JO Warner, JA Warner, EA Miles, AC Jones

Abstract

The prevalence of asthma and related allergic disorders has increased considerably over the last 20-30 years. As genetic stock has not changed, environmental factors must have influenced the phenotype. Studies have shown that the key events leading to sensitization and the development of allergic disease are operative early in life. Indeed, our own studies would suggest that primary sensitization frequently occurs in utero. Postnatal allergen exposure then localises the cells to target organs where inflammation develops and disease manifests. The characteristics of the allergic immune response are now clearly elaborated with distinct subclasses of lymphocyte generating a particular set of peptide regulatory factors (cytokines) being pivotal in controlling both the production of immunoglobulin E and the activation of eosinophils and mast cells. Insights into the mechanisms leading to sensitization are beginning to identify therapeutic targets which may in the future reduce the prevalence of allergic disease in a highly cost effective manner. The interventions will include modification of the environment, immune modulation and targeted pharmacotherapy.

Over the last thirty years, we have seen an unprecedented rise in the prevalence of all allergic diseases in many countries around the world. Thus, there has been an increase in the prevalence and severity of allergic disorders and in particular asthma in children, though clear-cut epidemiological evidence to support this has been slow to accumulate, mainly because of lack of an agreed definition of asthma suitable for population surveys. One study from South Wales, using identical ascertainment amongst 12-year olds showed a change in point prevalence between 1973 and 1988 from 4 to 9% for asthma, 5 to 16% for eczema and 9 to 15% for hayfever.¹ This increase has occurred in many countries and has been demonstrated in Finnish military conscripts,² in Taiwanese schoolchildren,³ Australian children⁴ and adolescent Maories in New Zealand.⁵ While diagnostic transfer might account for the increase in some of the studies, it is clearly not the case for the majority.⁶ Furthermore, there have been enormous increases in hospital admissions for childhood asthma over the last 8-10 years with no reduction in severity on admission, no increase in readmission ratio and no evidence of diagnostic transfer.⁷ A relatively small shift in population susceptibility due to changes in the environment could account for the increase in frequency of disease and the even greater increase in numbers experiencing severe disease.

There is no sign that this progressive increase in allergic problems is abating. The International Study for Asthma & Allergy in Children now being applied in many countries round the world is showing further remarkable increases in prevalence which have occurred over the last 5 years. Thus for the UK ISAAC Survey, the cumulative prevalence of wheezing at the age of 12 had reached the dizzy heights of 48%. Wheezing in the last year and receiving treatment for asthma was a staggering 20% of all 13 year olds.⁸ Over the same three decades that allergic disease has increased enormously in prevalence there has, of course, been a progressive increase in our understanding of the immunopathology and a very considerable improvement in the therapeutic options available. One might, therefore, question whether the increase is real or merely due to improved awareness. However, many of the studies quoted above have used identical ascertainments in two consecutive periods strongly indicating that the increases are real. Thus, the key question must be: Why has there been an increase in allergic diseases in most, if not all, countries in the developed world with similar, though more delayed, increases in developing countries?

Genetics

Most of the increases in allergic disease have been observed in communities where there has been no obvious change in genetic stock. Thus the explanations must be environmental. However, it is clear that all atopic diseases have a strong familial tendency. Indeed, detailed family studies of atopy, based on measurement of IgE/IgE antibodies and the detection of positive skin prick tests would suggest a dominant mode of inheritance.⁹ However, penetrance is variable. Even amongst identical twins, concordance for allergic disease may be less than 50%, though the concordance for positive allergy tests may be as high as 85%.¹⁰

In recent years, a number of putative genes have been suggested to be involved in the inheritance of allergy. The first such gene identified was on the long arm of chromosome 11 and has been shown to code for a portion of the high affinity IgE receptor.¹¹ However, many groups have been unable to replicate the original linkage studies,¹² and stronger associations have been found between the inheritance of atopy and a gene or genes associated with the cytokine gene cluster on the long arm of chromosome 5.¹³ This is a much more credible observation as it is clear that cytokines have a pivotal role in influencing the production of IgE. The only way in which an abnormality of the IgE receptor could contribute to atopy, would be if there was a down-regulating effect of receptor activation on IgE production which has hitherto not been identified.

