Antigen-specific Treatment

Prior to 1900 there was already clear evidence that patients with asthma had eosinophils, Charcot-Leyden crystals and Curschmann’s spirals in their sputum. These findings left little doubt that there was an inflammatory component to this lung disease. Evidence about the role of allergens as a trigger factor for asthma was also reported in the last century, and, in 1921, Kern reported that a large proportion of patients with chronic asthma had positive skin tests to dust from their own house.

However, neither the importance of allergens nor the inflammatory nature of asthma was widely accepted. Over the past 15 years three major developments have strongly supported the view that indoor allergens are an important cause of asthma. These are:

1. epidemiological evidence that a large proportion of children with perennial asthma have immediate hypersensitivity to one or more of the now well-defined indoor allergens;

2. experimental evidence that allergen challenge of the lung can produce eosinophil-rich inflammation and that avoidance can decrease both bronchial hyper-reactivity (BHR) and inflammation; and

3. biopsy studies that have demonstrated ‘inflammation’ in the lungs of even mild asthmatics.

In parallel with these developments, there have been many studies reporting increases in asthma. One could estimate that three-quarters of the children who have asthma today would not have had symptoms in 1960. Thus we appear to be studying a moving target in which there is a progressive increase in the number of children who have ‘eosinophilic bronchitis’, have positive skin test to common allergens and are presenting with symptoms of wheezing. The rationale for allergen-specific treatment is that allergens play a major role in the chronic inflammation which now seems to be undoubted. However, there are several simple questions that are directly relevant to allergen-specific treatment but to which we do not have clear answers.

1. If the patients are allergic to indoor allergens, what role does current exposure play in symptoms?

2. Has exposure to allergens in houses increased sufficiently to explain the increase in asthma?

3. Has there been an increase in the number of allergic individuals, or an increase in wheezing among the allergic individuals? If there has been an increase in ‘wheezing’ among allergic individuals, does this reflect increased inflammation or some other change in the physiology of the lung?

In this chapter we will discuss the role of allergen exposure in asthma and then address three different approaches to allergen-specific treatment. Although these approaches are distinct, in each case the results have, or would have, implications relevant both to the treatment and understanding of the causes of asthma.

Increased Exposure to Allergens and Increased Asthma

Allergen avoidance as a treatment strategy for patients presenting with symptoms is focused almost entirely on indoor allergens. This assumes that current exposure inside houses is contributing to inflammation and wheezing (the word current means within the last few days or weeks). Indirectly, the strategy assumes that much of the increase in asthma has been related to increasing exposure to indoor allergens. Epidemic increase in asthma first became clear in 1972 and the evidence during the 1970s related to mite-allergic children.

When considered in 1980, it seemed likely that the major changes in houses that had occurred in the U.K. between 1960 and 1975 could have increased mite allergens sufficiently to increase asthma prevalence and severity. Since then the argument has become more complicated. The prevalence of asthma has continued to increase in countries where dust mites are important but there does not appear to have been any significant change in housing since 1975.

In addition, increases in asthma have been observed in countries where dust mite antigens are not relevant. Interestingly, in Finland, and probably also in Sweden, asthma prevalence started to increase around 1960, even though the increase was not reported until about 1990. The most remarkable feature of the epidemic that has been documented in Scandinavia, the U.K. and Australia is that prevalence has risen almost continuously from about 1960, and still appears to be increasing in the 1990s.

In those areas where (because of low humidity), dust mites are not important, sensitization to other indoor allergens has been associated with asthma. In Scandinavia and the mountain states of the U.S.A., cats and dogs appear to be the primary source of allergens; by contrast, in the large cities of the U.S.A., sensitization to allergens derived from the German cockroach is strongly associated with asthma. The only allergen derived from outdoor sources that has been associated with perennial asthma is the fungus Alternaria. There is a problem with Alternaria in that it is difficult to measure fungal antigens accurately. We do not know what form Alternaria is inhaled in, i.e. hyphae or spores, and we cannot answer whether exposure is predominantly indoors or outdoors.

