Mold Allergy

People are exposed to aeroallergens in various settings, both at home and at work. Fungi are ubiquitous airborne allergens and are important causes of human diseases, especially in the upper and lower respiratory tracts. These diseases can occur in persons of various ages.

Exposure to molds can cause human disease through several well-defined mechanisms. In addition, many new mold-related illnesses have been hypothesized in recent years that remain largely or completely unproven. Concern about mold exposure and its effects are so common that all health care providers are frequently faced with issues regarding these real and asserted mold-related illnesses.

Fungi as aeroallergens

Airborne spores and other fungi particles are ubiquitous in nonpolar landscapes, especially among field crops, and often form the bulk of suspended biogenic debris. The term mold is often used synonymously with the term fungi. A definition more precise than this specifies that molds lack macroscopic reproductive structures but may produce visible colonies. Respiratory illness in subjects exposed to rust and dark-spored imperfect fungi was described more than 60 years ago, and human sensitization to diverse fungi is now well recognized. Because fungus particles are commonly derived from wholly microscopic sources, exposure hazards are assessed by directly sampling a suspect atmosphere in most circumstances. Because of their small size, fungal emanations present special collection requirements to ensure particle viability for culture-based studies.

Functional biology of fungi

Fungi have 2 basic structures. Yeast grows as single cells by means of central division of eccentric buds to form daughter units. Most other familiar fungi are composed of branching threads, 3-10 µm in width, termed hyphae. A mycelium is an aggregate of hyphae. Hyphae are modified to bear the simple reproductive parts of many microfungi and form the structural tissue of fleshy fungi (eg, mushrooms, puff balls).

In general, familiar allergenic molds reproduce asexually. However, 2 large and distinctive classes, Ascomycetes and Basidiomycetes, also produce innumerable sexual spores for atmospheric dispersion. In its life cycle, a single fungus organism produces both sexual and asexual spores from morphologically different structures respectively termed perfect and imperfect stages.

In considering known and potential allergens, 5 major classes of fungi have particular clinical significance: Oomycetes, Zygomycetes, Ascomycetes, Basidiomycetes, and Deuteromycetes.

Most molds require elemental oxygen during growth. Traces of formed carbohydrate are also essential. Vegetative hyphae of most fungi grow best at 18-32°C, and, although most become dormant at subfreezing temperatures, a few may sporulate below 0°C. At the other extreme, although 71°C is generally lethal for molds, certain types thrive at slightly cooler temperatures. Aspergillus fumigatus and Aspergillus niger tolerate a wide range of temperatures (see the image below).

Aspergillus.

Atmospheric moisture affects not only the growth and fruiting of fungi but also the dispersion of spores and resultant prevalence. Spore counts typically rise with rainfall and fog and with damp, nocturnal conditions. Rain and dew splash also foster dispersion of slime spores. As a result, atmospheric recoveries of Fusarium, Phoma, Cephalosporium, and Trichoderma species peak with rainfall.

The reproductive units of many fungi are detached by direct wind scouring or wind-induced substrate motion. Such dry spore dispersal increases as airspeed rises and relative humidity falls, peaking often during summer afternoons. At such time, typical spores of Cladosporium, Alternaria, Epicoccum, Helminthosporium, Rhizopus, Aspergillus, and Penicillium species may also peak (see the images below).

Bipolaris.

Cladosporium (Hormodendrum).

Curvularia.

Dreschlera (Helminthosporium).

Epicoccum.

Penicillium.

Penicillium.

Stachybotrys.

Rhizopus.

The circadian trends in changes of temperature, humidity, airspeed, and light intensity frequently interact to promote diurnal airborne spore levels. All data emphasize that regional vegetation strongly affects the local airborne spore levels.

Assessing the prevalence of fungi in air

Studies of airborne fungi provide prevalence data that are important to estimate patients' exposures to molds. A common method of sampling molds is to use an Anderson air-sample volumetric collector (Anderson Instruments; Atlanta, Georgia). The collector machine is allowed to sample the designated space for 5 minutes, trapping air particles in the filter. The filter then is placed on a Petri dish with media containing Sabouraud glucose, potato dextrose, and malt extract agar. Colonies grow on the agar plate, which an experienced mycologist can often use to identify the species on the basis of its gross appearance. Spore counts may be expressed as the number of colonies from a cubic meter of air. If the counts are higher than 200 spores in a cubic meter of air, patients with allergy are most likely to have symptoms.

Clinical relevance of allergenic fungi

Several fungal species (usually molds) cause allergic reactions in humans. The most common and best described mold allergen sources belong to the taxonomic group fungi imperfecti (usually asexual stages of Ascomycetes), which includes Alternaria, Cephalosporium, and Aspergillus species. Species of Basidiomycetes and yeast, such as Candidiasis albicans, are also important allergen sources.

Alternaria and Cladosporium species are common in outdoor environments worldwide. Airborne spores and mycelium debris of Cladosporium and Alternaria species are present during spring, summer, and especially autumn because of the degradation of leaves and other biomaterial. In indoor environments, Aspergillus and Penicillium species predominate with relatively few characteristic seasonal changes.

In early 1970, the United States faced an unexpected energy crisis because of the political climate in the world. The heavy dependence on foreign oil suddenly became a national issue. In responding to the call for conservation, the housing industry used more energy-saving insulation in buildings. However, the heavy insulation unexpectedly resulted in an excessive increase of humidity inside those buildings. This led to increase in mold-related health issues because the increased humidity led to higher mold counts within the buildings.

Similarities of allergen epitopes (antigenic [Ag] determinants) have been reported among some mold species, as observed in the closely related genera Alternaria and Stemphyllium. Otherwise, no immunochemical similarities have been detected among the major allergens of these species. The preparation of allergen extracts from cultured mold is very difficult secondary to low protein and high carbohydrate contents and the presence of potent proteolytic enzymes.

The Pollution and the Young (PATY) study included more than 58,000 children.[1] The study was conducted in Russia, North America, and 10 countries in Western Europe. The children were aged 6-12 years. The investigators studied the association between visible molds reported in the household and a spectrum of 8 respiratory and allergic symptoms within each study. Positive association between exposure to mold and children's respiratory symptoms were consistently noted across studies and across outcomes. For instance odds ratios ranged from 1.3 (95% confidence interval [CI], 1.22-1.39) for nocturnal cough to 1.5 (95% CI, 1.31-1.73) for morning cough.

A study in Finland showed the most common mold to induce occupational rhinitis was A fumigatus.[2] Association between the immunoglobulin E (IgE) sensitization and exposure level was statistically significant. The mold that grew in conjunction with moisture damage was the leading cause of occupational rhinitis.

A study indicated that IgE sensitization of fungi mirrors fungal phylogenetic systematics.[3] A database was compiled from recorded serum IgE antibody levels in response to 17 different fungal species from 668 individuals sensitized to at least one of the 17 species. By applying a cluster method to this data set, the fungal species were grouped into a hierarchical organization. The resulting organization was compared with published fungi findings. The results of this study showed that the hierarchical structure of fungi based in IgE antibodies in sensitized individuals reflected the phylogenetic relationship. Examples include the distinct separation of basal fungi from the subkingdom Dikarya, as well as individual cluster formations of fungi belonging to the subphylum Saccharomycotina and order Pleosporales.

This is the first study that demonstrates a close relationship between molecular fungal systematics and IgE sensitization to fungal species. Because close evolutionary organisms typically have a higher degree of protein similarity, IgE cross reactivity is likely the main reason for obtained organization.

Culturable molds in indoor air and the association with moisture-related problems and asthma and allergy among Swedish children has been reported.[3] Although mold spore exposure indoors has been suggested as a possible explanation for airway problems such as asthma and allergy among people living in buildings with moisture-related problems, this study could not find any associations between the spore concentrations in indoor air and signs of dampness and moldy odor reported by parents or observed by professional inspectors.

No association between the indoor spore concentration and asthma or allergy among children was noted. With these results, the authors concluded that one-time air sampling of mold colony-forming unit (CFU) in indoor air was not indicated to identify risk factors for asthma or allergy in children living in Scandinavian countries.

In contrast, in a study of environmental factors associated with poor asthma control in Montreal, suboptimal asthma appeared to be mostly associated with traffic, along with mold and moisture conditions.[4] The mold and moisture control thus have a greater public health impact.

In another European study, authors reviewed the projection of the effects of climate change on allergic asthma, in particular the contribution of aerobiology.[5] The authors believe climate change is unequivocal and reprensts a possible threat for patients affected by allergic conditions. However, they acknowledged numerous limitations that make prediction uncertain. More stress on pollen and spore exposure in the diagnosis and treatment guidelines of respiratory and allergic diseases are recommended. Collection of aerobiological data in a structured way at the European level and support of multidisciplinary research teams in this area was highly emphasized.

In one study in the United Kingdom in the asthmatic patients, it was shown that Aspergillus fumigates detection in sputum is associated with A fumigates -IgE sensitization, neutrophilic airway inflammation, and reduced lung function compared to asthmatics with IgG sensitization or asthmatics without sensitization to A fumigatus. This supports the concept that allergic inflammation could significantly lead to fixed airway obstruction in asthma, as illustrated with effect of airway colonization and sensitivity with A fumigatus.[6]

One of the problems with mold exposure estimates is the lack of quantitative, standardized methods for describing the residential mold burden. A metric called the Environmental Relative Moldiness Index (ERMI) has been developed and validated in a national survey of homes.[7]  A DNA-based, mold-specific quantitative polymerase chain reaction of 26 species formed the basis of the ERMI. The ERMI scale usually ranges from approximately -10 to 20 and is divided into quartiles, with the highest-quartile homes (ERMI value >5) having the highest mold burden.[7]

Immunologic evolution of allergy

Allergen-specific IgE produced by B cells mediate allergic diseases. The allergen sensitization begins with the processing of mold Ags by Ag-presenting cells (APC), such as dendritic cells. APCs present processed mold allergens to naive T-helper (Th) cells, which differentiate into the effector stage type 2 Th (Th2) cells and produce Th2 cytokines (interleukin [IL]-4, IL-5, and IL-13). IL-4 is essential for isotype switching to IgE and with additional signaling provided by the Th2 cells, B cells begin to produce IgE specific for allergens.

The Fc portion of IgE antibody binds to high-affinity Fcε receptors (FcεR) expressed on the cell surface of mast cells in tissue, which, in turn, stabilizes Fcε. IgE bound to FcεR is stable for several weeks. When allergens bind to adjacent 2 IgE molecules bound to FcεR (cross-linking), an activation signal is elicited, leading to the release of preformed and newly formed mediators from mast cells (mast-cell activation).

These mediators include histamine, leukotrienes, and prostaglandins, which cause acute tissue inflammation. Mast-cell activation also lead to release of various chemotactic factors, such as leukotriene B4, platelet-activating factor, and eosinophil chemotactic factor, resulting in an influx of eosinophils, neutrophils, and mononuclear cells into the site of mast-cell activation. Mast cells also produce IL-4, IL-5, and IL-13, further augmenting Th2 responses and IgE production.

Granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-3, and IL-5 derived from Th2 cells, mast cells, and other lineage cells induce the differentiation of eosinophil precursors in the bone marrow. IL-5 is thought to be crucial for eosinophil trafficking to the peripheral circulation, leading to eosinophilia. Various chemotactic factors, including chemokines, then recruit eosinophils to the site of allergen exposure. Thus, IgE-mediated immune reactions result in eosinophil-dominant inflammation. The initial inflammatory process initiated by mold allergens may be further compounded by the waves of inflammatory cell infiltration. Clinical features of mold allergy differ in the upper or lower respiratory tract that can also vary in each individual, influenced by age, genetic predisposition, exposure to other environmental allergens-irritants, etc.

