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Microorganisms in Built Environments: Impacts on Human Health

How do the microbiomes of the different indoor environments in which humans spend time for working, living, learning, and playing impact human health and well-being? What building conditions support microbial communities that benefit or harm human health and well-being? If most microorganisms do not infect humans, do those that thrive in indoor environments influence human health for good or bad, and if so, by what mechanisms? These questions are among those that motivate the study of microbiomes of the built environment. This chapter begins by laying the groundwork for understanding how microorganisms found in buildings may influence health. The chapter then addresses, in turn, infection transmission in indoor environments, noninfectious health outcomes associated with indoor microorganisms, and potential benefits of microbial exposures. The chapter concludes with summary observations and a discussion of knowledge gaps in the area of health impacts of built environment microbial exposures. Chapters 3–5 examine how building characteristics and occupants shape the indoor microbiome (see Chapter 3), tools that can be used in research on microbiomes of the built environment (see Chapter 4), and potential interventions that can alter these microbiomes (see Chapter 5).

INFLUENCE OF BUILDING MICROBIOMES ON HUMAN HEALTH: ECOLOGIC AND BIOLOGIC PLAUSIBILITY

Several considerations support the plausibility of the influence of building microbiomes on human health. First, in developed areas of the world, indoor environments are the primary ecosystems inhabited by people. Second, the environments people inhabit may influence the human microbiome, which may in turn impact human health. For example, microorganisms present in the environment may proliferate in niche-specific ecosystems of the human host—such as in airways, the gut, and on skin. Third, a wide array of microbial components and characteristics are known to impact

human health. Finally, a number of sources of microorganisms within indoor environments impact human health.

Implications of Building Microbiomes for the Diversity of the Human Microbiome

In developed areas of the world, humans are born and spend the vast majority of their lives indoors, which may limit the diversity of microorganisms to which they are exposed. A building’s envelope (foundation, walls, windows, and roofs) separates the indoor and outdoor environments, thus reducing exposure to microorganisms that thrive outdoors and potentially increasing exposure to organisms that thrive indoors.

The diversity of the microbiomes of the built environments in which humans live may impact the microbiomes of their bodies. Studies have shown that humans who spend significant time outdoors or live in dwellings with more open building envelope designs that result in high levels of unfiltered or minimally filtered air exchange with the outdoors have more diverse microbiomes relative to those who live in dwellings with less open designs (Clemente et al., 2015; Hanski et al., 2012).

The extent to which the indoor microbiome contributes to this diversity or lack thereof is not well understood, however. It has also been suggested that exposure to reduced microbial (especially bacterial) diversity may be less a function of the microbial content of buildings than a side effect of the modern human diet, which is less diverse than that of our ancestors: it varies little with the seasons; may be affected by the use of antibiotics; and may select for a limited number of human microbial taxa, particularly in the gut (Yatsunenko et al., 2012). This diversity may benefit human health as the microbiomes to which humans are exposed may be important for immune development and the processing of nutrients in the gut, which may not function as well when gut microbial communities change. People in economically disadvantaged and less developed societies who spend more time outdoors can have higher infectious disease risk and higher infant mortality (Clemente et al., 2015; Hanski et al., 2012). However, this may be due more to their health when exposed to infectious agents than to the diversity of the microorganisms to which they are exposed; as noted, some evidence suggests beneficial immune system effects from exposure to diverse microbes (see the section on “Beneficial Effects of Microbes”). Thus, the relative lack of microbial diversity may have positive or adverse effects on human physiologic and immune responses and health and may in turn influence risk of chronic noninfectious symptoms and diseases. By separating themselves from the outdoors, humans may have eroded the diversity of their own, as well as their environmental, microbiomes.

Environmental Influences on the Human Microbiome

Mounting evidence indicates that the human microbiome is influenced by the environment and that it is integral to human development. One of the most studied influences is the transmission of particular infectious microorganisms. For example, fomites are surfaces or objects on which microorganisms can deposit and that allow for transmission to a host (Julian, 2010). Fomites are well documented in the spread of infectious disease, and there is research associated with human exposure to indoor pathogens (Dick et al., 1987; Wong et al., 2010).

Another known influence of the environmental microbiome on the human microbiome is the process of birth. Each individual’s microbiome is acquired both in utero and from the environment at birth. Babies delivered vaginally and by Cesarean delivery show differences in their microbiome composition (Bokulich et al., 2016; Hill et al., 2017; Rutayisire et al., 2016). Yet the human microbiome does not fully stabilize to adult patterns until 2–3 years of age (Dethlefsen et al., 2006). New technologies and bioinformatics techniques for genomic analysis of microbial DNA extracted from environmental samples are providing insights in this area not previously possible (see Box 2-1). One topic of interest is the nature of nonpathogenic interactions between indoor and human microbiomes.

Neonatal studies provide evidence that the microbes from the environment that are of human origin may influence the human microbiome. Other studies also have provided evidence that dogs and humans have bacteria in common (Song et al., 2013). Yet there is no concrete evidence that the human microbiome can be colonized by bacteria that originate from a building. For example, an in-depth study of the indoor and human microbiomes in which seven families were followed over 6 weeks indicated that the majority of the building microbiome measurable on home surfaces originated from the occupants. This study also found that the building microbiome did not appear to influence the occupants’ skin microbial structure or composition (Lax et al., 2014). Further research will be needed to understand the reproducibility and generalizability of the findings of this study, and how temperature, humidity, building materials, and the integrity of the building structure impact the interchange between the indoor and human bacterial microbiomes.

Microbial Components Associated with Human Health Effects

Microorganisms can impact human health through a variety of mechanisms. The dominant microbial components linked to human health include pathogen-associated molecular patterns (PAMPs). PAMPs are molecules such as endotoxin and lipopolysaccharide (LPS) (a component of bacterial cell

membranes), flagellin (from bacteria), and (1–3)-β-D glucans (also referred to as triple helical glucan, from fungi wall membranes). These molecules are associated with groups of microbes (bacteria or fungi) that may influence human innate immune system responses, interact with airway epithelial cell or irritant receptors (Lambrecht and Hammad, 2013, 2014), or have toxic effects. For example, many indoor fungi produce metabolites that can induce respiratory or systemic toxicity upon exposure (Kuhn and Ghannoum, 2003).

Mycotoxins, products of fungal metabolism (Robbins et al., 2000), can also provoke physiological responses. These fungal metabolites have been shown in mechanistic, toxicological studies to be relevant to human health, and more than 300 mycotoxins are potentially harmful with respect to food contamination (Alshannaq and Yu, 2017). This situation is much less clear for inhalation exposure to indoor-relevant mycotoxins. Only a handful of studies support a role of these compounds in inflammatory processes when combined with exposure to other microbial components (endotoxin, glucans) (Korkalainen et al., 2017). The potential airway epithelial toxicity of microbial components may be increased by the presence of tobacco smoke or other factors that disturb the epithelial barriers, tight junctions, antimicrobial production, or mucocilliary ability to clear bacteria (Lambrecht and Hammad, 2013, 2014).

A large respiratory and allergy literature that has evolved over two decades suggests complex positive, as well as negative, associations of various PAMPs with allergy and respiratory outcomes. In the observational epidemiologic literature, the directionality (whether the risk or protective factors) and the magnitude of associations with microbially produced molecules such as LPS/endotoxin appear to be dependent on dose, human body compartment (e.g., airway, gut), host, and stage of life (Perzanowski et al., 2006; Sordillo et al., 2010). Recent experimental literature also provides supporting evidence that PAMPs and other fungal (e.g., chitin) (Mohapatra et al., 2016; O’Dea et al., 2014) and bacterial components may “train” innate immune responses, with downstream effects on the body’s ability to deal with either infection or allergic responses. While experimental models find direct effects of bacterial or fungal components (e.g., endotoxin or glucans), more recent observational birth cohort studies suggest that endotoxin and other PAMPs may be markers for complex communities of environmental bacteria and fungi, many of which have previously not been associated with disease (Manor et al., 2014).

