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Prognostic models for estimating severity of disease and predicting 30-day mortality of Hypervirulent Klebsiella pneumoniae infections: a bicentric retrospective study
BMC Infectious Diseases volume 23, Article number: 554 (2023)
Abstract
Background
Hypervirulent Klebsiella pneumoniae (hvKP) is emerging globally and can cause various, severe infections in healthy individuals. However, the clinical manifestations of hvKP infections are nonspecific, and there is no gold standard for differentiating hvKP strains. Our objective was to develop prognostic models for estimating severity of disease and predicting 30-day all-cause mortality in patients with hvKP infections.
Methods
We enrolled 116 patients diagnosed with hvKP infections and obtained their demographic and clinical data. Taking septic shock and acute respiratory distress syndrome (ARDS) as the primary outcomes for disease severity and 30-day all-cause mortality as the primary outcome for clinical prognosis, we explored the influencing factors and constructed prognostic models.
Results
The results showed that increased Acute Physiologic and Chronic Health Evaluation (APACHE) II score [odds ratio (OR) = 1.146; 95% confidence interval (CI), 1.059–1.240], decreased albumin (ALB) level (OR = 0.867; 95% CI, 0.758–0.990), diabetes (OR = 9.591; 95% CI, 1.766–52.075) and high procalcitonin (PCT) level (OR = 1.051; 95%CI, 1.005–1.099) were independent risk factors for septic shock. And increased APACHE II score (OR = 1.254; 95% CI, 1.110–1.147), community-acquired pneumonia (CAP) (OR = 11.880; 95% CI, 2.524–55.923), and extrahepatic lesion involved (OR = 14.718; 95% CI, 1.005–215.502) were independent risk factors for ARDS. Prognostic models were constructed for disease severity with these independent risk factors, and the models were significantly correlated with continuous renal replacement therapy (CRRT) duration, vasopressor duration, mechanical ventilator duration and length of ICU stay. The 30-day all-cause mortality rate in our study was 28.4%. Younger age [hazard ratio (HR) = 0.947; 95% CI, 0.923–0.973)], increased APACHE II score (HR = 1.157; 95% CI, 1.110–1.207), and decreased ALB level (HR = 0.924; 95% CI, 0.869–0.983) were the independent risk factors for 30-day all-cause mortality. A prediction model for 30-day mortality was constructed, which had a good validation effect.
Conclusions
We developed validated models containing routine clinical parameters for estimating disease severity and predicting 30-day mortality in patients with hvKP infections and confirmed their calibration. The models may assist clinicians in assessing disease severity and estimating the 30-day mortality early.
Introduction
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 [1,2,3,4,5].
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 [10,11,12]. 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.
Materials and methods
Study setting and design
Patients with hvKP infections firstly diagnosed at Binhaiwan Central Hospital of Dongguan and Dongguan Tungwah Hospital from September 2017 to September 2022, meeting the inclusion and exclusion criteria, were enrolled in this retrospective study. Demographic and clinical data were collected by two individuals. The protocol for this study was approved by the Medical Ethics Committee of Binhaiwan Central Hospital of Dongguan (No. 2021014).
Inclusion and exclusion criteria
The inclusion criteria were as follows:1. KP-infected patients with string test positive. 2. KP strains with one or more of genotype (rmpA, rmpA2, iucA, iroB, magA and peg344) positive [8, 13, 14]. 3. patients with complete clinical data.
The exclusion criteria were as follows: 1. Patients younger than 18 years old. 2. Patients giving up an active rescue. 3. Immunocompromised patients with history of malignancy (under treatment or in remission for less than five years), immunosuppressive disorders (congenital/acquired immunocompromise), use of immunosuppressive regimens (corticosteroid therapy 1 mg/kg/day prednisone equivalent or corticosteroid therapy for longer than one month, use of another immunosuppressant drug in a high dosage or for longer than one month) [15,16,17].
