Clinical characteristics, organ failure, inflammatory markers and prediction of mortality in patients with community acquired bloodstream infection

Background Community acquired bloodstream infection (CABSI) in low- and middle income countries is associated with a high mortality. This study describes the clinical manifestations, laboratory findings and correlation of SOFA and qSOFA with mortality in patients with CABSI in northern Vietnam. Methods This was a retrospective study of 393 patients with at least one positive blood culture with not more than one bacterium taken within 48 h of hospitalisation. Clinical characteristic and laboratory results from the first 24 h in hospital were collected. SOFA and qSOFA scores were calculated and their validity in this setting was evaluated. Results Among 393 patients with bacterial CABSI, approximately 80% (307/393) of patients had dysfunction of one or more organ on admission to the study hospital with the most common being that of coagulation (57.1% or 226/393). SOFA performed well in prediction of mortality in those patients initially admitted to the critical care unit (AUC 0.858, 95%CI 0.793–0.922) but poor in those admitted to medical wards (AUC 0.667, 95%CI 0.577–0.758). In contrast qSOFA had poor predictive validity in both settings (AUC 0.692, 95%CI 0.605–0.780 and AUC 0.527, 95%CI 0.424–0.630, respectively). The overall case fatality rate was 28%. HIV infection (HR = 3.145, p = 0.001), neutropenia (HR = 2.442, p = 0.002), SOFA score 1-point increment (HR = 1.19, p < 0.001) and infection with Enterobacteriaceae (HR = 1.722, p = 0.037) were independent risk factors for in-hospital mortality. Conclusions Organ dysfunction was common among Vietnamese patients with CABSI and associated with high case fatality. SOFA and qSOFA both need to be further validated in this setting. Electronic supplementary material The online version of this article (10.1186/s12879-018-3448-3) contains supplementary material, which is available to authorized users.


Background
Bloodstream infection (BSI) is a common cause of sepsis and is associated with significant morbidity and in-hospital mortality worldwide [1]. It is ranked the 11th leading cause of death among adults in USA in 2014, with an age-adjusted death rate of 10.7 per 100,000 standard population [2]. In South and Southeast Asia, the incidence rate of community-acquired BSI in the period of 2004-2010 increased from 16.7 to 38.1 per 100,000 people per year and the 30 days mortality rate can reach up to 37.5% [3].
In patients with BSI, an increasing number of organs with dysfunction is correlated with increased morbidity and mortality [4]. Multiple organ dysfunction is a leading cause of morbidity and mortality in patients admitted to intensive care units (ICUs) in Europe, with an in-hospital mortality of 34.2% [5]. Sequential organ failure assessment (SOFA) score, and the related qSOFA (quickSOFA) score have been recently recommended for identifying sepsis and predicting outcome by the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) [6]. qSOFA was originally designed for use outside the ICU, but it's simplicity, brevity and lack of laboratory results, make it compelling for use in emergency departments and resource-constrained setting. However the validation of qSOFA is not consistent among studies quantifying the risk of death in those presenting with suspected infection in critical care [6][7][8][9]. Development and validation of these scores were mostly carried out in high income countries, with limited data on their validity in low-and middle income countries (LMICs) [7,8,10]. Additionally there have been few studies looking specifically at patients with BSI, a population with an associated increase in mortality.
This study aims to describe the clinical manifestations and associated organ dysfunctions as described by Sequential [Sepsis-related] Organ Failure Assessment (SOFA) scores and its correlation with mortality in patients with community acquired bloodstream infection at the time of presenting to a large teaching hospital in Vietnam, and their associated mortality.

Study design
This was a retrospective, cohort study of patients hospitalised at the National Hospital for Tropical Diseases (NHTD) (a tertiary referral infectious disease hospital) in northern Vietnam between January 2011 and December 2013. As a referral centre, this hospital often receives patients with specific infections (eg. central nervous system infections), complicated infections and those with severe infections who have failed on treatment elsewhere. Additionally, at the time of the study, the hospital had not establish a separate emergency department and intensive care unit (ICU), therefore we refer to the critical care unit (CCU) for the unit with both ventilated and unventilated beds, available haemodynamic support and renal replacement therapy. A convenience sampling method was used to select medical notes from the list of all hospitalised patients with positive bacterial blood cultures during the study period. The inclusion criteria were having a blood culture, taken within 48 h of hospitalisation (to any institution) for the current admission, positive for a recognised pathogen according to the US CDC's National Healthcare Safety Network (NHSN) list [11]. Patients with infection with more than one bacterium were excluded, as were cases considered to be pseudobacteraemia [12].

