Cohabiting with domestic mites

Transcription

1 Thorax 1993;48:5-9 Cohabiting with domestic mites 5 As lorng ago as 1662 it was realised that the inhalation of dust particles in the air could lead to symptoms now recognised as typical of an allergic reaction. John Baptista van Helmont, a Flemish physician, wrote of one of his patients (a monk): "... as oft as any place is swept or the wind doth otherwise stir up the dust, he presently falls down, being almost choked." Not until the 1960s, however, did Voorhorst et al' and Miyamoto et al2 independently establish that the house dust mite was a major source of allergen in house dust. Miyamoto subsequently showed experimentally that inhaling mite extracts could induce asthmatic symptoms. Identification of domestic mites as the major source of allergens has prompted research to isolate and characterise the allergens concerned, to identify the mechanisms and the timing of sensitisation, and to evaluate measures for mite avoidance. Mites and asthma Studies in different populations have shown that up to 85% of people with atopic asthma but only 5-30% of the nonasthmatic population are skinprick sensitive to mites.' A causal relation between asthma and sensitivity to mites is unproved, but there is considerable evidence to suggest it. Inhalational challenge with mite extracts causes both early and late asthmatic responses, with an accompanying increase in non-specific bronchial reactivity. The introduction of Western style bedding, with high concentrations of mites, in populations previously free of asthma has been associated with a dramatic increase in the incidence of asthma and in mite sensitivity, found in as many as 91 %. A longitudinal study of a cohort of children in England has shown a strong correlation between levels of mite exposure and the subsequent development of bronchial hyperreactivity and asthma.8 This is supported by a study of patients with newly diagnosed asthma, showing that they were exposed to higher concentrations of mites in their homes than were controls.9 Similarly, in New Zealand the assessment of risk factors for the development of asthma has shown that an atopic response to mites represents an independent risk variable.'0 Point prevalence correlations between exposure, sensitivity and asthma have been found in many studies in Europe, North and South America, China, India, Korea, Australia, New Zealand, Brunei, and New Guinea.3 If continued exposure to mites exacerbates asthma a reduction in the level of exposure might be expected to produce a reduction in the expression of symptoms and bronchial reactivity. Sending patients to Alpine sanatoria has long been recognised as a means of reducing asthmatic symptoms, and more recently concentrations of mite allergen have been found to be very low at these altitudes." Subsequently several studies have confirmed that clinical improvement occurs when asthmatic patients are moved to such sites.'2 Similarly, avoidance of allergen associated with admission to hospital has been shown to be related to an improvement in asthma.'3 Whether the use of acaricidal agents to reduce concentrations of mites in the home is beneficial remains controversial, but some studies have shown benefit (see below). Ecology and biology of mites SPECIES With spiders, scorpions, etc, mites belong to the class Arachnida. Their ecology is relatively well described.'""8 At least 50 species have been found in domestic house dust, and in temperate climates the most important, both clinically and numerically, are the mites Dermatophagoides pteronyssinus and D farinae (and its sibling species microceras) of the family Pyroglyphidae. In the last few years it has been suggested that another species, Euroglyphus maynei, may be clinically important Storage mites, such as Acarus spp, Tyrophagus spp, and Glycophagus spp, may be relevant to occupational asthma. In tropical and subtropical regions mites from the genus Blomia have been shown to be clinically important.2'"23 In view of the widening range of mites believed to have important clinical effects, the term "domestic" mites has been proposed.'8 LIFE CYCLE AND PHYSIOLOGY Mites are small and invisible to the naked eye. Identifying species and determining viability may be difficult, but the main morphological characteristics are well described.'4 Mites hatch from eggs and proceed through larval, protonymphal, and tritonymphal stages before reaching adulthood, when they are about 400 gum in length. The average life cycle is three months, during which the female may lay up to 300 eggs. Up to mites may live in one square metre of carpet. Mites feed on desquamated human skin and fungi that grow on the skin scales. Some species of mites (Cheylitidae spp) feed on other mite species,24 but this appears to be of little consequence with respect to controlling mite numbers. Mites have a well developed gastrointestinal tract with digestion and food absorption primarily in the midgut and water resorption in the hindgut.' In the posterior midgut the food is enveloped by a fluid that solidifies to form a peritrophic membrane27 and the resulting food balls later coalesce to be excreted as faecal pellets. These vary in size from 10 to 40 gum and each mite will produce about 20 pellets a day. In contrast to the gastrointestinal system, mites have no specialised respiratory structure and oxygen is obtained by passive