Sources of Indoor Microbiomes That Are Relevant to Human Health

Recent observations suggest that occupants and outdoor microbes entering buildings through ventilation and tracked in through dust are the dominant origin of indoor environmental bacteria, particularly those that can be airborne (Adams et al., 2015; Prussin et al., 2015). Occupants contributing to the indoor microbiome include humans and nonhuman occupants, such as rodents and cockroaches, as well as pets, which are sources of bacteria and therefore can be direct sources of bacterial PAMPs (Thorne, 2015). In farm studies, likely sources for indoor PAMPs have included animal feed and farm animals. In urban environments, LPS/endotoxin sources include not only pets but also associations with moisture, such as that due to concrete basements, humidifiers (Park et al., 2001), and water damage in situations less extreme than flood conditions. Endotoxin on dirt and decaying plant material can be tracked into a house by its inhabitants. On the other hand, the relative contribution of endotoxin- or microbe-containing outdoor airborne particles to the suite of indoor microbial components (Hanson et al., 2016; Manzano-León, 2013) is not well understood. Although not causal or definitive, there is evidence that LPS/endotoxin exposures may be protective against the development of allergies in rural (Thorne, 2015) and U.S. urban environments (Park et al., 2001).

Sources of fungi indoors vary. Typically, in non-water-damaged buildings, fungi enter a building through leakage in the building envelope and through ventilation systems, are carried indoors by occupants, or may be brought indoors in association with building materials. The growth of fungi

is generally moisture dependent. In cases of extreme water damage—as in flooding in New Orleans, Louisiana (Mitchell et al., 2012); in Cedar Rapids, Iowa (Hoppe et al., 2012); or in Boulder, Colorado (Emerson et al., 2015)—high levels of fungi not originating from building occupants have been measured on building surfaces and in air. Even in non-water-damaged buildings, fungi can grow in or on building materials when sufficient moisture is present (Adan and Samson, 2011; Macher et al., 2017), and their growth is affected by such factors as the chemical composition of building materials.

Less is currently understood about the origins of viruses in the built environment (beyond transmission of specific pathogens). Evidence suggests, however, either enhanced sources of bacteria relative to viruses indoors or preferential removal of viruses as air penetrates indoors (Prussin et al., 2015). See Chapter 3 for greater detail.

TRANSMISSION OF INFECTION IN INDOOR ENVIRONMENTS

Much prior work investigating the impact of environmental conditions on the survival of microorganisms and their transmission to and between humans has focused on infectious organisms. As noted earlier, fomites (Julian, 2010) are well documented in the spread of infectious disease, and there is research documenting aerosol transmission of pathogens in different nonresidential indoor environments (Dick et al., 1987; Wong et al., 2010). This section examines the modes of transmission and complex, mixed exposures or coinfections for selected pathogens.

Modes of Transmission

Some viruses, bacteria, fungi, protozoa, and algae in the indoor environment have long been known to be pathogens, with the potential to cause infectious disease or allergic illness (Burge, 1980). Potentially infectious organisms can vary in terms of their transmissibility (ease of spread), their mode of spread indoors, and their virulence (a quantitative measure of pathogenicity or potential to cause disease). Subspecies within a bacterial species also may have highly divergent health effects, highlighting the need for detailed microbial information (Ponnusamy et al., 2016). Transmissibility, virulence, and mode of spread all influence the mode and effectiveness of infection control, a topic generally beyond the scope of this report. Recent interventions to reduce transmission of tuberculosis¹ indoors, for example, have shown the benefit of advancing understand-

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¹ Tuberculosis is caused by infection with the bacterium Mycobacterium tuberculosis.

ing of transmissibility and drug resistance patterns (Barrera et al., 2015; Dharmadhikari et al., 2014; Mphaphlele et al., 2015; Nardell, 2016).

Table 2-1 summarizes modes of transmission for selected pathogens that have been associated with infection due to exposure in the indoor environment. The organisms listed in this table vary widely in their transmissibility and virulence. Influenza A, for example, can be challenging to contain, as person-to-person transmission can begin on contact with asymptomatic individuals or 24 hours before symptoms are present. Severe acute respiratory syndrome (SARS), a virus more virulent than influenza A, may be somewhat easier to contain, in that symptoms are likely to be present when the virus is transmissible. Viral pathogens such as influenza also may have multiple modes of transmission—for example, by droplet inhalation or by fomite contact—that may vary in their relative contribution to transmission according to such building conditions as indoor temperature and humidity (Koep et al., 2013). Although some of the organisms listed in Table 2-1 have infectious potential, some may be present in buildings but are not highly virulent and rarely cause infection in people with healthy lungs and healthy immune systems. For example, many immunocompetent people breathe in a variety of Aspergillus species (including Aspergillus fumigatis) indoors on a regular basis without becoming infected.

Figure 2-1 illustrates various routes of transmission of infectious agents in the indoor environment. Chapter 3 explores indoor sources and reservoirs of microorganisms in greater detail, but one important pathway for human exposure is inhalation of microorganisms carried or resuspended in room air, as well as microorganisms found in building water systems that become aerosolized. Relevant exposure routes include both aerosolization of fine particles that can travel into the deep lung and inhalation of coarse particles that may be deposited in the upper respiratory system (Hatch, 1961) or be translocated to the gastrointestinal tract via the mucociliary escalator (Harada and Repine, 1985).

Another important route of transmission is via fomites, in which the microorganism is transferred from a surface. The initial deposition of microorganisms onto a fomite can occur by deposition of aerosols or dusts or by transference via contact from an individual. A susceptible host can become infected by touching a microbially laden fomite and subsequently touching the mouth, eye, nose, or other body surface. Many microorganisms can be transmitted in this manner, especially viruses, including rhinovirus, influenza virus, coronavirus, norovirus, rotavirus, hepatitis A virus, adenovirus, and astrovirus (Boone and Gerba, 2007). Multiple modes of transmission often occur for a particular microorganism (Nicas and Jones, 2009). For example, influenza may be transmitted by aerosolization or by contact with a virus-laden fomite, and the predominant mode of transmission may be related in part to the absolute humidity inside the building

TABLE 2-1 Mode of Transmission for Selected Pathogens Implicated in Infections Due to Inhalation or Fomite Interactions

SOURCES: Table created using data from Burrell (1991), Couch (1981), and Yu et al. (2004).

(McDevitt et al., 2010; Tellier, 2009; Yang and Marr, 2011). Thus, transmission of microorganisms within the built environment is a complex process that is contingent not only on the class of microorganism itself but also the state of the building (e.g., its humidity or ventilation) and the number and behavior of building occupants.

A recently recognized class of pathogens, termed saprozoic (Ashbolt, 2015), is capable of amplifying on wetted surfaces such as those that may be found in built environments. In some cases, amplification is facilitated by growth of amoebae in biofilms that may harbor pathogens. A recent report suggests that fungi may also facilitate growth of saprozoites (Alum and Isaacs, 2016). Organisms of this class, which have been shown to be transmitted by indoor aerosolization or from fomites, include nontuberculosis Mycobacterium spp. Legionella pneumophila can similarly grow in association with biofilms, in this case in water systems. L. pneumophila can cause legionellosis and Pontiac fever, a nonfatal flu-like respiratory disease with a short incubation period and for which recovery usually occurs without medical intervention (OSHA, 2017; Principe et al., 2017). Locales in which amplification may occur along with subsequent aerosolization and infection include hot tubs and whirlpools (Falkinham, 2003); indoor fountains

and architectural features (Haupt et al., 2012; O’Loughlin et al., 2007); shower heads and hoses (Feazel et al., 2009; Schoen and Ashbolt, 2011); heating, ventilation, and air conditioning (HVAC) systems and humidifiers (Stetzenbach, 2007); and toilets (Azuma et al., 2012).

