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Are there effective interventions to prevent hospital-acquired Legionnaires' disease or to reduce environmental reservoirs of Legionella in hospitals? A systematic review
ARTICLE IN PRESS American Journal of Infection Control ■■ (2016) ■■-■■
Contents lists available at ScienceDirect
American Journal of Infection Control
American Journal of Infection Control
j o u r n a l h o m e p a g e : w w w. a j i c j o u r n a l . o r g
State of the Science Review
Are there effective interventions to prevent hospital-acquired Legionnaires’ disease or to reduce environmental reservoirs of Legionella in hospitals? A systematic review Dejanira Almeida MSc a,*, Elisabete Cristovam MSc a, Daniel Caldeira MD b,c, Joaquim J. Ferreira MD, PhD b,c, Teresa Marques MD, PhD a a b c
Laboratory of Microbiology and Molecular Biology, Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal Laboratory of Clinical Pharmacology and Therapeutics, Faculty of Medicine, Universidade de Lisboa, Lisbon, Portugal Clinical Pharmacology Unit, Instituto de Medicina Molecular, Lisbon, Portugal
Key Words: Legionellosis Cross-infection Disinfection Treatment outcome Prevention and control
Background: Legionnaires’ disease (LD) is recognized as an important hospital-acquired disease. Despite the several methods available, the optimal method to control hospital-acquired LD is not well established and their overall efficacy requires further evaluation. Objective: To systematically review all controlled trials evaluating the efficacy of interventions to prevent hospital-acquired LD in patients at high risk of developing the disease and its effects on environmental colonization. Methods: A database search was performed through PubMed and the Cochrane Central Register of Controlled Trials (inception-November 2014). Eligible studies included all controlled studies evaluating interventions to prevent hospital-acquired LD in patients at high risk or evaluating the effect on environmental colonization. Both individual and pooled risk estimates were reported using risk ratio (RR) and 95% confidence intervals (95% CIs). Results: There were no studies evaluating the risk reduction in hospital-acquired LD, but 4 studies evaluated the influence of copper-silver ionization and ultraviolet light in the reduction of environmental reservoirs of Legionella. The meta-analysis showed a significant 95% risk reduction of Legionella positivity in environmental samples using copper-silver ionization (RR, 0.05; 95% CI, 0.01-0.17) and 97% risk reduction with ultraviolet light (RR, 0.03; 95% CI, 0.002-0.41). Conclusions: The best available evidence suggests that copper-silver ionization and ultraviolet light are effective in reducing Legionella positivity in environmental samples. Nevertheless, the low quality of evidence weakens the robustness of conclusions. © 2016 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.
BACKGROUND Legionnaires’ disease (LD) is a severe multisystem illness and a potentially fatal form of pneumonia that is caused by Legionella.1,2 LD is recognized as an important hospital-acquired disease because the institutional water systems can be easily colonized by these bacteria.3,4 Reports of epidemics and outbreaks of hospital-acquired
* Address correspondence to Dejanira Almeida, MSc, Laboratory of Microbiology and Molecular Biology, Centro Hospitalar de Lisboa Ocidental, Rua da Junqueira, 126, 1349-019 Lisboa, Portugal. E-mail address: [email protected] (D. Almeida). Financial support: None reported. Conflicts of interest: None to report.
LD pneumonia occurring in association with Legionella colonization of potable water systems of hospitals have become common.3,4 Therefore, health care systems have an important role in the prevention of this condition. Accurate data about the incidence of hospital-acquired infections is not available because LD is likely to be underdiagnosed and underreported.4,5 Despite the increased awareness and the advances regarding its treatment, the mortality rate for hospitalacquired Legionella pneumonia, according to the World Health Organization, remains high in immunocompromised patients when left untreated (case-fatality rate, 40%-80%).6 When cases are diagnosed in a timely manner and directed therapy is applied, the casefatality rate may be reduced to 5%-30%.6 In immunocompetent individuals the expected mortality rate reaches 10%-15%.6 Because Legionella eradication is not possible in hospital environments, mea-
0196-6553/© 2016 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajic.2016.06.018
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sures to minimize the bacteria proliferation in potential reservoirs and to decrease the risk of infection are crucial. Despite the several methods available, the optimal method to prevent hospital-acquired LD is not well established and their overall efficacy requires further evaluation. We are unaware of any prior systematic review evaluating these interventions. In the present analysis, we performed the first systematic review and meta-analysis to assess the efficacy of interventions to prevent hospital-acquired LD in hospitalized patients at high risk of developing the disease and its effects on environmental colonization. METHODS Literature search An electronic database search was performed through PubMed and Cochrane Central Register of Controlled Trials, including all records from inception through November 2014. Reference lists of retrieved studies and review articles were also cross-checked to identify further published studies for possible inclusion in the review. There were no restrictions in the search, but eligible records were restricted to studies published in English, Portuguese, Spanish, French, or Italian languages. Selection criteria Eligible studies included all controlled studies evaluating interventions to prevent hospital-acquired LD in hospitalized patients at high risk of developing the disease (such those hospitalized in bone marrow transplant units, solid organ transplant units, and hematologyoncology units4,7,8). We also studied the effect of the intervention on the environmental colonization (eg, water samples) hospital distal sites not necessarily related to units of high-risk patients. Thus, we considered all controlled studies; that is, those having 2 independent groups: an intervention group, and a control group (without intervention). Both groups were required to be exposed to the same conditions and were assessed simultaneously, because there are factors that can change over time and the possible difference in the outcomes may not only be due to the intervention itself (eg, water supply repair, variability of Legionella concentration in water, and temporary measures for the use of bottled water in respiratory therapy equipment). Eligible interventions include temperature control, coppersilver ionization, chlorination, ultraviolet light (UVL), and point-ofuse filtration. We considered those patients hospitalized in increased risk areas to be at high risk of developing hospital-acquired LD. The primary outcome was the incidence of hospital-acquired LD based on active clinical surveillance. The secondary outcome was the rate of Legionella positivity in hospital environmental samples. To determine the efficacy of the interventions, the studies had to report any of these outcomes data. Studies were further excluded if performed at a nonhospital environment, under not-comparable conditions in test and control groups, without an intervention or control group, or provided inadequate outcomes.