Although it seems certain that inhalation of allergens has played an important role in asthma, it seems very unlikely that progressive increases in several different allergens have occurred in parallel. Furthermore, repeated measurement of dust mite allergens in 70 British houses over the period 1979-1990 did not demonstrate an increase. Thus, increases in the concentration of allergens in house dust are no longer an adequate explanation.

In order to explain the epidemic we need to identify some other change that has occurred progressively over the last 30 years and has acted predominantly on allergic individuals. The change that we are looking for appears to be a feature of Western society, since asthma is still rare among children living a traditional rural life in Africa, Papua New Guinea or Australia. The adoption of a Western life-style and the changes in the Western world since 1960 include many closely interrelated changes.

These changes can be broadly divided into three groups: changes that have (or could have) increased the quantities of house dust-derived allergens that are inhaled; changes that could have systematically altered the immune or inflammatory response to allergens; and the complex effects associated with increasing sedentary entertainment (Table What Has Really Changed). There are a variety of well-defined enhancers that have been shown to increase the inflammatory response to allergens (e.g. ozone, rhinovirus infection, β₂ agonists, endotoxin and diesel particulates) (Figure Sensitizers, enhancers and triggers for asthma).

However, none of these has been shown to have increased in sufficient places or to have increased progressively over 30 years. Our objective over the last 20 years in studying the role of allergens in asthma has been both to understand the disease and to develop specific treatments. However, if, as now seems likely, there are other changes in life-style, etc. that are acting non-specifically to increase asthma, it may not be surprising that treatment is less than fully effective. Furthermore, one would predict that the incomplete response to treatment would be observed equally with allergen avoidance, immunotherapy and pharmacotherapy.

Table What Has Really Changed — 1960-1997

* Changes that have been progressive.

Allergen Avoidance as an Anti-Inflammatory Treatment

If asthma is an inflammatory disease and inhalation of allergens is an important cause of the inflammation, then reducing exposure is the logical first line of anti-inflammatory treatment. The new asthma treatment guidelines recommend that all patients with persistent asthma should be tested for sensitization and given education about reducing exposure to relevant allergens. The bulk of the evidence in favour of this view relates to dust mite-allergic individuals and the protocols for reducing exposure to the debris of these Acarids are well defined. Decreased non-specific bronchial reactivity has been documented both with avoidance in a hospital setting, in a sanatorium and also in patients’ houses. Furthermore, studies on mite-allergic children at Misurina in the Dolomites have demonstrated progressive decreases in eosinophils and eosinophil-derived proteins in induced sputum during periods of time in a mite-free environment.

The question remains as to whether it is possible to decrease cat or cockroach allergens in a dwelling. The primary method for reducing exposure to cat allergen is to remove the animal or at least to keep it outside the house. However, a large proportion of cat-allergic patients will refuse to remove the animal. In these cases it is reasonable to recommend alternatives. From experimental studies, a protocol including removing carpets, washing the cat weekly and room air filtration has been recommended. Despite different results related to washing, two groups have recently reported good clinical results with this protocol.

Clearly, more work is needed. Reducing the level of cockroach allergen in a home has not been studied extensively, but effective control requires considerable effort on the part of the family. Obsessional cleaning, enclosure of all food and, if possible, control of water supplies are essential. Without controlling food supplies bait stations will have little effect because the insects are not hungry. In a recent, controlled trial among inner city children it became clear that the measures proposed were effective for controlling mite allergens but did not consistently decrease cockroach allergens. Among the 59 children who were studied in detail over one year, 29 were allergic to dust mites and were exposed to high levels of dust mite allergen. Among these 29 children decreased acute visits for asthma correlated significantly with decrease in dust mite allergen concentration (p< 0.02).