Detection of virulence-associated features and genes
Hypermucoviscosity was identified by the positive string test. A positive string test was defined as the formation of a viscous string > 5 mm in length when bacterial colonies on an agar plate were stretched with an inoculation loop [3]. All KP isolates were stored at − 80 °C until they were sent to relevant institutions (Guangzhou Huayin Health Medical Group Co., Ltd.) for detection of virulence-associated features through targeted next-generation sequencing. The genotypic analysis was investigated by polymerase chain reaction with previously described primers [13]. High-throughput sequencing was performed using the Illumina MiSeq Reagent Nano Kit. The reads that were correctly aligned at both ends were compared with the reference gene sequence of each virulence gene in the virulence gene data, and finally, the number of reads for each virulence gene in each sample was obtained.
Variables collection and definition
Clinical features including age, gender, history of smoking or alcohol consumption, community acquired pneumonia (CAP), comorbidities [diabetes mellitus, hepatopathy, chronic kidney disease (CKD), cardiovascular disease], septic shock, ARDS, and APACHE II score were collected. Laboratory data within 24 h after admission were as follows: white blood cell count (WBC), neutrophil count (NEUT#), lymphocyte count (LYMPH#), monocyte count (MONO#), hemoglobin (HGB), platelet (PLT), C-reactive protein (CRP), procalcitonin (PCT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), direct bilirubin (DBIL), albumin (ALB), glucose (GLU), creatinine (CREA), coagulation plasma prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), partial pressure of oxygen (PO2), partial pressure of carbon dioxide (PCO2), fraction of inspired oxygen (FIO2), oxygenation index (OI), positive end expiratory pressure (PEEP) and lactate (LAC). Data on lesions and antimicrobial regimens were as follows: infection lesion, number of lesions, number of pathogens, hepatic abscess, pulmonary abscess, bacteremia, initial antimicrobial regimens [piperacillin/third generation of cephalosporins (ceftazidime, ceftriaxone, cefixime), piperacillin/third generation of cephalosporins combined with beta-lactamase inhibitor (cefoperazone-sulbactam, piperacillin-tazobactam, cefotaxime-sulbactam), carbapenemes (meropenem, imipenem, biapenem), quinolones (levofloxacin, moxifloxacin), aminodycosides (amikacin), second generation of cephalosporins (cefamandole, cefuroxime)], and number of antimicrobials. Clinical outcomes: continuous renal replacement therapy (CRRT) duration, vasopressors duration, mechanical ventilator duration, length of intensive care unit (ICU) stay, length of hospital stay and 30-day survival status. Indices of CRRT, vasopressors, mechanical ventilator and ICU were defined as CRRT duration/length of hospital stay, vasopressors duration/length of hospital stay, mechanical ventilator duration/length of hospital stay, and length of ICU stay/length of hospital stay, respectively.
The primary outcomes for the severity of disease were septic shock and ARDS, while the primary outcome for the clinical prognosis was 30-day all-cause mortality.
Statistical analysis
SPSS software (version 13.0) was used for data analysis. Normally and nonnormally distributed continuous variables were summarized as the mean ± standard deviation (SD) and the median with interquartile range (IQR), respectively. Continuous variables were compared using Student’s t test or the Mann–Whitney U test, and categorical variables were analyzed by using the χ2 test or Fisher’s exact test. P < 0.05 was considered statistically significant.
Univariate and multivariate logistic and Cox regression analyses were used to evaluate the risk factors. Variables with P < 0.05 in the univariate analysis were analyzed in the multivariate model using the likelihood-ratio test. R software (version 4.2.1, CRAN) was used for the nomogram, validation calibration curve, forest plot, scatterplot, receiver operating characteristic (ROC) curve and Kaplan–Meier (K-M) curve.
Results
Clinical features of the patients
A total of 116 patients were enrolled in our study (Fig. 1), their average age was 55.94 ± 15.93 years and 83 (71.6%) patients were male (Table 1). No significant differences were observed in age, gender, history of smoking/alcohol consumption, CAP, or comorbidities (diabetes mellitus, hepatopathy, CKD, cardiovascular disease) between the two hospitals.