Data from studies satisfying the inclusion criteria were extracted by 2 reviewers independently. The characteristics of the study design, setting, participants, type of interventions (carefully extracting as many details as possible about the nature of the intervention) outcomes, results, and risk of bias, were extracted using data extraction forms. Risk of bias in included studies The Cochrane Collaboration Tool was adapted to assess risk bias and to evaluate reporting quality through the following items: random sequence generation method, blinding of investigators, incomplete outcome data, description of withdrawals, the evaluation of patients/units at high-risk of hospital-acquired LD, or any other risk of bias features.9 Studies were qualitatively classified for each domain as low risk of bias, unclear risk of bias, or high risk of bias. When more than 50% of the characteristics (at least 3 out of 5) were considered to be at high risk of bias, the individual study was also classified at being at high risk of bias. Studies were not excluded based on risk of bias assessment. Data analysis Statistical analyses were performed using RevMan 5.3 software (The Nordic Cochrane Centre, The Cochrane Collaboration, London, UK). Individual studies and meta-analysis estimates were derived and are presented in forest plot graphs. For the meta-analysis we used the random-effects model to estimate pooled risk ratios (RRs) and 95% confidence intervals (95% CIs).10 This method was used by default independent of the heterogeneity of the pooled analysis because it provides more conservative estimates. RRs were chosen to report the results because relative measures tend to be more similar across studies compared with absolute estimates in different settings.11 When zero cells were present in 1 arm, RevMan automatically added 0.5 to them to perform the calculations. Heterogeneity was assessed using the I2 statistic, which measures the percentage of total variation between studies due to heterogeneity.12 Heterogeneity was considered to be substantial if I2 ≥50%.7 RESULTS The results of the comprehensive literature search are outlined in Figure 1. Included studies The literature search did not find any study reporting data about the influence of interventions on the incidence of hospital-acquired LD in high-risk patients. Four controlled trials met the inclusion criteria, based on environmental surveillance, by reporting the rate of Legionella positivity in environmental samples. Three studies assessed copper-silver ionization,13-15 and 1 study assessed UVL.16 The copper-silver ionization studies evaluated Legionella positivity by swabbing distal sites,13-15 whereas the UVL study evaluated water samples.16 The main characteristics of included studies are summarized in Table 1.
Studies selection and data extraction Risk of bias in included studies One reviewer initially screened the titles and abstracts of the search results and retrieved potentially relevant reports in fulltext for further assessment. Two reviewers independently reviewed all relevant reports according to the predefined criteria to determine which studies would persist for inclusion in the review. Disagreements were solved by consensus.
Figure 2 shows the risk of bias assessment for each included study. None of the included studies had a randomized design (ie, the intervention was not randomly allocated to hospital/buildings) and there were no descriptions about methods to blind investigators and outcome assessors to intervention in each hospital/building. There-
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Fig 1. Flowchart of studies identified in the literature search.
fore, all studies are considered to be at high risk of selection, performance, and detection biases (Fig 2). None of the included studies had missing outcome data (Fig 2). Only Farr et al16 evaluated distal sites in a unit for a set of high-risk patients (renal transplantation patients). Therefore, this study was considered to be at low risk of bias. Information about factors such as delay between samples collection and microbiologic testing and the exact number of samples collected was insufficient to assess whether an important risk of bias exists. Overall, the present evidence was considered by the reviewers to be at high risk of bias because most of the evaluated features (>50%) were at high risk of bias in all studies. Effects of copper-silver ionization versus no intervention Three studies,13-15 including 132 distal sites samples, compared copper-silver ionization versus no intervention. The meta-analysis showed a significant 95% risk reduction of Legionella positivity in distal sites using copper-silver ionization (RR, 0.05; 95% CI, 0.010.17) (Fig. 3). There was no evidence of heterogeneity between studies’ results (I2 = 0%). Effects of UVL versus no intervention One study,16 comprising 166 hot water samples, also showed a significant risk reduction of Legionella positivity in water samples through UVL (RR, 0.03; 95% CI, 0.002-0.41) (Fig. 3).
