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11 SUMMARY OF RESEARCH RECOMMENDATIONS AND oVERALL ConC[USiONS I his chapter summarizes the research recommendations of- fered by the committee in the preceding chapters and draws some general conclusions regarding the reportJs findings. PATHOPHYSIOLOGIC BASIS OF ASTHMA Collectively, the evidence reviewed by the committee under- scores the need to further identify the mechanistic interplay be- tween specific inflammatory cells, cell adhesion molecules, and the changes in airway function that characterize the asthmatic condition. It emphasizes that much more research, based on com- bining data from genetic analyses with those identifying patho- physiological processes involved in asthma, is needed to ulti- mately determine the genetic basis of asthma, as well as the potential development of new strategies for therapeutic intervention. ANIMAL ALLERGENS The associations between dust mite allergen, asthma exacer- bation, and asthma development are much more well defined than the associations between larger animals and asthma. This is only partly a function of the number of years and intensity of 394

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RESEARCH RECOMMENDATIONS AND OVERALL CONCLUSIONS 395 efforts to investigate the health effects of dust mites. Compared with dust mite allergen, once the allergen source is present, cat and dog allergens are more easily dispersed throughout the household. Cat and dog allergens remain airborne for much longer than dust mite. The potential for exposure to allergens out- side the home is markedly greater for cats and dogs than for dust mites. The potential for home exposure to cat or dog allergen in homes without cats or dogs has also been underestimated. The absence of adequate information regarding allergen exposure may, in part, account for contradictory data regarding the effects of cats or dogs in the home on the development of asthma. Research is needed to assess whether removal of the cat or dog from the home results in sufficient reduction in overall aller- gen exposure to reduce symptoms and improve bronchial reac- tivity in specifically sensitized asthmatics. Further research is needed to assess the level of animal allergen exposure (cat and dog) in day care centers and schools. When significant levels are noted, the potential for lowering exposure should be investigated. Since so many cat- or dog-allergic asthmatics are emotionally at- tached to their pets, investigators should explore the success of efforts that recommend the removal of the pet for sensitized symptomatic child and adult asthmatics. Further research is also needed to evaluate the effect of mitigation measures short of ani- mal removal on asthma symptoms, Jung function, or bronchial responsiveness in specifically sensitized asthmatics. Although fre- quent animal washing and HEPA filter use are widely recom- mended, their efficacy in reducing asthma severity has not been proven. The relationship between cat or dog allergen exposure in early childhood, the development of sensitization, and the develop- ment of asthma merits further investigation. This investigation will require better assessment of exposure. It is likely that the ge- netic phenotype will modify the response to cat or dog allergen at different levels of exposure, but gene-by-environment interactions cannot be effectively explored until the genetics of asthma is bet- ter understood. Further research is needed to evaluate rodent allergen expo sure in the home as a potential factor in the exacerbation of asthma in rodent-sensitized asthmatics. Particularly in socially disadvan

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396 CLEARING THE AIR taged populations, research should focus on effective reduction of rodent allergen and its effect on symptoms or Jung function in s ?ecifically sensitized asthmatics. Researchers should also consider the possibility that animal (or animal allergen) exposure may be either protective or aller- genic. The effects may depend on the mode of exposure, the ge- netic characteristics of the populations, the timing in the life cycle when exposure occurs, and many other cofactors (e.g., early-life viral, bacterial, and parasitic infection experience). COCKROACH The committee's review of the literature suggests there is still a need for fundamental research on cockroach allergens and asthma outcomes. Future research should focus on the efficacy of cockroach allergen reduction in the homes of asthmatic patients, the aerodynamic properties of cockroach allergen, the efficacy of cockroach immunotherapy, and B and T cell reactive epitopes. Further studies are also needed to better elucidate any relation- ship between cockroach allergen exposure and asthma develop- ment; explore the interaction of cockroach allergen with infectious agents, irritants, and other allergens in causing asthma; and ex- amine the influences of genetics, socioeconomic status, and loca- tion on exposure and sensitization. HOUSE DUST MITES Although more is known about dust mite allergen and its im- pact on asthma than most indoor exposures, research remains to be done. Particularly important is additional work on the effec- tiveness of specific environmental interventions in limiting asthma exacerbations and development (rather than simple mea- surement of allergen levels). Several studies now under way are evaluating whether aggressive allergen avoidance regimes have an effect on the subsequent development of asthma. The results of such studies will inform the question of whether primary pre- vention of dust mite-induced asthma is possible, although the burdensome nature of such interventions suggests they may be difficult to implement in many circumstances. The development

