Overview

What is the research question and why is it important?

Contrary to public expectation, the potential for contracting a microbial pathogen is highest within a hospital environment, and these infections are much more likely to be fatal. The Centers for Disease Control and Prevention identified 1.5 million cases of environmentally-contracted notifiable diseases in the United States for 2002 [1], 15,743 of which resulted in death (1 %) [2]. In comparison, during the same year, estimates of healthcare associated infections (HAI) in the United States was 1.7 million, a rate of 4.5 infections per 100 hospital admissions, which contributed to an astonishing 99,000 deaths (6%) [3]. This sobering statistic places HAIs as the 6th leading cause of death, ahead of diabetes, influenza/pneumonia, and Alzheimer’s [4]. Circumstantial evidence suggests that agent transfer between surfaces and humans is the most important transmission route, and therefore, hospitals are likely to be the foremost ecosystem for studying the transfer of microorganisms between humans and a built environment.

How microbial communities persist and change in indoor environments is of immense interest to public health bodies and scientists. Our recent work on the Home Microbiome Project (www.homemicrobiome.com) shows that humans alter the microbiome of a space when they begin to occupy that space. The length of time taken to demonstrate a change (e.g. on the carpet of a bedroom) can range from 4-6 days, suggesting that the rate of succession in a microbial community can be influenced by the way in which the occupants interact with that space. The building materials (e.g. HVAC system, paint, flooring type, etc) in each of the houses in this study were also found to influence both the rate of succession in communities and the community composition. Here we apply the expertise developed during this first APSF funded initiative to a more intriguing system, a hospital. In the Home Microbiome Project, we examined the rate of succession as people moved into a new home; in this study we will take advantage of a unique opportunity to examine the rate and structure of succession of a hospital microbiome as the hospital starts accepting staff and patients. We hypothesize that these changes in demographics, how they interact with spaces, and the building materials used to create different spaces, will all influence the development and composition of microbial communities. We place this in the public health domain by examining the relationship between these changes and the health of patients. While this initial investigation will look for co-occurrence patterns between community structure and host health factors, this has the potential to lead to far more detailed exploration of the potential development of HAIs.

To highlight the current effort and provide a focus for ongoing funding initiatives, we have created the www.hospitalmicrobiome.com website, which currently details the plans outlined in the APSF funded workshop on the Hospital Microbiome Project, held in Chicago on June 7th 2012. This website provides details of the background and significance of this study, the study design and analytical approaches. We also identify the goals, highlight the working group structure, and the timeline of activities. By making this information public we hope to engage more fully with the multi –disciplinary community on the approaches outlined by this landmark study. Importantly, this effort is just the start of a potential new field. This will be complemented by the development of a Hospital Microbiome Consortium (HMC) detailed within this proposal.

As a study site, hospitals offer numerous advantages over personal residences. Variables such as building materials, temperature, humidity, air source, HVAC, square footage, and cleaning procedures/schedules are relatively consistent across individual patient rooms, thereby enhancing our ability to measure the effect of individual occupants on microbial diversity. Additionally, patients in the long-term care ward of this hospital (floor 10 is dedicated to oncology) will occupy their room nearly 100% of the time, allowing their body’s microbiota to potentially acclimate entirely with the room under observation (if the rates of acclimation mirror what was observed in the Home Microbiome Project). The absence of macrofauna such as pets, insects, and additional long-term residents in these rooms establishes a defined set of sources responsible for the introduction of microorganisms – sources that will be monitored throughout the study (staff, air, water, patients).

In the military hospital, the patients entering the facility are typically in transit from the theater of combat; stabilized for transport and proceeding towards definitive care and the company of loved ones. Thus, staff members are very careful with infection control and visitors do not attend the patients at length; there is little opportunity for patients to cycle between the hospital and the local community. As a model perturbation of any room by an occupant, studying the hospital room around the patient is thus a relatively simple case. The climate for research is also enhanced because hospital staff members, more than staff at other kinds of facilities, are likely to be aware of microbiology and experienced with microbiology research.