If the increase in asthma prevalence was really a result of increased quantities of allergen in houses then one could predict that decreasing exposure would be very effective. Although highly significant improvement in symptoms and bronchial hyper-reactivity can be achieved, avoidance measures are not ‘fully effective.’ Furthermore, avoidance studies in houses are not as consistently effective as moving children to high-altitude sanatoria. In part, this may reflect the practical problems of decreasing allergens in the home. The alternative is that the regime in the sanatoria is beneficial in other ways. Thus the conclusion is that, while avoidance measures for mite are a primary part of the treatment of asthma, the results do not show that avoidance measures alone will provide effective treatment. For other allergens there is still a need for detailed studies to define the correct measures and the best method of convincing patients to carry out these protocols.

Discussion

We appear to be in the middle of an epidemic of symptomatic eosinophilic bronchitis. The scale of the epidemic is very disturbing: in many areas a prevalence of 4-8% has been reported, but in some areas >15% of school-age children have been prescribed inhalers. This is for a disease that was rare in the last century and probably had a prevalence < 1% prior to 1950. Any approach to treatment based on specific antigens assumes that we understand the role of allergen exposure in the disease.

However, it is clear that there are many different points in the immunopathogenesis of the disease where changes other than increased exposure could have had an effect on prevalence or severity (Figure Sensitizers, enhancers and triggers for asthma, Table What Has Really Changed — 1960-1997). One of the major practical issues is whether the primary effect of allergens occurs in very early childhood. If exposure in the first two years is critical, then clearly avoidance measures would be most effective at that period of life.

In our prospective study of asthma in the U.K., the concentration of mite allergen in the child’s bedroom at age 1-2 years correlated with early onset of asthma. Skin tests and serum antibodies were not detectable until age 3 years or greater. In the first two years of life almost all children are infected with respiratory syncytial virus (RSV). It has been suggested that the response to RSV dictates the subsequent immune response to allergen. It seems more likely that response to respiratory syncytial virus indicates the form of response the child is going to make to allergens. Another recent study reported an inverse relationship between delayed skin test responses induced by BCG immunization and the development of atopy.

However, that study is also best interpreted as showing that the immune response to BCG demonstrates the potential of the children, rather than suggesting that BCG immunization can alter the response. That early exposure to allergens may play an important role is suggested both by prospective data and by results showing that the month of birth influences the immune response to allergens. It is still difficult to answer whether early exposure is a major determinant, but studies to address this issue are in progress. Some individuals develop immune response including IgE Ab and Th2 cells later in life and present with intrinsic asthma.

What controls immune responses of this kind in adults is not clear. There are no convincing data on the genetics of intrinsic disease or of chronic sinusitis. Both diseases are eosinophilic but neither has a strong relationship to a family history of atopic disease. It is more likely that these responses occur because of persistent exposure to a foreign antigen. In adult life the antigen is generally not an inhaled allergen. On the other hand, it is clear that immune responses with a Th2 or Th0 phenotype are a cardinal feature of asthma in all age groups.

What is the link between an immune response giving rise to IL-5 or other cytokines that can induce local eosinophilia and symptomatic asthma? At present we have very little insight into why some allergic individuals have asthma, while others who appear to be equally allergic have no disease. It is easy to speculate about differences in airborne exposure; about the details of the inflammatory response in the lung; the rate of healing of the response; or some physiological difference in the lung. The allergen exposure data explain patterns of sensitization but have not provided a clear answer about symptoms.

Knowing both the sensitization and concentration of the relevant allergen still does not allow accurate prediction of symptoms. More important, we still do not have sufficient data to answer whether the increase in asthma symptoms reflects an increase in the number of allergic individuals or an increase in inflammation among atopic individuals. In native communities living in villages, asthma remains rare or very rare. In Ethiopia and Kenya, recent studies have confirmed very low rates of asthma among children and adults living a rural life.

Similarly, in the villages of New Guinea, asthma is almost non-existent among children. The epidemic of asthma in New Guinea was restricted to a small area of the highlands and was only among adults. In each of these areas, some of the asymptomatic people have positive skin tests; however, it is not known whether they have inflammation in their lungs.

