MITE ALLERGY IN ASTHMA - THE ROLE OF MITE CONTROL

INTRODUCTION: Allergy or Atopy refers to a type of immune response that approximately 30% of children have. It is mediated through a subpopulation of T Helper Lymphocytes (TH2) which form certain soluble factors (cytokines) when activated by specific antigen. This in turn leads to cellular activity including inflammation associated with accumulation of eosinophils, basophils and mast cells and the formation of Immunoglobulin E class antibodies by B Lymphocytes. This immune response occurs in relation to certain stereotypic antigens or allergens including foods (food sensitivity in children occurs primarily in the first few years of life with 6 or 7 foods creating 60 - 80% of the sensitivities) and later (around age 3), aeroallergens, a progression termed the allergic march. The aeroallergens include mites, danders, pollens and moulds. In experimental challenge situations, it can be shown that challenge of individuals who have asthma and are allergic, will lead to accumulation of eosinophils and other inflammatory components in the airways. Asthma is thought to result from this inflammation in the lower respiratory airways and allergic rhinitis from inflammation in the upper airways.

In this review, I will first cite data that supports the role of allergy in pediatric asthma and then the data that supports a role for mite sensitivity. The data very strongly suggests that mite sensitivity can aggravate asthma although there is still controversy as to whether allergy, including mite sensitivity is capable of creating asthma. It has been suggested that reduction in contact of mite-sensitive asthmatics with mite allergen can lead to a decrease in the level of asthma and therefore a reduction in the need for medication. I will review some of the data that suggests this result. For many years, it has been suggested that by doing mite control in bedrooms, there can be improvement in mite-allergic patients with asthma. I will review more recent data that have examined this question in controlled studies.

It must be remembered that it is not possible in humans to fulfill Koch's postulates to prove the role of mite allergy in asthma, that is, it is not ethically possible to try to create the disease in human subjects to prove that mite allergy causes asthma. The animal models for asthma are not very good so that most asthma studies are done in humans. Many studies take the form of epidemiologic evaluation of populations to show a relationship between allergy and asthma using regression analysis which examines the strength of association between a particular factor (such as mite sensitivity) and the outcome measure, in this case, asthma. Such studies can never prove causality no matter how strong the association even thought epidemiologists would like to believe that a strong association suggests causality. The main problem with those studies is inadvertent bias in the population selected for study. Other studies are cross-sectional controlled studies to again examine relationships and finally, there are limited inhalent challenge studies. There are also recent controlled studies examining whether mite avoidance, particularly in bedrooms is associated with improvement in asthma. It can take many years to definitively answer a clinical question and often the conclusions are dependent on the "weight of evidence" or in modern terminology the "Level of Evidence".

ALLERGY IN ASTHMA

We found that the level of asthma grade in patients selected from an outpatient department at the Hospital for Sick Children, Toronto was related to the "dose of allergy" that is, the more allergic the asthmatic child was, the higher the grade of asthma as assessed by the amount and type of medication required for their treatment.  Zimmerman 1988 These findings have been confirmed by other investigators Sarpong 1998  Posonby 2002 Celedon 2002  but not all  Siroux 2003.

EVIDENCE SUPPORTING ROLE OF MITE ALLERGY IN ASTHMA:

EPIDEMIOLOGIC STUDIES:

Peat et al. hypothesised that if there were an important relationship between mite allergy and childhood asthma, the concentration of mites in the subjects' homes should correlate with the severity of the asthma. Peat 1996. They found a direct relationship between the severity of asthma in this cohort and their exposure to dust mites. They suggested that reducing contact with mites should improve asthma. However not all studies have shown a direct relationship between the concentration of mites in homes and the severity or prevalence of asthma.

Sporik and co-workers followed a cohort of British children at risk for allergic disease because of family history, prospectively from 1978 to 1989 to examine the relation between exposure to the house-dust mite allergen, Der p I and the development of sensitization and asthma. The numbers of patients followed were small (67) and only some of them became allergic (35), but they measured dust mites in the environment of the infants and concluded early childhood exposure to house-dust mite allergens was an important determinant of the subsequent development of asthma. Children with exposure to higher levels of mites were more likely to become sensitized and develop asthma. Sporik 1990  Arshad et al. recruited infants born into high risk families to study the effect of allergen avoidance on the development of asthma. They followed 58 subjects in the avoidance group and 62 controls and found that strict allergen avoidance in infancy in high risk children reduced the development of allergic sensitisation to house dust mite. This seemed to also reduce the risk of asthma although the data in that respect was not as strong. Arshad 2003

Other investigators have not been able to demonstrate a similar relationship between high dust mite level in the bedrooms of infants and the development of asthma later in childhood. Burr 1993 Carter 2003 Cole Johnson 2004  Cole Johnson followed a larger number of children than Sporik and in many respects the design of their study was similar. They could not find a relationship between mite allergen levels in the environment of infants at high risk for atopy and asthma and the later development of asthma and cast doubt on this relationship. At the time of the Sporik study, it was widely felt to be strong evidence for the causal role of mite sensitivity in the development of atopic asthma in childhood. The more recent studies make the association less likely.

