Risk Factors of Healthcare-associated Infections Among Pediatric Hospitalized Patients in Chinese General Hospitals From 2001 to 2020: A Systematic Review and Meta-Analysis

Background: Healthcare-associated infections (HAIs) have been an increasing global public health threat to the globe. Paediatric hospitalized patients are particularly to HAIs and the identication of risk factors is essential to help policy-makers and hospital managers to develop prevention and control strategies. This study aims to determine the risk factors associated with HAIs among paediatric hospitalized patients in Chinese general hospitals. Methods: Medline, EMBASE and Chinese Journals Online databases were searched. The search was limited to studies published from January 1 st 2001 and December 31 st 2020. Meta-analyses of OR in the prevalence were estimated. Heterogeneity between studies was assessed based on the B 2 and I 2 statistics to select the meta-analysis model. Reviewer Manager 5.3 was employed and P<0.05 was considered as the statistical signicance. Results: 205 published articled were searched from the databases, in which 25 studies were included in the quantitative synthesis and meta-analysis for the risk factors of HAIs among paediatric hospitalized patients in Chinese general hospitals. 61,773 paediatric patients were incorporated in the included studies, which covered 13 regions in 10 provinces in China. Of them, 2,438 paediatric patients had HAIs. The meta-analyses showed that the ORs of younger age(2.25[1.32-3.85]), hormone(3.66[1.73-7.74]), invasive procedures(5.62[4.27-7.40]), longer hospitalization stay (7.79[6.38-9.50]), malnutrition(3.72,[1.80-7.70]), over 3 kinds of antibiotics (3.25,[2.66-3.96]), over 3 kinds of underlying disease (4.24[1.84-9.78]), large room (2.22[1.28-3.85)), and autumns and winter (1.56[1.04-2.35)) were the independent risk factors that had a negative impact on HAIs with a statistical signicance (P<0.05). Conclusions: Under the age of 1 year, application of hormone, experiencing invasive procedure, hospitalization stay more than 7 days, malnutrition, using more than 3 kinds of antibiotics, beyond 3 kinds of underlying disease, large room, and autumn and winter were the main risk factors associated with the higher prevalence of HAIs among paediatric hospitalized patients in Chinese general hospitals. This provided the evidence base to inform the policy-makers and hospital managers. The conrmed successful and cost-effective prevention and control measures need to be adopted to reduce the occurrence of HAIs.


Introduction
Healthcare-associated infections (HAIs) have been an increasing global public health threat to the globe, taking place in a hospital setting after patients are admitted to the hospital more than 48 hours (1,2).
Evidence has shown that HAIs have not only increased the mortality, morbidity and prolonged hospitalization for the patients, especially when the antimicrobial resistant microorganisms caused HAIs, but also led to high economic burden for the whole society (3,4). China is certainly affected by HAIs and has reported that HAIs could result in the direct economic burden around ¥ 10 to 15 billion (5). Besides, a study conducted in 68 Chinese hospitals estimated that HAIs increased the hospitalization stay of 10.4 days (6). It is essential to take cost effective measures to reduce the presence of HAIs, such as the surveillance system of HAIs and China has established the National Nosocomial Infection Surveillance System.
As the increasing number of the special susceptible populations, paediatric hospitalized patients are particularly vulnerable to HAIs, due to their internal characteristics and external factors such as immature immune systems, immuno-de ciencies, total parenteral nutrition, congenital malformations, and stay in an intensive care (ICU) (7,8). A study undertaken in the developing countries showed that the incidence of HAIs in neonate intensive care (NICU) is nearly 30% and is responsible for 4-56% of all causes of reported neonatal deaths (9,10). Specially, the prevalence of HAIs was reported with a range from 10 to 25 % in paediatric intensive care (PICU) in China (11,12).
Current literature has con rmed that up to 70% of HAIs cases could be preventable (13,14). This shows that the identi cation of the risk factors on HAIs is essential to help the policy-makers and hospital managers to develop the prevention and control strategies and allocate the relevant resources to protect the susceptible hospitalized patients, resulting in the reduction on the occurrence of HAIs (15). However, limited risk factor analysis studies on HAIs among paediatric hospitalized patients have been conducted only in individual hospitals and no comprehensive study is yet to be undertaken in China. Therefore, our systematic review and meta-analysis aims to determine the risk factors associated with HAIs among paediatric hospitalized patients in Chinese general hospitals, which are different from specialty hospitals.

