Prognostic models for estimating severity of disease and predicting 30-day mortality of Hypervirulent Klebsiella pneumoniae infections: a bicentric retrospective study

Hypervirulent Klebsiella pneumoniae (hvKP) has become a global pathogen in recent years [1]. hvKP, an invasive type of Klebsiella pneumoniae (KP), is characterized by severely invasive community-acquired infections in young and immunocompetent individuals with rare sites of infections, rapid progression, severe disease and poor prognosis [1‐5].

Currently, the hvKP strain is differentiated from classic Klebsiella pneumoniae (cKP) based on some phenotypic, genotypic properties and determining factors [6]. Li G et al. reported that Galleria mellonella killing assay in conjugation with the string test could be used to accurately assess KP virulence and differentiate hvKP from cKP strains [7]. Russo TA et al. noted that peg-344, iroB, iucA, prmpA, prmpA2, and siderophore production greater than 30 μg/ml could accurately identify hvKP strains [1, 8, 9]. However, there is no universal standard for identifying all hvKP strains [10]. Furthermore, detections of genotype and the determining factors are not widely available, especially in developing countries, making it difficult to recognize hvKP infections early.

Clinical manifestations of hvKP infections, lacking specificity, vary upon the organ involved. Clinically, some patients with hvKP infections soon develop to to septic shock, acute respiratory distress syndrome (ARDS), multiorgan failure and death at final. Early identification of hvKP infections and prediction of disease severity and outcomes are crucial to improve the survival of hvKP-infected patients. Previous studies showed that risk factors for mortality included gastrointestinal fistula, increased Acute Physiology and Chronic Health Evaluation (APACHE) II score and Pitt bacteraemia score, metastatic infection, septic shock, acute respiratory failure and gas formation on imaging [10‐12]. To date, there is few report on risk factors for disease severity. Most of the existing studies of hvKP mainly focus on virulence factors or drug resistance factors at the genetic level, and little attention has been paid to clinical aspects, especially the disease assessment and prognosis models. Therefore, we concentrated on clinical aspects, retrospectively analyzed the demographic and clinical data of hvKP-infected patients to determine the risk factors and tried to construct the prognostic models for disease severity and prognosis.

hvKP infections have emerged as a major clinical and public health threat over the past decade [1, 10, 18, 19]. As clinical manifestations of hvKP infections are nonspecific, and differentiation of hvKP strains is mainly based on phenotypic and genotypic features without universal standards, it is difficult to identify hvKP infections early. Currently, knowledge of risk factors for disease severity and mortality remains limited. Few studies have investigated the risk factors for mortality in patients with hvKP infections, while no study has explored the risk factors or a prognostic model for disease severity. Since genetic testing is not easy to perform clinically, we summarize the routine clinical parameters to investigate risk factors associated with disease severity and 30-day mortality and construct the prognostic models. This may be the first study to report the risk factors for the severity of hvKP infection, and prognostic models of disease severity and 30-day mortality clinically.

Some hvKP-infected patients develop septic shock, ARDS. In our study, the median diagnosis times of septic shock and ARDS were 11.63 (4.00, 26.00) and 26.00 (18.17, 41.50) hours after admission, respectively. Furthermore, patients with septic shock and ARDS had longer CRRT duration, vasopressor duration, mechanical ventilator duration and length of ICU stay. The results suggest that septic shock and ARDS are reasonable predictors for assesssing disease severity in patients with hvKP infections.