Th2 responses are predominant to immune responses to mold allergens, but a type 1 T-helper (Th1) response characterized by cell-mediated immunity may also contribute to mold-induced inflammatory condition. The known clinical disorders related to immune reactions to molds are listed below.

Mold-induced respiratory symptoms may be notably delayed at the onset, and they may be associated with bacterial superinfection. This may reflect the fact that the concomitant microbial agents (and endotoxin) present in wild sources of mold growth, such as dusts from decomposing plant material, can compound the clinical manifestations.

Determinants of allergic fungi

The cross-reactivity (shared epitopes) of allergens derived from common airborne fungus spores remains controversial. Allergenic cross-reactivity such as observed between Phoma and Alternaria extracts more likely reflect the presence of shared epitopes in the species' reproductive stages. Establishing biologic or allergenic properties among molds is difficult, especially imperfect fungi. Therefore, defining Ag determinants is important when a mold allergen extract is prepared.

Total airborne fungi in North America range from extremely low levels during periods of below-freezing temperature to peak levels that usually occur in late summer and early autumn. This pattern parallels variations in dominant Cladosporium and Alternaria species in many areas. Penicillium species most often lack a defined annual pattern; A fumigatus may be more prominent from December-April in some areas but can be unpredictable in other regions. Mold allergy may account for persistent respiratory symptoms in individuals during nonpollen seasons.

Fungi readily invade indoor environments, and indoor growth can cause perennial allergic symptoms. Penicillium and Aspergillus species are commonly found in enclosed spaces, followed by Rhizopus and Mucor species. Soiled upholstery and garbage containers are favored sites of indoor fungal growth. The porosity of rubber and synthetic foams and their tendency to remain moist favor fungalgrowth.Basements, window molding, shower curtains, and plumbing fixtures are common sites for indoor fungal growth (see the image below).

Bathrooms are favorite habitats for mold.

Poorly maintained cold-mist vaporizers and some console humidifiers can emit dense microbial aerosols during operation. If high relative humidity and condensation persist in indoor environments, mold is likely to recur after decontamination.

The clinical relevance of cross-reactivity among the different fungal species has been largely unknown. However, progress in molecular cloning of fungal allergens and the availability of more than 40 completely sequenced fungal genomes facilitates characterization, cloning, and production of highly pure recombinant allergens; identification of homologous and orthologous allergens; in silico prediction; and experimental in vitro and in vivo verification of cross-reactivity between homologous panallergens.[8] These studies indicate that cross-reactivity is an important component of fungal sensitization.

However, a new study among Swedish children indicated that no association was found between the spore concentration and signs of dampness and moldy odor reported by parents or by professional inspectors. No association was found between the indoor spore concentration and asthma or allergy among children. Thus, one-time air sampling of mold CFU in indoor air is not indicated to identify risk factors for asthma or allergy in children living in Scandinavian countries.

Contradictory to the above study, a population-based study in Montreal children suggests home environmental factors associated with poor asthma control.[4] Of 980 children with active asthma, 36% met criteria of poor control of their diseases. The population's characteristics were related with lack of asthma control, after adjustment, and included children living along high-traffic density streets (PR, 1.35; 95% CI, 1-1.81) and those with their bedroom or residence at the basement level (PR, 1.30; 95% CI, 1.01-1.66). The study concluded suboptimal asthma control appears to be associated with traffic, along with mold and moisture conditions; the latter is a more frequent exposure and, therefore, has a greater public health impact.

The therapeutic potential of pathogen-derived products

Several pathogen-derived products have been shown to possess therapeutic potentials for allergic diseases. It has been suggested the glucan of the wall component of a variety of fungi may have that potential. Kawashima et al, using an animal study, examined the effect of curdlan, a linear beta-(1-3)-glucan, on the development of allergic airway inflammation.[9] They found that an injection of curdlan significantly inhibited Ag-induced eosinophilic recruitment and Th2 cytokine productions in the airways. They found that STAT6-aided IL-10 production by CD4+ T cells in the presence of curdlan contributed to this process. It underscores the therapeutic potential of curdlan for various fungus-related allergic diseases.

Animal models of allergic airway diseases

Animal models of disease are an invaluable tool for contributing to the understanding of the pathophysiology of allergic airway diseases. Hoselton et al reported such model using A fumigatus. Balb/c mice were challenged with A fumigatus via intranasal inoculation. They were previously sensitized with intraperitoneal injections with soluble A fumigatus in alum. After a single challenge of inhalation, allergic pulmonary inflammation and airway hyperresponsiveness were significantly increased compared with control animals. Later, a significant increase in epithelial thickness, global cell metaplasia, and peribronchial collagen deposition was noted. The authors concluded this was the first time they demonstrated that the consistent development of fibrosis and smooth muscle changes accompany exposure to inhaled fungal conidia in a mouse model.

Clinical forms of mold allergy - Allergic rhinitis, allergic conjunctivitis and allergic asthma

Allergic rhinitis and/or allergic conjunctivitis are common problems in both children and adults. Allergic rhinitis or allergic conjunctivitis is usually a perennial problem, with seasonal fluctuation of symptoms in regions such as the southern part of the United States, where humidity and temperatures are high.

Many indoor fungal allergens (eg, Alternaria, Aspergillus, Cephalosporium, Curvularia, Epicoccum, Fusarium, Helminthosporium, Hormodendrum, Mucor, Penicillium, Phoma, Pullularia, Rhizopus, and Stemphylium species) can cause allergic symptoms. They are the result of type 1 (IgE-mediated) hypersensitivity reactions.

Patients should have detectable IgE antibody to provoke mast-cell activation with fungal exposure. Studies also indicated the close association of mold allergy with prolonged coldlike symptoms in winter, sinusitis, and the presence of adenoid hypertrophy in children.[10]

Allergic asthma or IgE-mediated asthma: Patients with fungal spore–induced asthma often have IgE antibodies to more prevalent fungi, such as Alternaria and Cephalosporium species. As many as 25% of patients with asthma have skin prick test reactivity to a mixture of 4 species of Aspergillus. The fungal allergen-induced asthma can occur in both children and adults as a result of a type 1 hypersensitivity reaction. These patients manifest potent late-phase reactions.

Clinical forms of mold allergy - Allergic fungal sinusitis (AFS)

Allergic Aspergillus sinusitis primarily occurs in patients with nasal polyps and mucoid impaction of the sinuses. The mucus typically contains eosinophils, Charcot-Leyden crystals (breakdown products of eosinophils), and hyphae of A fumigatus. AFS can also be induced with exposure to other fungi, including Bipolaris, Curvularia, Alternaria, Exserohilum, Helminthosporium, and Rhizopus species. This condition is relatively rare in the pediatric population and is a result of type 1, type 3 (immune complex), and type 4 (delayed type) hypersensitivity reactions. Manning et al reported on 6 patients aged 8-16 years who had findings typical to allergic Aspergillus sinusitis.[11]

A review of allergic fungal rhinitis and rhinosinusitis indicated epidemiologic studies have failed to demonstrate a direct relationship between fungal allergy and allergic rhinitis either via outdoor or indoor exposure.[5] The author indicated fungal allergy is clearly linked to a subset of chronic rhinosinusitis (CRS) known as allergic fungal rhinosinusitis (AFRS). The condition represents an intense allergic response against colonizing fungi that give rise to formation of allergic (eosinophilic) mucin, mucostasis, and sinus opacification.

A broader role for colonizing fungi has been postulated in CRS, owing to the demonstration of fungi in mucus in the vast majority of cases of CRS and in vitro studies that have demonstrated certain fungi, particularly Alternaria, modify an allergic response in patients with CRS that is independent of IgE.

Clinical forms of mold allergy - Allergic bronchopulmonary aspergillosis (ABPA)

This is a well-recognized form of hypersensitivity pneumonitis, with nearly every case occurring in patients with previously diagnosed asthma or cystic fibrosis (CF).

ABPA rarely occurs in the absence of clinical asthma. The pulmonary immune system responds to a saprophytic fungus present in bronchial mucus, leading to bronchial wall widening (bronchiectasis) and distal small-airway fibrosis (bronchiolitis obliterans). It is characterized by clinical, immunologic, radiologic, and pathologic findings that range from mild asthma to end-stage fibrotic lung disease.

Children with CF are susceptible to ABPA with mucoid impaction of Aspergillus species. A fumigatus is the most frequent Aspergillus species to infect humans. Spores are 2-3.5 µm, which permits penetration to smaller airways. ABPA is the result of types 1, 3, and 4 hypersensitivity reactions.

Clinical forms of mold allergy - Non-Aspergillus allergic bronchopulmonary mycosis (ABPM)

The most common cause of ABPM is C albicans. Isolated cases of ABPM caused by other fungi in asthma patients have been described; pathogens included Cladosporium and Curvularia species. ABPM has been described in patients with CF. A child with CF was reported to have developed ABPM with Trichosporon beigelii.[12] The disease is the result of types 1, 3, and 4 hypersensitivity reactions.

Clinical forms of mold allergy - Extrinsic allergic alveolitis (EAA)

EAA encompasses a broad spectrum of pulmonary interstitial and alveolar diseases caused by repeated (occupational) exposure to a wide variety of organic dusts, microbes, and chemicals.

Repeated exposure to various molds can also cause EAA. Mold-induced EAA includes wood pulp worker's lung (Alternaria species), malt worker's lung (Aspergillus clavatus), farmer's lung (A fumigatus), maple bark stripper's lung (Cryptostroma corticale), and sewage worker's lung (Cephalosporium species).

The inflammatory process of EAA involves mast-cell activation, immune complex formation (type 3 hypersensitivity tissue injury), and influx of immune cells producing proinflammatory cytokines, such as IL-1, IL-2, IL-3, IL-12, interferon-γ (IFN-γ), and GM-CSF. The disease is likely the result of type 3 and type 4 hypersensitivity reactions.

Clinical forms of mold allergy - Hypersensitivity pneumonitis (HP) caused by fungi

The clinical course of this disease widely varies, and its diagnosis is clinically challenging because no specific test or biomarker allows a consistent diagnosis.[13] Therefore, a combination of symptoms, bronchoalveolar lavage findings, chest imaging, laboratory results, and biopsies are needed for an accurate diagnosis.

Regardless of the cause or the responsible environment, the histopathology is similar and usually consists of a granulomatous interstitial bronchiolocentric pneumonitis characterized by the presence of poorly formed granulomas and a prominent interstitial infiltrates composed of lymphocytes, plasma cells, and macrophages. Importantly, patients with chronic HP may evolve to interstitial fibrosis or develop emphysematous changes. Identification of biomarkers that may predict outcome and progression is essential for the success of the treatment.

Frequency

United States

Depending on patients' geographic locations, their mold allergies can be seasonal (most often fall) or perennial. Perennial mold allergies are prevalent in humid and warm climates secondary to persistent presence of molds in indoor environments. Among preschool aged children living in the southern United States with documented reactivity to indoor allergens, 80% had reactivity to mold spores, house dust mites, or both. No data are available for the prevalence of the 5 other clinical disorders listed in Pathophysiology section. EAA is considered to be more prevalent among workers whose occupations predispose them to repeated exposure to causative reagents.

International

No epidemiologic data are currently available. However, in recent years, mold exposure in schoolchildren has become a major concern of parents and healthcare professionals worldwide. The increase in mold allergy symptoms in susceptible children may be partly attributed to improper repair of moisture-damaged buildings or congested homes of the inner city.

An interesting observation was reported in Poland.[13] A survey of art conservators found that 85% of art conservators and museum workers reported allergic symptoms. Cladosporium, Alternaria, and yeasts were the species that played the most important role in the development of fungal hypersensitivity. A duration of occupational exposure of longer than 5 years, the presence of domestic animals (especially a cat at home), elevated total IgE level, allergic rhinitis, and skin sensitivity to common allergens (eg, grass pollens, mites) are significant risk factors for the development of hypersensitivity to fungi among those museum workers.

