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100  |  wileyonlinelibrary.com/journal/wvn Worldv Evid-Based Nu. 2022;19:100–111.© 2022 Sigma Theta Tau International

Received: 22 March 2021  | Revised: 23 July 2021  | Accepted: 2 August 2021

DOI: 10.1111/wvn.12574

E V I D E N C E R E V I E W

Occurrence rate and risk factors for long- term central line- associated bloodstream infections in patients with cancer: A systematic review

Silvia Belloni MSc, PhDs, RN1  | Rosario Caruso MSc, PhD, RN2  | Daniela Cattani MSc, RN3 | Giorgia Mandelli RN3 | Daniela Donizetti RN1 | Beatrice Mazzoleni MSc, PhDs, RN3 | Michele Tedeschi MD4

1Educational and Research Unit, Humanitas Research Hospital IRCCS, Rozzano, Milan, Italy 2Health Professions Research and Development Unit, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy 3Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy 4Humanitas Research Hospital IRCCS, Rozzano, Milan, Italy

Correspondence Silvia Belloni, Educational, Research and Development Unit, Humanitas Research Hospital IRCCS, Via A. Manzoni 56, 20089 Rozzano, Milan, Italy. Email: [email protected]

Funding information This research received no specific grant from any funding agency in the public, commercial, or not- for- profit sectors.

Abstract Introduction: Central line- associated bloodstream infection (CLABSI) is a public health problem that harms patients' outcomes and healthcare costs, especially in susceptible populations such as patients with cancer. Overall, systematic queries about etiology, risks, and epidemiology are explained by data from observational studies, which bet- ter underline the relationship between factors and incidence of disease. However, no recent systematic reviews of observational studies on adult patients with cancer have been conducted on this topic, considering the wide range of all potential factors which can contribute to the increase in infection rate in the hospitalized adults with cancer. This study systematically reviewed observational studies investigating the oc- currence rate of CLABSI and its risk factors for long- term inserted central catheter- related infections in hospitalized adult cancer patients. Methods: A systematic review was performed on four databases from the earliest available date until December 2020. Retrospective and prospective cohort studies focused on the occurrence rate of CLABSI and its risk factors in hospitalized adult cancer patients. The pooled occurrence rate of CLABSI (95% CI) was calculated by applying a random- effects model. Results: Of 1712 studies, 8 were eligible, and the data of device- related infection rate were meta- analyzed. The pooled occurrence rate of CLABSI was roughly 8% (95% CI [4%, 14%]). The device characteristics, device's management aspects, therapies ad- ministration, and select patients' clinical conditions represent the main risk factors for long- term catheter- related infection in cancer patients. Linking Evidence to Action: Considering the substantial infection rate among cancer patients, identifying risk rate factors is pivotal to support evidence- grounded preven- tive strategies and maximize cancer patient safety. This study's results could guide policymakers and healthcare leaders and future research studies to disseminate ap- propriate risk- reducing management culture and implement standardized research and clinical approach to the investigated phenomenon as an infection surveillance strategy.

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INTRODUC TION

Central line- associated bloodstream infection (CLABSI) is a public health problem and one of the major challenges for healthcare sys- tems (Baier et al., 2020; Leeman et al., 2020; Stevens et al., 2014). According to the Centers for Disease Control and Prevention (CDC) definition, a CLABSI is a laboratory- confirmed bloodstream in- fection not related to another site of infection that occurs within 48 h of a central line placement (CDC & National Healthcare Safety Network, 2021). Recent literature reported a central venous catheter- associated bloodstream infections occurrence of 10.6 cases per 1000 central venous catheter days in hematologic and on- cologic patients (Baier et al., 2020), and 91% of infections are caused by coagulase- negative staphylococci (Luft et al., 2010). CLABSI is associated with negative clinical outcomes such as a higher signif- icant risk of mortality (e.g., OR = 2.75; 95% CI [1.86, 4.07]; Ziegler et al., 2014), especially in susceptible populations such as patients with cancer where the mortality at day 30 was 22% and reached 70% without an appropriate antimicrobial treatment (Islas- Muñoz et al., 2018).

