Is Primary Prevention of Asthma Possible?

Allan B. Becker, MD, FRCPC*

SUMMARY. The increased prevalence of asthma over the past quarter century has become a
major public health problem for the industrialized world. Asthma is a disease process which has
a strong heritable component which is impacted by multiple environmental factors. Given the
rapid increase in asthma prevalence, it is difficult to ascribe the change to a genetic alteration.
Therefore, the focus for understanding the changing prevalence of asthma must be on environ-
mental factors. This article reviews factors which may contribute, in whole or in part, to the
development of the disease process. In questioning whether it is possible to prevent develop-
ment of a disease (primary prevention), it is critical to understand these factors. The environment
may even have an impact on the fetus during intrauterine life. There does appear to be a
window of opportunity in early life where a variety of factors, including food and inhalant
allergen exposure, exposure to pollutants, and infection with both viral and bacterial agents, may
be important in initiating the development of asthma and allergy. Potential approaches to primary
prevention of asthma and allergy must consider each of these important factors. Given that
asthma is a multifactorial disease with both complex genetic and environmental components, it
is unlikely that any single intervention will significantly decrease the prevalence of asthma.
Pediatr Pulmonol. 2000; 30:6372. 2000 Wiley-Liss, Inc.
Key words: asthma; allergy; allergens; airway hyperresponsiveness; airway
inflammation; environment; genetics; intrauterine; infections; cytokines;
T lymphocytes; Th1; Th2 phenotype; primary prevention.
INTRODUCTION
Over the past quarter century, the prevalence of
asthma has increased to epidemic proportions in the in-
dustrialized world.
1
Although there is some dispute about
the increased incidence of asthma among children and
young adults,
2
there is a general consensus that this in-
crease is real.
35
Although there is an obvious change in
diagnostic preference among physicians for a diagnosis
of asthma, we demonstrated that the shift in diagnosis
from other respiratory illnesses accounted for approxi-
mately one quarter of the doubling increase in physician-
diagnosed asthma in Manitoba during the 1980s.
5
Asthma is the most common cause of any chronic disease
for emergency room visits and admission to hospital for
children,
6
and it remains an important cause of absence
from school for children and absence from work for their
parents. There is a substantial economic burden for
asthma, including both direct and indirect costs.
7,8
The focus of this review will be to question whether it
is possible to prevent the development of asthma and
whether it is possible to prevent the concomitant devel-
opment of allergy. For patients with diagnosed asthma,
we provide tertiary prevention in the form of pharma-
cotherapy and environmental therapy. For example,
avoidance of house dust mite exposure in a patient with
asthma who has allergy to dust mites is a form of envi-
ronmental therapy. Similarly, avoidance of environmen-
tal tobacco smoke exposure will be an important form of
tertiary prevention for all patients with asthma. Second-
ary prevention can be defined as the attempt to prevent
the development of asthma in an atopic infant with al-
lergy-associated disease such as food allergy or atopic
dermatitis. In that child, decreasing exposure to house
dust mite allergy may decrease the potential for devel-
opment of asthma. Primary prevention implies a pro-
cess whereby the intervention considered precedes dis-
Section of Allergy and Clinical Immunology, Department of Pediatrics
and Child Health, University of Manitoba, Winnipeg, Manitoba,
Canada.
*Correspondence to: Allan B. Becker, M.D., F.R.C.P.C., Section of
Allergy and Clinical Immunology, Department of Pediatrics and Child
Health, University of Manitoba, AE101-840 Sherbrook St., Winnipeg,
Manitoba R3A 1S1, Canada. E-mail: becker@cc.umanitoba.ca
Received 31 May 1999; Accepted 2 March 2000.
Pediatric Pulmonology 30:6372 (2000)
State of the Art
2000 Wiley-Liss, Inc.
ease development and does not simply modify the
process once it has been established. For example, de-
creasing exposure to house dust mites for newborns at
high risk for development of asthma represents a pri-
mary prevention approach. A recent review by Holt et
al. outlines the immunologic considerations underlying
an approach to primary prevention of asthma.
9
If primary
prevention is to be considered, it is critically important to
understand those factors which may contribute, in whole
or in part, to the development of the disease process.
Those factors which appear to play an important role will
be discussed below.
FACTORS CRITICAL TO THE DEVELOPMENT
OF ASTHMA
Genetic Predisposition
Atopy is the tendency to develop allergic disorders
such as asthma, allergic dermatitis, allergic rhinitis, and
food allergy. Atopic children are at much greater risk for
the development of asthma than nonatopic children.
1014
The paradigm for balance of immune responses con-
trolled by CD4+ lymphocytes which underlies atopy and
asthma
15
has been a simplistic, but helpful concept (Fig.
1). While there is a clear heritable contribution to both
Abbreviations
BCG Bacillus Calmette et Guerin
ETS Environmental tobacco smoke
GM-CSF Granulocyte macrophage colony-stimulating factor
HEPA High-efficiency particulate air filter
IFN Interferon
IL Interleukin
ISS Immunostimulatory sequence
PIV3 Parainfluenza virus type III
RSV Respiratory syncytial virus
Th1 T-helper lymphocyte type I phenotype
Th2 T-helper lymphocyte type II phenotype
TNF Tumor necrosis factor
Fig. 1. The simplistic concept of a Th1/Th2 paradigm, derived
from a murine model (by Mosman et al.