Mortality/Morbidity

Anaphylaxis due to a mold allergy is extremely rare, but a mold allergy could cause a severe respiratory reaction if the patient has allergic bronchial asthma due to mold sensitivity. How much mold allergy contributes to mortality in asthma patients is unknown.

Morbidity associated with mold allergy is high in pediatric population because most children develop allergic symptoms early in their lives following exposure to mold allergens.

Although the patient number is limited, those who develop ABPA, ABPM, AFS, or EAA generally experience chronic, relapsing clinical courses. These patients must be aggressively treated during relapse. When ABPA, ABPM, hypersensitive pneumonitis, or EAA is not well controlled, it can result in substantial disability or even death.

The frequency of prolonged coldlike symptoms in winter, sinusitis, and adenoid hypertrophy is higher among the children who have mold allergy than those without mold allergy.

Demographics

Mold allergy is prevalent in all age groups, and it may occur in young children secondary to indoor exposure to mold.

Allergic rhinitis and allergic asthma can occur in children and adults. ABPM and EAA are rare in children. ABPA has been reported in children of all ages, especially in those with CF.

In children with Alternaria-sensitive moderate-to-severe asthma, an increased type 2 helper cell (Th2) sensitivity to Alternaria stimulation was noted.[14] This was associated with a human leukocyte antigen (HLA)-DR restriction, and with increased frequency of HLA-DRB1*13 and HLA-DRB1*03. A decreased frequency of HLA-DQB1*03 was noted in Alternaria -sensitive moderate-to-severe asthma, suggesting HLA-DQB1*03 may be protective to the development.

Allergic rhinitis and conjunctivitis

Because molds can grow in indoor environments, many children are exposed to them from birth. How early children can become allergic to mold Ags is unclear; however, nearly 40% of children with allergic rhinitis have positive skin test or radioallergosorbent testing (RAST) reactivity to mold allergens.

Symptoms of allergic rhinitis include runny nose, itchy nose, sneezing, nasal congestion, sniffling, sore throat, cough, itchy eyes, and runny eyes and may be worse when patients are indoors. Symptoms may be most severe in hot and humid seasons, but some molds are prevalent throughout the year. The most characteristic symptoms are injected conjunctivae, headache, and fatigability.

Children typically have a history of recurrent respiratory infections (including sinus infections) and otitis media.

One study revealed that mold allergy may be most prevalent in winter secondary to the airtight insulation used in homes built in recent years.[15, 16] History of prolonged cold symptoms that last for more than 2 weeks in winter may indicate mold allergy.

Although uncommon, sinusitis or lower respiratory tract disease (eg, allergic bronchitis, bronchial asthma) subsequently develops in some patients.

An increased prevalence of adenoid hypertrophy is reported in children with mold allergy.

Allergic asthma

The history of mold-induced asthma may not differ from that of any other allergic asthma. The onset may be acute or insidious. The patient's history usually includes cough, wheezing, and tachypnea with dyspnea with prolonged expiration.

Symptoms may be precipitated by exposure to molds, viral infections, or exposure to any irritants, especially when patients have become hyperresponsive.

Allergic bronchopulmonary aspergillosis (ABPA), allergic bronchopulmonary mycosis (ABPM), and extrinsic allergic alveolitis (EAA)

Molds are ubiquitous microorganisms; therefore, unless the prevalence of the offending fungi is known, eliciting a history of fungal exposure leading to chronic inflammation and disease development is difficult.

In EAA, because of the relationship between the disease and exposure to specific fungi in particular professions, the diagnosis can be suspected at an early stage. The period from exposure to onset of disease may be months to years in EAA.

The frequency of familiar occurrence of ABPA was determined in 164 patients with ABPA diagnosed over a period of 22 years in one study.[17] The familiar occurrence of ABPA was found only in 4.9% of the 164 patients.

Allergic fungal sinusitis (AFS)

This disease appears to be most common in areas with hot, humid climates and high ambient mold-spore counts. Most AFS cases caused by Bipolaris spicifera are reported in Texas, Louisiana, and Georgia. At least 6 cases of allergic Aspergillus sinusitis were reported in the state of Texas.[11]

Other new form of Allergic fungal diseases

Although only described in case reports, it is important to recognize the increasing number of new fungal allergic diseases being reported. Acute eosinophilic pneumonia was reported in a 36-year-old man. It was confirmed by positive delayed skin testing (8 h and 24 h), lymphocyte stimulation testing, inhalation provocation testing, and selective production of interleukin 5 only by C albicans.[18] A case of systemic allergic contact dermatitis[19] and a case of hypersensitive pneumonitis[20] were reported after exposure to raw but edible shiitake mushrooms.

Clinical manifestations of mold allergies are primarily limited to the upper and lower respiratory tracts.

Allergic rhinitis and/or allergic conjunctivitis

Signs include allergic shiners, Dennie lines (the accentuated lines below the margin of lower eyelids), frequent otitis media, and pale and swollen turbinates.

The conjunctivae are often injected, with prominent palpebral conjunctivae and/or frequent tearing.

Persons who chronically breathe through their mouth typically have narrow and elevated palates, enlarged tonsils, and a cobblestone appearance of the posterior pharyngeal wall.

Children often have elongated adenoid facies with signs of overbite. They often speak with heavily nasal voices.

Allergic asthma

Signs include cough, wheezing, prolonged expiration, and tachypnea.

A deformed chest wall (eg, pigeon breast, barrel chest) is sometimes observed in children, especially in those with chronic allergic asthma.

Depending on the frequency of wheezing in the daytime and nighttime, asthma can be classified as mild intermittent, mild persistent, moderate persistent, or severe persistent according to the National Asthma Education and Prevention Program Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma published by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH).[21]

In murine model of chronic fungal asthma, toll-like receptor 2 (TLR2) mediated signaling was shown to be a major contributing factor to maintain type 2 T-helper (Th2)-cytokine driven, anti-fungal innate response.

Allergic bronchopulmonary aspergillosis (ABPA) and allergic bronchopulmonary mycosis (ABPM)

Cough, purulent sputum, dyspnea, wheezing, low-grade fever (< 38.5°C), chest pain, hemoptysis, and malaise are common.

In the acute stage, symptoms can be minimal or can be accompanied by occasional crackles. In chronic cases, clubbing, cyanosis, tachypnea, and cor pulmonale are common. In children with cystic fibrosis (CF), ABPA may cause rapid weight loss, lethargy, fever, and productive cough.

Allergic fungal sinusitis (AFS)

AFS generally produces a subacute or chronic course of sinus involvement. All pediatric patients presented with nasal polyposis and progressive facial deformity.

Patients may report dull pressure on the face or head. Persistent, sometimes unilateral, nasal stuffiness, hyposmia, purulent and postnasal secretion, sore throat, fetid breath, and malaise are always present. The secretions often pool in the nasopharynx at night. The increasing postnasal drainage with resultant cough may be accompanied by wheezing.

Extrinsic allergic alveolitis (EAA)

EAA may occur in an acute, intermediate, or chronic form.

In the acute stage, patients may have flulike illness accompanied by coughing and undue breathlessness hours after exposure. Malaise, fever, chills, widespread aches and pains, anorexia, and tiredness may also be present.

In the chronic form, EAA is a slowly progressive illness causing undue breathlessness, dry cough but no wheeze, possible weight loss, and, in rare cases, clubbing. Patients gradually have respiratory failure, pulmonary hypertension, or right heart failure.

All of the clinical disorders related to mold allergy are caused by repeated exposures to molds and the immune responses of susceptible individuals. The relationships between specific molds and particular disorders are discussed in Pathophysiology.

Molds are potential problems in outdoor and indoor environments. Nearly 20 allergenically important molds are related to the household environment. Among them, Alternaria and Hormodendrum species are the most well recognized.

Favorite habitats include damp, dark places (eg, cellars, bathrooms, garages, attics); rotting leaves or vegetation, indoor plants, and organic plant containers (eg, wicker, straw, hemp); old foam-rubber pillows and peeling wallpaper; furniture stuffed with decaying kapok or cotton; rubber gaskets on old refrigerator doors; dishwashers, drainage sinks, and washing machines; and garbage cans. Water-damaged areas, such as leaky roofs, walls with dry rot, and wet carpets, or areas with poor drainage are also prime habitats for mold (see the images below).

Moisture is trapped in the wall behind a vinyl wall covering.

Large amounts of moisture support fungal growth, as is the case with this dry wall covering.

Glues can collect mold.

Soapy shower doors collect fungi.

Wet drywall collects mold.

Wall coverings can pucker because of mold.

Depending on the areas where surveys are conducted, sterile mycelia and the fungi of the genera Cladosporium, Penicillium, Alternaria, Epicoccum, Aspergillus, Pullularia, and Drechslera are most commonly encountered. Studies have also shown that poorly maintained landscaping, high shade levels, and large amounts of organic debris near the home (including ivy, compost, and bark chips) are highly correlated with the accumulation of indoor molds. Also, the development of mold in room-air humidifiers, cold-mist vaporizers, and air-conditioning systems has received much attention.

When mold allergens bind to specific IgE on mast cells of susceptible individuals, mast-cell activation causes an immediate reaction, leading to the early release of histamine. As in the case of other airborne allergens, a delayed allergic reaction is expected to follow, with infiltration of various inflammatory cells that serve to magnify the inflammatory process, which may last for days. Immediate and late mucosal inflammatory processes lead to the development of the signs and symptoms of allergy (see Pathophysiology).

Although genetic factors are known to influence the development of allergies, the exact genetic transmission of each disorder listed in Pathophysiology is currently unknown. Environment plays an important role. In addition to the presence of mold allergens, smoking increases the frequency of allergic rhinitis and asthma. A child with CF is at increased risk for ABPA. Many cases of EAA occur as occupational diseases among individuals working in environments infested with specific molds.

The diagnosis of fungal sensitivity heavily depends on skin tests with fungal allergens. However, the variability and complexity of fungal extracts often hamper diagnosis. One of the breakthroughs of antigenic (Ag) preparation occurred when a recombinant form of a fungal allergen became available. Asturias et al compared a purified natural Aspergillus Ag (nAlt a) and recombinant Ag (rAlt a 1).[22] They found a statistically significant correlation in specific immunoglobulin E (IgE) levels to both Ags by using skin test and immunoblotting/inhibition analysis. Therefore, the use of recombinant Ag may help in reducing the inconsistency of test results with the use of natural Ags.

Allergic rhinitis and/or conjunctivitis - Immediate hypersensitivity skin testing

Immediate hypersensitivity skin testing is the most useful method to detect IgE antibody against mold allergens. Testing can be performed by using the prick or intradermal method. The preferred site is the upper part of the back for the prick method or the arms for the intradermal method. Histamine and normal sodium chloride solution are most commonly used as positive and negative controls, respectively. Results are recorded 15 minutes after the test is performed. Wheal diameter more than 3 mm above the reaction of the negative control is considered a positive result. Mold allergen extracts used for the skin test depend on the prevalence of various molds in the region, as identified with annual atmospheric sampling. The most common molds are Alternaria, Aspergillus, Cephalosporium, Curvularia, Epicoccum, Fusarium, Helminthosporium, Hormodendrum, Mucor, Penicillium, Phoma, Pullularia, Rhizopus, and Stemphyllium species.

Allergic rhinitis and/or conjunctivitis - Radioallergosorbent testing (RAST)

A positive result confirms allergen-specific IgE in the peripheral blood. The test is indicated in individuals who have clinically significant dermatographism or extensive skin disease, those who cannot discontinue antihistamines or other medications with antihistamine actions (eg, tricyclic antidepressants), or those who have a history of anaphylactic reaction (because direct application of the suspected allergen may precipitate recurrent anaphylaxis). RAST is not generally considered as sensitive as skin testing.