In fact other population studies have concluded that the relationship between mite allergen sensitivity may not be causal for childhood asthma although the sensitivity can aggravate established asthma. The relationship between allergen sensitivity and the development of asthma was examined in the German multicentre allergy study. 1314 newborn infants were enrolled in five German cities in 1990, and follow-up data at age 7 years were available for 939 children (72%). There was a strong association between sensitisation to mite or cat allergens and wheezing, which became significant at 3 years of age. The sensitization to mite did not seem to create asthma but later in life there was a significant association between mite allergy and childhood asthma. Furthermore, children with sensitisation to indoor allergens showed higher bronchial responsiveness (ie, a steeper dose response slope) at age 7 years than those without sensitisation (median dose-response slope 15·3 [IQR 7·7-47·8] vs 9·2 [4·9-16·5], p<0·0001). Indoor allergen exposure was strongly related to specific sensitisation at age 3-7 years; however, at 7 years, this effect was more pronounced for mite allergens than for cat allergens. Lau 2000  These investigators concluded that "sensitisation to indoor allergens was associated with asthma, wheeze and increased bronchial responsiveness". However, no relationship between early indoor allergen exposure and the prevalence of asthma, wheeze and bronchial responsiveness was seen. They suggested that "while there is a relationship between sensitization to indoor allergens and childhood asthma, this sensitivity is not clearly causal." Lau 2002 This study has been criticized for the low levels of mites in the homes of the subjects followed suggesting an association between mite allergen and onset of asthma could have been missed in this population. However, the study by Cole Johnson and co-workers, included higher average levels of mites in the study homes, also failed to find a relationship between high mite levels in infant bedrooms and the later development of asthma.

Brunekreef et al. initiated a Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort study in 1996. Children born to allergic mothers were enrolled in a double-blind placebo-controlled trial for evaluating the use of mite-impermeable mattress and pillow covers (855 subjects) vs a control "natural history" population (3291 subjects). They found that that the intervention measure had a significant effect on mite-allergen levels, without important clinical benefits up to age 2 years old. However it is well known that pre-school children often suffer viral-induced asthma that they "outgrow" as they become older provided they do not become atopic. This study, which is ongoing, will become more interesting as the children age and declare themselves allergic. It will then be possible to determine whether reduction in mite levels in the intervention group, reduced the level of allergic sensitivity to mites and whether that in turn reduces the level of asthma in the population. Brunekreef 2002  They did find that allergic families lived in homes with fewer 'triggers' such as pets, smoking and carpets than the non-allergic families, regardless of the intervention. This suggests that allergic parents institute allergen avoidance in the home. This represents a potential bias that must always be kept in mind in population studies for example in studies examining the relationship between animals in the home and the development of allergy to the pets. It has been suggested that having a pet in the home of an infant can reduce the likelihood of the child becoming sensitized to the animal. However this same Dutch Investigation group actually showed that families where the mother is allergic have lower levels of cat allergen in the home. van Strien 2002  and therefore children with a familial risk for allergy might be selectively part of a population that does not keep pets.

Thus, while it seems clear that sensitivity and exposure to dust mites can be associated with asthma, it is not clear that exposure to mites actually induces the asthma.

A cross-sectional study was performed by Miraglia Del Giudice et.al on 1426 children attending at a Pediatric Asthma and Allergy Center at the University of Naples. They found that 629 (44%) were atopic and 769 (56%) were not atopic. Asthma occured in the same proportion of atopic and non-atopic children (64%) but there was a significant age difference in the non-atopic asthmatics and the atopic asthmatics with the former being younger than the latter. Children less than age 3 were significantly more non-atopic than atopic while older children (around age 7) were significantly more atopic than non-atopic. There was a significant association of sensitivity to house dust mite and asthma in the older group (odds ratio 4.8). Miraglia Del Giudice 2002 Because of the cross-sectional nature of this study and the fact that the patients were selected from referrals to a clinic, there is a high likelihood of selection bias but the results were similar to several epidemiologic studies that have demonstrated that young pre-school children with asthma are less likely to be allergic than older children. Moreover if the young children remain non-allergic, they have a high likelihood of outgrowing the asthma. see Preschool asthma pages

AIRWAY HYPERREACTIVITY AND PULMONARY FUNCTION IN RELATION TO MITE SENSITIVITY:

Ernst et al. reported a prospective study of Montreal school children, examining the determinants of bronchial hyperreactivity according to the child's pubertal status; 156 male children and 168 female children without a prior diagnosis of asthma were followed for an average of 4.6 yrs. The major determinant of BHR was a positive skin test to dust-mite antigen. Ernst 2002  Similar results had been reported from the Dunedin cohort. Skin-test reactions to house dust mite and cat were strongly correlated with any degree of measurable airway responsiveness (PC20 FEV1 < or = 25 mg/ml) in children with rhinitis (P<0.00001), and remained significantly correlated even in children without current asthma, without asthma ever and without rhinitis (P<0.001). Atopy was a major determinant of airway hyperresponsiveness in children, not only in those with reported histories of asthma and wheezing, but also in the absence of any history suggesting asthma and rhinitis. Sears 1993  Sherrill had previously examined various aspects of lung function and atopy in the same cohort of New Zealand children. 696 children were followed from age 9 - 15. Atopic status was assessed at age 13 by skin-prick testing to 11 allergens. In children demonstrating airway hyperresponsiveness, FEV1 increased with age at a slower rate, and the FEV1/VC ratio had a faster rate of decline through childhood, compared to non-responsive children. Subjects with positive skin tests to house dust mite and cat dander also had lower mean FEV1/VC ratios than the control group. Any reported wheezing was associated with slower growth of FEV1 and VC in males. They concluded that in New Zealand children with airway responsiveness and/or atopy to house dust mite or cat, growth of spirometric lung function was impaired. Sherrill 1992 The data suggested that there was a clear relationship between airway hyperreactivity and other lung function abnormalities in allergic children especially when allergic to house dust mites. A Dutch study related seasonal variation in dust mite concentrations in living rooms and bedrooms and reported that seasonal increases in the concentration of mites was associated with seasonal increases in airway hyperreactivity. van der Heide 1997

The studies cited are only a few of the many studies that show a relationship between sensitization to house dust mite (and othe indoor perennial allergens) and asthma in children. In contrast there is general agreement between the studies that sensitization to outdoor allergens such as the pollens is not related to asthma in children. Moreover there is a relationship between the concentration of mites in the home with the likelihood of sensitization and this occurs more commonly in more allergic children as determined by the total number of positive skin tests. This was nicely shown in the CAMP study (Childrens' Asthma Management Program) which is a study following treatment outcomes in children with asthma over time.  Huss 2001  However this leads to the question of whether control of house dust mites in the environment of allergic children can either prevent or reduce the level of their asthma.

ALLERGEN AVOIDANCE AND ASTHMA:  STUDIES AT HIGH ALTITUDE

A series of studies were published in which children allergic to dust mites and living in a coastal area of Britain were moved to an asthma research institute in the Italian Alps where there were no mites present. The studies showed that the children had improvement in their symtoms and objective measures of asthma while living at high altitude as well as a decrease in their need for asthma medication. When they returned to their homes at sea-level the asthma recurred.   Boner 1985 Peroni 1994 Piacentini 1996. Similar results were reported from a Swiss Asthma center: Simon 1994  and a Dutch Asthma Center in Davos, Switzerland: examining markers of inflammation. van Velzen 1996 and clinical and inflammatory markers of asthma. Grootendorst 2001. It could be argued that while these studies support the idea that environmental control can reduce asthma, there might be other factors involved apart from reduction of dust mite levels.

Moreover even if it seems that allergen avoidance at high altitude reduces the level of asthma in mite allergic children, the question remains whether doing dust mite control in bedrooms can achieve the same effect. The first question concerns whether mite impermeable barriers on mattresses and pillows can reduce the level of mite antigen in the bedroom. Most studies find that the techniques recommended for mite control in bedrooms do reduce the concentration of mite allergen in the room. The next question concerns whether reducing the level of allergen in the bedroom can influence aspects of clinical sensitivity and clinical asthma. Arshad et al. in a European multicentre study of allergy (SPACE) examined whether allergy control measures in the bedrooms of children age 5 -7 years could reduce the further sensitization to mites. The children were all atopic but not sensitized to mites at the onset of the study. The study was blind-controlled with 127 children in the active reduction group and 117 children in the placebo reduction group. At the end of 1 year significantly more children had become sensitized to mites in the control group compared to the active reduction group. Arshad 2002 Similarly in the same European Multicentre study examined the question of whether mite control in the environment of infants at risk for allergy could prevent sensitization to mites. They found that the sensitization rate to a panel of aero- and food allergens could be effectively decreased through the use of impermeable mattress encasings and the implementation of easy-to-perform preventive measures. Halmerbauer 2003 The European study had three arms, with school-aged children, preschool children and infants. In the same study performed with toddlers and preschoolers (mean age 3.1 years), it was found that simple mite prevention techniques (a combination of education and mite impermeable barriers) sigificantly reduced sensitization to mites over the course of 1 year of follow-up. Tsitoura 2002 The study also suggested a reduction in clinical allergic disease, including asthma in the group with the dust mite prevention procedures. The problem with these studies done after 1 year of follow-up is the small number of subjects who became mite sensitive in that period of time. The results for 2 year follow-up have been published for the infants and they are much less encouraging. Mite avoidance did not show a protective effect on the development of sensitization to mites or symptomatic allergy in children at age 24 months. Horak 2004

DUST MITE CONTROL MEASURES - DO THEY IMPROVE ASTHMA?