Central line- associated nosocomial bloodstream infections have a considerable negative impact on healthcare costs (attributable me- dian costs was 8810 € for each CLABSI case, considering the differ- ence in costs between patients with CLABSI compared to patients without CLABSI) and length of stay (47 vs. 22 days between patients with CLABSI compared to non- CLABSI cases), exceeding the health reimbursements (Baier et al., 2020). Long- term central lines repre- sent a significant economic burden for patients in countries with private healthcare systems where the total cost attributable is ex- pressed as the difference in cost between patients with long- term central line catheters who develop a CLABSI compared with those long- term lines without bloodstream infection, which was $3528.60. The total cost was associated with the intensive care unit setting, type of pathogenic microorganism, age, and catheter number (Cai et al., 2018).

The risk of CLABSI depends on several factors. Some factors are intrinsically related to patients' diagnosis and comorbidities, whereas others are linked to patients and devices (Gao et al., 2015; Lee et al., 2020; Pepin et al., 2015). Among patients with cancer, the risk of infection highly depends on their health condition at the time of central venous catheter insertion, such as malnutrition and bone marrow aplasia (Viana Taveira et al., 2017). In practice, patients with cancer are frequently immunosuppressed and at risk for a wide range of opportunistic and healthcare- associated infections (Thom et al., 2013). However, central lines represent an indispensable part of some cancer patients’ treatment as they generally provide a safe administration of antineoplastic therapy (Sousa et al., 2015). Specifically, comparing different central venous catheters, long- term

central access should be preferred for patients with cancer (Schiffer et al., 2013; Sousa et al., 2015).

However, a considerable percentage of CLABSIs are not asso- ciated with central line care, whereas CLABSI complies with the definition of the National Healthcare Safety Network (NHSN) mu- cosal barrier injury- associated laboratory- confirmed bloodstream infection (MBI- LCBI; Dandoy et al., 2020; Kato et al., 2018; Metzger et al., 2015). Cytotoxic chemotherapy regimens in cancer patients may damage the mucosal barriers and cause oral and gastrointestinal flora translocation into the bloodstream. In 2013, the CDC’s NHSN adopted a new definition for MBI- LCBI surveillance to prevent mis- classification of bloodstream infections caused by oral or intestinal microbiota in cancer patients and boost the comparability of CLABSI rates (Steinberg & Coffin, 2013).

The spread of the infection control discipline has played a cru- cial role in cancer treatments’ progress, allowing patients to receive new therapies safely. CLABSIs cause treatment delays, lower doses of chemotherapies, and, consequently, suboptimal treatment (Raad & Chaftari, 2014). For this reason, infection control strategies have become an essential part of modern oncologic care and encompass a multilevel approach, including the patient, the healthcare environ- ment and facilities, community outbreaks, and healthcare workers (Ariza- Heredia & Chemaly, 2018). Specifically, nurses play a pivotal role in preventing and controlling infection transmission through the implementation of standard precautions, maintenance of the health- care environment, and educational programs (Carrico et al., 2018). Then, identifying which factors increase cancer patients' risk of ac- quiring central line- associated bloodstream infections in a hospital context and the occurrence rate of the phenomenon is strategic to minimize the risk throughout implementing preventive measures.

A recent systematic review was performed on risk factors for CLABSI in the non- cancer pediatric population (Rosado et al., 2018). However, many clinical aspects cannot be investigated in random- ized controlled trials (RCTs) for ethical or methodological reasons. Considering that roughly 80% of the published research have an ob- servational design (Mueller et al., 2018), the synthesis of evidence derived from these studies could be strategic for framing the knowl- edge regarding the occurrence rate of CLABSI, as observational studies are often employed to investigate the CLABSI epidemiologi- cally. A pooled occurrence rate of CLABSI could be pivotal to frame a realistic portrait of CLABSI in hospitalized adults with cancer. Thus far, no systematic reviews of observational studies on hospitalized adult cancer patients have been conducted on this topic to estimate a pooled occurrence rate of CLABSI and describe the wide range of its potential risk factors. Therefore, this study provides a compre- hensive systematic review of observational studies (retrospective and prospective studies) regarding the occurrence rate and risk fac- tors of CLABSI in hospitalized adult cancer patients.