Allergic rhinitis and/or conjunctivitis - Nasal cytology

The presence of more than 10% of eosinophils in the cell population in the nasal secretion supports the diagnosis. Hansel staining is used to identify eosinophils. Eye swab results can be used to diagnose allergic conjunctivitis. If neutrophils are present in more than 90% of the cell population, bacterial infection should be considered.

Sinus images may depict sinusitis or adenoid hypertrophy.

Allergic asthma - Skin test or RAST

These tests are helpful in determining the offending airborne allergens.

Allergic asthma - Pulmonary function testing

Simple spirometry to measure airway flow rates can help in identifying reversible or fixed airway obstruction. A reduced forced vital capacity in the absence of airflow obstruction is supportive evidence of restrictive lung disease. Spirometry can be performed during the initial workup or a follow-up visit in an outpatient clinic. The patient can use a peak flow meter to monitor his or her airflow at home. Airflow rates can be helpful in determining necessary adjustments for medications, depending on the patient's clinical course.

Allergic fungal sinusitis (AFS) -Allergy skin test or RAST

These tests can help in identifying immediate hypersensitivity to suspected fungi.

Allergic fungal sinusitis (AFS) - Nasal cytology

This test is most critical for establishing the diagnosis. Mucus samples are obtained. If positive, they should contain clinically significant amounts of eosinophils, Charcot-Leyden crystals, and hyphae of fungi (A fumigatus or Bipolaris, Curvularia, Alternaria, Exserohilum, Helminthosporium, or Rhizomucor species).

Allergic fungal sinusitis (AFS) - Fungal culture

Fungal cultures may further support the identification of the offending fungi. A sensitivity test can help in choosing an antifungal agent should such treatment be indicated.

Allergic fungal sinusitis (AFS) - Total serum IgE

A clinically significant elevation can be corroborative evidence for the diagnosis of AFS.

Allergic fungal sinusitis (AFS) - Precipitin test

The presence of immunoglobulin G (IgG) in blood against the offending fungi can be corroborative evidence for the diagnosis of AFS.

Allergic bronchopulmonary aspergillosis (ABPA) and allergic bronchopulmonary mycosis (ABPM) - Skin test or RAST

These tests are used to confirm immediate hypersensitivity to A fumigatus or other offending fungi.

Allergic bronchopulmonary aspergillosis (ABPA) and allergic bronchopulmonary mycosis (ABPM) - Precipitin test

Precipitin test is used to confirm the presence of a high titer of IgG antibody against specific fungal Ags. Healthy individuals may have circulating IgG antifungal antibodies in the absence of any fungal-related disease.

Allergic bronchopulmonary aspergillosis (ABPA) and allergic bronchopulmonary mycosis (ABPM) - Total serum IgE

This measurement is usually more than 400 IU/mL.

Allergic bronchopulmonary aspergillosis (ABPA) and allergic bronchopulmonary mycosis (ABPM) - Sputum analysis

Sputum may appear brown, orange, or gray. Hyphae of Aspergillus species or other fungi can be observed, or they grow from culture.

Allergic bronchopulmonary aspergillosis (ABPA) and allergic bronchopulmonary mycosis (ABPM) - Other

Persistent eosinophilia of more than 0.5 X 109/L (>500/µL) may be present.

One report indicated the bronchial alveolar lavage (BAL) typically reveals bronchial lymphocytosis with increased CD8+ T cells in patients with hypersensitive pneumonitis.[23] Lymphocyte counts from 30% to more than 50% are common. BAL fluid with less than 30% lymphocytes should put the diagnosis of hypersensitivity pneumonitis in question.

Extrinsic allergic alveolitis (EAA) - Immediate hypersensitivity intradermal skin test

If results are positive, they may reveal both immediate (20 min) and late-phase (4-6 h) reactions.

Extrinsic allergic alveolitis (EAA) - Precipitin test

This test reveals positive IgG antibody against Ags of the offending fungi.

Extrinsic allergic alveolitis (EAA) - Assay for cell-mediated immunity

A delayed-type skin reaction against offending fungal Ags may be positive, with wheal formation after 24-48 hours after the intradermal application of fungal Ag. Positive results on lymphocyte transformation tests against the offending fungi indicate type IV hypersensitivity. The test is not practical for clinical use.

Extrinsic allergic alveolitis (EAA) - Laboratory-based inhalation challenge test with aerosolized solutions of soluble Ags of the suspected fungus

This test may be used to reproduce symptoms. It should be performed only in a pulmonary function testing center with personnel who have extensive expertise in this area.

Extrinsic allergic alveolitis (EAA) - Monitoring

Serial monitoring of temperature, changes in circulating neutrophil and lymphocyte blood counts, and lung vital capacity may help in monitoring disease activity.

Allergic rhinitis and/or conjunctivitis

Sinus radiographs are not usually necessary unless they are used to look for superimposed sinusitis.

Allergic asthma

Chest radiographs are used only to look for an ongoing infection, such as middle-lobe syndrome or pneumonia, or for chronic changes of the lung in chronic asthma. A barium swallow study may be used to exclude tracheoesophageal fistula or vascular ring in infants with chronic wheezing.

Sinus radiographs are used to exclude sinusitis in recalcitrant asthma unresponsive to conventional therapy. Look for air-fluid level, mucosal thickening, or opacity in the sinus cavity.

CT scanning of the paranasal sinuses may help in excluding sinusitis in asthma that is unresponsive to conventional therapy. CT scanning of the paranasal sinuses is useful if surgery is indicated for a sinus infection. A lateral view helps in identifying patients with adenoid hypertrophy.

Allergic fungal sinusitis (AFS)

CT scanning of the paranasal sinuses may reveal a persistently opacified sinus cavity despite prolonged antibiotic therapy. AFS commonly causes unilateral sinus opacification due to obstruction of the sinus ostium with thick, inspissated mucus. CT scanning should reveal a persistently opacified sinus cavity that may be expansile. CT scanning may also reveal high attenuation in the opacified sinus due to high protein concentration. In a series of 6 children with a diagnosis of allergic Aspergillus sinusitis, all 6 had CT findings of diffuse expansile sinus disease, and 4 had evidence of bony erosion, which raised the suspicion for malignancy.

Corresponding lesions have a characteristic hypointense appearance on T1-weighted and T2-weighted images on sinus MRIs. Such lesions are nearly pathognomic for AFS, but they are not always present.

Allergic bronchopulmonary aspergillosis (ABPA) and allergic bronchopulmonary mycosis (ABPM)

Diagnostic signs on chest radiograph include pulmonary infiltrate, mucus plugging and the finger-in-glove sign (ie, distal occlusion of bronchi packed with secretion), and bronchiectasis. Another reason for chest imaging is to look for late changes of lung tissues, such as fibrosis, blebs, bullae, and/or spontaneous pneumothorax. A dilated bronchus is seen as a ring shadow on en face. On a coronal view, the dilated bronchus may be seen as a parallel line shadow. Both are unique to ABPA and ABPM.

Conventional CT scanning provides an axial perspective and can demonstrate proximal and distal bronchiectasis.

Bronchography demonstrates bronchiectasis, but it is associated with complications and generally not necessary since CT scanning is available. Bronchography is not recommended for children because of the need for general anesthesia.

Extrinsic allergic alveolitis (EAA)

A widespread ground-glass appearance or an alveolar filling pattern, particularly in the lower and middle zones, can be seen on a chest radiograph when the disease is moderately severe. The lesions may resolve after exposure ceases. If exposure continues, a nodular pattern or honeycombing may develop. When the upper zone is affected, it manifests as irreversible fibrosis.

In subacute cases, CT scans reveal reticular or nodular infiltration in parenchyma. In chronic cases, a similar pattern of fibrosis can be seen throughout the lung fields. Expiratory images may reveal patchy areas of increased lucency, indicating airtrapping.

Pulmonary function tests are recommended for all fungal-induced pulmonary diseases, including asthma, ABPA, ABPM, and extrinsic allergic alveolitis (EAA), as a means for longitudinal monitoring of the clinical course.

BAL is not indicated in clinical practice. However, studies demonstrated that, in ABPA, BAL samples yields higher IgE levels against the fungal Ag than do peripheral blood samples. This finding suggests the local production of IgE against Aspergillus species. In EAA, BAL is no more helpful than the demonstration of serum precipitins.

Rhinoscopy

Specimens obtained from the sinus cavity can be diagnostic in AFS by showing abundant eosinophils, Charcot-Leyden crystals, and hyphae of fungi. Rhinoscopy is also useful for culture for fungi and to determine if a nasal polyp is present.

For patients with chronic allergic rhinitis that is recurrent or resistant to conventional therapy, the procedure is helpful for identifying adenoid hypertrophy, chronic adenoiditis, nasal polyps, or ethmoidal bullae. If rhinitis is complicated with sinusitis, it helps to determine the obstruction of ostium of sinus tract and/or to collect discharge for microbiologic study.

Bronchoscopy

Bronchoscopy is indicated only for selected patients for tissue diagnosis. It is not considered a routine procedure for any of the lower respiratory tract disorders, such as ABPA, ABPM, and EAA.

Allergic rhinitis and/or conjunctivitis

In acute cases, submucosal cellular infiltration is limited.

Edema and vasodilation are obvious, indicating an immediate phase reaction. In subacute or recurrent rhinitis, goblet cells are increased.

Eosinophil, neutrophil, and plasma-cell infiltration is significant in the submucosal area.

In chronic cases, epithelial cells are often severely damaged or disrupted, exposing the submucosal layer. More mononuclear cells are found in the submucosa. Increased deposition of collagens is present. Immunohistochemical studies reveal heavy deposition of eosinophil cationic protein in the submucosa.

Allergic asthma

Hyperinflation and airway plugging with exudate and mucus, especially in the bronchioles, can be seen postmortem.

Eosinophil infiltration is present in submucosa, and creola bodies are present. Surface epithelium shows significant disruption or loss.

The reticular basement membrane is homogeneously thickened with hyaline deposition. Smooth muscle in the larger airways is hypertrophied.

Edematous tissue is always present.

Bronchial glands are also enlarged.

Cellular infiltration is prominent with mononuclear cells positive for CD3, CD4, CD25, and IL-2 receptor (IL-2R), as well as many degranulated (activated) eosinophils.

Mast cells are notably increased in tissues.

Allergic fungal sinusitis (AFS)

The swollen mucosa is covered with thick sinus secretions that appear as allergic mucin and are loaded with degranulating eosinophils. Charcot-Leyden crystals can be found. Hyphae of the offending fungi should be visible.

Sinus mucosal tissue characteristically shows intense chronic inflammation with a large number of eosinophils.

In 6 children with allergic Aspergillus sinusitis, all had multiple sinuses densely packed with greenish black, inspissated mucin.

Allergic bronchopulmonary aspergillosis (ABPA) and allergic bronchopulmonary mycosis (ABPM)

The bronchi contain thick, tenacious mucus with fibrin, eosinophils, and Charcot-Leyden crystals.

Aspergillus (in ABPA) or other fungi hyphae may be identified with special stains. No invasion of the bronchial wall occurs despite a large number of hyphae.

The upper lobe bronchi may be dilated and partially collapsed, whereas smaller bronchi are occluded with mucus.

Bronchial wall inflammation with mononuclear cells and/or eosinophils often is observed.

Some changes from asthma are expected to be apparent.

Extrinsic allergic alveolitis (EAA)

In patients with acute and subacute forms of EAA, lung biopsy specimens may reveal noncaseating granulomas with foreign-body giant cells, large numbers of lymphocytes, foamy macrophages, and bronchiolitis fibrosa obliterans associated with centrolobular pneumonia.

