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Does copper treatment of commonly touched surfaces reduce healthcare-acquired infections? A systematic review and meta-analysis

Published:September 08, 2020DOI:https://doi.org/10.1016/j.jhin.2020.09.005

      Summary

      Background

      Healthcare-acquired infections (HAIs) cause substantial morbidity and mortality. Copper appears to have strong antimicrobial properties under laboratory conditions.

      Aim

      To examine the potential effect of copper treatment of commonly touched surfaces in healthcare facilities.

      Methods

      Controlled trials comparing the effect of copper-treated surfaces (furniture or bed linens) in hospital rooms compared with standard rooms on HAIs were included in this systematic review. Two reviewers independently screened retrieved articles, extracted data, and assessed the risk of bias of included studies. The primary outcome was the occurrence of HAIs.

      Findings

      In total, 638 records were screened, and seven studies comprising 12,362 patients were included. All included studies were judged to be at high risk of bias in two or more of the seven domains. All seven studies reported the effect of various copper-treated surfaces on HAIs. Overall, this review found low-quality evidence of potential clinical importance that copper-treated hard surfaces and/or bed linens and clothes reduced HAIs by 27% (risk ratio 0.73, 95% confidence interval 0.57–0.94; I2 = 44%, P=0.01).

      Conclusion

      Given the clinical and economic costs of HAIs, the potentially protective effect of copper treatment appears to be important. The current evidence is insufficient to make a strong positive recommendation. However, it would appear worthwhile and urgent to conduct larger publicly funded clinical trials into the impact of copper treatment.

      Keywords

      Introduction

      Healthcare-acquired infections (HAIs) are infections acquired directly or indirectly by patients while receiving health care. HAIs are a major cause of preventable harm, result in substantial morbidity, prolong hospitalization, increase the cost of healthcare delivery, and contribute to mortality [
      World Health Organization
      Report on the burden of endemic health care-associated infection worldwide.
      ,
      • Zimlichman E.
      • Henderson D.
      • Tamir O.
      • Franz C.
      • Song P.
      • Yamin C.K.
      • et al.
      Health care-associated infections: a meta-analysis of costs and financial impact on the US health care system.
      ]. Despite current efforts aiming to prevent and control HAIs, recent estimates suggest that they remain among the most prevalent and preventable challenges to patient safety worldwide [
      • Magill S.S.
      • Edwards J.R.
      • Bamberg W.
      • Beldavs Z.G.
      • Dumyati G.
      • Kainer M.A.
      • et al.
      Multistate point-prevalence survey of health care-associated infections.
      ,
      • Umscheid C.A.
      • Mitchell M.D.
      • Doshi J.A.
      • Agarwal R.
      • Williams K.
      • Brennan P.J.
      Estimating the proportion of healthcare-associated infections that are reasonably preventable and the related mortality and costs.
      ].
      One strategy to control HAIs is to reduce the transmission of fomite pathogens that can occur if common objects such as door handles, stair banisters, table surfaces, utensils or taps are contaminated [
      • Prem K.
      • Liu Y.
      • Russell T.W.
      • Kucharski A.J.
      • Eggo R.M.
      • Davies N.
      • et al.
      The effect of control strategies to reduce social mixing on outcomes of the COVID-19 epidemic in Wuhan, China: a modelling study.
      ]. Cleaning shared surfaces is one proposed preventive mechanism, but would require frequent and extensive cleaning.
      Copper appears to have strong bactericidal and viricidal properties, and substantially reduces the duration of pathogen viability on surfaces from days to 30–60 min under laboratory conditions [
      • Warnes S.L.
      • Keevil C.W.
      Inactivation of norovirus on dry copper alloy surfaces.
      ]. The inactivation property of copper has been demonstrated for both norovirus and coronavirus species with inactivation occurring in less than 60 min [
      • Warnes S.L.
      • Keevil C.W.
      Inactivation of norovirus on dry copper alloy surfaces.
      ]. Inactivation also occurs on copper alloys, and the activity appears to be directly proportional to the percentage of copper present in the alloy. This property has led researchers to examine the potential for copper plating common surfaces to reduce HAIs with multi-drug-resistant bacteria as well as viruses, with attempts made to copper plate common shared surfaces in hospital wards [
      • Chyderiotis S.
      • Legeay C.
      • Verjat-Trannoy D.
      • Le Gallou F.
      • Astagneau P.
      • Lepelletier D.
      New insights on antimicrobial efficacy of copper surfaces in the healthcare environment: a systematic review.
      ]. These include surfaces such as bedrails, door handles and table surfaces, as well as soft textiles such as bed linen, patient gowns and towels.
      If treatment of commonly touched surfaces in hospital rooms with copper/copper alloys could reduce HAIs, the impact could be substantial in both health and economic terms [
      • Dunne C.P.
      • Askew P.D.
      • Papadopoulos T.
      • Gouveia I.C.
      • Ahonen M.
      • Modic M.
      • et al.
      Anti-microbial coating innovations to prevent infectious disease: a consensus view from the AMiCl COST Action.
      ]. Therefore, this review aimed to examine the potential for copper plating common shared surfaces in hospitals. The aim was to identify all controlled trials that had compared copper-treated surfaces in hospital rooms or items with standard rooms or items.