Multivariate logistic analysis showed that increased APACHE II score, lower ALB, diabetes, high PCT were independent risk factors for septic shock. Studies on the correlation between APACHE II score and severity of hvKP infections have not been found. A sepsis patient’s serum ALB can decrease due to various factors including hypermetabolic state, gastrointestinal dysfunction, capillary leakage [20]. There is a causal relationship between hypoalbuminemia and an increased risk of primary and secondary infections, hypoalbuminemia has an effect on the pharmacokinetics and pharmacodynamics of anti-infective drugs, which in turn affects the clinical outcome of infections [21]. Hematocrit (HCT)-ALB difference can be a potential predictor for the prognosis of elderly sepsis patients [20]. In addition, lower ALB is a risk factor for elderly people with bacterial infections [22], and early infusion of albumin seems to reduce the mortality of patients with sepsis [23, 24]. ALB replacement in addition to crystalloids improves the haemodynamics of patients with severe sepsis during the first 7 days [25]. Ongoing research on the ALB administration supports the potential for ALB to improve sepsis survival [23]. Therefore, it is suggested that correcting hypoalbuminemia possibly reduces the risk of hvKP infections progressing to septic shock, and improves the clinical outcome of hvKP infections. Diabetes mellitus is considered a significant risk factor for acquiring hvKP infections [26‐29], which primarily affects male individuals aged 55–60 years [30]. Diabetes is an independent risk factor for KP pyogenic liver abscess [31], as poor glycaemic control might impair neutrophil phagocytosis and promote pathogen growth in tissues, while metabolic disturbances might negatively affect the liver [32, 33]. Moreover, diabetes, which is more likely to progress hvKP infections, especially hvKP-bloodstream infections (BSIs) [26, 28], is an independent risk factor for hvKP-BSIs [12]. No studies have been found on the association of PCT with the severity of hvKP infections. However, the PCT level has been shown to be significantly higher in hvKP group compared with cKP group [34]. And PCT has been a prognostic biomarker in patients with severe sepsis and septic shock [35]. In addition, serum procalcitonin ≥ 5 ng/mL was found to be associated with 30-day mortality of carbapenem-resistant KP infections [36]. Our research shows that PCT [19.07(2.95,42.01) ng/mL] is an independent risk factor for septic shock, indicating that PCT is one of the factors predicting the risk of septic shock in patients with hvKP infections.

Multivariate analysis showed that increased APACHE II score, CAP and extrahepatic lesion involved were independent risk factors for ARDS. The APACHE II score is also an independent factor predicting septic shock, so the APACHE II score is very important for the evaluation of hvKP infections. Furthermore, hvKP infections are usually community-acquired [3, 37, 38], CAP has been showed to be associated with high mortality in patients with hvKP infections [39]. Patients with KP pyogenic liver abscesses with sepsis have higher rates of septic shock and acute respiratory distress syndrome [40]. Severe hvKP infections with pyogenic liver abscesses in healthy adults have been reported previously [10, 31, 37, 41]. Moreover, liver abscess is a significant risk factor for hvKP infecitons [42], and abscess has been identified as an independent predictor for associated with hvKP-BSIs [43]. Nevertheless, our study revealed that hvKP infections with extrahepatic lesion involved were more serious (OR = 14.718), which seems to be inconsistent with previous results. Usually, due to the good permeability of the hepatic sinusoid of the liver, it can promote material exchange between liver cells and blood flow, which is more likely to cause bacteraemia and accelerate the spread of lesions. When the foci of hvKP infections is limited to the liver, which may be related to the immune function of the liver. As a line of defence for immunity, the liver causes a localized lesion and reduces the transfer and dissemination of bacteria to a certain extent, thus reducing the occurrence of bacteraemia and the progression of ARDS.

We constructed prognostic models to assess disease severity, validated the effects of these models, and performed correlation analyses between model scores and clinical outcomes including CRRT duration, vasopressors duration, mechanical ventilator duration and length of ICU stay. Since there were not enough additional cases, only internal validation was performed in this study, and the matching degree of internal validation was good. In the correlation analysis between scores of hvKP infections severity (septic shock, ARDS) and CRRT duration, vasopressors duration, mechanical ventilator duration, and length of ICU stay, the correlation coefficient R (0.43–074) indicated that the correlation was moderately positive. Therefore, septic shock and ARDS are suitable as observation indicators for evaluating the condition of hvKP infections. Due to the small sample size of cases included in this study, further clinical research is needed for verification.