Vasculitis is rare.

In chronic disease, the lesions become nonspecific as the granulomas disappear and fibrosis supervenes.

Interstitial pneumonitis persists, and bronchiolitis fibrosa obliterans may lead to peripheral destruction of alveolar walls.

The overall picture is a variable mixture of scarring pneumonitis, honeycombing, and emphysema.

Staging of mold allergy diseases depends on the affected organs. Staging of each of the 6 diseases discussed in this article is as follows:

Allergic rhinitis and/or conjunctivitis

Mold allergy–induced allergic rhinitis and/or conjunctivitis usually manifests with perennial or year-round allergic symptoms; in the seasonal form of allergic rhinitis, symptoms correspond with seasonal changes. No staging is apparent from a clinical standpoint.

Allergic asthma

According to Global Initiatives for Asthma: Global Strategy for Asthma Management and Prevention, asthma can be classified into 4 stages according to its severity, as follows:

• Stage I - Mild intermittent (symptoms < 1 time per wk, nighttime symptoms < 2 times per mo)

• Stage II - Mild persistent (daytime symptoms >2 times per wk, nighttime symptoms >2 times per mo)

• Stage III - Moderate persistent (symptoms daily, nighttime symptoms >1 time per wk)

• Stage IV - Severe persistent (symptoms continuous, nighttime symptoms frequent)

Allergic fungal sinusitis (AFS)

Most diagnoses of AFS are made after patients have prolonged sinusitis. The acute stage is not clinically apparent.

Allergic bronchopulmonary aspergillosis (ABPA) and allergic bronchopulmonary mycosis (ABPM)

In stage I (acute), diagnostic criteria are met (ie, asthma without infiltrate, peripheral eosinophilia >8%, histologic diagnosis of mucus impaction, sputum positive for Aspergillus species or other fungus, positive skin test and precipitin to fungus, elevated total serum IgE).

Stage II (remission) occurs after therapy with prednisone and with the lack of any subsequent radiologic findings for 6 months. IgE levels decline and stabilize. This stage may be permanent, but exacerbation may occur.

In stage III (exacerbation), radiologic findings include increased infiltrates, and the total serum IgE level at least doubles. Symptoms, including wheezing, fever with a temperature around 38.5°C, myalgia, and sputum production, may be increased.

Stage lV (prednisone-dependent asthma) occurs when repeated efforts to taper steroids fail. Diagnosis is established in some patients at this stage. Levels of IgE specific to fungi are elevated, as are precipitin antibody values. New infiltrates may be apparent if the prednisone dose is low.

Stage V (fibrotic) is end-stage fibrotic lung disease. Irreversible obstructive and restrictive pulmonary physiologic abnormalities occur. Anti-fungal antibody titers remain high. Patients develop honeycomb fibrosis, cyanosis, arterial hypoxemia, and respiratory failure. Death occurs with cor pulmonale. No patients regress from stage V to stage lV.

Extrinsic allergic alveolitis (EAA)

The acute form is easily recognized because symptoms are quickly distressing and incapacitating and have a high degree of specificity. Patients have repeated episodes of an influenza-like illness accompanied by coughing and undue breathlessness 3-9 hours after exposure to the offending fungi. The sensitizing period may vary from weeks to years. Affected patients may soon be able to identify the causative environment. The exposure level determines the severity of the disease.

In the chronic form, a slowly increasing loss of exercise tolerance occurs because of shortness of breath. This is the result of diffuse pulmonary fibrosis, which has been progressing for years. Eventually, hypoxia and pulmonary hypertension may supervene, and the right heart fails.

Depending on the level of fungal Ags exposed and the host responses, various intermediate forms of EAA can be recognized. Therefore, acute exacerbation may occur in those with a chronic form of the disease with only a limited degree of recovery following cessation of exposure. However, in some cases, fibrotic damage continues, regardless of the cessation of exposure.

The most important aspect of patient care is providing information to the patient and, if the patient is a child, the parent. Successful treatment depends on the patient understanding the nature of the disease and that it may be a lifelong ailment. Successful treatment of symptoms largely depends on the cooperation of the patient. Books or pamphlets can often be helpful.

Allergen avoidance

The measures below can be applied to any of the 6 clinical conditions related to mold allergy.

Symptoms can be alleviated by decreasing exposure to the specific allergens. For mold allergy, the local environment should be kept dry, and dense vegetation around the house should be eliminated. The affected individual may also find that avoiding raking leaves or engaging in other activities likely to stir up mold spores in the immediate atmosphere is helpful. Eliminating other local irritants as much as possible is also helpful.

The importance of a nonsmoking environment cannot be stressed enough.

Humidifiers and vaporizers are sources of indoor mold growth if they are not well maintained. A dehumidifier may be useful if the house is located in a humid environment. Roof leaks or wet walls can be sources of mold infestation in the house. A report indicated that an air-conditioned car can be a potential source of fungal allergens. A study in Kansas City indicated that fungal allergens were highest in the homes of children with asthma.

In occupation-related mold allergy leading to allergic bronchopulmonary aspergillosis (ABPA), allergic bronchopulmonary mycosis (ABPM), or extrinsic allergic alveolitis (EAA), the allergen can sometimes be removed from the environment. Otherwise, individuals perhaps should not work in that environment. Eliminating exposure helps control the disease in affected individuals and may prevent sensitization in unaffected but exposed individuals.

Simply altering the moisture content in the air and temperature can help. Avoiding or reducing the proliferation of normal airborne microbial contaminants that invariably occurs in the stagnant collection of water in air systems is crucial. Biocidal sterilizing agents must be considered for their low intrinsic toxicity and sensitizing potency. Recirculating filtered air is most economic but requires a high level of maintenance to decrease the load of respirable microbial allergens.

A study that examined in-home high fungal concentrations (>90th percentile), measured once within the first 3 months of life, as predictors of doctor-diagnosed allergic rhinitis in the first 5 years of life in 405 children in the Boston area indicated high measured fungal concentrations and reports of water damage, molds, or mildew in homes may predispose children with a family history of asthma or allergy to the development of allergic rhinitis.[24]

A study was conducted to evaluate the use of high efficiency in-duct air cleaners in patients with asthma triggered by fungal exposure. The results indicate the use of the system provide an effective means of controlling allergen levels not only in single room, like a portable air cleaner, but the entire house. The findings are useful for evaluating potential benefits of high efficiency in-duct filtration system.

In Cincinnati, Ohio, a study was conducted to determine whether mold exposure at the ages of 1 and/or 7 years was associated with asthma at the age of 7 years. Mold was assessed by a DNA-based analysis for the 36 molds that make up the Environmental Relative Moldiness Index (ERMI) at age 1 and 7 years. They found children living with a high ERMI-value (>5.2) home at age 1 year had more than twice the risk of developing asthma than those in low-ERMI value home (< 5.2). The study also showed air-conditioning at home reduced the risk of asthma development. This may be the first study that predicts the early exposure to molds at age 1 year would have significantly increased risk of asthma at age 7 years.[25]

Pharmacotherapy

Avoiding mold allergens all of the time is not easy. Therefore, pharmacotherapy remains a mainstay of medical management of all conditions related to mold allergy. Details of drug management for each condition are discussed further in Medication.

Pharmacotherapy - Allergic rhinitis and/or conjunctivitis

Antihistamines with or without decongestant, eye drops, and steroid nose sprays are available. Combined use of these drugs depends on the severity of the disease.

Pharmacotherapy - Allergic asthma

Depending on the severity of the disease according to the classification of the National Guideline of Asthma Education and Management, patients may receive one or more of the following agents: mast-cell stabilizer, short-term bronchodilator, long-term bronchodilator, leukotriene antagonists, inhalation corticosteroid, systemic corticosteroid, and theophylline.[21]

Patients with moderate-to-severe asthma who react to perennial allergens despite using inhaled corticosteroids may benefit from omalizumab treatment.

Two pivotal, 52-week, phase III trials were conducted in 1071 patients aged 12-76 years. The coprimary endpoint was mean asthma exacerbations per patient. Patients were randomly selected to receive subcutaneous omalizumab or placebo every 2-4 weeks. Inhaled corticosteroid doses were kept stable over the initial 16 weeks (stable-steroid phase) then tapered over 12 weeks (steroid-reduction phase). As add-on therapy to inhaled corticosteroids, omalizumab reduced exacerbations by 33-75% and 33-50% during the stable-steroid and steroid-reduction phases, respectively. The reductions were confirmed by improvements in other measurements of asthma control, including symptom scores (eg, nocturnal awakenings, daytime asthma symptoms).

The use of antifungal treatment for severe asthma with fungal sensitization was not well known. One study showed addition of itraconazole was beneficial. The study concluded severe asthma with fungal sensitization responded to oral antifungal therapy as judged by large improvement in quality of life in about 60% of patients.

Pharmacotherapy - Allergic fungal sinusitis (AFS)

A systemic corticosteroid is the treatment of choice. A high-potency intranasal corticosteroid should also be used.

Pharmacotherapy - Allergic bronchopulmonary aspergillosis (ABPA) and allergic bronchopulmonary mycosis (ABPM)

A systemic corticosteroid is the treatment of choice. When indicated, supportive therapy may include the use of a high-potency inhaled corticosteroid, adrenergic agonists, nedocromil, or theophylline. The results of trials with antifungal agents have not been convincing.

Several reports appeared sporadically about the success of treating ABPA by using antifungal agents. The antifungal treatment ranged from the use of a combination of oral erythromycin and fluconazole, the use of oral itraconazole alone, or inhalation of amphotericin B alone. At the initial stage, most studies reported the concomitant use of a corticosteroid and these antifungal agents. However, these are only case reports.

A single dose of 300 mg of the anti-IgE antibody, omalizumab, resulted in a dramatic and rapid improvement of symptoms and lung function in a 12-year-old girl with cystic fibrosis and ABPA.[26] . Another report also showed good response for 2 pediatric patients with CF and ABPA after an injection with omalizumab. Their admission number was significantly decreased. Additionally, their free IgE level decreased by 87.9% in one and by 95.6% in the other. The authors suggested free IgE measurement is useful for monitoring the clinical response.[27]

Pharmacotherapy - Extrinsic allergic alveolitis (EAA)

A systemic corticosteroid produces a rapid recovery. It may be supplemented with a bronchodilator.

Immunotherapy

For patients with allergic rhinitis and/or conjunctivitis, immunotherapy may offer lasting relief of symptoms. In general, results have not been as positive as those for patients with pollen allergy. Likewise, immunotherapy for allergic asthma due to mold allergy is not highly recommended. Immunotherapy has not been useful for patients with AFS, ABPA, or ABPM.

However, Hall and deShazo, after reviewing several studies of immunotherapy on AFS, found evidence that allergen immunotherapy is effective in the treatment of symptoms of AFS and may decrease the rate of postoperative exacerbation and further operation. There was no evidence that it induces immune complex disease. Thus, they concluded allergen immunotherapy could be a useful adjunctive therapy for AFS. However, they cautioned that if the therapy is administered before the removal of fungal contents, it could worsen sinusitis. More studies are pending on this issue.[28]

There is also a published report that the efficacy of sublingual specific immunotherapy (SLIT) in patients with respiratory allergy to Alternaria alternata is confirmed. Fifty-two subjects with a mean age of 20 +/- 9 years were studied. Clinical improvement was seen in 97% of the SLIT group, in contrast to 27% of the control group. The authors concluded SLIT, based on the blinded, controlled, 3-year study, should be considered for future therapy for respiratory allergy to fungi.[29]

The only clinical disease caused by mold allergy that is benefited by surgery is AFS. Surgical removal of the allergic mucin that obstructs sinus drainage opens the sinus ostium and removes the mucin, which is laden with fungi.

