Cold-inducible RNA-binding protein might determine the severity and the presences of major/minor criteria for severe community-acquired pneumonia and best predicted mortality

The mortality of community-acquired pneumonia (CAP) remains unacceptably high, in spite of substantial advances in treatment and the emergence of well validated pneumonia severity scoring systems [1‐5]. Therefore, the assessment of severity is still crucial in the management of CAP. In 2007, the Infectious Disease Society of America and the American Thoracic Society (IDSA/ATS) issued guidelines, with the aim to guide intensive care unit (ICU) admission, which defined severe CAP—when one of two major criteria or three of nine minor criteria are fulfilled [2]. The minor criteria established by IDSA/ATS are of unequal weight in predicting mortality, and arterial oxygen pressure/fraction inspired oxygen (PaO₂/FiO₂) ≤ 250 mmHg, confusion, and uremia were the most predictive minor criteria strongly associated to mortality [6‐9]. Interestingly, we further found that the combination of the most predictive minor criteria predicted more severity and higher mortality in patients with CAP compared with others [10], and that the patients with non-severe CAP fulfilling the most predictive minor criteria demonstrated unexpectedly higher sequential organ failure assessment (SOFA) and pneumonia severity index (PSI) scores and mortality rates compared with the patients with severe CAP not meeting the most predictive minor criteria [11]. Salih et al. [12] reported that the minor criteria could be simplified by removing three infrequent variables, but could not improve the prediction of mortality and ICU admission. We further discovered that the minor criteria could be simplified to five variables and then be modified to orchestrate improvements in predicting mortality in CAP patients [13]. Hence, the IDSA/ATS major/minor criteria might at least be stratified to predict better (Table 1). On the basis of the limitations of IDSA/ATS minor criteria, including cumbersome application and less accurate mortality prediction, additional more accurate biomarkers are necessary to improve our ability to predict bad CAP outcomes and then aid clinical triage decisions.

Severity of CAP depends on microbial pathogenicity, load and virulence, and immune responses to infection. Both exogenous pathogen-associated molecular pattern molecules and endogenous damaged-associated molecular pattern molecules are recognized by immune cells through a group of pattern-recognition receptors, e.g. Toll-like receptors [14‐16]. After engaging with the receptors responsible for the perception of signature molecules that herald infection, signal transduction is activated, triggering inflammatory responses, e.g. the release of numerous inflammatory mediators including cytokines, chemokines, and vasoactive peptides [17‐19]. Sepsis is a systemic response to infection, and symptoms are produced by host defense systems rather than by the invading pathogens. Exaggerated immune responses are usually shown in patients with CAP, which may lead to severe sepsis and multiple organ failure. Cold-inducible RNA-binding protein (CIRP) is a damage-associated molecular pattern molecule that plays a pivotal role in triggering inflammatory response, and antisera to CIRP attenuate shock-induced inflammation, tissue injury, and lethality [20]. CIRP induces excessive neutrophil extracellular traps, which cause inflammation and tissue damage, in the lungs during sepsis [21]. Intravenous injection of recombinant murine CIRP in C57BL/6 mice causes lung injury, evidenced by vascular leakage, edema, increased leukocyte infiltration and cytokine production in the lung tissue. The CIRP-induced lung damage is accompanied with endothelial cell activation and pyroptosis [22]. Therefore, we speculated that the expression of CIRP triggered by invading microorganisms might determine disease severity and mortality in patients with sepsis. An elevated plasma concentration of CIRP was significantly associated with poor prognosis among patients with sepsis [23]. It is unclear whether the major/minor criteria might be strongly and positively associated with the immune responses, e.g. CIRP. Therefore, a prospective cohort study was conducted to determine the intriguing hypothesis.

The main findings of the current study comprise the following: Severe CAP patients meeting the major criteria had the highest concentrations of CIRP, PCT, IL-6 and CRP, SOFA and PSI scores, and mortality rates. The numbers of most predictive minor criteria present were strongly and positively associated with the concentrations of CIRP, PCT, IL-6 and CRP, SOFA and PSI scores, and mortality. The patients with non-severe CAP meeting the most predictive minor criteria demonstrated unexpectedly higher concentrations of CIRP, PCT, IL-6 and CRP, SOFA and PSI scores, and mortality rates, compared with the patients with severe CAP not fulfilling the criteria. CIRP was strongly linked to the major/minor criteria, SOFA and PSI scores, mortality, PCT, IL-6 and CRP, had a significant increased OR for mortality, and best predicted mortality, indicating that it might determine the severity of CAP and the presences of IDSA/ATS major/minor criteria and suggesting that it might be a novel and intriguing biomarker for pneumonia to monitor host response and predict mortality. A CIRP of ≥ 3.50 ng/mL might be more valuable cut-off value for severe CAP, with 61.4% sensitivity and 88.9% specificity.