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RESEARCH RECOMMENDATIONS AND OVERALL CONCLUSIONS 397 of methods to identify individuals, especially infants, at high risk would provide the information needed to focus primary preven- tion activities. A major issue in this regard is whether sensitiza- tion can occur before birth. ENDOTOXIN Given the significant body of data on the exquisite sensitivity of the innate immune system to small quantities of endotoxin, the hypotheses that domestic endotoxin exposure may influence the development of the immature immune system or affect the sever- ity of asthma warrant further investigation. The committee's review suggests several avenues of research directed at understanding the role of endotoxin exposure and en- dotoxin susceptibility in the pathogenesis of asthma. These in- clude studies of gene-environment interactions and the risk of developing atopy or asthma, preferably with prospective assess- ment of endotoxin exposure from birth, improved endotoxin ex- posure assessment across populations likely to have significant differences in exposure, and studies of endotoxin exposure and asthma severity. Gene-environment interactions between the CD14 polymor- phism and endotoxin exposure should take into account that CD14 is a pattern receptor and thus not specific for LPS-LBP com- plexes. Thus, future studies should include an assessment of ex- posure to other bacterial products that stimulate innate immunity via CD14 such as peptidoglycan. Prospective studies will be re- quired to determine whether endotoxin exposure early in life plays a role in determining the direction of immune system de- velopment. Studies that can compare populations with possibly larger variations in exposure to endotoxin and other components of organic dusts than can be found within an urban or suburban area would likely have increased power to detect the effects of endotoxin exposure. Because the CD14 polymorphism is associ- ated with atopy, a focus on specific and nonspecific IgE and TH phenotypes will likely be the most important variables for these studies. Given that the Limulus bioassay has limitations and that "un- usual" lipid A structures dominate the composition of house and

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398 CLEARING THE AIR other organic dusts, additional exposure assessment methods that can detect the range of environmental LPS should be employed along with Limulus assays in future studies. The possibility that endogenous sources of endotoxin exposure may be important in modulating the level of tolerance to environmental exposure (or vice versa) should also be examined. FUNGI Few fungal allergens have been identified, and patterns of cross-reactivity among fungal allergens have not been docu- mented. Standardized methods for assessing exposure to fungal allergens are essential, preferably based on measurement of aller- gens rather than culturable or countable fungi. Acquisition of these data is a necessary step before adequate estimates of the role of fungal allergen in asthma can be documented. Studies seeking to find environmental factors that either lead to the development of asthma or precipitate symptoms in exist- ing asthmatics must include good measures of fungal exposure. No studies have attempted to control exposure to fungal aller- gens either indoors or out. Intervention studies that seek to con- tro! indoor exposure to fungi are especially needed. INFECTIOUS AGENTS Numerous studies suggest an association between the infec- tions discussed in Chapter 5 and asthma exacerbations, although uncertain ascertainment of asthma and questions about the iden- tity of the specific infections responsible limit the confidence with which some conclusions can be drawn. Advances in analysis tech- niques that allow more sensitive and confident identification of viruses, such as PCR and ELISA, will facilitate research on this topic. These advances will also aid studies of other viruses that may be associated with asthma such as adenovirus, coronavirus, cytomegalovirus, and parainfluenza. Research on the possible association between infectious agents and asthma development is continuing and is encouraged. There are gaps in the knowledge concerning the mechanisms by which agents may promote asthma and whether particular inter

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RESEARCH RECOMMENDATIONS AND OVERALL CONCLUSIONS 399 mentions aimed at limiting infections result in decreased rates of asthma. Among the interesting questions are whether the lower respiratory tract acts as a potential reservoir for common respira- tory viruses and whether maternal immunization has the poten- tial to protect both the mother and the infant. Research on the impact of building characteristics on the transmission of infec- tious agents, which is in its infancy, may yield important public health benefits. PLANTS Further research is needed to determine whether or not houseplants release fungal spores into the air. This research will benefit both the allergy community and the infectious disease lit- erature. Additionally, research should be conducted to determine what risks, if any, are associated with occupational exposure to plant materials. Studies should be conducted to evaluate the ambiguous rela- tionship between pollen exposure, sensitivity, and asthma. Addi- tional research is also needed to discover the extent of indoor pol- len allergen exposure and the interactions between pollen sensitivity and air pollutants. NITROGEN DIOXIDE (NO2} Future research into the relationship between indoor NO2 and asthma should target population subgroups that are likely to be most exposed. These include women and infants, especially those at the lower end of the socioeconomic spectrum, who may spend more time in kitchens during cooking. Further research is needed on the distributions of peak and mean personal exposures, on the relationship between exposure and asthma, and on the exacerba- tion of asthma among those with preexisting asthma. Research is also needed into the development of practical, economical venti- lation methods for kitchens. PESTICIDES The most immediate need for research in this area is for infor

