Risk factors associated with nosocomial infections among end stage renal disease patients undergoing hemodialysis: A systematic review.

BACKGROUND: Profound healthcare challenges confront societies with an increase in prevalence of end-stage renal disease (ESRD), which is one of the leading causes of morbidity and mortality worldwide. Due to several facility and patient related factors, ESRD is significantly associated with increased morbidity and mortality attributed to infections. AIMS AND
OBJECTIVE: The aim of this study was to assess systematically the characteristics of patients and risk factors associated with nosocomial infections among ESRD patients undergoing hemodialysis.
METHODS: A systematic literature search was performed to identify eligible studies published during the period from inception to December 2018 pertaining to risk factors associated with nosocomial infections among hemodialysis patients. The relevant studies were generated through a computerized search on five databases (PubMed, EBSCOhost, Google Scholar, ScienceDirect and Scopus) using the Mesh Words: nosocomial infections, hospital acquired infections, healthcare associated infections, end stage renal disease, end stage renal failure, hemodialysis, and risk factors. The complete protocol has been registered under PROSPERO (CRD42019124099).
RESULTS: Initially, 1411 articles were retrieved. Out of these, 24 were duplicates and hence were removed. Out of 1387 remaining articles, 1337 were removed based on irrelevant titles and/or abstracts. Subsequently, the full texts of 50 articles were reviewed and 41 studies were excluded at this stage due to lack of relevant information. Finally, nine articles were selected for this review. Longer hospital stay, longer duration on hemodialysis, multiple catheter sites, longer catheterization, age group, lower white blood cell count, history of blood transfusion, and diabetes were identified as the major risk factors for nosocomial infections among hemodialysis patients.
CONCLUSION: The results of this review indicate an information gap and potential benefits of additional preventive measures to further reduce the risk of infections in hemodialysis population. Moreover, several patient-related and facility-related risk factors were consistently observed in the studies included in this review, which require optimal control measures.

Introduction

Profound health care challenges confront societies with an increase in prevalence of end-stage renal disease (ESRD), which is one of the leading causes of morbidity and mortality throughout the world [1]. It has been estimated that the global prevalence of patients undergoing maintenance hemodialysis (HD) increased by 1.7 times from 165 patients per million population (pmp) in 1990 to 284 patients pmp in 2010 [2]. Moreover, the global prevalence of ESRD and use of renal replacement therapy (RRT) have been projected to more than double by the next decade [1, 3]. Chronic diseases, such as ESRD, limit daily activities and affect health-related quality of life (HRQoL) of patients. Cardiovascular diseases (CVD) and infections are the major causes of deaths among these patients, together accounting for up to 70% of all deaths [4].

ESRD is significantly associated with higher mortality attributed to infections, which account for almost 20% of all deaths in these patients [4]. These patients have frequent hospital visits and more extended hospital stays, which make them more vulnerable to nosocomial infections [5]. It is possible that this complication is related to alterations in the immune system in ESRD, as uremia is linked with a state of immune dysfunction characterized by immunosuppression [4]. In addition, patients with immunodeficiency who undergo RRT could be malnourished, and the resulting imbalance in bacteria, viruses, fungi, and other microorganisms in the body could also increase the risk of nosocomial infections [6]. These infections not only affect the quality of life (QOL) of ESRD patients, but also add extra economic burden [7].

Risk factors associated with nosocomial infections in ESRD patients who are on HD are still poorly understood, and the clinical epidemiology of these infections has still not been defined adequately in the previous literature. Therefore, this review was conducted to assess systematically the characteristics of patients and risk factors associated with nosocomial infections in these patients who were receiving HD.

Methods

We systematically identified the articles related to risk factors associated with nosocomial infections among ESRD patients, which had been published in scientific literature during the period from inception to December 2018. We followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines for the preparation of this review [8]. The protocol of this systematic review has been registered under PROSPERO (CRD42019124099).

Data sources and search methods

Relevant papers published in the literature were generated through a computerized search on five databases (PubMed, EBSCOhost, Google Scholar, ScienceDirect and Scopus) using the following Mesh Words: nosocomial infections, hospital acquired infections, healthcare associated infections, end stage renal disease, end stage renal failure, HD, and risk factors. These Mesh words search was performed through title and abstract only. For PubMed search, the Boolean search of (("Cross Infection"[Mesh]) AND ("Kidney Failure, Chronic"[Mesh] OR "Renal Dialysis"[Mesh] OR "Hemodialysis, Home"[Mesh] OR "Hemodialysis Units, Hospital"[Mesh]) AND ("Risk Factors"[Mesh])) was used. The same search terms were used for EBSCOhost, Google Scholar, ScienceDirect, and Scopus databases.

Inclusion/Exclusion criteria

Studies on risk factors associated with nosocomial infections among ESRD patients undergoing HD published during the period from inception to December 2018 were included in this review. Moreover, studies conducted on ESRD patients who were on HD with one or more episodes of nosocomial infections were included. Only quantitative studies and studies done on patients above 12 years of age were considered. Systematic literature reviews, abstracts, scientific correspondence, posters, animal studies, case reports, advertisements, thesis, and opinions were excluded. In addition, studies conducted on ESRD patients with infections other than nosocomial infections were also excluded. Qualitative studies and studies published in a language other than English were not included in this review. Similarly, studies without clearly stated outcomes or studies conducted in pregnant patients were excluded.

Data extraction (Selection and coding)

Retrieved articles, after preliminary searches, were imported to Endnote X7 and the duplicates were removed. Two reviewers, SHA and RAA, independently evaluated the articles for eligibility through screening of the titles and abstracts. After a preliminary screening, a full-text assessment was carried out for the final selection of articles. Any disagreement regarding the eligibility of studies between the two authors was resolved through agreement and discussion in the team meetings. Finally, all authors agreed with the selection of the final studies for the review. One reviewer (SHA) rechecked selected studies for the validation of screening procedure.

A data extraction form was developed to retrieve all the relevant information from the selected articles. The items of the data extraction form were finalized after mutual agreement between two authors SHA and RAA. These items included, author’s name, year and duration of the study, study design, respondents, demographics of the patients (sample size, gender, and age), type of nosocomial infections studied, type of pathogens involved, and risk factors associated with nosocomial infections.