DISCUSSION The focus of this review was to assess the efficacy of interventions preventing hospital-acquired LD in hospitalized patients and the effect on environmental colonization that is associated with the risk of developing hospital-acquired LD. The main results of our systematic review were: studies that evaluate the influence of therapeutic interventions in the risk reduction of hospital-acquired LD in patients at high risk are scarce, there are no data regarding the efficacy of interventions in the reduction of the incidence of hospital-acquired LD, and copper-silver ionization and UVL decreased the risk of Legionella positivity in environmental samples. According to guidelines from the American Society of Heating, Refrigerating, and Air Conditioning Engineers, copper-silver ionization has been used successfully in hospitals, although the optimal concentration of copper and silver ions for controlling Legionella in water is not known.17 The latter conclusion of this review was based on 4 controlled studies (3 studies with copper-silver ionization and 1 study with UVL). These studies were based on environmental surveillance data, reporting the influence of preventive measures on the colonization of the water distribution systems, which may be considered the best available surrogate outcome for hospital-acquired LD in the absence of direct clinical data. However, these data alone do not always allow us to assess comprehensively the effectiveness of interventions and predict future cases of disease.18 Therefore, it is
ARTICLE IN PRESS D. Almeida et al. / American Journal of Infection Control ■■ (2016) ■■-■■
Prospective controlled trial Farr 198811
UVL, ultraviolet light; VA, Veterans Affairs. *The total number of samples collected is not reported. We assumed that number of samples is equal to number of distal sites tested.
9 mo UVL 16 rooms used by renal transplant patients
Prospective controlled trial Liu 199810
2 wards of the University of Virginia Hospital
Copper-silver ionization 60 distal sites from 3 hospital buildings*
Prospective controlled trial Liu 19949
541-bed VA medical center in Pennsylvania
Copper-silver ionization 47 distal sites from 2 hospital buildings*
23 mo
12 mo
6 mo
Outcomes
Rate of Legionella positivity in swab samples from 21 distal sites in test buildings and 4 in the control building Rate of Legionella positivity in swab samples of the surfaces of showerheads and inner surfaces of water spigots Rate of Legionella positivity in swab samples from 20 distal sites in each building and were cultured Rate of Legionella positivity in a total of 166 hot water samples
Duration Location of intervention Interventions Study sites
25 distal sites from 3 hospital buildings*
1,266-bed medical center made up of 3 buildings (A,B,C) located in Taiwan 541-bed VA medical center in Pennsylvania
Setting Design
Prospective, controlled trial Chen 20088
Author and year
Table 1 Characteristics of included studies
Copper-silver ionization
Point-of-entry of buildings A and B, of both hot and cold water. Building C was the control building without ionization Hot recirculation line in 1 building. A second building was the control building without ionization Hot-water recirculation line of 2 buildings. A third building was the control building without ionization Both hot and cold water pipes leading into 8 rooms. Eight comparable rooms on the same 2 hospital wards served as control without UVL
4
Fig 2. Assessment of each risk of bias item for each included study. Red symbols indicate that the study is at high risk of bias for the characteristic. Green symbols indicate that the study it at low risk of bias for the characteristic.
important to have active clinical surveillance to accurately identify cases of hospital-acquired LD. Incident cases (rather than water positivity for Legionella) should be actively assessed to determine the efficacy of interventions. The limited number of controlled trials investigating the efficacy of measures to prevent hospital-acquired LD may be due to several factors. The feasibility of conducting a trial for the evaluation of a hospital preventive measure for LD is challenging because of the great diversity and particular features of water distribution systems, environmental variability of Legionella contamination, opportunity of having a control group, the absence of any established standard for comparison, the need for accurate in-house laboratory methods, and high costs and effort involved in conducting this type of investigation. Another important aspect, which can lead to underpowered data or to the lack of information regarding this subject, is the fact that LD is an underdiagnosed and underreported disease in all countries. Legionella prevention is a complex and developing field of public health where decision makers, hospital planners, and especially infection control practitioners, need to be kept informed of the best evidence available from around the world. The best available evidence suggests that copper-silver ionization and UVL are effective in reducing Legionella positivity in environmental samples. Researchers, policy makers, engineers, hospital epidemiologists, and users of prevention strategies for hospital-acquired LD may find this information useful. However, primary studies showed methodologic weaknesses, and therefore, the results of this review do not allow a robust conclusion regarding the efficacy of interventions for preventing hospital-acquired LD. Implications for research Further research with large, well-design and well-conducted trials, with consistent and high-quality protocols are needed to
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Fig 3. Forest plot evaluating copper-silver ionization or ultraviolet light versus no intervention regarding the incidence of positive Legionella samples. 95% CI, 95% confidence interval.
determine whether the eligible interventions are beneficial in the prevention of hospital-acquired LD, and thus provide unequivocal evidence on the efficacy of this type of intervention. Future studies may consider the evaluation of factors that can help stakeholders in the decision-making process, such as an economic evaluation of interventions, to provide further evidence on the most effective/cost-effective approach, and implications of drug toxicity and development of microbial drug resistance.