K E Y W O R D S cancer, central venous catheter, infections, observational studies, systematic review

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METHODS

This study is a systematic review (SR) with a meta- analysis of ob- servational studies describing occurrence rates and risk factors of CLABSI in cancer patients. Despite some controversies reported in the literature on the study design selection in performing system- atic reviews (Stroup et al., 2000), the choice to include only obser- vational studies is based on the guidance of “Conducting Systematic Reviews and Meta- Analyses of Observational Studies of Etiology,” that is, COSMOS- E group on conducting systematic reviews and meta- analyses of observational studies of etiology (Dekkers et al., 2019). Specifically, as observational designs are used for epidemi- ological purposes (Mueller et al., 2018), the need of performing a systematic review of observational studies is supported by the pos- sibility to select the relevant literature encompassing an occurrence rate of CLABSI and associations between exposure (risk factors) and health- related outcome (CLABSI). Observational studies are relevant to study exposures, such as cohort studies, where exposed and un- exposed people are followed over time. Theoretically, the exposures differ from interventions that aim to influence health outcomes, as occur in interventional studies such as RCTs which are unable to de- scribe the relationship between exposure and outcome. An obser- vational study is the most appropriate approach for epidemiological research questions on a phenomenon's risk factors and occurrence rate (Dekkers et al., 2019). For conducting this SR and meta- analysis, we followed the Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) statement and flowchart (Moher et al., 2009). The protocol is registered on the PROSPERO International Prospective Register of Systematic Reviews (CRD42020188772). The study reporting is consistent with the “Meta- analyses of Observational Studies in Epidemiology” (MOOSE) Checklist (see Appendix S1).

Search strategy and sources

We searched the literature for all peer- reviewed articles focused on risk factors for CLABSI in patients with cancer. The systematic search was conducted in the following databases: PubMed, CINAHL, Web of Science, and EMBASE. The four databases were selected for their representativeness of the health area. According to recent rec- ommendations (Li et al., 2019), the search strategy was constructed to balance sensitivity and specificity in observational studies selec- tion. Hand searching and reference list checking were performed to identify additional primary studies. The Clinicaltrials.gov database was searched to identify any unpublished ongoing clinical trials.

The electronic search was performed on databases, including ar- ticles published between January 2010 and December 2020, to re- trieve the most updated evidence. No limitation was initially set for the articles' language. Firstly, the search strategy was designed for the PUBMED database using MESH headings words and free- text words. Then, it was shaped for the other databases as appropriate. Additional methods, such as hand searching and reference checking,

were applied to maximize findings. The search strategy is displayed in Appendix S2.

Inclusion and exclusion criteria

The selection of reference studies was conducted according to the population (adults with cancer), exposure (long- term central line), and outcomes (CLABSI) framework. The following inclusion crite- ria were included: (1) observational studies (prospective and ret- rospective cohort studies) focused on detection of risk factors for long- term central line- associated bloodstream infections in cancer patients; (2) observational studies which consider occurrence rates and risk factors for long- term central venous catheter- associated bloodstream infection as the primary outcome; (3) abstract avail- able; (4) published between 2010 and 2020 to highlight the most up- to- date evidence on this topic; (5) original research articles published in English language; and (6) prospective and retrospective cohort studies with an appropriate sample size (pilot studies, case report, and feasibility studies will be excluded).

Articles published in languages other than English were conse- quently excluded during the selection of titles and abstracts, unless they were highly significant for the review's purposes, to reduce any potential misinterpretation. We excluded studies that considered patients with central lines inserted via the internal or external jugu- lar vein because this systematic review focuses on infections associ- ated with long- term central venous catheters in patients undergoing chemotherapy treatment. The choice of including studies of an ap- propriate sample size can be challenging in the systematic review of observational studies (Dekkers et al., 2019; Greenland, 1994). Therefore, underpowered studies and observational pilot studies were excluded as they often provide little information (Turner et al., 2013). Studies performed in home- care and critical care settings were also excluded from the inclusion process because they were not congruent with the study aim.

Selection of studies and outcomes of interest

Two reviewers (SB and RC) independently reviewed titles and ab- stracts to select pertinent studies for full- text reading and separately selected full texts for final inclusion based on selection criteria. Discrepancies in the selection process were solved by discussion to reach a consensus. The PRISMA flow diagram (Moher et al., 2009) represents the selection process and reasons for article exclusion.