15
), has been helpful in
understanding the immunopathology of allergy and asthma.
CD4+ lymphocytes (and almost certainly other lymphocytes
such as NK cells) can develop a Th1 phenotype with production
of cytokines that promote cell-mediated immunity and suppres-
sion of IgE production, or a Th2 phenotype with production of
cytokines that promote a humoral immune response and par-
ticularly a shift to production of IgE with induction of an atopic
predisposition.
64 Becker
atopy and asthma, the genetic contribution toward airway
hyperresponsiveness, airway remodelling, and airway in-
flammation is poorly understood. Given the rapid in-
crease in asthma prevalence over the last quarter century,
it is difficult to ascribe the change to genetic alteration.
The gene (or genes) responsible for atopy and/or asthma
has (have) not yet been identified. Therefore, the focus
for understanding this changing prevalence of asthma has
turned to environmental factors.
The Intrauterine Environment
The potential for development of atopy and asthma
may begin in the interuterine environment. There is in-
creasing evidence that successful pregnancy is a Th2
phenomenon. In murine studies, injection of interleu-
kin-3 (IL3) or granulocyte macrophage colony-
stimulating factor (GM-CSF) enhances fetal survival and
promotes intrauterine growth, whereas injection of IL2,
tumor necrosis factor (TNF), or interferon- (IFN) (Th1
cytokines) lead to fetal destruction.
16
There is also clini-
cal evidence
15
that pregnant women undergo immuno-
logic changes consistent with weakening of cell mediated
immunity and strengthening of humoral immunity. This
is clinically apparent with improvement during preg-
nancy in 70% of women who have rheumatoid arthritis (a
cell-mediated autoimmune disorder), and worsening of
systemic lupus erythematosis (a humoral driven disor-
der).
17
Wegmann et al.
16
suggest that the placenta acts as
an immunoabsorbent which is capable of removing large
amounts of anti-fetal antibody without damage, whereas
cell-mediated immunity is not well buffered by the pla-
centa. They suggest that a healthy feto-placental unit pri-
marily supports a humoral immune response and is re-
sponsible for driving this Th2 environment. As a result,
at delivery the infants immune system is preferentially
biased toward continuing this intrauterine established
Th2 immune status. Umbilical cord mononuclear cells
stimulated by allergen have a Th2-like phenotype for
cytokine production, and the cells responsible for pro-
duction of these Th2 cytokines appear to be T-
lymphocytes.
18
Further, in atopic children, there appear
to be continued Th2 responses during the first year of life
associated with decreases in neonatal IFN (Th1) pro-
duction.
19
However, in a recent study assessing umbilical
cord blood mononuclear cell response to house dust mite
in infants at high risk for development of asthma, no
correlation could be found between cord blood mono-
nuclear cell proliferative response to house dust mite at
birth and the development of an asthma-like phenotype
or allergic rhinitis at 12 months of age.
20
Exposure to Allergens
Food Allergens
In the first year or two of life, development of allergy
is primarily associated with food sensitivity. Breastfeed-
ing has been advocated as a method of preventing allergy
and asthma. Studies suggest that atopic dermatitis can be
delayed, but not necessarily prevented by breastfeeding
infants for the first 4 to 6 months of life.
21
As one com-
ponent of an allergen avoidance program, breastfeeding
has been shown to decrease total allergy, eczema, and
positive allergy skin tests in children up to 4 years of
age.
22
In that study, asthma was decreased at 1 year, but
not at 2 years of age in the intervention group compared
to the control group.
22
While breastfeeding has not been
shown to be effective in preventing the development of
asthma, it does decrease the incidence of respiratory in-
fections during infancy.
23
Of interest, diet may continue to be important in later
life. A recent study
24
noted that children who ate fresh,
oily fish (greater than 2% fat) had a significantly reduced
risk of developing asthma (odds ratio, 0.26; 95% CI,
0.090.72).
Inhalant Allergens
Sensitization to indoor inhalant aeroallergens is more
important than sensitization to outdoor aeroallergens in
asthma. Indoor aeroallergens, including house dust mites,
companion animals, and cockroaches, appear to be im-
portant factors for asthma development. Studies have
shown that risk for development of asthma is greater in
children whose homes had high dust mite allergen levels
during the first year of life.
25
Moreover, the higher the
levels of exposure, the earlier children developed symp-
toms and the more severe were those symptoms.
2527
In areas where house dust mite concentrations are low,
asthma and airway hyperresponsiveness tend to correlate
better with allergy to cats.
28
Unlike house dust mite al-
lergens which are present on relatively large particles and
settle quickly after being disturbed, cat allergen is present
on very small particles which readily become airborne
and which are subsequently widely distributed in the
home and in the community. In low socioeconomic status
housing, cockroach allergen plays an important role.
29
Although there has been some recent debate,
30
the
preponderance of evidence suggests that in patients with
asthma who are sensitized to allergens, environmental
control can result in significant improvement of asthma
symptoms and lung function (i.e., tertiary preven-
tion).
3135
Thus, it appears that early life exposure (at
least to house dust mites) is associated with subsequent
development of asthma and that ongoing allergen expo-
sure has a role in perpetuating the disease process once it
has become established. Whether avoidance of inhalant
allergens in early life is capable of preventing the devel-
opment of allergy and asthma remains to be proven.
Pollutants/Adjuvants
Environmental tobacco smoke (ETS) is important in
the development of childhood asthma and in worsening
Primary Prevention of Asthma 65
of asthma in children and adults.
