Asthma: Prevalence, Pathogenesis, and Prospects for Novel Therapies

The prevalence of asthma has increased sharply in the United States and around the world in the past 30 years. In the United States, data from the National Health Interview Survey show that the annual prevalence of asthma increased from 3.1% in 1980 to 5.4% in 1994.¹ A review of studies performed in 17 countries during the 1960s and repeated in the 1990s confirms an international increase in asthma prevalence.² Although the increasing prevalence of asthma is a global phenomenon, the scope of the problem differs greatly among countries. The International Study of Asthma and Allergies in Childhood, which examined the prevalence of asthma in 56 different countries in the 1990s, found that prevalence ranged from 2% to 3% in Eastern Europe, Indonesia, Greece, Uzbekistan, India, and Ethiopia to 20% in the United Kingdom, Australia, and New Zealand.³ The finding that affluent countries have higher asthma prevalence rates than poor countries has prompted speculation about the effects of affluence, modernization, or "western lifestyle" on risk factors for asthma.

Until very recently, asthma mortality has risen in conjunction with increasing prevalence. Mortality data from 10 countries from the mid-1970s to the mid-1980s uniformly demonstrated increasing mortality.² In the United States, asthma mortality more than doubled from 8 per 1 million population in 1977 to 20 per 1 million in 1989.⁴ Notably, asthma mortality disproportionately affects certain segments of US society. African Americans have higher age-adjusted asthma mortality than whites (38.5 vs 15.1 per 1 million in 1993-1995) and more numerous emergency department visits and hospitalizations for asthma.¹ In Hispanic populations, asthma mortality is high among those of Puerto Rican heritage (40.1 per 1 million), but not those of Cuban or Mexican heritage (15.8 and 9.2 per 1 million, respectively).⁵ It is not known whether high mortality among African Americans and Puerto Rican Americans relates solely to societal factors (access to education, health care, medications, or insurance) or whether specific environmental or genetic influences differentially affect these ethnic groups. Fortunately, for reasons that are unclear, overall asthma mortality in the United States stabilized at 20 to 21 per 1 million persons between 1989 and 1997.⁴

Concepts of asthma pathogenesis have changed significantly during the past 10 to 15 years. Current hypotheses propose that asthma results from the combined effects of allergic airway inflammation and dysfunction of airway smooth muscle. The central effector cell of airway inflammation in asthma is considered to be the CD4⁺ T lymphocyte (Figure 1). Specifically, a subset of CD4⁺ T cells called T helper 2 (T_H2) cells, identified based on their secretion of specific cytokines that include interleukin (IL)-4, IL-5, IL-9, and IL-13, is being studied.⁶ These cytokines promote eosinophil growth, migration, and activation, as well as mast cell differentiation and IgE production. They are therefore considered candidate mediators of pathologic and functional abnormalities in asthma. Genes for these cytokines cluster in the same locus on chromosome 5 (5q31), a region consistently associated with asthma in linkage studies.⁷ Furthermore, transgenic mice that overexpress these cytokines usually exhibit airway hyperresponsiveness and have airway pathology that is remarkably similar to the characteristic pathology of asthma.⁸ For all of these reasons, the T_H2 subset of CD4⁺ T cells is currently placed at the center of mechanistic schemes for asthma,⁹ and T_H2 cells and their cytokine products are considered important therapeutic targets.

Another subset of CD4⁺ T cells, T helper 1 (T_H1), secrete cytokines such as interferon gamma (IFN-γ) and IL-12 that counteract T_H2-associated cytokines and attenuate allergic inflammation. Thus, T_H1 and T_H2 cells may be thought of as striking a balance. The "T_H2 hypothesis" holds that an imbalance in favor of T_H2 cells leads to allergic inflammation and asthma.⁹ This imbalance may develop in infancy. In utero, the developing immune system appears to have an intrinsic bias toward T_H2 immune responses.¹⁰ In early infancy, normal immune development is thought to involve conversion to T_H1 responses and the development of tolerance to environmental allergens.¹¹ During this critical period, exposure to allergens or infectious agents might influence the development of irreversible T_H2 or T_H1 polarized responses, respectively. It has been found that IL-4 and IL-10 are important mediators of T_H2 differentiation, whereas IL-12 is an important mediator of T_H1 differentiation.¹²

Based on this understanding of asthma pathogenesis, researchers have proposed hypotheses regarding the increase in asthma prevalence that focus on events occurring during early childhood. One hypothesis is that increased allergen exposure in early childhood might predispose an individual to allergic sensitization and asthma. This hypothesis is supported by studies showing a positive relationship between the development of asthma and household exposure to aeroallergens, such as house dust mite and Alternaria,¹³ cat dander,¹⁴ or cockroach allergens.¹⁵ However, the data are not consistent. One study found an association between allergen exposure and allergen sensitization but no association between sensitization and asthma.¹⁶ Another study found that high exposure to cats at an early age protects against asthma.¹⁷ Therefore, although exposure to aeroallergens in early life is a risk factor for allergen sensitization, it may not be a risk factor for asthma. This question is being further examined in ongoing prospective studies of indoor allergen avoidance for the prevention of asthma.¹⁸

Another theory that might explain the global increase in asthma is the "hygiene hypothesis," first formulated by Strachan in 1989.¹⁹ Proponents of the hygiene hypothesis posit an inverse relationship between infections early in life and allergic diseases. According to this hypothesis, the global increase in asthma may stem from societal changes such as smaller family size, improved household hygiene, vaccinations, and the use of antibiotics. These changes may decrease childhood exposure to infectious diseases, which are thought to promote T_H1 immune responses during critical periods of immune development in early childhood. This hypothesis has support from studies that show lower asthma prevalence in children at increased risk for infections (eg, children who have multiple older siblings or attend day care) and studies that show an inverse relationship between asthma and a history of BCG vaccination or childhood infection with hepatitis A or pertussis.^{20 - 21}

