Table of Contents

Whole Allergen

m6 Alternaria alternata

m6 Alternaria alternata Scientific Information

Type:

Whole Allergen

Display Name:

Alternaria alternata

Route of Exposure:

Inhalation

Family:

Pleosporaceae

Species:

Alternaria alternata

Latin Name:

Alternaria tenuis

Summary

Alternaria alternata (A. alternata) is a predominantly outdoor mold, but it can also be found indoors. A member of the Pleosporaceae family, the genus Alternaria comprises more than 270 species of dematiaceous (black) hyphomycetes. Geography, seasonality, atmospheric conditions and time of the day influence their distribution. A. alternata spores spread widely on dry, warm, and windy days and usually peak during summer and early autumn. They can also be found in soil. A. alternata is a cosmopolitan mold and one of the most frequent fungal sensitizers, with a sensitization prevalence varying from 0.2% to 14.4% across the globe. Inhalation of A. alternata spores is associated with upper and lower respiratory hypersensitivity, mainly asthma and allergic fungal rhinosinusitis. Allergic bronchopulmonary mycosis and hypersensitivity pneumonitis may also develop. Allergens of A. alternata are found in both conidia and mycelia. Twelve molecular allergens of A. alternata have been approved by the World Health Organization/International Union of Immunological Studies (WHO/IUIS) Allergen Nomenclature Sub-Committee (www.allergen.org, accessed Feb 3^rd, 2021). Alt a 1 is a major allergen and a marker of genuine sensitization to A. alternata. Sensitization to A. alternata is often associated with sensitization to other molds and to other airborne allergenic sources such as pollens and mites. Co-sensitization and cross-reactivity to some food allergens have also been reported.

Allergen

Nature

Alternaria is a huge, complex genus comprising characteristic dematiaceous hyphomycetes. They mainly consist of saprotrophs and plant pathogens (1-3). A. alternata is regarded as one of the common species of this genus and its fungal spores are found all-round the year, predominantly outdoors (2, 3).

A. alternata grows fast in colonies of dark color ranging from gray, olive to olive brown. They have dark-colored hyphae divided by septa and forming septate conidiospores (3). The conidia (spores) are medium brown with short, cylindrical beaks, forming long and profusely branched-chain structures (1, 3).

Habitat

A. alternata is a prominent outdoor mold found ubiquitously in various environments all over the globe. The saprotroph species are mostly found in the soil, plants, and foodstuffs and parasitic species are present in animals, humans, and plants (2, 3).

The fungal spores are airborne and usually disperse when the weather becomes dry, warm, and windy. They achieve their peak levels in late summer to fall while absent in winters. The spores can survive at 2-32℃ temperatures with the optimum being 20°C (2, 3).

A. alternata is also found in indoor environments, particularly in damp, water-damaged buildings, and is one of the molds associated with the “sick building syndrome”. Moreover, they can be found in textiles (carpets or beddings) and bed dust samples (3).

Taxonomy

Alternaria is a complex and morphologically diverse genus. The Alternaria taxa have been classified based on either the size of conidia or host specificity. There are more than 270 species in the genus Alternaria. A. alternata is the most common species of this genus (1-3).

The taxonomic tree of A. alternata is as given in the table (2-4) as accessed on February 11, 2021:

*Taxonomic tree of A. alternata* (2-4)**
Domain	Eukaryota
Kingdom	Fungi
Phylum	Ascomycota
Class	Dothideomycetes (Euascomycetes)
Order	Pleosporales
Family	Pleosporaceae
Genus	Alternaria
Species	A. alternata

Tissue

Allergens of A. alternata are found in both conidia and mycelia. The hyphae that make up the mycelia are brown and septate. The conidia are simple, large, measuring 45-50×36 μm and, occur either singly or in the form of chains. Conidia are typically large, uniform with extended tips. However, if grown in cool and dry conditions, tips are shorter. Spores are released from the conidiophores in dry air passively and also by strong wind gusts (3).

Epidemiology

Worldwide distribution

While the true prevalence of A. alternata sensitization is unknown and the recorded prevalence of Alternaria immunoglobulin (IgE) reactivity in humans varies widely, it is reported to induce potent respiratory allergic reactions such as rhinitis, asthma, dermatitis, and human infections (5).