Systematic search strategy
The PICO/S (Population, Intervention, Comparison, Outcome, and Study type) tool was applied to de ne the scope of the literature. The speci c details are as follows. Chinese corresponding search terms in the title, abstract and keywords included healthcare-associated infections/cross infections/hospital acquired infections/nosocomial infections, risk factors/in uencing factors, paediatric department/children/adolescent and China for the Chinese databases (CNKI, Wan Fang, and VIP ). As to Medline and EMBASE, the medical subject heading (MeSH) terms in keywords were adopted, including "cross infection" AND "risk factors" AND "paediatrics" OR "children" OR "adolescent" OR "child" OR "paediatrics" AND "China".

Inclusion and exclusion criteria
The inclusion criteria were as follows: 1) risk factors analysis with a case-control, cohort or cross-sectional study; 2) a multi-centre study or a single-centre study; 3) study language being either English or Chinese; 4) general hospital(s) (non-speciality hospitals); 5) any study published between 1st January 2001 and 31st December 2020.
The exclusion criteria were as follows: 1) conference papers or editorials/letters; 2) duplicate studies and repeated data published in different journals or in theses and journals concomitantly; 3) any study outside China; 4) any study reporting only on speci c hospital units rather than overall hospital setting (e.g. neurosurgery) or disease (e.g. pneumonia) or infection type (e.g. ventilator-associated pneumonia); 5) only description on the prevalence or landscape of HAIs; 6) risk factors concluded without any statistical inference (e.g. only description or summary) and only based on the researchers' perspective.

Data abstraction
Three independent reviewers (D.Y., L. C. and X.L.) searched the relevant published articles on risk factors for HAIs among paediatric hospitalized patients from the included databases. Initial screening of the searched published articles was conducted by screening the titles, abstracts and keywords. The eligibility for the articles was scrutinized by reading the full text according to the inclusion and exclusion criteria. The eligibility for 10% of the included studies screened by each reviewer was checked again by other two reviewers to determine whether it was appropriate. Disagreement on the included studies was dealt with based on the discussion within the three reviewers.

Quality assessment
The JBI' (Joanna Briggs Institute) critical appraisal tools were employed to assess the quality of the included studies conducted by the three reviewers (D.Y., L. C. and X.L.) (16). This tool includes 8 questions to identify the quality of a cross-sectional study, 10 questions to determine the quality of a case-control study, and 11 questions to assess the quality of a cohort study. For each question, there are 4 options to choose (Yes, Unclear, No and Not applicable). The less the number of a positive option (Yes) is, the more the uncertainty of a study is. Otherwise, the quality of a study is better. Besides, 0-2 points were assigned to each question. That is, 'Yes' is equal to 2 points; 'Unclear or Not applicable' is equal to 1 point; and 'No' is equal to 0. Therefore, the higher scores of a study get, the better quality of this study is.

Statistical analysis
Review Manager 5.3 software was deployed to estimate the risk factor odds ratio (OR) to show the level of risk that each factor between the HAIs pediatric hospitalized patients and the pediatric hospitalized patients without HAIs. Moreover, the forest plot was applied to show the results of the pooled OR of each risk factor.
Heterogeneity between studies was assessed based on the 2 and I 2 statistics to select the meta-analysis model. When results had a 2 (P ≤ 0.05) and/or I 2 > 50%, data were considered heterogeneous and thê τ ˆ τ random-effects model was used; otherwise, the xed-effects model was used. P < 0.05 was set as the statistical signi cance.

