Comparison of Hospital- and Community-Acquired Septic Shock in Children: A Single-Center, Cohort, Retrospective Study

Guoyun Su Pediatric Intensive Care Unit, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health Chaonan Fan Pediatric Intensive Care Unit, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health Boliang Fang Pediatric Intensive Care Unit, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health Zhengde Xie Laboratory of Infection and Virology, Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health Suyun Qian (  syqian2020@163.com ) Pediatric Intensive Care Unit, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health


Background
Septic shock, which is caused by a severe in ammatory response to infection, is the leading cause of mortality and morbidity in hospitalized patients worldwide [1,2]. It occurs in 10% of intensive care unit (ICU) patients with a mortality rate of nearly 30-60% [3][4][5]. Septic shock is the most severe complication of sepsis [6]. Sepsis usually results in tissue necrosis, multiorgan failure, and death [7]. The essence of sepsis is infection, which can be categorized as nosocomial and community-acquired infections according to the location from where the infection was acquired. It has been documented that the morbidity and mortality rates of sepsis caused by nosocomial infections are signi cantly different from those caused by community-acquired infections. Understanding these differences is essential in avoiding the risk factors of death, which is a signi cant factor in preventing and treating septic shock.
In a four-center cohort study of 250,000 adult sepsis patients, Rothman and his team found that 77-93% of inpatients had community-acquired infections with an average mortality rate of 12%, and 7-23% had nosocomial infections with an average mortality rate of 35% [8]. A prospective, multi-center INSEP study of 11,883 patients enrolled in 133 ICUs from 95 German hospitals, 12.6% (1,503) were diagnosed with severe sepsis or septic shock, of which 57.2% (860) were nosocomial infections. The mortality rate of severe sepsis or septic shock was 34.3% in the ICU and 40.4% in the hospital [9]. These studies have been conducted on adult patients in developed countries. However, data on such studies in Chinese patients are limited. A subsequent analysis of a population-based database in China showed that among 21,191 hospitalized patients, 935 met the diagnosis of SEP-3, among which 498 had severe sepsis or septic shock, and 62.1% of SEP-3 patients had community-acquired infections. The mortality rate of patients with severe sepsis or septic shock was 53.4%, and that of patients with SEP-3 was 32.0% [10].
Nevertheless, adequate data on nosocomial and community-acquired infections in children with septic shock in developing countries, especially China, is not yet available. Additionally, obtaining national or regional data is not an easy process. Therefore, with limited data, we designed this single-center retrospective study to understand the differences in patient characteristics, treatment, prognosis, outcomes, and risk factors of patients with hospital-(HASS) and community-acquired septic shock (CASS).

Study design and subjects
We conducted a single-center retrospective cohort study for a 4-year period from January 1, 2016 to December 31, 2019. The study included eligible children from the pediatric intensive care unit (PICU) of Beijing Children's Hospital. Inclusion criteria were 29 days to 18 years old patients, and all patients were diagnosed with septic shock according to the 2015 Chinese expert consensus diagnostic standard [11].
Children with incomplete medical records and lost to follow-up were excluded. The study protocol was reviewed and approved by the ethics committee of Beijing Children's Hospital (2020-Z-040). The patient's informed consent has been waived.

Groups
In this study, the participating patients were divided into HASS and CASS groups according to whether the sepsis was due to nosocomial or community-acquired infections. HASS group included patients with infections that occurred 48 hours after admission or were acquired in the hospital and developed into septic shock. CASS group included patients with infections that occurred at admission or within 48 hours after admission and developed into septic shock.

