Dust Mite Allergens: Mitigation and Control
Director, Research & Development
C.B.F. LETI, S.A.
Abstract
In recent years greater attention has been given to the role of indoor
allergens as a cause of sensitization and allergic respiratory diseases.
Although indoor allergen control measures to reduce symptoms in individuals
allergic to mites have produced controversial results, environmental allergen
avoidance is today one of the 4 primary goals of asthma management recommended
in several guidelines of asthma treatment. Exposure to high indoor aeroallergen
levels, especially to house dust mite allergens, is an important environmental
risk factor for allergic sensitization and the subsequent development and
exacerbation of asthma. Therefore, effective aeroallergen avoidance is of use
to prevent and treat allergic diseases.
Although endotoxin exposure may
be protective in early life, it has been demonstrated that the inhalation of
endotoxin may exacerbate asthma in house dust mite sensitized patients with established. Mite allergic asthmatic patients should
be aware of the dangerous combination of mite allergen exposure associated with
high endotoxin levels in house dust. These two immunologically active
substances have been associated with severe asthma and seasonal exacerbation of
symptoms.
Effective house dust mite allergen avoidance will
never be achieved using a single control measure; various methods are required
to affect the multiple factors which facilitate high indoor allergen levels.
Education of the patients and their family is also important component of
environmental control strategies.
Introduction
Asthma morbidity and mortality has increased over the past 2 decades in
all age groups but especially in children residing in inner city apartments in
the USA, where hygiene conditions could be less than desirable. The prevalence
of asthma is increasing in both, the USA and Europe. These changes have been
too rapid to be associated with genetic modifications and, apparently, this
increment cannot be attributed to variations in diagnostic criteria. The
reasons for this trend may include inappropriate medication use, poor access to
quality medical care and environmental factors, such as increased exposure to
indoor and outdoor pollutants and environmental allergen exposure. There is also emerging evidence
that exposure early in life to endotoxin may drive the development of the
immune system away from the Th2-mediated allergy and asthma phenotype. The “Hygiene Hypothesis” proposes that overcrowding and unhygienic
contacts in early life may protect from atopic diseases by facilitating
exposure to microbes[1]. Studies
have recently shown that among subjects exposed early in life to other children
at home, or at day care, the risk of wheezing steadily declined with age to
levels significantly lower than controls. A lower prevalence of atopic
sensitization among children raised in farms has also been reported[2].
However,
it has also been demonstrated that asthmatic individuals allergic to house dust
mites when exposed to endotoxin and (1-3)-b-D-glucans experience an
exacerbation of their clinical symptoms of asthma[3],[4],[5].
Daycare centers may also contain detectable levels indoor allergens, such as
cat, and a recent study has shown high mite allergen levels in daycare centers
in Florida[6].
Sensitization to indoor
aeroallergens is more important for the development of asthma than
sensitization to outdoor allergens. Studies have shown that the risk for development
of asthma is greater in children who live in homes with high mite allergen
levels during the first year of life[7].
Moreover, at higher levels of exposure, children develop more severe and
earlier symptoms. Recently, a study of children living at high altitude with
low levels of house dust mite allergens failed to demonstrate any significant
decrease in the development of asthma[8].
In these areas, where house dust mite concentrations are low, asthma and airway
hyperresponsiveness tend to better correlate with sensitization to pets[9]
and molds[10],[11].
A meta-analysis has recently attempted to determine
whether mite sensitive asthmatics benefit from measures designed to reduce
their exposure to dust mite allergen in homes[12].
It concluded that current chemical and physical methods aimed at reducing
exposure to dust mite allergens seem to be ineffective and cannot be
recommended for mite sensitive asthmatics. Only 4 of 23 trials achieved a
reduction in mites/allergen levels and were sufficiently long to show an effect
on outcomes and showed evidence of clinical benefit[13].
Allergen avoidance for children should begin as early
as possible, even before birth, especially if one of the parents is allergic.