Other surgical procedures are related only to the adverse effects of the primary disease. For instance, an otolaryngologic surgery may be indicated for a patient with allergic rhinitis who develops chronic ear effusion, adenoid hypertrophy, or chronic adenoiditis.

An allergist/immunologist and/or a pulmonologist should be consulted for the diagnosis and long-term follow-up care of patients with any conditions related to mold allergy.

An allergist/immunologist can offer advice on how to avoid allergens and may perform skin tests or initiate a course of immunotherapy in patients with allergic rhinitis or conjunctivitis if clinically indicated.

Pulmonologists can offer valuable expertise on the care of patients with ABPA, ABPM, or EAA, especially if the patient progresses to chronic stage or end-stage lung disease.

An otolaryngologist can help with the surgical removal of allergic mucin or mucus plugging that obstructs the ostium of sinus tracts in patients with AFS.

A radiologist can help identify sinusitis or adenoid hypertrophy.

Patients should try to remain in mold-free environments. For EAA, susceptible individuals should not work in high-risk environments.

Various drugs are used for the treatment of upper airway diseases. For allergic rhinitis and conjunctivitis, antihistamine/decongestant and/or intranasal corticosteroid and anticholinergic nose sprays are the treatments of choice. For allergic asthma, short-acting or long-acting bronchodilators, mast-cell stabilizers, antileukotriene agents, corticosteroid inhalers, oral corticosteroids, anticholinergic inhalers, or theophylline may be indicated, depending on the stage of the disease. For allergic fungal sinusitis (AFS), allergic bronchopulmonary aspergillosis (ABPA), allergic bronchopulmonary mycosis (ABPM), and extrinsic allergic alveolitis (EAA), an oral corticosteroid is the treatment of choice; in AFS, it may be supplemented with a corticosteroid inhaler. In ABPA and ABPM, it may be supplemented with a corticosteroid inhaler or theophylline. In EAA, it may be supplemented with a bronchodilator.

Class Summary

These agents compete with histamine to bind to H1 receptors on the endothelium and smooth muscle. Histamine is a central vasoactive mediator in allergic rhinitis, and prophylactic use of antihistamines typically provides substantial control of symptoms. Dosage of traditional (first-generation) antihistamine classes is limited by the appearance of undesirable adverse effects including sedation, restlessness, dry mouth, urinary retention, constipation, and blurred vision. For this reason, new-generation antihistamines that are mostly free of such adverse effects are welcome options for treatment. Many first-generation antihistamines are available without a prescription, and loratadine, a second-generation antihistamine, is currently available over-the-counter (OTC).

Loratadine (Claritin)

Loratadine is a nonsedating second-generation antihistamine. It has fewer adverse effects than first-generation medications. It selectively inhibits peripheral histamine H1 receptors.

Desloratadine (Clarinex)

Desloratadine relieves nasal congestion and the systemic effects of seasonal allergies. It is a long-acting tricyclic histamine antagonist selective for the H1-receptor. It is a major metabolite of loratadine, which, after ingestion, is extensively metabolized to the active metabolite 3-hydroxydesloratadine.

Cetirizine (Zyrtec)

Cetirizine selectively inhibits histamine H1 receptor sites in blood vessels, the GI tract, and the respiratory tract, which, in turn, inhibits the physiologic effects that histamine normally induces at H1 receptor sites. Once-daily dosing is convenient. Bedtime dosing may be useful if sedation is a problem.

Levocetirizine (Xyzal)

Levocetirizine is a histamine1-receptor antagonist. It is an active enantiomer of cetirizine. Peak plasma levels are reached within 1 hour and the half-life is about 8 hour. It is available as a 5-mg breakable (scored) tablet and a 0.5-mg/mL oral solution. It is indicated for seasonal and perennial allergic rhinitis.

Fexofenadine (Allegra)

Fexofenadine is a nonsedating second-generation medication with fewer adverse effects than first-generation medications. It competes with histamine for H1 receptors in the GI tract, blood vessels, and the respiratory tract, reducing hypersensitivity reactions. It does not sedate, and it is available in daily or twice-daily preparations.

Class Summary

Antihistamines are most useful for symptoms of itching, sneezing, tearing, or postnasal drip. Decongestants relieve nasal congestion, reducing symptoms of sniffling. Many are available OTC in various combinations of an antihistamine plus pseudoephedrine.

Pseudoephedrine/loratadine (Claritin-D)

Pseudoephedrine/loratadine is a second-generation long-acting antihistamine/decongestant combination with 120 mg or 240 mg of pseudoephedrine.

Cetirizine/pseudoephedrine (Zyrtec-D)

Cetirizine selectively inhibits histamine H1 receptor sites in blood vessels, the GI tract, and the respiratory tract, which, in turn, inhibits the physiologic effects that histamine normally induces at H1 receptor sites. Once-daily dosing is convenient. Bedtime dosing may be useful if sedation is a problem.

Pseudoephedrine stimulates vasoconstriction by directly activating alpha-adrenergic receptors of the respiratory mucosa. It also induces bronchial relaxation and increases heart rate and contractility by stimulating beta-adrenergic receptors.

Pseudoephedrine/fexofenadine (Allegra-D)

Fexofenadine is a nonsedating second-generation medication with fewer adverse effects than first-generation medications. It competes with histamine for H1 receptors in the GI tract, blood vessels, and respiratory tract, reducing hypersensitivity reactions. It does not sedate.

Pseudoephedrine stimulates vasoconstriction by directly activating alpha-adrenergic receptors of the respiratory mucosa. It also induces bronchial relaxation and increases the heart rate and contractility by stimulating beta-adrenergic receptors.

Class Summary

These agents locally relieve nasal symptoms more effectively than oral antihistamines. They are often used with oral antihistamine.

Azelastine (Astelin, Astepro)

Azelastine is an aqueous nasal spray used to treat seasonal and perennial allergic rhinitis.

Class Summary

These agents prevent mast-cell activation and, thus, degranulation. Degranulation releases mediators (eg, histamine), which causes tissue swelling and chemotactic factors to attract eosinophils to the site. This leads to delayed-phase inflammation. This process is obvious in allergic rhinitis and allergic asthma but may also be involved in other clinical conditions related to mold allergy. Nedocromil may have more anti-inflammatory effect than other agents.

Cromolyn sodium (NasalCrom)

NasalCrom (5.2 mg per spray, nasal solution) is used for mast-cell stabilization in allergic rhinitis. The cromolyn sodium nebulizer solution (20 mg/2 mL, nebulizer solution) is used to prevent asthma.

Class Summary

Although oral antihistamines are useful for allergic conjunctivitis, ophthalmic drops offer immediate relief of eye symptoms from allergies (eg, itching, tearing, conjunctival swelling). Not indicated to relieve an acute asthma attack.

Olopatadine (Patanol, Pataday)

Olopatadine is an ophthalmic antihistamine solution indicated for temporary prevention of ocular itching due to allergic conjunctivitis. It is an inhibitor of histamine release from mast cells and is devoid of effects on serotonin, alpha-adrenergic, muscarinic, and dopamine receptors. Patanol is available as an ophthalmic solution 0.1%. Pataday is available as an ophthalmic solution 0.2%.

Class Summary

Corticosteroids are potent anti-inflammatory agents that affect activation of many cells (eg, mast cells, eosinophils, macrophages, lymphocytes) and effect of mediators (eg, histamine, eicosanoids, interleukins [ILs], cytokines) that are important in allergic inflammatory process or hypersensitivity reactions. Therefore, they are important for treatment of the various diseases attributable to mold allergy.

Mometasone (Nasonex)

Mometasone has demonstrated no mineralocorticoid, androgenic, antiandrogenic, or estrogenic activity in preclinical trials. It decreases rhinovirus-induced up-regulation in respiratory epithelial cells and modulates pretranscriptional mechanisms. It reduces intraepithelial eosinophilia and inflammatory cell infiltration (eg, eosinophils, lymphocytes, monocytes, neutrophils, plasma cells). It is available as an aqueous nasal spray of 50-mcg per spray.

Fluticasone intranasal (Flonase, Veramyst)

Fluticasone intranasal is used to treat allergic rhinitis. It is available as an aqueous nasal spray. The propionate (Flonase) delivers 50 mcg per actuation, whereas the furoate (Veramyst) delivers 27.5 mcg per actuation. Fluticasone furoate is well tolerated compared with the older propionate version, particularly in children.

Budesonide inhaled (Rhinocort Aqua)

Budesonide inhaled inhibits bronchoconstriction mechanisms, produces direct smooth muscle relaxation, and may decrease the number and activity of inflammatory cells, in turn decreasing airway hyperresponsiveness. It has extremely potent vasoconstrictive and anti-inflammatory activity. It alters the level of inflammation in airways by inhibiting multiple types of inflammatory cells and decreasing the production of cytokines and other mediators. It decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing capillary permeability. It is used for the treatment of allergic rhinitis.

Flunisolide

Flunisolide inhibits bronchoconstriction mechanisms, produces direct smooth muscle relaxation, and may decrease number and activity of inflammatory cells, in turn decreasing airway hyperresponsiveness. It decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing capillary permeability. It does not depress the hypothalamus.

Ciclesonide (Omnaris)

Ciclesonide is a corticosteroid nasal spray indicated for allergic rhinitis. It is a prodrug that is enzymatically hydrolyzed to the pharmacologic active metabolite C21-desisobutyryl-ciclesonide following intranasal application. Corticosteroids have a wide range of effects on multiple cell types (eg, mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (eg, histamines, eicosanoids, leukotrienes, cytokines) involved in allergic inflammation. Each spray delivers 50 mcg. It is well tolerated in children.

Class Summary

These are potent anti-inflammatory agents because of their effects on several cell types (eg, mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and on the production and secretion of mediators (eg, histamine, eicosanoids, leukotriene, cytokines) in inflammatory process. Inhalers listed below are valuable for the treatment of mild-to-moderately persistent or severe forms of allergic asthma and are used as supplemental therapy for ABPA, ABPM, and EAA. Oral inhaled corticosteroids allow avoidance of severe adverse effects associated with systemic corticosteroids.

Fluticasone inhaled

Fluticasone inhaled is indicated for the maintenance and treatment of asthma as prophylaxis; it is also used in patients requiring long-term systemic corticosteroid treatment to attempt gradual tapering and discontinuation of oral corticosteroids. It is available as Flovent MDI (44, 110, or 220 mcg per actuation), Flovent Rotadisk (50, 100, or 250 mcg per actuation), and dry powder in blister packs for inhalation with an inhalation device.

Budesonide inhaled (Pulmicort Flexhaler)

Budesonide inhaled inhibits bronchoconstriction mechanisms, produces direct smooth muscle relaxation, and may decrease the number and activity of inflammatory cells, in turn decreasing airway hyperresponsiveness. It has extremely potent vasoconstrictive and anti-inflammatory activity. It alters the level of inflammation in airways by inhibiting multiple types of inflammatory cells and decreasing the production of cytokines and other mediators. It decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing capillary permeability. It is used for the treatment of allergic rhinitis.

It is available as Pulmicort Flexhaler (90 mcg per actuation or 180 mcg per actuation delivers 80 mcg per inhalation or 160 mcg/inhalation) or Pulmicort Respules inhalation suspension (0.25 mg/2 mL, 0.5 mg/2 mL).

Triamcinolone inhaled (Azmacort)

Triamcinolone inhaled is indicated for the maintenance and treatment of asthma as prophylaxis; it is also used in patients requiring long-term systemic corticosteroid treatment to attempt gradual tapering and discontinuation of oral corticosteroids. It is available as Azmacort (75 mcg per actuation) and MDI with an attached Aerochamber device.