36
The earlier, longer,
and greater the degree of ETS exposure in early child-
hood, the greater the likelihood of asthma developing in
children.
3740
ETS is by far the single most important
pollution exposure factor associated with asthma in in-
fants and children.
Environmental pollutants other than ETS may also be
a problem.
41
These include diesel particulates and nox-
ious gases such as ozone, sulphur dioxide, and nitrous
oxides. Exposure to nitrous oxides occurs from a variety
of sources, such as incomplete oxidation of natural gas,
and is also present in ETS. The classic visible pollution
which is apparent as overt discoloration of the air is not
necessarily associated with increased prevalence of
asthma and allergy. Changes which may be far less ob-
vious, particularly in industrialized societies, appear to
be rather more important, as evidenced by data from the
former East and West Germany.
42
Infections
Respiratory viruses may play an important role in the
development of asthma.
43,44
The onset of asthma after
respiratory syncytial virus (RSV) bronchiolitis in infants
has been well-documented;
45,46
however, the role of both
viral and bacterial infections is complicated. In the highly
susceptible host, such as infants with biparental atopy,
viral infections such as RSV and parainfluenza type 3
(PIV3) appear to be associated with the development of
allergy and onset of clinical disease.
47
Other infections,
both bacterial and viral, are important in determining the
shift from Th2 to Th1 lymphocyte predominance in in-
fancy.
48
Absence of these infections in an industrialized,
well-immunized society may not allow for this shift to
occur and may influence the increase in allergy and
asthma. There are data suggesting that family size and
birth order are important factors associated with the
changing prevalence of allergy and asthma.
49
This may
reflect the increased exposure of younger siblings early
in life to repeated infections from their older siblings.
Immunization and better hygiene in industrialized soci-
eties decrease the prevalence of a variety of infectious
diseases, with a resulting decrease in the morbidity and
mortality that may have occurred from these dis-
eases.
4850
A recent study of immunization with BCG for
the prevention of tuberculosis showed a decreased inci-
dence of current atopy and asthma and increased remis-
sion from asthma in children with evidence of delayed-
type hypersensitivity (cellular immunity) to tuberculin.
50
This has been interpreted as suggesting a protective ef-
fect for allergy and asthma from BCG immunization.
Bacterial cell wall DNA contains sequences of bases
(centred on CpG dinucleotides) which induce Th1-like
responses.
5153
Mycobacterial infections may well be ca-
pable of inducing this response, associated with the pres-
ence of such an immunostimulatory sequence (ISS) in its
cell wall, and bacterial DNA may be implicated in the
development of innate immunity. However, it has been
suggested that the primary trigger for a shift to a Th1-like
phenotype is not likely to be from infectious organisms,
but rather from normal bacterial commensals, particu-
larly those in the gastrointestinal tract (GIT).
53
Holt et al.
suggest that microbial products typified by cell wall-
derived lipopolysaccharides (LPS) are recognized as na-
tures Th1 adjuvant.
54
Certain viral infections appear to be important in pro-
moting the development of a Th1 phenotype. In particu-
lar, infection with measles
55
or hepatitis
56
appears to be
protective for the development of atopy. On the other
hand, other infections such as RSV appear to promote the
development of allergy and asthma.
47
The mechanism
for this is not well understood, but appears to be associ-
ated with the production of Th2 cytokines
57
and particu-
larly with the promotion of prolonged eosinophilic air-
way inflammation.
57,58
Of interest, those viral infections
associated with asthma are potent stimulators of a novel
pleotropic cytokine, IL-11
59
(Table 1). Expression of IL-
11 in an animal model has been shown to be associated
with airway inflammation, airway remodelling, and air-
way hyperresponsiveness, all important features in
asthma.
59,60
In one study, children with an upper respi-
ratory tract infection (URI) had significantly increased
IL-11 in nasal secretions compared to healthy controls.
59
Those children with a URI who also had clinical evi-
dence of bronchospasm had significantly higher levels
of IL-11 than those children without evidence of bron-
chospasm.
59
Further, bacterial infections such as Pneu-
mococcus, Staphylococcus, and Streptococcus which do
not induce or exacerbate asthma do not appear to induce
production of IL-11 (Table 1).
5961
Avoidance of diseases such as measles and tuberculo-
sis and/or modification of the normal gastrointestinal
flora, perhaps by better hygiene and excessive use of
antibiotics, may allow for perpetuation of a Th2 pheno-
type in young children and thus promote the develop-
ment of allergy and asthma. Those infections which con-
tinue to be a common problem during childhood (RSV,
TABLE 1Infections and IL-11 Production
IL-11
Human rhinovirus +
Respiratory syncitial virus +
Parainfluenza virus (Type 3) +
Herpes simplex virus (Type 2)
Adenovirus
Cytomegalovirus
Pneumococcus
Staphylococcus
Streptococcus
Production of IL-11 from cell monolayers (A549) compared to un-
stimulated cells.
59,61
66 Becker
PIV3, and human rhinovirus) appear to contribute to the
development of asthma and allergy. The occurrence of
one of these viral illnesses in an atopic individual has the
potential to greatly enhance production of IL-11, which
may then promote development of asthma to a much
greater degree
61
(Fig. 2). This combination of insults as
the cause for asthma has been described as the double
hit theory.