Limitations This was a systematic review with meta-analysis of controlled studies; thus, all limitations related to data analysis at the studylevel should be considered. Furthermore, our data are limited by the overall high risk of bias of the included studies. In this setting, placebo-controlled trials do not exist and may not be practical/feasible in the future, so the evaluation of interventions against a null control to establish efficacy was considered to be adequate. In the absence of established efficacy, the interpretation of studies that compare different active interventions may mislead. Therefore, these studies were excluded in our systematic review. We aimed to include the best-available evidence in this review, yet despite our efforts (eg, contacting the authors and journal, and making requests for full-text) we were not able to determine whether the study by Wireman et al19 fulfils the inclusion criteria.
CONCLUSIONS In this review we did not find any studies evaluating the influence of therapeutic interventions in the risk reduction of hospitalacquired LD in patients at high risk. The best available evidence suggests that copper-silver ionization and UVL are effective in reducing Legionella positivity in environmental samples. Nevertheless, these data should be framed with their methodologic weaknesses and limitations. Therefore, despite the statistically significant results,
the quality of the body of evidence does not allow a robust conclusion regarding the efficacy of interventions for preventing hospital-acquired LD. Acknowledgments The authors thank the São Francisco Xavier Hospital Library staff for providing assistance with articles acquisition and the Laboratory of Clinical Pharmacology and Therapeutics, Faculty fo Medicine, University of Lisbon, for providing assistance in the methodology and for the help in the preparation and edition of the manuscript. References 1. Fields BS, Benson RF, Besser RE. Legionella and legionnaires’ disease: 25 years of investigation. Clin Microbiol Rev 2002;15:506-26. 2. Silva MT. Contribuição para o estudo do género Legionella e sua ocorrência em Portugal. PhD Dissertation 1996. 3. Lin YE, Stout JE, Yu VL. Prevention of hospital-acquired legionellosis. Curr Opin Infect Dis 2011;24:350-6. 4. Sabria M, Yu VL. Hospital-acquired legionellosis: solutions for a preventable infection. Lancet 2002;2:368-73. 5. Murdoch DR. Diagnosis of Legionella infection. Clin Infect Dis 2003;36: 64-9. 6. World Health Organization. Legionellosis. Available from: http://www .who.int/mediacentre/factsheets/fs285/en. 2011. Accessed November 8, 2011. 7. Marques T, Froes F, Brum G, Esteves ACS. Doença dos Legionários: Protocolo de diagnóstico. Ministério da Saúde (Portugal); 2003. 8. Marques T. A propósito do lançamento do Programa de Vigilância Epidemiológica Integrada da Doença dos Legionários. Revista de Infecções Respiratórias 2005;1:28-32. 9. Higgins JPT, Altman DG, Sterne JAC. Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration; 2011. Available from: http://handbook.cochrane.org/. 10. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177-88. 11. Deeks JJ. Issues in the selection of a summary statistic for meta-analysis of clinical trials with binary outcomes. Stat Med 2002;21:1575-600. 12. Deeks JJ, Altman DG, Bradburn MJ. Statistical methods for examining heterogeneity and combining results from several studies in meta-analysis. In: Egger M, Davey Smith G, Altman DG, editors. Systematic reviews in health care: meta-analysis in context. 2nd ed. London: BMJ Publication Group; 2001:313-35.
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13. Chen YS, Lin YE, Liu Y-C, Huang WK, Shih HY, Wann SR, et al. Efficacy of pointof-entry copper-silver ionisation system in eradicating Legionella pneumophila in a tropical tertiary care hospital: implications for hospitals contaminated with Legionella in both hot and cold water. J Hosp Infect 2008;68:152-8. 14. Liu Z, Stout JE, Tedesco L, Boldin M, Hwang C, Diven WF, et al. Controlled evaluation of copper-silver ionization in eradicating Legionella pneumophila from a hospital water distribution system. J Infect Dis 1994;169:919-22. 15. Liu Z, Stout JE, Boldin M, Rugh J, Diven WF, Yu VL. Intermittent use of coppersilver ionization for legionella control in water distribution systems: a potential option in buildings housing individuals at low risk of infection. Clin Infect Dis 1998;26:138-40.