The European Community Respiratory Health Survey (ECRHS) I (2000-2002) studied 11,355 members of the general adult population for allergies caused by common allergens through skin prick tests (SPT) and specific IgE testing. The study, across 37 centers in 17 countries, including Australia, the United States of America (USA), the United Kingdom (UK), and Iceland, reported a 4.4% prevalence of sensitization to A. alternata allergens, varying from 0.2% to 14.4% in various centers (6, 7).

A multi-center, open-label study by the Global Asthma and Allergy European Network (GA2LEN) assessed clinically relevant sensitization rates of several allergens in 14 European countries. It involved 3,034 individuals suspected of having allergic diseases including allergic rhinitis (AR), asthma, atopic dermatitis (AD), and food allergies. The clinically relevant sensitization rate of A. alternata across Europe was found to be 6.1%, again with wide geographical variations: 0.0% (UK), 1.5% (Finland). 2.6% (Austria), 3.0% (Italy), 3.5% (Poland), 4.1% (Switzerland), 4.2% (France), 4.9% (Belgium), 5.5% (The Netherlands), 7.3% (Portugal), 7.9% (Germany), 8.2% (Denmark), 10.4% (Hungary) to as high as 18.7% (Greece) (8). A study conducted in Austria among 4,962 allergic patients with respiratory symptoms (rhinitis and asthma) found A. alternata sensitization in 12.6% (410/3248) allergic patients based on positive SPT to at least one allergenic source and in 66.1% (410/621) fungi-allergic patients (9). Another study in Finland found a 2.8% prevalence of IgE-mediated sensitization to A. alternata among 1,504 allergic patients (10).

Furthermore, a cross-sectional study among 1006 allergic patients in Iran reported sensitization to Alternaria to be 5.3% based on SPT reactivity (11). In the Guangdong province of China, sensitization to A. alternata among asthmatic children was found to be 14.9% (59/397) while among patients with AR it reached 44.9% (730/1625) (12).

Risk factors

Individuals working on farms and in sawmills are at a high risk of allergic reactions and infections induced by A. alternata due to the high level of its allergen count in these environments. Also, among people with respiratory allergy, younger individuals are at greater risk of developing sensitization to A. alternata than elderly people (5). Immune suppression is a risk factor for fungal opportunistic infections including alternariosis (1).

Environmental Characteristics

Worldwide distribution

Alternaria is one of the most common fungi in the world (13). The distribution of A. alternata is highly affected by geographical location, season, atmospheric conditions, and time of the day (5). It usually occurs in warm climates and tropical and sub-tropical zones, with spore counts remaining high throughout the year, while in temperate climates, the spores mainly occur from May to November (3). It is known to be present worldwide, in Asia especially China, Europe, the USA, Australia, and New Zealand (12, 14), while data from African countries are scarce (15).

Route of Exposure

Main

A. alternata fungal spores can enter the upper and lower respiratory tract through inhalation (5, 16).

Clinical Relevance

A. alternata has been identified as one of the major allergenic sources for the development and severity of respiratory allergic diseases. The allergenic threshold count of Alternaria spores (100 spores/m³) in the air is anticipated to be low as compared to Cladosporium spores (3000 spores/m³). Severe respiratory allergic symptoms, hospital admissions, and deaths due to asthma were found to be directly proportional to the levels of fungal spores in the atmosphere (5).

Allergic rhinitis

Sensitization to Alternaria species (spp.) is considered to be associated with the development of AR in children (17). However, it is not found to be associated with severity of AR as demonstrated in two studies conducted in Iran (18, 19). The first case control study reported the overall prevalence of sensitization to Alternaria spp. (positive SPT reactivity) to be 32.8% of the 58 AR patients with 45.5% having mild AR and 58.3% having moderate to severe. The study also reported that Alternaria sensitization was significantly associated (p<0.018) with the presence of Alternaria fungi in the nasal cavity of patients with AR (19). The second study conducted among 567 AR patients also found that severity of asthma was not significantly different (p=0.2) among intermittent AR (14.2%) or persistent AR (85.8%) patients sensitized to A. alternata (18).

Sensitization to A. alternata (positive SPT or IgE) in mold allergic patients (89-90%) conveys greater risk for development of asthma and intermittent AR than other molds, as reported in a study conducted in 239 mold allergic patients (20).