      Methods

      This review aimed to find, appraise and synthesize eligible studies that have compared the effect of copper-treated hospital room surfaces with standard room surfaces on HAIs. This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, and the review protocol was developed prospectively [
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      PRISMA Group
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ].

      Eligibility criteria

      Participants

      Studies of patients of any age and with any condition in acute and long-term care settings [including intensive care units (ICUs), rehabilitation centres and aged care facilities] were included in this review.

      Interventions

      Studies that evaluated interventions involving copper (or copper alloy)-treated rooms or objects in patient care rooms/spaces were included in this review. The intervention was expanded to include studies that evaluated copper-treated soft textiles such as bed linens, clothes and gowns as sufficient data were available.

      Comparators

      Studies with any comparator were included in this review, as long as the comparator did not involve the use of copper or copper alloy surfaces.

      Outcomes

      The primary outcome was the incidence of HAIs (e.g. bacterial or viral infections, not colonizations) in patients. The secondary outcomes were the incidence of death and any skin reactions in patients, and any HAIs (bacterial or viral) in hospital staff and visitors. Studies that only reported the rate of colonization (not infection) were excluded from this review.

      Study design

      Randomized and pseudo-randomized (e.g. alternate allocation) controlled trials were included in this review.

      Search strategies to identify studies

      Database search strings

      PubMed, Cochrane CENTRAL and Embase were searched from inception to 25th March 2020. A search string was designed in PubMed that included the following concepts: copper AND infections AND healthcare facility AND controlled trial. The PubMed search string was translated using the Polyglot Search Translator [
      • Clark J.
      • Sanders S.
      • Carter M.
      • Honeyman D.
      • Cleo G.
      • Auld Y.
      • et al.
      Improving the translation of search strategies using the Polyglot Search Translator: a randomised controlled trial.
      ] and run in the other two databases (Appendix 1, see online supplementary material).

      Restriction on publication type

      No restrictions by language or publication date were imposed. Publications that were published in full were included in this review. In addition, publications available as abstract only (e.g. conference abstracts) were included if they had a clinical trial registry record, or other public report, with the additional information required for inclusion. Publications available as abstract only (e.g. conference abstracts) with no additional information available were excluded from this review.

      Other searches

      On 26th March 2020, a backwards (cited) and forwards (citing) citation analysis was conducted in Scopus on the studies identified by the database searches. These were screened against the inclusion criteria. Clinical trial registries were searched on 25th March 2020 via Cochrane CENTRAL, which includes the World Health Organization International Clinical Trials Registry Platform and clinicaltrials.gov.

      Study selection and screening

      Two authors (LA, OB) independently screened the titles and abstracts against the inclusion criteria. One author (JC) retrieved the full-texts, and two authors (LA, OB) screened the full-texts for inclusion. Any disagreements were resolved by discussion or by reference to a third author (PG). The selection process was recorded in sufficient detail to complete a PRISMA flow diagram (Figure 1) and a list of excluded full-text articles with reasons for exclusions (see Appendix 2, see online supplementary material).
      Figure 1
      Figure 1PRISMA flow diagram of included articles.

      Data extraction

      A data extraction form was used for study characteristics and outcome data, which was piloted on two studies in the review. Two authors (LA, OB) extracted the following data from the included studies:
      • methods: study authors, location, study design, duration of study, duration of follow-up;
      • participants: number, age (mean or median; range), gender, diagnosis or infection type at admission, ward or room type of admission (e.g. ICU, acute care, long-term care);
      • interventions and comparators: type of copper coating (e.g. percentage of copper in the alloy), type of surfaces covered by copper/copper alloy (e.g. bed controls, tables, etc.), type of comparator, average duration of stay in the room; and
      • outcomes: incidence of HAIs (e.g. bacterial or viral infections) in patients (primary outcome) or hospital staff/visitors (secondary outcome), and number of deaths (secondary outcome) and skin reactions (secondary outcome).

      Assessment of risk of bias in included studies (assessment of quality of studies)

      Two review authors (LA, OB) independently assessed the risk of bias for each included study using Risk of Bias Tool 1, as outlined in the Cochrane Handbook [
      • Higgins J.P.
      • Altman D.G.
      • Gotzsche P.C.
      • Juni P.
      • Moher D.
      • Oxman A.D.
      • et al.
      The Cochrane Collaboration's tool for assessing risk of bias in randomised trials.
      ]. All disagreements were resolved by discussion or by referring to a third author (PG). The following domains were assessed:
      • random sequence generation;
      • allocation concealment;
      • blinding of participants and personnel;
      • blinding of outcome assessment;
      • incomplete outcome data;
      • selective outcome reporting; and
      • other bias (focusing on potential biases due to funding or conflict of interests).
      Each potential source of bias was graded as low, high or unclear, and each judgement was supported by a quote from the relevant trial.

      Measurement of effect and data synthesis

      Risk ratios or rate ratios (RR) were used for dichotomous outcomes – risk ratios for results reporting the number of patients with an event, and rate ratios for the results reporting the number of events alone. Meta-analyses were only undertaken when meaningful (when at least two studies or comparisons reported the same outcome); a random effects model was used in anticipation of considerable heterogeneity. Review Manger 5 was used to calculate the intervention effect.