16. Farr BM, Gratz JC, Tartaglino JC, Getchell-White SI, Groschell DHM. Evaluation of ultraviolet light for disinfection of hospital water contaminated with Legionella. Lancet 1988;669-71. 17. STANDARD, ASHRAE. Minimizing the risk of legionellosis associated with building water systems. EEUU: ASHRAE; 2000. 18. Allen JG, Myatt TA, Macintosh DL, Ludwig JF, Minegishi T, Stewart JH, et al. Assessing risk of health care-acquired legionnaires’ disease from environmental sampling: the limits of using a strict percent positivity approach. Am J Infect Control 2012;40:917-21. 19. Wireman JM, Schmidt A, Hutchins DT. Chlorine, heat: popular ways to beat Legionella. Am Health Facil Manage 1992;5(5):28, 30, 32-4.
Contents lists available at ScienceDirect
American Journal of Infection Control
American Journal of Infection Control
j o u r n a l h o m e p a g e : w w w. a j i c j o u r n a l . o r g
State of the Science Review
Are there effective interventions to prevent hospital-acquired Legionnaires’ disease or to reduce environmental reservoirs of Legionella in hospitals? A systematic review Dejanira Almeida MSc a,*, Elisabete Cristovam MSc a, Daniel Caldeira MD b,c, Joaquim J. Ferreira MD, PhD b,c, Teresa Marques MD, PhD a a b c
Laboratory of Microbiology and Molecular Biology, Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal Laboratory of Clinical Pharmacology and Therapeutics, Faculty of Medicine, Universidade de Lisboa, Lisbon, Portugal Clinical Pharmacology Unit, Instituto de Medicina Molecular, Lisbon, Portugal
Key Words: Legionellosis Cross-infection Disinfection Treatment outcome Prevention and control
Background: Legionnaires’ disease (LD) is recognized as an important hospital-acquired disease. Despite the several methods available, the optimal method to control hospital-acquired LD is not well established and their overall efficacy requires further evaluation. Objective: To systematically review all controlled trials evaluating the efficacy of interventions to prevent hospital-acquired LD in patients at high risk of developing the disease and its effects on environmental colonization. Methods: A database search was performed through PubMed and the Cochrane Central Register of Controlled Trials (inception-November 2014). Eligible studies included all controlled studies evaluating interventions to prevent hospital-acquired LD in patients at high risk or evaluating the effect on environmental colonization. Both individual and pooled risk estimates were reported using risk ratio (RR) and 95% confidence intervals (95% CIs). Results: There were no studies evaluating the risk reduction in hospital-acquired LD, but 4 studies evaluated the influence of copper-silver ionization and ultraviolet light in the reduction of environmental reservoirs of Legionella. The meta-analysis showed a significant 95% risk reduction of Legionella positivity in environmental samples using copper-silver ionization (RR, 0.05; 95% CI, 0.01-0.17) and 97% risk reduction with ultraviolet light (RR, 0.03; 95% CI, 0.002-0.41). Conclusions: The best available evidence suggests that copper-silver ionization and ultraviolet light are effective in reducing Legionella positivity in environmental samples. Nevertheless, the low quality of evidence weakens the robustness of conclusions. © 2016 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.
BACKGROUND Legionnaires’ disease (LD) is a severe multisystem illness and a potentially fatal form of pneumonia that is caused by Legionella.1,2 LD is recognized as an important hospital-acquired disease because the institutional water systems can be easily colonized by these bacteria.3,4 Reports of epidemics and outbreaks of hospital-acquired
* Address correspondence to Dejanira Almeida, MSc, Laboratory of Microbiology and Molecular Biology, Centro Hospitalar de Lisboa Ocidental, Rua da Junqueira, 126, 1349-019 Lisboa, Portugal. E-mail address: [email protected] (D. Almeida). Financial support: None reported. Conflicts of interest: None to report.
