key: cord-0929570-a9yars6r
authors: Albarqouni, Loai; Byambasuren, Oyuka; Clark, Justin; Scott, Anna Mae; Looke, David; Glasziou, Paul
title: Does Copper treating of commonly touched surfaces reduce healthcare acquired infections? A Systematic Review and meta-analysis
date: 2020-09-09
journal: J Hosp Infect
DOI: 10.1016/j.jhin.2020.09.005
sha: c5b895d5dd7fdb798c5503b46fd42e432c48cca1
doc_id: 929570
cord_uid: a9yars6r

BACKGROUND: Healthcare acquired infections (HAIs) cause substantial morbidity and mortality. Copper appears to have strong antimicrobial properties under laboratory conditions. AIM: We conducted a systematic review to examine the potential effect of copper treating of commonly touched surfaces in healthcare facilities. METHODS: We included controlled trials comparing the effect of copper-treated surfaces (furniture or bed linens) in hospital rooms versus standard rooms on hospital acquired infections (HAIs). Two reviewers independently screened retrieved articles, extracted data, and assessed the risk of bias of included studies. The primary outcome was the occurrence of healthcare acquired infections. FINDINGS: We screened 638 records; 7 studies comprising 12362 patients were included. From risk of bias assessment, all included studies were judged to be at high risk in ≥2 of the 7 domains of bias. All 7 included studies reported the effect of various copper-treated surfaces on HAIs. Overall, we found low quality evidence of a potential clinical importance that copper-treated hard surfaces and/or bed linens and clothes reduced healthcare acquired infections by 27% (RR 0.73; 95% CI 0.57 to 0.94; I(2) = 44%, p-value = 0.01). CONCLUSION: Given the clinical and economic costs of healthcare acquired infections, the potentially protective effect of copper-treated surfaces appears important. However, the current evidence is insufficient to make a strong positive recommendation. However, it would appear worthwhile and urgent to conduct larger scale publicly funded clinical trials of the impact of copper coating.

Background 47

Healthcare acquired infections (HAIs) cause substantial morbidity and mortality. Copper appears to 48 have strong antimicrobial properties under laboratory conditions. 49

Aim 50 We conducted a systematic review to examine the potential effect of copper treating of commonly 51 touched surfaces in healthcare facilities. 52

Methods 53 We included controlled trials comparing the effect of copper-treated surfaces (furniture or bed 54 linens) in hospital rooms versus standard rooms on hospital acquired infections (HAIs). Two 55 reviewers independently screened retrieved articles, extracted data, and assessed the risk of bias of 56 included studies. The primary outcome was the occurrence of healthcare acquired infections. 57

Findings 58

We screened 638 records; 7 studies comprising 12362 patients were included. From risk of bias 59 assessment, all included studies were judged to be at high risk in ≥2 of the 7 domains of bias. All 7 60

included studies reported the effect of various copper-treated surfaces on HAIs. Overall, we found 61 low quality evidence of a potential clinical importance that copper-treated hard surfaces and/or bed 62 linens and clothes reduced healthcare acquired infections by 27% (RR 0.73; 95% CI 0.57 to 0.94; I 2 = 63 44%, p-value = 0.01). 64

Conclusion 65

Given the clinical and economic costs of healthcare acquired infections, the potentially protective 66 effect of copper-treated surfaces appears important. However, the current evidence is insufficient to 67 make a strong positive recommendation. However, it would appear worthwhile and urgent to 68 conduct larger scale publicly funded clinical trials of the impact of copper coating. Coronavirus species with inactivation occurring in less than 60 minutes 6 . Inactivation also occurs on 89 copper alloys and the activity appears directly proportional to the percentage of copper present in 90 the alloy. This property has led researchers to examine the potential for copperplating of common 91 surfaces to reduce healthcare acquired infections with multi-resistant bacteria as well as viruses with 92 attempts to copperplate common shared surfaces in hospital wards 7 . These include surfaces such as 93 bedrails, door handles, infections, the impact could be substantial in both health and economic terms 8 . Therefore, we aimed 98

to examine the potential of copper coating of common shared surfaces in hospitals. We aimed to 99 find all controlled trials which had compared copper-treated surfaces in hospital rooms or items with 100 standard rooms or items. 101 102

We aimed to find, appraise, and synthesize eligible studies that have compared the effect of copper-105 treated hospital room surfaces versus standard room surfaces on healthcare acquired infections. 106

This systematic review is reported following the Preferred Reporting Items for Systematic Reviews 107

and Meta-Analyses (PRISMA) statement and the review protocol was prospectively developed 9 . 108