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400 CLEARING THE AIR mation on whether prolonged exposures to low to moderate con- centrations of airborne pesticides can elicit an irritative asthma response in susceptible individuals. Animal models may be help- ful in this regard a presently unpublished study on a microbial biopesticide used against cockroaches suggests it can induce asthma in mice. It has been suggested that Flinders Sensitive Line rats, which exhibit increased responses to an agent similar to com- monly used organophosphate pesticides, may be useful in the study of asthma outcomes. PLASTICIZERS Research characterizing residential exposure to plasticizer and evaluating asthma outcomes while controlling for known confounders would help resolve the question of their influence. VOLATILE ORGANIC COMPOUNDS With the advent of small, unobtrusive passive diffusion moni- tors capable of measuring microgram quantities of VOCs in 48- hour samples, it should be possible to incorporate personal VOC exposure assessment into future epidemiologic studies address- ing environmental factors and asthma, yielding an expanded data base on which to judge the possible role of VOCs in asthma de- velopment and exacerbation. Prospective cohort studies that characterize time-averaged personal VOC exposures of study subjects using passive badges and then follow subjects to assess the development and/or exac- erbation of asthma could generate information that would allow a more confident assessment of any potential risk. No specific asthma-related research is recommended for formaldehyde, a member of the VOC family. FRAGRANCES Future research on fragrance exposures has to carefully con- tro] for confounding factors such as odor perception and to focus on objective measures of respiratory health. Additional research elucidating the mechanism or mechanisms underlying adverse

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RESEARCH RECOMMENDATIONS AND OVERALL CONCLUSIONS 401 respiratory reactions to nonacute exposure to fragrances or their component chemicals would also be helpful. ENVIRONMENTAL TOBACCO SMOKE (ETS} A better understanding is needed of the mechanisms by which ETS and its individual constituents may impair the normal development of the airways in the fetus, promote allergic sensitization, promote respiratory infections, promote early wheezing illness, and (possibly) induce pathophysiologic changes that may pro- mote the establishment of asthma. Research is also needed to understand the nature of the inter- actions, both at the population or epidemiologic level and at the molecular and cellular levels, between the genetic predispositions to allergic sensitization and bronchial hyperresponsiveness and ETS exposure as they relate to the development of asthma. The respective roles of antenatal and postnatal exposure to ETS in the pathophysiologic changes associated with asthma and other res- piratory illnesses are in need of further investigation. Behavioral research also is needed to better understand the factors that lead to the initiation of smoking in adolescents, espe- cially young women, and to the maintenance of smoking in preg- nant women and mothers. Additionally, there is a need to develop more effective interventions to achieve sustained pre- and post- natal smoking cessation in pregnant women and mothers, espe- cially those whose children are at higher risk of developing asthma due to their family history, socioeconomic status, and place of residence. Since ETS exposure of children at greatest risk for adverse asthma outcomes (especially low-income and minor- ity children of African-American ancestry) may come from other caregivers as well as the mother or parents (i.e., other family mem- bers with whom the mother and child live and from day care pro- viders), interventions must be developed that will be effective in reducing the child's exposure from all sources. The effectiveness