LD pneumonia occurring in association with Legionella colonization of potable water systems of hospitals have become common.3,4 Therefore, health care systems have an important role in the prevention of this condition. Accurate data about the incidence of hospital-acquired infections is not available because LD is likely to be underdiagnosed and underreported.4,5 Despite the increased awareness and the advances regarding its treatment, the mortality rate for hospitalacquired Legionella pneumonia, according to the World Health Organization, remains high in immunocompromised patients when left untreated (case-fatality rate, 40%-80%).6 When cases are diagnosed in a timely manner and directed therapy is applied, the casefatality rate may be reduced to 5%-30%.6 In immunocompetent individuals the expected mortality rate reaches 10%-15%.6 Because Legionella eradication is not possible in hospital environments, mea-
0196-6553/© 2016 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajic.2016.06.018
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sures to minimize the bacteria proliferation in potential reservoirs and to decrease the risk of infection are crucial. Despite the several methods available, the optimal method to prevent hospital-acquired LD is not well established and their overall efficacy requires further evaluation. We are unaware of any prior systematic review evaluating these interventions. In the present analysis, we performed the first systematic review and meta-analysis to assess the efficacy of interventions to prevent hospital-acquired LD in hospitalized patients at high risk of developing the disease and its effects on environmental colonization. METHODS Literature search An electronic database search was performed through PubMed and Cochrane Central Register of Controlled Trials, including all records from inception through November 2014. Reference lists of retrieved studies and review articles were also cross-checked to identify further published studies for possible inclusion in the review. There were no restrictions in the search, but eligible records were restricted to studies published in English, Portuguese, Spanish, French, or Italian languages. Selection criteria Eligible studies included all controlled studies evaluating interventions to prevent hospital-acquired LD in hospitalized patients at high risk of developing the disease (such those hospitalized in bone marrow transplant units, solid organ transplant units, and hematologyoncology units4,7,8). We also studied the effect of the intervention on the environmental colonization (eg, water samples) hospital distal sites not necessarily related to units of high-risk patients. Thus, we considered all controlled studies; that is, those having 2 independent groups: an intervention group, and a control group (without intervention). Both groups were required to be exposed to the same conditions and were assessed simultaneously, because there are factors that can change over time and the possible difference in the outcomes may not only be due to the intervention itself (eg, water supply repair, variability of Legionella concentration in water, and temporary measures for the use of bottled water in respiratory therapy equipment). Eligible interventions include temperature control, coppersilver ionization, chlorination, ultraviolet light (UVL), and point-ofuse filtration. We considered those patients hospitalized in increased risk areas to be at high risk of developing hospital-acquired LD. The primary outcome was the incidence of hospital-acquired LD based on active clinical surveillance. The secondary outcome was the rate of Legionella positivity in hospital environmental samples. To determine the efficacy of the interventions, the studies had to report any of these outcomes data. Studies were further excluded if performed at a nonhospital environment, under not-comparable conditions in test and control groups, without an intervention or control group, or provided inadequate outcomes.
Data from studies satisfying the inclusion criteria were extracted by 2 reviewers independently. The characteristics of the study design, setting, participants, type of interventions (carefully extracting as many details as possible about the nature of the intervention) outcomes, results, and risk of bias, were extracted using data extraction forms. Risk of bias in included studies The Cochrane Collaboration Tool was adapted to assess risk bias and to evaluate reporting quality through the following items: random sequence generation method, blinding of investigators, incomplete outcome data, description of withdrawals, the evaluation of patients/units at high-risk of hospital-acquired LD, or any other risk of bias features.9 Studies were qualitatively classified for each domain as low risk of bias, unclear risk of bias, or high risk of bias. When more than 50% of the characteristics (at least 3 out of 5) were considered to be at high risk of bias, the individual study was also classified at being at high risk of bias. Studies were not excluded based on risk of bias assessment. Data analysis Statistical analyses were performed using RevMan 5.3 software (The Nordic Cochrane Centre, The Cochrane Collaboration, London, UK). Individual studies and meta-analysis estimates were derived and are presented in forest plot graphs. For the meta-analysis we used the random-effects model to estimate pooled risk ratios (RRs) and 95% confidence intervals (95% CIs).10 This method was used by default independent of the heterogeneity of the pooled analysis because it provides more conservative estimates. RRs were chosen to report the results because relative measures tend to be more similar across studies compared with absolute estimates in different settings.11 When zero cells were present in 1 arm, RevMan automatically added 0.5 to them to perform the calculations. Heterogeneity was assessed using the I2 statistic, which measures the percentage of total variation between studies due to heterogeneity.12 Heterogeneity was considered to be substantial if I2 ≥50%.7 RESULTS The results of the comprehensive literature search are outlined in Figure 1. Included studies The literature search did not find any study reporting data about the influence of interventions on the incidence of hospital-acquired LD in high-risk patients. Four controlled trials met the inclusion criteria, based on environmental surveillance, by reporting the rate of Legionella positivity in environmental samples. Three studies assessed copper-silver ionization,13-15 and 1 study assessed UVL.16 The copper-silver ionization studies evaluated Legionella positivity by swabbing distal sites,13-15 whereas the UVL study evaluated water samples.16 The main characteristics of included studies are summarized in Table 1.
Studies selection and data extraction Risk of bias in included studies One reviewer initially screened the titles and abstracts of the search results and retrieved potentially relevant reports in fulltext for further assessment. Two reviewers independently reviewed all relevant reports according to the predefined criteria to determine which studies would persist for inclusion in the review. Disagreements were solved by consensus.
Figure 2 shows the risk of bias assessment for each included study. None of the included studies had a randomized design (ie, the intervention was not randomly allocated to hospital/buildings) and there were no descriptions about methods to blind investigators and outcome assessors to intervention in each hospital/building. There-
ARTICLE IN PRESS D. Almeida et al. / American Journal of Infection Control ■■ (2016) ■■-■■
3
Fig 1. Flowchart of studies identified in the literature search.
fore, all studies are considered to be at high risk of selection, performance, and detection biases (Fig 2). None of the included studies had missing outcome data (Fig 2). Only Farr et al16 evaluated distal sites in a unit for a set of high-risk patients (renal transplantation patients). Therefore, this study was considered to be at low risk of bias. Information about factors such as delay between samples collection and microbiologic testing and the exact number of samples collected was insufficient to assess whether an important risk of bias exists. Overall, the present evidence was considered by the reviewers to be at high risk of bias because most of the evaluated features (>50%) were at high risk of bias in all studies. Effects of copper-silver ionization versus no intervention Three studies,13-15 including 132 distal sites samples, compared copper-silver ionization versus no intervention. The meta-analysis showed a significant 95% risk reduction of Legionella positivity in distal sites using copper-silver ionization (RR, 0.05; 95% CI, 0.010.17) (Fig. 3). There was no evidence of heterogeneity between studies’ results (I2 = 0%). Effects of UVL versus no intervention One study,16 comprising 166 hot water samples, also showed a significant risk reduction of Legionella positivity in water samples through UVL (RR, 0.03; 95% CI, 0.002-0.41) (Fig. 3).
