The proportion of immunocompromised CKD population among critical care patients is continuously increasing. Typical immunocompromised states include patients requiring oral immunosuppressive therapy for more than 3 months for primary disease, autoimmune diseases, and solid organ transplant recipients [2]. Both the primary diseases and the pharmacological interventions significantly affect patients’ innate and adaptive immune function. It is widely recognized that the immune response to pathogens, rather than the pathogens themselves, is the main driving factor for the development of life-threatening organ dysfunction after infection [8]. Immunocompromised patients, due to their altered pathogen-immune system interactions, often present different clinical manifestations compared to immunocompetent individuals. In previous clinical research on sepsis, populations with immunosuppression were often excluded from the study cohort, but our research focuses specifically on this group of patients. We collected clinical and laboratory data of immunocompromised CKD patients treated for severe infections at the National Clinical Research Center of Kidney Diseases at the Jinling Hospital from January 2012 to January 2024. By using logistic regression, we identified relevant indicators and constructed a nomogram to establish a novel predictive model for the prognosis of severe infections in immunocompromised patients, demonstrating superior performance over the SOFA score and qPBS score. This is the first nomogram on the prognosis of severe infection in immunocompromised patients.

Previous studies have explored bloodstream infections in immunocompromised patients, revealing that age over 60 years and increased procalcitonin levels are independent predictors of mortality within 60 days post-infection [8]. However, these studies encompassed a diverse range of immunocompromised conditions including solid tumors, hematological disorders, transplants, autoimmune diseases, diabetes, cirrhosis, post-surgical critical illnesses, and burns, thereby leading significant heterogeneity. Florence et al. reported on ICU-acquired infections in 98 patients with systemic rheumatic diseases receiving immunosuppressive therapy, with a hospital mortality rate of 17.3%. Renal replacement therapy and mechanical ventilation were independent predictors of mortality [9]. Andry et al. conducted a retrospective study on patients with impaired immune function and concomitant acute respiratory failure, and the results suggested that the population with bacteremia had a higher proportion of hematological malignancies and higher SOFA scores, as well as a greater need for organ support. Bacteremia was associated with higher ICU crude mortality rate, but not with in-hospital mortality rate or 90-day mortality rate [10]. Previous studies have already demonstrated that the use of mechanical ventilation, vasoactive drugs, and TBIL are independent risk factors for in-hospital mortality in critical care patients, and these factors are incorporated into the SOFA score [11, 12]. Our study also included the TBIL level, the application of vasoactive drugs, and mechanical ventilation. This conclusion indicates that severe respiratory and circulatory also represent significant risk for mortality following severe infections in immunocompromised CKD patients.

In our study, we incorporated PL as one of the significant indicators for predicting our patient prognosis. However, the definition of PL remains non-standardized. Drewry et al. investigated PL in patients with normal immune function who developed sepsis. They defined severe lymphocytopenia as an absolute lymphocyte count (ALC) below 600 cells/µl and proposed a duration of four days to classify it as persistent, based on evidence suggesting a significantly reduced mortality risk when ALC returns to normal within four days [13]. Similarly, another study investigating the outcomes of critical care patients following emergent surgery identified a correlation between increased survival rates and the normalization of ALC by the fifth day [14]. In the context of immunocompromised individuals, severe lymphocytopenia has been characterized as an ALC ranging between 300 and 500 cells/µl [6, 15]. For the purposes of our study, we have defined PL as an ALC of less than 400 cells/µl persisting for a duration of four days.

Lymphocytes, including T cells, B cells, and natural killer cells, are essential components of the human immune system. These cells are responsible for antibody production, direct cell-mediated killing of virus-infected and tumor cells, and regulation of the immune response. Previous studies have consistently demonstrated that lymphopenia reflects an impairment of the adaptive immune system and is associated with an increased risk of infection and higher in-hospital mortality rates following severe infections. Adrie et al. showed that PL predicted increased 28‑day mortality in ICU patients [16]. Jing et al. concluded in a retrospective cohort study that septic patients with PL have higher mortality, worse conditions, increased risk of secondary infection, and poor prognosis regardless of shock [17]. Adigbli et al. extracted conclusions from two ICU patients’ databases that PL is common in critically ill patients and associated with increased risk of death [18]. Furthermore, Research has indicated that reversing lymphopenia can improve patient outcomes. Intravenous administration of CYT107(a glycosylated recombinant human IL‑7) resulted in a two-threefold increase in absolute lymphocyte counts, and was associated with increase in organ support free days [19].

