Reviews and feature article
Fungi and allergic lower respiratory tract diseases

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Asthma is a common disorder that in 2009 afflicted 8.2% of adults and children, 24.6 million persons, in the United States. In patients with moderate and severe persistent asthma, there is significantly increased morbidity, use of health care support, and health care costs. Epidemiologic studies in the United States and Europe have associated mold sensitivity, particularly to Alternaria alternata and Cladosporium herbarum, with the development, persistence, and severity of asthma. In addition, sensitivity to Aspergillus fumigatus has been associated with severe persistent asthma in adults. Allergic bronchopulmonary aspergillosis (ABPA) is caused by A fumigatus and is characterized by exacerbations of asthma, recurrent transient chest radiographic infiltrates, coughing up thick mucus plugs, peripheral and pulmonary eosinophilia, and increased total serum IgE and fungus-specific IgE levels, especially during exacerbation. The airways appear to be chronically or intermittently colonized by A fumigatus in patients with ABPA. ABPA is the most common form of allergic bronchopulmonary mycosis (ABPM); other fungi, including Candida, Penicillium, and Curvularia species, are implicated. The characteristics of ABPM include severe asthma, eosinophilia, markedly increased total IgE and specific IgE levels, bronchiectasis, and mold colonization of the airways. The term severe asthma associated with fungal sensitization (SAFS) has been coined to illustrate the high rate of fungal sensitivity in patients with persistent severe asthma and improvement with antifungal treatment. The immunopathology of ABPA, ABPM, and SAFS is incompletely understood. Genetic risks identified in patients with ABPA include HLA association and certain TH2-prominent and cystic fibrosis variants, but these have not been studied in patients with ABPM and SAFS. Oral corticosteroid and antifungal therapies appear to be partially successful in patients with ABPA. However, the role of antifungal and immunomodulating therapies in patients with ABPA, ABPM, and SAFS requires additional larger studies.

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Prevalence of fungal sensitivity

The precise prevalence of fungal sensitivity is unclear. The National Health and Nutrition Examination Survey III study11 reported that among US citizens aged 6 to 59 years, 12.9% have positive skin prick test (SPT) responses to Alternaria species, whereas in another US study 21% of 102 atopic subjects had positive skin test results to 1 or more fungal allergens.12 In European studies 78% of 824 Spanish patients with allergic respiratory symptoms had positive SPT responses to Alternaria species.

Development of sensitization

Sensitization arises from a combination of genetic factors and exposure. Sensitization to Alternaria species has been associated with increased risk of maternal sensitization in patients’ offspring to this allergen, although the risk of asthma is unknown.20 Environmental exposure to fungi occurs both indoors and outdoors. A recent study showed that in fungus-sensitized asthmatic children, outdoor mold exposure rather than indoor mold exposure was linked with asthma exacerbations.21

Role of climate change in fungus-related respiratory tract diseases

Further factors that might influence the frequency of fungal sensitization and lower respiratory tract disease in the future are the effects of global climate change.30, 31 There is growing evidence of the effect of climate change on other aeroallergens, including mold sporulation.32, 33, 34, 35, 36 The plant response to increasing CO2 concentrations includes greater biomass and a greater carbon/nitrogen ratio of plant tissues; thus fungi growing on plant materials encounter changes in

Fungi associated with lower airway allergy

Aerobiological studies have shown the majority of fungal spores in outdoor air to be from the phyla Ascomycota and Basidiomycota (Table I).43 The most commonly studied allergenic fungi are conidia-producing anamorphs of ascomycetes, such as Alternaria, Aspergillus, Botrytis, Cladosporium, Epicoccum, Fusarium, and Penicillium species. Asexually produced conidia represent 30% to 60% of the spores present in outdoor air, the remainder being comprised mostly of teleomorphic (sexual) spores of the

Fungal allergens

Most fungi possess multiple and diverse allergens. Some are metabolic products secreted outside the organism; others are cytoplasmic and structural components released on lysis or autolysis of the fungal cell. On the basis of the catalog of fungal allergens approved by the Allergen Nomenclature Sub-committee of the International Union of Immunological Societies (IUIS),67 allergens that are fully characterized are listed in Table II. This listing includes isoallergens and variants from 25 fungal

ABPA and related conditions

First described in 1952, ABPA is commonly caused by A fumigatus, an ubiquitous mold common indoors and frequently found around farm buildings and compost heaps.80, 81, 82, 83, 84, 85 ABPA is characterized by exacerbations of asthma, recurrent transient chest radiographic infiltrates, and peripheral and pulmonary eosinophilia, especially during an exacerbation. ABPA is a TH2 hypersensitivity lung disease caused by bronchial colonization with A fumigatus that affects approximately 0.7% to 3.5% of

β-Glucan and dectin receptors

(1→3)-β-D-glucans are part of the carbohydrate structures in the cell walls of molds, some bacteria, and plants; up to 60% of the dry weight of the cell wall of fungi might be glucans.102 An association between high β-glucan levels and increased peak expiratory flow variability has been observed in children with asthma.103 The presence of visible mold and exposure to β-glucan in infancy appear to be risk factors for asthma by age 3 years.104 On the other hand, high levels of β-glucan exposure

ABPA

Exacerbations of ABPA are best treated with a course of oral steroids over 3 to 6 weeks (Table III).132 No prospective studies with corticosteroids have been conducted to evaluate efficacy rates, optimum dose, and duration or relapse rates. There are conflicting data concerning the clinical utility of inhaled corticosteroids in reducing exacerbation frequency, but they are important in controlling underlying asthma (Table III).133, 134 The potential utility of systemic antifungal therapy for

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