diffusion across their cuticle. As a result of this relatively hard but pervious layer they are very sensitive to water loss and are essentially in equilibrium with the atmosphere, the ambient humidity determining their water content. NATURAL FACTORS INFLUENCING DISTRIBUTION AND ABUNDANCE D pteronyssinus and D farinae appear to thrive best at 80% relative humidity and 250C.'4 As the humidity falls, however, they stop reproducing and become immobile, and below 50% relative humidity they are likely to die. Although eggs and protonymphs survive at lower relative humidity the water content of the air still appears to be a factor in the distribution and abundance of mites in the home, and this is reflected in the seasonality associated with mites in some parts of the world. Modern energy efficient housing with air conditioning, reduced ventilation, and heating may also be influencing the abundance, distribution, and seasonality of mite populations. As well as being humidity dependent, mites are photophobic, and these two factors influence their choice of habitat-namely, at the base of carpets; inside mattresses; and in bedding, soft toys, and soft furnishings Mite allergens ALLERGEN IDENTIFICATION AND NOMENCLATURE Patients who are allergic to house dust mites produce

2 6 specific IgE antibodies against various mite allergens. If more than 90% of a population allergic to mites produce IgE antibodies to a specific allergen then it is regarded as a major allergen.28 Although as many as 30 mite allergens have been identified only five or six appear to predominate Most mite allergens are proteins that are soluble in water and are found in the faecal pellets of mites." Immunological, physicochemical, and molecular biological techniques have been used to isolate, characterise, sequence, and clone specific allergens.' This has now been done for several allergens, and with libraries of mite complementary DNA available detailed knowledge of further allergens may be expected. Initially, there was no standard procedure for naming allergens and confusion has occurred as different research groups isolated similar allergens. The International Union of Immunological Societies has issued guidelines for allergen nomenclature and these have been adopted for mite allergens.36 The recommended nomenclature uses the first three letters ofthe genus (for example, Der) followed by the first letter of the species (for example, p) followed by sequential numbering of the allergens in the order in which they were identified. With Dermatophagoides pteronyssinus, for example, the allergens that have been identified and characterised are referred to as Der p I, Der p II, Der p III, and Der p IV. The known Dfarinae equivalents are Derf I, Der f II, and Der f III, and similar allergens from other mite species are put in the same groups (I-IV). There are amino acid sequence homologies of 81% between the group I allergens Der p I and Derf I, of 88% between the group II allergens Der p II and Der f II, and of 75% between the group III allergens Derp III and Derf III.3-39 Although other allergens have been partially characterised, they do not as yet fit into this categorisation.' Monoclonal and polyclonal antibodies to mite allergens have been prepared by several research groups and monoclonal antibodies to group I, II, and III allergens are available.4 42 These antibodies have proved extremely useful not ony for isolating allergens but also for quantifying allergen exposure in the environment. STRUCTURE AND ACTIVITY OF KNOWN ALLERGENS Group I Der p I is a single chain protein containing 222 amino acid residues and has a molecular weight of about daltons.4344 This and the equivalent allergens from D farinae and E maynei have been cloned and found to be cysteine proteases with substantial homology with papain, actinidin, and cathepsin B and H.'47 Cysteine proteases have a cysteine residue in the catalytic site that is analogous to the serine residue found in serine proteases such as trypsin and chymotrypsin. The homology shown by the allergen has been sufficient for a three dimensional structure to be assigned to it, based on the structures of actinidin and papain. Such three dimensional modelling is helping to facilitate the localisation of likely T and B cell epitopes, which are currently being mapped with the help of peptides produced by both chemical and molecular biological techniques.4>50 The group I allergens appear to be associated with faecal particles, which become airborne with domestic activity.53 Because of their size, faecal pellets do not stay airborne for long, and measurable quantities in the air disappear within minutes. Once such particles have landed on a moist surface, such as a mucosal membrane, Der p I and other allergens are leached out within 30 seconds Group II Der p II is a single chain protein containing 129 amino acid Feather, Warner, Holgate, Thompson, Stewart residues and has a molecular weight of about daltons Der p II and Der f II have both been cloned and sequenced, but so far no biological activity has been ascribed to Der p II, though its physicochemical properties strongly suggest it may be lysozyme.56 Currently only B cell epitopes have been described Although group II allergens are thought to be associated with mite bodies there is evidence that they can be found in faecal particles and they have also been detected in the