Risk of bias/Quality assessment

Risk of bias (quality) assessment was undertaken by two reviewers (SHA and RAA) by using Newcastle Ottawa scale (NOS) for observational studies [9]. In Newcastle Ottawa scale, stars are awarded for three categories: “Selection,” “Comparability,” and “Outcome,” and each of these three categories was divided into subcategories. For each study, a maximum one star could be awarded for each subcategory. However, a maximum of two stars could be given for “Comparability” category [9]. The maximum number of 9 stars could be achieved for a single study, which indicates the complete the absence of any bias [9]. The Newcastle Ottawa scale scores were later converted into Agency for Healthcare Research and Quality (AHRQ) standards (good, fair, and poor), for final quality assessment of the studies. The number of stars for each study was calculated and this indicated the quality of the study as good, fair and poor. For good quality, a study must have 3 or 4 stars, 1 or 2 stars and 2 or 3 stars in ‘Selection’, ‘Comparability’ and ‘Outcome’ domains respectively. Similarly, for fair quality, a study must 2 stars, 1 or 2 stars, and 2 or 3 stars in ‘Selection’, ‘Comparability’ and ‘Outcome’ domains respectively. Finally, for poor quality, a study must have 0 or 1 star, 0 star, or 0 or 1 star in ‘Selection’, ‘Comparability’ and ‘Outcome’ domains respectively [9, 10]. Decision on quality and eligibility of studies was based on consensus, and SSC acted as an adjudicator in case of any disagreement.

Data synthesis

A systematic review was performed to make sure that all data synthesis done was sourced from the maximum possible, and complete collection of relevant literature. Furthermore, a reference check and contact with reference authors were also performed to identify relevant work and studies. Only qualitative analysis was undertaken.

Results

Initially, 1411 studies were retrieved. Out of these, 1039 studies were retrieved from EBSCOhost, 193 from ScienceDirect, 68 from Scopus, 66 from Google scholar, and 45 from PubMed database. Twenty four (24) of these 1411 studies were duplicates, and hence they were excluded. The remaining 1387 studies were screened based on titles and abstracts, of which 1337 articles with irrelevant titles and/or abstracts were removed. Subsequently, the full texts of remaining 50 articles were reviewed, where 41 of these studies were removed as they did not contain the relevant information or failed to meet our inclusion criteria. Eventually, nine articles were selected for this review (Fig 1).

Fig 1

Schematic diagram showing the assortment of studies and study selection process (2009 PRISMA flow diagram) [8].

Evaluation of study quality

The quality rating of majority of the studies in this review was fair [11-16], while three studies had a maximum score, and were rated as good quality studies [17-19]. Table 1 shows the detail quality scoring of the studies.

Table 1

Quality assessment using the Newcastle Ottawa Scale and AHRQ guidelines [9, 10].

First Author	Selection				Comparability	Outcome		Total quality scores	Quality rating according to guidelinesa
	Representativeness of the sample	Sample size justified/Not justified	Non- Respondents	Ascertainment of the exposure (Risk factor)	Comparability of different outcome groups	Assessment of the outcome	Statistical test
D’Agata (2000)[11]	*	Nil	*	Nil	*	**	*	6	Fair
MatíasGnass (2014)[12]	*	Nil	*	Nil	*	**	*	6	Fair
Luyu Tang (2016)[17]	*	Nil	*	*	*	**	*	7	Good
Jae-Uk Song (2017)[13]	*	Nil	*	Nil	*	**	*	6	Fair
Geoffrey Taylor (2003)[14]	*	Nil	*	Nil	*	**	*	6	Fair
Ping-huai Wang (2016)[15]	*	Nil	*	Nil	*	**	*	5	Fair
CokordaAgung (2016)[16]	*	Nil	*	Nil	*	**	*	7	Fair
Hussein Yousif (2018)[18]	*	Nil	*	*	*	**	*	7	Good
Komal Patel (2015)[19]	*	Nil	*	*	*	**	Nil	7	Good

aNOS rating conversion to AHRQ standards (good, fair, and poor):

For good quality, a study must have 3 or 4 stars, 1 or 2 stars and 2 or 3 stars in ‘Selection’, ‘Comparability’ and ‘Outcome’ domains respectively.

For fair quality, a study must 2 stars, 1 or 2 stars, and 2 or 3 stars in ‘Selection’, ‘Comparability’ and ‘Outcome’ domains respectively.

For poor quality, a study must have 0 or 1 star, 0 star, or 0 or 1 star in ‘Selection’, ‘Comparability’ and ‘Outcome’ domains respectively.

A maximum of one star can be awarded for each subcategory within the Selection and Outcome categories. A maximum of two stars can be awarded for Comparability category.

Characteristics of the selected studies

The major characteristics of 9 studies included in this review are described in Table 2. Two studies were conducted in the United States (US) [11, 12], and one each in of the China [17], South Korea [13], Canada [14], Taiwan [15], Indonesia [16], Iraq [18], and India [19]. Five studies utilized cross-sectional [12, 13, 15, 16, 18] study designs, one was retrospective cohort and case control study [11], and two were longitudinal or prospective studies [14, 19]. Tang et al. 2016, adopted a mixed study design (incorporating both cross-sectional and longitudinal study designs) [17]. There were large variations in sample size of the included studies, ranging from 105 [13] to 890 participants [17]. In a case-control study conducted by Erika et al. 2000, only 29 cases and 29 controls were included [11].

Table 2

Study characteristics.