The primary outcome of interest was the CLABSI rate (as defined by the CDC & National Healthcare Safety Network, 2021) during hospital stay of adult cancer patients with long- term central venous catheters. A long- term central venous access has been defined as a device that remains in place for more than 6 weeks (Galloway & Bodenham, 2004). The phenomenon refers to the surveillance of healthcare- associated bloodstream infections (excluding the mu- cosal barrier injury– laboratory- confirmed bloodstream infection,

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MBI- LCBI) in non- research settings where differences exist in the application of diagnostic laboratory investigations and outcomes among providers, patients, units, and healthcare facilities (Sexton et al., 2010; Shah et al., 2013). The CLABSI rate was calculated by dividing the number of events (long- term inserted central ve- nous catheter- related infections) by the total number of patients screened. We analyzed risk factors and predictors for developing a long- term central venous catheter- associated infection in cancer patients as secondary outcomes.

A total of 1712 articles were identified, and 1267 were selected after removing duplicates. After reading the titles and abstracts, 25 papers were selected for full reading. Of these, eight studies (Freire et al., 2013; Gao et al., 2015; He et al., 2018; Lee et al., 2020; Mollee et al., 2011; Touré et al., 2013; Wang et al., 2015; Zhang et al., 2018) fulfilled the eligibility criteria and were included in the systematic re- view. The flowchart of the selection process and the reasons for ex- clusion are presented in Figure 1. References of the excluded studies in the final step of the process are presented in Appendix S3.

Data extraction and quality assessment

Two authors (SB and RC) extracted the relevant information through a structured extraction form, which underwent a piloting process (Li et al., 2020). The following data were extracted: first author/year, title, country, study design, site of cancer, the total number of pa- tients (sample size), number of events, and outcome results. Any dis- agreements between authors in the selection process were solved by discussion.

Two reviewers (SB and RC) independently evaluated the selected studies’ methodological quality using the Newcastle Ottawa Scale (NOS) for cohort studies (Wells et al., 2014). The NOS has eight items within three domains: (1) selection (representativeness), com- parability (due to design or analysis), and (3) outcomes (assessment and follow- up). For each item, a point is awarded, except for a com- parison which can be rated up to 2 points. In this review, we assigned 1 point if the main confounding variables were detected and 2 points if the main variables were also controlled under the comparability

F I G U R E 1  Flow diagram of the studies' selection process 1

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domain. A consensus discussion solved disagreements between the two reviewers in the quality of the rating process. However, the NOS does not allow for an overall scoring of the quality of evidence and the risk of bias. Thus, we used the adapted Newcastle- Ottawa Scale (NOS) to assess the risk of bias for the included cohort studies, con- sidering an overall rating equal to 6 as a moderate risk of bias, and higher than 6 as a low risk of bias (Balshem et al., 2011).

Data synthesis

Initially, we conducted sensitivity analyses on the common risk fac- tors from the included studies, restricting evidence on studies with low risk of bias, and exploring whether any contradictory effect for the between- group comparisons could be explained by age, sex, or type of cancer. However, the results differed across sensitivity anal- yses, indicating that the results have to be interpreted with caution. Furthermore, the high clinical and methodological heterogeneity between the included studies as to reported outcomes for risk fac- tors precluded the adoption of meta- analytic methods (McKenzie & Brennan, 2021). For this reason, the authors synthesized data on risk factors for CLABSI using narrative analysis. In the context of evidence synthesis, narrative approaches can raise concerns on transparency and adequacy of reporting (Campbell et al., 2019). Narrative synthesis throughout a structured tabulation of results across studies has been used in systematic reviews beside systematic searching and appraisal techniques, thus representing one of the acceptable synthesis meth- ods (Dixon- Woods et al., 2005; McKenzie & Brennan, 2021).

Based on the availability of the occurrence rates of CLABSI, we quantitatively pooled the rates, indicating the pooled rate and its 95% CI. Because included studies had a prospective and retrospec- tive design, we assumed a high potential for heterogeneity between studies, and accordingly, a random- effects model was used to cal- culate the pooled event rate. Heterogeneity across studies was as- sessed by the random- effect model of the inverse variance, and the magnitude of inconsistency was estimated by Chi- squared (Q) and I- square statistics (I²; Higgins & Thompson, 2002). The comparison- adjusted funnel plot was used to evaluate small- study effects for outcomes, considering that a funnel plot that is asymmetrical for the line of the summary effect implies differences between the esti- mates derived from small and large studies. This assessment is useful to evaluate the reporting bias. Data analyses were performed using the Comprehensive Meta- Analysis software (v. 2.2.057).