DISCUSSION The focus of this review was to assess the efficacy of interventions preventing hospital-acquired LD in hospitalized patients and the effect on environmental colonization that is associated with the risk of developing hospital-acquired LD. The main results of our systematic review were: studies that evaluate the influence of therapeutic interventions in the risk reduction of hospital-acquired LD in patients at high risk are scarce, there are no data regarding the efficacy of interventions in the reduction of the incidence of hospital-acquired LD, and copper-silver ionization and UVL decreased the risk of Legionella positivity in environmental samples. According to guidelines from the American Society of Heating, Refrigerating, and Air Conditioning Engineers, copper-silver ionization has been used successfully in hospitals, although the optimal concentration of copper and silver ions for controlling Legionella in water is not known.17 The latter conclusion of this review was based on 4 controlled studies (3 studies with copper-silver ionization and 1 study with UVL). These studies were based on environmental surveillance data, reporting the influence of preventive measures on the colonization of the water distribution systems, which may be considered the best available surrogate outcome for hospital-acquired LD in the absence of direct clinical data. However, these data alone do not always allow us to assess comprehensively the effectiveness of interventions and predict future cases of disease.18 Therefore, it is
ARTICLE IN PRESS D. Almeida et al. / American Journal of Infection Control ■■ (2016) ■■-■■
Prospective controlled trial Farr 198811
UVL, ultraviolet light; VA, Veterans Affairs. *The total number of samples collected is not reported. We assumed that number of samples is equal to number of distal sites tested.
9 mo UVL 16 rooms used by renal transplant patients
Prospective controlled trial Liu 199810
2 wards of the University of Virginia Hospital
Copper-silver ionization 60 distal sites from 3 hospital buildings*
Prospective controlled trial Liu 19949
541-bed VA medical center in Pennsylvania
Copper-silver ionization 47 distal sites from 2 hospital buildings*
23 mo
12 mo
6 mo
Outcomes
Rate of Legionella positivity in swab samples from 21 distal sites in test buildings and 4 in the control building Rate of Legionella positivity in swab samples of the surfaces of showerheads and inner surfaces of water spigots Rate of Legionella positivity in swab samples from 20 distal sites in each building and were cultured Rate of Legionella positivity in a total of 166 hot water samples
Duration Location of intervention Interventions Study sites
25 distal sites from 3 hospital buildings*
1,266-bed medical center made up of 3 buildings (A,B,C) located in Taiwan 541-bed VA medical center in Pennsylvania
Setting Design
Prospective, controlled trial Chen 20088
Author and year
Table 1 Characteristics of included studies
Copper-silver ionization
Point-of-entry of buildings A and B, of both hot and cold water. Building C was the control building without ionization Hot recirculation line in 1 building. A second building was the control building without ionization Hot-water recirculation line of 2 buildings. A third building was the control building without ionization Both hot and cold water pipes leading into 8 rooms. Eight comparable rooms on the same 2 hospital wards served as control without UVL
4
Fig 2. Assessment of each risk of bias item for each included study. Red symbols indicate that the study is at high risk of bias for the characteristic. Green symbols indicate that the study it at low risk of bias for the characteristic.
important to have active clinical surveillance to accurately identify cases of hospital-acquired LD. Incident cases (rather than water positivity for Legionella) should be actively assessed to determine the efficacy of interventions. The limited number of controlled trials investigating the efficacy of measures to prevent hospital-acquired LD may be due to several factors. The feasibility of conducting a trial for the evaluation of a hospital preventive measure for LD is challenging because of the great diversity and particular features of water distribution systems, environmental variability of Legionella contamination, opportunity of having a control group, the absence of any established standard for comparison, the need for accurate in-house laboratory methods, and high costs and effort involved in conducting this type of investigation. Another important aspect, which can lead to underpowered data or to the lack of information regarding this subject, is the fact that LD is an underdiagnosed and underreported disease in all countries. Legionella prevention is a complex and developing field of public health where decision makers, hospital planners, and especially infection control practitioners, need to be kept informed of the best evidence available from around the world. The best available evidence suggests that copper-silver ionization and UVL are effective in reducing Legionella positivity in environmental samples. Researchers, policy makers, engineers, hospital epidemiologists, and users of prevention strategies for hospital-acquired LD may find this information useful. However, primary studies showed methodologic weaknesses, and therefore, the results of this review do not allow a robust conclusion regarding the efficacy of interventions for preventing hospital-acquired LD. Implications for research Further research with large, well-design and well-conducted trials, with consistent and high-quality protocols are needed to
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Fig 3. Forest plot evaluating copper-silver ionization or ultraviolet light versus no intervention regarding the incidence of positive Legionella samples. 95% CI, 95% confidence interval.