Author	Year and study duration	Study design	Respondents	Demographics	Type of infections	Type of microorganismsn (%)	Percentages of nosocomial infections n (%)	Risk factors
D’Agata et al. [11]	1995 to 199730 months	Retrospective cohort and case control study	Case group -ESRD patients undergoing HD with nosocomial infectionControl group—ESRD patients on HD without nosocomial infections	N = 365 Patients for overall studyN = 58 patients for Case-control studyMean age = 55 (SD = 8) years	- Pneumonia,- Primary bloodstream infections,- UTIs,- Diarrhoea	Enterococcus spp: 6 (13%), Candida spp: 8 (17%), Enterobacter spp: 6 (13%), Pseudomonas aeruginosa: 5 (10%), Staphylococcus aureus: 3 (6%), and Escherichia coli: 3 (6%)	Total 47 (100%) UTIs 22 (47%),BSI = 13 (28%),Pneumonia 9 (19%),Clostridium difficile diarrhoea 3 (6%)	- Chronic HD (RR, 2.4; 95% CI, 1.8 to 3.2; P—0.001).
MatíasGnass et al. [12]	2011 to 201224 months	Cross sectional study	Patients on HD	N = 619Mean (SD) age: 57 (15) years	- HABSIs	Total 14 (100%)–gram positive cocci: 9 (64%) with a predominance of 8 staphylococcal infections Candida spp: 3 (21%).	HABSI 14 (100%)	- Length of hospital stay (r = 0.82; 95% CI: 0.79–0.83, P <0.05)- Number of HD sessions (r = 0.56; 95% CI: 0.52–0.61, P <0.05)- HbA1c levels greater than 7% (OR, 3.62; 95% CI: 1.15–11.4, P <0.05).
Tang et al. [17]	2012 to 201436 months	Cross sectional and longitudinal study (Mixed study design)	Patients on HD	N = 890	All nosocomial infections	Total 98 (100%)—Gram negative bacilli—47 (47.94%), Gram positive bacilli—44 (44.9), and Fungi—7 (7.14%)	Total 110 (100%)–LRTI = 43 (39%),URTI = 23 (20.9%),- catheter-related infection19 (17.27%),- UTIs 13 (11.81%),- and GIT infection. 4 (3.6%)	- Multiple comorbidities (OR, 1.66; 95% CI:1.35~2.49)- Longer duration of HD (OR, 1.79; 95% CI: 1.35~2.59)- More catheter sites (two or more) (OR, 1.12; 95% CI: 1.02~1.85)- Low Hb concentration (OR, 0.19; 95% CI: 0.09~0.33)- Low WBC count (OR, 0.3; 95% CI: 0.14~0.42)- Long duration of catheterization (OR, 1.2; 95% CI: 1.09~1.44)
Jae-Uk et al. [13]	2011 to 201560 months	Cross sectional study	Patients on HD	N = 105Median age—71 years	- HDAP	Total 53 (100%)–S. aureus 17 (16.1%)K. pneumoniae 11 (10.4%), S. pneumoniae 10 (9.5%).	HDAP (100%)	- PSI score > 147 (OR, 1.023; 95% CI: 1.005–1.041)- Recent hospitalization (OR, 2.951; 95% CI:1.022–8.518)
Taylor et al. [14]	1998 to 19996 months	Longitudinal or Prospective studies	Group 1: All new patients on HDGroup 2: HD with a new vascular access	N = 527 (Cohort study)N = 186(Case control study)	Blood stream infection (BSI)	Total 96 (100%); coagulase-negative staphylococci 45%,S aureus 28.1%, enterococcus 8.8%, aerobic gram-negative bacilli 8.6%.	HABSI—100%	- Prior BSI (OR, 6.56; P = .004),- Poor patient hygiene (OR, 3.48; P = .001),- Contiguous infection (OR, 4.36; P = .002).
Wang et al. [15]	2005 to 201072 months	Cross sectional study	They were enrolled if they fulfilled the criteria for HCAP	N = 530 (48 HD, 482 Non-HD)Mean Age = 68.3 ± 11.3 (HD group),75.8 ± 12.8 years (Non-HD group)	- HCAP	Total 48 (100%)–β-Streptococcus 2(4.2%), K. pneumoniae 2(4.2%), E. coli 3(6.3%)Causative pathogens resistant to CAP antibiotics regimenMRSA 5(10.4%),P. aeruginosa 8(16.7%)	HDAP (100%)	- Wound care (OR, 4.73; 95% CI: 1.13–19.7),- Old age (more than 70 years) (OR, 3.81; 95% CI: 1.07–13.5)- PSI V (OR, 3.49, 95% CI: 1.08–12.1).
Agung et al.[16]	20164 months	Cross sectional study	All hospitalized patients who underwent HD.	N = 267Mean (SD) age = 54.07 (0.80) years	Hepatitis B infection	HBV (100%)	Hepatitis B infection (100%)	- Duration of HD (OR, 1.07; 95% CI: 1.03–3.74)- History of previous transfusion(OR, 2.49; 95% CI: 1.29–8.18)
Hussein et al. [18]	2015 to 20166 months	Cross sectional study	All hospitalized patients who underwent HD.	N = 510Mean (SD) age = 48 (12) years	Hepatitis B and C infection	HBV and HCV (100%)	Hepatitis B and hepatitis C infection (100%)	HBsAg positivity:- Young age (mean age: 39.2 ± 14.6 years) (P < 0.04),- History of HD (P = 0.005).HCV positivity:- Old ages (mean age: 55 ± 12years) (P < 0.05),- Longer duration of HD (P < 0.05),- History of surgical and dental procedures (P < 0.05)
Patel et al. [19]	2014 to 201515 months	Longitudinal or Prospective studies	Patients who were on HD for a minimum period of 1 month and were likely to be available for follow-up for at least 6 months, were included in the study.	N = 170	Hepatitis B and C infection	HBV and HCV (100%)	Hepatitis B and Hepatitis C infection (100%)	- Positive history of blood transfusions- Number of blood transfusions

HD = Hemodialysis, ESRD = End stage renal disease, UTI = Urinary tract infection, LRTI = Lower respiratory tract infection, URTI = Upper respiratory tract infection, HCAP = Healthcare associated pneumonia, HDAP = Hemodialysis associated pneumonia, CAP = Community acquired pneumonia, GIT = Gastrointestinal tract,BSI = Bloodstream infection, MRSA = Meticillin resistant staphylococcus aureus, HBV = Hepatitis B virus, HCV = Hepatitis C virus,HBsAg = Hepatitis B surface antigen, HABSI = Hemodialysis associated bloodstream infection, WBC = White blood cell, HB = Hemoglobin, N = Sample size, PSI = Pneumonia severity index, SD = Standard deviation, OR = Odd ratio, CI = Confidence interval, RR = Relative risk.

Most of the studies included only elderly people undergoing HD. The mean age was utilized for the analysis of all the studies. Erika et al. 2000, conducted a case control study, whereby ESRD patients undergoing HD with and without nosocomial infections were assigned to case and control groups respectively [11]. In the study by Wang et al. 2016, the respondents were patients with nosocomial infections, and further subgroups were formed based on patients with and without HD [15].

Two studies were conducted specifically on HD associated blood stream infections (HABSI) [12, 14], while another two studies were on HD associated pneumonia (HDAP) [13, 15]. Erika et al. 2000, reported risk factors related to four nosocomial infections, including, pneumonia, urinary tract infections (UTIs), bloodstream infections, and diarrhoea [11]. Various risk factors associated with all types of nosocomial infections were studied by Tang et al. 2016. [17].

The most frequent pathogens associated with nosocomial infections varied among different studies. Erika et al. 2000, found that candida species (spp) and enterococci were the most common pathogens involved in infections among patients undergoing chronic HD [11]. Another study identified staphylococcus as the main pathogen causing HD-associated nosocomial infections, followed by candida spp [12]. Jae-Uk et al. 2017, found that of the total 53 pathogens responsible for nosocomial infections, the main pathogen involved was Staphylococcus aureus (16.1%), followed by Klebsiella pneumoniae (10.4%) and Streptococcus pneumonia (9.5%) [13]. Similarly, the microbial aetiology of nosocomial infections found by Taylor et al. 2003, were coagulase-negative staphylococci 45%, S. aureus 28.1%, enterococcus 8.8%, and aerobic gram negative bacilli 8.6% [14].