General information
In this study, we rst enrolled 325 children with septic shock. Of these, 21 patients were excluded from the study because their data were incomplete, and another 6 patients were excluded as they were lost to follow-up. Therefore, 298 patients who met our criteria were included in this study (Fig. 1). Of these, 91 patients (30.5%) were categorized into the HASS group and 207 patients (69.5%) were in the CASS group. In the HASS group, 37 patients (40.7%) were from the hematology department, 28 patients (30.8%) were from other hospitals, 11 patients (12.1%) were from other internal medicine departments, 10 patients (11.0%) were from the PICU, and 5 patients (5.5%) were from the surgery department. Moreover, the median age was 5.2 (1.2-10.8) years, and 64.8% (59/91) of patients in the HASS group were male. The pediatric index of mortality 2 (PIM2) score at PICU admission was 9.6 (4.1-14.8) in the HASS group. In the CASS group, the median age was 2.3 (0.6-8.2) years, 60.9% (126/207) of patients were male, and the PIM2 score at the time of PICU admission was 8.5 (5.1-16.1) ( Table 1). Quantitative data with normal distribution were represented as mean ± standard deviation and quantitative data with non-normal distribution were represented as median and quartile. Classi cation variables were represented as count (percentage). ALB: Albumin; ALT: alanine aminotransferase; APTT: activated partial thromboplastin time; AT III: antithrombin III; BE: base excess; CR: creatinine; CRP: C-reactive protein; DBP: diastolic blood pressure; HR: heart rate; INR: international normalized ratio; IQR: interquartile range:; LAC: lactate; N: Neutrophil ratio; PCT: procalcitonin; PICU: pediatric intensive care unit; PIM2: pediatric index of mortality 2; PLT: platelet; PT: prothrombin time; RR: respiratory rate; SBP: systolic blood pressure; TBil: total bilirubin; WBC: white blood cell.
The number of children who had no obvious underlying disease was higher in the CASS group (67.7%) compared with that of the HASS group(23.1%%); whereas, the number of children with hematologic/oncologic diseases was higher in the HASS group (65.9%) compared with that of the CASS group(14.5%). There were no statistical differences in other types of underlying diseases (Table 1).
Compared with patients in the HASS group, the main complaints (fever, convulsions, listlessness, disturbance of consciousness, and cough) occurred in higher number of patients in the CASS group (p < 0.05) ( Table 1). Heart rate (HR), respiratory rate (RR) and systolic blood pressure (SBP) of patients in the HASS group were higher than those of the CASS group when the septic shock was found (Table 1).
Statistical differences were observed in the counts of white blood cells (WBCs), platelets (PLTs), Creactive protein (CRP), and total bilirubin (TBil) between the two groups. WBC and PLT counts in the HASS group were lower than that in the CASS group; whereas, levels of CRP and TBil in HASS group were higher than that in the CASS group (p < 0.05) ( Table 1).

Infection Sites And Distribution Of Causative Microorganisms
In this study, we observed that the most common infection sites were the digestive tract, respiratory tract, bloodstream, and central nervous system. Bloodstream infection was dominant in the HASS group (36.3%) compared with that of CASS group (11.1%); whereas, the CASS group had more number of patients with respiratory (25.1%) and central nervous system infections (22.2%) ( Table 1). Table 2. There was no statistical difference in the pathogen detection rate and positive rate of sterile body uid culture between the two groups. However, statistical differences were observed in pathogen distribution. Patients in the CASS group had more Gram-positive bacteria than that in the HASS group (p < 0.001). Among Gram-positive pathogens, a higher rate of infection from Staphylococcus aureus was observed in patients of CASS group (10.1%) compared with that of HASS group (1.1%; p < 0.001).

Supportive And Antimicrobial Therapies
In this study, no statistical difference was seen in the utilization rates of oxygen therapy, respiratory support, vasoactive drugs, glucocorticoids, and renal replacement therapy between the two groups.
However, a statistically signi cant difference was observed in the use of empirical antimicrobial therapy on the rst day between the two groups. The patients in the CASS group were mainly given two antimicrobial drugs (55.1%). In contrast, more than two antimicrobial drugs were used in patients of the HASS group (54.9%; Table 3).

