Asthma

The Prevalence of Asthma

Asthma is one of the most common chronic diseases in the United States and it prevalence is cause for considerable concern among public health professionals. In 2000, it was estimated that there were over 17 million people with asthma in the US (Hartert, 2000). Tragically, asthma was listed as the underlying cause of death in 4487 of the 2.4 million deaths recorded (Morb Mort Wkly Rep 52:381-384). Although by many measures the health of Americans is improving, CDC notes the self-reported prevalence rate for asthma increased 75% from 1980 to 1994 (Mannino et al, 1998). Nor is the phenomenon limited to the United States as the prevalence of asthma in other parts of the world, such as Great Britain and Australia, exceeds that of the United States (NIH, 1995).

The economic burden of asthma on society is dramatic. US statistics reveal that during 2000, there were 465,000 asthma hospitalizations, many of which occurred for children less than 15 years of age (Morb Mort Wkly Rep 52:381-384). In 1998, there were approximately 11.9 million medical visits for asthma, of which 1.9 million were in emergency rooms (Schappert, 1998). Total emergency and hospitalization expenditures for asthma have been estimated to be 1.3 billion, or approximately 1% of US health care costs (Weiss et al 1992). Coupled with the loss of work-days and/or reduced worker productivity, the total economic burden of asthma in the US has been estimated to range from $5.8 to $6.2 billion per year (Smith et al. 1997, Weiss et al 1992). More importantly, the incidence of disease has increased dramatically in recent years, particularly in industrialize countries. In 1960, it was estimated that 2.3 % of the US population suffered from asthma. By 2000, this number had increased to 5.8 - 7.2 %. From 1960-1994, the number of hospital visits increased 69%. (Mannino et al, 1998). This striking increase in disease incidence positions asthma as an emerging health crisis of the 21st century.

Asthma may present in all age groups, but most studies suggest the in the majority of patients asthma will present before puberty (Barbee et al, 1985; Marinez et al, 1995). Indeed, asthma is the most common chronic medical condition affecting children. Estimates from the US National Health Interview Survey (NHIS) suggest that 7.4% of children 5-14 years of age had asthma in 1994 (Mannino, 1998). Prevalence estimates from other countries range from 2.2-2.7% of 17-18 year olds in Israel to 12-15% in 5 to 17 year olds in Great Britain (Stachan et al, 1994; Sacher et al, 1994). More disturbing, the worldwide prevalence of asthma in children appears to be increasing: the number of children reported as disabled by their asthma is also increasing as is the number of children hospitalized and the number of deaths attributed to asthma (Stachan et al, 1994; Ulrick et al, 1996). Data from The US National Health Interview Survey revealed that between 1980 to 1994, the prevalence of asthma in children 5-14 years of age had increased from 4.3 to 7.4%. In Scotland, the prevalence in children 4 to 17 years of age increased from 7 to 11% between 1982 and 1992 (Ninam and Russel, 1992). In Australia, the prevalence of disease for this age group increased from 9 to 16% from 1981-1990 (Peat et al, 1992).

This increase in cases of childhood asthma is of critical health concern because the onset of asthma in children is particular debilitating. Although with some children, symptoms will decrease in adulthood, approximately 50% will continue to be affected throughout their life. The effects of asthma on children and adolescent social role function, including children's ability to play, participate in school activities, and construct meaningful social and family relationships, are important to consider in accounting for the overall burden of this disease. There is a growing body of evidence suggesting substantial and cumulative impact of early exposures to adverse social and biological conditions on health status through the life course (Hertzman, 1994; Schwartz et al, 1995) In fact, some of the evidence on the life long impact of childhood disease comes from longitudinal studies of children with asthma (Martin et al, 1980; Oswald et al, 1994; Strachan et al, 1996).

The Causes of Asthma

Agents that can exacerbate asthma may generally be thought of in two categories: nonspecific respiratory tract irritants and specific allergens. Exposure to nonspecific irritants, such as cigarette smoke, may lead to asthma symptoms in any person with asthma. Allergens, on the other hand, are only problematic for individuals who are allergic to them. It is important to note that approximately 80% of asthma in children is allergic asthma.