Risk factors associated with disease severity
Risk factors associated with septic shock
47/116 (40.5%) patients developed septic shock. The median diagnosis time was 11.63 (4.00, 26.00) hours after admission. There were no significant differences in smoking, alcohol consumption, hepatopathy, CKD or cardiovascular disease between the non-septic shock and septic shock cohorts (P > 0.05). Compared with patients with non-septic shock, the septic shock patients had higher levels of APACHE II score, CRP, PCT, TBIL, DBIL, GLU, CREA, PT and APTT, but lower levels of LYMPH#, MONO#, PLT and ALB. Additionally, there were significantly higher proportions of septic shock patients with CAP, diabetes, bacteremia, extrapulmonary lesion involved, multiple lesions than non-septic shock patients. Regarding clinical outcomes, the septic shock group had longer CRRT duration, vasopressors duration, mechanical ventilator duration and length of ICU stay. (Table 1).
Univariate analysis showed that APACHE II score, PLT, CRP, PCT, ALB, GLU, PT, APTT, CAP, diabetes, bacteremia, extrapulmonary lesion involved and multiple lesions were risk factors for septic shock. Multivariate logistic analysis showed that increased APACHE II score [odds ratio (OR) = 1.146; 95% confidence interval (CI), 1.059–1.240], decreased ALB level (OR = 0.867; 95%CI, 0.758–0.990), diabetes (OR = 9.591; 95%CI, 1.766–52.075) and high PCT level (OR = 1.051; 95%CI, 1.005–1.099) were independent risk factors for septic shock (Fig. 2).
To assess the probability of septic shock, a nomogram with the independent risk factors was constructed, and the calibration curves of the nomogram showed high consistencies between the predicted and actual septic shock probability (Fig. 3A, B). To further investigate the validation of the nomogram, we calculated the septic shock predicted score and drew a correlation analysis scatter plot with CRRT duration, vasopressors duration, mechanical ventilator duration and length of ICU stay respectively. Positive correlations between predicted scores and indices of CRRT, vasopressor, mechanical ventilator and ICU were observed (Fig. 3C-F).
Risk factors associated with ARDS
Seventy-nine (68.1%) patients developed ARDS. The median diagnosis time was 26.00 (18.17, 41.50) hours after admission. No significant difference was found in terms of smoking, alcohol consumption, diabetes, hepatopathy or CKD between the non-ARDS and ARDS groups (P > 0.05). Compared with non-ARDS patients, ARDS patients had higher levels of APACHE II score, GLU, PT and APTT, but lower levels of MONO#, ALB. The ARDS patients had significantly higher proportions of CAP, cardiovascular disease, abscesses, hepatic abscesses and extrahepatic lesion involved and multiple pathogens. For clinical outcomes, the ARDS patients had longer CRRT duration, vasopressors duration, mechanical ventilator duration and length of ICU stay. (Table 1).
Univariate analysis showed that APACHE II score, ALB, GLU, PT, APTT, CAP, cardiovascular disease, abscess, hepatic abscess, extrahepatic lesion involved and multiple pathogens were significantly associated with ARDS. Multivariate logistic analysis showed that increased APACHE II score (OR = 1.254; 95% CI, 1.110–1.147), community-acquired pneumonia (CAP) (OR = 11.880; 95% CI, 2.524–55.923), and extrahepatic lesion involved (OR = 14.718; 95% CI, 1.005–215.502) were the independent risk factors for ARDS (Fig. 4).
To assess the probability of ARDS, a nomogram with the independent risk factors was constructed, and the calibration curves of the nomogram showed high consistencies between the predicted and actual ARDS probability (Fig. 5A, B). To further validate the nomogram, we calculated the ARDS predicted score and drew a correlation analysis scatter plot with CRRT duration, vasopressors duration, mechanical ventilator duration and length of ICU stay. Positive correlations between predicted scores and indices of CRRT, vasopressors, mechanical ventilator and ICU were observed (Fig. 5C-F).