RESULTS

Search results and characteristics of the included studies

The eight cohort studies were performed in different countries worldwide and published between 2011 and 2020. The sample in- cluded 5318 male and female participants affected by different types

of hematological and solid tumors, who underwent insertion of a long- term inserted central venous catheter (tunneled lines, implant- able port, and peripherally inserted central catheter). Characteristics of the included studies are presented in Table 1.

Methodological assessment and risk of bias evaluation

Collectively, the studies achieved a NOS score ranging from 4 to 7 (Appendix S4). A total of four studies (Freire et al., 2013; Gao et al., 2015; Mollee et al., 2011; Wang et al., 2015) did not include data on the comparability of cohorts based on the design or analysis, as confounders were not considered and adjusted. None of the stud- ies mentioned the follow- up adequacy for the included cohorts. As described in Table 2, the risk of bias was assessed as moderate in five studies (Freire et al., 2013; Gao et al., 2015; Lee et al., 2020; Mollee et al., 2011; Zhang et al., 2018) and high in three studies (He et al., 2018; Robinson et al., 2018; Touré et al., 2013; Wang et al., 2015).

Pooled occurrence rate of long- term inserted central venous catheter- related infections among patients with cancer

For hospitalized adults with cancer with a long- term central line, the pooled occurrence rate of long- term central venous catheter- related infection was roughly 8% (pooled rate = 0.0845; 95%CI [0.039, 0.139]; p < .001; Q = 292.98). The pooled analysis indicated mod- erate statistical heterogeneity, intended as the percentage of total variation across studies due to heterogeneity rather than chance: I2 = 58% (p < .00001; Figure 2).

The funnel plot of the occurrence rate of long- term central venous catheter- related infections showed moderate asymmetry (Appendix S5). This result suggested the possibility of a slight publi- cation bias, in particular for studies with small sample size. However, this result is consistent with the number of studies included in the systematic review, as they are less than 10. This situation reduced the likelihood of the test to distinguish a real asymmetry (Higgins & Thomas, 2021).

Risk factors for long- term inserted central venous catheter- related infections in hospitalized patients with cancer

Concerning the characteristics of the device, patients with double lumen central catheters (HR = 5.466, 95% CI [1.26, 23.77], p = .024; Lee et al., 2020) were significantly associated with an higher risk of CLABSI compared to other types of central lines. Other factors re- lated to the device's management were associated with higher infec- tion occurrence, such as catheter care delay (>7 days; OR = 2.612, 95% CI [1.37, 4.97], p = .031), in- summer placement (OR = 4.784,

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95% CI [2.68, 8.54], p < .001; Gao et al., 2015), in- hospital insertion (OR = 3.97, 95% CI [2.86, 5.51, p < .001; Freire et al., 2013), catheter retention time (≥30 days; OR = 4.21, 95% CI [2.20, 8.71], p < .05), operator experience for insertion (OR = 2.80, 95% CI [1.04, 4.71], p < .05; He et al., 2018), right- sided lines (HR = 1.60, 95% CI [1.05, 2.44], p = .027), and the number of prior lines (HR = 1.20, 95% CI [1.03, 1.41], p = .022; Mollee et al., 2011).

Patients who received steroid therapy (HR = 3.41, 95% CI [1.55, 7.47], p = .002; Zhang et al., 2018), antibiotic therapy (HR = 2.854, 95% CI [1.08, 7.53], p = .034; Lee et al., 2020), total parenteral nutri- tion (HR = 5.66, 95% CI [2.86, 11.23], p < 0.001; Touré et al., 2013), and chemotherapy (HR = 11.421, 95% CI [2.43, 53.59], p = .002; HR = 1.00, 95% CI, p < .001; Lee et al., 2020; Wang et al., 2015) were significantly more likely to develop long- term central venous catheter- related infection. In some clinical conditions, a significant increased risk of CLABSI was found, such as in patients with hema- tological malignancies (Mollee et al., 2011; Wang et al., 2015; re- spectively, HR = 4.00, p < .001; HR = 3.17, p = .0007), head and

neck cancer (HR = 4.11, p < .001), and in particular in women with gynecologic cancer (HR = 13.55, p < .001; Wang et al., 2015).