Numerous studies have explored the causes of PL. In our patient cohort, the occurrence of PL could be attributed to several factors: (1) Primary disease induced PL: For instance, Patients with SLE often exhibit T cell dysfunction, particularly an increased proportion of exhausted T cells [20], decreased IL-2 secretion [21], and a breakdown of B cell tolerance mechanisms leading to polyclonal activation and production of numerous autoantibodies [22]. Research indicates that in SLE patients, the RNA-binding protein serine/arginine-rich splicing factor 1 (SRSF1) is associated with lymphocyte reduction. Overexpression of SRSF1 can rescue the survival of T cells in SLE patients [23]. (2) Medication-induced PL: Previous studies have demonstrated that the use of various immunosuppressants, especially glucocorticoids, is the most significant risk factor affecting patients’ innate and adaptive immunity. Chen et al. explored the impact of glucocorticoids on lymphocytes in the nephrotic syndrome population. They found that glucocorticoids inhibit the mTORC1 pathway through DNA methylation, FOXP3 upregulation, and ultimately exert a long-term suppressive effect on lymphocytes by regulating T cells [24]. (3) Severe Infections: The inability to eradicate persistent pathogens may result in the prolonged suppression of immune function. Studies have shown that persistent viral infections can induce T cell exhaustion, characterized by high expression of immunological checkpoint inhibitors such as PD1 and Tim3, thereby producing a suppressive effect [25, 26]. Huang et al. showed that in sepsis patients, Tim3 expression is increased on CD4+ T lymphocytes. This increase could inhibit the NFκB pathway through binding with the ligand HMGB1, and lead to reduced proliferative capacity and increased expression of inhibitory markers in T cells [27]. Damien et al. explored the expression of exhaustion-related markers on CD8+ T lymphocytes in sepsis patients. They found that CD8+ T lymphocytes with immunological characteristics of 2B4hiPD-1hiCD160low and 2B4hiPD-1lowCD160hi showed abnormal cytokine production and were associated with an increased risk of death [28]. In our patient cohort, the incidence of viral and fungal infections was higher in the death group, raising the question of whether this led to T lymphocyte exhaustion and subsequent persistent lymphocyte reduction, a topic warranting further exploration.

Our predictive model also incorporated LDH as a significant indicator. Under hypoxic conditions, cells generate energy through anaerobic metabolism, where LDH catalyzes the conversion of lactate to pyruvate, providing energy via lactate fermentation. Previous research has explored the relationship between LDH and mortality in patients with sepsis. A study by Liang et al. indicated that the serum LDH to albumin ratio (LAR) is significantly associated with both in-hospital and long-term adverse outcomes in patients with sepsis-related acute kidney injury [29]. Research conducted by Tang et al. demonstrates that within immunocompromised patients, elevated levels of LDH serve as a crucial indicator for prognostic assessment of pneumocystis jirovecii pneumonia [30]. In our study population, we observed a higher breath rate among patients in the mortality group. We hypothesize that such patients are more prone to hypoxia, and consequently, elevated levels of LDH are a significant factor in predicting mortality. However, further validation with a larger sample size is required.

The accessibility of inclusion indicators is also a key standard for evaluating the clinical utility of a model. The included indicators such as TBIL and LDH can be obtained from routine clinical biochemical tests and are part of the routine admission examinations, which are convenient for clinical application. PL requires dynamic monitoring of the patient’s complete blood count after admission, which is also a routine examination for critically ill patients after admission. Although this requires multiple monitoring within the first week of admission and may increase the medical burden, we believe it is worthwhile for critically ill patients with severe infections. We have included the use of mechanical ventilation and vasoactive drugs, which only require accurate clinical recording and are also easily obtained data.

However, this study has some potential limitations. As a retrospective study, selection bias and the exclusion of patients with missing data may have influenced our results. Although we compared the included data with the excluded patients’ data and found no statistically significant differences, analysis of larger-scale clinical data is still necessary, which is ongoing in our current work. Additionally, the data included in this study were from a single center and were not externally validated with data from other centers, which may also affect the applicability of our model to a broader population, although we have validated the reliability of the model in a validation set. In the future, we will validate the model based on publicly available databases and conduct prospective multicenter studies to further verify its reliability. Third, although the patients included in this study were based on the current mainstream definition of immunosuppressed status, it is undeniable that there is heterogeneity among the population we included, such as the impact of primary diseases and previous treatments on patient status. Although our sample size is relatively large, which may mitigate the impact of this heterogeneity on the results to some extent, and our results suggest that PL appears to have a significant impact on the prognosis of patients with severe infections regardless of their immunosuppressive status, in-depth exploration of single diseases is still necessary in the future, which we are currently undertaking. Fourth, our study lacks long-term follow-up data. Since the main focus of this study is to explore the in-hospital status of patients, severe infections may have an impact on the long-term prognosis and quality of life of immunosuppressed kidney disease patients, which is also a topic worthy of attention. We will further explore this issue in future studies.

In conclusion, we identified risk factors for in-hospital mortality following severe infection in immunocompromised CKD patients and visualized these through a Nomogram. This model demonstrates superior predictive efficiency compared to both the SOFA score and the qPBS score. To our knowledge, this is the first prognostic prediction model specifically designed for severe infections in immunocompromised CKD patients.