Most of the studies included in this review studied one particular nosocomial infection, such as HD-associated bloodstream infection (HABSI), hospital acquired pneumonia (HAP), and certain viral infections [12–16, 18, 19]. Erika et al. 2000, showed that out of 47 episodes of nosocomial infections, nosocomial UTIs were the most common nosocomial infection among HD population, accounting for nearly half of these infections (47%), followed by bloodstream infections (28%), and pneumonia (9%) [11]. Another study reported 110 cases of nosocomial infection occurred, including 66 cases of respiratory tract infections (RTIs), 19 cases of catheter-related infections, 13 cases of urinary tract infections, 4 cases of gastrointestinal infections, and 8 cases of infections in other organ systems [17].

Outcomes

Some studies reported that longer duration of HD was a risk factor associated with nosocomial infections [16-19], while a positive correlation was determined between HABSI and diabetes, number of HD sessions, and length of hospital stay [12]. Risk for a HABSI increased significantly with HbA1c levels above 7% [12]. There were studies which showed a significant relationship between nosocomial infections and age of patients [15, 16, 18], with HBV infections being more common in relatively younger individuals (mean age: 39.2 ± 14.6 years), while there was a strong relationship between HCV infections and relatively older age group (mean age: 55 ± 12 years) [16, 18]. A positive history and number of blood transfusions were both significantly associated with HBV or HCV infection [16, 19]. Moreover, patients with multiple co-morbidities, with more catheter sites (two or more), low hemoglobin concentration, low white blood cells count, and longer duration of catheterization were found to be at more risk of developing nosocomial infections [17]. Another study showed that history of bloodstream infections, contiguous infections at surgical site and poor patient hygiene were all independently associated with the occurrence of bloodstream infections [14].

Discussion

The comprehensive search strategy applied in this review identified nine studies which described the characteristics of patients and risk factors associated with nosocomial infections in ESRD patients receiving HD. Except for one study [11], the results of all the studies were consistent with a positive direction of association between several risk factors and the occurrence of infections in hemodialysis HD patients [12-19]. This review used sensitive search strategy with a broad definition of ESRD, for a comprehensive and inclusive search. The results of this review are consistent with previous narrative reviews that is, an association between ESRD and infections is likely, but still there is a scarcity of the available evidence regarding the risk factors and nosocomial transmission of these infections. Based on the published literature, several risk factors associated with nosocomial infections in HD population were identified. These included factors indicating reduced patient health status such as co-morbidities, poor patient hygiene, prior infections, advanced age, low WBCs count, low hemoglobin, and catheterization. Other important risk factors included longer hospital stay, longer duration on HD, and more HD sessions. The risk factors identified are biologically convincing, which suggests that patients with more health problems that is, those with multiple co-morbidities, have higher in-hospital exposure time, and/or are undergoing longer and more complex procedures are at an increased risk of acquiring nosocomial infections. Major risk factors identified in the current review are depicted in Fig 2.

Fig 2

Major risk factors identified in this review.

Longer duration on HD is an important risk factor for nosocomial infections in HD population [16, 18, 19], since patients on chronic HD are at a higher risk of exposure to pathogens than those patients with lesser time on HD. Furthermore, an increase in the duration of dialysis increased the number of venipuncture events and therefore, the risk of related infections [17]. These results are consistent with that of previous studies which showed that the duration of dialysis was longer for patients who were seroconverted than those who remained seronegative for HBV and HCV infections [20-24]. The high incidence of infections in patients on HD for 2 years or more suggests that conditions in the hemodialysis HD unit might have contributed to nosocomial infections [25]. However, the duration on HD is not a modifiable factor and hence, the focus should be on other modifiable factors that can be altered through the implementation of strict infection control guidelines. In the present review, HABSI was significantly associated with risk factors including length of hospital stay and number of HD sessions [12]. Both of these factors directly exposed the patients to the infection agents for prolonged period of time, hence making them more prone to nosocomial infections.

In the present review, patients with diabetes were at higher risk of getting a nosocomial infection than non-diabetes patients [12]. The same was found with increasing HbA1c values above 7% [12]. Better glycemic control has been associated with longer survival in diabetes patients with ESRD undergoing HD, and poor glycemic control increases mortality due to infectious diseases [26-28]. Furthermore, HbA1c ≤ 8% and good glycemic control provide reasonable protection against infections caused by hyperglycemia [29]. It has been well documented that diabetes patients on HD have higher risk of morbidity and mortality due to infections compared to non-diabetes patients [29, 30].

Hyperglycemia caused many adverse effects on immune system mechanisms, both cellular and humoral [31]. Moreover, increased virulence of pathogens, reduced production of interleukins in infection, decreased chemotaxis and phagocytosis, immobilization of neutrophils, glycosuria, urinary and gastrointestinal dysmotility are the main pathogenic mechanisms for infections to occur in the hyperglycemic environment [31]. This implies that good glycemic control reduces the risk of infections in diabetes patients with ESRD and on HD. Even in non-diabetes patient population, stress due to HD often leads to hyperglycemia and hence, this should be monitored and treated. Efficient management of glycemic levels can help to reduce the occurrence of infections.

The results of the present review show that HBV infection is more common in relatively younger patients [16, 18]. This is in agreement with another study done in Libya [32], but the reason for this is unclear. On the other hand, patients infected with HCV were on an average older than non-infected individuals [18]. This observation is congruent with other studies, which showed that the prevalence of HCV infection in HD patients was higher in age group of 40 to 50 years [22, 33]. This may be due to the higher rate of renal diseases in older people than younger people. The aggregation of clinical co-morbidities with advancing age (as on an average, those who are 75 year old have 3 to 4 chronic diseases) [34], management of HD-related issues such as vascular access and infection complications, must be addressed with caution. Therefore, clinicians must incorporate screening and treatment strategies for various HD associated complications in elderly people, including infections, in their routine plan of care.

A positive history and number of blood transfusions are both significantly associated with HBV or HCV infections [16, 19]. Previous studies have shown that the risk of acquiring HBV or HCV infections increases with an increase in the number of blood transfusions [35-37]. Before the use of an effective screening process, blood transfusions were recognized as a major source of nosocomial transmission of HBV and HCV infections. It is still possible that blood donors with HBV or HCV are being overlooked by the current screening procedures and this may need to be readdressed [38]. Therefore, thorough screening of blood donors for HBV and HCV is essential to prevent nosocomial transmission.