Neutropenia (<500 neutrophils/m3; OR = 1.55, 95% CI [1.02, 2.36], p = .04; Freire et al., 2013) and hypoalbuminemia (<3.5 mg/ dl; HR = 5.03, 95% CI [1.14, 22.16], p = .03; Zhang et al., 2018) at the time of device implantation were clinical predictors for early and overall port infections, respectively. Table 3 summarizes the emerged risk factors.

DISCUSSION

The purpose of this systematic review was to offer a comprehensive overview of the long- term inserted central venous catheter- related in- fection occurrence rate among hospitalized adults with cancer and the potential risk factors associated with the insertion of a long- term cen- tral line for cancer treatments. Although the original literature search returned nearly 1,710 results, only eight studies fulfilled the selection

TA B L E 1  Characteristics of the included studies

First author, year of publication Title Country Study design

Type of cancer

N total

N events Main results

Mollee, 2011 (Mollee et al., 2011)

Catheter- associated bloodstream infection occurrence and risk factors in adults with cancer: a prospective cohort study.

Australia Prospective cohort study

Mixed 727 129 CVADsa infection

Freire, 2013 (Freire et al., 2013)

Infection- related to implantable central venous access devices in cancer patients: epidemiology and risk factors.

Brazil Prospective cohort study

Mixed 933 184 CVADsb infection

Tourè, 2013 (Touré et al., 2013)

Propensity score analysis confirms the independent effect of parenteral nutrition on the risk of central venous catheter- related bloodstream infection in oncological patients.

France Prospective cohort study

Gastric 425 55 Port infection

Gao, 2015 (Gao et al., 2015)

The occurrence rate and risk factors of peripherally inserted central catheter- related infection among cancer patients.

China Prospective cohort study

Mixed 912 94 PICC infection

Wang, 2015 (Wang et al., 2015)

Occurrence rate and risk factors for central venous access port- related infection in Chinese cancer patients

China Prospective cohort study

Mixed 1391 370 Port infection

He, 2018 (He et al., 2018)

Risk analysis on infection caused by peripherally inserted central catheter for bone tumour patients.

China Retrospective cohort study

Bone tumor 223 18 PICC infection

Zhang, 2018 (Zhang et al., 2018)

Clinical predictors of port infections in adult patients with hematologic malignancies.

USA Retrospective cohort study

Hematologic 223 26 Port infection

Lee, 2020 (Lee et al., 2020)

Prevalence and predictors of peripherally inserted central venous catheter- associated bloodstream infections in cancer patients: A multicentre cohort study.

Korea Retrospective cohort study

Mixed 484 25 PICC infection

Abbreviation: CVADs, Central venous access devices aCVADs = Tunneled, Implantable port, and PICC (peripherally inserted central catheter). bCVADs = subcutaneous venous ports, cuffed totally implantable catheters (PermCath), and Hickman catheters.

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    |  107INFECTION RISK FOR ADULTS WITH CANCER

criteria and were analyzed to quantify the phenomenon's occurrence rate. This literature review provides an epidemiological description of the occurrence rate of CLABSI among adults affected by solid and

hematological tumors with a long- term central line, which was different from the aims of previous literature reviews aimed at describing the as- sociations between CLABSI and clinical outcomes (Ziegler et al., 2014).

TA B L E 3  Risk factors long- term central venous catheter- related infections in hospitalized cancer patients

Risk factors Study Effect size, 95% CI p- value

Characteristics of the device

Double lumen central catheter Lee, 2020 (Lee et al., 2020) HR = 5.466 (1.26– 23.77) p = .024

Clinical management

Catheter care delay (>7 days) Gao, 2015 (Gao et al., 2015) OR = 2612 (1.37– 4.97) p = .031

In- summer placement of the device Gao, 2015 (Gao et al., 2015) OR = 4.784 (2.68– 8.54) p < .001

In- hospital insertion Freire, 2013 (Freire et al., 2013) OR = 3.97 (2.86– 5.51) p < .001

Catheter retention time (≥30 days) He et al., 2018 (He et al., 2018) OR = 4.21 (2.20– 8.71) p < .05