Risk factors associated with 30-day mortality
The 30-day all-cause mortality rate in patients with hvKP infections was 28.4% (33/116). There were no significant differences in the percentages of diabetes, hepatopathy, CKD and cardiovascular disease between the survivors and non-survivors (P > 0.05). Compared with survivors, levels of APACHE II score, CREA, PT and APTT were higher in non-survivors, while the level of ALB was lower. Furthermore, our results revealed that the non-survivors group had significantly higher proportions of smoking, alcohol consumption, CAP, septic shock and ARDS. The non-survivors had longer CRRT duration, vasopressors duration and mechanical ventilator duration, whereas the length of hospital stay was shorter for non-survivors. (Table 2).
As shown in Fig. 6, APACHE II score, ALB, smoking, alcohol consumption, CAP, septic shock, ARDS, abscess and initial antimicrobial regimens were significantly associated with 30-day mortality. According to multivariate analysis results, younger age [hazard ratio (HR) = 0.947; 95% CI, 0.923–0.973)], increased APACHE II score (HR = 1.157; 95% CI, 1.110–1.207), and lower ALB (HR = 0.924; 95% CI, 0.869–0.983) were independent risk factors for 30-day mortality.
We constructed a nomogram of 7-day and 30-day mortality and the calibration curves showed high consistencies between the predicted and actual mortality (Fig. 7A-C). Furthermore, to compare the predictive effects of the prognostic model of 30-day mortality and the APACHE II score, we drew ROC curves of the survival predicted score and APACHE II score. The results showed that the cut-off value of the survival predicted score was 88.765 [area under the curve (AUC) 0.951, specificity 0.792, sensitivity 0.967], and the cut-off value of the APACHE II score was 19.5 (AUC 0.944, sensitivity 0.778, specificity 1.000) (Fig. 7D). We divided the survival predicted score into low-risk group (survival predicted score < 88.765) and high-risk group (survival predicted score ≥ 88.765), and then drew a K-M curve, which showed that the survival rate of the high-risk group was significantly lower than that of the low-risk group (34.1% vs. 98.3%, p < 0.0001) (Fig. 7E).
Discussions
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 [26,27,28,29], 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, 44,45,46,47]. 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, 53,54,55]. 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.
We constructed the prognostic models of 30-day mortality with the variables including age, APACHE II score and ALB level. According to ROC curves of the survival predicted score and APACHE II score, we took survival predicted score = 88.765 as the cut-point, and drew the K‒M curves. K‒M survival analysis showed that the 30-day mortality of the high-risk group (score ≥ 88.765) was significantly higher than that of the low-risk group (score < 88.765) (34.1% vs. 98.3%, p < 0.0001). The model not only had a good internal validation effect, but also was consistent with previous results.
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.
Conclusions
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.
Availability of data and materials
Please contact Yi Chen if someone wants to request the data from this study. Authors have not specified any datasets in this data configuration file. The data that have been used is confidential. It is collected by the authors in the hospital medical record system, and have not been published anywhere. Due to the sensitive nature of the questions asked in this study, survey respondents were assured raw data would remain confidential and would not be shared.
Abbreviations
- hvKP :
-
Hypervirulent Klebsiella pneumoniae
- cKP :
-
Classic Klebsiella pneumoniae
- ARDS:
-
Acute respiratory distress syndrome
- APACHE II:
-
Acute Physiology and Chronic Health Evaluation II
- CAP:
-
Community-acquired pneumonia
- CKD:
-
Chronic kidney disease
- WBC:
-
White blood cell count
- NEUT#:
-
Neutrophil count
- LYMPH#:
-
Lymphocyte count
- MONO#:
-
Monocyte count
- HGB:
-
Hemoglobin
- PLT:
-
Platelet
- CRP:
-
C-reactive protein
- PCT:
-
Procalcitonin
- ALT:
-
Alanine aminotransferase
- AST:
-
Aspartate aminotransferase
- TBIL:
-
Total bilirubin
- DBIL:
-
Direct bilirubin
- ALB:
-
Albumin
- GLU:
-
Glucose
- CREA:
-
Creatinine
- PT:
-
Plasma prothrombin time
- APTT:
-
Activated partial thromboplastin time
- FIB:
-
Fibrinogen
- PO2:
-
Partial pressure of oxygen
- PCO2:
-
Partial pressure of carbon dioxide
- FIO2:
-
Fraction of inspired oxygen
- OI:
-
Oxygenation index
- PEEP:
-
Positive end expiratory pressure
- LAC:
-
Lactate
- CRRT:
-
Continuous renal replacement therapy
- ICU:
-
Intensive care unit
- SD:
-
Standard deviation
- IQR:
-
Interquartile range
- ROC:
-
Receiver operating characteristic
- K-M curve:
-
Kaplan–Meier curve
- AUC:
-
Area under (the) curve
- OR:
-
Odds ratio
- CI:
-
Confidence interval
- HR:
-
Hazard ratio
- BSIs:
-
Bloodstream infections
- GNB:
-
Gram-negative bacilli
References
Russo TA, Marr CM. Hypervirulent Klebsiella pneumoniae. Clin Microbiol Rev. 2019;32(3):e00001-00019.