      Assessment of heterogeneity and reporting biases

      Both clinical and methodological heterogeneity were considered among the included studies (i.e. differences between included studies in terms of population, intervention, comparison, outcomes and study designs). This assessment of clinical and methodological heterogeneity was supplemented with information regarding statistical heterogeneity, assessed using Chi-squared test (a significance level of P<0.10 was considered to indicate significant heterogeneity) in conjunction with the I2 statistic (I2≥75% indicates considerable heterogeneity) [
      • Higgins J.P.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analyses.
      ]. As fewer than 10 trials had been included, a funnel plot was not created.

      Dealing with missing data

      Investigators or study sponsors were contacted to provide missing data.

      Subgroup and sensitivity analyses

      The intention was to perform a subgroup analysis by type of infection/patient and a sensitivity analysis by including vs excluding studies at high risk of bias; however, these analyses were not undertaken due to the low number of studies included in this review.

      Results

      In total, 638 titles and abstracts, and 16 full-text articles were screened for inclusion in this review. After exclusion of six articles, 10 articles pertaining to seven studies were included [
      • Borkow G.
      • Marcus E.L.
      • Yosef H.
      • Caine Y.
      • Sasson A.
      • Moses A.E.
      Reduction of healthcare-associated infection related events by replacing regular hospital textiles with copper oxide impregnated textiles: crossover, double-blind, controlled study in chronic, ventilator-dependent patients.
      ,
      • Marcus E.L.
      • Yosef H.
      • Borkow G.
      • Caine Y.
      • Sasson A.
      • Moses A.E.
      Reduction of health care-associated infection indicators by copper oxide-impregnated textiles: crossover, double-blind controlled study in chronic ventilator-dependent patients.
      ,
      • Marik P.E.
      • Shankaran S.
      • King L.
      The effect of copper-oxide-treated soft and hard surfaces on the incidence of healthcare-associated infections: a two-phase study.
      ,
      • Michels H.T.
      • Keevil C.W.
      • Salgado C.D.
      • Schmidt M.G.
      From laboratory research to a clinical trial: copper alloy surfaces kill bacteria and reduce hospital-acquired infections.
      ,
      • Rivero P.
      • Brenner P.
      • Nercelles P.
      [Impact of copper in the reduction of hospital-acquired infections, mortality and antimicrobial costs in the adult intensive care unit].
      ,
      • Salgado C.D.
      • Sepkowitz K.A.
      • John J.F.
      • Cantey J.R.
      • Attaway H.H.
      • Freeman K.D.
      • et al.
      Copper surfaces reduce the rate of healthcare-acquired infections in the intensive care unit.
      ,
      • Schmidt M.G.
      Copper surfaces in the ICU reduced the relative risk of acquiring an infection while hospitalized.
      ,
      • Sifri C.D.
      • Burke G.H.
      • Enfield K.B.
      Reduced health care-associated infections in an acute care community hospital using a combination of self-disinfecting copper-impregnated composite hard surfaces and linens.
      ,
      • von Dessauer B.
      • Navarrete M.S.
      • Benadof D.
      • Benavente C.
      • Schmidt M.G.
      Potential effectiveness of copper surfaces in reducing health care-associated infection rates in a pediatric intensive and intermediate care unit: a nonrandomized controlled trial.
      ,
      • Zerbib S.
      • Vallet L.
      • Muggeo A.
      • de Champs C.
      • Lefebvre A.
      • Jolly D.
      • et al.
      Copper for the prevention of outbreaks of health care-associated infections in a long-term care facility for older adults.
      ]. In addition, five relevant clinical trial registries (two for studies already identified and included, and three for studies that have not been published) were included. Figure 1 shows the PRISMA flow diagram of studies. Excluded full-text articles are presented in Appendix 2 (see online supplementary material) with reasons for exclusion.