determine whether the eligible interventions are beneficial in the prevention of hospital-acquired LD, and thus provide unequivocal evidence on the efficacy of this type of intervention. Future studies may consider the evaluation of factors that can help stakeholders in the decision-making process, such as an economic evaluation of interventions, to provide further evidence on the most effective/cost-effective approach, and implications of drug toxicity and development of microbial drug resistance.
Limitations This was a systematic review with meta-analysis of controlled studies; thus, all limitations related to data analysis at the studylevel should be considered. Furthermore, our data are limited by the overall high risk of bias of the included studies. In this setting, placebo-controlled trials do not exist and may not be practical/feasible in the future, so the evaluation of interventions against a null control to establish efficacy was considered to be adequate. In the absence of established efficacy, the interpretation of studies that compare different active interventions may mislead. Therefore, these studies were excluded in our systematic review. We aimed to include the best-available evidence in this review, yet despite our efforts (eg, contacting the authors and journal, and making requests for full-text) we were not able to determine whether the study by Wireman et al19 fulfils the inclusion criteria.
CONCLUSIONS In this review we did not find any studies evaluating the influence of therapeutic interventions in the risk reduction of hospitalacquired LD in patients at high risk. The best available evidence suggests that copper-silver ionization and UVL are effective in reducing Legionella positivity in environmental samples. Nevertheless, these data should be framed with their methodologic weaknesses and limitations. Therefore, despite the statistically significant results,
the quality of the body of evidence does not allow a robust conclusion regarding the efficacy of interventions for preventing hospital-acquired LD. Acknowledgments The authors thank the São Francisco Xavier Hospital Library staff for providing assistance with articles acquisition and the Laboratory of Clinical Pharmacology and Therapeutics, Faculty fo Medicine, University of Lisbon, for providing assistance in the methodology and for the help in the preparation and edition of the manuscript. References 1. Fields BS, Benson RF, Besser RE. Legionella and legionnaires’ disease: 25 years of investigation. Clin Microbiol Rev 2002;15:506-26. 2. Silva MT. Contribuição para o estudo do género Legionella e sua ocorrência em Portugal. PhD Dissertation 1996. 3. Lin YE, Stout JE, Yu VL. Prevention of hospital-acquired legionellosis. Curr Opin Infect Dis 2011;24:350-6. 4. Sabria M, Yu VL. Hospital-acquired legionellosis: solutions for a preventable infection. Lancet 2002;2:368-73. 5. Murdoch DR. Diagnosis of Legionella infection. Clin Infect Dis 2003;36: 64-9. 6. World Health Organization. Legionellosis. Available from: http://www .who.int/mediacentre/factsheets/fs285/en. 2011. Accessed November 8, 2011. 7. Marques T, Froes F, Brum G, Esteves ACS. Doença dos Legionários: Protocolo de diagnóstico. Ministério da Saúde (Portugal); 2003. 8. Marques T. A propósito do lançamento do Programa de Vigilância Epidemiológica Integrada da Doença dos Legionários. Revista de Infecções Respiratórias 2005;1:28-32. 9. Higgins JPT, Altman DG, Sterne JAC. Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration; 2011. Available from: http://handbook.cochrane.org/. 10. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177-88. 11. Deeks JJ. Issues in the selection of a summary statistic for meta-analysis of clinical trials with binary outcomes. Stat Med 2002;21:1575-600. 12. Deeks JJ, Altman DG, Bradburn MJ. Statistical methods for examining heterogeneity and combining results from several studies in meta-analysis. In: Egger M, Davey Smith G, Altman DG, editors. Systematic reviews in health care: meta-analysis in context. 2nd ed. London: BMJ Publication Group; 2001:313-35.
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16. Farr BM, Gratz JC, Tartaglino JC, Getchell-White SI, Groschell DHM. Evaluation of ultraviolet light for disinfection of hospital water contaminated with Legionella. Lancet 1988;669-71. 17. STANDARD, ASHRAE. Minimizing the risk of legionellosis associated with building water systems. EEUU: ASHRAE; 2000. 18. Allen JG, Myatt TA, Macintosh DL, Ludwig JF, Minegishi T, Stewart JH, et al. Assessing risk of health care-acquired legionnaires’ disease from environmental sampling: the limits of using a strict percent positivity approach. Am J Infect Control 2012;40:917-21. 19. Wireman JM, Schmidt A, Hutchins DT. Chlorine, heat: popular ways to beat Legionella. Am Health Facil Manage 1992;5(5):28, 30, 32-4.