Hospital-acquired infections (also called nosocomial infections) are usually acquired between 48 hours and 4 days after a patient has been admitted to the hospital, and currently affect 5% of patients admitted to US medical facilities, with the total number exceeding 1 million people with 1.7 million HAIs requiring >170 million patient days [3]. These infections are normally viral or bacterial in origin, but fungal infections have not been ruled out. The vast majority of these cases occur while the patient is being treated for the ailment that resulted in the hospital admission in the first place. Approximately 36% of these infections could be linked to professional error, through improper attention to protocols for cleanliness in the hospital environment (www.hhs.gov/ash/initiatives/hai/tier2_ambulatory.html). While these numbers are shocking, they also highlight a considerable lack of evidence regarding both the source and development of nosocomial infections.

Despite considerable interest in developing hospitals with reduced nosocomial infection rates, there has been no systematic analysis of the source, presence, and development of either pathogenic or non-pathogenic microbial reservoirs in hospital environments. Indeed, there is currently very limited evidence as to the actual source of the infections; if these are airborne then any transmission agent that interacts with the hospital environment could be a potential source of transmission. This is why it is so essential that we systematically explore the action of populating a hospital to at least qualitatively assess the mode of microbial transmission. The Hospital Microbiome Project will characterize the taxonomic composition of surface-, air-, water-, and human-associated microbial communities in a newly constructed hospital to monitor changes in community structure following the introduction of patients and hospital staff. The specific aim is to determine the influence of population demographics, how the demographic interfaces with a space, and the building materials used to create that space, on the community succession and rate of microbial colonization over the course of 1 year. The proposed sampling design will test several hypotheses concerning the microbial interaction of multiple demographics with the hospital infrastructure, and develop possible recommendations for best practice in reducing HAIs. Four hypotheses that will be tested are:

  1. Microbial community structure on hospital surfaces can be predicted by human demographics, physical conditions (e.g. humidity, temperature), and building materials for each location and time. The null-hypothesis states that “microbial community structure exists independently on human interaction and physical conditions of the built system”. While this hypothesis has been tested in different environments, the current study will be testing it to determine if defined relationships exist that could help predict the succession of microbial communities, including potential pathogen reservoirs.
     
  2. A patient-room microbiota is influenced by the current patient and their duration of occupancy, and shows community succession with the introduction of a new occupant. The null-hypothesis states that “the patient’s interaction with a room has little impact on microbial community structure on the surfaces of that room, and this relationship is not changed by duration of occupancy”. The duration of occupancy for patients in this new hospital will vary considerably, indeed the experimental design will focus on two different modes, oncology (floor 10) will have long residence times of >2-3 weeks, while surgery (floor 9) will have short residence times of <3 days on average. By monitoring 5 patient rooms on these two floors at different temporal scales (daily and weekly) it will be possible to determine the impact of the patient’s occupancy on the composition and structure of the microbial communities in the room.
     
  3. The colonization of the surfaces and patients by potential pathogens is influenced by composition and diversity of the existing microbial community derived from previous occupants of the space. The null-hypothesis states, “Existing microbial communities associated with a surface do not influence the colonization, succession or development of a new community”. Validation of the hypothesis would indicate that existing microbial communities could be useful in altering the development of new, potentially pathogenic, organisms on a surface. This will be vitally important in determining how microbes interact in this complex, dynamic system, and how we can potentially change the paradigm view of bacteria in a hospital, in that some may be beneficial to a healthy environment.
     
  4. The rate of microbial succession is driven by demographic usage and building materials. The null-hypothesis states “community structure and composition evolves independently of human population demographics and occupancy and of the building materials used to construct the room and surfaces”. This hypothesis explicitly focuses on the rate of succession of the community, and will be explored by comparing different temporal resolutions of observation, and defining how rapidly communities change on different surfaces, and in rooms with different patient, and health-care worker turnover rates.

Systematically characterizing the potential changes in the building microbiota due to the natural evolution of microbial community succession associated with different built environments inside the building will enable the generation of datasets that could have considerable impacts upon how hospitals are designed, and the use of the space following the build. Fundamentally, a better understanding of these processes may potentially impact population handling even inside hospitals that are already built. A key aspect will be determining the influence of each human group on the microbial ecology of the building (air, water and surfaces) and the potential development of microbial reservoirs. Hence, exploring correlations of community profiles with information regarding the abundance and types of people using specific locations will help to determine the relationships between the development of the indoor microbiome in the hospital and the human social interaction with that space.