Biofilms can also exist in piping systems and provide habitats for pathogen amplification (Wang et al., 2012). Corroded pipes may provide a more favorable environment for this microbial amplification, and this factor has been associated with a spike in legionellosis cases in Flint, Michigan (Schwake et al., 2016) (see Box 2-2).

Building design and operational characteristics can affect the relative importance of different modes of transmission (Li et al., 2007), as can cleaning and handwashing practices (Sandora et al., 2008) and the use of masks (Wei and Li, 2016). For example, in multiunit residential (and likely commercial) buildings, cross-transmission of aerosols via the ventilation system may serve as a conduit for disease transmission (Mao and Gao, 2015; Nardell et al., 1991).

Complex, Mixed Exposures

The potential exists in any environmental exposure for multiple agents to affect a single host concomitantly. Outbreaks of legionellosis have provided evidence that coinfection can adversely impact patient outcomes, although it is not clear whether the coinfections occurred following the initial L. pneumophila exposure (e.g., in a hospital) (Fernandez et al., 2002). Animal studies have shown that coinfections can modulate immune system response to one of the challenges (Redford et al., 2014). However, reports of multiple pathogen impacts in the context of indoor exposures in the built environment are currently unavailable.

Somewhat more information is available on the interaction between exposure to infectious agents and concomitant respiratory exposure to adverse chemical or physical agents. Most of this information is derived from animal models. Controlled rodent experiments showed that susceptibility to inhaled Klebsiella was increased by prior exposure to nitrogen dioxide (NO₂), as well as to aerosols of cadmium and nickel (as chloride) (Gardner, 1982). Intratracheal administration of combustion particles to mice was found to increase the lethality of inhaled Streptococcus (Hatch et al., 1985). Using a similar assay, Arany and colleagues (1986) showed that inhalation of a variety of volatile organic compounds either enhanced lethality or reduced the mice’s ability to fight off the inhaled Klebsiella infection. It can be anticipated that many human exposures in the built environment will be complex, and future studies will need to explore in more detail the potentially interacting or modulating effects of combined chemical, physical particulate matter, and microbial exposures on health.

In summary, the indoor environment can be a venue for exposure to a variety of infectious agents, including bacteria, protozoa, fungi, and viruses. These exposures may occur via inhalation (including of aerosols from premise plumbing) or contact with fomites. For bacteria, in particular, wetted surfaces can serve as a habitat for biofilms, which can amplify certain species, including several pathogens. These exposures are likely to

be from a combination of multiple microorganisms, which can affect how the microorganisms impact the human host in a variety of ways, many of which have not yet been studied.

DAMP INDOOR ENVIRONMENTS, INDOOR MICROBIAL EXPOSURES, AND RESPIRATORY OR ALLERGIC DISEASE OUTCOMES

Another area in which there has been much previous work is the impacts of damp indoor environments on human health. This research has typically focused on a number of noninfectious² health effects from exposures to indoor microorganisms, with the greatest number of studies focusing on dampness, observations of microbial growth or detection of mold odors, and respiratory and allergic symptoms.

Damp building conditions promote the growth of mold, bacteria, and other microbial agents. Damp buildings may also contain other living organisms, such as dust mites and cockroaches (along with their associated microbial communities), which can potentially contribute to exacerbation of respiratory issues. Occupants in damp buildings can be exposed to pollutants in the air not only from biological contaminants but also from the deterioration of building materials, which can be accelerated by the presence of dampness inside the building.

Table 2-2 summarizes evidence from three review publications that damp buildings influence health (IOM, 2004; Mendell et al., 2011; WHO, 2009). There is a larger body of literature on upper and lower respiratory outcomes, with more limited attention to nonrespiratory outcomes. Over the years since the 2004 Institute of Medicine (IOM) report Damp Indoor Spaces and Health was issued, the evidence has become stronger for an association between damp buildings and the exacerbation of asthma and, importantly, the development of asthma. Furthermore, the 2011 review by Mendell and colleagues evaluates a number of health outcomes not considered by the IOM committee in 2004 (Mendell et al., 2011). Not all health effects that have been suggested as having possible associations with damp indoor environments have been the subject of sufficient published literature to enable evaluation. The 2004 IOM report lists a number of health outcomes as having inadequate or insufficient evidence with which to determine whether an association exists, including airflow obstruction (in otherwise healthy persons), skin symptoms, mucous membrane irritation

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² The term “noninfectious” is used here to represent potential health associations that are not known to be due to specific infection, although conventional clinical testing through pathogen culture methods may not fully consider the breadth of diversity and community structure of indoor microbiomes that has been increasingly characterized.

TABLE 2-2 Associations Between Health Outcomes and Exposure to Damp Indoor Environments

*Evidence judged to be strongly suggestive of causation.

syndrome, gastrointestinal tract problems, chronic obstructive pulmonary disease, fatigue, inhalation fevers (nonoccupational exposures), neuropsychiatric symptoms, lower respiratory illness in otherwise healthy adults, cancer, acute idiopathic pulmonary hemorrhage in infants, reproductive effects, and rheumatologic and other immune diseases. In their 2011 review, Mendell and colleagues identify altered lung function as having inadequate evidence available.

These reviews indicate stronger evidence for adverse health effects due to signs of dampness relative to those due to measures of indoor environmental microorganisms, a point reiterated in a recent review on the associations of health effects with observational assessment of dampness and mold (Mendell and Kumagai, 2017). The potential benefits of reducing moisture problems in buildings have been discussed in the literature (Mendell, 2007; Mendell and Kumagai, 2017; Mendell et al., 2008; Mudarri and Fisk, 2007; WHO, 2009).

The rest of this section selectively discusses studies published in the past decade concerning indoor dampness and respiratory or allergic health outcomes, and it addresses the question “Can specific indoor microbial exposures account in part for the adverse respiratory effects of building dampness?” In summary, results have been inconsistent from study to study, and it is currently not understood which specific contaminants or combinations thereof in damp indoor environments cause the various health effects under what circumstances.

A review by Quansah and colleagues (2012) on dampness and mold in homes and asthma development found that associations with the presence of visible mold and with mold odor were evidence for mold-related causal agents for asthma (Quansah et al., 2012). In a recent review Sharpe and colleagues (2015) conclude that there is some evidence that in indoor environments Penicillium, Aspergillus, Cladosporium, and Alternaria species are associated with asthma development and with worsening of asthma symptoms, but that more work is needed on the role of fungal diversity. Another recent review on indoor exposures associated with the exacerbation of asthma found that many indoor exposures exacerbated asthma, including indoor dampness or dampness-related agents such as endotoxin, culturable Penicillium, and total fungi (Kanchongkittiphon et al., 2015). On the other hand, in an earlier paper, Hägerhed-Engman and colleagues (2009) report no association between concentrations of measured mold species and asthma in the Swedish Dampness in Buildings and Health study (Hägerhed-Engman et al., 2009). Similarly, a recent study of Danish schools found that high classroom dampness was associated with lower lung function and wheezing, but microbial components were not consistently associated with health outcomes (Holst et al., 2016).

