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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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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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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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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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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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Representative terms from entire chapter:
air cleaning