Results
Characteristics of the eligible studies from the database search Figure 1 exhibits that generally, 205 published articles were screened from the database search. After screening the full text with the inclusion and exclusion criteria, 15 publications were included in the quantitative synthesis and meta-analysis for the risk factors associated with the HAIs prevalence among paediatric hospitalized patients. Table 1 presents that totally, 61,773 paediatric hospitalized patients were included in the 15 included studies, which covered 13 regions in 10 provinces of China. Speci cally, 2,438 patients were identi ed as having HAIs, while 59,335 patients did not have HAIs. The majority (11/15) of the included studies were retrospective cross-sectional studies; 2 studies were retrospective case-control studies; one was retrospective cohort study; and one was retrospective and prospective study. Besides, most of the studies (9/15) were conducted in tertiary hospitals, while the rest were undertaken in secondary hospitals.
Frequency of the identi ed risk factors from the included studies Table 2 shows a total of 20 risk factors on HAIs were identi ed from the 15 included studies. The most frequent risk factors were length of hospitalization (14/15), age (10/15), gender (5/15) and number of kinds of antibiotics use (5/15). The risk factors were not incorporated in the meta-analyses since the frequency was less than 2. In addition, although the classi cation of the age and length of hospitalization was different among the included studies, we adopted the most frequent classi cation used in the included studies for the meta-analyses. With regard to the length of time of antibiotics use, due to the inconsistent classi cation used in both studies (17,18), it was also excluded in the meta-analysis.

Quality assessment of all the included studies
With regard to the 13 cross-sectional studies, the median points were 10 (medium points). It indicated the overall quality of the cross-sectional studies was fair, which needed to be improved. All of the studies clearly de ned the inclusion for the pediatric hospitalized patients and set the outcomes measured in a valid and reliable way. However, some of the cross-sectional studies needed to be improved in study design, including describing the study setting in more detail, providing the speci c de nition and inclusion and exclusion criteria for the HAIs pediatric hospitalized patients etc. Only two case-control and one cohort studies were included in this systematic review. The overall quality of the case-control studies was good since one study got 17 points, while the other study got 18 points. Both of them also needed to provide the clear information about the outcome measurements and how to measure the exposure. The quality of the cohort study was poor (10 points). It did not clearly depict the follow-up time and how to deal with the incomplete follow-up. Also, it did not provide the clear information about the outcome measurements and how to measure the exposure. Quality assessments of the included studies are exhibited in Supplementary material (Appendix 1: Table 1, 2, and 3).
Meta-analyses of the included risk factors Table 3 presents the pooled ORs of the risk factors estimated in the meta-analyses between the paediatric hospitalized patients with HAIs and the paediatric hospitalized patients without HAIs. 11 risk factors were analysed in the meta-analysis. Speci c information is as follows. The forest plots of the included risk factors are shown in Supplementary material (Appendix 2: Figure 1-1 to 1-11).

