Association of interleukin-6 with acute lung injury risk and disease severity in sepsis

Abstract

Sepsis is a life-threatening condition caused by a dysregulated response of the body in response to an infection that harms its tissues and organs. Interleukin-6 (IL-6) is a significant component of the inflammatory response as part of the pathogenesis of sepsis. It aids in the development of Acute lung injury and, subsequently, multiple organ dysfunction syndrome. This letter probes into the correlation between plasma IL-6 levels and the risk of developing acute lung injury and multiple organ dysfunction syndrome in critically ill patients with sepsis. While it shows promising results, limitations like its observational study design, a limited sample size, a single center involvement, single-time-point measurement, and a lack of a control group restrain its cogency. The study is a big step in identifying IL-6 as a biomarker to improve patient care.

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

Core Tip: The study explores the association of interleukin-6 levels with the risk of developing acute lung injury and multiple organ dysfunction syndrome in critically ill sepsis patients. It underscores its potential as a valuable biomarker for prognosis and guiding treatment in intensive care settings. However, limitations like an observational study design, a limited sample size, a single center involvement, single-time-point measurement, and no control group should be considered in further research.

TO THE EDITOR

Sepsis is a critical condition that results from a malfunctioned host response to infection caused by pathogens such as bacteria, viruses, etc[1]. The World Health Organization discerns sepsis as a critical health issue, advising member states to prioritize the management of the condition[2]. Sepsis is frequently a direct cause of death in critically ill patients in an intensive care unit (ICU). It remains one of the foremost sources of morbidity and mortality in the world, putting a crushing burden on the global healthcare system and threatening the well-being of millions[3]. It was outlined in the Burden of Diseases report that 48.9 million cases of sepsis were documented globally in 2017, resulting in a mortality rate of 22.5%, contributing to nearly 20% of deaths worldwide[4]. While the condition can quickly advance into septic shock and multiple organ dysfunction syndrome (MODS) if not treated timely, the lung is the first and most commonly affected organ[5]. Acute lung injury (ALI) is one of the most severe complications associated with sepsis that contribute to the development of MODS[6].

Interleukin-6 (IL-6) is a cytokine produced by various immune cells like activated monocytes and macrophages, adipocytes, and endothelial cells, playing a role in multiple biological activities[7]. IL-6 is implicated as a mediator in sepsis, secreted during the acute inflammatory reaction[8]. The monocytes released during the inflammatory response in sepsis transform into macrophages. The macrophages release pro-inflammatory cytokines IL-6, among others. It has been implicated in the development of ALI and MODS in sepsis patients. In sepsis-induced ALI, pro-inflammatory cytokines, particularly IL-6, along with systemic coagulation abnormalities, expedite the progression of the disease. This leads to a systemic inflammatory cascade, immune dysfunction, and worsened lung injury, impacting patient prognosis negatively[9].

Due to its role in the pathophysiology of sepsis and its role in ALI and MODS, it has potential as a prognostic indicator. We aim to shed light on the relationship between plasma IL-6 levels and the risk of developing ALI and MODS in critically ill sepsis patients and assess the use of IL-6 as a biomarker. By reviewing the findings of studies like Liu et al[10], we intend to understand the impact and role of IL-6 on ALI and MODS in critically ill sepsis patients so we can improve patient care and potentially improve therapeutic strategies for septic patients.

LUNG INJURY AND MODS

Liu et al[10] conducted a prospective observational study, probing the correlation between IL-6 levels and the risk of developing ALI and MODS in critically ill sepsis patients. The study employed 83 septic patients, whose diagnoses were established by the Sepsis-3 criteria, who were placed in the intensive care unit of a tertiary care hospital between January 2021 and December 2022. The study assessed the severity of the disease using APACHE II, while the SOFA scores were used to evaluate the severity of sepsis and predict clinical outcomes. Blood samples were obtained within 24 hours of admission to the ICU to assess plasma IL-6 levels, and the patients were closely observed during their entire hospital stay for the inception of ALI and MODS. The results exhibited that sepsis patients who became stricken with ALI or MODS during their stay had significantly raised plasma IL-6 than those who did not. IL-6 Levels were strongly correlated with APACHE II and SOFA scores, signifying that higher IL-6 levels were related to more severe illness and organ dysfunction. Increased IL-6 levels demonstrate great predictive ability for the onset of ALI and MODS, pinpointing the optimal thresholds for each condition. The study findings bring IL-6 to the fore as a potential biomarker in sepsis.

The study’s prospective design ensures the data is collected systematically, starting from ICU admission, minimizing recall bias and enhancing the precision of data related to patient characteristics and clinical outcomes. On the contrary, the study’s observational nature can merely demonstrate association but cannot definitively attest to causality. Despite efforts to adjust for confounding variables in the study, other unmeasured variables, such as genetics, may influence the relationship.

The study incorporates only 83 patients in a single center; this dramatically limits the sample size and the generalizability of the findings. A small sample size increases the probability of type II errors, where actual effects are missed. Understanding the correlation in different age groups, ethnicities, or comorbidities becomes difficult. Conducting the study at a single tertiary care hospital restricts the applicability of the results to other settings with different patient demographics, clinical practices, and resource availability. A multi-center study with a much more diverse sample size would ensure broader applicability and further corroborate the findings.

The study involved single-time-point measurement of IL-6 within 24 hours of ICU admission. This restricts the apprehension of the temporal relationship between IL-6 levels and the development of ALI and MODS, as it may need to accurately capture the dynamic changes in IL-6 levels throughout the progression of the disease. Continual measurements over time can provide a better understanding of the temporal relationship. The use of APACHE II and SOFA grants credibility to the study as these scores are widely recognized in critical care research and offer a reliable measure of patient condition; however, they come with their own set of limitations due to their static nature. It measures the patient’s condition at a single time point, which may not consider the ongoing changes in clinical condition, further limiting understanding of the temporal relationship. They do not consider the complicated interactions between organ systems, possibly resulting in inaccurate risk estimation for specific complications like ALI and MODS.

Lastly, the study failed to include a control group of critically ill patients without sepsis. Incorporating a control group would have established whether the relationship between the elevated levels of IL-6 and the development of ALI and MODS is specific to sepsis or is a common feature observed in other critical illnesses. This hampers the study's overall robustness.

CONCLUSION

The research by Liu et al[10] provides compelling evidence of a solid and positive relationship between raised plasma IL-6 levels and the development of ALI and MODS in critically ill sepsis patients. The research underscores a salient finding of a correlation between IL-6 levels and both APACHE II and SOFA scores, highlighting the potential of IL-6 as a promising biomarker for evaluating disease severity and predicting adverse outcomes in sepsis. This can aid in crafting targeted and appropriate therapeutic interventions and patient care protocols. While the study provides valuable insights, to ultimately establish the clinical usefulness of IL-6, further research should be done that incorporates a larger and diverse sample size from multiple centers, uses longitudinal measurements, and includes a control group of critically ill patients without sepsis to establish IL-6 as a biomarker for sepsis-related complications definitively. Nevertheless, the study lays solid ground for future research, underscoring the need for further investigation into IL-6’s role in sepsis and its potential to improve patient outcomes.