      Characteristics of included studies

      Seven controlled studies, which enrolled a total of 12,362 participants, were included in this review [
      • Marcus E.L.
      • Yosef H.
      • Borkow G.
      • Caine Y.
      • Sasson A.
      • Moses A.E.
      Reduction of health care-associated infection indicators by copper oxide-impregnated textiles: crossover, double-blind controlled study in chronic ventilator-dependent patients.
      ,
      • Marik P.E.
      • Shankaran S.
      • King L.
      The effect of copper-oxide-treated soft and hard surfaces on the incidence of healthcare-associated infections: a two-phase study.
      ,
      • Rivero P.
      • Brenner P.
      • Nercelles P.
      [Impact of copper in the reduction of hospital-acquired infections, mortality and antimicrobial costs in the adult intensive care unit].
      ,
      • Salgado C.D.
      • Sepkowitz K.A.
      • John J.F.
      • Cantey J.R.
      • Attaway H.H.
      • Freeman K.D.
      • et al.
      Copper surfaces reduce the rate of healthcare-acquired infections in the intensive care unit.
      ,
      • Sifri C.D.
      • Burke G.H.
      • Enfield K.B.
      Reduced health care-associated infections in an acute care community hospital using a combination of self-disinfecting copper-impregnated composite hard surfaces and linens.
      ,
      • von Dessauer B.
      • Navarrete M.S.
      • Benadof D.
      • Benavente C.
      • Schmidt M.G.
      Potential effectiveness of copper surfaces in reducing health care-associated infection rates in a pediatric intensive and intermediate care unit: a nonrandomized controlled trial.
      ,
      • Zerbib S.
      • Vallet L.
      • Muggeo A.
      • de Champs C.
      • Lefebvre A.
      • Jolly D.
      • et al.
      Copper for the prevention of outbreaks of health care-associated infections in a long-term care facility for older adults.
      ]. Included studies had been conducted in the last decade in the USA (N=3 [
      • Marik P.E.
      • Shankaran S.
      • King L.
      The effect of copper-oxide-treated soft and hard surfaces on the incidence of healthcare-associated infections: a two-phase study.
      ,
      • Salgado C.D.
      • Sepkowitz K.A.
      • John J.F.
      • Cantey J.R.
      • Attaway H.H.
      • Freeman K.D.
      • et al.
      Copper surfaces reduce the rate of healthcare-acquired infections in the intensive care unit.
      ,
      • Sifri C.D.
      • Burke G.H.
      • Enfield K.B.
      Reduced health care-associated infections in an acute care community hospital using a combination of self-disinfecting copper-impregnated composite hard surfaces and linens.
      ]), Chile (N=2 [
      • Rivero P.
      • Brenner P.
      • Nercelles P.
      [Impact of copper in the reduction of hospital-acquired infections, mortality and antimicrobial costs in the adult intensive care unit].
      ,
      • von Dessauer B.
      • Navarrete M.S.
      • Benadof D.
      • Benavente C.
      • Schmidt M.G.
      Potential effectiveness of copper surfaces in reducing health care-associated infection rates in a pediatric intensive and intermediate care unit: a nonrandomized controlled trial.
      ]), France (N=1 [
      • Zerbib S.
      • Vallet L.
      • Muggeo A.
      • de Champs C.
      • Lefebvre A.
      • Jolly D.
      • et al.
      Copper for the prevention of outbreaks of health care-associated infections in a long-term care facility for older adults.
      ]) and Israel (N=1 [
      • Marcus E.L.
      • Yosef H.
      • Borkow G.
      • Caine Y.
      • Sasson A.
      • Moses A.E.
      Reduction of health care-associated infection indicators by copper oxide-impregnated textiles: crossover, double-blind controlled study in chronic ventilator-dependent patients.
      ]). Three of the studies were set in adult ICUs [
      • Marik P.E.
      • Shankaran S.
      • King L.
      The effect of copper-oxide-treated soft and hard surfaces on the incidence of healthcare-associated infections: a two-phase study.
      ,
      • Salgado C.D.
      • Sepkowitz K.A.
      • John J.F.
      • Cantey J.R.
      • Attaway H.H.
      • Freeman K.D.
      • et al.
      Copper surfaces reduce the rate of healthcare-acquired infections in the intensive care unit.
      ,
      • Sifri C.D.
      • Burke G.H.
      • Enfield K.B.
      Reduced health care-associated infections in an acute care community hospital using a combination of self-disinfecting copper-impregnated composite hard surfaces and linens.
      ], one in a paediatric ICU [
      • von Dessauer B.
      • Navarrete M.S.
      • Benadof D.
      • Benavente C.
      • Schmidt M.G.
      Potential effectiveness of copper surfaces in reducing health care-associated infection rates in a pediatric intensive and intermediate care unit: a nonrandomized controlled trial.
      ], one in an aged care facility [
      • Zerbib S.
      • Vallet L.
      • Muggeo A.
      • de Champs C.
      • Lefebvre A.
      • Jolly D.
      • et al.
      Copper for the prevention of outbreaks of health care-associated infections in a long-term care facility for older adults.
      ], one on an acute care ward [
      • Rivero P.
      • Brenner P.
      • Nercelles P.
      [Impact of copper in the reduction of hospital-acquired infections, mortality and antimicrobial costs in the adult intensive care unit].
      ] and one in a long-term care facility for ventilator-dependent patients [
      • Marcus E.L.
      • Yosef H.
      • Borkow G.
      • Caine Y.
      • Sasson A.
      • Moses A.E.
      Reduction of health care-associated infection indicators by copper oxide-impregnated textiles: crossover, double-blind controlled study in chronic ventilator-dependent patients.
      ]. The duration of the studies ranged from 7 to 16 months.
      Four of the included studies evaluated the effect of copper plating commonly touched hard surfaces such as bed rails and tables, intravenous poles, door handles and taps on HAIs [
      • Rivero P.
      • Brenner P.
      • Nercelles P.
      [Impact of copper in the reduction of hospital-acquired infections, mortality and antimicrobial costs in the adult intensive care unit].
      ,
      • Salgado C.D.
      • Sepkowitz K.A.
      • John J.F.
      • Cantey J.R.
      • Attaway H.H.
      • Freeman K.D.
      • et al.
      Copper surfaces reduce the rate of healthcare-acquired infections in the intensive care unit.
      ,
      • von Dessauer B.
      • Navarrete M.S.
      • Benadof D.
      • Benavente C.
      • Schmidt M.G.
      Potential effectiveness of copper surfaces in reducing health care-associated infection rates in a pediatric intensive and intermediate care unit: a nonrandomized controlled trial.
      ,
      • Zerbib S.
      • Vallet L.
      • Muggeo A.
      • de Champs C.
      • Lefebvre A.
      • Jolly D.
      • et al.
      Copper for the prevention of outbreaks of health care-associated infections in a long-term care facility for older adults.
      ]. Two studies evaluated copper-treated linens (bedding, patient gowns and towels) [
      • Marcus E.L.
      • Yosef H.
      • Borkow G.
      • Caine Y.
      • Sasson A.
      • Moses A.E.
      Reduction of health care-associated infection indicators by copper oxide-impregnated textiles: crossover, double-blind controlled study in chronic ventilator-dependent patients.
      ,
      • Marik P.E.
      • Shankaran S.
      • King L.
      The effect of copper-oxide-treated soft and hard surfaces on the incidence of healthcare-associated infections: a two-phase study.
      ] and one study included both hard surfaces and linens [
      • Sifri C.D.
      • Burke G.H.
      • Enfield K.B.
      Reduced health care-associated infections in an acute care community hospital using a combination of self-disinfecting copper-impregnated composite hard surfaces and linens.
      ]. All included studies reported the effect of copper on HAIs in patients (i.e. primary outcome); none of the included studies reported the effect of copper on hospital staff or visitors (i.e. secondary outcome) (see Table I).
      Table ICharacteristics of included studies (N=7)
      Study ID, year and locationStudy type and durationParticipants, settingInterventionControlPrimary outcomes
      As reported by the authors of included studies; however, only the outcomes proposed in the Methods were extracted (e.g. if authors reported both colonization and HAIs, only HAIs were extracted and reported, as per the proposed methods).
      (as reported in original studies)
      Salgado 2013 (USA) [
      • Salgado C.D.
      • Sepkowitz K.A.
      • John J.F.
      • Cantey J.R.
      • Attaway H.H.
      • Freeman K.D.
      • et al.
      Copper surfaces reduce the rate of healthcare-acquired infections in the intensive care unit.
      ]
      Double-blind randomized controlled trial, 11 months614 adult ICU patients (60.4 years)Copper-treated surfaces