Discussion
Our systematic review and meta-analysis rst provided the pooled ORs of the risk factors associated with the higher HAIs prevalence among the paediatric hospitalized patients in Chinese general hospitals, which covered 61,773 paediatric hospitalized patients were included in the 15 included studies distributing 13 regions in 10 provinces of China. Of them, 2,438 patients were identi ed as having HAIs. Besides, our study shows that age, gender, hormone, invasive procedures, length of hospitalization, malnutrition, number of kinds of antibiotics, number of underlying disease, room size, and seasons were the independent risk factors associated with the higher HAIs prevalence among the paediatric hospitalized patients with a statistical signi cance (P < 0.05). Our ndings could provide the evidence bases to develop the personalised prevention and control measures to reduce the HAIs occurrence among paediatric hospitalized patients in China.
Our review found that paediatric hospitalized patients under the age of 1 year were at higher risk to get HAIs than those beyond the age of 1 year. This is similar to another study carried out in Pennsylvania among paediatric healthcare-associated pneumonia, which showed that children who were younger than 1 year were the most cases (33,34). Among the children patients below the age of 1 year, particularly the neonates (age ≤ 30 days), due to the increasing number of low weight children, preterm infants, and critically ill children, they are more hazardous to acquire HAIs, especially those in NICU (35). Jansen et al. recommended that human milk feeding is one of the cost effective measures to reduce the likelihood of getting HAIs, because human milk feeding contains numerous substances and bioactive compounds with putative antimicrobial actions, thus decreasing the risk of acquiring HAIs (1). Furthermore, the neonates should be set as the particular high-risk patients given special protective measures.
Application of hormone, malnutrition, and presence of more than 3 kinds of underlying disease among paediatric hospitalized patients was found as main risk factors for acquiring HAIs in our review. Although hormone, especially glucocorticoid, could resist virus, in ammation, and allergy and so on, the long-term use of hormone severely impairs the children's growth and development, and internal secretion, thus increasing the chance of getting HAIs (21). Nutrition is one of the ways to build up the children's immune systems, thereby increasing the resistance to HAIs (36). However, the underlying disease increases the susceptibility of paediatric hospitalized patients, so that they are more prone to getting secondary infections due to the reduction of the patients' immune response (3,37).
Our review also found that paediatric hospitalized patients with invasive procedure were over 5 times more hazardous to obtain HAIs than their counterparts. Many studies have reported that invasive procedure, such as surgery, mechanical ventilation, and central venous catheter and so on increased the risk of obtaining HAIs among paediatric hospitalized patients (11,38). The hazard of getting HAIs among paediatric hospitalized patients staying in hospital more than 7 days was over 7 times higher than their counterparts. This nding is consistent to the current literature (3,11). The prolonged hospitalization stay increases the likelihood of acquiring HAIs, whereas the presence of HAIs also extends the hospitalization stay, which is a positive association (23). This further aggravates the di culty of treatment of the disease and augments the medical expenditure.
The risk of acquiring HAIs in paediatric hospitalized patients who used more than 3 kinds of antibiotics were over 3 times higher than those using less than 3 kinds of antibiotics, which is consistent with the study conducted among paediatric hospitalized patients with multi-drug resistant infection in PICU (11). Multiple varieties of antibiotics applied in paediatric hospitalized patients change the children's physiology and biochemistry, leading to weakening the children's immune system to the bacteria (11,39). This can increase the risk of obtaining HAIs. The United States has acknowledged that the antimicrobial treatment is the most sensitive proxy indicator for the presence of HAIs (40). This indicates that the clinical doctors need to be prudent when giving antibiotics prescription to the paediatric hospitalized patients. Overuse of antibiotics is associated with the presence of antimicrobial resistance (AMR), which further impairs the patients' safety (4).
Paediatric hospitalized patients staying in a large inward and admitted to the hospitals in autumn or winter were more likely to acquire HAIs than their counterparts suggested by our review. On one hand, children need to be cared for by their parents or guardians when they are in hospital, which results in quite frequent visits, especially in a large paediatric room (23). Therefore, this leads to increasing the occurrence of cross infection. Frequent disinfection based on the perfect execution, decreasing visits to the wards and effective isolation measures are necessary for the reduction of HAI among paediatric hospitalized patients. On the other hand, healthcare-associated respiratory infections are the most common HAIs in paediatric inwards, which happens more frequently in autumn and winter. Therefore, it is essential to contain HAIs in autumn and winter.
After completing the identi cation of the risk factors associated with higher HAIs prevalence among paediatric hospitalized patients, it is necessary to adopt corresponding prevention and control measures to reduce the occurrence of HAIs, thus decreasing the mortality, morbidity and economic burden for patients and the whole society. Generally, a number of evidence-based prevention and control measures are recommended in current studies and have been con rmed successful (1). For example, washing hands is supposed to be the easiest cost-effective measure to decrease the risk of HAIs. Jansen et al. have recently suggested that quality improvement on cooperation and benchmarking is most promising for reduction in HAIs. Identifying and implementing the best practices, and selecting the quantitative measurements are two of the examples recommended in this study (1).
Our systematic review and meta-analysis has some limitations as well. First, our systematic review only included the Chinese general hospitals. Other types of hospitals, like speciality hospitals were excluded. Therefore, the whole picture of the risk factors for HAIs among paediatric hospitalized patients in China is not yet to be shown in this review. Second, present included studies lack quality in study design. It calls for a more comprehensive study design to conduct the similar study in the future in China.

Conclusions
Under the age of 1 year, application of hormone, experiencing invasive procedure, hospitalization stay longer than 7 days, malnutrition, using more than 3 kinds of antibiotics, beyond 3 kinds of underlying disease, large room, and autumn and winter were the main risk factors associated with the higher prevalence of HAIs among paediatric hospitalized patients in Chinese general hospitals. This provided the evidence base to inform the policy-makers and hospital managers when developing prevention and control strategies. The con rmed successful and cost-effective prevention and control measures need to be adopted to reduce the occurrence of HAIs.

Declarations
Ethics approval and consent to participate It is not applicable.

Consent for publication
It is not applicable.

Availability of data and materials
The datasets and materials analysed during the current study are available from the corresponding author on reasonable request.

Competing interests
Page 10/17 The author(s) declared no potential con icts of interest with respect to the research, authorship, and/or publication of this article.