Other potential linkages have been demonstrated in relation to genes coding for the T-cell receptor¹⁴ and those affecting major histocompatibility complex (MHC) molecules.¹⁵ The latter may be associated with susceptibility to sensitization by specific allergens. This has been particularly demonstrated in relation to allergy to minor determinants in ragweed pollen. In our study of house dust mite sensitive asthma, we have failed to find any MHC linkage with allergy. Nevertheless amongst atopic families, we have found an association between a particular MHC haplotype and the absence of allergy.¹⁶ This might suggest that some forms of tissue type are protective against sensitization, presumably because the relevant allergens cannot be appropriately presented to T-lymphocytes.

Some studies have suggested that inheritance of atopy occurs much more strongly through the female line.^9,17 In other words, the maternal influence on atopy in the next generation is far stronger than the paternal effect. This is particularly apparent in the early manifestations of allergy in childhood. This could either be due to genetic imprinting or far more probably, an effect on the intrauterine environment. This would point to a very early life origin for atopy.

The Intrauterine Environment

Most studies of the origin of allergy have concentrated on environmental experience immediately postnatally and have suggested that there is a major effect of allergen and adjuvant exposure in infancy on the development of subsequent allergy and allergic disease. However, it has always been known that even newborn babies can occasionally generate IgE antibodies to specific allergen and, indeed, cord blood total IgE has been suggested as one specific, though insensitive, predictor of subsequent disease.¹⁸ Our studies of a cohort of 150 babies born to atopic asthmatic parents have shown that there are remarkable differences in T-lymphocyte activity at birth which predicts not only the development of subsequent allergic disease but also the specific allergies involved.¹⁹ Thus, newborn babies who have subsequently developed milk- and egg-induced atopic dermatitis have had increased T-lymphocyte proliferative responses on exposure to milk and egg but have additionally failed to generate significant quantities of Interferon-γ (IFN-γ). This lack of IFN-γ production is associated with an increased expression of the intra-cellular message (mRNA) for IL-10. We are now beginning to find similar differences in cord blood T-cells in relation to responses to cat allergen in infants who have subsequently developed cat allergy and recurrent wheezing.

At this point it is, therefore, necessary to elaborate a little on the cytokine influences on allergy. When exposed for the first time to an allergen, antigen presenting cells, phagocytose particles and antigenic proteins are broken down into peptides. These are then re-presented on the surface of the cell in association with MHC molecules. In the case of stimulation of T-helper lymphocytes, this involves MHC class 2 molecules. The molecule is recognised by the T-cell receptor which can then transmit the specific antigenic message to the lymphocyte which then becomes sensitized. The T-lymphocyte, in turn, stimulates B-lymphocytes to produce antibodies specific for the relevant antigen. The intercellular communication is predominantly orchestrated by a range of peptide regulatory factors known as cytokines. The T-lymphocyte releases a wide range of such cytokines which influence the type of antibody produced. The normal immunising response associated with the production of IgG antibodies, and activation of natural killer cell, is orchestrated through a series of cytokines including IFN-γ. However, a type 1 hypersensitivity response with the generation of IgE antibodies is triggered predominantly by IL-4 and IL-13. It has now been shown that there are two sub-types of T-helper lymphocytes designated 1 and 2. One predominantly produce cytokines which orchestrate a normal immunising response, whilst the Th-2 cells release those cytokines which promote an allergic response. IFN-γ down-regulates the effects of IL-4 and, therefore, reduces its effects in increasing IgE production. Conversely, Th2 cells also generate IL-10 which down-regulates the production of IFN-γ, possibly through an intermediary cytokine known as IL-12 which is released from antigen presenting cells. Th-2 cells also generate IL-5 which increases eosinophil production and survival and promotes eosinophil activation, this cell obviously being very important in allergic immunopathology.²⁰ Thus it can be seen that from our studies, the Th-2 response to allergens is already present at birth and predicts the development of subsequent allergic disease. This highlights the issue of intrauterine environment which must have been instrumental in producing an allergic switch-on in some fetuses.