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402 CLEARING THE AIR of ETS exposure reduction interventions in actually improving asthma outcomes should be evaluated as well. INDOOR DAMPNESS, MOISTURE PROBLEMS, AND MOISTURE CONTROL With respect to the association of dampness problems with asthma development and symptoms, research is needed to clearly identify the causative agents (e.g., molds, dust mite allergens) and to document more accurately the relationship between dampness and allergen exposure. Research is also needed to characterize and demonstrate the reductions in asthma morbidity from pre- vention or remediation of moisture problems. Regarding characterization of moisture problems, research is needed to: 1. develop accurate, standardized protocols for assessing moisture problems in buildings; 2. develop and document the effectiveness of specific mea- sures for dampness reduction in existing buildings; and 3. develop standardized, effective protocols for flood cleanup that will limit microbial growth. In addition to these research needs, there is a need for im- proved education of the public about the consequences of mois- ture problems and for better education of building professionals regarding means of preventing moisture-related problems. NONRESIDENTIAL INDOOR ENVIRONMENTS The few available studies suggest the importance of building factors in relation to asthma, but further research is critical to as- sessing the attributable risks, remediable risk factors, and means of hazard assessment. Development of methods for representa- tive quantitative assessment of bioaerosols of fungal and bacte- rial origin is a high priority for health outcome studies and haz- ard assessment. In addition, knowledge of the epidemiology of building-related asthma in problem buildings where there are ex- cess chest complaints among occupants, in comparison to build

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RESEARCH RECOMMENDATIONS AND OVERALL CONCLUSIONS 403 ings where there are no complaints, can advance our understand- ing of specific bioaerosols in relation to asthma. Research should focus on exposure-response studies of many building environ- ments and populations; clinical investigation of patients with building-related asthma; and intervention studies, even without knowing the specific etiology involved. This research agenda re- quires new partnerships among academic investigators, clini- cians, public health agencies, industrial hygienists, and building scientists. VENTI~TION Additional research is needed on ventilation, but only a small proportion of these research needs are critical to advancing our understanding of the relationship of ventilation to asthma. At the present time, our understanding of the influence of changes in ventilation rates on concentrations of (or exposures to) indoor- generated pollutants associated with asthma is very limited ac- cordingly, mode] predictions that have not been adequately evalu- ated are the best source of information. Experiments in actual buildings, with manipulation of ventilation rates, are the pre- ferred approach for quantifying the direct (i.e., via pollutant re- moval) influence of changes in ventilation rates on the indoor con- centrations of these pollutants. Because indoor pollutant source strengths can vary temporally, experiments should be repeated several times. To assess how changes in ventilation rates affect indoor humidities and, in turn, the proliferation of dust mites and molds in buildings will require either long-term experiments last- ing a year or more or large cross-sectional studies with control for confounding factors. Airtight building envelopes and low rates of ventilation have been cited as factors that may contribute to asthma incidence or symptoms or may explain recent increases in asthma; however, very few relevant data are available. The evidence of a linkage of ventilation rates with asthma is not sufficient to justify large stud- ies intended to resolve only this issue. However, measurements of ventilation rates should be included, when possible, in future asthma case-control studies or cross-sectional surveys. Ventilation

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404 CLEARING THE AIR measurements in houses can be performed using nonobtrusive tracer-gas methods with passive tracer-gas emitters and samplers. Finally, research is needed to advance our very limited cur- rent knowledge about microbiological contamination of HVAC systems, its influence on microbial exposures, and its influence on asthma development or asthma symptoms. AIR CLEANING The results of existing experimental studies are inadequate to draw firm conclusions regarding the benefits of air cleaning for asthmatic and allergic individuals. Many of the existing studies have important limitations, such as small study size, lack of blind- ing, a small or undefined rate of air cleaning, placebo air cleaners that may significantly remove the larger particles associated with asthma, and no exposure assessment or inadequate assessment. Additional research to assess the benefits of air cleaning is clearly warranted, but future studies must overcome as many of these limitations as possible. Because air cleaning is most promising for reducing indoor concentrations of particles smaller than a couple of micrometers, future research should emphasize these agents. Sensitization to allergens a critical step in the development of allergic asthma often occurs early in life. No information is available to indicate whether air cleaning of spaces occupied early in life can reduce the rate of allergic sensitization. Research is needed to address this issue. As described in Appendix A, particles larger than a few mi- crometers have a complex and inadequately understood behav- ior in the indoor environment, including rapid rates of gravita- tional settling, resuspension from surfaces, and possibly incomplete mixing with the indoor air. Consequently, the influ- ence of air cleaning systems on exposures to particles in this size range is not well understood and the associated benefits from air- cleaning cannot be predicted with a high degree of confidence. A combination of aerosol science and air-cleaning research is needed to fill this gap in our knowledge. The limited data on the size distribution of many of the bioaerosols and allergens associated with asthma limit our un