Data from large cross-sectional studies of approximately 46,000 8- to 12-year-old children in 20 countries during phase two of the International Study of Asthma and Allergies in Childhood (ISAAC) found significant and consistent associations of current exposure to dampness or visible mold in homes with respiratory and allergic symptoms (Weinmayr et al., 2013). Associations with current exposure included wheezing, coughing up phlegm without a cold, rhinitis, rhinoconjunctivitis, and eczema. Children

were similarly affected by dampness regardless of whether they had allergic sensitization or parents with allergy.

Studies of individual episodes of water-damaged buildings using detailed exposure measures and precise case definitions have subsequently produced stronger evidence that a variety of definable microbial groups may be partly responsible for associations between damp environments and respiratory health. In a water-damaged 20-story office building in the Northeast United States, linear associations were found between respiratory illnesses (particularly physician-diagnosed asthma) and hydrophilic fungi and ergosterol (a molecule in fungal cell membranes) (Park et al., 2008). In another study of a water-damaged U.S. building, associations were found between adverse respiratory functioning and thermophilic actinomycetes (a phylum of bacteria) and nontuberculosis mycobacteria (Park et al., 2017). While these cases are instructive, the range of microbial ecosystems in the built environment that may have long-term adverse effects on respiratory health is not well defined.

Higher fungal counts, specific fungal or bacterial species, and higher endotoxin/LPS levels have been associated with building dampness (Park et al., 2008). The absence of a gold standard for measuring mold (Chew et al., 2016) means that complementary measurement methods often yield a better perspective on which mold or mold component exposures linked to dampness may be relevant to health. As discussed by Cox-Ganser and colleagues (2011), mycotoxins have been posited as contributors to these symptoms, but their effects in the context of damp and poorly maintained buildings are not well understood.

Outright flooding, building-related water damage, indoor point sources of dampness and water, suboptimally maintained cooling towers, or poor maintenance of buildings leading to indoor moisture problems may lead to proliferation of microbial communities that can cause noninfectious adverse allergic and nonallergic respiratory responses. This is the case particularly in susceptible populations such as children and people with preexisting asthma.

Association with Asthma Development and Worsening of Asthma Control

Living, working, or attending school in damp indoor environments has been associated with onset or worsening and exacerbation of asthsma in children and adults. A meta-analysis of 33 studies estimates that exposure to dampness and mold in the home raises the risk for asthma development, history of asthma, and current asthma by about 30–50 percent (Fisk et al., 2007). It has been estimated that 21 percent of current asthma cases in the United States can be attributed to dampness and mold, which translates to 4.6 million of the 21.8 million U.S. asthma cases at the time of the esti-

mate (Mudarri and Fisk, 2007). This study also estimates the annual cost of asthma attributable to exposure to dampness and mold at $3.5 billion.

Recent evidence suggests that both allergic and nonallergic asthma are more frequent in damp indoor environments. This evidence is important because it suggests that not all of the effects of dampness result from allergic responses to allergens from microbial and nonmicrobial sources (e.g., allergens on dust mites and cockroaches) that proliferate in damp conditions. As mentioned previously, microorganisms include components other than allergens. Fungal and bacterial components such as PAMPs, for example, can cause irritant or inflammatory symptoms through nonallergic biologic pathways.

While inheritance is presumed to play a role in how children or adults respond to exposures to indoor microorganisms such as fungi and bacteria, the genetics that might modulate either adverse or protective microbial responses resulting in the development or worsening of allergic or nonallergic respiratory disease is not well understood. Fungal components (e.g., chitin [Da Silva et al., 2008]) or bacterial components (e.g., LPS [Simpson and Martinez, 2010]) are known to stimulate innate pathways that are under genetic regulation, but the implications of this knowledge for characterization of susceptibility to disease are not well defined. Gene–environment interactions are likely to be complex and may even be sex-specific, since investigators of genes related to immununoglobulin E (IgE) or asthma have identified sex-specific polymorphisms of genes that regulate asthma or allergy responses, such as interleukin-17 receptor B (IL17RB) and thymic stromal lymphopoietin (TSLP) (Hunninghake et al., 2008, 2011). To complicate matters, a genetic polymorphism may be a risk factor for asthma, but it may increase the protective effects (on allergic asthma) of an environmental exposure such as the fungal and bacterial microbes on a farm (Loss et al., 2016).

A 9-year prospective follow-up study on onset of asthma was conducted on 7,104 young adults from 13 countries who had participated in the European Community Respiratory Health Survey (ECRHS) I and II and had not reported baseline respiratory symptoms or asthma (Norback et al., 2013). The findings strongly support the connection between indoor dampness and/or visible mold and new onset of asthma or bronchial hyperresponsiveness.

Various articles have reviewed the accumulating literature strengthening the links among dampness, dampness-related agents, and asthma exacerbation occurring in nonallergic as well as allergic children (Kanchongkittiphon et al., 2015). For example, a 2010 study of inner-city children indicated that indoor fungi originating from both indoor and outdoor sources could worsen asthma (Pongracic et al., 2010).

Prior work by investigators from the U.S. National Institute for Occupational Safety and Health showed that in occupants of a historically

water-damaged office building, asthma was associated with concentrations of hydrophilic fungi in floor dust (Park et al., 2008) and that there was a synergistic effect of fungal and endotoxin exposure in respiratory health effects (Park et al., 2006). Other analyses of this office building population found evidence for exacerbation of building-related asthma. The onset of posthire asthma was associated with a lower prevalence of positive skin-prick reactions to common allergens, including indoor and outdoor mold mixes (Cox-Ganser et al., 2005). In summary, this study showed that building occupants who had developed asthma after working in the building were less allergic to common allergens, so the asthma must have developed directly in concert with something present in the building.

Fungi are a source of many different components that may have health effects. Allergens and other antigens on indoor fungi are one set of microbial components known to worsen respiratory symptoms in people who have established asthma and are allergic to the specific fungal allergen they inhale. Paradoxically, in early life, higher exposure to some nonmicrobial allergens (e.g., peanut allergen) may actually promote tolerance and protection from allergic responses (Du Toit et al., 2015). However, it is not known whether tolerance can occur with early-childhood exposure to fungal allergens. Overall, early-life fungal exposures worsen the health of young children, but many of the negative effects in early life may not be due to the allergens. Annex Table 2-1 at the end of this chapter summarizes epidemiologic studies that explore interventions aimed at reducing exposures and improving asthma outcomes.

Association with Rhinitis

Jaakkola and colleagues (2013) conducted a meta-analysis of the literature on the association between exposure to fungi in damp buildings and rhinitis (nasal inflammation). They concluded that there is evidence that dampness and mold exposures at home can cause or exacerbate rhinitis and its subcategories of allergic rhinitis and rhinoconjunctivitis (which produces nose and eye symptoms such as sneezing and itching). The strongest associations occurred with the presence of mold odor, which suggests that microbial agents were involved in some fashion in the development or exacerbation of this health effect.

The Role of Microbial Metabolic Compounds

The largest body of research on potential health associations of exposures to microbial metabolites focuses on fungi. Work by Miller and colleagues (2010) and Rand and colleagues (2011, 2013) on effects of fungal secondary compounds (mycotoxins) indicates that these compounds, in

concentrations that may be found in indoor environments, can cause inflammation on a cellular level that points toward nonallergic asthma. With their models, they have shown that exposure to very low concentrations of these compounds precipitates such lung changes as secretion and modification of mucoids on lung surfaces, as well as changes in the respiratory cell composition obtained from sampling. This has been found with many pure compounds from a range of xerophilic, mesophilic, and hydrophilic fungi, as well as triple helical glucan. Moreover, it has been demonstrated that these compounds act on well-understood receptors (e.g., dectin-1 and NfkB). In addition, these compounds significantly modulate downstream gene transduction, transcription, and cytokine expression patterns associated with a variety of immune system pathways related to inflammatory and/or asthma provocation (including TH1, TH2, and TH3) in compound-, dose-, and time-dependent ways.