We are now investigating this phenomenon by acquiring blood specimens from very premature deliveries. It is apparent that T-cells become responsive to allergens to which the mother has been exposed either in her diet or by inhalation at between 22 and 24 weeks' gestation. This is much earlier than has hitherto been considered the case. Early in the second trimester from 18 weeks' gestation onwards, it is possible to identify T-lymphocytes which have some degree of response to non-specific stimulation such as with phytohaemagglutinin.²¹ Remarkably, the majority of these cells appear to leak large quantities of IFN-γ even without stimulation. At the same time, the placenta is generating large quantities of IL-4. This is considered to be an important phenomenon in preventing fetal immunological rejection by the mother.²² The presentation of feto-paternal antigens together with IL-4 to the mother will lead to the generation of an allergic rather than immunising and rejecting response. This has led to the suggestion that preservation of pregnancy is an allergic phenomenon. However, this production of IL-4 by the placenta would theoretically make all fetuses allergic. The fact that this is usually not the case might be because of the counteracting effect of spontaneous release of IFN-γ by the fetal cells. We are currently investigating the hypothesis that the early origins of atopy rest with the subtle balance between the fetus, the placenta and the mother. Anything that upsets this interaction might be predicted to increase subsequent atopy. That this is the case in relation to maternal cigarette smoking, would support the overall hypothesis.²³

It is also fascinating to note that variations in maternal nutrition may influence atopy. Fetuses with a rapid growth trajectory due to good maternal nutrition have larger head circumferences at birth. However, many such fetuses are not necessarily of increased birth weight because in the latter stages of pregnancy, placental factors limit the delivery of nutrients needed by the rapidly growing fetus. Under such circumstances, the brain-sparing reflexes produce relative depletion of nutrient delivery to the body resulting in minor aberrations in immune development. It has been shown that babies with larger head circumference subsequently have higher IgE levels, perhaps because the higher nutrient demands of the fetus in later pregnancy lead to an imbalance in the Th-1 and Th-2 activity.²⁴ Such observations might be consistent with the notion that allergic disease is a function of affluence and, therefore, better nutrition.²⁵

Postnatal Environmental Experience

We and others have shown that high concentration aeroallergen exposure in early infancy increases the risk of sensitization and subsequent allergic problems in relation to that allergen.²⁶ Thus, being born at a time of high pollen exposure increases the risk of pollen sensitivity and seasonal symptoms. Possessing a pet such as a cat or a dog in the first year of life, produces a far greater probability of asthma and allergy to the animal dander than if the pet is introduced at any stage beyond 1 year.

For house dust mite, it has even been possible in our prospective studies to identify a lower threshold for exposure below which sensitization is very unlikely to occur. This level is at approximately 0.5 ng of the major house dust mite allergen Der p I/m² area from which the dust is sampled. However we have been unable to identify a lower threshold for sensitization to cat dander, may be because of exposure outside the domestic environment or more likely that the allergen is more potent or able to penetrate further into the respiratory tract because the allergen is on particles of very small size. Nevertheless, we have also shown that the critical time period for sensitization is in the first month of life with relatively less effect from exposure subsequently.

The levels of allergen necessary to produce on-going sensitivity in subsequent disease are rather higher than those producing sensitization. For house dust mite, we have found the critical level to be associated with not only positive skin tests but also wheezing illnesses to be 7 ng of Der p I/m². These figures are somewhat lower, though not too dissimilar, to those that have been suggested by retrospective study in the past.²⁷

It has been possible to demonstrate that high concentration of exposure to house dust mite, animal danders, birch tree pollen and alternaria mould, all increase the risks of subsequent sensitization and the development of disease. However, it is very unclear how adjuvant factors might affect this process. There is little evidence that postnatal environmental tobacco smoke exposure has a significant effect. Furthermore, if anything, living in a highly polluted environment reduces the risk of allergy and allergic disease. This has been well shown in comparison of manifestations of allergic disease and skin test positivity in children in Eastern German Leipzig compared with West German Munich.²⁸ Birth order has a significant effect on allergic manifestations. First born children are at much higher risk of developing allergic problems than subsequent born.²⁹ Putting the observations in relation to pollution together with the birth order effect might suggest that early respiratory infection, more common in babies in polluted cities and in second and subsequent born children in families, might actually protect against allergic sensitization. At an immunological level, a simple explanation might be that infection promotes the generation of IFN-γ which, in turn, down-regulates any allergic sensitizing response.