Patients with two or more catheter sites or longer catheterization duration are significantly more likely to have nosocomial infections than those with one catheter site and shorter catheterization duration [17, 39, 40]. Catheter related infection (CRIs) in HD patients is one of the major causes of increased morbidity, mortality, and cost of therapy [41-43]. The most effective prevention strategy for these infections is to reduce the use of catheters [44]. Efforts should be made through patient education and vascular access coordinator to reduce the use of catheters by identifying and addressing barriers to permanent vascular access placement and catheter removal [45]. Centers for disease control (CDC) has also recommended other interventions such as hand hygiene, patient and staff education and skin antisepsis to decrease the risk of these infections [46].

In regard to type of vascular access, a study has shown that infection rates were highest for non-tunneled catheters (5.5 per 1,000 hemodialysis sessions), followed by AV grafts (13.51 per 1,000 hemodialysis sessions), tunneled catheters (2.39 per 1,000 hemodialysis sessions), and AV fistula (0.9 per 1,000 hemodialysis sessions) [12]. Another study reported that infection rates per 10,000 procedures were 40.26 for uncuffed CVCs and 45.26 for cuffed CVCs, 7.97 for arteriovenous grafts, and 5.02 for arteriovenous fistula [14].

The present study also showed that low blood Hb concentration was associated with nosocomial infections [17]. Previous observational study which investigated risk factors for bloodstream infections (BSIs) in HD patients concluded that low Hb concentration (approximately 105 g/L) was significantly associated with these infections [47]. One of the possible explanations is the prevalence of malnutrition in dialysis patients, as evidenced by reduced blood Hb and albumin which may lead to dysfunction of the immune system and hence, an increase risk of nosocomial infections [17]. Secondly, since the renal function is compromised, the kidneys decrease or cease the production of erythropoietin which leads to anemia or low Hb in ESRD patients [48]. Thus, the provision of nutritional support for patients on HD is important to help patients improve their immunity function.

Despite the worldwide spread of nosocomial infections, data regarding the risk factors associated with such infections is still lacking. The results of this review suggest a gap and potential benefit of additional preventive options to further reduce the risk of infections in HD population. Moreover, several patient-related and facility-related risk factors have been consistently identified in the studies under this review, which may help to initiate strategies to achieve optimal control measures. Based on the results, widespread adoption of preventive measures and system development should be undertaken to ensure better control of these infections. The comprehensive nature of risk factor consideration and study eligibility criteria are strengths of this review. All observational studies regarding risk factors associated with nosocomial infections among HD population were considered for inclusion in this review. Patient and facility related parameters were obtained from each study, which provided a broad view of risk factors as observed across various clinical settings.

The comprehensive nature of this review also posed some limitations. The studies included in this review varied in the study designs, including retrospective cohort and case control, cross-sectional and longitudinal or prospective study. The heterogeneity nature of the studies included in this review, with various methodologies and risk factors presented challenges in quantitative synthesis of the results. Therefore, only qualitative synthesis was performed as the type of data obtained was not appropriate for meta-analysis. As such, the interpretation of results was mainly focused on the direction of effect, as opposed to its magnitude. Results of this review summarized the range of studies, and differences in sample size, study designs, time period and quality of studies were not taken into consideration. Although, the variability between different studies hindered a single quantitative estimation for individual risk factors, the review provided support in evidence of the association of factors, such as longer duration on HD, advancing age, positive history of blood transfusion, which were consistently identified as risk factors for nosocomial infections.

Due to a lack of research in the area and despite using broad definition of risk factors and comprehensive search terms, only 9 studies could be identified for inclusion in this review. Therefore, more research is needed to fill the information gap pertaining to nosocomial infections in HD patients. Future research should focus on the risk factors and their control measures to decrease the prevalence of nosocomial infections in HD population. Moreover, more studies are needed before a quantitative estimation of individual risk factors and its impact in this high-risk population can be determined.

Conclusions

This comprehensive and thorough review of published literature revealed many factors that can contribute towards the occurrence of nosocomial infections in HD population. Controlling and minimizing the effects of these factors will not only improve the patients’ health related quality of life (HRQoL) but will also decrease economic burden. Increasing life expectancy and improving HRQoL are the two main health targets in patients with ESRD and can be achieved by minimizing infection complications in this population. Collaborative effort among health care professionals (nephrologists, pharmacists, nurses), caregivers and patients is needed to overcome this health-related issue. In addition to providing a conventional therapy, health care professionals should take special measures to minimize the risk of infections in these patients. The relationship between ESRD and nosocomial infections is intriguing and needs more research to better understand individual risk factors and to develop optimum control measures for them.

I. List of major exclusions:

Incidence and risk factors for bloodstream infections stemming from temporary hemodialysis catheters [49].

Hepatitis B and C infection in haemodialysis patients in Libya: prevalence, incidence and risk factors [32].

Prevalence of Vancomycin-Resistant Enterococci colonization and its risk factors in chronic hemodialysis patients in Shiraz, Iran [50].

Occurrence of infectious diseases in dialysed patients [51]

Hepatitis B virus infection in Haemodialysis Centres from Santa Catarina State, Southern Brazil. Predictive risk factors for infection and molecular epidemiology [52].

A prospective study of infections in hemodialysis patients: patients hygiene and other risk factors for infection [53].

Data Underscore Risk of Nosocomial Infections in Chronic HD Patients [54].

Risk Factors for Infection-Related Hospitalization in In-Center Hemodialysis [55]

Risk factors for morbidity and mortality of bloodstream infection in patients undergoing hemodialysis: a nested case–control study [56].

Surveillance of chronic haemodialysis-associated infections in southern Israel [57].

Prevalence of Hepatitis c virus (HCV) infection and related risk factors among Iranian patients on hemodialysis [58].

A prospective study of infections in hemodialysis patients: Patient hygiene and other risk factors for infection [59].

Risk factors for catheter-related infections in patients on hemodialysis [60].

Viral hepatitis C and B among dialysis patients at the Rabat University Hospital: prevalence and risk factors [61].

Hemodialysis catheter-related infection: rates, risk factors and pathogens [42].

Incidence and risk factors of bloodstream catheter-related infections in hemodialysis patients [62].

Central venous catheter for hemodialysis: incidence of infection and risk factors [63].

Risk factors for candidemia with non-albicans Candida spp. in intensive care unit patients with end-stage renal disease on chronic hemodialysis [64].