Class Summary

Short-term bronchodilators are beta2-agonists that act to relieve bronchospasm by elevating cyclic adenosine monophosphate (AMP) in cells. They are used for acute relief of bronchospasm and for prophylaxis, especially prior to exercise.

Albuterol (Proventil, Ventolin, Proair)

Albuterol is a beta-agonist for bronchospasm refractory to epinephrine. It stimulates adenyl cyclase to convert ATP to cAMP and causes bronchodilation. It relaxes bronchial smooth muscle by action on beta2-receptors, with little effect on cardiac muscle contractility. It may decrease mediator release from mast cells and basophils and inhibit airway microvascular leakage.

The frequency may be increased. Institute a regular schedule in patients on anticholinergic drugs who remain symptomatic.

The following list of albuterol products are for acute relief of asthma in various stages. It is most commonly used alone in intermittent asthma or as prophylaxis, especially before exercise.

It is available as a tablet at 2 or 4 mg, extended-release tablets are 4 or 8 mg, syrup at 2 mg/5 mL, hydrofluoroalkane (HFA) MDI 90 mcg per actuation, and inhalation solution for nebulization 0.083% (0.83 mg/mL, 2.5 mg/3 mL) or 0.5% (5 mg/mL).

Pirbuterol (Maxair)

Pirbuterol directly acts on beta 2-receptors to relax bronchial smooth muscle, relieving bronchospasm and reducing airway resistance.

Levalbuterol (Xopenex)

Levalbuterol is used for acute relief of asthma in various stages. It is used alone more commonly in intermittent asthma or as prophylaxis for asthma, especially before exercise.

Class Summary

One of the advantages of long-acting beta-agonists is prolonged relief for patients with obstructive lung disease (eg, asthma). They are especially useful for patients with nocturnal cough. However, long-acting beta(2)-adrenergic agonists including salmeterol and formoterol have a black box warning regarding an increase in risk of asthma-related deaths. Because of this risk, salmeterol use is contraindicated without a concomitant long-term asthma control medication such as an inhaled corticosteroid. To ensure compliance with therapy, a fixed-dose combination product containing both an inhaled corticosteroid and LABA is recommended in pediatric and adolescent patients.[30]

Salmeterol/fluticasone inhaled (Advair)

Fluticasone inhibits bronchoconstriction mechanisms, produces direct smooth muscle relaxation, and may decrease the number and activity of inflammatory cells, in turn decreasing airway hyper-responsiveness. It also has vasoconstrictive activity.

Salmeterol relaxes the smooth muscles of the bronchioles in conditions associated with bronchitis, emphysema, asthma, or bronchiectasis, and can relieve bronchospasms. Effects may also facilitate expectoration.

Adverse effects are more likely to occur when administered at high or more frequent doses than recommended. Two delivery mechanisms are available (ie, powder for inhalation [Diskus], metered-dose inhaler [MDI]). Diskus is available as a combination of salmeterol 50-mcg with fluticasone 100 mcg, 250 mcg, or 500 mcg. MDI is available as 21 mcg salmeterol with fluticasone 45 mcg, 115 mcg, or 230 mcg.

Budesonide/formoterol (Symbicort)

Formoterol relieves bronchospasm by relaxing the smooth muscles of the bronchioles in conditions associated with asthma.

Budesonide is an inhaled corticosteroid that alters level of inflammation in airways by inhibiting multiple types of inflammatory cells and decreasing production of cytokines and other mediators involved in the asthmatic response.

It is available as an MDI in 2 strengths; each actuation delivers formoterol 4.5 mcg with either 80 or 160-mcg of budesonide

Class Summary

These are potent anti-inflammatory agents because of their effects on many cell types (eg, mast cells, eosinophils, neutrophils, macrophages, basophils, lymphocytes) and on the production and secretion of mediators (eg, histamine, eicosanoids, leukotrienes, cytokines) in inflammation. Many conditions related to mold allergy (eg, allergic asthma, ABPA, AFS, ABPM, EAA) require systemic corticosteroids from the onset of disease.

When disease activity decreases, reducing the dose to the lowest effective level and trying to further taper it to an every-other-day schedule are advisable. Also, a oral inhaled corticosteroid may be used to replace a systemic steroid to reduce adverse effects.

For allergic asthma, systemic corticosteroids are indicated when patients have a severe form of asthma resistant to other forms of therapy.

Prednisone

Prednisone remains the mainstay oral systemic corticosteroid. Starting doses in each condition or different stages of same disease may differ. The main concerns with systemic corticosteroids, especially with long-term use, are adverse effects, which are more apparent than those of oral inhaled corticosteroids. Various tablet strengths and liquids are available to customize doses and ease tapering.

Prednisolone (Pediapred, Prelone, Millipred)

Starting doses in each condition or in different stages of the same disease may differ. The main concern with systemic corticosteroids, especially with long-term use, is their adverse effects, which are more apparent than those of oral inhaled corticosteroids. Various tablet strengths and liquids are available to enable customized doses and tapering ease.

Class Summary

In asthma, leukotriene is an important mediator released in the airway that causes constriction of smooth muscle. This is most apparent in a delayed-phase reaction. Therefore, use of leukotriene antagonists is an important part of treatment to control asthma. These agents are indicated for forms of asthma ranging from mild intermittent to severe. For children, it is a valuable treatment for the night cough or wheeze. Inhibition of lipoxygenase reduces production of leukotriene at peripheral tissue and achieves results similar to those of leukotriene antagonists.

Montelukast (Singulair)

Montelukast is a leukotriene receptor antagonist indicated for the long-term treatment of asthma. It is available as 4- and 5-mg chewable tablets, 4-mg granules, 10-mg oral tablets.

Zafirlukast (Accolate)

Zafirlukast is indicated for prophylaxis and long-term treatment of asthma. It is a leukotriene receptor antagonist.

Zileuton (Zyflo, Zyflo CR)

Zileuton is indicated for prophylaxis and long-term treatment of asthma. It is a 5-lipoxygenase inhibitor.

Class Summary

These agents directly relax smooth muscles of bronchial airways and pulmonary blood vessels, acting as bronchodilators and smooth muscle relaxants. They are used to supplement other asthma drugs, typically in moderately severe or severe asthma. Their effects in other forms of pulmonary diseases (eg, ABPA, ABPM, EAA) are unknown, though anecdotal evidence indicates that they have been tried in the chronic stage of the diseases.

Theophylline (Theo-24, Theolair)

Theophylline is available in a wide variety of dosage forms (tab, cap, extended release [ER], sprinkles, liquid), which enables ease of dosing. It is indicated for treatment of asthma, especially moderate-to-severe forms, as a supplement to other anti-inflammatory drugs.

Class Summary

These agents bind selectively to human IgE on the surface of mast cells and basophils.

Omalizumab (Xolair)

Omalizumab is a recombinant, DNA-derived, humanized IgG monoclonal antibody that selectively binds to the Fc portion of free IgE and thereby blocks binding to receptors on mast cells and basophils. It reduces mediator release, which promotes an allergic response. It is indicated for moderate-to-severe persistent asthma in patients who react to perennial allergens in whom symptoms are not controlled by inhaled corticosteroids.

Class Summary

An increase of local production of acetylcholine may cause tissue reaction in the case of hypersensitivity. This is most common in IgE-mediated hypersensitivity. Anticholinergic agents may be useful for allergic rhinitis or allergic asthma.

Ipratropium bromide (Atrovent)

Ipratropium bromide is available as a 0.03% (21 mcg per spray) or 0.06% (42 mcg per spray) nasal spray. It is suitable for allergic rhinitis. It is also available as an oral inhaler (18 mcg per actuation) indicated for moderate persistent or severe persistent asthma.

Allergic rhinitis and allergic conjunctivitis

A skin test for environmental allergens should be performed to establish the diagnosis of mold allergy.

Once the diagnosis is made, the patient should be given instructions regarding home environmental care, pharmacotherapy, and possible indications for immunotherapy.

Pharmacotherapy should include an antihistamine with or without decongestant, antihistamine nasal spray, mast-cell stabilizer nasal spray, and, most likely, a corticosteroid nasal spray.

These patients should be monitored regularly, at least every 3 months.

Sinus radiography or CT scanning of paranasal sinuses may be needed if sinusitis fails to respond to a proper therapy.

Children with obstructive apnea should undergo rhinoscopy or lateral imaging to identify adenoid hypertrophy.

Allergic asthma

The diagnostic workup, including skin testing and pulmonary function testing, is performed on an outpatient basis.

Prescription of drugs depends on the patient's stage of asthma, as follows:

• Mild intermittent - Short-acting bronchodilator inhaler or mast-cell stabilizer

• Mild persistent - Short-acting bronchodilator for acute relief, long-acting bronchodilator for long coverage, especially at night, leukotriene antagonist at night, and corticosteroid inhaler as needed

• Moderate persistent - Short-acting bronchodilator for relief, long-acting bronchodilator for long coverage, leukotriene antagonist at night, and corticosteroid inhaler on a regular basis

• Severe persistent - Oral corticosteroid daily (The patient may be allowed to use a corticosteroid inhaler as the oral steroid drug is tapered.) short-acting bronchodilator for acute attack, perhaps the addition of long-acting bronchodilator, a daily leukotriene antagonist, and the option of adding theophylline

Spirometry is used at the clinic. A peak flow meter is used at home.

Allergic bronchopulmonary aspergillosis (ABPA) or allergic bronchopulmonary mycosis (ABPM)

Diagnosis can be established on an outpatient basis by finding eosinophilia, elevated total serum IgE value, and a skin test positive for the suspected fungi; by finding precipitin antibody against suspected fungi; or by finding hyphae or positive sputum culture results for fungi.

Drug therapy begins with an oral corticosteroid followed by a corticosteroid inhaler if the condition improves. Patients should be monitored every 3 months with spirometer measurement of airflow.

Allergic fungal sinusitis (AFS)

For a patient with chronic sinusitis, use the same criteria for diagnosis as used for ABPA and ABPM listed above.

CT scans and sinus radiographs are needed on a regular basis.

Treatment should include sinus surgery and a prolonged course of an oral corticosteroid. If improvement occurs, a trial of a corticosteroid nasal spray to replace the oral steroid is appropriate.

Follow-up visits should occur every 3 months.

Extrinsic allergic alveolitis (EAA)

The diagnosis can be established on an outpatient basis with a carefully taken history regarding exposure, especially occupational exposure.

Chest radiography, pulmonary function testing, and lung scanning may be appropriate, depending on the clinical stage.

Treatment should begin with an oral corticosteroid for a lengthy period. Patients should remain in mold-free environments. An additional option of an inhaled corticosteroid or bronchodilator can be considered. In chronic stage disease, patients may need oxygen to avoid hypoxemia.

Pulmonary function should be tested on each clinic visit, which should occur every 3 months.

Allergic rhinitis and allergic conjunctivitis

Inpatient care is rarely necessary unless patients develop complications, such as adenoid hypertrophy, chronic retention of effusion in the middle ear, or complications of sinusitis.

Allergic asthma

Most patients have relief with proper home-environmental control, pharmacotherapy, and perhaps immunotherapy (for a small number of patients). However, acute asthma attacks are often medical emergencies that require emergency care. Therefore, some patients may visit the emergency department frequently. Unless patients develop impending respiratory failure because of a recalcitrant asthma attack, they are most likely to be monitored in an outpatient setting.

Allergic fungal sinusitis (AFS)

Patients are likely to be monitored on an outpatient basis while the condition is considered chronic sinusitis until the correct diagnosis is established. After the correct diagnosis is made, patients require sinus surgery, which may entail a short stay in the hospital. Treatment does not change while the patient is in the hospital.