Complications And Prognosis
The CASS group had more patients with cerebral dysfunction than HASS group. No signi cant differences were observed in the proportion of other complications and multiple organ dysfunction syndrome (MODS) between the two groups. The total 28-day mortality rate of the two groups was 45.0% (134/298); statistically signi cant differences were observed between the HASS (62.6%) and CASS groups (37.2%; p < 0.001). The in-hospital mortality rate in HASS group (33.3%) was higher than that of CASS group-(12.1%; p < 0.001; Table 4). Predictive risk factors for 28-day mortality in children with septic shock In this study, all the variables mentioned previously (as given in Table 5) were enrolled in the univariate logistic regression analysis of 28-day mortality rates. The risk factors of the 28-day mortality in the HASS group were combined hematologic/oncologic diseases, PLT, invasive mechanical ventilation therapy, MODS, vasoactive drugs therapy, positive pathogen detection, and positive blood detection. However, the risk factors of the 28-day mortality in the CASS group were PIM2, activated partial thromboplastin time, prothrombin time, international normalized ratio, blood urea nitrogen, creatinine, neutrophil ratio, heart rate, potential of hydrogen (pH), lactate, invasive mechanical ventilation therapy, respiratory failure, renal injury, disseminated intravascular coagulation, cerebral dysfunction, and renal replacement therapy (Table 5). In the present study, due to the sample size limitation in the HASS group, only three coe cients with the lowest p-value in the univariate logistic regression analysis were generated into the multivariate analysis model. The independent risk factor for the 28-day mortality rate in the HASS group was MODS. In the CASS group, seven coe cients with the lowest p-value in the univariate logistic regression analysis were generated into the multivariate analysis model. The independent risk factor for the 28-day mortality rate in the CASS group was the need for invasive mechanical ventilation therapy (Table 6).