Some studies suggest that avoidance of ingested and inhaled allergens and
tobacco smoke delay the onset of allergy and allergy associated diseases,
including asthma[14],[15].
It has also been shown that admission of dust mite sensitive asthmatics to a
hospital with low mite allergen levels decreases bronchial hyperreactivity[16].
A
pronounced improvement in nonspecific airways responsiveness has also been
shown after allergen avoidance, suggesting a reduction in airway inflammation
following avoidance of aeroallergens[17],[18],[19].
Although indoor allergen control measures to reduce
symptoms in individuals allergic to mites have produced controversial results,
environmental allergen avoidance is today one of the 4 primary goals of asthma
management recommended in several guidelines of asthma treatment. Exposure to
high indoor aeroallergen levels, especially to house dust mite allergens, is an
important environmental risk factor for allergic sensitization and the
subsequent development and exacerbation of asthma. Therefore, effective
aeroallergen avoidance is of use to prevent and treat allergic diseases. This
subject has been reviewed extensively in recent publications[20],[21],[22].
House dust mite and asthma
In 1921, Kern[23]
reported an association between asthma and house dust sensitization. However,
it was not until the 1960s when the importance of house dust mites of the genus
Dermatophagoides was established as
the main source of house dust allergens in Holland[24]
and in Japan[25]. House dust
is the main reservoir of indoor allergens. It is comprised of a variety of
inorganic and organic matter, the latter of which includes fibers, mold spores
and debris, bacteria, pollen grains, insects and insect feces, mammalian
danders, and mites and mite feces.
The term "indoor allergen" applies to a
variety of allergens, which occur within human dwellings. Indoor allergens are
byproducts of living organisms such as cats, dogs and other pets, as well as
insects, molds, bacteria and mites. Allergenic substances can be found in most
familiar and occupational environments. Immunochemical methods have been
developed to identify and estimate their concentrations in the air and in
settled dust[26],[27].
These techniques help to understand the natural distribution of airborne, or
settled indoor allergens and determine concentrations, which are associated
with sensitization, or allergic respiratory symptoms.
In recent years, homes have been carpeted, heated,
cooled and/or humidified to make them more energy efficient, which has provided
an ideal habitat for dust mites and cockroaches, and mold and bacteria in air
conditioning ducts. These all play a role in sensitizing home dwellers, in
particular, those with an atopic background. The adjuvant effect of some
bacterial products, such as endotoxins must also be considered.
House dust mites are the main source of indoor
allergens worldwide. Allergic
asthma, rhinitis and conjunctivitis, diseases caused by sensitization and
exposure to airborne allergens, have been associated with the inhalation of
house dust mite allergens. Symptoms produced by the inhalation of house dust
allergens vary from mild irritation to severe bronchoconstriction, or
incapacitating disease. It has been estimated that 40-80% of all the asthmatic
individuals are sensitized to one or more of these house dust allergens. In
tropical and subtropical climates, sensitization to several species of mites in
asthmatic children can be greater than 90%[28].
High specific IgE titers to mite, cat and cockroach allergens are also highly
prevalent among asthmatic individuals treated in emergency rooms in the
southeastern United States and the
Caribbean[29],[30],[31],[32].
The association between exposure to some allergens and
symptoms may be obvious, especially with cats and other mammalian species.
However, the association between exposure to house dust mites and symptoms is
not as clear. Even so, many house dust allergic individuals with perennial
allergic rhinitis and or asthma note exacerbation of symptoms while exposed to
house dust. Exacerbation of atopic dermatitis (eczema) has also been associated
with sensitization to house dust mites. The World Health Organization has recognized
house dust mite allergy as a universal health problem[33].
The clinical importance and major health and economic problems caused by these
tiny arthropods far outweigh their size.
There is
good evidence that sensitization to house dust mites is a major independent
risk factor for asthma in all areas where climate is conducive to support mite
population growth[34],[35],[36].