atmosphere after disturbance of dust.5960 Group III The group III allergens, only recently been described, have molecular weights of about daltons.3942 Biochemically they are trypsins and partial amino acid sequences have been reported. Der p III appears to be a major allergen and reacts with the serum of every person allergic to mites.39 Mite extracts have been shown to contain several proteases,6164 including a chymotrypsin and an elastase like enzyme. Chymotrypsin is allergenic but whether the others are is not yet known. Immunoblotting studies, however, indicate that several allergens have similar molecular weights, and this raises the possibility that each is allergenic.35 Recent studies have shown that trypsin activity can also be found in E maynei extracts. Group IV Der p IV is a single chain protein and has a molecular weight of about daltons.65 It is an amylase like enzyme and is recognised by up to 46% of individuals allergic to mites. This enzyme is also found in both D farinae and E maynei extracts.66 BIOCHEMISTRY OF ALLERGENS Interestingly, Der p I is a cysteine protease, Der p III trypsin, and Der p IV amylase. Although this reflects the source of the allergens-namely, the gut-it also raises the possibility that the enzymatic activity of these allergens facilitates their interaction with the host's immune system. This is supported by the observation that enzymatically active Der p I increases the permeability of respiratory epithelium and is able to hydrolise IgG and activate the kallikrein-kinin system. SENSITISATION TO MITE ALLERGENS Domestic mites are found in most inhabited areas. Not everyone in contact with them becomes sensitised, however, and not everyone who is sensitised experiences symptoms of allergic disease. The reasons for this are not clear. The atopic predisposition has a strong genetic component, however: ifone parent is allergic the child has a 50% chance of developing an allergic disease, and if both parents are allergic the proportion rises to 80%.69 Recently the gene putatively responsible for atopy has been reported to be resident on chromosome 11 and to be transmitted in an autosomal dominant fashion.70 Irrespective of the inheritance ofatopy, however, disease of specific organs and expression of symptoms remain highly variable and are likely to depend on a multiplicity of environmental factors, the most important of which is likely to be the level of exposure to the sensitising allergen. Evidence is accumulating that exposure to potential allergens early in life is important. More specifically, the nature of the first allergens encountered, their concentrations, and the timing of the exposure seem fundamental. Sporik et al have shown that the risk of sensitisation relates not only to the intensity of the exposure but also to the timing, the degree of sensitisation at 11 years of age correlating best with the exposure levels documented at 1 year of age.8 Other studies have suggested that the critical

3 Editorials timing might be even earlier. For example, individuals born just before or during the birch pollen season in Scandinavia have a 28% greater chance of developing an allergy to birch pollen than those born after the season, who are therefore not exposed until they are about 9 months old.7' This suggests a vulnerable period in the first three to six months of life. Minimum concentrations of mite allergens causing sensitisation and promoting disease have been proposed. Initial sensitisation has been proposed to occur in a susceptible individual if the concentration of Der p I is above 2 pg/g ofhouse dust.372 A concentration of 10 jg/g of house dust has been proposed as a concentration that triggers episodes of asthma but this has been based on data on concentrations from the homes of patients attending emergency departments.73 As such these values do not signify discrete threshold values, but rather may be useful in identifying populations "at risk" and serving as goals for mite eradication programmes. More recently it has been questioned whether concentrations of allergen measured in settled dust are representative of the concentrations to which people are exposed, and it has been suggested that concentrations of airborne allergen are more likely to correlate with the degree of allergic lung disease. This has been supported by data showing that in a group of asthmatic children living in Greater London 80% of mite sensitive individuals had detectable quantities of airborne Der p I in their homes, whereas in the carpets only 37% had concentrations greater than 2 4ug/g of dust.74 It seems sensible therefore to exercise caution when the use of these thresholds in avoidance studies is being advocated as they may be inappropriate-and, despite the enormous effort required, reducing concentrations to these levels may not be sufficient to prevent sensitisation. It is also obvious that the types of furnishings, the amount of ventilation, and the degree of human activity within the home may all exert an influence on the amounts of allergen to which people are exposed. Despite the inherent problems of preventing sensitisation, investigation of new techniques for reducing allergen should in the first instance prove useful in the treatment of sensitised patients. Mite avoidance as a therapeutic option Currently treatment of asthma is based on various pharmacological agents, ranging from immediate