Operator experience He et al., 2018 (He et al., 2018) OR = 2.80 (1.04– 4.71) p < .05

Right- sided lines Mollee, 2011 (Mollee et al., 2011) HR = 1.60 (1.05– 2.44) p = .027

Number of prior lines Mollee, 2011 (Mollee et al., 2011) HR = 1.20 (1.03– 1.41) p = .022

Therapy administration

Steroid therapy Zhang, 2018 (Zhang et al., 2018) HR = 3.41 (1.55– 7.47) p = .002

Antibiotic therapy Lee, 2020 (Lee et al., 2020) HR = 2.854 (1.08– 7.53) p = .034

Total parenteral nutrition Tourè, 2013 (Touré et al., 2013) HR = 5.66 (2.86– 11.23) p < .001

Chemotherapy Lee, 2020 (Lee et al., 2020) HR = 11.421 (2.434– 53.594) p = .02

Wang, 2015 (Wang et al., 2015) HR = 1.00 p < .001

Clinical conditions

Hematological malignancies Wang, 2015 (Wang et al., 2015) HR = 4.00 p < .001

Mollee, 2011 (Mollee et al., 2011) HR = 3.17 (1.63– 6.16) p = .0007

Head and neck cancer Wang, 2015 (Wang et al., 2015) HR = 4.11 p < .001

Gynecologic cancer Wang, 2015(Wang et al., 2015) HR = 13.55 p < .001

Neutropenia (<500 neutrophils/m3) Freire, 2013 (Freire et al., 2013) OR = 1.55 (1.02– 2.36) p = .04

Hypoalbuminemia (<3.5 mg/dl) Zhang, 2018 (Zhang et al., 2018) HR = 5.03 (1.14– 22.16) p = .03

Note: Results from multivariate analysis, the significant level at p < .05. Abbreviations: CI, confidence interval; HR, hazard ratio; OR, odds ratio.

F I G U R E 2  Pooled occurrence rate for CLABSI in hospitalized adults with cancer

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We found an 8% pooled occurrence rate of CLABSI among adults affected by solid and hematological tumors with a long- term central line from this meta- analysis. This study's obtained estimate was higher than the risk reported by a prior meta- analysis, including studies conducted on a general population admitted in intensive care units (RR = 2.02; 95% CI [0.19, 22.1]; p = .6; Ramritu et al., 2008). Besides the differences in the clinical setting and population reflected by the different occurrence rates in the included studies (from 0.01% to 19%), the risk variation in CLABSI might reflect the different cen- tral devices considered in the studies, whose related risk highly var- ies from the insertion site (Arvaniti et al., 2017; Parienti et al., 2012) and the type of inserted long- term inserted central venous catheter (Chopra et al., 2013; Fang et al., 2017). However, hospitalized cancer patients constitute a vulnerable population that is susceptible to bac- terial colonization (Gedik et al., 2014). This vulnerability results from various comorbidities representing potential risk factors for develop- ing catheter- related bloodstream infections (Kampmeier et al., 2018).

Our narrative synthesis showed a wide range of modifiable and non- modifiable risk factors of CLABSI related to the cathe- ter's characteristics, device's management aspects, therapies ad- ministration, and some patients' clinical conditions. Considering the device's characteristics, we observed a higher risk of infec- tion in patients with a double lumen catheter than a single lumen device, which was in accordance with a previous meta- analysis (Dezfulian et al., 2003). Regarding clinical management, risk fac- tors of CLABSI were related to catheter care delay (>7 days), in- summer device placement, in- hospital insertion (vs. outpatients' clinics), catheter retention time (≥30 days), operator experience for the catheter insertion, right- sided lines, and the number of prior lines inserted. Unfortunately, the studies did not provide specific information about operator experience and the number of prior lines inserted. Thus, these aspects could not be interpreted further. In light of these results, practices should be adopted based on evidence from another systematic review on the effec- tiveness of educational interventions for healthcare providers and the specific management strategies for reducing risks of CLABSI (Ramritu et al., 2008). Notably, a protective healthcare environ- ment, including air quality control and isolation measures, plays a crucial role in preventing infections in susceptible cancer patients (Schlesinger et al., 2009), and recent evidence supports the im- plementation of outpatient cancer care programs as an infection control strategy (Ariza- Heredia & Chemaly, 2018).