The prevalence of A. alternata sensitization (positive SPT reactivity) in AR shows wide geographical variation. It was reported to be 10-15% among AR patients (n=656) in Southwestern Iran (21) and 5.72% (n=699) in Northeastern Iran (11). Further, AR and allergic rhino-conjunctivitis were observed in 27.5% and 17.5% of 40 Finnish patients sensitized to A. alternata or C. herbarum (10). Looking into the Asian prevalence, Alternaria spp. sensitization was reported to be 17.6% in Malaysia (Malay, Chinese and Indian ethnicity) among 85 adult patients (age> 15 years) with AR (22) while prevalence in India was found to be only 2.6% among 4263 patients (age: 2-82 years) with AR and asthma (23). Similar prevalence (0-5%) was reported in Nepal in a cross-sectional study among 170 AR patients (age: 18-66 years) (24).

Interestingly, Alternaria spp. is also related to another phenotype of AR known as local allergic rhinitis (LAR), often in the Mediterranean areas. LAR is confirmed usually based on nasal production of specific IgE without any systemic sensitization (25). The role of Alternaria spp. in LAR was demonstrated in two studies. The first one was conducted on 56 children with AR, of whom, 37.5% were sensitized to Alternaria based on positive SPT while 80.3% of children were found positive for nasal IgE test to Alternaria spp. A nasal provocation test was performed to establish the relationship of Alternaria spp. with LAR and was found to be significant in patients with positive nasal IgE than in patients with positive SPT (26). Further, the second prospective study conducted on 84 adult patients with LAR found Alternaria spp. sensitization in 3.6% of patients (27).

Asthma

Sensitization to A. alternata is frequent in asthmatic patients (28). Its clinical relevance resides in its association with the severity of asthma (14, 29, 30) and the occurrence of exacerbations (30). Indeed, sensitization to A. alternata is considered to be a significant risk factor [Odds ratio (OR) – 2.03, 95% Confidence Interval (CI), p<0.001] for severe asthma (especially asthma attacks following storms, termed thunderstorm-asthma) as found in the ECRHS in European countries, US and Australia/New Zealand (5, 14).

Its overall prevalence was 11.9% among 1132 asthmatic patients across the globe in a multicenter cross-sectional epidemiological survey (ECRHS). The proportions of participants with asthma showing sensitization to A. alternata varied among study sites, from 28.2% (Portland, US), 17.6% (UK and Ireland), 13.7% (Central Europe), 10.5% (Australia and New Zealand), 10.2% (Northern Europe) to 4.7% (Southern Europe) (14). In a cohort study of 656 patients with asthma, AR or AD in Iran, sensitization to Alternaria spp. was reported in ~15% of patients with asthma (21). However, stratification as mild, moderate and severe persistent asthma in another study conducted with 187 patients found SPT reactivity to A. alternata in 34.2%, 51.9% and 13.9% respectively, without a significant difference (18).

Tariq et al. (1996) addressed fungal sensitization in an Isle of Wight birth cohort of 981 children (4-year-old) at risk for atopic disease. Of these, 6% reacted to A. alternata. In this study, typical outdoor molds A. alternata and C. herbarum were the third most common cause of sensitization, after house dust mite and pollens (31).

Taking it the other way, asthma was observed in 16 out of 40 Finnish patients showing positive SPT to A. alternata or C. herbarum (10). Furthermore. an Australian prospective cohort study involving 399 school children with positive SPT to one or more aeroallergens found significantly increased airway responsiveness in children sensitized to Alternaria as compared to other allergens. This study suggested that sensitized patients in areas with a high spore count of Alternaria can develop severe asthmatic reactions (13). asdad

Atopic Dermatitis

Similar to AR, the prevalence of sensitization to A. alternata in AD patients shows important variations as a function of the environment and the study population. In a study in Finland, AD was observed in 58% of 40 patients showing positive SPT to A. alternata or C. herbarum (10). Another study among 60 AD patients in Czech republic reported sensitization to fungal allergens in 35 patients, of which 13 (22% of the study population) were sensitized to A. alternata allergens Alt a 1 and Alt a 6 (32).

Wide geographical variation was also observed in the prevalence of A. alternata sensitization (positive SPT or IgE reactivity) among AD patients in Iran. Sensitization rates varied from 32% in northern regions to around 3% in the South (33). (21). (34). (35). Such discrepancy may also be related to the demographic and clinical features of the study populations.

Other diseases

Alternaria mycotoxins such as alternariol are contaminants of cereals, fruit, and fermented foods (3).