For other allergens, the relationship depends mainly on the climate, and
socio-economic characteristics of the community. It has been demonstrated that
there is a significant dose-response relationship between exposure to mite
allergens and subsequent sensitization[37],[38],[39].
Another important consideration is that many important mite allergens are
potent enzymes. A recent study has suggested that exposure
to house dust mite antigen can induce airway epithelial shedding even in
subjects with low eosinophil airway infiltration, thus supporting the idea that
epithelial damage in asthmatics sensitized to Dermatophagoides may be due to a proteolytic activity of the mite
allergens[40].
Mites and ticks comprise a large group of arthropods belonging to the
subclass Acari of the class Arachnida. They are distinguished from insects
because the adult stage has four pairs of legs. Mites vary considerably in their anatomy and habitat; some feed
on plants while others have developed complex parasitic relationships with
other animals. More than 30,000 species have been identified. Their life cycle
consists of egg, larvae, one to three nymphal stages and adult stage. Their
digestive system is completely developed and produces spherical fecal pellets
measuring 10-40 µm in diameter. They lack a closed body fluid circuit and their
respiration is cutaneous with the skin serving as a barrier through which both
gas and water vapor are exchanged.
The order Astigmata is divided into two suborder,
Acaridia and Soroptidia (parasitic mites). Generally, all the Astigmata mites,
which in the adult stage live in association with insects, vertebrate, or other
animals, are included in the suborder Acaridia. Free-living Astigmata commonly
occur in decaying organic matter and in nests of birds, insects, and mammals.
Many of these mites infest stored foods and certain species are of economical
importance because they may inflict serious damage to stored grains. Several
species in this group are capable of producing IgE mediated respiratory
allergic diseases and contact dermatitis and have heteromorphic deutonynphs
(hypopus) which invade hair follicles or subcutaneous tissues of mammals or
birds and cause cutaneous reactions. It has been estimated that 34 genera of 10
families of the order Astigmata can be found in stored products and/or house
dust[41].
The family Pyroglyphidae consists of
47 species in 17 genera. Most live in nests of birds and small mammals but 11
species in 5 different genera are found in house and mattress dust of which Dermatophagoides pteronyssinus (Figure 1), D.
farinae and Euroglyphus maynei are
the most important.
Storage mites normally inhabit stored food and hay and
require abundant food and humidity for survival. The most common species belong
to the genera Tyrophagus, Tyreophagus, Glycyphagus, Acarus, Lepidoglyphus, Chortoglyphus, Carpoglyphus,
Aleuroglyphus, Suidasia, Blomia and Tarsonemus. These mites usually found in
stored grain, barns, hay and straw, have also been identified in house dust.
Allergic rhinitis, contact dermatitis, urticaria and asthma have been
associated with storage mites. Another mite species, which seems to be of
clinical importance, is Blomia tropicalis.
B. tropicalis is a domestic mite
commonly found in tropical and subtropical environments. B. tropicalis can be considered as a mite of clinical importance,
especially in tropical and subtropical countries, where this mite is endemic,[42],[43]. House dust and storage mites that are found
in house dust have received the denomination of domestic mites. Recently, mites
have also been implicated in several cases of idiopathic anaphylaxis in mite
allergic patients after eating mite infested foods. These facts extend the
scope of environmental control beyond house dust and it is recommended that
flour, or any other material susceptible of being contaminated with mites,
should be kept refrigerated[44],[45].
Mites feed on human and animal skin scales and can be found in carpets,
on floors, in mattresses, pillows, overstuffed furniture, soft toys[46],
clothing[47],
human scalps[48] and stored
food40. The relative humidity (RH) is the most important abiotic
factor influencing the reproduction, survival, geographical distribution and
seasonal fluctuations of domestic mites. The water loss of the mite body
conditions colonization and population growth. House dust mites are capable of
extracting water vapor from unsaturated air by means of a hygroscopic salt
solution in the supracoxal gland. This can only happen if the absolute indoor
humidity is above 7-8 g/m3 (equivalent to approximately 50% relative
humidity at 20ş C). If the humidity falls below this critical level, the salts
crystallize, block the entrance of the gland and slow down the rate of
dehydration. At lower humidity, they dehydrate and die. The process of water
uptake also depends on the temperature. D.
farinae maintains water balance and survives at relative humidities of about
45% at 25ş C, and 65% at 30ş C. This ability to survive at relative humidities
below saturation accounts for their successful colonization of human dwellings.