relief of symptoms with the "bronchodilators" to "antiinflammatory" or "preventive" treatment with drugs such as sodium cromoglycate, nedocromil sodium, and inhaled and oral corticosteroids. If, however, allergy to domestic mites has a central role in the development of asthma and the maintenance of the hyperreactive asthmatic state it seems prudent to attempt to reduce exposure to mites in those at risk. Although the benefits of mite avoidance measures have yet to be confirmed in a large, well controlled trial (with respect to reducing both the risk of sensitisation in "at risk" individuals and expression of symptoms in those already sensitised), several strategies for reducing allergen exposure have been tried. These have concentrated primarily on reducing the numbers of mites in bedding or altering the overall environment within the home. Few of these studies have been well controlled, many of them not including a control group and others comparing changes within groups rather than across the control and intervention groups.75 Bedding, soft furnishings and carpets are the areas most heavily colonised by mites, and therefore the main target of avoidance measures. Intervention studies focusing on using bedding materials less conducive to mite colonisation, or using barrier methods to separate the mites from the sleeper, have tended to show some benefit, either in reduced mite allergen concentrations or in the symptoms assessed. The use of liquid nitrogen on bedding has been shown to reduce the numbers of mites substantially, and a modest decrease has also been achieved by the use of electric blankets to reduce the humidity in the bedding materials.7677 In contrast, simple cleaning and vacuuming alone have been shown to be of negligible benefit. The benefit of removing carpets and soft furnishings as an isolated measure is unproved, but should be considered as complementary to the use of alternative bedding materials. An alternative approach is to alter the overall interior of the home to make it less conducive to colonisation by mites. This can be achieved by modification of temperature and humidity. Unfortunately, the environment created by a modern energy efficient home, with central heating and limited ventilation to reduce energy costs, is ideal for the growth and reproduction of mites. To make the environment less suitable for mites the indoor humidity would need to be substantially reduced. In cooler climates, such as that of the United Kingdom, this could be achieved with increased ventilation; but this would be associated with an increase in energy requirements to maintain indoor temperature, which is not environmentally attractive. Heat exchange ventilation systems may offer an alternative. Older dwellings affected by ground moisture would also need modification. The use of acaricidal agents is currently under investigation and in some instances safety and efficacy have yet to be demonstrated. A wider range of products is becoming available and a particular advantage of these is that, in addition to killing mites, some contain agents such as tannic acid that minimise the allergenicity of the offending proteins, providing an almost immediate reduction in allergen exposure.78 Once achieved, however, a lower level of exposure would need to be maintained indefinitely, as any benefit to the sensitised individual would rapidly reverse when he was re-exposed. Studies with acaracides have either shown a reduction in numbers of mites without assessing patients' symptoms or simply failed to reduce mite numbers or diminish symptoms. Woolcock et al have used a commercially available acaricidal agent containing tannic acid to reduced mite numbers and simultaneously found a reduction in the allergenicity of the dust.79 More recently studies from the same group have failed to show benefit in the home80; others, however, have suggested that a higher concentration of tannic acid may be beneficial.8' In this issue of Thorax a further study is reported by Kalra et al,8' where the interventions studied against the control group were liquid nitrogen and an acaricidal agent and the endpoint was measured levels of Der p I. Although both these treatments might be expected to alter numbers of the live mites authors report little or no effect on allergen levels at any of the time points. This study used only a single application and leaves open the question of whether repeated applications of either the acaricide or the liquid nitrogen would be more efficacious. Even if statistically significant reductions in Der p I levels were obtained, however, clinical endpoints such as reduction of symptoms would be needed. The distinction between reducing mite numbers, reducing allergen levels, and reducing expression of symptoms is one of the major difficulties in assessing this work. A change in levels of allergen or numbers of mites must be related to a clinical benefit for these studies to have any real application. Nevertheless, this study does help us to place in some perspective the increasing enthusiasm for these forms of intervention. 7

