To the best of our knowledge, this study is the first to demonstrate an L-shaped relationship between PNI and in-hospital mortality in patients with sepsis. We utilized threshold effect analysis to identify a pivotal point (inflection point of 33.99). The findings of this study indicate that individuals with a low PNI had higher rates of in-hospital mortality. Furthermore, COX proportional risk regression analysis revealed a strong association between a low PNI and an increased risk of in-hospital mortality in sepsis patients.
Albumin is a protein synthesized by the liver that has both colloidal and non-colloidal functions in the body and is often used clinically to maintain plasma osmolality and to supplement protein[19]. Albumin can also bind multiple inflammatory mediators and modulate the immune response to systemic inflammation and sepsis[20]. Patients with sepsis are often comorbid with hypoalbuminemia under the influence of several factors affecting protein-energy metabolism, such as severe infections, stress, and electrolyte disorders. Our results show that albumin levels are significantly associated with survival status in sepsis patients(P = 0.006). Previous studies have also demonstrated a consistent correlation between low levels of albumin and unfavorable prognosis among sepsis patients. Furthermore, it has been identified as a highly reliable predictor of mortality in this population[21-23]. Although serum albumin levels can be used as a general marker of the severity of a sepsis patient's condition, albumin is an acute-phase protein that fluctuates as the patient's condition fluctuates[24]. As a result, researchers have combined albumin with other biomarkers to derive a number of prognostic indicators, such as lactate dehydrogenase-to-albumin ratio (LAR), C-reactive protein-to-albumin ratio (CAR), and procalcitoninogen-to-albumin ratio (PAR), which have been shown to correlate strongly with prognosis in septic patients[9, 11].
Lymphocytes are crucial immune cells within the body, playing a vital role in both the innate and adaptive immunity of organisms. Sepsis is characterized by a continuous cycle of pro-inflammatory and anti-inflammatory responses, which ultimately results in immune suppression and poor prognosis, and lymphocyte depletion and dysfunction are important causes of immune suppression[7]. Extensive research has consistently demonstrated that lymphopenia is a significant risk factor for poor prognosis in sepsis[25-27]. Rico-Feijoo et al. conducted a retrospective study involving 7215 sepsis patients, which revealed a positive association between lymphopenia and elevated short- and long-term mortality rates. Among the patients, 74.1% exhibited lymphopenia, and 66.3% failed to restore normal levels of lymphocytes during their stay in the ICU[28]. A prospective population-based study of 98,344 patients in Denmark showed a positive association between lymphopenia and risk of infection and infection-related deaths[29].
PNI is a multiparametric index of nutritional status based on serum albumin (ALB) levels and peripheral lymphocyte counts calculated by Onodera et al. in 1984[30]. PNI was originally employed to evaluate the nutritional and immune status of patients prior to surgery, as well as to predict postoperative complications. However, further investigations revealed a correlation between PNI and adverse outcomes in infected patients. Xie, T et al. investigated the predictive value of PNI and Neutrophilic lymphocyte ratio (NLR) for acute kidney injury in patients with sepsis, and the results showed that the predictive value of PNI was superior to that of NLR, and the area under the curve of both were PNI (AUC = 0.760; 95% CI:0.731-0.789, P < 0.001), NLR (AUC = 0.749; 95% CI:0.722-0.777, P < 0.001)[16].A multicenter retrospective study in Korea showed that PNI was significantly associated with poor prognosis in patients with sepsis and that mortality in septic patients receiving mechanical ventilation was linearly associated with PNI[31]. In a study of 1196 neonates with suspected sepsis, Li, T et al. found that PNI was lower in septic neonates and decreased significantly with increasing severity of sepsis, and after adjusting for confounders, PNI proved to be an independent risk factor for the presence of sepsis (OR = 0.967, 95% CI: 0.955-0.979, P < 0.001), and the best cutoff value for PNI to predict neonatal sepsis was 50.63, with a sensitivity of 66% and a specificity of 61% (AUC = 0.66, 95% CI: 0.63-0.70, P < 0.001)[32]. A retrospective study by Wu, H et al. demonstrated that PNI ≥ 29.3 was an independent predictor of mortality within 30 days in patients with sepsis (HR = 0.65; 95% CI: 0.56-0.76)[33]. These findings suggest that PNI is closely associated with poor prognosis in sepsis, which is also in general agreement with our findings.
Patients with sepsis exhibit heightened production of inflammatory mediators and catabolic hormones, which contribute to catabolism while hindering anabolism. This results in severe malnutrition, immunosuppression, and inflammatory responses. The precise correlation between PNI and the unfavorable prognosis in sepsis patients remains not completely understood. Individuals with low PNI levels often display reduced albumin levels, indicating malnutrition and impaired protein synthesis. Studies have demonstrated a strong connection between disorders in nutritional metabolism and the clinical prognosis of patients[34, 35]. In addition, a decrease in lymphocytes can also lead to low PNI. Lymphocytes have a huge impact on the host immune response, and continuous stimulation by pathogens induces a large number of lymphocytes to increase in value and activate, and in order to prevent the immune response from going out of control, the body restricts the immune response by inducing cellular demise, which leads to a decrease in the number of lymphocytes in the body[36].Thus, there is an association between PNI and the prognosis of patients with sepsis, and notably, our study found an L-shaped association between PNI and in-hospital mortality in patients with sepsis, with the risk of death increasing dramatically when PNI was below 33.99.
Meanwhile, our study has some limitations: (1) this is only a single-center, retrospective study, and the applicability of its results may be limited, and more prospective, multicenter studies are needed to validate it; (2) some patients missing the indicators needed for the study will not be included, and the study data may be biased to a certain extent; (3) PNI is calculated at the time of admission to the ICU, and continuous monitoring of PNI may provide a more important guideline in the diagnosis, treatment, and prognostic assessment of patients with sepsis; (4) the present study could not validate the presence of a cause-and-effect relationship between PNI and the risk of death of patients with sepsis, and further studies are needed in the future.