Numerous studies have found strong correlations between asthma and exposure to the allergens of dust mites, cockroaches, cat dander, and fungal spores. Perhaps the most intensively studies allergens in relation to asthma are those produced by the common house dust mite, which occur world wide. As such, research into dust mite exposure has been relatively thorough in comparison to other documented sources of potential indoor allergens. In respect to fungi, there are more than 1,000,000 species with at least 200 different types to which people are routinely exposed. Exposure occurs universally, both outdoors and indoors, and is impossible to avoid completely. In contrast to dust mite exposure, fungal exposure is complex in the respect to disease agents and usually includes allergens, irritants, toxins, and potentially infectious units. These factors have led to some uncertainty on the extent of interactions and the complete role of fungi in the onset of asthma. However, clearly and unequivocally, fungal exposure does cause allergic, toxic, and infectious disease, and it remains only to document the extent of the problem, factors leading to disease, and approaches for control.

Fungi may play a role in asthma in several ways. The most obvious of these is via fungal allergen exposure that leads to sensitization and the subsequent development of asthma. Fungi produce an enormous array of compounds that are potentially allergenic. Each fungus produces many different allergens of a range of potency. Table 1 lists the major defined allergens isolated from fungi. Others have been identified, but they are generally minor (few patients react to them). Many others, possible hundreds, remain to be identified.

Fungal allergen production varies by isolate, species and genera (Burge et al, 1989). Allergen amounts and profiles can also differ between spores and mycelium (Cruz et al, 1997, Fadel et al 1992), although spores are the most frequent form of exposure for most individuals. Fungi also contain and release irritants that may enhance the potential for sensitization, potentiate allergen-induced symptoms, and possibly exacerbate asthma in non-sensitized people. Fungal cell walls are composed of chitin fibrils embedded in a matrix of ß-D-glucans, which may be chemically bound to the chitin or form a more soluble matrix (Sietsma and Wessels, 1981). Soluble glucans have an effect in the lung similar to that of endotoxin, which can cause airway inflammation and airflow obstruction (Fogelmark et al 1994). Glucans may be involved in the development of fungal-induced hypersensitivity pneumonitis by affecting the inflammation-regulation capacity of airway macrophages. They also probably play a role in organic dust toxic syndrome in workers exposed to dust that includes high concentrations of fungal spores.

Finally, fungal toxins could play a role in modulation of the immune response and may cause direct lung damage leading to pulmonary disease other than asthma. Many mycotoxins are cytotoxic and interfere with protein synthesis, causing cell lysis and death. Some mycotoxins are potent carcinogen, and a few affect cell division or are estrogenic or vasoactive. Some cross the blood-brain barrier and affect the central nervous system. Some mycotoxins selectively kill macrophages (Nikulin et al, 1997). Some fungal components directly cause the release of mediators of inflammation, including cytokines, reactive oxygen metabolites, and chemotactic factors (Shahan et al 1998). Although the role of fungal irritants and mycotoxins in the development and exacerbation of asthma has not been effectively studied, the presence of these factors together with the known allergenic properties of fungi is cause for concern and future research.

The potential serious nature of exposure to asthmatic individuals sensitized to fungal allergens is further demonstrated by the fact that fungal allergens have also been implicated in asthma deaths. Campbell et al (1997) studied the pattern of deaths from asthma in England and Wales and found that the pattern varies with the age of the patients. For individuals 65 years of age and older, the peak of asthmas deaths occurs in winter when many elderly remain indoors for extended periods. However, for individuals younger than 45 years of age, the peak of asthma deaths occurs during the summer (July and August), which corresponds to peaks in outdoor mold spore counts. Targonski et al (1995) studied asthma deaths in individuals 5 to 34 years of age in Chicago from 1985 through 1989 and found that mold spore levels (but not grass, tree, or ragweed pollen levels) were high on days when asthma deaths peaked. The odds of an asthma-related death were 1.2 times higher for every increase of 1000 spores per cubic meter in the daily mold spore level. Additional supporting data come from O'Hollaren et al (1991) who identified 18 episodes of sudden-onset respiratory arrest in 11 adolescents and young adults. All these occurred in the summer and early fall, the typical peak period in the United States for Alternaria and other mold spores. Ten of the 11 patients (91%) had positive skin-prick test results for Alternaria compared with 31% of 99 age-matched control subjects.

Several studies have shown that the pattern of allergic sensitization in asthma differs in different environments. It has often been shown that in humid environments, sensitization to dust mites is more prevalent whereas in dry environments sensitization to fungal allergens is more prevalent. Peat et al (1993) revealed differences in asthma/allergen associations between coastal and desert environments in Australia. Along the seacoast, dust mites were the major asthma-associated allergen, but Alternaria lternate was the major allergen in desert regions. The association of Alternaria lternate as a major allergen in desert areas has also been confirmed in studies conducted in Kuwait and Israel (Ezeamuzie et al, 2000; Katz et al, 1999). Most critically for Arizonans, Alternaria alternate was determined to be the major asthma-associated allergen in the Tucson area as well (Halonen et al, 1997).