Discussion
In our study, we observed several differences between HASS and CASS, with both internal and external factors. Several studies have been conducted on this aspect. However, research on differences between HASS and CASS in children and in China is limited.
Internal factors, including the patients' underlying diseases, determine their susceptibilities. Signi cant differences have been observed between HASS and CASS patients [13,14]. Studies state that patients with HASS were mainly older children with underlying diseases (76.9%); whereas, 65.9% patients had hematologic/oncologic diseases. Research also suggests that most of the blood malignancies in HASS patients can lead to immune de ciency, which is a risk factor for infection and death [15][16][17]. Compared with CASS, children with HASS had signi cantly lower WBCs and thrombocytopenia. At the same time, neutropenia was also one of the factors that increased the risk of infection [18]. In comparison, 67.7% of the CASS patients were infants without underlying diseases.
In our study, the major differences were seen in external factors between the two groups. (1) Differences in infection sites: HASS patients mostly had bloodstream and digestive tract infections, which is similar to the ndings of study by Westphal et al. and Baker [19]. According to the study by Baker, the chemotherapy damages the gastrointestinal mucosa; therefore, enterogenic sepsis and bacteremia mainly occurs in hospitals [20]. In our study, the infection sites of CASS were primarily the respiratory tract, central nervous system, and digestive tract. The infection sites of CASS varied widely among studies; however, the main site was the respiratory tract, which is in line with the ndings of our study [19].
(2) Differences in chief complaint symptoms: Fever was the principal symptom in both groups.
Interestingly, we discovered that patients in the HASS group had signi cantly fewer chief complaints than those in the CASS group. Similar ndings were noted in the study by Heinz et al. He found that in patients with neoplasm of neutropenia, the signs and symptoms of infection usually atypical or not obvious. He also stated that fever may be the sole clinical symptom [21]. Therefore, early attention should be paid to fever in HASS patients. (3) Differences in in ammatory indicators: CRP in the HASS group was higher than that in the CASS group; whereas PCT was lesser than that in the CASS group. Study by Matta stated that CRP in nosocomial infection was higher than that in the community-acquired infections [13].
However, opinions vary on PCT between the groups. The research by Johansson suggested that the PCT level of patients infected by Streptococcus pneumoniae is higher than that of other bacteria [22]. Some studies found that Gram-negative bacteria results in higher PCT levels than Gram-positive bacteria in patients with neutropenia [23][24][25]. Another study suggested that PCT levels in patients with surgical enterogenic sepsis were higher than that in patients with medical sepsis [26]. Charles [27] believed that PCT value depends on many factors, such as type and degree of infection, systemic in ammation, pathogens, immune status, sample duration, and even previous infection events. However, Jensen et al [28] pointed out that anti-infection treatment would cause PCT levels to stop or reduce the synthesis rate, resulting in the rapid decrease of its plasma concentration. (4) Differences in pathogen distribution: No difference was observed in pathogen detection rate between the two groups. The HASS group had higher positive rate of blood culture and was dominated by Gram-negative bacteria. A review indicated that Gram-negative bacteria, especially K. pneumoniae and P. aeruginosa, were still common in tumor patients, which is consistent with ndings of our study. However, the review also found that Gram-positive bacteria had an increasing trend in recent years [17]. The reason for this difference was related to the underlying diseases of the patients. Under the in uence of gastrointestinal mucositis caused by chemotherapy and long-term neutropenia, children with nosocomial infection, mostly with hematologic neoplasms, are at high risk for Gram-negative bacteremia [20]. However, it seems to be generally accepted that the predominant type of pathogen in CASS is Gram-positive bacteria [29]. However, there are still reports of community-acquired infections with Gram-negative bacteria, such as P. aeruginosa; however, these patients often had underlying diseases [30]. At the same time, our study found that the 28-day mortality rate of children in the HASS group was 3.661 times higher than that of children in the CASS group. Therefore, more attention should be paid to patients with HASS once the blood culture is positive.
There are some difference in treatment and complications between the two groups. Patients with HASS received two or more antimicrobial therapies (54.9%); however, 86.8% patients had MODS; 33.3% was the in-hospital mortality rate and 62.6% was the 28-day mortality rate, which were signi cantly higher than those with CASS. Similar studies have been reported in literature, which suggested that the number of antimicrobial agents is not related to death due to septic shock [14,31]. The different mortality rates between the two groups were similar to those of another multi-center cohort study, in which the mortality from nosocomial infection was 64.6% and community infection was 37.5% [32].
Furthermore, because of the abovementioned differences, the predictors of 28-day mortality in the two groups varied remarkably. In the multivariate logistic regression analysis, we found that MODS was the risk factor for death in 28 days during treatment in the HASS group. For the HASS children who had MODS, the mortality was 10.524 times higher than that without MODS. Several studies also found MODS was an independent predictor of sepsis mortality [33,34]. In our research, we found that MODS was a predictor of mortality only in HASS patients and not in CASS patients. We analyzed the clinical data again and found that 69.6% patients with MODS in the HASS group showed irreversible organ damage during the treatment. However, in CASS patients with MODS, 60.9% of them recovered their organ function after treatment. Therefore, although there was no statistical difference in the number of patients diagnosed with MODS between the two groups, these patients' prognoses differed. Mortality rate in the CASS group was predicted on mechanical ventilation, similar to those of several studies [35,36]. The need for invasive mechanical ventilation was considered as a risk factor for mortality due to the following reasons: (1) The patients treated with invasive ventilator had more severe condition: PIM2 at the ICU admission of CASS patients requiring mechanical ventilation was 11 (6.3, 25.9). In comparison, PIM2 during the ICU admission of CASS patients without mechanical ventilation was 5.5 (2.6, 9.4).
(2) Adverse effects of invasive ventilation on hemodynamics: An international consensus stated that invasive mechanical ventilation can aggravate the condition of septic shock patients, and the reason for the aggravation of the condition is the deterioration of hemodynamics [37].
We also found that infection sites, bacterial species, and MDR bacteria were not related to outcome, which was consistent with an earlier report in another literature [38]. Simultaneously, the in ammation indexes (CRP and PCT) were not correlated with the outcome in sepsis patients [39,40].
Our study had some limitations. First, this study is of single-center retrospective cohort nature that relies on routine clinical data, with lost cases and a small amount of missing data in the data variables.
Second, although the total number of cases was nearly 300, data of multifactor regression analysis after grouping were relatively small. The number of included parameters needed to be 0.1 of the data number, while only 34 patients in the nosocomial infection group survived; therefore, three parameters were provided for regression. Although we got the expected results, we could have acquired more data, resulting in a much better conclusion.

Conclusions
The results of this study concluded that the underlying diseases, pathogens, complications, and prognosis were considerably different between HASS and CASS patients. HASS patients had a higher mortality rate than that of CASS. We also observed that MODS is associated with the 28-day mortality rate in HASS patients. Moreover, this study states that the need for invasive mechanical ventilation therapy is an independent impact factor of the 28-day mortality rate in CASS patients.

Declarations
Ethics approval and consent to participate The study protocol was reviewed and approved by the Ethics Committee of Beijing Children's Hospital (2020-Z-040). The patient's informed consent has been waived by the Ethics Committee of Beijing Children's Hospital because the study was carried out on the premise of not violating patient privacy disclosure and keeping patient information con dential. All methods were performed in accordance with the relevant guidelines and regulations (Declaration of Helsinki).

Consent for publication
Not applicable.
Availability of data and materials Flowchart of the study.