Despite these modifiable risk factors, our systematic synthesis also identified an extensive number of non- modifiable risk factors of CLABSI concerning clinical patients' conditions and cancer treat- ments. Cancer treatments, such as antibiotic therapy, chemotherapy administration, and parenteral nutrition, raised concerns about the interpretability, as these studies did not supply information about the treatments' regimens, nor did they control for confounding fac- tors. For this reason, it was difficult to establish a cause– effect link between the specific agent and the infection outcome. According to previous evidence (Kampmeier et al., 2018), some clinical conditions like neutropenia, hypoalbuminemia, and hematological malignancies

expose patients to a higher risk of CLABSI. Further studies are re- quired to better understand the mechanism that mediates the re- lationship between a specific type of cancer, like gynecologic and head and neck, and the higher risk to develop a CLABSI.

Limitations

The results of this systematic review need to be interpreted in light of several limitations. Firstly, we conducted a systematic review of obser- vational studies, which can raise controversies related to confounding and quality biases (Stroup et al., 2000). We found heterogeneous and incomplete data about the variables, treatment regimens, laboratory procedures, and criteria for long- term central venous catheter- related in- fections diagnosis, aspects related to the device's management, and not all the variables included in the studies were controlled for confounding factors. This heterogeneity was also found in the terminology adopted by each included study to describe the investigated phenomenon, as lit- erature encompasses highly variable definitions for local or systemic in- fections related to the insertion of a central line (Tomlinson et al., 2011). Although these differences could undermine surveillance for CLABSI, the sensitivity and specificity of the CLABSI framework in cases detec- tion granted the development of the CDC’s National Healthcare Safety Network, which represents the most broadly used healthcare- associated infection tracking system (CDC, 2021; Shah et al., 2013). According to the study's aim, our analysis encompassed patients with different cancer diagnoses, including hematological malignancies, who may have a differ- ent infection profile risks. However, it was unfeasible to describe differ- ent potential trends of these specific cancer populations considering our results. Moreover, as previously stated, not all the studies eligible for this review reported information on patients’ treatment regimens, implanta- tion, and management techniques. Therefore, these factors may have influenced the resulting infection rate. These issues generated concerns about the synthesis and interpretability of the systematic review's re- sults. Despite these limitations, this study offers a synthesis of a relevant phenomenon in a vulnerable population, such as cancer patients.

LINKING EVIDENCE TO ACTION

• Healthcare professionals' awareness of an appropriate risk- reducing management culture is relevant to safe, evidence- based practice in oncological settings.

• These results outline the utility of standardized research and clin- ical approach to the investigated phenomenon as an active infec- tion surveillance strategy in cancer patients.

• Research in the field of CLABSI incorporates prevention, imple- mentation, detection, and reporting throughout standardized evidence- based approach.

• Healthcare professionals play a pivotal role in ensuring patients' safety and reduce hospital costs by implementing evidence- based practices and quality improvement strategies to reduce the CLABSI’s incidence.

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CONCLUSION

This study presents an epidemiological synthesis of infection oc- currence rates associated with a device's insertion in patients with cancer, describing its potential risk factors. We found a substantial infection rate among cancer patients. This considerable infection rate is associated with a wide range of risk factors concerning the central line's characteristics, device's management aspects, thera- pies administration, and some patients' clinical conditions. This study's results could guide policymakers and healthcare leaders and future research studies in disseminating appropriate risk- reducing management culture and implementing standardized research and clinical approach to the investigated phenomenon as an active infec- tion surveillance strategy in cancer patients.

CONFLIC T OF INTERE S T No conflicts of interest were declared by the authors.

DATA AVAIL ABILIT Y S TATEMENT All data relevant to the study are included in the article or uploaded as Supplementary Information.

ORCID Silvia Belloni https://orcid.org/0000-0002-5187-2410 Rosario Caruso https://orcid.org/0000-0002-7736-6209

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How to cite this article: Belloni, S., Caruso, R., Cattani, D., Mandelli, G., Donizetti, D., Mazzoleni, B. et al. (2022) Occurrence rate and risk factors for long- term central line- associated bloodstream infections in patients with cancer: A systematic review. Worldviews on Evidence- Based Nursing, 19, 100– 111. https://doi.org/10.1111/wvn.12574

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