4 8 Future perspectives Despite problems in the past, immunotherapy may yet prove a useful treatment for allergy to mites. Purification and sequencing of mite related allergens and production of recombinant allergens may increase the efficacy of this mode of treatment. Recently allergen-antibody complex inoculations have produced a minor side effect while producing benefits.83 Immunotherapy has been discouraged, especially in the United Kingdom, because of the risks. Allergen modification and the possibility of selective presentation to the suppressive component of the immune system, without evoking an acute response, makes this form of treatment an interesting and challenging future prospect. In view of past experiences and the special risks posed by asthmatic patients, however, this mode of treatment is likely to remain in specialist centres and be applicable only to a carefully selected subgroup. It is becomingly increasingly clear that the long term goal should be to reduce the level of sensitisation in the population. This seems likely to be achievable by reducing exposure levels from the time of birth for the population at risk. This is not an inconsiderable task and will require considerable modifications to lifestyle. If mite avoidance is practised in the community it will take at least a generation for these benefits to be realised. Equally important, however, is the reduction of exposure of those already sensitised, so that symptom expression and morbidity may be reduced. The route to this ultimate goal of prevention will necessarily include acceptance of new housekeeping practices and new interior and structural housing design, as well as the introduction of new technologies for bedding, acaricidal agents, and measuring assays for allergen in the field. Carefully controlled studies designed to establish the efficacy of mite control measures and the optimal time for their implementation are still required before major changes in lifestyle can be confidently recommended. Conclusions A causal relationship between domestic mites and asthma is strongly suggested but has not been unequivocally proved. The close relationships between mite exposure, mite sensitivity and asthma make it very likely, however, that domestic mites are a major contributor to the development and expression of symptoms in atopic asthma. Asthma is a common disease in our community and the evidence suggests that both its incidence and its severity are increasing. Strategies for dealing with this important cause of morbidity and mortality must be directed to tackling the environmental cause of the problem. Allergy to dust mites is almost certainly one environmental factor that could be modified. A concerted research effort is needed not only to ascertain with confidence the part played by domestic mites in diseases such as asthma, rhinitis, and eczema but also to continue efforts designed to reduce the levels of the mite allergens to which the population is exposed. This will be one of the greatest environmental challenges of preventive medicine in the coming decade, but if effective one that is likely to yield great benefits. I H FEATHER J A WARNER S T HOLGATE Southampton University Faculty of Medicine, Southampton General Hospital, Southampton P J THOMPSON Department of Medicine, University of Western Australia, Perth G A STEWART Western Australian Research Institutefor Child Health, Perth, Australia Reprint requests to: Dr I H Feather, University of Medicine, Southampton General Hospital, Southampton S09 4XY. Feather, Warner, Holgate, Thompson, Stewart 1 Voorhorst R, Spieksma F, Varekamp H, Leupen M, Lyklema A. 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London: Academic Press, 1975: Lind P, Lowenstein H. Identification of allergens in Dermatophagoides pteronyssinus mite body extract by crossed radioimmunoelectrophoresis with two different rabbit antibody pools. ScandJImmunol 1983;17: Krilis S, Baldo BA, Basten A. Antigens and allergens from the common house dust mite Dermatophagoides pteronyssinus. Part II. Identification of the major IgE-binding antigens by crossed radioimmuoelectrophoresis. J Allergy Clin Immunol 1984;74: Baldo BA, Ford SA, Tovey ER. Towards a definition of the complete spectrum and rank order of importance of the allergens from the house dust mite, Dermatophagoides pteronyssinus. In: Allergy and molecular biology. Proceedings of the DPC First International Symposium on Allergy and Molecular Biology. Adv Biosci 1989;74: Tovey ER, Chapman MD, Platts-Mills TA. Mite faeces are a major source of house dust allergens. Nature 1981;289: Stewart GA, Lake FR, Thompson PJ. 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5 Editorials allergen Derf II. Clin Exp Allergy 1991;21: Stewart GA, Ward LD, Simpson RJ, Thompson PJ. The group III allergen from the house dust mite Dermatophagoides pteronyssinus is a trypsin-like enzyme. Immunology 1992;75: Tovey ER, Johnson MC, Roche AL, Cobon GS, Baldo BA. Cloning and sequencing of a cdna expressing a recombinant house dust mite protein that binds human IgE and corresponds to an important low molecular weight allergen (erratum: J Exp Med 1990;171:1387). J Exp Med 1989; 170: Chapman MD, Heymann PW, Wilkins SR, Brown MJ, Platts-Mills TAE. Monoclonal immunoassays for major dust mite (Dermatophagoides) allergens, Der P I and Derf I, and quantitative analysis of the allergen content of mite and house dust extracts. J Allergy Clin Immunol 1987;80: Heymann PW, Chapman MD, Aalberse RC, Fox JW, Platts-Mills TAE. Antigenic and structural analysis of group II allergens (Derf II and Der p II) from house dust mites (Dermatophagoides spp). 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