Clinical epidemiology of pneumonia in hemodialysis patients: the USRDS waves 1, 3, and 4 study [65].

Risk Factors of HCV Seroconversion in Hemodialysis Patients in Tabriz, Iran [66].

Epidemiology of hemodialysis vascular access infections from longitudinal infection surveillance data: Predicting the impact of NKF-DOQI clinical practice guidelines for vascular access [67].

Prevalence and risk factors of hepatitis C and B virus infections in hemodialysis patients and their spouses: A multicenter study in Beijing, China [68].

Hepatitis C virus infection in hemodialysis or continuous ambulatory peritoneal dialysis patients: Results of comparative analysis [69].

Vancomycin-resistant enterococci colonization in patients at seven hemodialysis centers [70].

Detection of hepatitis C virus in patients with terminal renal disease undergoing dialysis in southern Brazil: prevalence, risk factors, genotypes, and viral load dynamics in hemodialysis patients [71].

Risk factors for nosocomial infections in hemodialysis patients and nursing interventions [72].

Analysis and countermeasures of risk factors of nosocomial infection in hemodialysis patients [73].

Occurrence rates, risk factors and direct economic losses of healthcare-as-sociated infection in hemodialysis patients in a tertiary first-class hospital [74].

Risk Factors and Prevention of Nosocomial Infection Inpatients with Hemodialysis [75].

Infection Episode and Related Risk Factors in Continuous Hemodialysis Patients: A Survey [76].

Risk Factors of Hospital Infection in Hemodialysis Department: Prevention and Control [77].

Clinical features of nosocomial infections in chronic renal failure patients who underwent hemodialysis and related risk factors [78].

Risk Factors of Hospital Infection in Hemodialysis Department: Prevention and Control [79].

Department of Nephrology The First Affiliated Hospital of Guangdong College of Pharamcy, Guangzhou 510080, China; Analysis of Pulmonary Infection and Related risk Factors in Hemodialysis Patients [80]

Distribution and risk factors of infection in patients with maintenance hemodialysis [81].

Clinical characteristics and risk factors of nosocomial infection in patients with chronic renal failure Hemodialysis [82].

Infection control in hemodialysis units: a quick access to essential elements [83].

Multidisciplinary health team in control of risk factors for colonization and infection caused by MRSA in hemodialysis [84].

Vascular access infection among hemodialysis patients in Northern Jordan: incidence and risk factors [85].

Molecular epidemiology of a hepatitis C virus outbreak in a hemodialysis unit in Italy [86].

Prevalence of Vancomycin-Resistant Enterococci Among Children with End-Stage Renal Failure [87].ss

Data extraction sheet.

(XLSX)

Click here for additional data file.

29 Jan 2020

PONE-D-19-32738

Risk factors associated with nosocomial infections among end stage renal disease patients undergoing hemodialysis: A systematic review

PLOS ONE

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Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

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Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: N/A

Reviewer #3: No

Reviewer #4: Yes

Reviewer #5: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Saad Hanif Habbasi has considered 9 studies in order to evaluate the risk factor associated with nosocomial infections among the ESRD ( End-Stage Renal Disease) hemodialyzed patients.

The argument is crucial and has a big impact in the national health services and in the daily life of patients.

However there are some considerations.

Firstly the author should specify the type and the site of vascular access for hemodialysis.

The 2006 KDOQI vascular access guidelines considers AV fistula the first option followed by prothesic grafts if AV fistula is not possible. So the long term vascular catheter should be placed as last choice . Sometimes it could be necessary to occur to a vascular catheter temporarily if fistula is not matured and it should be indicated for how long.

It is well known that vascular catheter for dialysis has a higher risk of bloodstream infections in comparison to AV fistula. In addition patients who are cvc dependent for dialysis are more sick than patients with AV fistula

Secondly the nine studies are conducted in different period of time and this makes results difficult to be interpreted. Recent data show a reduction of CLABSIs (central line–associated bloodstream infection) since 2001 as a result of prevention programs in many hospitals around the world. In additon in the 2016 the CDC ( Centers for Disease Control and Prevention) estimates that CLABSIs decreased by 50% between 2008-2014 .

Finally the risk of bacteremia and infections depends on the intrinsic defence mechanism and therapies of patients. Most of the studies included elderly people who are more exposed to risk of hospitalisation and nosocomial infections because of the accumulation of comorbid disease with age and poor adherence to medical treatment.

Reviewer #2: In this manuscript, dr. Aftab and colleagues performed a systematic literature review aimed at identifying risk factors for noscomial infections in patients with end-stage renal failure undergoing hemodyalisis.

The topic is relevant, given the expected increase in the number of patients who will require intermittent hemodyalisis in the next future, and costs associated with noscomial infections. The manuscript is overall well conducted from a methodological point of view, with multiple databases searched, description of search strategy, independent screening, and risk of bias assessment.

The major flaw of this study is lack of a statistical analysis of the results, although I acknowlegde that the type of study make it difficult to perform a quantitative analysis.

I have a few comments for the Authors which I hope will help them to improve their manuscript:

1. The introduction is too long. I suggest to shorten it, and to focus on why the Authors decided to undertake this study

2. Given that no quantitative analysis was performed, the paragraph can be deleted. A sentence a the end of the Methods section is sufficient

3. Please provide a list of the 41 major exclusions, together with references, in a Supplementary Appendix

4. Please rewrite the Discussion, underlying the relationship of present study to previous literature, the significance of study findings, what present study add to current knowledge, and future directions. The detailed discussion of each risk factor is not necessary

Minor comment

1. in the paragraph "Characteristics of the Selected Studies" on lines 11-13 the Authors write "in some studies, there were participants aged 12 years and above". As per exclusion criteria, all studies with participants aged < 12 should have been excluded.

Reviewer #3: I am grateful for the opportunity to review the manuscript entitled "Risk factors associated with nosocomial infections among end stage renal disease patients undergoing hemodialysis: A systematic review ".

I have some comments for the author. I hope that my comments may contribute improving your papers.

Manuscript is well written, really clear and sections length is adequate. Moreover,reference are uptodate.

Nonetheless, there are two main issues.

1)There are few studies included. Nine studies are a limited number for a systematic review. Moreover, studies included are different in study design, population, inclusion/exclusion criteria and ESRD definition.

2)Lack of meta-analysis is probably the major issue of this paper. Without a proper analysis I believe most of your results and discussion remain unproven. I would suggest author to try to synthetize results whenever possible for key outcomes.

Introduction:You begin your manuscrit with the second reference, please number the reference accordingly to first appearance.