More recently, much larger and more properly controlled studies have been performed and almost uniformly, these studies failed to find a positive effect of dust mite control interventions. Luczynska et al. performed a blind controlled trial comparing dust mite barrier covers versus sham control covers in the bedrooms of mite allergic patients with asthma and dust mite antigen in their bedrooms. They randomized 30 subjects to the mite covers and 25 to the sham covers and followed the subjects for 12 months. There was no effect on peak flow or asthma symptoms in a simple comparison of the treatment and placebo groups. The results suggested that using a bed cover as a single mite control procedure was ineffective. However the study has been criticized because although there was a significant fall in mite antigen concentration in the active group, at the end of the study there was no difference in the mite concentration in the bedrooms of the active versus control subjects, where there should have been higher levels.  Luczynska 2003  Woodcock et al also recruited subjects into a randomized control trial of mite impermeable bed covers. The primary outcomes were morning peak flows and reduction in steroid usage of 560 patients in each group of whom 366 were mite allergic. The subjects were followed over the course of 12 months. There was no difference between the active intervention group versus the control group. They concluded that the use of mite impervious covers as a single intervention was ineffective in adult asthmatics.  Woodcock 2003

Mite Control: Studies in Children

There are two blind controlled studies in children done by two groups of good investigators. The studies both showed a decrease in mite levels in the bedroom but the study by Frederick et al.   1997  (31 mite sensitive asthmatic children monitoring mite antigen levels before and after covering the mattress, duvet and pillow with active and placebo covers for 3 months, in a single-blind, cross-over trial) found no effect on the clinical asthma. However a second study by Halken et al.   2003  (prospective, double-blind, placebo-controlled study 60 children (age range, 6-15 years) with asthma and mite allergy were randomized to active (allergy control) or placebo mattress and pillow encasings, followed every 3 months for a year) found that significantly more of the children in the treated group were able to reduce their inhaled steroid usage by 50% or more compared to the controls.

Both of these studies can be faulted for the same reason i.e. the relatively small number of subjects involved. Until a larger number of patients are studied in a multi-centered trial, it is not possible to decide which answer is correct. However the Fredrick trial was only 3 months in length compared to a year for the Halken study and was single blind. The positive result on reduction in inhaled steroid was not seen in the Halken study until the ninth month of study. The Halken trial was double-blinded and was a stronger trial than the Fredrikson but because of the small number of patients, cannot be considered a definitive answer. The outcome of mite control in the bedroom of children could be different from adults since that allergic inflammation in the airways of asthmatic children seems more prominent than in adults and allergy seems to play a greater role in children than adults.

Conclusions

The Dutch group Rijssenbeek editorial review has concluded

1. that the use of anti-allergic dust mite covers as a solo intervention in allergic asthma does not result in clinical benefit.
2. there can be exposure to large amounts of mite allergen during the day in other parts of the environment.
3. the extremely low levels of dust mites exposure at high altitude can not be achieved at sea-level
4. allergic asthma is influenced by factors other than mite exposure, including other allergens, viruses and air pollution
5. in more advanced stages of asthma there can already be structural changes in the airways which will not be influenced by mite control and can result in failure of this treatment modality

Tom Platts-Mills who is a worker who has been strongly identified with studies on the role of mite sensitivity in asthma,  2004 has concluded that effective avoidance requires both education and a comprehensive protocol. Platts-Mills is critical of even the more recent larger multi-centred trials of mite control suggesting that the problem with the studies is that such things as entry criteria are not rigorously enforced the way that a drug-company trial of medication would be. This leads to outcomes that are not correct.

RECOMMENDATIONS: I would suggest that these authors are too emotionally invested in the belief that mite control must be a helpful procedure in allergic asthma since it is so logical. However nature's logic is not always the same as ours. It is possible that mite control, especially in the bedroom may not be helpful in the management of childhood allergic asthma. However at this point I would still recommend rigorous mite control in the bedroom in mite allergic, asthmatic children since the study by Halken et al. did achieve an outcome that would be clinically desirable i.e. a reduction in the amount of inhaled steroid needed to treat the children. BUT if a larger controlled trial fails to confirm those results, then it is time to move on, much as we would like to believe that if nature would just behave the way we think is logical, life would be a lot more sensible.