Interestingly, the current study discovered that CIRP might determine the severity of CAP and the presences of IDSA/ATS major/minor criteria, had a significant increased OR for mortality, and best predicted mortality. The classic SOFA scoring system was well established and employed to assess organ dysfunction/failure [26]. The valuable PSI scoring system was created to evaluate pneumonia severity [4]. SOFA and PSI scoring systems are well-validated clinical tools and regarded as benchmarking. The IDSA/ATS major/minor criteria responsible for clinical triage were well validated [7‐9]. The rank correlation coefficients between CIRP and SOFA and PSI scores were very high in the current study (0.843 and 0.952, respectively). As a result, CIRP might determine CAP severity, in other words, the presences of IDSA/ATS major/minor criteria, and ultimately the rates of mortality, which might have implications for more accurate clinical triage decisions. Future prospective multicenter larger cohort studies are warranted to assess the generalisability of the current findings.

An elevated PCT level was a risk factor for death from CAP (risk ratio 4.38, 95% CI 2.98–6.43), particularly in patients with a low CURB-65 score. For critically ill patients, an elevated PCT level was associated with an increased risk of mortality (risk ratio 4.18, 95% CI 3.19–5.48) [27]. But later studies favored the idea that PCT had limited predictive value. PCT is not an independent predictor of 30-day mortality, albeit predicts pneumonia severity in patients with pneumonia acquired outside the hospital [28]. PCT demonstrated moderate predictive value for the prognosis of hospitalized CAP [29]. Elevated IL-6 indicates a higher risk of 30-day mortality [84% sensitivity, 87% specificity and 0.934 AUC (95% CI 0.864–1.000)]. Moreover, IL-6 levels have been shown to have a good correlation with various clinical severity scores (e.g. PSI) [30]. Admission CRP <  100 mg/L has reduced risk for 30-day mortality, need for mechanical ventilation and/or inotropic support, and complicated pneumonia. CRP is an independent marker of severity in CAP [31]. In this study, CIRP was strongly associated with PCT, IL-6 and CRP, the correlations of CIRP with mortality and SOFA and PSI scores were the closest among these biomarkers, and CIRP was performed best in mortality prediction among these indices. Therefore, CIRP might be a novel and intriguing biomarker for pneumonia to monitor host response and predict mortality. Much more research is needed to investigate this matter, especially data on the trajectory of CIRP level during the patients’ hospital journey in particular correlation between witnessed decline in the value and patient length of hospital stays.

We found that the optimal cut-off value of CIRP level for predicting mortality was ≥ 3.50 ng/mL, which at least corresponded with the average value of severe CAP patients meeting two of the most predictive minor criteria, whose mortality increased to 16.7%, and that the mortality of patients fulfilling such high level rose sharply to 40.3%. Hence, this cut-off value might be regarded as a threshold to distinguish the patients with severe CAP who might require intensive care from those with non-severe CAP. This finding requires external validation before recommendation for decision making in clinical practice.

The well-validated IDSA/ATS major/minor criteria was widely used because it is a helpful tool to help stratify sick CAP patients, but the major problem associated with the minor criteria might be a lack of consideration of weight in prediction in clinical practice. We previously reported that the numbers of minor criteria present were not positively associated with SOFA and PSI scores and mortality [11], and that scored minor criteria orchestrated improvements in predicting mortality and severity in patients with CAP [32]. These might be envisaged to interpret the reason why the minor criteria were not strongly linked to SOFA and PSI scores and mortality, and predicted mortality worst in the current study.

CIRP levels were strongly correlated with the IDSA/ATS major/minor criteria. CIRP might determine the severity of CAP and the presences of major/minor criteria and best predicted mortality, and a CIRP of ≥ 3.50 ng/mL might be more valuable cut-off value for severe CAP, suggesting that CIRP might be a novel and intriguing biomarker for pneumonia to monitor host response and predict mortality, which might have implications for more accurate clinical triage decisions.