      Copper plating of bed rails, overbed tables, IV poles and arms of the visitor's chair (nurses' call button, computer mouse, bezel of touchscreen monitor, and palm rest of laptop differed depending on the hospital)
      Regular ICUIncidence rate of HAI and/or MRSA or VRE colonization. HAIs were determined using NHSN definitions (i.e. infections on and after third day of admission)
      Rivero 2014 (Chile) [
      • Rivero P.
      • Brenner P.
      • Nercelles P.
      [Impact of copper in the reduction of hospital-acquired infections, mortality and antimicrobial costs in the adult intensive care unit].
      ]
      Controlled trial, 13 months440 adult ICU patients (51 years)Copper-treated surfaces

      C11000 copper alloy (99% copper) equivalent to approximately 80% of the areas most touched by patients (four bed rails, patient's table and two IV poles)
      Regular ICUHAIs, associated mortality, cost of antimicrobials
      von Dessauer 2016 (Chile) [
      • von Dessauer B.
      • Navarrete M.S.
      • Benadof D.
      • Benavente C.
      • Schmidt M.G.
      Potential effectiveness of copper surfaces in reducing health care-associated infection rates in a pediatric intensive and intermediate care unit: a nonrandomized controlled trial.
      ]
      Non-randomized, unmasked, controlled clinical trial, 12 months65 PICU patients (1 year)Copper-treated surfaces

      Copper plating of bed rails, bed rail levers, IV poles, sink handles and the nurses' workstation
      Regular PICUDiagnosis of an HAI event associated with patient stay within the PICU or PIMCU. HAIs were determined by standard definitions used by the National Surveillance System of the Ministry of Health of Chile (i.e. infections on and after third day of admission)
      Zerbib 2020 (France) [
      • Zerbib S.
      • Vallet L.
      • Muggeo A.
      • de Champs C.
      • Lefebvre A.
      • Jolly D.
      • et al.
      Copper for the prevention of outbreaks of health care-associated infections in a long-term care facility for older adults.
      ]
      Controlled trial, 16 months556 nursing home residents (85.4 years)Copper-treated surfaces

      Copper alloy (containing 90% copper) treatment of 438 door handles, 322 m of handrails and 10 grab bars
      Regular nursing home settingRates of infection during outbreak (five cases in 4 days)
      Marcus 2017 (Israel) [
      • Marcus E.L.
      • Yosef H.
      • Borkow G.
      • Caine Y.
      • Sasson A.
      • Moses A.E.
      Reduction of health care-associated infection indicators by copper oxide-impregnated textiles: crossover, double-blind controlled study in chronic ventilator-dependent patients.
      ]
      Double-blind, controlled crossover trial, 7 months (2 x 3 months, separated by a 1-month washout period)112 ventilator-dependent patients in a long-term care facility (69.8 vs 71.3 years)Copper-treated textiles

      Copper-oxide-impregnated linen and hospital patients' clothes and towels
      Regular ICUATIEs, fever-days, days of antibiotic treatment, and antibiotic defined daily dose per 1000 hospitalization-days. This review used ATIEs as an indirect indication for HAIs
      Marik 2020 (USA) [
      • Marik P.E.
      • Shankaran S.
      • King L.
      The effect of copper-oxide-treated soft and hard surfaces on the incidence of healthcare-associated infections: a two-phase study.
      ]
      Prospective, cluster, crossover, randomized control trial, 11 months (2 x 5 months separated by 2 weeks of washout)1282 adult ICU patients (60 years)Copper-treated textiles