This proposal aims to determine the development of microbial communities associated with surfaces, air, water, and the human-body over a year starting one month before a new hospital pavilion opens at the University of Chicago, and also conduct a highly detailed analysis of a room in a US military hospital for a shorter time. The importance of studying these two different hospital environments cannot be underestimated, with the civilian hospital coping with very different medical cases to the wounded soldiers associated with the military instillation. In addition, the direct association with the Department of Defense will have ramifications for the potential of this study to develop practical opportunities for further development. This proposal is derived from the outcome of the APSF funded workshop on the best practice for performing such an analytical observational study. The working-group comprised building design, construction, out-fitting professionals, as well as project managers, medical staff, management, microbiologists, virologists, building scientists, and standards officials, whose remit was to define the most appropriate sampling regime to capture the development of microbial communities in a new hospital building, and to potentially tie this development to the origin and development of HAIs.

What is the state of the research on this question?

On the whole we are indoor animals, spending up to 90% of our time inside buildings [5]. However, the current literature regarding the relationship between the indoor environment and humans primarily explores the development of fungal contamination with damp-surfaces [6–9], the role of hygiene in removing microbial communities [10,11], and the length of time microbes can survive on surfaces [12]. There have been a number of studies to explore the microbial diversity of communities associated with dust [13–15] and air [16,17]. One study that investigated temporal succession of microbial communities performed on indoor dust, found seasonal patterns, and these were building- specific, probably as a result from skin-cells shed from inhabitants within the buildings [15]. These existing studies demonstrate fundamental principles regarding experimental design, explicitly regarding the types of environmental conditions that will need to be monitored (e.g. surface material, moisture, HVAC system, etc), and the observation of architectural design for an indoor space that will influence the potential community structure and hence human health [18]. The influence of air ventilation and the number of people in a space must be explored with regard to the impact on microbial community structure [19,20]. Additionally, the variability associated with body-sites [21,22] will have a major impact on the interpretation of the analyses, as different body sites interact with different surfaces differently. The most diverse skin sites are the driest areas and hence are less likely to be transferred to a surface with sebaceous exudates. This will affect the time that the microbial community maintains structural cohesion with reference to relative abundances of members on a surface [12]. A recent addition to the literature explores the relationship between airflow inside hospital rooms and the microbial community composition [20]. The conclusions from this study were that indoor air, especially that from mechanical ventilation (versus an open window) was less diverse than outdoor air, which has also been shown in other studies [23,24]. Also, importantly for the prevalence of nosocomial infections, the hospital air was enriched in organisms closely related to human pathogens. This study demonstrates that the architectural design of the hospital will impact the community composition of microbial communities, and the relative abundance of potential human pathogens.

The essential point of any nosocomial or healthcare associated infection is that hospitals can be risky places for those with suppressed immunity. A new patient will be exposed to potential pathogen infection risk during a care-related visit to a health care facility, and the risk will be multiplied during invasive treatments [25]. The most predominant types of nosocomial infections are those related to surgical or invasive procedures, including catheter- associated infections which impact the urinary tract, pneumonia spread through ventilator systems, infection at the site of surgery, and infections borne by catheter intrusion into the bloodstream. Groups most immediately at risk include patients of advanced age or premature birth and immunodeficiency. The latter can be developed inside the hospital due to drugs, illness or irradiation, all of which can be a direct result of treatments [25]. The rise in deaths related to Clostridium difficile and methicillin-resistant Staphylococcus aureus bacteraemia in the UK over the last 10 years has been shocking, with more than 10,000 deaths per year related to these HAIs [26]. While the factors associated with the disease etymology and pathogenicity have often been explored, and intervention strategies expounded [27–29], the problem is not going away. There have however been regional successes that have made considerable ground in the removal of specific HAIs, including enabling a 60-70% reduction in central line- associated bloodstream infections in Intensive Care Units [30]. Such successes have led to calls for action from the community, especially regarding a call for data to enable a reaction to existing and emerging threats [31].