Association with Eczema

In a recent analysis of data on children in the ISAAC study, residential exposure to dampness and mold was found to be significantly associated with eczema, a type of skin inflammation, in the previous year. Dampness and mold in the first year of life also was associated with higher odds of the child’s ever having had eczema, by parental report. Allergic sensitization of the child did not modify the association, suggesting that dampness or mold might increase the risk of eczema through mechanisms other than IgEmediated allergy, although parental allergic disease did increase the odds of eczema with exposure (Tsakok et al., 2015). Occupational studies support the possibility of other mechanisms through which dampness-associated microbes of the built environment could increase the incidence of eczema, including contact dermatitis. However, little is known about mechanisms in the context of the indoor environments in which the children lived.

Association with Hypersensitivity Pneumonitis

Hypersensitivity pneumonitis, also known as allergic alveolitis, is a condition in which inhaled dust, fungi, or chemicals lead to inflammation in the lung. This condition has been recognized in relation to nonindustrial indoor environments for decades. Early publications on outbreaks usually implicated microbial dissemination from humidification and ventilation systems, although the specific organism(s) were rarely identified. Ventilation- and humidifier-related hypersensitivity pneumonitis may have decreased with recognition of the need for design changes and maintenance of cleanliness in these systems. More recent publications have implicated damp indoor environments, along with other exposures (e.g., chemicals),

in causing hypersensitivity pneumonitis. Buildings with long-standing water damage from roof leaks, other building envelope water incursion, plumbing leaks, and below-grade moisture problems have all had reported clusters of hypersensitivity pneumonitis (Borchers et al., 2017).

NONAIRWAY AND NONALLERGY EFFECTS

The impact of bacterial or fungal communities in buildings on health outcomes other than those related to respiratory conditions or allergy is less well established. Epidemiologic and toxicologic data suggest that effects of environmental microbial exposures on human health are likely to be dependent on dose, stage of life, physiologic compartment (e.g., gut, nose, lung, skin), and/or host (including sex).

Endocrine Disruption and Child Development

Viable indoor microbes likely metabolize chemicals present in the built environment. A number of chemicals found in common household products or furnishings, such as bisphenol A, perfluorooctane sulfonate (PFOS), and perfluorooctanoate (PFOA), have been shown when ingested to influence endocrine function (e.g., glucose metabolism or diabetes risk) and child growth, including the risk of becoming overweight or obese (Heindel et al., 2017). Laboratory experiments show that environmental microbes can metabolize these and other chemicals with endocrine disruptive properties, sometimes creating more bioactive or bioavailable chemicals and sometimes reducing their toxicity (Blavier et al., 2016; Bradley et al., 2016; Gramec and Mašič, 2016; Janicki et al., 2016; Koestel et al., 2017; Vejdovszky et al., 2017). However, the chemical metabolites of indoor microbes have not been well characterized. Moreover, little is known about the ingestion, inhalation, transdermal, or other exposures of small children to chemical by-products of microbial metabolism and whether they influence endocrine function or growth. Fungi themselves can also produce mycotoxins that affect the production of estrogen, but the relevance of this finding to health and whether these fungi are found in buildings are similarly unknown (Vejdovszky et al., 2017).

In addition to producing active metabolites or metabolizing chemicals in the indoor environment, the indoor environmental microbiome itself may influence the human microbiome in ways that lead to health effects. The skin and its commensal microbial communities are instrumental in protection against the environment. These communities, which vary in composition by location on the body, are determined largely by environmental and physiologic conditions. The microbial communities on the skin modulate the health status of the body through immune responses that

maintain health or, in specific situations, may promote disease (Barnard and Li, 2017). While knowledge has grown about the diversity and characteristics of skin microbial communities, relatively little is understood about the strains responsible for the function of these communities in maintaining protection and health or in promoting disease (Barnard and Li, 2017; Belkaid and Segre, 2014). Personal care products and other household chemicals that can act as endocrine disruptors have been shown to affect the skin and its microbiome (Bouslimani et al., 2015, 2016). However, there are no data to suggest that the indoor environmental microbiome influences the composition or structure of the skin microbiome (Lax et al., 2014).

Toxicologic and epidemiologic studies provide supporting evidence that specific groups of chemicals in plastics, furnishings, and personal care products may have endocrine-disrupting properties that increase the risk of hormone-related conditions such as diabetes or obesity, particularly in children exposed in early life. While it is known that microbes metabolize chemicals, and limited data show that building materials influence microbial degradation of those materials, it is not known whether metabolism of building materials, furnishings, or household chemicals by microbes results in active metabolites relevant to human health, specifically to endocrine disruption. These chemicals can also impact the skin microbiome and its ability to protect the body against disease, but modulation of the skin microbiome and its direct impact on human health is also not yet well characterized. While degradation or metabolism of building materials by microbes may be partly related to moisture, additional factors play into the health and safety aspects of these materials and the likelihood of their degradation by microbes. Further research in this area may inform the choice of “healthy” building materials and furnishings.

Future studies could focus on testing whether environmental microorganisms or by-products of household chemicals with endocrine-disrupting properties interact at major sites when encountering the human body. Research could elucidate whether these encounters lead to systematic changes in how the body functions and develops, with influences on endocrine or immune function or child growth. Such potential sites of interaction include the skin; airway; and gastrointestinal tract, including the oropharyngeal sites. Concurrently with the present study, a study by another committee of the National Academies of Sciences, Engineering, and Medicine (Advancing Understanding of the Implications of Environment–Chemical Interactions with Human Microbiomes) is under way, focused on developing a research agenda to guide the chemical risk assessment community in understanding how chemical exposures may modulate the human microbiome and how the human microbiome may modulate the effects of chemical exposures (via metabolism of chemicals) on human health outcomes. With that study’s focus on the human microbiome and

risk assessment for health outcomes related to indoor and other environmental chemical exposures, the proposed research agenda is likely to be of interest to the built environment community as it will likely suggest gaps in research needed to better understand the concerns outlined in this section.

Brain Health and Neurologic Outcomes

Studies in the United States and internationally have suggested that adult or child brain health may be influenced by aspects of homes or public buildings such as offices, schools, and hospitals. These studies have evaluated outcomes ranging from central nervous system (CNS) symptoms such as headaches, to mood (e.g., depression) and sleep disorders, to changes in neurocognitive or behavioral function. The findings of these studies have prompted investigators to posit that indoor microbial communities may mediate a portion of the observed associations of brain health outcomes with building characteristics or with other potential microbial sources within or proximal to buildings.

There are several potential pathways by which such effects could occur. Airborne indoor microbial components or metabolites may enter the brain directly via the olfactory bulb (Block et al., 2012). Alternatively, they may have indirect neurologic effects through airway autonomic stimulation or by causing airway or systemic inflammation. Microorganisms and their metabolites are also found in building water systems. Under certain circumstances, microbial deterioration of building or indoor plumbing materials may result in release of toxic chemicals into the indoor water system, and the absorption of these chemicals may lead to negative brain effects. To date, with specific exceptions, evidence to support these hypotheses is scant, in part because of methodologic challenges in exposure and outcome measurement and because of the potential complexity of the biologic response to exposures.

