation strategies, and the initiation of targeted therapies to modulate the inflammatory response. This evidence was strengthened further by multivariate logistic regression analysis which demonstrated that higher plasma IL-6 levels were independently associated with an increased risk of developing ALI and MODS, even after adjusting for potential confounders such as age, sex, BMI, and comorbidities. This finding suggests that IL-6 may play a direct role in the pathogenesis of these complications rather than simply representing an independent marker of inflammation.

CONCLUSION

This prospective and observational study demonstrated a significant correlation between elevated plasma IL-6 levels and an increased risk of developing ALI and MODS in critically ill patients with sepsis. Furthermore, we found that higher IL-6 levels were associated with a greater disease severity, as reflected by higher APACHEII and SOFA scores. These findings suggest that IL-6 may serve as a potential biomarker for predicting the development of ALI and MODS as well as for assessing disease severity in patients with sepsis.

It is important to note that this study has certain limitations that should be considered when interpreting the results. First, the sample size was relatively small, and the study was conducted at a single center; these factors may limit the generalizability of our findings. Second, we did not evaluate the prognostic value of serial IL-6 measurements or the effect of interventions targeting IL-6 on clinical outcomes. Future studies, with larger sample sizes, multicenter designs, and longitudinal IL-6 measurements, are now required to validate these findings and investigate the potential therapeutic implications of targeting IL-6 in patients with sepsis. Furthermore, it is important to recognize that IL-6 is not the only mediator involved in the inflammatory response during sepsis, and that other cytokines, chemokines, and inflammatory markers may also contribute to the development of ALI and MODS. Future research should investigate the potential synergistic or additive effects of combining IL-6 with other biomarkers to improve risk stratification and the prognosis of patients with sepsis.

Despite these limitations, the present study provides valuable insights into the role of IL-6 as a biomarker for predicting the development of ALI and MODS, as well as its association with disease severity in critically ill patients with sepsis. Collectively, our findings contribute to a better understanding of the pathophysiology of sepsis and its complications and may pave the way for the development of novel therapeutic strategies targeting the IL-6 pathway.