Since house dust mites cannot regulate internal body temperature, at low
temperatures egg production and population growth declines and mortality rates
and the duration of the life cycle increases. Altitude also effects their
survival, but this is due to the effects of altitude on temperature and
humidity rather than the altitude itself. In Switzerland and France, above
1,200 meters, the numbers and species of mites decrease due to lower
temperatures and absolute humidity. Mite allergic asthmatics transferred to
such high altitude environments have shown clear and objective signs of
improvement[49]. This
latter study clearly shows that allergen avoidance in asthmatic children not
only decreases nonspecific bronchial hyperresponsiveness, but also decreases
allergen sensitivity, late allergen-induced bronchial reactions, and
enhancement of bronchial hyperreactivity by allergen challenge.
Although house dust mites are considered perennial
allergens, marked seasonal variations in house dust populations do exist. The
abundance of house dust mites in homes in temperate regions exhibit a seasonal
change, with the peak occurring during the summer and the lowest density during
the late winter months. Several studies in the United States have demonstrated
a seasonal rise in mite numbers, which correlated with increases in humidity,[50],[51].
These studies, conducted in Ohio and Virginia have demonstrated an increase in
mite numbers and mite allergen levels during the summer months. Mite allergen
levels were determined monthly for one year in 12 homes in Central Virginia.
This study demonstrated that more than twenty fold variations in allergen
content can occur in house dust samples collected in various sites in homes of
allergic or not allergic individuals. Mite allergen levels started to increase
in July and from August to December, allergen levels were significantly higher
than in April to May. This study also demonstrated that mite allergen levels
remained high even after a decline in the mite population, especially in sofas.
Arlian et al. studied 5 homes in Ohio and demonstrated that seasonal
fluctuations in mite numbers were significantly correlated with the changes in
relative humidity (p < 0.01). Mite population declined during the fall and
was lowest during December through April. Based on this data, it seems logical
that the winter and early spring are the best times of the year to aggressively
clean mattress and carpets to kill the few mites which survived the late fall
and winter and reduce the chances of a large infestation during the summer
months. To the best of my knowledge no studies have contemplated the convenience
of introducing aggressive environmental control measures depending on the month
of the year and the life cycle of the mite population in the home.
Theoretically, the efficacy of acaricides would be better when treating a
smaller population of mites in the carpet.
Mite allergens are present in mite bodies, secreta and
excreta. It has been demonstrated that mite faeces are an important source of
allergens and that 95% of the allergen accumulated in mite cultures is derived
from fecal particles[52].
The nature of the exposure causing airway disease is not clear in many cases,
but, in the case of mites, it has been proposed that relatively small numbers
of intact or fragmented fecal (mite) particles may enter the respiratory tract
during sleep and, occasionally, during routine household activities[53],[54].
Bronchial lavage fluid obtained from individuals living in environments with
high Der p 1 concentrations in settled dust (above 10 µg/gm) contained
detectable but low concentration of this allergen (0.17 ± 0.03 ng/ml)[55].
There is good evidence that settled dust levels above 2 µg/g are associated
with sensitization in children, although lower levels have also been proposed.
In the last years,
several mite allergens have been purified by conventional methods or produced
as recombinant proteins. Sequence similarity searches have identified the
biological function of many cloned allergens. Mite allergens are grouped based
on heir chronological characterization or homology with Dermatophagoides allergens. A list of these allergens is shown in
Table 1.
