Sepsis remains an underrecognized global health issue that causes millions of premature deaths annually and has been described as “the quintessential medical disorder of the 21st century” (1, 2). Although hundreds of clinical trials involving tens of thousands of patients and substantial funding have been conducted over the past several decades, a novel drug with a highly effective target against sepsis has yet to be developed (3). According to recent epidemiological studies, the mortality rate in sepsis remains between 25 and 30% and can reach as high as 50% in septic shock. Furthermore, most statistical data came from high-income nations. Indeed, the mortality rate is probably understated (4, 5).

Infection, the etiology of sepsis, is the root cause of a subsequent series of complex complications. Severe infection in sepsis causes immune dysfunction, which renders the body more susceptible to infection: a vicious circle (6). Immune disorders are significant contributors to sepsis’s poor prognosis. If treatment fails to restore immune function, it may have been in vain. Although organ dysfunction is temporarily alleviated, secondary bacterial infection, a vivo-derived opportunistic pathogen, and viral reactivation will attack the body and impair immune function: a new vicious cycle (3, 6). Thus, restoring immune system function is essential for the management of sepsis. Notably, septic shock is a more severe form of sepsis in which immune dysfunction is more pronounced.

The development of novel immunotherapy approaches for patients with septic shock requires a comprehensive understanding of the immune system’s extensive changes. In this study, we examined the fluctuations of immune-related markers in patients within 48 h of the onset of septic shock. On this basis, we have proposed some immunotherapy recommendations for septic shock.

In this study, we comprehensively analyzed immune system changes in patients with septic shock. We found inflammatory stimulation existed in septic shock patients including increased neutrophil counts, activation of the complement system, and cytokine storm. Immunosuppression also existed including lymphocyte depletion, decreased antibody levels secreted by B cells, and impaired CD4⁺ T cell functions. These results provide a theoretical foundation for assessing the prognosis of patients with septic shock and exploring immunotherapy.

We observed significant increases in infection biomarkers and neutrophil counts in patients with septic shock. Normally, the half-life of circulating neutrophils is brief (7–12 h in vivo). However, the decreased sensitivity of neutrophils to apoptosis during sepsis significantly lengthened their lifespan, which may be one of the reasons for their increase (10–12). Neutrophils: a double-edged sword in sepsis (13). They have potent phagocytic activity and serve as the “front line” of defense against pathogenic microorganisms (14). However, lysosomal enzymes released by neutrophils can damage blood vessels and surrounding tissues, thereby increasing the likelihood of organ failure (15, 16). During sepsis, neutrophils exhibited obvious abnormalities, including reduced ROS production, increased immature neutrophils, impaired migration and bacterial clearance, and cytokine secretion disorder. All of these changes were associated with an increased mortality risk in sepsis (17–19). Consequently, excessive abnormal neutrophil consumption may aid in enhancing the prognosis of septic shock. An earlier study supported the notion that neutrophil consumption ameliorated LPS-induced systemic inflammation and liver injury in a mouse model (20).

Consistent with previous studies, we found that the serum cytokine levels of septic shock patients significantly increased and were characterized by cytokine storms (21). Moreover, studies have shown that elevated levels of IL-6, IL-8, and IL-10 are strongly associated with mortality (21–23), which is consistent with our findings. For many years, an excessive systemic inflammatory response was believed to contribute to sepsis-related death. In light of the general increase in serum cytokines, it has been suggested that inhibiting the inflammatory response to prevent cytokine storm syndrome could aid in reducing mortality. However, this method failed to significantly improve the prognosis. In some instances, this method may even worsen the prognosis (21, 24, 25). In this study, we found that although the levels of multiple cytokines increased in nonsurvivors, they were not risk factors for mortality. Therefore, cytokine storms in sepsis may be merely a biological marker of disease severity and not the cause of organ damage (26). Cytokines play an important role in the maintenance of the innate immune response and efficient pathogen clearance. Moreover, during sepsis, most inflammatory mediators exhibit pleiotropic effects on the downstream pathway and interdependent biological activities (27). Inhibiting the innate immune response to reduce elevated cytokine levels should therefore be approached with caution.