Maheswaranathan M, Ngo T, Rockey DC. Identification and management of the Hypervirulent invasive Klebsiella pneumoniae syndrome: a unique and distinct clinical entity. J Invest Med High Impact Case Rep. 2018;6:2324709618806552.
Shon AS, Bajwa RP, Russo TA. Hypervirulent (hypermucoviscous) Klebsiella pneumoniae: a new and dangerous breed. Virulence. 2013;4(2):107–18.
Lee CR, Lee JH, Park KS, Jeon JH, Kim YB, Cha CJ, et al. Antimicrobial resistance of Hypervirulent Klebsiella pneumoniae: epidemiology, hypervirulence-associated determinants, and resistance mechanisms. Front Cell Infect Microbiol. 2017;7:483.
Guo MY, Liu Y, Fei B, Ren YY, Liu XW, Zhao ZJ, et al. Research progress on virulence factors of Hypervirulent Klebsiella pneumoniae. Zhonghua Yu Fang Yi Xue Za Zhi. 2021;55(11):1357–63.
Karampatakis T, Tsergouli K, Behzadi P. Carbapenem-resistant Klebsiella pneumoniae: virulence factors, molecular epidemiology and latest updates in treatment options. Antibiotics (Basel, Switzerland). 2023;12(2):234.
Li G, Shi J, Zhao Y, Xie Y, Tang Y, Jiang X, et al. Identification of Hypervirulent Klebsiella pneumoniae isolates using the string test in combination with Galleria mellonella infectivity. Eur J Clin Microbiol Infect Dis. 2020;39(9):1673–9.
Russo TA, Olson R, Fang CT, Stoesser N, Miller M, MacDonald U, et al. Identification of biomarkers for differentiation of Hypervirulent Klebsiella pneumoniae from classical K. pneumoniae. J Clin Microbiol. 2018;56(9):e00776-00718.
Yang P, Liu C, Wu Z, Zheng J, Yi J, Wu N, et al. Clinical outcomes, microbiological characteristics and risk factors for difficult-to-treat resistance to Klebsiella pneumoniae Infection. Infect Drug Resist. 2022;15:5959–69.
Choby JE, Howard-Anderson J, Weiss DS. Hypervirulent Klebsiella pneumoniae - clinical and molecular perspectives. J Intern Med. 2020;287(3):283–300.
Lee SS, Chen YS, Tsai HC, Wann SR, Lin HH, Huang CK, et al. Predictors of septic metastatic infection and mortality among patients with Klebsiella pneumoniae liver abscess. Clin Infect Dis. 2008;47(5):642–50.
Li J, Ren J, Wang W, Wang G, Gu G, Wu X, et al. Risk factors and clinical outcomes of hypervirulent Klebsiella pneumoniae induced bloodstream infections. Eur J Clin Microbiol Infect Dis. 2018;37(4):679–89.
Saki M, Amin M, Savari M, Hashemzadeh M, Seyedian SS. Beta-lactamase determinants and molecular typing of carbapenem-resistant classic and hypervirulent Klebsiella pneumoniae clinical isolates from southwest of Iran. Front Microbiol. 2022;13:1029686.