The 30-day all-cause mortality of hvKP-infected patients in our study was 28.4%, which is close to previously reported data (4.5%-37.1%) [12, 44‐47]. In our study, younger age, increased APACHE II score, and decreased ALB level were independent risk factors for 30-day mortality. It has been noted that the detection rate of hvKP among the KP isolates increases in the elderly individuals, indicating that ageing can be an elevated risk for hvKP infections [26, 28, 48, 49], but age is not statistically significant for hypermucoviscous KP infections [27]. The median age of nonsurvivors in our study was 54.15 ± 17.82 years, and younger age was a risk factor for increased mortality, which may be contributed by the violent inflammatory reaction in young people, most of whom showed multiple organ dysfunction, septic shock and ARDS. This point also reminds clinicians that in the face of hvKP infections in young and middle-aged adults, modulating the host immune response may be an effective regimen to reduce mortality. In our study, the APACHE II score (HR = 1.157) in the nonsurvivors group was 34.30 ± 9.95. Previous studies have shown that a higher APACHE II score is correlated with a higher 30-day all-cause mortality rate of hvKP infections [12, 50], which is consistent with our findings. A low ALB level predicts worse outcomes for patients with BSIs caused by Enterobacteriaceae [51], and for mortality in liver transplant recipients with gram-negative bacilli (GNB) bacteraemia [52].These results are consistent with our findings.

Although most hvKP strains are rarely resistant to common antimicrobials, antibiotic-resistant hvKP isolates have been increasing over the past few years, and no literature has yet reported which antimicrobial is the most effective [4, 53‐55]. In our study, the initial antimicrobial regimens included piperacillin/third-generation of cephalosporins (10.5%), piperacillin/third-generation of cephalosporins combined with beta-lactamase inhibitor (43.0%), carbapenems (21.1%), quinolones/second-generation of cephalosporins (11.4%), piperacillin/third-generation cephalosporins combined with quinolones/aminodycosides (3.5%), piperacillin/third-generation cephalosporins combined with beta-lactamase inhibitor and quinolones/aminodycosides (7.9%), and carbapenems combined with quinolones (2.6%). Multiple comparisons have revealed that carbapenems combined with quinolones had higher mortality rates than piperacillin/third-generation cephalosporins combined with beta-lactamase inhibitor and quinolones/aminodycosides (100.0% vs. 0.0%, P = 0.005) and piperacillin/third-generation cephalosporins (100.0% vs. 8.3%, P = 0.009). Univariate analysis suggested that, compared with the prognosis of the combination of carbapenems and quinolones (HR = 1.000), piperacillin/third-generation cephalosporins (HR = 0.026; 95%CI, 0.003–0.260; P = 0.002), piperacillin/third-generation cephalosporins combined with beta-lactamase inhibitor (HR = 0.115; 95%CI, 0.031–0.422; P = 0.001), carbapenems (HR = 0.137; 95%CI, 0.035–0.538; P = 0.004) and quinolones/second-generation cephalosporins (HR = 0.049; 95%CI, 0.008–0. 308; P = 0.001) conferred better prognosis. Thus, carbapenems seem not to be the first choice for hvKP infections unless they are chosen based on drug sensitivity tests. However, due to the insufficient number of cases, further verifications in prospective studies are needed.

There were several limitations in our research. Firstly, it was a retrospective study and the sample was quite small. In addition, it was a regional study that all the cases came from Dongguan, which was a labor-intensive city with a large inflow of young people. Finally, external validations of the prognostic models were not feasible due to a lack of additional data. Further investigations are required to confirm these results.

In this retrospective study, increased APACHE II score, decreased ALB, diabetes, higher PCT, CAP and extrahepatic lesion involved were identified as independent risk factors for septic shock and ARDS in patients with hvKP infections. The prognostic models constructed for disease severity with these conventional parameters, were significantly correlated with clinical outcomes, making them potentially practical for clinicians. Moreover, younger age, increased APACHE II score, and lower ALB were independent risk factors for 30-day all-cause mortality. The prediction model for 30-day mortality had a good validation effect. In summary, we constructed the prognostic models for disease severity and 30-day mortality in patients with hvKP infections, and the models were helpful for making more practical and effective therapeutic decisions.