Participants. We included studies of patients of any age and with any condition in acute and long-110 term care settings (including intensive care units, rehabilitation centres, and aged-care facilities). 111

Interventions. We included studies that evaluated interventions involving copper (or copper alloy) 112

surfaced rooms or objects in patient care rooms/spaces. We expanded the intervention to include 113 studies evaluated copper-treated soft textiles such as bed linens, clothes, and gowns as sufficient 114 data was available. 115 J o u r n a l P r e -p r o o f Comparators. We included studies with any comparator, as long as it did not involve the use of 116 copper or copper alloy surfaces. 117

Outcomes (primary, secondary). The primary outcome was the incidence of healthcare acquired 118

infection (e.g. bacterial or viral infectionsnot colonisations) in patients. The secondary outcomes 119

were the incidence of deaths and any skin reactions in patients, and any healthcare acquired 120

infection (e.g. bacterial or viral) in hospital staff and visitors. We excluded studies that only reported 121 the rate of colonisations (not infections). 122

Study design. We included randomised and pseudo-randomised (e.g. alternate allocation) controlled 123 trials. 124

Database search strings 126

We searched PubMed, Cochrane CENTRAL and Embase from inception until 25 March 2020. We 127 designed a search string in PubMed that included the following concepts: Copper AND infections 128 AND healthcare facility AND controlled trial. The PubMed search string was translated using the 129

Polyglot Search Translator 10 and run in the other two databases (Appendix 1) 130

Restriction on publication type 131

No restrictions by language or publication date were imposed. We included publications that were 132 published in full; publications available as abstract only (e.g. conference abstract) were included if 133 they had a clinical trial registry record, or other public report, with the additional information 134 required for inclusion. We excluded publications available as abstract only (e.g. conference abstract) 135

with no additional information available. 136

Other searches 137

On 26 March 2020 we conducted a backwards (cited) and forwards (citing) citation analysis in 138

Scopus on the included studies identified by the database searches. These were screened against the 139 inclusion criteria. Clinical trial registries were searched on 25 March 2020 via Cochrane CENTRAL, 140

which includes the WHO ICTRP and clinicaltrials.gov. 141

Two authors (LA, OB) independently screened the titles and abstracts for inclusion against the 143 inclusion criteria. One author (JC) retrieved full-texts, and two authors (LA, OB) screened the full-144 texts for inclusion. Any disagreements were resolved by discussion, or reference to a third author 145 (PG). The selection process was recorded in sufficient detail to complete a PRISMA flow diagram (see 146 Figure 1 ) and a list of excluded full-text articles with reasons for exclusions (see Appendix 2). 147

We used a data extraction form for study characteristics and outcome data, which was piloted on 149 two studies in the review. Each potential source of bias was graded as low, high or unclear, and each judgement was supported 171 by a quote from the relevant trial. 172

We used risk ratios or rate ratios for dichotomous outcomes -risk ratios for results reporting the 174 number of patients with an event, and rate ratios for the results reporting the number of events 175

only. We undertook meta-analyses only when meaningful (when ≥2 studies or comparisons reported 176 the same outcome); anticipating considerable heterogeneity, we used a random effects model. We 177

used Review Manger 5 to calculate the intervention effect. 178

We considered both clinical and methodological heterogeneity among included studies (i.e. 180

differences between included studies in terms of population, intervention, comparison, outcomes, 181

and study designs). We supplemented this assessment of clinical and methodological heterogeneity 182 with information regarding statistical heterogeneity, assessed using the Chi² test (we considered a 183 significance level of P < 0.10 to indicate statistically significant heterogeneity) in conjunction with the 184 I² statistic (I² ≥ 75% indicates considerable heterogeneity) 12 . Because we included fewer than 10 185 trials, we did not create a funnel plot. 186

Dealing with missing data 187 We contacted investigators or study sponsors to provide missing data. 188

We planned to do a subgroup analysis by type of infection/patient and a sensitivity analysis by 190

including versus excluding studies at high risk of bias, however, due to a low number of included 191 studies, these analyses were not done. 192 193

We screened 638 titles and abstracts and assessed 16 full-text articles for inclusion. After excluding 6 195 articles, we included 10 articles pertaining to 7 studies 13-22 . We also identified 5 relevant clinical trial 196 registries (2 for studies already identified and included and 3 registries for studies that have not 197 been published). Figure 1 