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RESEARCH RECOMMENDATIONS AND OVERALL CONCLUSIONS 405 derstanding of the benefits of air cleaning. Additional data are needed particularly for pet allergens and pollens. As stated in Chapter 10, HEPA filter units have been widely recommended for allergy and asthma patients who desire to use air cleaners. Air cleaner manufacturers have responded by ag- gressively marketing air cleaners with HEPA filters and offering few other products. However, experimental data and theoretical predictions indicate that air cleaners with a lower efficiency rat- ing are likely to be equally effective in reducing the concentra- tions of most, and perhaps all, of the indoor-generated particles associated with allergies and asthma. These lower-efficiency air cleaners could have a lower product cost, less powerful or noisy fans, higher rates of airflow and particle removal, and reduced energy consumption. The scientific and medical community should develop revised recommendations regarding the selection of air cleaners by allergic and asthmatic individuals, and air cleaner manufacturers should respond by providing new air- cleaning products. OVE - LL CONCLUSIONS This report represents a summary of the best available evi- dence the committee could find from a wide variety of sources including: published peer reviewed scientific studies, presenta- tions by recognized experts, and personal knowledge. In many cases the conclusions the committee reached were neither as firm nor as broad as the committee would have liked, primarily be- cause of limitations in the available information. Many of the pub- lished studies reviewed by the committee suffered from potential problems such as small numbers of study subjects, subjects who were not representative of large segments of the population, or studies evaluating the effect of only a single allergen or pollutant rather than the multiple agents encountered by most persons. The lack of large, well-conducted, epidemiologic studies made it diffi- cult for the committee to make judgments about the relative im- pact or proportion of asthma caused by different agents. Even when suggestive information was available, it was often difficult to determine whether the effects of an agent would be the same in different areas of the country since there is little information con

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406 CLEARING THE AIR cerning regional variations in exposure to various indoor agents that may be related to asthma outcomes. The indoor air problems that are the greatest concern in the northern U.S. are in many cases different from those found in the South or West. Similarly, indoor air problems are likely to be quite different in cities compared to suburbs or rural areas. More comprehensive studies are needed to resolve many important issues concerning the health effects of . . . nuoor alr. The report's review of the epidemiology and etiology of asthma reflects the complex nature of the disease. While a num- ber of indoor exposures are or may be associated with asthma, none is by itself a necessary cause, since asthma is associated with other factors. Each factor is probably not a sufficient cause, since each likely functions through an interaction with other environ- mental agents and with genetic factors. Nevertheless, for some of the factors discussed, it seems pos- sible and reasonable to institute mitigation with a reasonable hope of reducing the rate of asthmatic attacks. However, often it is not known what degree of mitigation would be necessary to reduce the risk of attacks in known asthmatic individuals. Mitigation generally involves two components: reducing the existing levels of exposure and preventing any increases in exposure as a result of further introduction of the suspected agent into the environ- ment. The level of effort that should be recommended for mitigat- ing a given factor will depend on how clear the evidence both of association or causation and of the effectiveness of mitigation is, as well as the importance attached to the problem of asthma by the individual, his family, and community. Clearly, individual sensitivity is a major consideration. The factors that lead to the development of asthma and sensitivity are generally not well understood. Most of the factors discussed play a role in exacerbating existing asthma in sensitive individuals. A major problem in choosing and implementing an interven- tion to mitigate an exposure is the generally limited data avail- able. The limitations exist in regard to both the quantity and the quality of research data. Many of the studies reported are not based on rigorous protocols. Definition of clinical outcome espe- cially in infants, measurement of exposure, rigorous study de- sign, appropriate population selection, and dealing with issues of

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RESEARCH RECOMMENDATIONS AND OVERALL CONCLUSIONS 407 generalizability of the findings are often not adequately ad- dressed. The distinction between association and causation is of- ten not clear. It has proven difficult to assess the individual roles of the factors implicated and to determine whether any effects noted are indeed the results of the specific exposures studied or of confounders. Furthermore, the interaction of different environ- mental exposures with genetic susceptibilities must be elucidated. Although considerable work has been done and is being done on asthma per se, increased research efforts are needed to address the characteristics of healthy indoor environments. Asthma re- search clearly needs interdisciplinary involvement not only of clinicians, immunologists, and researchers in related biologic ar- eas but also of engineers, architects, materials manufacturers, and others who are responsible for the design and function of indoor environments.

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