      Copper-oxide-treated linens (top sheets, fitted sheets, pillowcases, under pads, wash cloths, towels and patient gowns)
      Regular ICUHCAIs were determined using NHSN definitions (i.e. infections on and after third day of admission)
      Sifri 2016 (USA) [
      • Sifri C.D.
      • Burke G.H.
      • Enfield K.B.
      Reduced health care-associated infections in an acute care community hospital using a combination of self-disinfecting copper-impregnated composite hard surfaces and linens.
      ]
      Quasi-experimental study with a control group, 10 months9961 adult acute care patients (58.5 vs 60.5 years)Combined copper-treated textiles and surfaces 16% copper-oxide-impregnated composite countertops (sinks, vanities, desks, computer stations, soiled utility rooms, nurses' workstations) and moulded surfaces (overbed tray tables, bedrails), and copper-impregnated woven linens (patient gowns, bedding, washcloths, towels, bath blankets, thermal blankets)Regular ICUIncidence rate of hospital-onset infections (Clostidioides difficile or MDROs). HAIs were determined using NHSN definitions (i.e. infections on and after third day of admission)
      ICU, intensive care unit; HAI, healthcare-acquired infection; MRSA, meticillin-resistant Staphylococcus aureus; VRE, vancomycin-resistant enterococci; PICU, paediatric ICU; PIMCU, intermediate paediatric care unit; HCAI, healthcare-associated infection; MDRO, multi-drug-resistant organism; NHSN, National Healthcare Safety Network; IV, intravenous; ATIE, antibiotic treatment initiation event.
      a As reported by the authors of included studies; however, only the outcomes proposed in the Methods were extracted (e.g. if authors reported both colonization and HAIs, only HAIs were extracted and reported, as per the proposed methods).

      Risk-of-bias assessment (quality of studies)

      All seven included studies were judged to be at high risk of bias in two or more domains. Of the seven studies, five were judged to be at high or unclear risk for selection bias (either random sequence generation or allocation concealment). All seven studies were judged to be at high or unclear risk for blinding of participants or personnel and conflict of interest (recorded as ‘other risk of bias’). All seven studies were judged to be at low risk for attrition bias (i.e. incomplete outcome data) and reporting bias (i.e. selective reporting).

      Effects of copper-treated surfaces

      Healthcare-acquired infections

      All seven included studies reported the effect of copper-treated surfaces on HAIs. Overall, copper-treated hard surfaces and/or bed linens and clothes were found to reduce HAIs by 27% [RR 0.73; 95% confidence interval (CI) 0.57–0.94] (Figure 2).
      Figure 2
      Figure 2Forest plot of healthcare-acquired infections (HAIs) for copper-treated surfaces vs no copper. ICUs, intensive care units; PICUs, paediatric ICUs; CI, confidence interval. Marcus 2017 data refer to antibiotic treatment initiation events rather than HAIs, and are reported as the number of events per hospitalization-day.

      Copper-treated hard surfaces (four studies)

      Four studies (2125 participants) that evaluated the effect of copper-treated hard surfaces on HAIs were identified [
      • Rivero P.
      • Brenner P.
      • Nercelles P.
      [Impact of copper in the reduction of hospital-acquired infections, mortality and antimicrobial costs in the adult intensive care unit].
      ,
      • Salgado C.D.
      • Sepkowitz K.A.
      • John J.F.
      • Cantey J.R.
      • Attaway H.H.
      • Freeman K.D.
      • et al.
      Copper surfaces reduce the rate of healthcare-acquired infections in the intensive care unit.
      ,
      • von Dessauer B.
      • Navarrete M.S.
      • Benadof D.
      • Benavente C.
      • Schmidt M.G.
      Potential effectiveness of copper surfaces in reducing health care-associated infection rates in a pediatric intensive and intermediate care unit: a nonrandomized controlled trial.
      ,
      • Zerbib S.
      • Vallet L.
      • Muggeo A.
      • de Champs C.
      • Lefebvre A.
      • Jolly D.
      • et al.
      Copper for the prevention of outbreaks of health care-associated infections in a long-term care facility for older adults.
      ]. There was no significant reduction in HAIs among participants hospitalized in facilities with copper-treated surfaces compared with no copper (RR 0.76, 95% CI 0.56–1.04; I2=38%).

      Copper-treated bed linens and clothes (two studies)

      Two studies (276 participants) that evaluated the effect of copper-treated bed linens and clothes on HAIs were identified [
      • Marcus E.L.
      • Yosef H.
      • Borkow G.
      • Caine Y.
      • Sasson A.
      • Moses A.E.
      Reduction of health care-associated infection indicators by copper oxide-impregnated textiles: crossover, double-blind controlled study in chronic ventilator-dependent patients.
      ,
      • Marik P.E.
      • Shankaran S.
      • King L.
      The effect of copper-oxide-treated soft and hard surfaces on the incidence of healthcare-associated infections: a two-phase study.
      ]. A significant 25% relative reduction in HAIs among participants hospitalized in facilities with copper-treated bed linens and clothes was observed compared with no copper (RR 0.75, 95% CI 0.58–0.98; I2=0%).