Data collection
Data was extracted from patients' medical notes using a case-report form that captured patient demographics, reported history of prior medical illness, clinical manifestations, laboratory results, inflammatory markers within the first 24 h of admission to the study hospital and outcome at hospital discharge.
BSI with concurrent meningitis was defined in bacteremic patients who had cerebrospinal fluid examination within 24 h of blood drawn for microorganism isolation showing at least one of the following criteria: (1) turbid appearance; (2) leukocytosis (> 100 cells/mm3) or (3) leukocytosis from 10 to 100 cells/ mm3) and either an elevated protein (> 100 mg/dl) or decreased glucose (< 40 mg/dl) [13]. BSI with concurrent pneumonia was confirmed by radiology within 24 h of blood drawn for microorganism isolation. Gastrointestinal tract infection and urine tract infection were defined by the CDC/ NHSN Surveillance Definitions for Specific Types of Infections [14]. Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score, and quick SOFA (qSOFA) score were calculated using the worst parameters recorded within the first 24 h of admission to the study hospital and missing values were considered to be normal [6]. Organ dysfunction was defined by organ-specific SOFA scores ≥1. Failure of kidney function was further evaluated using the RIFLE criteria with RIFLE-F (Failure) defined as patients with a serum creatinine greater than three times the age adjusted upper limit of serum creatinine [15]. Neutropenia was defined as an absolute neutrophil count < 1500 cells/mm 3 , severe anemia as hemoglobin concentration was < 80 g/L and thrombocytopenia as a platelet count below 100 × 10 3 cells/mm 3 .
The outcome at hospital discharge was defined as death for those who died in hospital or were palliatively discharged (discharged home for palliative care with the expectation of an early death, as per common practice in Vietnam) and 'survived' in all other cases.

Data analysis
Data was analysed using IBM SPSS Statistics for Windows (IBM Corp., Armonk, NY). Depending on the distribution, continuous data were presented as mean (95% confidence interval) or median (interquartile range) and categorical data as number (percentage). To evaluate the predictive value of SOFA, qSOFA score, white blood cell counts, C-Reactive Protein (CRP) and procalcitonin levels, a receiver operating characteristic (ROC) curve and the area under the curve (AUC) were calculated along with the sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios associated with the cut-off value that gave the highest difference between sensitivity and (1-specificity) (Youden index). Since procalcitonin level was obtained by a semi-quantitative test that was only quantitatively measured for levels under 100 ng/mL, the result of "above 100 ng/mL" was considered as 100 ng/mL. The Mann Whitney U test and Kruskal Wallis test were used to analyze continuous variables and the Chi-square and Fisher's exact were used for bivariate analyses as appropriated. Logistic regression models were used to calculate unadjusted odds ratios (ORs) and 95% confidence intervals (CIs) for associations between clinical, laboratory characteristics and case fatality rate. Comparison of AUC between different ROC curves was performed using a nonparametric approach [16]. Cox proportional hazards regression was used to identify variables that predicted clinical outcomes. Variables for inclusion were selected by review of the literature (age, HIV infection status, neutropenia, SOFA score and aetiology of CABSI). All tests were two-tailed and differences were considered statistically significant at p values ≤0.05.

Clinical characteristics, aetiology of CABSI and organ failure
The median age of patients included was 48 years (IQR 36-60), with 271 males and a male to female ratio of 2.2:1. There was a history of chronic disease in 27% of patients, with the highest prevalence in patients with Enterobacteriaceae BSI, 34% (38/200). Thirty-eight percent (150/393) of patients were transferred from another hospital (< 48 h) for the current illness episode. The median time from onset of illness to hospitalisation at the study site was 5 days and 36.9% (145/393) were admitted directly to critical care.