Liu C, Du P, Zhao J, Li B, Wang C, Sun L, et al. Phenotypic and genomic characterization of virulence heterogeneity in multidrug-resistant ST11 Klebsiella pneumoniae during inter-host transmission and evolution. Infect Drug Resist. 2020;13:1713–21.
Azoulay E, Russell L, Van de Louw A, Metaxa V, Bauer P, Povoa P, et al. Diagnosis of severe respiratory infections in immunocompromised patients. Intens Care Med. 2020;46(2):298–314.
Di Pasquale MF, Sotgiu G, Gramegna A, Radovanovic D, Terraneo S, Reyes LF, et al. Prevalence and etiology of community-acquired pneumonia in immunocompromised patients. Clin Infect Dis. 2019;68(9):1482–93.
Lemiale V, Resche-Rigon M, Azoulay E. Early non-invasive ventilation for acute respiratory failure in immunocompromised patients (IVNIctus): study protocol for a multicenter randomized controlled trial. Trials. 2014;15:372.
Harada S, Aoki K, Yamamoto S, Ishii Y, Sekiya N, Kurai H, et al. Clinical and molecular characteristics of Klebsiella pneumoniae isolates causing bloodstream infections in Japan: occurrence of Hypervirulent infections in health care. J Clin Microbiol. 2019;57(11):e01206-01219.
Russo TA, MacDonald U. The galleria mellonella infection model does not accurately differentiate between Hypervirulent and classical Klebsiella pneumoniae. mSphere. 2020;5(1):00850–00819.
Wang Z, Zhang L, Li S, Xu F, Han D, Wang H, et al. The relationship between hematocrit and serum albumin levels difference and mortality in elderly sepsis patients in intensive care units-a retrospective study based on two large database. BMC Infect Dis. 2022;22(1):629.
Wiedermann CJ. Hypoalbuminemia as surrogate and culprit of infections. Int J Mol Sci. 2021;22(9):4496.
Higashikawa T, Okuro M, Ishigami K, Mae K, Sangen R, Mizuno T, et al. Procalcitonin and albumin as prognostic biomarkers in elderly patients with a risk of bacterial infection. J Int Med Res. 2018;46(7):2606–14.
Semler MW, Rice TW. Sepsis resuscitation: fluid choice and dose. Clin Chest Med. 2016;37(2):241–50.
Rochwerg B, Alhazzani W, Sindi A, Heels-Ansdell D, Thabane L, Fox-Robichaud A, et al. Fluid resuscitation in sepsis: a systematic review and network meta-analysis. Ann Intern Med. 2014;161(5):347–55.
Caironi P, Tognoni G, Masson S, Fumagalli R, Pesenti A, Romero M, et al. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med. 2014;370(15):1412–21.
Li W, Sun G, Yu Y, Li N, Chen M, Jin R, et al. Increasing occurrence of antimicrobial-resistant hypervirulent (hypermucoviscous) Klebsiella pneumoniae isolates in China. Clin Infect Dis. 2014;58(2):225–32.
Guo Y, Wang S, Zhan L, Jin Y, Duan J, Hao Z, et al. Microbiological and clinical characteristics of hypermucoviscous Klebsiella pneumoniae isolates associated with invasive infections in China. Front Cell Infect Microbiol. 2017;7:24.
Liu C, Guo J. Hypervirulent Klebsiella pneumoniae (hypermucoviscous and aerobactin positive) infection over 6 years in the elderly in China: antimicrobial resistance patterns, molecular epidemiology and risk factor. Ann Clin Microbiol Antimicrob. 2019;18(1):4.
Li L, Yuan Z, Chen D, Xie X, Zhang B. Clinical and microbiological characteristics of invasive and Hypervirulent Klebsiella pneumoniae Infections in a teaching hospital in China. Infect Drug Resist. 2020;13:4395–403.
Shao C, Xin L, Mi P, Jiang M, Wu H. Phenotypic and molecular characterization of K54-ST29 Hypervirulent Klebsiella pneumoniae causing multi-system infection in a patient with diabetes. Front Microbiol. 2022;13: 872140.