APPROACH TO ASTHMA PREVENTION
Primary prevention is the approach to intervening be-
fore the development of any allergy or allergy-associated
disease, including asthma, can occur in any individual.
Obviously this is the ideal. Given the review of data
relating to factors which appear to play an important role
in asthma, we must now ask whether we have sufficient
data to appropriately design an effective approach to the
primary prevention of asthma and allergy in infants.
Asthma Vaccine or Immunization
Several approaches to vaccination/immunization for
prevention of allergy and asthma have been suggested.
Holt
63
suggested a vaccine strategy for asthma and aller-
gies consisting of parenteral vaccination with a cocktail
of major inhalant antigens in early childhood. The cock-
tail would be combined with an adjuvant specifically
designed to stimulate the Th1 response. Hsu et al.
64
stud-
ied allergen gene immunization in rats. They used in-
tramuscular injection of a plasmid DNA (naked DNA)
encoding a house dust mite allergen into the legs of rats.
This induced a transient IgG response to the gene, but no
IgE response. These studies are of interest and suggest a
Fig. 2. The presence of TGF- in the airway of an atopic individual produced by macrophages (M), particularly an individual
exposed to an allergen to which he or she is sensitized (thus with increased histamine in the airways from mast cells (MC) and
basophils), causes production of IL-11 by a variety of resident airway cells, resulting in airway inflammation, remodeling, and
hyperresponsiveness.
5861
Primary Prevention of Asthma 67
number of new potential approaches to the control of
allergy. In general, these strategies propose an approach
to trigger switching of the immune response in infants to
a Th1 phenotype, thus hopefully decreasing the potential
for subsequent development of asthma. However, this
may not be effective with infants or newborns who are
already sensitized to environmental triggers. Similarly, it
has been suggested that immunization with BCG may
have the potential to shift the immune response balance
toward a Th1 phenotype.
50
Recent studies in murine
models have demonstrated the ability of BCG immuni-
zation to act as a Th1 adjuvant and suppress allergic
sensitization, airway inflammation, and airway hyperre-
sponsiveness.
65,66
However, this may not be true of the
protective effect of BCG in individuals with a strong,
heritable predisposition to atopy.
67
Dietary Intervention
Because of the strong relationship of allergy (albeit
more specifically to inhalants) and asthma, attempts to
decrease the turn on of the Th2 immune process appear
logical. Given that allergy to foods is usually the first
manifestation of an atopic immune process, consider-
ation should be given to dietary intervention. Data on the
influence of breastfeeding date to the 1930s with the
recognition that breast-fed infants had less atopic derma-
titis than bottle-fed infants.
68
Although not all studies of
breastfeeding demonstrated a decrease in atopic derma-
titis, there appears to be a consensus that breastfeeding
for 46 months will at least delay, if not prevent, atopic
dermatitis.
69
Given that allergens such as cows milk and
egg protein are present in breast milk, it was also thought
that the maternal diet may be important.
70
In one study,
all breast-fed infants who developed allergy to cows
milk had received supplements of cows milk formula in
the nursery.
70
Thus, accidental exposure to cows milk
itself appears to be far more important than the very
small amount of cows milk transmitted through breast
milk. Nevertheless, maternal avoidance of highly aller-
genic foods during breast feeding has been shown to
delay, but not prevent, subsequent development of aller-
gic disease.
21,70
For a variety of sound clinical reasons,
breastfeeding for the first 46 months of life should con-
tinue to be encouraged. Delay of exposure of infants to
cows milk and other highly allergenic foods also ap-
pears to be helpful.
21,6870
A recent epidemiologic
study
71
demonstrates a significant reduction in the risk of
childhood asthma if exclusive breastfeeding is continued
for at least 4 months after birth. Avoidance of cows milk
introduction appeared more important statistically than
the actual duration of breastfeeding.
71
Another issue is the use of an even earlier maternal
exclusion diet during pregnancy. Reduced intake of
highly allergenic foods in the last trimester has not been
shown to be helpful in the prevention of allergic disease
in children at high risk for allergies because of a strong
family history.
7072
Further, an exclusion diet may place
mothers at risk for inadequate nutrition intake. One dif-
ficulty with studies relating to maternal diet on allergen
exposure relates to our lack of understanding as to when
the elimination diet should be initiated and to our lack of
ability to measure intrauterine allergen exposure. Both
timing and levels of exposure may be critically important
in the promotion of allergy and perpetuation of the Th2
phenotype.
Environment Control: What Can We Do and What
Might Be Effective?
Environmental control appears to be important, begin-
ning at (or very possibly even before) birth. Data from a
limited number of studies suggest that avoidance of al-
lergens, both ingested and inhaled, and avoidance of ETS
may at least delay onset of allergy and allergy-associated
diseases, including asthma.
21,22
Allergen Avoidance
Indoor aeroallergens. Given their strong relationship
to asthma, avoidance of house dust mite, companion ani-
mal (particularly cat), and cockroach allergens appears to
have the greatest potential for benefit.
13,25,2834,74,75
Treatment to control house dust mites is the least con-
troversial and least problematic of this group. House dust
mites thrive in high humidity. Decreasing indoor humid-
ity to less than 50% is associated with lower house dust
mite concentrations. Simply encasing mattresses in a va-
por-impermeable barrier is effective in decreasing house
dust mite exposure.
76
Laundering bed linens in hot water
will also decrease dust mite concentrations.