Allergic bronchopulmonary aspergillosis (ABPA) and allergic bronchopulmonary mycosis (ABPM)

Most patients are initially monitored on an outpatient basis during diagnostic workup. Inpatient care is likely when the patients' conditions are unresponsive to adequate corticosteroid therapy. Frequent inpatient care is anticipated when patients' clinical conditions become chronic (stage lV or V). A superimposed infection notably compromises the respiratory system. Patients may require frequent, short hospital stays for pulmonary medical care. If the patient has an underlying condition, such as cystic fibrosis (CF), urgent inpatient care may be needed.

Extrinsic allergic alveolitis (EAA)

In the acute stage, inpatient care may be needed to establish the diagnosis. Otherwise, patients are likely to be seen regularly in the outpatient setting. However, as the disease continues to advance and respiratory function is compromised further, and with superimposed infection, the chance of inpatient care steadily increases. This is more apparent with change of heart condition, such as development of cor pulmonale or right heart failure. Whether these patients are candidates for lung transplantation remains uncertain.

General

Most mold allergy–related problems can be managed on an outpatient basis. If patients require inpatient care for acute conditions, the drugs used for outpatient care still apply.

Allergic rhinitis

Drugs are as follows:

• Oral antihistamine (Claritin, Zyrtec, Allegra) or over-the-counter (OTC) drugs

• Oral antihistamine-decongestant (Claritin D 12 h, Claritin D 24 h, Zyrtec D, Allegra D) or OTC drugs

• Astelin nasal spray

• Corticosteroid nasal spray (Flonase, Nasonex, Rhinocort, Nasarel, Nasalide)

• NasalCrom or Atrovent nasal spray (if indicated)

Allergic conjunctivitis

Drugs are as follows:

• Patanol eye drops

• Oral antihistamine (Claritin, Zyrtec, Allegra)

• OTC drugs with antihistamine effect

• Corticosteroid eye drops (rarely needed)

Allergic asthma

Drugs are the same for inpatient care and outpatient care, as follows:

• Mild intermittent - Cromolyn, Nedocromil, short-acting beta2-agonist bronchodilator

• Mild persistent - Cromolyn, Nedocromil, short-acting beta2-agonist bronchodilator, long-acting beta2-agonist, corticosteroid inhaler, leukotriene antagonist

• Moderate persistent - Long-acting beta2-agonist, leukotriene antagonist, corticosteroid inhaler

• Severe persistent - Long-acting beta2-agonist, corticosteroid inhaler, oral corticosteroid, leukotriene antagonist, theophylline, anticholinergic inhaler

Allergic bronchopulmonary aspergillosis (ABPA) and allergic bronchopulmonary mycosis (ABPM)

Drugs are the same for inpatient care and outpatient care. The drugs used for moderate persistent or severe persistent asthma may be added if the clinical picture resembles that of asthma. Oral corticosteroid and corticosteroid inhaler are indicated.

Allergic fungal sinusitis (AFS)

Inpatient care is necessary for surgery. Drugs are the same for inpatient care and outpatient care, as follows:

• Oral corticosteroid

• Corticosteroid inhaler

• Corticosteroid nasal spray

• Oral decongestant

Extrinsic allergic alveolitis

Drugs are the same for inpatient and outpatient care, as follows:

• Oral corticosteroid

• Corticosteroid inhaler

• Long-acting bronchodilator

Patients with allergic rhinitis and/or conjunctivitis, AFS, or allergic asthma do not require transfer.

Patients with ABPA, ABPM, or EAA, because of the relapsing nature of these diseases and their propensity to advance to a chronic stage in a subset of patients, may require transfer to a tertiary care medical center, in part for easy access to diagnostic procedures and greater expertise in dealing with these conditions.

Total avoidance of airborne mold allergens is virtually impossible; however, minimizing exposure should be encouraged. Measures may include the following:

• Remove the individual from the mold-infested area.

• Reduce indoor humidity.

• Remove mold stains on the walls, especially from wet surfaces.

• Apply fungicidal agents for cleaning.

• Remove carpet from cement floors.

• Avoid raking leaves or hay.

• Avoid exposure to outside air on foggy days.

• Use an air cleaner with a high-efficiency particulate air (HEPA) filter and regularly maintain it.

In indoor settings, an effort should be made to reduce mold growth by decreasing excessive moisture. A dehumidifier or fan should be considered to improve circulation in a room or building.

An air cleaner with a HEPA filter may help remove floating mold spores indoors. Several studies indicate that, with proper education on how to maintain the machine, an air cleaner with a HEPA filter benefits patients, especially those with allergic rhinitis, conjunctivitis, or allergic asthma.

One study indicated that an air-conditioning unit in an automobile can be a source of mold infestation when cars are left in hot environments. Patients are advised not to roll up the car windows until the air conditioning unit has been in full operation for 10 minutes.

Other pollution factors can always aggravate mold allergy symptoms. Cigarette smoking is especially harmful for susceptible individuals.

Allergic rhinitis and/or conjunctivitis

Long-term complications among persons who consistently breathe through their mouths include adenoid hypertrophy, adenoiditis, and recurrent sinus infections, all of which can lead to poor quality of sleep. Some individuals may develop obstructive sleep apnea. Chronic sinus drainage can cause bronchitis, pneumonia, or bronchiectasis. For some children, sinusitis can lead to orbital or periorbital cellulitis.

Allergic asthma

Poorly treated mold allergy asthma can have the same clinical results as any other form of allergic asthma. This includes status asthmaticus, which can lead to acute death. Other acute complications include pneumothorax and pneumomediastinum. Chronic relapsing asthma can lead to cor pulmonale or right heart failure, which may lead to death. In children, chronic asthma may lead to chest deformity such as a pigeon breast or barrel chest.

Allergic fungal sinusitis (AFS)

Poorly managed cases can result in chronic sinusitis, bronchitis, asthma, pneumonia, or bronchiectasis.

Allergic bronchopulmonary aspergillosis (ABPA) and allergic bronchopulmonary mycosis (ABPM)

Poorly treated cases gradually develop into stage IV disease, which is steroid dependent. As a result, the patient may develop signs of hypercorticism and metabolic changes. When patients develop stage V disease (fibrosis), the condition is generally considered irreversible. Patients may advance to cor pulmonale, right heart failure, and death.

Extrinsic allergic alveolitis (EAA)

In patients whose conditions are poorly managed, chronic disease, characterized by pulmonary fibrosis, may develop. Patients are liable to develop cor pulmonale and right heart failure and possibly die.

Allergic rhinitis and/or conjunctivitis

With the advent of oral nonsedating long-term antihistamine, antihistamine nasal spray, and various corticosteroid nasal sprays, many options are available for treating patients with differing degrees of symptom severity. With improvement of environmental care and immunotherapy available to those in whom it is indicated, the prognosis is good for most patients. The newer eye drops available should also help those with allergic conjunctivitis.

Allergic asthma

With the advent of revised national guidelines of asthma education and management the NIH sponsored and professional organizations supported, asthma can now be classified into 4 stages. Treatments are recommended for each stage. The availability of anti-inflammatory inhalers, long-acting bronchodilators, leukotriene antagonists, and other treatments should improve the outcome for patients with asthma.

The annual death rate has not declined, especially among teenagers in locations such as inner cities; this suggests that death can occur because of multiple factors, such as poor access to medical facilities, poor environmental control, and poor adherence to medical treatment. Given the number of people with asthma in the general population, strong public education is needed for asthma care. Another concern is that primary care physicians have not aggressively prescribed anti-inflammatory inhalers, especially to patients who already have moderate persistent asthma.

Allergic fungal sinusitis (AFS)

The prognosis for people with AFS is generally good if the treatment combines the surgical removal of allergic mucin, opening of breakage at the ostium of sinus tracts, and the use of a systemic corticosteroid. If poorly treated, AFS may cause chronic damage to the sinus cavity, which leads to chronic sinusitis.

Allergic bronchopulmonary aspergillosis (ABPA) and allergic bronchopulmonary mycosis (ABPM)

According to a Northwestern University follow-up study, if patients' conditions are properly diagnosed and treated, especially with a systemic corticosteroid, most should not progress beyond stage IV clinical disease.[31, 32] However, once patients enter stage V (fibrosis), the condition is almost irreversible. Those patients may also develop emphysema, cor pulmonale, and right heart failure. Early and aggressive treatment with a corticosteroid is critical in preventing advancement of the disease. Whether adding an antifungal agent improves the prognosis is debatable.

Extrinsic allergic alveolitis (EAA)

If the diagnosis is delayed or the patient remains in the mold-contaminated environment, the disease is liable to become chronic. No data are available regarding the prognosis for people with EAA. One might assume that those with chronic disease are likely to develop cor pulmonale followed by right heart failure.

General

Avoidance of mold exposure and adherence to medical treatment should be the main themes of patient education for each of the clinical disorders related to mold allergy.

Allergic rhinitis and/or conjunctivitis

Try to reduce humidity in the home environment. Use a dehumidifier in the house or turn up the air conditioner, changing the air filter frequently.

Remove any visible mold stains from the surface of wet areas, such as the bathroom, with a fungicidal agent.

Fix leaky roofs and/or wet walls.

Consider removing carpet from cement floors.

Do not rake leaves or hay.

Consider using an air cleaner with a HEPA filter in the bedroom. Make sure the machine is well maintained.

Do not allow children to lie on the carpet at home.

Make sure all rooms in the house or workplace are well ventilated.

Remember that air conditioning units in cars can harbor molds. Allow the air conditioner to run for 10 minutes before rolling up the windows.

Clean the air-duct system in the house or building periodically, especially in humid regions.

Smoking cessation among family members or workers is crucial. Never smoke in the house, a building, or the car.

Allergic asthma

All of the avoidance measures listed above apply.

Use national guidelines for asthma education and treatment sponsored by the NIH as a guide to treat each patient. Encourage adherence to medical advice.

Do not be afraid to use an anti-inflammatory (corticosteroid) inhaler, even in early stage asthma. Rinse your mouth after each use.

Maintain a good rapport with medical professionals about asthma care.

Exercise moderately to physical capability. Do not overexert. Ensure proper hydration.

Allergic fungal sinusitis (AFS)

All of the avoidance measures listed for allergic rhinitis apply.

Adhere to medical advice. Do not be afraid to take a systemic corticosteroid. This is the treatment of choice.

Report any adverse effects of medication to the physician.

Allergic bronchopulmonary aspergillosis (ABPA) and allergic bronchopulmonary mycosis (ABPM)

Patients with ABPA should be advised of the source of Aspergillus in the environment. Decomposing organic matter serves as a substrate for the growth of Aspergillus species. Also, Aspergillus species have been recovered from potting soil, wood chips, mulches, freshly cut grass, decaying vegetation, crawl spaces, and sewage treatment facilities, as well as from outdoor air. Aspergillus spores also grow in excreta from birds.

The same information should be given to patients who develop ABPM from exposure to specific fungi.

Extrinsic allergic alveolitis (EAA)

This group of patients becomes sensitized against a mold or molds in the work environment exclusively through exposure. The list of fungi includes thermophilic actinomycetes and Alternaria, Aspergillus, Aureobasidium, Cephalosporium, Cryptostroma, Mucor, Penicillium, Saccharomonospora, Streptomyces, Sporobolomyces, and Trichosporon species.

Individuals should be educated that in some professions they may develop precipitin antibodies against fungi along with abnormal pulmonary function tests or radiographic findings suggestive of mold-related disease even though they are still asymptomatic. These patients, especially those with symptoms in a particular environment, require regular checkups.

For excellent patient education resources, see eMedicineHealth's Asthma Center. Also, visit eMedicineHealth's patient education articles, Asthma, Asthma FAQ, Occupational Asthma, and Asthma Medications.