eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology

Mold Allergy

Author: Shih-Wen Huang, MD, Medical Director of Allergy Service, Professor, Department of Pediatrics, Division of Immunology and Infectious Diseases, University of Florida College of Medicine
Contributor Information and Disclosures

Updated: Jun 15, 2009

Introduction

Background

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.

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.

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. 

Pathophysiology

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 fungal growth. Basements, window molding, shower curtains, and plumbing fixtures are common sites for indoor fungal growth.

• Allergic rhinitis and/or allergic conjunctivitis
  • These 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.⁴
• 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.
• 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.⁵
• 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.
• 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 recently been described in patients with CF. A child with CF was reported to have developed ABPM with Trichosporon beigelii. The disease is the result of types 1, 3, and 4 hypersensitivity reactions.
• 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.

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.

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.

Race

No racial predilection is known.

Sex

No sex predilection is known.

Age

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.

Clinical

History

• 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.^6,7 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.⁸ 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.⁵

Physical

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).⁹
  • In murine model of chronic fungal asthma, toll-like receptor 2 (TLR2) was shown to be a major contributor to the maintenance of adaptive type 2 t-helper cells (Th2)-cytokine driven and antifungal innate response.
• ABPA and 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.
• 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.
• 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.

Causes

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.

• 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 recent 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.

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