The Group 1 contains
25 kDa glycoproteins with sequence homology and thiol protease function similar
to the enzymes papain, bromelain, ficin, actinidin and cathepsin H and B
(19-21). Der p 1 and Der f 1 have a 81% sequence homology.
Group 1 allergens are cysteine proteases, which can cleave the low affinity IgE
receptor (CD23) from the surface of human B cell lymphocytes[56].
This receptor is also present on eosinophils, follicular dendritic cells,
macrophages and platelets. Because soluble CD23 promotes IgE production, it is
hypothesized that fragments of CD23 released by Der p 1 may enhance IgE synthesis. It has also been suggested that Der p
1 cleaves the a subunit of the IL-2 receptor (IL-2R or CD25) from the surface of human
peripheral blood T cells and, as a result, these cells show markedly diminished
proliferation and interferon g
secretion in response to potent stimulation by anti-CD3 antibody[57].
The authors conclude that since IL-2R is pivotal for the propagation of Th1
cells, its cleavage by Der p 1 may consequently bias the immune response
towards Th2 cells. The cleavage of CD23 and CD25 by Der p 1 enhances its
allergenicity by creating an allergic microenvironment[58].
More recent studies have demonstrated that the
proteolytic activity of the major dust mite allergen Der p 1 enhances the IgE
antibody response to bystander antigens. It has been suggested that the
cysteine protease activity of the major dust mite allergen Der p 1 seems to
selectively enhance the immunoglobulin E antibody response and that the
proteolytic activity of the major mite allergen Der p 1 conditions T cells to
produce more IL-4 and less IFN-gamma[59],[60].
Other group 1 allergens include Eur m 1 from E. maynei, Der s 1 from D. siboney and Der m 1 from D. microceras.
Endotoxin and house dust
mite allergens
Microbial organisms present in house dust may
induce pulmonary and systemic symptoms upon inhalation. Bacterial
lipopolysaccharide is a major component of the outer membrane of gram-negative
bacteria, responsible for toxic manifestations of severe gram negative
infections and generalized inflammation. Animal studies have suggested that the
effects of endotoxin may be mediated via proinflammatory cytokines, such as
interleukin 6, TNF-a and INF-g. Macrophages exposed to picogram quantities of
endotoxin produce TNF-a, IL-1 and IL-6 and platelet activating factor
(PAF). These potent mediators activate other immune effector cells. Endotoxin
are also potent adjuvants for humoral and cellular immunity. After a primary
exposure, a subsequent exposure to inflammatory agents can cause a ten-fold
greater release of inflammatory mediators. After inhalation, endotoxin causes
an airway response and an increase in airway responsiveness[61].
Inhaled endotoxin produces a dose-related bronchoconstriction which develops 4
to 6 hours after exposure, which is more accentuated among patients with
hyperresponsive airways. Michel et al. showed that endotoxin and not dust mite
antigen levels correlated with severity of asthma[62],[63].
The article by Rizzo et al.3, which evaluated endotoxin and Der p 1
exposure in asthmatic children in Sao Paolo, Brasil is agreement with these
studies. The highest endotoxin levels were detected in
January and November, whereas the lowest levels were detected in April and
August (p < 0.05), demonstrating a distinct seasonal distribution. The
highest Der p 1 levels in bedding were observed in July and the lowest in
February (p < 0.05). Symptom and medication scores were evaluated monthly in
the group of asthmatic children. There was a significant correlation (p <
0.05, r = 0.63) between clinical symptom scores and ET exposure, however no
significant correlation was found for mite exposure (p > 0.05, r = 0.19).
The results suggested that ET exposure exacerbates asthmatic symptoms in mite
allergic, asthmatic children.
Endotoxin exposure may be
protective in early life, but a risk factor later on in patients with established disease and sensitized to house dust mites. Mite allergic asthmatic patients need to
be aware of the dangerous combination of high mite allergen levels associated
with high endotoxin levels in house dust. The presence of these to two
immunologically active substances has been shown to be associated with severe
asthma and seasonal exacerbation of symptoms. The strongest predictor of
endotoxin levels in homes is the presence of a dog[64].