Discussion
This retrospective study describes the clinical characteristics and outcomes in this high-risk group of patients with community acquired BSI. Multi-organ dysfunction and case-fatality rates were high in all aetiological bacterial groups. SOFA score on CCU admission had good prognostic accuracy for in-hospital mortality whilst qSOFA, WBC, CRP and PCT did not.
BSI patients admitted directly to CCU in our study had a median SOFA score of 7 (IQR 4-12), comparable with large-scale validation studies of Sepsis-3 criteria in the US (median of 6, IQR 3-9) [10] and Australia and New Zealand (median of 5, IQR 3-8) [7]. The proportion of bacteraemic patients with qSOFA of 2 or above in our study (39.4%) was also higher than in studies of sepsis conducted in high income countries (10-27%) [8,10]. The percentage of patients with pneumonia in our CABSI cohort (24.9%) was lower than or similar to other studies on CABSI (24-38%) [17][18][19]. K. pneumoniae was the most common pathogen isolated from bacteremic patients with pneumonia in our study, reflecting its role here as an important cause of community acquired pneumonia [20]. We also confirmed the role of S. suis as the leading pathogen causing BSI associated with meningitis in Viet Nam [21]. Our findings further confirmed the reduction of Neisseria meningitidis in Viet Nam which was reported in 0.5% of blood isolates [22] and around 4.4% of cerebral spinal fluid (CSF) isolates before 2005 [23]. We also report the high prevalence of Enterobacteriacaea (18.1% or 13/72) as a cause of meningitis in adult BSI patients compared to previous studies from Viet Nam (13.5% or 30/222 of CSF isolates from 1996 and 2005) [23], Iceland (11.3% or 12/106   [25]. The high prevalence of meningitis associated with Enterobacteriaceae in this setting may be related to Strongyloides hyperinfection, given the evidence for high seroprevalence of Strongyloides infection in this population [26]. A review of CABSI in south and Southeast Asia from 1990 to 2010 showed the most frequent isolates in adult patients were Salmonella enterica (37.8%), S. aureus (12.6%) and E. coli (12%) with an overall case fatality rate of 9% [27]. In North America and Europe, there was a significant increase in bloodstream infection caused by Gram-negative bacteria, and case fatality rates in the period 1992-2008 were 13-20.6% in patients with CABSI [1]. The overall case fatality of 28% in our CABSI patients was lower than in a study in Thailand [3] [28]. The higher case fatality in Thailand and our study may relate to the shift in the aetiology of CABSI from Salmonella to other Gram-negative bacteria observed since the last decade.
Organ dysfunction is strongly associated with in-hospital mortality. In a multicentre study of severe sepsis in Spain, case fatality in patients with more than 4 organs with dysfunction was 78.4% [29]. From a large prospective European study, case fatality in patients with more than 3 organs with dysfunction was 58% and the, highest in-hospital mortality rates were observed in patients with coagulation failure (45%) [5]. In high income settings, among ICU patients with suspected infection, the predictive accuracy for in-hospital mortality is higher using SOFA than qSOFA (AUC = 0.74; 95% CI, 0.73-0.76; vs AUC = 0.66; 95% CI, 0.64-0.68) whilst outside of ICU, the predictive validity of qSOFA (AUC = 0.81; 95% CI, 0.80-0.82) was better than SOFA (AUC = 0.79; 95% CI, 0.78-0.80; P < 0.001) [10]. In a prospective study of patients with suspected infection admitted to an emergency department in Norway, the qSOFA had poor performance to predict 7-day and 30-day mortality with AUCs < 0.6 in both multiple imputation and complete case analysis [30]. The usefulness of qSOFA in low-and middle income countries has not been well established. Procalcitonin levels can serve as a useful marker to rule out sepsis and discriminate contamination from true bloodstream infection [31,32]. Our study shows a poor prediction of initial PCT and CRP in prediction of mortality.
Our study has some major limitations. Firstly, as the study site is a referral hospital specialising in infectious diseases, the aetiologies, clinical manifestations, severity and response to the treatment may be different from those presenting to a general hospital. Secondly, SOFA and qSOFA was calculated based on the worst parameters within 24 h of admission to the study hospital which may not accurately present the severity of infection at arrival. Thirdly, due to the retrospective design, the data collection was incomplete and unbalanced distribution of missing data can be a bias in the prediction models The utilisation of SOFA and qSOFA needs to be validated prospectively in other setting at different time points of assessment.

Conclusions
In conclusion, community acquired BSI has a high rate of organ dysfunction and mortality in this setting. SOFA performed well at predicting those at risk of death admitted directly to CCU, whilst qSOFA performed poorly. Further prospective validation in low-and middle income settings is needed.

Additional file
Additional file 1: Table S1. The aetiology of BSI by the foci of infection (DOCX 19 kb).