77
The ability
to reduce house dust mite allergen in carpeting (textile
floor coverings) is rather more controversial, but short-
term decreases in house mite concentrations have been
noted with various acaricides and with use of liquid ni-
trogen to freeze carpeting.
76
Removal of carpeting is the
most effective method to decrease the floors house dust
mite concentration.
78
Removal of the pet from the home is the most effective
means to reduce cat or dog allergen.
79
However, this is
loaded with psychosocial issues and is not easily dealt
with. There are data demonstrating a decrease in airborne
cat allergen with the use of HEPA filters and the removal
of textile floor covering (which acts as a reservoir for the
cat allergen).
34,80
After removal of a cat, it can take more
than 6 months for cat allergen levels to return to base-
line.
79
The issue of weekly washing of the cat has not
been clearly defined, and there is debate as to its value at
68 Becker
present. Cat allergen exposure also occurs in public en-
vironments such as schools and hospitals, associated with
upholstered furniture and textile floor coverings. To a
widespread degree, the cat has become a community-
based allergen.
Cockroach infestation is predominately a socioeco-
nomic problem of poor and inner-city environments. De-
crease in cockroach exposure in those settings will re-
quire increased awareness of this community problem at
a political level. Changes in housing to impact on this
problem will require not only scientific understanding,
but also social and political changes.
Out-of-door aeroallergens. Out-of-door aeroallergens
are generally much less of a problem. However, in agrar-
ian, semiarid, prairie environments, Alternaria is a major
sensitizer and is often associated with asthma (frequently
with severe asthma). This mold spore has marked sea-
sonality, with peaks of exposure in the spring, late sum-
mer, and fall.
81
Air conditioning systems and indoor air
filters have the potential to decrease exposure to this
allergen.
Pollutants
Exposure to ETS in early life must be avoided. Such
exposure carries the greatest risk for subsequent devel-
opment of allergy and asthma.
36,37
The dangers of smok-
ing during pregnancy appear to be well recognized.
Mothers and other family members must be educated on
the importance of avoidance of ETS exposure for infants
and toddlers. Societal change should be encouraged
through education and increased taxation of cigarettes.
CONCLUSIONS
Given that asthma is a multifactorial disease, with
complex genetic and environmental components (Fig. 3),
it is unlikely that any single intervention currently avail-
able will significantly decrease the prevalence of asthma.
If the double hit concept proves critical to the devel-
opment of asthma, then it will be increasingly important
to modify environmental factors and to define interven-
tions to control viral infections and/or the immune sys-
Fig. 3. Genetic predisposition provides a large heritable com-
ponent to atopy and asthma. With the intrauterine environment
predisposing infants to a Th2-like phenotype, the impact of the
external environment after birth becomes critical. In the indus-
trialized world, infants are protected from a variety of bacterial
and viral infections and have altered normal bacterial com-
mensals, particularly in the gastrointestinal tract (GIT). This
modifies the adjuvant effect of the immunostimulatory se-
quence of oligodeoxynucleotides (ISS-ODN) from these bacte-
ria which may provide an immune response balance in promot-
ing a Th1-like phenotype after birth.
Primary Prevention of Asthma 69
tems balanced response to those environmental factors
and infections. High-risk populations should be targeted
for ongoing research. Pregnancy and the first year of life
appears to be a critically important window during
which time allergies and the potential for asthma de-
velop. Large, well-controlled multicenter studies should
be encouraged in an effort to better understand the chang-
ing prevalence of asthma in a variety of environmental
settings. The primary prevention of diseases, including
asthma, offers the best potential for significant decrease
in disease prevalence in the future.
REFERENCES
1. Bjorksten B, Kjellman BN-IM, Zeiger RS. Development and pre-
vention of allergic disease in childhood. In: Middleton E Jr, Reed
CE, Ellis EF, Adkinson NF Jr, Yunginger JW, Busse WW, editors.
Allergy: principles and practice. St. Louis: Mosby-Yearbook, Inc.;
1998. p 816837.
2. Magnus P, Jaakkola JJ. Secular trend in the occurrence of asthma
among children and young adults: critical appraisal of repeated
cross sectional surveys. Br Med J [Clin Res] 1997;314:1795
1799.
3. Peat JK, van den Berg RH, Green WF, Mellis CM, Leeder SR,
Woolcock AJ. changing prevalence of asthma in Australian chil-
dren. Br Med J [Clin Res] 1994;308:15911596.
4. Aberg N, Hesselman B, Aberg B, Eriksson B. Increase of asthma,
allergic rhinitis and eczema in Swedish schoolchildren between
1979 and 1991. Clin Exp Allergy 1995;25:815819.
5. Manfreda J, Becker AB, Wang PZ, Roos LL, Anthonisen NR.
Trends in physician-diagnosed asthma prevalence in Manitoba
between 1980 and 1990. Chest 1993;103:151157.
6. Wilkins K, Mao Y. Trends in the admission to hospital and death
from asthma among children and young adults in Canada during
the 1980s. Can Med Assoc J 1993;148:185190.
7. Krahn MD, Berka C, Langlois P, Detsky AS. Direct and indirect
costs of asthma in Canada, 1990. Can Med Assoc J 1996;154:
821831.
8. Weiss KB, Gergen PJ, Hodgson TA. An economic evaluation of
asthma in the United States. N Engl J Med 1992;326:862866.