In the United States there are separate geographical and socio-economic groups who have different allergen exposure. In each area the sensitization of asthmatics reflects the mean level of allergen in the patients’ houses. Thus, in Los Alamos, the houses contain high levels of cat and dog allergen, and sensitization to these allergens is the dominant association with asthma. Among children living in inner city apartments in the north-east the combination of cockroach sensitization and exposure (in their bedrooms) is an important predictor of hospitalization among asthmatic children. In central Virginia and also in Atlanta, dust mite group I allergen is present in ≥80% of the houses and sensitization to mites was the dominant association with asthma. These results clearly support the view that exposure to indoor allergens is causally related to asthma.

However, paradoxically, the fact that high prevalence of asthma is associated with three separate allergens is one of the reasons why it now seems very unlikely that increasing exposure to indoor allergens is the main cause of the world-wide increase in asthma. Given progressive increases over a 30-year period it is extremely unlikely that three or more separate allergens have increased in parallel, or that the increases have been sufficient to explain the scale of the phenomenon.

In 1997 many aspects of asthma are much better understood than they were at the time of the First International Conference on Asthma in 1972. In particular, the nature of the immune response and the related inflammation has been defined. This is important because it firmly establishes asthma as an immunological disease for which by far the best defined foreign antigens are those that make up house dust. Thus, logically, indoor allergen avoidance or reducing other sources of antigen such as fungal infection are first-line treatments for asthma. However, it is clear that many other factors can make a major contribution to the severity of symptoms.

Conclusions

Taking one step back from the present situation, it is necessary to ask why so many different treatments appear to be necessary for a disease that was not previously a major problem? The implication is either that the treatments are all slightly off the mark, or, put another way, that the real cause of the increase in asthma is not being addressed. Thus, we have the enigma of an allergic/immunological disease where the causes are increasingly well defined and which is increasing in prevalence and probably morbidity, but where the real cause of the increase is not clear. Thus, it is essential to continue thinking about all the steps that contribute to symptoms, i.e. inducers, enhancers and triggers (Figure Sensitizers, enhancers and triggers for asthma). In turn, it is necessary to consider the changes that have happened in Western society over the past 30 years, and are happening today in many developing countries. Analysis of the changes leads to three main hypotheses.

1. Exposure to indoor allergens has increased because of changes in houses that both improve conditions for production of allergens, increase the reservoirs in the house and decrease ventilation. In addition, exposure has increased because of increased time indoors.

2. Changes in diet, including increased sodium, decreased fish, decreased fresh vegetables and increased excess calories, have changed the immune response. The hypothesis is that children raised in this way are more prone to make immune and inflammatory responses to inhalant allergens and consequently develop asthma. Thus, this hypothesis would propose a positive interaction between increased exposure and increased responsiveness.

3. The secondary effects of increased indoor/sedentary entertainment have altered the physiological response of the lungs. Indoor entertainment increases the amount of time indoors with resulting increased exposure to house dust. At the same time there is a major decrease in the amount of time spent in playing, walking or exercising outdoors. While it is possible that prolonged time spent sitting is directly harmful to the lungs, it seems more likely that prolonged ‘normal’ breathing as in walking or outdoor play have a protective effect against wheezing.

What is clear is that in Western society, where children have increasingly stopped traditional outdoor exercise (i.e. play), receive broad-spectrum antibiotics every time they have a fever and live on an increasingly preserved and artificially coloured diet, a very large proportion of the children are complaining of breathing symptoms that induce their doctors to treat them with a variety of inhaled and oral medicines. It seems that it should be simple to reverse the progress of the last 30 years; however, at the moment, progress appears to be winning. Despite some encouraging changes in hospitalization and mortality data, the prevalence of asthma may still be rising.

Albuterol

Epinephrine

Metaproterenol

Cortisone

Prednisone

John Buducci

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