Lin YC, Cao X, Mo YC, Xie CP, Zhang YF, Li N, et al. Successful treatment of hypervirulent Klebsiella pneumoniae bacteremia with combination carbapenem and rifampicin. IDCases. 2021;26: e01276.
Foo NP, Chen KT, Lin HJ, Guo HR. Characteristics of pyogenic liver abscess patients with and without diabetes mellitus. Am J Gastroenterol. 2010;105(2):328–35.
Lin JC, Siu LK, Fung CP, Tsou HH, Wang JJ, Chen CT, et al. Impaired phagocytosis of capsular serotypes K1 or K2 Klebsiella pneumoniae in type 2 diabetes mellitus patients with poor glycemic control. J Clin Endocrinol Metab. 2006;91(8):3084–7.
Yang F, Wang L, Zhao Q, Wu J, Jiang L, Sheng L, et al. Epidemiological features of Klebsiella pneumoniae infection in the hepatobiliary system of patients in Yantai, China, based on clinical and genetic analyses. Infect Drug Resist. 2022;15:3427–36.
Huang MY, Chen CY, Chien JH, Wu KH, Chang YJ, Wu KH, et al. Serum procalcitonin and procalcitonin clearance as a prognostic biomarker in patients with severe sepsis and septic shock. Biomed Res Int. 2016;2016:1758501.
Chen J, Yang Y, Yao H, Bu S, Li L, Wang F, et al. Prediction of prognosis in adult patients with Carbapenem-resistant Klebsiella pneumoniae infection. Front Cell Infect Microbiol. 2021;11: 818308.
Siu LK, Yeh KM, Lin JC, Fung CP, Chang FY. Klebsiella pneumoniae liver abscess: a new invasive syndrome. Lancet Infect Dis. 2012;12(11):881–7.
Pomakova DK, Hsiao CB, Beanan JM, Olson R, MacDonald U, Keynan Y, et al. Clinical and phenotypic differences between classic and hypervirulent Klebsiella pneumonia: an emerging and under-recognized pathogenic variant. Eur J Clin Microbiol Infect Dis. 2012;31(6):981–9.
Yamamoto H, Iijima A, Kawamura K, Matsuzawa Y, Suzuki M, Arakawa Y. Fatal fulminant community-acquired pneumonia caused by hypervirulent Klebsiella pneumoniae K2-ST86: case report. Medicine. 2020;99(21): e20360.
Li S, Yu S, Peng M, Qin J, Xu C, Qian J, et al. Clinical features and development of Sepsis in Klebsiella pneumoniae infected liver abscess patients: a retrospective analysis of 135 cases. BMC Infect Dis. 2021;21(1):597.
Wang JH, Liu YC, Lee SS, Yen MY, Chen YS, Wang JH, et al. Primary liver abscess due to Klebsiella pneumoniae in Taiwan. Clin Infect Dis. 1998;26(6):1434–8.
Hao Z, Duan J, Liu L, Shen X, Yu J, Guo Y, et al. Prevalence of community-acquired, Hypervirulent Klebsiella pneumoniae isolates in Wenzhou, China. Microbial Drug Resist (Larchmont, NY). 2020;26(1):21–7.
Namikawa H, Yamada K, Sakiyama A, Imoto W, Yamairi K, Shibata W, et al. Clinical characteristics of bacteremia caused by hypermucoviscous Klebsiella pneumoniae at a tertiary hospital. Diagn Microbiol Infect Dis. 2019;95(1):84–8.
Hwang JH, Handigund M, Hwang JH, Cho YG, Kim DS, Lee J. Clinical features and risk factors associated with 30-day mortality in patients with pneumonia caused by Hypervirulent Klebsiella pneumoniae (hvKP). Ann Lab Med. 2020;40(6):481–7.
Gomez-Simmonds A, Greenman M, Sullivan SB, Tanner JP, Sowash MG, Whittier S, et al. Population structure of Klebsiella pneumoniae causing bloodstream infections at a New York City tertiary care hospital: diversification of multidrug-resistant isolates. J Clin Microbiol. 2015;53(7):2060–7.