Another possible mechanism for the influence of indoor environmental microorganisms on brain development is through their potential interactions with the human gut microbiome. However, apart from the increasingly well-documented association of indoor dogs (Fujimura et al., 2014) or farm animals with the enrichment of certain beneficial microbes in the human gut and the diversification of home microbial communities, data to support a relationship between the indoor microbiome and the human microbiome are scant. As noted previously, the human microbiome can be influenced by the environment. For example, the ElderMet study found that subjects in long-term care facilities had different and less diverse gut microbiomes relative to those living in the community, although such factors as diet and health status appear to play important roles in explaining this variability (Claesson et al., 2012).

The question then arises of whether the environmental microbiome can influence the gut or respiratory microbiome. From a compartmental and stage-of-life point of view, infants and toddlers are more likely than adults to ingest environmental microbes, which may in turn influence the composition and function of the gut microbiome. A preliminary investigation using data on 20 infants from the Canadian Healthy Infant Longitudinal Development (CHILD) study, for example, found associations between house dust and fecal samples for several classes of bacteria (Konya et al., 2014). Other potential mechanisms by which environmental microbes might influence brain health might not require the ingestion or proliferation of microbes, and they could include responses to airway or skin encounters with microbial components or metabolites. Accumulating evidence suggests an association between microbiota present in the gut and brain function (Burokas et al., 2015), as the existence of bidirectional neural and immune interactions between the intestine and the brain has been proven (Keunen et al., 2015). While the exact mechanisms by which the microbiome can influence the development of the CNS are not completely understood, proposed communication between these systems is termed the microbiome–gut–brain axis. There are numerous complex interactions between the microbes that reside in the gastrointestinal tract and immune, endocrine, and neurologic systems. The vagus nerve directly connects the gastrointestinal nervous system to the brain. The immune system monitors the presence of microbes and reacts to changes in their structure and composition, transmitting this information to the CNS. Furthermore, human commensal organisms release metabolites that are precursors of important neurotransmitters such as gamma amino-butyric acid (GABA) and serotonin precursors (e.g., 5-hydroxytryptophan [5-HT]) or might induce the production of 5-HT by enteroendocrine cells, which in turn influences the nervous system and the brain (O’Mahony et al., 2015).

Altered microbial community structure, or dysbiosis, in the setting of stress and disease has been associated with alterations in behavior, cognition, emotion, and levels of inflammatory cells (Cryan and Dinan, 2012). Germ-free mice demonstrate altered risk-taking behavior, memory, and anxiety (Al-Asmakh et al., 2012; Cryan and Dinan, 2012; Neufeld et al., 2011). Diaz Heijtz and colleagues (2011) used an elegant experiment to demonstrate the role of the microbiome in brain and CNS development: germ-free mice had an altered neurologic response when subjected to stress tests, and this response was reversed only when bacteria were transplanted into the mouse caecum during infancy, rather than during adulthood.

Perturbing initial colonization and microbiome development has been shown to affect brain development and to pose a risk of developing neurologic disorders later in life (Borre et al., 2014; Diaz Heijtz et al., 2011). Therefore, environmental exposure to the built environment microbiome

early in life could have much more significant effects on neurologic development than those that occur later in life.

Studies supporting the influence of gut microbial composition and function on a complex and bidirectional gut–brain axis were recently reviewed by Jasarevic and colleagues (2016). Microbial metabolites, such as short chain fatty acids and chemotactic peptides, may influence the brain directly or may bind to intestinal epithelial cell receptors to enable the secretion of peptide neurotransmitters. Microbes can also interact with gut immune cells, and resulting cytokines may influence brain function. Centrally activated neural circuits that may be activated by various stressors may also influence gut microbial composition or function. In addition to the gut, the nasal or lower airway epithelial layer, including its mucus interface, is a barrier, interactive site, or portal through which microbes or their components may influence immune function (and perhaps brain function) through multiple mechanisms. These mechanisms may include disruption of the mucous barrier, stimulation of toll-like receptors (TLRs) or other immune receptors (Davies, 2014), or direct translocation from the upper respiratory tract to the brain.

Moisture-Damaged Buildings, Poor-Quality Housing, and Brain Health

Brain health outcomes have also been studied for associations with moisture-damaged buildings, poor housing conditions in disadvantaged communities, outdoor traffic proximal to schools and homes, pets in homes, and the construction of what is colloquially termed “green” housing (see the section on “Beneficial Effects of Microbes”). It is important to note that the use of the term “green” encompasses a variety of design and building approaches, potential interventions, and actual success at achieving more healthful or energy-efficient buildings.

In addition to the large literature linking damp buildings, buildings with water damage, and housing in poor repair with respiratory symptoms, some studies also link these conditions to reduction in brain health, with symptoms of headache, nausea, mood disorders, difficulty concentrating, or sleep difficulties (Ansarin et al., 2013; Casas et al., 2013; Chambers et al., 2016; Cox-Ganser et al., 2010, 2011; Faber et al., 2015; Francisco et al., 2016; Jacobs et al., 2015; Oudin et al., 2016; Park et al., 2008, 2017; Schiffman et al., 2005, Shiue, 2015; Singh and Kenney, 2013; Tiesler et al., 2015). In circumstances such as the post–Hurricane Katrina experience, victims living in trailers suffer from stress and mood disorders, but it has been difficult to disentangle the trauma of the experience from responses to the physical environment, including molds and their products, as well as other airborne exposures. Mold odors and visible mold have been linked to sleep difficulties (Ansarin et al., 2013; Chambers et al., 2016; Faber et al., 2015;

Jacobs et al., 2015; Oudin et al., 2016; Shiue, 2015; Singh and Kenney, 2013; Tiesler et al., 2015), and it is unknown whether proinflammatory upper airway influences combine with the direct brain effects from mold to contribute to such difficulties, including sleep-disordered breathing.

The physical exposures linked to poverty, and thereby connected to lower socioeconomic status, are compounded by many other disparities, including reduced access to an adequate diet, an enriching environment, health care, and education, as well as the presence of environmental toxins. Children in poverty have a significantly increased risk for developmental delay, poor school performance, and behavioral problems (Blay et al., 2015; Chambers et al., 2016; Evans and Schamberg, 2009; Hanson et al., 2013; Saigal and Doyle, 2008). Poverty has even been linked to changes in brain structure (Hanson et al., 2013; Jednorog et al., 2012). Many of the aspects associated with poverty (e.g., poor diet and health, depression, and anxiety) are associated with alteration of the human microbiome (Myles, 2014; Rook et al., 2014). Even less obvious factors, such as the number of caregivers and the indoor and outdoor home environment (e.g., presence of animals, access to outdoor green spaces), can significantly impact the human microbiome (Lax et al., 2015). Providing clean, dry, well-maintained housing has recently been shown to improve respiratory health (Colton et al., 2014), but it is not known whether this could occur in part through changing microbial exposures.

Epidemiologic and toxicologic studies, including studies using rodent models, provide growing evidence that outdoor particulate and gaseous pollutants influence brain health. The Outdoor Air Pollution and Brain Health Workshop (Block et al., 2012) was followed by additional studies providing evidence that outdoor pollutants have effects on the brain, including children’s neurodevelopment and neurocognitive and behavioral function in school (Basagana et al., 2016; Clifford et al., 2016; Dadvand et al., 2015; Harris et al., 2015; Kicinski et al., 2015; Sunyer et al., 2015), as well as cognitive function and decline in elders. A small but growing body of literature demonstrates the presence of microbes or microbial components on outdoor particles that may penetrate indoors and on indoor particles that may have both outdoor and indoor sources, which can be of local, regional, or even transoceanic origin (Frankel et al., 2012). Their contribution to effects on brain health is poorly understood. Although an in-depth discussion of outdoor environmental pollution is beyond the scope of this study, air, water, and other materials from the outdoor environment come indoors into built environments. The integration of disparate areas of knowledge that will underpin a clearer understanding of how indoor microbial exposures can lead to health outcomes and how this understanding could lead to practical application will include efforts to clarify the ties between the outdoors and the indoors.