The finding that exposure to Alternaria alternate allergens is directly linked to the incidence of asthma is critically important. However, the claim that the taxon responsible for sensitization is A. alternate is not without controversy. This is due to the taxonomic uncertainty that permeates the taxonomy of Alternaria in general, and the identification of A. alternate specifically. In 1986, the International Commission on Fungal Taxonomy ranked Alternaria as 10th among the 30 genera most in urgent need of critical taxonomic revision (Hawksworth 1986). In 1992, E. G. Simmons, recognized world-wide as the foremost authority on Alternaria, stated in a review of Alternaria taxonomy, "In summary, we currently have nothing even remotely resembling a comprehensive systematic treatment of Alternaria." (Simmons,1992). And still, in 2001, there may be less than a dozen mycologists world-wide critically trained in Alternaria taxonomy. Among these, only two, Dr. E. G. Simmons and Dr. T. Y. Zhang, Shandong Agricultural University, Shandong, China, are active in monographic work, having provided 67 of the 69 new Alternaria taxa described within the last ten years. The vast majority of these new species have been described from agricultural and horticultural hosts. Little work is being conducted on Alternaria species from natural environments, manufacturing environments, or human dwellings. And, with the exception of work conducted by Dr S. DeHoog, Centraalbureau voor Schimmelcultures, The Netherlands, on human pathogenic dematiacious Hyphomycetes, little critical taxonomic work has been conducted on Alternaria species important in medical mycology. This deficiency in the medical community to adequately address Alternaria taxonomy is clearly exemplified by the fact that antigenic preparations of Alternaria alternate used in skin prick assays are often marketed under the name Alternaria tenuis, a name that has been accepted as ambiguous and invalid by most classical mycologists since 1912 (Kiessler, 1912). Thus, despite the evidence linking Alternaria exposure and sensitivity to the development and severity of asthma, the specific role of the species Alternaria alternate and the development of asthma has not been effectively studied.

The uncertainty regarding Alternaria taxonomy is even more prevalent regarding small spored catenulate taxa of which A. alternate is a representative member. In two seminal studies, E. G. Simmons evaluated morphological diversity of small-spored catenulate Alternaria species recovered from pear and citrus, which were associates with the diseases black spot of pear and leaf blight of citrus, respectively (Simmons, 1993,1999). Previous work had documented that taxa that were primarily responsible for these diseases were A. alternate, or pathotypes of this fungus. However, Simmons demonstrated that typical A. alternate was, in fact, rarely associated with these diseases and that other morphologically similar, yet distinct taxa were the pathogenic agents. Simmons further concluded that typical A. alternate is rather an uncommon taxon and that it is likely one of the most frequently misidentified Alternaria species.

Complementary to morphological studies performed by Simmons, molecular characterization of small-spored catenulate species has advanced in several studies involving plant pathogenic taxa. Roberts et al (2000) demonstrated that morphologically similar, yet diagnostically distinct, small-spored catenulate taxa obtained from different host plants from several geographic areas were genetically distinct based upon RAPD fingerprint analysis of total genomic DNA. In similar studies, Pryor and Michailides (2001) revealed that small-spored Alternaria taxa recovered from pistachio and previously identified as A. alternate were, in fact, several distinct taxa (pathogenic and non-pathogenic) based upon RAPD analysis, PCR-RFLP analysis of the nuclear IGS region, and sequence analysis of the nuclear ITS region. These studies clearly demonstrate that taxa historically lumped together as Alternaria alternate are much more diverse than previously assumed. These studies also support the notion that A. alternate is a frequently misidentified fungus. Consequently, data obtained from studies on plant pathogenic taxa will have direct utility in an expanded study of small-spored catenulate Alternaria taxa associated with asthma.

The taxonomic work by E. G. Simmons has provided the fundamental techniques and procedures to critically evaluate the diversity of taxa within Alternaria, in particular, groups representing small spored catenulate taxa similar to A. alternate. Specific culture conditions have been described by Simmons which are critical for the elucidation of diagnostic morphological characters. Further definition of the culture condition useful for morphological examination of Alternaria species have been described by Pryor and Michailides (2001) in their work with small-spored catenulate taxa isolated from pistachio in California. In this study, a taxonomic key for separating small-spored taxa into distinct species-groups was developed, which facilitates the initial, crucial step in the diagnosis of plant pathogenic species. This key will have direct utility in the diagnosis of medically important taxa associated with asthma as well.