However, not all pollutants have the same effect. There is some evidence from Japanese studies that diesel particulates might in some circumstances adjuvantise sensitization to cedar tree pollens, and animal studies have suggested that ozone might also promote aeroallergen sensitization.³⁰

Remarkably, despite very high levels of exposure to mould spores, the frequency of mould allergy amongst our UK patients is relatively low. However, this may be because spores are relatively inert and unlikely to release allergenic proteins before they are cleared. It is only in circumstances when hyphal elements are inhaled that allergenic proteins might be released to produce sensitization. This only occurs in relatively drier environments than is the case in the United Kingdom. Thus in the south of France and southern USA, sensitivity to alternaria and other moulds is more common.

These facts facilitate the generation of an equation summarising the sensitization process. The development of aeroallergy is the product of host susceptibility factors which includes genes, age, maternal health, multiplied by the concentration of exposure which is a function not only of levels of allergen in the reservoir but their ability to be aerolised, and the particle size which influences the depth of penetration into the airway, multiplied by the presence of adjuvant factors such as selected pollutants, and the absence of frequent infection in infancy.²⁶

Early Therapeutic Intervention

It is apparent from this equation that whilst we may not be able to influence genes, having identified a susceptible population it may be possible to intervene to reduce the chances of the genotype becoming manifest. Such intervention would of necessity need to commence early in pregnancy with avoidance of environmental tobacco smoke, reduction in allergen exposure and optimisation of maternal health and nutrition. The environmental manipulations would then need to be maintained during the early susceptible period in infancy which may then offer the best opportunity for true prevention. This approach might be considered as a primary prophylaxis.³¹

If, however, the primary approach has failed, then a second target for intervention would be at the point that an allergic phenotype was detectable on immunological testing such as by looking at the T-helper cell cytokine repertoire and then employing some form of immunotherapy. It is conceivable that exposure to antigen in combination with appropriate cytokines might switch an individual from Th-2 to Th-1 responsiveness, thereby preventing the further evolution of the allergic disease. This could still be considered as primary prophylaxis as it occurs before the disease has appeared.³²

For the practising paediatrician, the key to management at present probably rests with secondary prophylaxis. Thus, the early detection of atopic disease at its onset might facilitate strategies of early intervention with pharmacotherapy which will prevent the evolution of atopic disease. There are, for instance, studies which are beginning to show that the use of high potency histamine-1 antagonists, such as Ketotifen and Cetirizine, might prevent the development of asthma in individuals that have atopic dermatitis. This may be because of the effects of antihistamines in preventing eosinophil migration.³³ It is also interesting to note that in vitro Sodium cromoglycate and indeed Nedocromil sodium prevent the gene deletional switch in B-cells induced by IL-4 from IgM to IgE production.³⁴ This would suggest that there may be potential for the administration of drugs which would prevent the generation of IgE even if the T-lymphocytes cannot be switched from Th-2 to Th-1 phenotype.

Once the disease is fully developed, then we only have palliation available. Admittedly the preventive anti-inflammatory therapies can be highly effective and indeed very safe for the management of asthma. However, none of the pharmacotherapeutic approaches have any impact on the natural history of the condition. Furthermore, at the stage that airway inflammation is well established, allergen avoidance in clearly allergic individuals does not achieve cure even if maintained for very long periods such as is the case when children are sent to special institutions at high altitude. Whilst there are improvements for the duration of the allergen avoidance as it is relaxed, the disease relapses.³⁵ Furthermore, the longer the allergy has been present, the less likely avoidance will achieve complete remission. There are very interesting parallels that might be drawn with occupational allergic lung disease. Provided individuals are removed from the allergen exposure early after the development of problems and provided they have no further exposure, they will not have any complications. However if duration of exposure is extended, then even removal from the adverse environment will not cure the condition and asthma will continue with other non-specific factors triggering the problem.³⁶

Conclusions

Asthma and related allergic disorders have their origins in very early life. The best prospects for cure lie in primary prevention and early intervention. Thus, 'The priest continues what the nurse began and thus the child imposes on the man.' (The Hind and the Panther-John Dryden) or perhaps more appropriately for the paediatrician: 'My heart leaps up as I behold a rainbow in the sky. So was it when my life began, so is it now I am a man or let me die. The child is father of the man.' (William Wordsworth).

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