9. Holt PG, Macaubas C, Stumbles PA, Sly PD. The role of allergy
in the development of asthma. Nature [Suppl] 1999;402:1217.
10. Horwood IL, Fergusson DM, Shannon FT. Social and familial
factors in the development of early childhood asthma. Pediatrics
1985;75:859868.
11. Sporik R, Holgate ST, Cogswell JJ. Natural history of asthma in
childhooda birth cohort study. Arch Dis Child 1991;66:1050
1053.
12. Clifford RD, Howell JB, Radford M, Holgate ST. Associations
between respiratory symptoms, bronchial response to methacho-
line and atopy in two age groups of school children. Arch Dis
Child 1989;64:11331139.
13. Peat JK, Salome CM, Woolcock AJ. Longitudinal changes in
atopy during a 4-year period: relation to bronchial hyperrespon-
siveness and respiratory symptoms in a population sample of Aus-
tralian schoolchildren. J Allergy Clin Immunol 1990;85:6574.
14. Martin AJ, Landau LI, Phelan PD. Natural history of allergy in
asthmatic children followed to adult life. Med J Aust 1981;2:470
474.
15. Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman
RL. Two types of murine helper T cell clone. I. Definition ac-
cording to profiles of lymphokine activities and secreted proteins.
J Immunol 1986;136:23482357.
16. Wegmann TG, Lin H, Guilbert L, Mosmann TR. Bidirectional
cytokine interactions in the maternal-fetal relationship: is success-
ful pregnancy a Th2 phenomenon? Immunol Today 1993;14:353
356.
17. Da Silva JA, Spector TD. The role of pregnancy in the course and
aetiology of rheumatoid arthritis. Clin Rheumatol 1992;11:189
194.
18. Prescott SL, Macaubas C, Holt BJ, Smallacombe TB, Loh R, Sly
PD, Holt PG. Transplacental priming of the human immune sys-
tem to environmental allergens: universal skewing of initial T-cell
responses towards the Th-2 cytokine profile. J Immunol 1998;
160:47304737.
19. Prescott SL, Macaubas C, Smallacombe T, Holt BJ, Sly PD, Holt
PG. Development of allergen-specific T-cell memory in atopic
and normal children. Lancet 1999;353:196200.
20. Chan-Yeung M, Ferguson A, Chan H, Dimich-Ward H, Watson
W, Manfreda J, Becker A. Umbilical cord blood mononuculear
cell proliferative response to house dust mite does not predict the
development of allergic rhinitis and asthma. J Allergy Clin Im-
munol 1999;104:317321.
21. Zeiger RS, Heller S, Sampson HA. Genetic and environmental
factors affecting the development of atopy from birth through age
4 in a prospective randomized controlled study of dietary avoid-
ance. J Allergy Clin Immunol 1992;89:192.
22. Hide DW, Matthews S, Tariq S, Arshad SH. Allergen avoidance
in infancy and allergy at 4 years of age. Allergy 1996;51:8993.
23. Woodward A, Douglas RM, Graham NMH, Miles H. Acute re-
spiratory illness in Adelaide children: breast feeding modifies the
effect of passive smoking. J Epidemiol Community Health 1990;
44:224230.
24. Hodge L, Salome CM, Peat JK, Haby MM, Xuan W, Woolcock
AJ. Consumption of oily fish and childhood asthma risk. Med J
Aust 1996;164:137140.
25. Sporik R, Holgate ST, Platts-Mills TAE, Cogswell JJ. Exposure to
house-dust mite allergen (Der p1) and the development of asthma
in childhood. N Engl J Med 1990;323:502507.
26. Ehnert B, Lau-Schadendorf S, Weber A, Buettner P, Schou C,
Wahn U. Reducing domestic exposure to dust mite allergen re-
duces bronchial hyperreactivity in sensitive children with asthma.
J Allergy Clin Immunol 1992;90:135138.
27. Chan-Yeung M, Manfreda J, Ward H, Lam J, Ferguson A, Warren
P, Simons E, Broder I, Chapman M, Platts-Mills T, Becker A.
Mite and cat allergen levels in homes and severity of asthma. Am
J Respir Crit Care Med 1995;152:18051811.
28. Sporik R, Rose G, Muller M, Claytor D, Price G, Ingram J, Suss-
man J, Honsinger R, Platt-Mills TAE. Allergen sensitization of
children with wheeze and bronchial hyperreactivity (BHR) resi-
dent at high altitude. Am Rev Respir Dis 1993;147:458.
29. Rosenstreich DL, Eggleston P, Kattan M, Baker D, Slavin RG,
Gergen P, Mitchell H, McNiff-Mortimer K, Lynn H, Ownby D,
Malveaux F. The role of cockroach allergy and exposure to cock-
roach allergen in causing morbidity among inner-city children
with asthma. N Engl J Med 1997;336:13561363.
30. Gotzsche PC, Hammarquist C, Burr M. House dust mite control
measures in the management of asthma: meta-analysis. Br Med J
[Clin Res] 1998;317:11051110.
31. Murray AB, Ferguson AC. Dust-free bedrooms in the treatment of
asthmatic children with house dust or dust mite allergy: a con-
trolled trial. Pediatrics 1983;71:418422.
32. Platts-Mills TAE, Tovey ER, Mitchell FB, Nock P, Mosroro H,
Wilkins SR. Reduction of bronchial hyper-reactivity during pro-
longed allergen avoidance. Lancet 1982;ii:675678.