All of the 7 included studies were judged to be at high risk in two or more of the domains of bias. Of 213 the 7 included studies, 5 were judged to be at high or unclear risk for selection bias (either random 214 sequence generation or allocation concealment). All of included studies were judged to be at high or 215 unclear risk in blinding of participants or personnel and conflict of interest (recorded as "other risk of 216 bias"). All of included studies were judged to be at low risk in attrition bias (i.e. incomplete outcome 217 data) and reporting bias (i.e. selective reporting). 218

Healthcare acquired infections (HAIs) 220

All 7 included studies reported the effect of copper-treated surfaces on healthcare acquired 221

infections. Overall, we found that copper-treated hard surfaces and/or bed linens and clothes 222 reduced healthcare acquired infections by 27% (RR 0.73; 95% CI 0.57 to 0.94) (Figure 2) . 223

Copper-treated hard surfaces (4 studies) 224 We identified 4 studies (2125 participants) that evaluated the effect of copper-treated hard surfaces 225 on healthcare acquired infections 17,18,21,22 . There was no statistically significant reduction in HAIs 226 among participants hospitalised in facilities with copper-treated surfaces compared to no copper (RR 227 0.76, 95% CI 0.56 to 1.04; I²=38%). 228

Copper-treated bed linens and clothes (2 studies) 229 We identified 2 studies (276 participants) that evaluated the effect of copper-treated bed linens and 230 clothes on HAIs 14,15 . We observed a statistically significant 25% relative reduction in HAIs among 231 participants hospitalised in facilities with copper-treated bed linens and clothes compared to no 232 copper (RR 0.75, 95% CI 0.58 to 0.98; I²=0%). 233

A single study of 9,961 participants evaluated the combined effect of both copper-treated hard 235 surfaces and bed linens and clothes on HAIs 20 . A statistically significant 86% relative reduction in 236

HAIs was observed among participants hospitalised in facilities with copper-treated surfaces 237 compared to no copper (RR 0.14, 95% CI 0.0.03 to 0.61). 238

Mortality 239

Of the 7 included studies, 3 studies (included a total of 1,569 participants) reported the effect of 240 copper-treated hard surfaces on mortality 17,18,21 . There was no statistically significant difference in 241 mortality between participants hospitalised in facilities treated with copper compared to no copper 242 (RR 1.06, 95% CI 0.83 to 1.36) (Figure 3) . developed skin rashes (9 were evaluated by a dermatologist and attributed to alternative aetiology 248 and 1 was discharged before evaluation) 20 . 249 250 We noted both clinical and methodological heterogeneity between included studies. For example, 251 we found differences on how included studies defined and measured the primary outcome (i.e. 252

HAIs). For instance, although 6 of the 7 included studies directly measured HAIs (i.e. infections not 253 just colonisations), the RCT of 112 ventilator-dependent patients in a long-term care did not 254 measure HAIs, instead, measured antibiotic initiation events as an indicator for HAIs 14 . Further, 4 of 255 the 7 included studies determined HAIs following comparable definitions: 3 used the National 256

Healthcare Safety Network (NHSN) definitions 15,18,20 and 1 used National Surveillance System of the 257

Ministry of Health of Chile (i.e. infections on and after third admission day) 21 ; but the remaining 3 258 studies did not clearly report how they define HAIs. Despite these differences, the quantified Q and 259 I 2 statistics did not identify substantial statistically heterogeneity -I² statistics of all metanalyses of 260 all outcomes ranges between 0% to 44%, with all not significant P > 0.10). 261 262 263

We found seven controlled trials, which when combined suggest that copper surfacing or use in bed 265

linen may have some effect on reducing healthcare acquired infections. The combined studies 266 suggest a modest but potentially important effect. 267 268

There are several limitations to our findings. First, many of the studies were poorly reported, 269

preventing a clear appraisal of the methods. Second, even when reporting was clear, the research 270 methods often involved flaws in study design which might introduce bias. Third, studies reported 271

HAIs caused by different organisms, most of them bacterial (e.g. Pseudomonas spp., meticillin-272

resistant Staphylococcus aureus, vancomycin-resistant enterococci) but also viral (e.g. norovirus and 273 adenovirus), and different body system affected (e.g. respiratory, bloodstream, urinary). Fourth, 274

although we did not identify substantial statistical heterogeneity (i.e. evaluated using Q test and I 2 275 statistics), observed clinical and methodological heterogeneity between studies limit our certainty in 276 the effect estimates and poses interpretive challenges. Finally, the small total numbers of infections 277 meant that the confidence intervals around effects were wide, indicating considerable uncertainty in 278 the size of any effect. The poor quality of reporting and methods, and small sizes of the studies 279 would both downgrade the overall quality of the evidence, rating it -in GRADE terms -as low-quality 280 evidence but of a potentially clinically important effect. In addition to these problems, many of the 281 investigator teams had a conflict of interest with companies involved in copper use. 282 283 We report one difference between the protocol and the review: we had initially intended to include 284 only studies of copper-plating of hard surfaces such as furniture. However, as several studies 285 assessed the impact of copper-treating of textiles (clothing and/or bed linens) we broadened our 286 inclusion criteria. This resulted in an inclusion of two clothing/linen-only studies 14,15 and one study 287

that assessed the impact of both furniture coating and Copper-impregnated textiles 20 . 288 289

