The Environment and HAI – Where does Biological Plausibility Come In?

This May's Infection Control and Hospital Epidemiology (ICHE) contained a randomized trial of copper-coated surfaces in ICU settings which reported a 50-70% reduction in several aggregate outcomes that included hospital-acquired infections and colonization with MRSA and VRE.  In this guest blog post, physician-scientists Dr. Matthias Maiwald from the KK Women’s and Children’s Hospital in Singapore and Dr. Stephan Harbarth from University of Geneva Hospitals in Geneva, Switzerland question the plausibility of these findings and put them in the larger context of what actually causes HAIs.

In 1965, Sir Austin Bradford Hill published a landmark paper, entitled “The Environment and Disease: Association or Causation?” in which he outlined what would become known as the “Bradford Hill Criteria.” The “Hill Criteria” help distinguish association from causation in epidemiological research. One of nine criteria was biological plausibility. Quoting: “It will be helpful if the causation we suspect is biologically plausible. But this is a feature I am convinced we cannot demand. What is biologically plausible depends upon the biological knowledge of the day.” As commented elsewhere, the spirit of this criterion is to check whether the proposed causation violates any of the known laws and facts of science of biology, and as Hill outlines, this depends on currently available knowledge. It is said that Hill did not intend the criteria to be applied rigidly in the sense of a checklist approach; instead, he regarded them as “viewpoints” that would merely help in the assessment.

Fast-forward to the May 2013 Special Topic Issue of ICHE concerning the role of the environment in infection prevention. In the issue’s introduction, Weber and Rutala quote figures from a 1991 article by Weinstein concerning the biologically plausible sources of healthcare-acquired infections (HAIs): “patients’ endogenous flora, 40-60%; cross infection via the hands of personnel, 20-40%; antibiotic-driven changes in flora, 20-25%; and other (including contamination of the environment), 20%.”

In the same issue, an article by Salgado and colleagues caught our attention. This clinical trial compares 614 patients randomly placed into standard ICU rooms or into rooms where 6 frequently-touched items (e.g. bed rails, overbed tables, intravenous poles, etc.) had been replaced with copper alloy surfaces. The measured primary outcomes, according to the paper’s methods, were:
   (a) any HAIs and
   (b) colonization with methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant enterococci (VRE). Besides HAI and colonization, outcomes presented in the results section included the numbers of patients who had
   (c) both HAI and colonization,
   (d) HAI and/or colonization,
   (e) HAI only but no colonization (i.e. number of patients who had HAI minus the ones who had both HAI and colonization), and
   (f) colonization only but no HAI.

Are you confused? Separate data for outcomes in each trial arm were only reported for (d-f) but not (a-c).

For HAI and/or colonization (d), the article reported what amounted to a 49% reduction in the copper rooms vs. non-copper rooms (21 vs. 41 patients; p=.02), for HAI only (e) a 62% reduction in the copper rooms (10 vs. 26; p=.013), and for colonization only (f), a 67% reduction (4 vs. 12; p=.063, NS). What was was not reported were the numbers of patients with (a) HAI and (b) colonization, listed separately for each trial arm, but the article concluded – in the discussion – that copper surfaces in rooms reduced the risk of HAIs by more than half. Conventional wisdom, however, would suggest that (a) any HAIs and (b) any colonization events, would be the most biologically relevant outcomes, and that it may not be so informative to combine these two events (under d) in the same statistical calculation, because they are biologically very different from each other. So, we extracted the missing numbers from the other numbers presented and arrived at (a) HAIs 17 vs. 29, and (b) colonization, 11 vs. 15 events. Putting these into our statistics calculator, they were – non-significant.

Now, let us revisit possible transmission routes in hospitals. We have: (i) endogenous transmission, from within the patient’s own flora, (ii) exogenous transmission via direct transfer, (e.g. as in handborne without surfaces), and (iii) exogenous transmission via surfaces and secondary transmission from surfaces onto the patients. If we look at (a) HAIs and (b) colonization with MRSA or VRE, then all three pathways can lead to HAIs, while only the two exogenous pathways can lead to colonization. If there is a >50% reduction of HAIs through copper surfaces (pathway iii), this would mean that the overall proportion of transmission from pathways (i) and (ii) plus the proportion of transmission from the remaining non-copper surfaces in the copper-treated rooms among pathway (iii) among all HAIs together would contribute less than 50% to overall HAIs.

The obvious question comes to mind: is that consistent with the known proportions of the different pathways leading to HAIs? The preliminary answer, given the Weinstein data (see above), would be, “given the biological knowledge of the day, apparently not.” It is also noted that the overall numbers of HAI and colonization events in the present article are relatively small.

Finally, anyone of us engaging in research can accidentally have outcomes that are surprising or do not quite add up with existing knowledge in the field. That is, in our opinion, where the intended purpose and scope of a discussion section of an article comes in, and where the Hill Criteria provide important food for thought. As one of us has put forward (Teleclass Feb. 7, 2013) on a different occasion and concerning a different topic, we would welcome the broad application of a check for biological plausibility when findings from clinical trials – and even systematic reviews – are reported. But we are not confident that our voices will be heard.

Image of Sir Austin Bradford Hill, source: toxipedia


  1. Thanks to Drs Maiwald and Harbarth for this thoughtful blog. I've been waiting for some time to get my hands on this study.

    The study team should be commended for the careful design and attention to detail in the execution of the study. For example, they performed a daily census of the items in the study to determine exactly who was exposed to copper surfaces, and for how long. This indicated that only half of the patients in ‘copper’ rooms were exposed to all six copper items for the duration of their stay, and 13% of patients in the ‘non-copper’ arm were exposed to some copper items during their stay. It’s important to note that the analysis was performed on an ‘intention to treat’ population, i.e. all patients randomized to the two groups, regardless of which items they were actually exposed to. It would have been interesting to see a sub-analysis on the ‘per protocol’ population (i.e. those patients admitted to ‘copper’ rooms and exposed to all six copper items vs. those patients admitted to ‘non-copper’ rooms and exposed to no copper items). Also, I’m not sure why they chose to analysis % acquisition rather than a comparison of rates between the groups. And then there’s the funding from the Copper Development Association. Notwithstanding these limitations, it does seem that the introduction of copper high-touch surfaces does reduce the transmission of hospital pathogens.

    The scale of the difference is incredible. And I mean just that. It lacks credibility. Many will dismiss the study simply because of the scale of the difference between the groups. So, can the introduction of 6 copper items into ICU rooms really reduce the rate of HAI by >50%?

    The degree to which contaminated surfaces contribute to the transmission of pathogens is up for debate. I was asked to give a talk at APIC 2012 on the role of the environment. Prior to the talk, I asked the expert faculty a question: ‘What is your estimation of the % of allC. difficile transmission in hospitals that is mediated, directly or indirectly, by contamination of the inanimate environment?’ The answers ranged from 25-75%, reflecting the uncertainty on this issue.

    A recently published study by Johns Hopkins (Passaretti et al 2013, CID) provides some illuminating findings (albeit indirectly). Extrapolating unadjusted acquisition rates from all study cohorts indicates that if rooms had been disinfected using hydrogen peroxide vapour (HPV) after every discharge, the overall rate of acquisition of MDROs would have been halved. Whilst it’s not feasible to disinfect all rooms using HPV at patient discharge, this does add some weight to the scale of the reduction identified in this copper study.

    It seems that the introduction of a handful of copper alloy high-touch sites had a profound impact on HAI rates. On reflection, I do believe it possible that the scale of reduction in study is “real”. However, questions remain over the practicality and durability of the widespread adoption of copper alloy surfaces in healthcare.


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