Exposure to microbial pathogens in childhood even in the absence of infection may be sufficient to confer protection against allergic diseases.²² This refinement of the hygiene hypothesis is supported by data showing lower asthma prevalence in children who are raised on a farm. The observed lower prevalence in these children may be due to high exposure to endotoxin or other bacterial components.²³ Although the evidence in support of the hygiene hypothesis is compelling, not all epidemiologic studies are supportive. In some studies, vaccination with BCG or a history of measles in childhood has not been associated with a lower prevalence of asthma.²⁴

Therapeutic strategies based on inhibiting T_H2 cytokine activity or on redirecting aberrant T_H2 responses to allergen to a more normal T_H1 response are emerging (Figure 1). For example, a monoclonal antibody against IL-5 that inhibits the activity of T_H2 cytokines has been developed and studied in human asthma. Surprisingly, although anti–IL-5 had immediate and long-lasting effects in reducing blood eosinophils after allergen challenge in subjects with asthma, it had no effect on allergen-induced bronchoconstriction.²⁵ These findings suggest that reducing eosinophils may not be an effective treatment for asthma.²⁶ Questions raised by the lack of efficacy of anti–IL-5 in this laboratory model of asthma (allergen challenge) may be resolved by data from a recently completed clinical trial of the effects of anti–IL-5 on asthma symptoms and pulmonary function.

A different strategy has been used to inhibit IL-4. Recombinant human receptor for IL-4 (IL-4R) is the soluble, extracellular portion of the full-length human receptor for IL-4; it binds and inactivates naturally occurring IL-4 without causing cell activation. A preliminary short-term study of a single dose of nebulized IL-4R in patients with moderate asthma showed efficacy in preventing asthma symptoms when steroid treatment was withdrawn.²⁷ Long-term studies of this strategy are awaited.

Since an important biological function of IL-4 is promotion of IgE isotype switching in B cells, a recombinant humanized monoclonal antibody also has been developed against IgE itself (rhuMAb-E25). RhuMAb-E25 administration neutralizes and eliminates free circulating IgE and any IgE dissociating from cell surface receptors. In this way, rhuMAb-E25 gradually disarms mast cells and basophils, and should prevent IgE-dependent allergic reactions. Because rhuMAb-E25 binds IgE at the same site normally recognized by IgE receptors, IgE already bound to receptors on mast cells and basophils cannot simultaneously be bound by rhuMAb-E25; therefore, mast cells and basophils cannot be activated by rhuMAb-E25. Treatment with rhuMAb-E25 has resulted in significant attenuation of both the early- and late-phase responses to allergen inhalation in bronchoprovocation studies^{28 - 29} and also improved asthma symptoms, exacerbations, and steroid requirements in a clinical trial.³⁰ However, rhuMAb-E25 has not been shown to improve airway obstruction as measured by forced expiratory volume in 1 second (FEV₁).³⁰ Thus, although rhuMAb-E25 may soon become available as a once- or twice-monthly subcutaneously administered treatment for asthma, the place and cost-effectiveness of this novel strategy relative to currently available asthma treatments will take several more years to determine.

Treatment strategies that are designed to redirect aberrant T_H2 responses are less well developed but have the potential to achieve long-lasting or even curative effects in asthma. One approach has been to administer IL-12 in an attempt to inhibit T_H2 and promote T_H1 immune responses. When IL-12 was tested in patients with asthma, the only evidence that its administration had any effect on T-cell subtypes was a reduction in blood eosinophils.³¹ However, the reduction in eosinophils was not accompanied by any effect on airway responses to inhaled allergen.³¹ In addition, IL-12 treatment was associated with significant adverse effects.

Other strategies to direct T cells away from allergic responses may be more effective and less toxic. Allergen immunotherapy may involve promotion of T_H1 polarized responses³² ; this action could explain why the beneficial effects of immunotherapy in allergic rhinitis can last for years after treatment is stopped.³³ Although immunotherapy is not as effective in asthma as in allergic rhinitis,³⁴ improving immunotherapy so that it is more immunogenic and less allergenic may render it more effective in asthma. Strategies to achieve this improvement center on modification of the injected allergen in at least 2 ways. One modification strategy is to conjugate allergens with immunostimulatory DNA. This strategy is based on the observation that bacterial DNA promotes a T_H1-biased immune response. The structural characteristic of bacterial DNA that confers this effect is a relatively high frequency of unmethylated cytosine guanine (CpG) dinucleotide motifs. In mice, when synthetic oligodeoxynucleotides (ODN) rich in unmethylated CpG dinucleotide motifs have been conjugated to aeroallergen such as ragweed, they promote a T_H1 immune response. In contrast, unconjugated ragweed allergen promotes a T_H2 response.³⁵ Clinical trials of the efficacy of CpG-conjugated immunotherapy are now under way in ameliorating allergic responses.

The construction of a cytokine fusion protein consisting of allergen fused to IL-12 has been used as another strategy for modification of the injected allergen.³⁶ DNA vaccines composed of allergen complementary DNA (cDNA) fused to IL-18 cDNA have also been proposed. In animal studies, these strategies have been shown to convert T_H2 immune responses to T_H1-dominated responses in an allergen-specific manner.³⁷ However, they have not yet been tested in humans.

The prevalence of asthma is increasing around the world, especially in affluent and developed countries. Hypotheses that attempt to explain the rising prevalence have been advanced but remain unproven, and uncertainty about the root cause of increasing asthma prevalence is a source of unease. Meanwhile, significant advances in understanding the immunologic basis of asthma are being translated into specific therapies, some of which may be available soon that hold promise for disease modification.