Currently there is a lot of misinformation about the whole idea of where infection comes from in the hospital setting, i.e. infected instruments, water supply, keyboards, human hands, noses, sheets, etc. The real question to ask is geo-spatially how does the microbiome of a hospital organize? The only way to know that is to study it before patients and personnel are there, and then to track how the structure (and key elements that it houses) become colonized, and from where the infection originates. Or if such colonization does not occur, what the potential mode of transmission might be. The new knowledge to be gained is that humans infect the structure, but the infected structure itself does not cause the infections (hypothesis to be tested). Sick patients enter the hospital with lots of pathogens (they have received antibiotics, chemotherapy, etc), they are then likely to leave a microbial/viral footprint in the locations they have been, whether by air or physical transmission. We then identify these microbes on objects like keyboards and personnel like nurses’ fingers, leading to misleading blame on the mode of transmission, when these most often, causally, represent rare events. There is circumstantial evidence that hands are the most common vehicle for the transmission of HAIs within a hospital, which has led to the assumption that hand-washing is the leading measure for preventing the spread of antimicrobial resistant infections [32]. Unpublished data suggests that hand washing reduces infection only by about 3-5%, and while this helps, infection rates are going up not down. The most compelling evidence we have of the association between environmental contamination and patient infection comes from unpublished studies that demonstrate circumstantial evidence of an increased risk for multi-drug resistant organism infections among hospital patients occupying a bed space that was previously occupied by an infected or colonized patient. However, these analyses are somewhat limited, even when multiple confounders are considered in the analysis. The need for education is highlighted by unpublished studies that explore aggregated hand hygiene performance, which typically only examines a limited number of hand hygiene opportunities, yet suggest that studies where hand- washing is reported may be woefully overestimating of rates.

Prior studies have identified numerous hospital-associated pathogens (HAPs) as well as routes of transmission between patients, staff, equipment, surfaces, and recycled air. HAPs that are of particular relevance to this study are coagulase-negative staphylococci, Staphylococcus aureus, Enterococcus species, Candida species, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacter species, Acinetobacter baumannii, and Klebsiella oxytoca, which have been previously found to collectively account for 84% of HAIs over a 21 month period in 463 hospitals [33]. These bacteria are commonly found on physician’s and nursing staff’s clothing [34–41], cell phones [42–47], stethoscopes [48], computer keyboards [49], telemetry leads [50], electronic thermometers [51], blood-pressure cuffs [52], and gels for ultrasound probes [53]. Even the air in patient rooms present levels of HAPs that are much higher than in other indoor environments [54–58]. The persistence of HAPs across multiple reservoirs implies that, despite the sensitivity of these microorganisms to inexpensive disinfectants, environmental sterilization practices are an incomplete approach to protecting patients. Understanding these HAPs in the context of the microbial communities they inhabit, which may affect their ability to infect, is a critical gap in knowledge.

What will be the output from the research project?

The results of this project will be of interest to the microbial ecology, health sciences, and building design communities. As such, we will publish in PLoS Pathogens, Nature Medicine, Science, and Indoor Air. Additionally, our findings will be made accessible to the general public through a website (www.hospitalmicrobiome.com) and social media networks (Twitter and Facebook). In addition, members of the team, including the PIs and postdoctoral researchers will give talks at national and international meetings, which will reflect the multi-disciplinary nature of the proposed research. We will develop a model that leverages building conditions to predict microbial succession and the potential for HAIs. Data will be deposited in MobeDAC and will be associated with the Earth Microbiome Project (www.earthmicrobiome.org). In addition, through the Hospital Microbiome Consortium, we will work towards the development of a new, multi-disciplinary community focused on determining the way in which people microbially interact with their built environment in hospitals. Specifically, we hope this consortium will act to re-focus disease control in hospitals, and lead to new knowledge regarding the potential ways to mitigate disease outbreaks, and utilize friendly bacteria to help in this activity. We will generate at least two workshop reports, which will be published in Standards in Genomic Science, for the two annual meetings of the consortium, and work towards the development of several key whitepapers outlining vision, and potential experimental and observational research to aid in characterizing these ecosystems.

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