While building conditions have been associated with adverse neurocognitive, behavioral, and other brain health outcomes, the specific contribution of the indoor microbiome to these adverse effects is unknown. The availability of evolving microbiologic, genomic, bioinformatics, and statistical technologies may facilitate a fuller assessment of whether and how brain health is influenced by indoor environmental microbes. An increased mechanistic understanding of how indoor microbes can act on neurologic outcomes would inform future environmental interventions designed to protect brain health. In addition, multiple adverse environmental exposures that are greater in disadvantaged populations and neighborhoods may add to or modify effects of indoor microbial exposures. Thus, it is important to conduct studies of indoor microbial effects on neurocognitive outcomes in built environments reflecting a range of socioeconomic circumstances and resources and to incorporate prospective longitudinal studies in future assessments.

BENEFICIAL EFFECTS OF MICROBES

Over the past two decades, interest in the potentially protective influences of indoor environmental microbes has been stimulated in part by farm community studies (see Box 2-3 and Annex Table 2-2 at the end of this chapter) that reproducibly demonstrate a reduced risk of allergic asthma with certain microbial exposures at home in early life. These exposures are estimated through measurement of bacteria components, microbial culture, or first-generation molecular biologic tools. Additionally, new metagenomics tools have opened a window into better understanding of the vast number of microbes that inhabit the human body and the microbial communities that are in the built environment.

Indoor microbes and their components and metabolites may have beneficial health effects in some circumstances and detrimental health effects in others. Characteristics of the built environment, the microbial community, and human behaviors within that environment may modulate the dose of the microorganism or the compartment exposed, and they may in turn influence whether the microorganism has a beneficial, adverse, or null effect on health. The same community of indoor microorganisms and their cell wall components may benefit human health in some circumstances and be detrimental in others depending on such circumstances as building characteristics, life stage of the person being exposed, exposure route, coexposures, dose, and genetic sensitivity. For example, a baby who ingests microorganisms while crawling on the floor may respond differently from an adult with asthma who inhales the same microorganisms. Potentially beneficial microbes include primarily microorganisms that train or modulate the human immune system (Kelly et al., 2005), produce small molecules

that mediate human health (Neish, 2009), or enable other functions that improve well-being in a human host (Reber et al., 2016; Rook and Lowry, 2008).

This knowledge has led to the identification of biomarkers that are associated with health benefit and an extensive body of research aimed at understanding the mechanisms of how microbial exposures could benefit human health (Heederik and von Mutius, 2012; Torow and Hornef, 2017; von Mutius, 2016; von Mutius and Vercelli, 2010; Wlasiuk and Vercelli,

2012). Annex Table 2-2 at the end of this chapter summarizes selected studies that have examined potential beneficial microbial exposures in the indoor environment.

This field of research needs many more targeted, longitudinal observational studies and intervention studies in order to pinpoint where beneficial tips into adverse, as well as the reverse, and to build the knowledge base needed to modulate built environments so as to positively impact human health.

Association of Microbial Exposures with Protection from Asthma and Respiratory Symptoms

While the adverse effects of microorganisms, their components, and their products have well-documented influence on the development, progression, or exacerbation of asthma and allergies (Eggleston et al., 1998; Lai et al., 2015; Quansah et al., 2012), there is also a substantive literature addressing protection from the development of asthma and allergy conditions through microbial exposures (Behbod et al., 2015; Celedón et al., 2007; Sordillo et al., 2010). Recent evidence suggests that the bacterial communities in dust in homes near farms may be reducing the incidence of asthma in certain populations (Stein et al., 2016) (see Box 2-3).

Dog-associated dust and the bacterial communities therein also have been shown to reduce atopy symptoms in mice (Fujimura et al., 2014), a finding suggesting that young children who live in homes with dogs may be less likely to develop asthma (Fall et al., 2015). The mechanism is hypothesized to be attributable to features of the microbial communities associated with animals. These microbes may act by shaping immune responses on skin, on airway mucosal surfaces, and in the gut (von Mutius, 2016). Differences in gut microbiota, including increased concentration of Veillonella spp., Lachnospira spp., and Faecalibacterium spp. from the phylum Firmicutes (Arrieta et al., 2015), in the first 3 months of life appear to play a role in asthma protection. Along with these taxa and Bacteroidetes (Lynch et al., 2014), increasing evidence suggests associations between exposure to high bacterial and fungal diversity in early life and protection from asthma and wheeze (Dannemiller et al., 2014; Ege et al., 2011; Tischer et al., 2016).

Exposure to insect and mammal stool within the first year of life has been shown to reduce the risk of development of preasthmatic wheeze (Dami and Bracken, 2016), while reduced exposure to certain species of Firmicutes and Bacteroidetes associated with house dust has been associated with an increase in atopy (Lynch et al., 2014). As these bacterial phyla are often associated with the mammalian gut, their absence suggests a reduction in stool in the environment. The observation that reducing mouse and cockroach stool can increase the probability of wheezing and asthma may

be seen as paradoxical, but it accords with current hypotheses that immune system challenges can reduce atopy.

In addition to the effects of exposures to bacteria discussed above, a small but growing literature indicates selected beneficial effects of early-life exposures to fungi in relation to the development of allergy and respiratory disease (Behbod et al., 2015; Tischer et al., 2016). However, especially in the case of fungi (but also to some extent in the case of bacteria), researchers still know very little about what products specific microbes are making or dispersing that may benefit human health if encountered in early life. More longitudinal studies of early-life microbial effects on subsequent child health are needed that define specific taxa and microbial community structure and function. Observations in these studies will need to be further validated in animal models to elucidate the mode of transfer from the environment to human compartments and biologic mechanisms of immune, physiologic, and/or other health effects. These studies may not result in recommendations that suggest reproducing the lifestyle or building structure that is associated with protection (e.g., most people will not live in a house with cows inhabiting a barn below), but they may help define the components of microbial exposures that are of potential therapeutic benefit for some people. As has been shown with endotoxin, it is likely that various microbial components may be good for some people and bad for others, depending on dose, compartment (whether inhaled or ingested), stage of life at which they are exposed (early life or adulthood), and/or susceptibility factors (heredity and additional environmental factors covarying with poverty). This concept is not easily applied to building design, where the goal is to provide healthier buildings for all. Nonetheless, longitudinal studies that include microbial measurements can define conditions and specific exposures that are adverse or protective for specific groups of people.

Potential Beneficial Effects Associated with Green Buildings and Green Spaces

Green Building Design

“Green building” design aims to promote environmental and energy sustainability, and the concept has become adopted more widely within the architectural and design community: the U.S. Green Building Council’s Leadership in Energy and Environmental Design (LEED) standard is one example. Green building designs reflect a mix of efforts focused on energy, water, and indoor environmental quality, but they offer no guarantees of meeting specific requirements for energy savings or healthful design. Green building design and what it entails is discussed in more detail in Chapter 3.

Green building design could potentially impact occupant health by improving air quality. Yet there have been no randomized trials of residents moving from conventional to green housing and how this change is associated with health outcomes. Findings of a few recent observational studies, some of them quite small, suggest that reducing home dampness through weatherization and by using green building approaches may improve asthma control.³ These findings are based on the assumption that appropriate standards and guidelines on outdoor air ventilation rates and selection of building materials should be followed. To the committee’s knowledge, there have been no published studies investigating ties among design, indoor microbiology, and health outcomes.