Minor issues:

Data extraction: I think it would be useful to include the data extraction form as supplementary material

Risk of Bias/Quality: Explain your strategy to overcome disagreements between assessors

Data synthesis: "A systematic review was performed to make sure that all data synthesis done was sourced from the maximum possible, and complete collection of relevant literature" I believe this sentence may expanded in order to clarify your efforts. (Examples: reference check, contacting the authors, contacting fields experts)

Results: "In some studies, there were participants aged above 12 years" The sentence is not clear. Inclusion criteria is >12 years, so all participants have to be aged > 12 years old. Please explain.

Reviewer #4: There’s no doubt we should consider this systematical review as an original research: ESRD people are increasing especially in front of life expectancy extension. Health care world may consider main infection risk factors in order to decrease morbidity, mortality and cost effectiveness. Despite we can trace principle elements implicated in ESRD nosocomial infection we don’t know exactly what we have to be afraid of and if we are able to prevent them.

As the author show, a lot of literature meet key words research, but as a matter of facts only few articles really describe patient’s characteristics and nosocomial infections risk factors. If they do usually concentrate themselves on a particular risk factor or subtype of population.

We can declare that results have not been published elsewhere and they have been obtained by proper/ analyses. We found in Cochrane library only a single review focused on “Interventions for preventing infectious complications in hemodialysis patients with central venous catheters” but it doesn’t consider patients characteristics and risk factors.

In this work Authors described in detail the protocol of their systematical review. They declared to follow PRISMA guidelines for the design study and they subscribe the protocol to PROSPERO specifying the registration number.

As a matter of fact the study is conformed to PRISMA statement. Every part is described in sufficient detail and flow chart is clear.

Some data about sources choose has been delete. On the other hand quality of the main studies has been evaluated and described following Otawa criteria. Data extraction form has been good described, considering items author’s name, year and duration of the study, study design, respondents, demographics of the patients (sample size, gender, and age), type of nosocomial infections studied, type of pathogens involved, and risk factors associated with nosocomial infections.

The article adheres to appropriate reporting guidelines and community standards for data availability.

We suggest minor revisions:

1) Please, report the systematic review registration number on PROSPERO in the abstract

2) Risk of bias assessment has been correctly evaluated with Newcastle Ottawa scale (NOS) for observational studies considering three categories: “Selection,” “Comparability,” and “Outcome. Studies have been classified as good, fair and poor quality. It would be useful to describe single limitations of the studies analyzed. In particular 2 have retrospective design and declare this aspect on their discussion.

3) An accurate and comprehensive systematic review has been performed and complete collection of relevant literature. Only qualitative analysis has been undertaken and not statistical analysis has been performed. Authors declare the limitations of their work for heterogeneity nature of the studies considered (retrospective cohort and case control, cross-sectional and longitudinal, prospective). However, it would be interesting to approach a univariate/multivariate analysis of similar studies to evaluate risk ratio or ODDs ratio for hemoglobin level/previous blood transfusion or HD duration in HBV/HCV infection (cross sectional studies). Moreove, HDAP rate, microorganism type, and infection risk in Chronic HD it would be obtained.

4) Methods are exhaustive described, but it would be useful to specify if references authors had been called looking for other works.

5) The manuscript meets the criteria of linguistic clarity and correctness required except for a wrong transcription: table 2, reference 17 (“D’Agata EMC et al, instead of: Erika et al”)

Reviewer #5: Please see attached word document for specific review comments on this manuscript. Thank you for the opportunity to review. I recommend a 'Minor Revision'.

Many Thanks,

**********

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Reviewer #1: No

Reviewer #2: Yes: Alessandro Belletti

Reviewer #3: No

Reviewer #4: No

Reviewer #5: Yes: Pasquale Nardelli

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7 Apr 2020

S. N. Comments Corrections

Overall comments:

Thank you for your comments. Kindly accept my sincere gratitude for your valuable input. I have made changes in the revised manuscript as advised by you.

Kind regards,

Specific comments:

Reviewer 1

1. The author should specify the type and the site of vascular access for hemodialysis.

The 2006 KDOQI vascular access guidelines considers AV fistula the first option followed by prothesic grafts if AV fistula is not possible. So, the long-term vascular catheter should be placed as last choice. Sometimes it could be necessary to occur to a vascular catheter temporarily if fistula is not matured and it should be indicated for how long.

It is well known that vascular catheter for dialysis has a higher risk of bloodstream infections in comparison to AV fistula. In addition, patients who are CVC dependent for dialysis are more sick than patients with AV fistula Agreed. Although it is well documented that CVC is associated with increased number of infections among hemodialysis patients, however the type and site of vascular access were not found by any study in this review as risk factors, hence they were not discussed. As this is a systematic review, the data were extracted from 9 studies that met our inclusion criteria and only those risk factors that were found significantly associated (p-value = <0.05) were discussed.

However, a paragraph is added on type of accesses as suggested. Refer to Page no. 26 and line no. 15.

2. The nine studies are conducted in different period of time and this makes results difficult to be interpreted. Recent data show a reduction of CLABSIs (central line–associated bloodstream infection) since 2001 as a result of prevention programs in many hospitals around the world. In addition, in the 2016 the CDC (Centers for Disease Control and Prevention) estimates that CLABSIs decreased by 50% between 2008-2014.

Agreed. The heterogeneity among studies included in this review was presented as it’s limitation and was discussed under ‘discussion’ section (Page No. 27 and line No. 23). Due to limited number of studies on nosocomial infections in HD patients, the difference in aspects, such as study designs, methodologies, time period were not taken into consideration.

Secondly, this review considered all the nosocomial infections including CRBSIs. Although, there might be reduction a in CLABSIs due to prevention programs, but still HD population is one of the most high-risk populations for CRBSIs, as indicated by many studies. Therefore, the risk factors for these and other nosocomial infections were elucidated in this review to help in the development of prevention guidelines against these factors. Moreover, CLABSIs is a broad terminology and not used specifically for access used in HD patients.

3. The risk of bacteremia and infections depends on the intrinsic defense mechanism and therapies of patients. Most of the studies included elderly people who are more exposed to risk of hospitalization and nosocomial infections because of the accumulation of comorbid disease with age and poor adherence to medical treatment. According to the inclusion criteria for this review, the studies done on patients of > 12 years of age were included. The studies under this review varied based on age of patients and mean ages ranged from 48 to 71. Age was identified as one of the risk factors in this review and discussed in ‘discussion section’ (Page No. 25 and Line no. 10).

Although, it is well known that with advancing age, there are more chances of acquiring an infection due to various reasons, few studies in this review reported that nosocomial infections were more common in relatively younger age group (Page No. 25 and line No. 10).