33. Boner AL, Nicro E, Antolini L, Vallotta AE, Gaburro D. Pulmo-
nary function and bronchial hyperreactivity in asthmatic children
70 Becker
with house dust mite allergy during prolonged stay at in the Italian
Alps (Misurina, 1756 m). Ann Allergy 1985;54:4245.
34. van der Heide S, Kauffman HF, Dubois AEJ, de Monchy JGR.
Allergen reduction measures in houses of allergic asthmatic pa-
tients: effects of air-cleaners and allergen-impermeable mattress
covers. Eur Respir J 1997;10:12171223.
35. Custovic A, Simpson A, Chapman MD, Woodcock A. Allergen
avoidance in the treatment of asthma and atopic disorders. Thorax
1998;53:6372.
36. Weiss ST, Tager IB, Schenker M, Speizer FE. The health effects
of involuntary smoking. Am Rev Respir Dis 1983;128:933942.
37. Ehrlich RI, Du Toit D, Jordaan E, Zwarenstein M, Potter P, Vol-
mink JA, Weinberg E. Risk factors for childhood asthma and
wheezing: importance of maternal and household smoking. Am J
Respir Crit Care Med 1996;154:681688.
38. Fergusson DM, Horwood LJ. Parental smoking and respiratory
illness during early childhood: a six year longitudinal study. Pe-
diatr Pulmunol 1985;1:99106.
39. Murray AB, Morrison BJ. The effect of cigarette smoke from the
mother on bronchial responsiveness and severity of symptoms in
children with asthma. J Allergy Clin Immunol 1986;77:575581.
40. Frischer T, Kuehr J, Meinert R, Karmaus W, Barth R, Hermann-
Kunz E, Urbanek R. Maternal smoking in early childhood: a risk
factor for bronchial responsivenss to exercise in primary-school
children. J Pediatr 1992;121:1722.
41. Committee of the Environmental and Occupational Health Assem-
bly of the American Thoracic Society. Health effects of outdoor
air pollution. Am J Respir Crit Care Med 1996;153:350.
42. Von Mutius E, Fritzsch C, Weiland SK, Roll G, Magnussen H.
Prevalence of asthma and allergic disorders among children in
united Germany; a descriptive comparison. Br Med J [Clin Res]
1992;305:13951399.
43. Weiss ST, Tager IB, Munoz A, Speizer FE. The relationship of
respiratory infections in early childhood to the occurrence of in-
creased levels of bronchial responsiveness and atopy. Am Rev
Respir Dis 1985;131:573578.
44. Busse WW. Respiratory infections: their role in airway respon-
siveness and the pathogenesis of asthma. J Allergy Clin Immunol
1990;85:671683.
45. Johnston SL. Influence of viral and bacterial respiratory infection
on exacerbations and symptom severity in childhood asthma. Pe-
diatr Pulmonol [Suppl] 1997;16:8889.
46. Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M,
Morgan WJ. Asthma and wheezing in the first six years of life.
The Group Health Medical Associates. N Engl J Med 1995;332:
133138.
47. Frick OL, German DF, Mills J. Development of allergy in chil-
dren. I. Association with virus infections. J Allergy Clin Immunol
1979;63:228241.
48. Cookson WO, Moffatt MF. Asthma: an epidemic in the absence of
infection? Science 1997;275:4142.
49. Strachan DP. Hay fever, hygiene, and household size. Br Med J
[Clin Res] 1989;299:12591260.
50. Shirakawa T, Enomoto T, Shimazu S, Hopkin J. The inverse
association between tuberculin responses and atopic disorder. Sci-
ence 1997;275:7779.
51. Pisetsky DS. The immunologic properties of DNA. J Immunol
1996;156:421423.
52. Sato Y, Roman M, Tighe H, Lee D, Corr M, Nguyen, Silverman
GJ, Lotz M, Carson DA, Raz E. Immunostimulatory DNA se-
quences necessary for effective intradermal gene immunization.
Science 1996;273;352354.
53. Kline JN, Waldschmidt TJ, Businga TR, Lemish JE, Weinstock
JV, Thorne PS, Krieg AM. Cutting edge: modulation of airway
inflammation by CpG oligodeoxynucleotides in a murine model
of asthma. J Immunol 1998;160:25552559.
54. Holt PG, Sly PD, Blorksten B. Atopic versus infectious diseases in
childhood; a question of balance? Pediatr Allergy Immunol 1997;
8:5358.
55. Shaheen SO, Aaby P, Hall AJ, Barker DJ, Heyes CB, Shiell AW,
Goudiaby A. Measles and atopy in Guinea-Bissau. Lancet 1996;
347:17921796.
56. Matricardi PM, Rosmini F, Ferrigno L, Nisini R, Rapicetta M,
Chionne P, Stroffolini T, Pasquini P, DAmelio R. Cross sectional
retrospective study of prevalence of atopy among Italian military
students with antibodies against hepatitis A virus. Br Med J [Clin
Res] 1997;314:9991003.
57. Schwarze J, Hamelmann E, Bradley KL, Takeda K, Gelfand EW.
Respiratory syncytial virus infection results in airway hyperre-
sponsiveness and enhanced airway sensitization to allergen. J Clin
Invest 1997;100:226233.