The only previous systematic review we could identify was a 2017 report prepared by Cochrane 290 Australia for Australia's National Health and Medical Research Council (NHMRC) which found 2 of 291 these studies 18,21 , and concluded that "With only two non-randomised trials, both with uncertain 292 results, it is not possible to draw conclusions from this evidence." The three trials since then, plus 293 two not identified in the 2017 review, have strengthened the body of evidence, but not sufficiently 294

to be able to make strong recommendations. 295 296

Finding effective and sustainable ways of reducing pathogen transmission is important for all 297 epidemics but particularly urgent in the current SARS coronavirus 2 (SARS-CoV-2) pandemic 23 . 298

Though the exact relative importance of different modes of transmission is currently unknown there 299 appears to be three main avenues, namely direct aerosol, contact with fomites, and the most 300 controversial, airborne transmission 24 . Reducing the incidence of infections will require addressing 301 all modes of transmission. While social distancing is widely promoted it may not completely prevent 302

fomite transmission if common objects such as door handles, stair banisters, 

Report on the burden of endemic health care-associated infection 332 worldwide. World Health Organization

Health care-associated infections: a meta-analysis of 334 costs and financial impact on the US health care system

Multistate point-prevalence survey of health care-337 associated infections

Estimating the 339 proportion of healthcare-associated infections that are reasonably preventable and the related 340 mortality and costs

The effect of control strategies to reduce social mixing on 342 outcomes of the COVID-19 epidemic in Wuhan, China: a modelling study

Inactivation of norovirus on dry copper alloy surfaces

New insights 347 on antimicrobial efficacy of copper surfaces in the healthcare environment: a systematic review

Anti-Microbial Coating Innovations to prevent 350 infectious disease: a consensus view from the AMiCl COST Action

Preferred reporting items for systematic 353 reviews and meta-analyses: the PRISMA statement

Improving the translation of search strategies using the 356

The Cochrane Collaboration's tool for assessing risk of 358 bias in randomised trials

Reduction of healthcare-associated infection related events by replacing regular hospital 362 textiles with copper oxide impregnated textiles: crossover, double-blind, controlled study in 363 chronic, ventilator-dependent patients. Open forum infectious diseases

Reduction of health care-366 associated infection indicators by copper oxide-impregnated textiles: Crossover, double-blind 367 controlled study in chronic ventilator-dependent patients

The effect of copper-oxide-treated soft and hard surfaces on the 370 incidence of healthcare-associated infections: a two-phase study

Copper Alloy Surfaces Kill Bacteria and Reduce Hospital-Acquired Infections

Copper surfaces reduce the rate of healthcare-379 acquired infections in the intensive care unit

 Figure 3 : Forest plot of mortality in copper treated surfaces versus no copper.Abbreviation: ICUs, Intensive Care Units; PICUs, Paediatric ICUs. (Israel) 14 Double-blind, controlled cross-over, 7 months (2 x 3 months, separated by a 1-month washout period) 112 ventilatordependent patients in a longterm care hospital (69.8 vs 71.3 yrs)

Copper oxide-impregnated linen and hospital patients' clothes and towels.

Antibiotic treatment initiation events (ATIEs), fever days, days of antibiotic treatment, and antibiotic defined daily dose (DDD) per 1,000 hospitalization days (HDs). We used ATIEs as an indirect indication for HAIs. 

A randomized controlled trial of the effect of accelerated copper textiles on healthcare-associated infections and multidrug-resistant organisms: The "investigating microbial pathogen activity of copper textiles" (impact) study

Abstract without enough information

The antimicrobial scrub contamination and transmission (ASCOT) trial: A three-arm, blinded, randomized controlled trial with crossover design to determine the efficacy of antimicrobial-impregnated scrubs in preventing healthcare provider contamination

Outcome -colonisation (not HAIs)

Superfici al rame e infezioni ospedaliere Assistenza Infermieristica e RicercaNo primary data