      Combined copper-treated hard surfaces and bed linens and clothes (one study)

      A single study of 9961 participants evaluated the combined effect of both copper-treated hard surfaces and bed linens and clothes on HAIs [
      • Sifri C.D.
      • Burke G.H.
      • Enfield K.B.
      Reduced health care-associated infections in an acute care community hospital using a combination of self-disinfecting copper-impregnated composite hard surfaces and linens.
      ]. A significant 86% relative reduction in HAIs was observed among participants hospitalized in facilities with copper-treated surfaces compared with no copper (RR 0.14, 95% CI 0.03–0.61).

      Mortality

      Of the seven included studies, three (1569 participants) reported the effect of copper-treated hard surfaces on mortality [
      • Rivero P.
      • Brenner P.
      • Nercelles P.
      [Impact of copper in the reduction of hospital-acquired infections, mortality and antimicrobial costs in the adult intensive care unit].
      ,
      • Salgado C.D.
      • Sepkowitz K.A.
      • John J.F.
      • Cantey J.R.
      • Attaway H.H.
      • Freeman K.D.
      • et al.
      Copper surfaces reduce the rate of healthcare-acquired infections in the intensive care unit.
      ,
      • von Dessauer B.
      • Navarrete M.S.
      • Benadof D.
      • Benavente C.
      • Schmidt M.G.
      Potential effectiveness of copper surfaces in reducing health care-associated infection rates in a pediatric intensive and intermediate care unit: a nonrandomized controlled trial.
      ]. There was no significant difference in mortality between participants hospitalized in facilities treated with copper compared with no copper (RR 1.06, 95% CI 0.83–1.36) (Figure 3).
      Figure 3
      Figure 3Forest plot of mortality for copper-treated surfaces vs no copper. ICUs, intensive care units; PICUs, paediatric ICUs; CI, confidence interval.

      Skin reactions

      Of the seven included studies, two reported data on skin reactions [
      • Sifri C.D.
      • Burke G.H.
      • Enfield K.B.
      Reduced health care-associated infections in an acute care community hospital using a combination of self-disinfecting copper-impregnated composite hard surfaces and linens.
      ,
      • von Dessauer B.
      • Navarrete M.S.
      • Benadof D.
      • Benavente C.
      • Schmidt M.G.
      Potential effectiveness of copper surfaces in reducing health care-associated infection rates in a pediatric intensive and intermediate care unit: a nonrandomized controlled trial.
      ]. von Dessauer et al. did not observe any adverse events (i.e. skin or other allergic reactions) among any participants in either group [
      • von Dessauer B.
      • Navarrete M.S.
      • Benadof D.
      • Benavente C.
      • Schmidt M.G.
      Potential effectiveness of copper surfaces in reducing health care-associated infection rates in a pediatric intensive and intermediate care unit: a nonrandomized controlled trial.
      ]. Sifri et al. reported that 10 (of 4707) patients hospitalized in copper-treated rooms developed skin rashes (nine were evaluated by a dermatologist and attributed to alternative aetiology, one was discharged before evaluation) [
      • Sifri C.D.
      • Burke G.H.
      • Enfield K.B.
      Reduced health care-associated infections in an acute care community hospital using a combination of self-disinfecting copper-impregnated composite hard surfaces and linens.
      ].

      Heterogeneity in included studies

      Both clinical and methodological heterogeneity between included studies were noted. For example, differences were found in how included studies defined and measured the primary outcome (i.e. HAIs). For instance, although six of the seven included studies measured HAIs directly (i.e. infection not just colonization), the randomized controlled trial of 112 ventilator-dependent patients in a long-term care facility did not measure HAIs, and instead measured antibiotic initiation events as an indicator for HAIs [
      • Marcus E.L.
      • Yosef H.
      • Borkow G.
      • Caine Y.
      • Sasson A.
      • Moses A.E.
      Reduction of health care-associated infection indicators by copper oxide-impregnated textiles: crossover, double-blind controlled study in chronic ventilator-dependent patients.
      ]. Further, four of the seven included studies determined HAIs following comparable definitions: three used the National Healthcare Safety Network definitions [
      • Marik P.E.
      • Shankaran S.
      • King L.
      The effect of copper-oxide-treated soft and hard surfaces on the incidence of healthcare-associated infections: a two-phase study.
      ,
      • Salgado C.D.
      • Sepkowitz K.A.
      • John J.F.
      • Cantey J.R.
      • Attaway H.H.
      • Freeman K.D.
      • et al.
      Copper surfaces reduce the rate of healthcare-acquired infections in the intensive care unit.
      ,
      • Sifri C.D.
      • Burke G.H.
      • Enfield K.B.
      Reduced health care-associated infections in an acute care community hospital using a combination of self-disinfecting copper-impregnated composite hard surfaces and linens.
      ] and one used the National Surveillance System of the Ministry of Health of Chile (i.e. infections on and after the third day of admission) [
      • von Dessauer B.
      • Navarrete M.S.
      • Benadof D.
      • Benavente C.
      • Schmidt M.G.
      Potential effectiveness of copper surfaces in reducing health care-associated infection rates in a pediatric intensive and intermediate care unit: a nonrandomized controlled trial.
      ]. The remaining three studies did not report clearly how they defined HAIs. Despite these differences, the quantified Q and I2 statistics did not identify substantial statistical heterogeneity; the I2 statistics of all meta-analyses of all outcomes ranged between 0% and 44% (all not significant, P>0.10).