We discovered that nonsurvivors had lower IgM levels than survivors. In addition, logistic regression analysis revealed that low IgM levels were a risk factor for mortality, indicating that IgM may play an important role in prognosis. Furthermore, numerous studies have shown that IgM levels are closely related to the prognosis of sepsis and have a significant protective effect in sepsis (28, 29). In clinical trials, receiving intravenous immunoglobulin containing only IgG (IVIG) did not demonstrate a clear benefit (30–32). However, the use of IgM-enriched immunoglobulin (IgGAM) appears to be an effective strategy. A meta-analysis of 19 clinical trials involving over 1,500 patients with sepsis evaluated the efficacy of IgGAM and revealed that its use could significantly reduce mortality (33). This observation was consistent with several other studies (34, 35). Therefore, we propose that IgM supplementation or the prevention of their decline merits further study. In addition, we observed a decline in serum complement C3 and C4 levels in septic shock patients, with the decrease being more pronounced in nonsurvivors. Moreover, lower C3 levels were found to be a risk factor for mortality, indicating that excessive complement system activation led to increased C3 and C4 consumption and was associated with patient outcomes. This is consistent with previous findings that sepsis-induced complement system activation causes endothelial dysfunction, coagulopathy, and cardiovascular abnormalities (36, 37). Inhibiting complement system activation was beneficial in sepsis (38–40). The complement levels (especially the C3 levels) may be a significant biomarker for prognostic stratification, as indicated by our findings, which support and expand upon previous research.

Lymphocyte depletion and dysfunction are important causes of immunosuppression (41–43). In this study, we observed a dramatic decrease in the lymphocyte, T cell, CD4⁺ T cell, CD8⁺ T cell, B cell, and NK cell counts of patients with septic shock. Similarly, the proportion of INF-γ positive CD4⁺ T cells decreased dramatically. Early immunosuppression due to lymphocyte compartment abnormalities was detected in septic shock patients, as indicated by these results. In addition, survivors and nonsurvivors had different lymphocyte, T cell, CD4⁺ T cell, and CD8⁺ T cell counts, and low CD4⁺ T cell counts were identified as a risk factor for mortality. Due to their capacity to interact with innate immune cells and adaptive immune cells, lymphocytes play a crucial role in the anti-infection immune response (44, 45). As described previously, excessive lymphocyte depletion worsens sepsis prognosis. In numerous animal models of sepsis, reducing lymphocyte depletion had positive effects (46, 47). In contrast to rapid and transient cytokine storms, immunosuppression caused by abnormal lymphocyte counts and function is typically long-lasting, progressive, and eventually fatal (48). Therefore, finding solutions for lymphocyte depletion may contribute to relieving immunosuppression and thus benefit septic shock patients.

This study has several limitations that should be noted. Firstly, although all data were collected within 48 h after the patient was diagnosed with septic shock, the results would be more convincing if the time range was reduced due to significant fluctuations in the immune system. Moreover, our study focused on a one-time point, and the inclusion of data at multiple time points would make a clearer description of immune system changes. Lastly, this is a prospective single-center study. The nature of our study determined our findings need to be verified by large, multi-center studies of rigorous design.

Significant immune system alterations occurred in patients with septic shock: Neutrophil counts, infection biomarkers, and cytokine levels increased significantly; Lymphocyte counts, immunoglobulin and complement protein levels, and lymphocyte subset counts declined dramatically; CD4⁺ T cell function decreased. In nonsurvivors, the levels of IL-6, IL-8, and IL-10 were greater than in survivors, whereas the levels of IgM, complement C3 and C4, and the counts of lymphocytes, T cells, CD4⁺ and CD8⁺ T cells were the opposite. Mortality risk factors include low lymphocyte counts, IgM levels, C3 levels, and CD4⁺ T cell counts. Suppressing the cytokine storm via the inhibition of the immune response should be approached with caution. Immunotherapy for eradicating excessively dysfunctional neutrophils, supplying IgM, inhibiting the overactivation of the complement system, and reducing lymphocyte depletion merits additional research.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Medical Ethics Committee of Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology. The patients/participants provided their written informed consent to participate in this study.

XD and MT conceptualized and designed the study. HT and SQ acquired the data. HT, SQ, ZL, and WG analyzed and interpreted the data. HT and SQ drafted the article. ZL, WG, XD, and MT critically revised the manuscript. HT and SQ contributed equally to this work. XD and MT share senior authorship. All authors contributed to the article and approved the submitted version.