58. Calhoun WJ, Dick EC, Schwartz LB, Busse WW. A common cold
virus, rhinovirus 16, potentiates airway inflammation after seg-
mental antigen bronchoprovocation in allergic subjects. J Clin
Invest 1994;94:22002208.
59. Einarsson O, Geba GP, Zhu Z, Landry M, Elias JA. Interleukin-
11: stimulation in vivo and in vitro by respiratory viruses and
induction of airways hyperresponsiveness. J Clin Invest 1996;97:
915924.
60. Tang W, Geba GP, Zheng T, Ray P, Homer RJ, Kuhn C III,
Flavell AR, Elias JA. Targeted expression of IL-11 in the murine
airway causes lymphocytic inflammation, bronchial remodeling,
and airways obstruction. J Clin Invest 1996;98:28452853.
61. Einarsson O, Geba GP, Zhou Z, Landry ML, Panettieri RA, Tris-
tram D, Welliver R, Metinko A, Elias JA. Interleukin-11 in re-
spiratory inflammation. Ann NY Acad Sci 1995;762:89100.
62. Zheng T, Nathanson MH, Elias JA. Histamine augments cytokine-
stimulated IL-11 production of human lung fibroblasts. J Immunol
1994;153:47424752.
63. Holt PG. A potential vaccine strategy for asthma and allied atopic
diseases during early childhood. Lancet 1994;344:456458.
64. Hsu CH, Chu KY, Tao MH, Lai YL, Wu HD, Huang SK, Hsieh
KH. Immunoprophylaxis of allergen-induced immunoglobulin E
synthesis and airway hyperresponsiveness in vivo by genetic im-
munization. Nat Med 1996;2:540544.
65. Erb KJ, Holloway JW, Sobeck A, Moll H, Le Gros G. Infection of
mice with mycobacterium bovis-Bacillus Calmette-Guerin (BCG)
suppresses allergen-induced airway eosinophilia. J Exp Med
1998;187:561569.
66. Herz U, Gerhold K, Gruber C, Braun A, Wahn U, Renz H, Paul K.
BCG infection suppresses allergic sensitization and development
of increased airway reactivity in an animal model. J Allergy Clin
Immunol 1998;102:867874.
67. Strannegard IL, Larsson LO, Wennergren G, Strannegard O.
Prevalence of allergy in children in relation to prior BCG vacci-
nation and infection with atypical mycobacteria. Allergy 1998;53:
249254.
68. Grulee CG, Sanford HN. The influence of breast and artificial
feeding on infantile eczema. J Pediatr 1936;9:223225.
69. Kramer MS. Does breast feeding help protect against atopic dis-
ease? Biology, methodology and a golden jubilee of controversy.
J Pediatr 1988;112:181190.
70. Zeiger RS, Heller S, Mellon MH, Forsythe AB, OConnor RD,
Hamburger RN, Schatz M. Effect of combined maternal and infant
food-allergen avoidance on development of atopy in early infancy:
a randomized study. J Allergy Clin Immunol 1989;84:7289.
71. Oddy WH, Holt PG, Sly PD, Read AW, Landau LI, Stanley FJ,
Kendeall GE, Burton PR. Association between breast feeding and
Primary Prevention of Asthma 71
asthma in 6 year old children: findings of a prospective birth
cohort study. Br Med J [Clin Res] 1999;319:815819.
72. Falth-Magnusson K, Kjellman N-IM. Development of atopic dis-
ease in babies whose mothers were receiving exclusion diet during
pregnancya randomized study. J Allergy Clin Immunol 1987;
80:868875.
73. Falth-Magnusson K, Kjellman N-IM. Allergy prevention by ma-
ternal elimination diet during late pregnancya 5-year follow-up
of a randomized study. J Allergy Clin Immunol 1992;89:709713.
74. Arshad SH, Matthews S, Gant C, Hide DW. Effect of allergen
avoidance on development of allergic disorders in infancy. Lancet
1992;339:14931497.
75. Hide D, Matthews S, Matthews L, Stevens M, Rideout S, Twisel-
ton R, Gant C, Arshad S. Effect of allergen avoidance in infancy
on allergic manifestations at age of two years. J Allergy Clin
Immunol 1994;93:842846.
76. Colloff M, Ayres J, Carswell F, Howarth P, Merrette T, Mitchell
E, Walshaw M, Warner JO, Warner JA, Woodcock A. The control
of allergens of dust mites and domestic pets. Clin Exp Allergy
[Suppl] 1992;22:128.
77. McDonald L, Tovey E. The role of water temperature and laundry
procedures in reducing house dust mite populations and allergen
content of bedding. J Allergy Clin Immunol 1992;90:599608.
78. Becker AB, Chan-Yeung M. Environmental control: an idea
whose time has come. Eur Respir J 1997;10:12031204.
79. Wood R, Chapman M, Adkinson NF, Eggleston P. The effect of
cat removal on allergen content in household-dust samples. J Al-
lergy Clin Immunol 1989;83:730734.
80. De Blay F, Chapman MD, Platts-Mills TAE. Airborne cat allergen
(Fel d l): environmental control with cat in situ. Am Rev Respir
Dis 1991;143:13341339.
81. Watson WTA, Al-Malik SM, Lilley MK, Gillespie CA, Cheang
MA, Simons FER, Becker AB. The association of aeroallergens,
precipitation, and environmental pollutants with emergency room
visits and hospitalizations for asthma on the Canadian prairies. J
Allergy Clin Immunol 1993;91:304.
72 Becker