      Discussion

      The literature search identified seven controlled trials which, when combined, suggest that copper plating of surfaces or the use of copper in textiles may have some effect in reducing HAIs. The combined studies suggest a modest but potentially important effect.
      There are several limitations to these findings. First, many of the studies were poorly reported, preventing a clear appraisal of the methods. Second, even when reporting was clear, the research methods often involved flaws in the study design which may have introduced bias. Third, studies reported HAIs caused by different organisms, most of them bacterial (e.g. Pseudomonas spp., meticillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci) but also viral (e.g. norovirus and adenovirus), and different body system affected (e.g. respiratory, bloodstream, urinary). Fourth, although substantial statistical heterogeneity (i.e. evaluated using Q test and I2 statistics) was not identified, observed clinical and methodological heterogeneity between the studies limits the authors' certainty in the effect estimates and poses interpretive challenges. Finally, the small total number of infections meant that the CIs around effects were wide, indicating considerable uncertainty in the size of any effect. The poor quality of reporting and methods, and small sizes of the studies downgrades the overall quality of the evidence, rating it – in GRADE terms – as low-quality evidence but of potential clinical importance. In addition to these problems, many of the investigator teams had a conflict of interests with companies involved with the use of copper.
      There was one difference between the protocol and the review. Initially, the intention was to include only studies of copper-plated hard surfaces, such as furniture. However, as several studies assessed the impact of treating textiles (clothing and/or bed linens) with copper, the inclusion criteria were broadened. This resulted in the inclusion of two studies on copper-treated clothing/linen alone [
      • Marcus E.L.
      • Yosef H.
      • Borkow G.
      • Caine Y.
      • Sasson A.
      • Moses A.E.
      Reduction of health care-associated infection indicators by copper oxide-impregnated textiles: crossover, double-blind controlled study in chronic ventilator-dependent patients.
      ,
      • Marik P.E.
      • Shankaran S.
      • King L.
      The effect of copper-oxide-treated soft and hard surfaces on the incidence of healthcare-associated infections: a two-phase study.
      ] and one study that assessed the impact of copper treatment of both furniture and textiles [
      • Sifri C.D.
      • Burke G.H.
      • Enfield K.B.
      Reduced health care-associated infections in an acute care community hospital using a combination of self-disinfecting copper-impregnated composite hard surfaces and linens.
      ].
      To the authors' knowledge, the only previous systematic review on this subject was published in 2017 by Cochrane Australia for Australia's National Health and Medical Research Council. This found two of the studies [
      • Salgado C.D.
      • Sepkowitz K.A.
      • John J.F.
      • Cantey J.R.
      • Attaway H.H.
      • Freeman K.D.
      • et al.
      Copper surfaces reduce the rate of healthcare-acquired infections in the intensive care unit.
      ,
      • von Dessauer B.
      • Navarrete M.S.
      • Benadof D.
      • Benavente C.
      • Schmidt M.G.
      Potential effectiveness of copper surfaces in reducing health care-associated infection rates in a pediatric intensive and intermediate care unit: a nonrandomized controlled trial.
      ] included in the present review, and concluded that ‘With only two non-randomised trials, both with uncertain results, it is not possible to draw conclusions from this evidence’. The three trials that have been performed since then, plus two studies that were not identified in the 2017 review, have strengthened the body of evidence, but not sufficiently to be able to make strong recommendations.
      Finding effective and sustainable ways to reduce the transmission of pathogens is important for all epidemics, but is particularly urgent in the current coronavirus disease 2019 (COVID-19) pandemic [
      • Wilder-Smith A.
      • Chiew C.J.
      • Lee V.J.
      Can we contain the COVID-19 outbreak with the same measures as for SARS?.
      ]. Although the exact relative importance of different modes of transmission is currently unknown, there appear to be three main avenues: direct aerosol, contact with fomites, and, the most controversial, airborne transmission [
      • Zhu N.
      • Zhang D.
      • Wang W.
      • Li X.
      • Yang B.
      • Song J.
      • et al.
      A novel coronavirus from patients with pneumonia in China, 2019.
      ]. Reducing the incidence of infections will require addressing all modes of transmission. While social distancing is widely promoted, it may not completely prevent fomite transmission if common objects such as door handles, stair banisters, table surfaces, utensils or taps are contaminated [
      • Prem K.
      • Liu Y.
      • Russell T.W.
      • Kucharski A.J.
      • Eggo R.M.
      • Davies N.
      • et al.
      The effect of control strategies to reduce social mixing on outcomes of the COVID-19 epidemic in Wuhan, China: a modelling study.
      ]. Therefore, the present findings may also be relevant to the current COVID-19 pandemic.
      Given the clinical and economic costs of HAIs, the potential effect of copper treatment appears to be important. The current evidence is insufficient to make a strong positive recommendation. However, it would appear worthwhile and urgent to conduct larger publicly funded clinical trials into the impact of copper treatment. If such studies were to be funded, it would also be important to collect additional data, such as the separation of bacterial and viral infections, and measuring outcomes for healthcare workers, particularly for viral infections.

      Conflict of interest statement

      None declared.

      Funding sources

      None.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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