In addition, the impact of diabetes as a comorbidity was also discussed separately (Page No. 24 and line No. 15).

Reviewer 2

1. The introduction is too long. I suggest to shorten it, and to focus on why the Authors decided to undertake this study. Agreed. The Introduction has been shortened as recommended.

2. Given that no quantitative analysis was performed, the paragraph can be deleted. A sentence at the end of the Methods section is sufficient Agreed and changes made as suggested. A sentence has been added at the end of the paragraph to indicate this: Only qualitative analysis was undertaken (Page no.7 and line no. 22)

3. Please provide a list of the 41 major exclusions, together with references, in a Supplementary Appendix Agreed. 41 major exclusions are stated in the Supplementary Appendix with references (Page no. 36).

4. Please rewrite the Discussion, underlying the relationship of present study to previous literature, the significance of study findings, what present study add to current knowledge, and future directions. The detailed discussion of each risk factor is not necessary. Agreed and the Discussion section has been revised to include reviewer’s suggestions.

5. In the paragraph "Characteristics of the Selected Studies" on lines 11-13 the Authors write "in some studies, there were participants aged 12 years and above". As per exclusion criteria, all studies with participants aged < 12 should have been excluded. Agreed. That sentence showed a repetition, and therefore was removed.

Reviewer 3

1. There are few studies included. Nine studies are a limited number for a systematic review. Moreover, studies included are different in study design, population, inclusion/exclusion criteria and ESRD definition. Agreed. The heterogeneity among the studies included in this review was presented as it’s limitation and was discussed under ‘discussion’ section (Page No. 27 and line No. 23). Due to lack of research and limited number studies on nosocomial infections in HD patients, the difference in aspects, such as study designs, methodologies, time period were not taken into consideration.

However, this review included studies on hemodialysis patients so ESRD definition and target population did not affect heterogeneity among the studies.

2. Lack of meta-analysis is probably the major issue of this paper. Without a proper analysis I believe most of your results and discussion remain unproven. I would suggest author to try to synthetize results whenever possible for key outcomes. Agreed. However, only descriptive analysis was performed as the type of data obtained was not appropriate for meta-analysis. The studies in this review had used different statistical methods. Some studies reported risk factors using odd ratios (OR) and confidence interval (CI), while others used correlation coefficients (r), relative risk (RR) and simple p-values to portray their results, as shown in Table 2 in a manuscript. Hence, no risk factors could be grouped together for quantitative synthesis.

3. Introduction: You begin your manuscript with the second reference, please number the reference accordingly to first appearance.

Agreed and changes have been made in the revised manuscript.

4. Data extraction: I think it would be useful to include the data extraction form as supplementary material. Agreed and data extraction sheet has been added as a supplementary material.

5. Risk of Bias/Quality: Explain your strategy to overcome disagreements between assessors. Agreed and this has been added in the revised manuscript (Page no. 7 and line no. 16).

6. Data synthesis: "A systematic review was performed to make sure that all data synthesis done was sourced from the maximum possible, and complete collection of relevant literature" I believe this sentence may expanded in order to clarify your efforts. (Examples: reference check, contacting the authors, contacting fields experts). Agreed and the information suggested has been added in the revised manuscript (Page no. 7 and line no.20).

Reviewer 4

1. Please, report the systematic review registration number on PROSPERO in the abstract. Agreed and the information suggested has been added in the revised manuscript (Page no. 2 and line no. 17).

2. Risk of bias assessment has been correctly evaluated with Newcastle Ottawa scale (NOS) for observational studies considering three categories: “Selection,” “Comparability,” and “Outcome. Studies have been classified as good, fair and poor quality. It would be useful to describe single limitations of the studies analyzed. In particular 2 have retrospective design and declare this aspect on their discussion. Agreed and the information suggested has been added in the revised manuscript. Refer to page no. 27 and line no. 21 for limitations of the study.

3. An accurate and comprehensive systematic review has been performed and complete collection of relevant literature. Only qualitative analysis has been undertaken and not statistical analysis has been performed. Authors declare the limitations of their work for heterogeneity nature of the studies considered (retrospective cohort and case control, cross-sectional and longitudinal, prospective). However, it would be interesting to approach a univariate/multivariate analysis of similar studies to evaluate risk ratio or ODDs ratio for hemoglobin level/previous blood transfusion or HD duration in HBV/HCV infection (cross sectional studies). Moreover, HDAP rate, microorganism type, and infection risk in Chronic HD it would be obtained. Agreed. However, only descriptive analysis was performed due to the type of data being unsuitable for meta-analysis. The studies in this review had used different statistical methods as some studies reported risk factors using odd ratios (OR) and confidence interval (CI), while others used correlation coefficients (r), relative risk (RR) and simple p-values to portray their results as shown in Table 2 in a manuscript. Hence, no risk factors could be grouped together for quantitative synthesis.

4. Methods are exhaustive described, but it would be useful to specify if references authors had been called looking for other works. Agreed and the information suggested have been added in the revised manuscript (Page no. 7 and line no. 20).

5. The manuscript meets the criteria of linguistic clarity and correctness required except for a wrong transcription: table 2, reference 17 (“D’Agata EMC et al, instead of: Erika et al”)

Agreed and changes made in the revised manuscript.

Reviewer 5

1. Ref. 1 is not called out in order the text. Please fix. Agreed and changes made in revised manuscript.

2. P. 10 L 11-13: I cannot understand. Please reword Agreed and changes made in revised manuscript.

3. P. 30 L 7-10: consider rewording Agreed and changes made in revised manuscript.

Submitted filename: Response to reviewers.docx

Click here for additional data file.

27 May 2020

Risk factors associated with nosocomial infections among end stage renal disease patients undergoing hemodialysis: A systematic review

PONE-D-19-32738R1

Dear Dr. Raja Ahsan Aftab,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

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With kind regards,

Laura Pasin

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

Reviewer #4: All comments have been addressed

Reviewer #5: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

Reviewer #4: N/A

Reviewer #5: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: In this manuscript, dr. Aftab and colleagues present a revised version of their manuscript

I believe that all of my comments have been adequately addressed

Reviewer #4: (No Response)

Reviewer #5: I thank the authors for their efforts. I believe the manuscript quality was improved in the review process.

No further comments.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: Yes: Alessandro Belletti

Reviewer #4: No

Reviewer #5: Yes: Pasquale Nardelli, MD

9 Jun 2020

PONE-D-19-32738R1

Risk factors associated with nosocomial infections among end stage renal disease patients undergoing hemodialysis: A systematic review

Dear Dr. Aftab:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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