Sheng Z, Li J, Chen T, Zhu Y, Yu X, He X, et al. Clinical and Microbiological Characteristics of Klebsiella pneumoniae Bloodstream Infection in a Chinese Hospital: Hypervirulent and Multiclonal. Infect Drug Resist. 2022;15:3981–90.
Liu YM, Li BB, Zhang YY, Zhang W, Shen H, Li H, et al. Clinical and molecular characteristics of emerging hypervirulent Klebsiella pneumoniae bloodstream infections in mainland China. Antimicrob Agents Chemother. 2014;58(9):5379–85.
Liu C, Shi J, Guo J. High prevalence of hypervirulent Klebsiella pneumoniae infection in the genetic background of elderly patients in two teaching hospitals in China. Infect Drug Resist. 2018;11:1031–41.
Li XJ, Wang QL, Feng JC, Guan XL, Chen ZJ, Hu B. Homology analysis and clinical infection characteristics of hypervirulent Klebsiella pneumonia. Zhonghua Yu Fang Yi Xue Za Zhi. 2021;55(8):945–51.
Wu X, Shi Q, Shen S, Huang C, Wu H. Clinical and bacterial characteristics of Klebsiella pneumoniae affecting 30-day mortality in patients with bloodstream infection. Front Cell Infect Microbiol. 2021;11: 688989.
Lu F, Ma D, Zhu W, Kong G, Wang X. Prognostic analysis of severe patients with bloodstream infection caused by Enterobacteriaceae bacteria. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2020;32(4):454–7.
Wan Q, Ye Q, Su T, Zhou J. The epidemiology and distribution of pathogens and risk factors for mortality in liver transplant recipients with Gram negative bacteremia. Hepatogastroenterology. 2014;61(134):1730–3.
Zhang Y, Zhao C, Wang Q, Wang X, Chen H, Li H, et al. High prevalence of Hypervirulent Klebsiella pneumoniae infection in China: geographic distribution, clinical characteristics, and antimicrobial resistance. Antimicrob Agents Chemother. 2016;60(10):6115–20.
Liu C, Guo J. Characteristics of ventilator-associated pneumonia due to hypervirulent Klebsiella pneumoniae genotype in genetic background for the elderly in two tertiary hospitals in China. Antimicrob Resist Infect Control. 2018;7:95.
Liao W, De Wang L, Li D, Du FL, Long D, Liu Y, et al. High prevalence of 16s rRNA methylase genes among Carbapenem-resistant Hypervirulent Klebsiella pneumoniae Isolates in a Chinese tertiary hospital. Microbial Drug Resist (Larchmont, NY). 2021;27(1):44–52.
Acknowledgements
This work was supported by Medical Research Foundation of Guangdong (Grant No. C2021111) and “Prominent Master from Overseas” project of Department of Science and Technology of Guangdong Province.
Funding
This work was supported by Medical Research Foundation of Guangdong (Grant No. C2021111) and “Prominent Master from Overseas” project of Department of Science and Technology of Guangdong Province.
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All authors contributed to the writing of the final manuscript. JE.H. collected data, analyzed data, wrote the main manuscript text and prepared Figs. 1– 7. YZ.C. collected data, wrote the manuscript text and revised the manuscript. M.L. extracted strains, cryopreserved strains and revived strains. SJ.X. extracted the strains from the specimens and identified the strains by the positive string test. Y.C. supervised the progress of the project, revised the manuscript text. ZS.G., HS.T. give comments on manuscript revisions.
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Informed consent was obtained from all subjects and/or their legal guardian(s). The protocol for this study was approved by the Medical Ethics Committee of Binhaiwan Central Hospital of Dongguan (No. 2021014). All methods were performed in accordance with the relevant guidelines and regulations. All methods were performed in accordance with the relevant guidelines and regulations.
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Huang, J., Chen, Y., Li, M. et al. Prognostic models for estimating severity of disease and predicting 30-day mortality of Hypervirulent Klebsiella pneumoniae infections: a bicentric retrospective study. BMC Infect Dis 23, 554 (2023). https://doi.org/10.1186/s12879-023-08528-x
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DOI: https://doi.org/10.1186/s12879-023-08528-x