Researchers also have attempted to link green building design to neurocognitive outcomes. In one recent study, moving from poorly maintained or extremely aging housing to newly renovated or constructed green housing was found to result in fewer self-reported lost schooldays or workdays; less disturbed sleep, sadness, nervousness, and restlessness; and improved child behavior (Jacobs et al., 2015). Yet these improvements may have resulted from living in newer and better maintained housing, irrespective of green design features. Furthermore, it is unknown whether environmental microbial exposures contributed to the reported improvements.

While green buildings have repeatedly been cited as an approach to improving health (Allen et al., 2015, 2016; NRC, 2006), the specific attributes of green buildings that may contribute to improved health need to be broken down in order to understand how or why certain approaches to improved construction and operation under specific ecologic conditions may make such contributions. It is important to understand as well that many features of green buildings may make no contributions to improved indoor environmental quality or to the health of occupants.

Green Space

Outdoor green space surrounding buildings has been associated with improved patient outcomes (see Center for Health Care Design, 1995; IOM, 2007; Ulrich et al., 2004) and overall health status (Gong et al., 2016; Nieuwenhuijsen, 2016). Scientists have posited that exposure to green space may contribute to health benefits through exposure to plant-associated environmental microbiota. Studies in Finland, for example, have shown that living close to green space and agriculture rather than close to a town increases the biodiversity of the skin microbiota and correlates with reduced allergic sensitization (Hanski et al., 2012). For a review of potential

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³ See http://www.enterprisecommunity.org/solutions-and-innovation/green-communities (accessed April 25, 2017).

links among green space, the microbiome, and immune system function, see Rook (2013). Rook and Knight (2015) recently called for city planning and architectural designs that optimize the biodiversity of microbial exposure in urban settings, with an emphasis on green spaces.

SUMMARY OBSERVATIONS AND KNOWLEDGE GAPS

Summary Observations

The ability of microorganisms within the built environment to affect human health is supported by data for many types of infectious bacteria, viruses, fungi, and protozoa. Selected examples of microorganisms that can be encountered by humans in the built environment and can result in infections from inhalation or from contacts with fomites are provided in Table 2-1 presented earlier in this chapter.

A variety of health effects that are not infectious in nature have also been reported. Extensive research demonstrates that exposure to damp, water-damaged buildings and “sick buildings” results in negative respiratory health effects for building occupants. These respiratory effects often are not directly related to allergy and may also be caused by irritant or proinflammatory components of microbes. Connections between the built environment and a number of nonrespiratory health outcomes have been suggested—including effects on child development, brain health, and mental health—although less is known about whether these effects are due to exposures to indoor environmental microbes and through which physiologic mechanisms they occur.

Beneficial effects on health from exposure to microorganisms in built environments have also been reported, particularly for exposures that occur in early life. Evidence for mechanisms by which microbial exposures can have positive effects is starting to accumulate and can be built upon to better understand what constitutes microbial communities that have such effects and the potential mechanisms of action involved. In particular, a small but growing literature shows that selected early-life microbial exposures are associated with positive benefits in relation to the development of allergy and respiratory disease.

Research connecting microbial exposures in the built environment with health impacts draws on a number of study approaches, including epidemiologic observational studies, such as longitudinal cohort studies, as well as dose-response studies. For example, results of observational studies that suggest connections between built environment microbiomes and human health can benefit from further validation in animal models to elucidate the microbial communities or components responsible for protective or adverse health responses, the modes of transfer from the environment to humans,

and the types and mechanisms of physiologic responses. There also may be opportunities to leverage data from existing health studies. These study designs are discussed in more detail in Chapter 4.

Knowledge Gaps

On the basis of the above summary observations and the information developed in this chapter connecting indoor microbial exposures to human health effects, the committee identified the following goals for research to address knowledge gaps and advance the field:

1. Improve understanding of the transmission and impacts of infectious microorganisms within the built environment. Continued elucidation of the transmission of infectious microorganisms in a variety of built environments would be useful, including studies on modes of transmission for emerging respiratory pathogens; for pathogens with evolving patterns of hosts (animal as well as human); and for pathogens with problematic characteristics, such as drug resistance (e.g., Mycobacterium tuberculosis, Clostridium difficile [Peng et al., 2017]). Improved understanding of the relationship between microbial transmission and the timing of symptom onset also would be useful in informing future strategies for minimizing exposures.
2. Clarify the relationships between microbial communities that thrive in damp buildings and negative allergic, respiratory, neurocognitive, and other health outcomes. A number of studies link human exposure to damp and water-damaged buildings with allergic and other respiratory health impacts. But further research is needed to identify how building conditions and maintenance result in dampness that leads to the proliferation of communities of microbes that can adversely affect respiratory health; to distinguish among the microbial and nonmicrobial effects of dampness; to understand the relationships among microbes, building materials, and chemicals within damp buildings; and to assess how human health is impacted when dampness is reduced.
3. Elucidate the immunologic, physiologic, or other biologic mechanisms through which microbial exposures in built environments may influence human health. A number of possible health impacts from microbial exposures have been suggested (beyond infectious disease and the association between dampness and respiratory health), including developmental and neurocognitive effects. Much remains unknown about how the composition of the microbial communities, stage of life, route of exposure, and other factors affect human biologic responses and potential health outcomes. For example, a

4. growing body of literature suggests that the human microbiome, particularly the microbial communities in the gut, can influence health. But questions remain about the extent to which indoor microbiomes influence the composition and function of the human microbiome (on the skin and in the gut, oral, or airway compartments) and what that may mean for health outcomes.

5. Gain further understanding of the beneficial impacts of exposures to microbial communities on human health. Several studies have documented associations between early-life microbial exposures and exposure to diverse microorganisms associated with animals and later protective health effects. Further longitudinal studies of the effects of early-life microbial exposures on subsequent child and adult health will be needed to understand these connections more fully. Also useful would be additional data with which to further explore the beneficial impacts of exposures to specific microbial communities and clarify such factors as the extent to which these impacts vary with the characteristics of a building’s occupants, stage of life, and the routes through which the occupants are exposed.
6. Develop an improved understanding of complex, mixed exposures in the built environment. Responses to the complex and compound exposures that occur routinely in built environments, such as exposures to multiple microorganisms and to combinations of microorganisms and chemicals, have not been thoroughly elucidated to date.
7. Design studies to test health-related hypotheses, drawing on the integrated expertise of health professionals, microbiologists, chemists, building scientists, and engineers. Many of the studies investigating how human microbial exposures relate to health outcomes have been conducted in ways that make them difficult to reproduce in other buildings and make it difficult to understand how specific building attributes affect both the microbial exposures and the health outcomes. A variety of further studies will need to be developed and implemented to ensure that the experiments are reproducible and produce results that can be translated into actionable outcomes.

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ANNEX TABLE 2-1 Selected Studies on Building/Home-Based Exposure Reduction and Asthma Outcomes in Children (2000–2017)

ANNEX TABLE 2-2 Beneficial Associations of Indoor Microbiota with Asthma or Allergy Outcomes in Selected Studies Using Metagenomics, Molecular Biologic, or Culture Methods to Measure Indoor Environmental Microbiota

NOTES: GI = gastrointestinal; N/A = not available; SSCP = single-strand conformation polymorphism analysis; tRFLP = terminal restriction fragment length polymorphism. Diversity: small numbers of microbial exposures may be sufficient to stimulate all pattern-recognition receptors.

*Same pattern-recognition receptors on multiple microbial taxa.

**Overgrowth of harmful bacteria might be achieved by a limited number of bacterial species.

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