High levels of Dermatophagoides species
are not strong predictors[65]
and it seems that they are mutually exclusive since house dust mite cultures do
not contain high levels of endotoxin. However, reported mold and the use of
cool mist humidifiers has been associated with increased endotoxin levels[66],
whereas the use of dehumidifiers is associated with decreased endotoxin levels
in family room air64. Cigarette smoke does also contain high levels
of endotoxin[67]. Two very
good review articles have been published recently on the subject of endotoxin,
allergy and asthma[68],[69].
Since
the frequency and severity of asthma in both atopic children and adults
correlates with home dampness and endotoxin concentrations in house dust, environmental control
measures should aim at a reduction of mite numbers and endotoxin levels in
homes. Based on the above mentioned studies, it is clear that a reduction in
humidity throughout the home, the use of dehumidifiers, which have shown
efficacy in reducing mite numbers[70],[71],
the removal of carpets and other dust reservoirs, the proper covering of
mattresses and pillows, washing bed linen and blankets in hot water and
prohibiting cigarette smoking in the home would have an effect on mite numbers
and endotoxin levels. Other factors such the seasonal variations in endotoxin
levels, the use of disinfectants to prevent colonization of gram negative
Bacteria, the identification of the main sources of endotoxins, indoors or
outdoors, and the understanding of ways by which they are dispersed into the
air need to be further evaluated.
Environmental control of indoor allergens is currently a controversial
subject, especially after the publication of the Cochrane meta-analysis. It is
increasingly evident that allergen avoidance is becoming more species specific.
What works for mites may not necessarily mean that it works for cats or
cockroaches. The methods for the prevention and control of indoor allergens
have not been adequately evaluated, and in most cases there are no approved
standards for the majority of suspected allergens, or adjuvants. Additional
information is needed about the dynamics of production of indoor allergens,
decay rates, and environmental factors that promote or create the sources of
indoor allergens. Environmental control depends on such knowledge.
Determination of the threshold concentrations that cause symptoms and
sensitization is needed to devise and evaluate control methods. Each indoor
environment is unique, and indoor allergen levels may vary from room to room.
Therefore recommendations on environmental control measures are usually
incomplete and less effective without a thorough investigation of the entire
building. Repairing humidity problems also seem of critical importance.
Allergen avoidance trials have been conducted almost
entirely with patients who are allergic to house dust mites. Positive trials
have involved moving patients to isolated environments with very low mite
allergen levels. Trials involving the modification of home environments have
been less consistent[72],[73].
Trials differ considerably in methodology and therefore, it is difficult to
group them and evaluate a given strategy in a reproducible manner. Trials,
which achieved mite or mite allergen reduction demonstrated improvements in
either asthma symptoms or airway hyperresponsiveness. In other trials, mite
allergen levels were not reduced significantly and symptoms were unchanged.
Successful studies on dust avoidance have used rigid avoidance measures
in bedrooms, including removal of carpets, covering of mattresses, and regular
washing of bedding in hot water. A successful mite control program should
combine the killing of mites and the removal, immobilization, or denaturation
of mite allergens throughout the house and it should achieve and maintain a
major reduction in allergen levels and be sufficiently long to have an adequate
effect. Studies have shown that high mite allergens concentrations are present
in sofas and carpets outside the bedroom, and that allergen levels remain high
throughout the year. Therefore, house dust mite control should include all the
rooms of the home and a thorough cleaning of the sofas. At present, the
reduction of dust mite allergen level required to achieve clinical improvement
has not been determined, although a significant reductions is needed. Effective
house dust mite allergen avoidance will never be achieved using a single control
measure; various methods are required to affect the multiple factors which
facilitate high indoor allergen levels. Education of the patients and their
family, also seems an important component of environmental control strategies[74].
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