Infections

A. alternata can cause human infections such as cutaneous and subcutaneous infections, oculomycosis, sinusitis, onychomycosis, and invasive diseases (36).

Hypersensitivity pneumonitis (HP)

HP is an immune-mediated interstitial lung disease, either acute or chronic, developing in genetically predisposed individuals experiencing prolonged exposure to certain organic or inorganic inhaled antigens (37). Molds such as A. alternata, Aspergillus, Cladosporium, Mucor, etc. are common causative agents of HP. A. alternata is mostly involved in occupational HP, typically as humidifier lung disease or woodworker’s lung disease (38). Other occupational sources of exposure to A. alternata followed by occupational PHS are more anecdotal, such as in shiitake mushroom farmers (39). The diagnosis of PHS requires thorough documentation of clinical and radiological features, home and occupational exposure, followed by determination of specific IgG (current test replacing the 20^th century “precipitins”) directed to the culprits (40). Elevated levels of IgG (not IgE) to A. alternata upon diagnostic work-up, decreasing as a result of antigen avoidance, e.g., during the patient’s holidays, support the diagnosis of PHS caused by this mold (40).

Allergic bronchopulmonary mycosis (ABPM)

A. alternata is an uncommon cause of ABPM, estimated as less than 1% in Aspergillus-unrelated cases of ABPM (41). Two cases of ABPM due to Alternaria are reported in the literature: a 21-year-old male from the UK with a history of atopy and exacerbation of asthma symptoms (42), and an immunocompromised patient from India (28).

Prevention and Therapy

Prevention strategies

Avoidance

A. alternata is difficult to avoid as it is predominantly detected outdoors. Therefore, patients sensitized to fungi are advised to avoid areas with high allergen/spore counts, use masks when outside, and follow appropriate therapy (5). However, Alternaria allergen concentrations can also be high indoors, requiring the implementation of general measures aiming at mold reduction. The dampness in the environment can be avoided or decreased by frequently checking the intrusion, condensation and leakage of water in homes. Contaminated non-porous surfaces can be cleaned regularly with soap-water solutions or with bleach. Limited use of humidifiers or cool mist, frequent cleaning of the carpets and air purifiers, and regular maintenance of ventilation systems, humidifiers and similar devices could also help lower the mold concentrations in the indoor environments (43).

Molecular Aspects

Allergenic molecules

Currently, 17 allergens of A. alternata have been recognized, 12 of which are officially listed in the database of the World Health Organization/International Union of Immunological Studies (WHO/IUIS) Allergen Nomenclature Sub-Committee (3, 5, 44).

The table below provides detailed information on each of the allergenic protein identified by WHO/IUIS as on February 11, 2021:

Allergens	Molecular Weight (kDa)	Biochemical name	Allergenicity
Alt a 1	16.4 kDa and 15.3 kDa (30 kDa non-red) (dimer)		Major allergen and a marker of genuine sensitization to A. alternata (5). IgE reactivity prevalence of 80% and 98% in 98 and 42 A. alternata sensitized patients are reported respectively (45, 46). Both IgE and IgG antibodies found in asthma/rhinitis and atopic dermatitis patients were found to be 93% and 47% respectively (47). Involved in spore germination (5).
Alt a 3	70	Heat shock protein	Minor allergen (5). Recognized by 5% of the 7 sera of atopic patients sensitized to A. alternata (48).
Alt a 4	57	Disulfide isomerase	Minor allergen (5). Positive immunoblot recognition by 42% of 98 A. alternata sensitized patients. (45).
Alt a 5	11	Ribosomal protein P2	Minor allergen (5). Previously known as Alt a 6. Recognized by 14% of the 7 sera of atopic patients sensitized to A. alternata (48).
Alt a 6	45	Enolase	Minor allergen (5). Previously known as Alt a 5 or Alt a 11. Recognized by 22% of the 23 sera of patients sensitized to A. alternata (49).
Alt a 7	22	YCP4 protein	Minor allergen (5). Positive immunoblot recognition by 7% of 98 A. alternata sensitized patients (45).
Alt a 8	29	Mannitol dehydrogenase enzyme	Minor allergen (5). IgE reactivity on immunoblots was found to be 41% in 22 A. alternata allergic patients (50).
Alt a 10	53	Aldehyde dehydrogenase	Minor allergen (5). Positive immunoblot recognition by 2% of 98 A. alternata sensitized patients (45).
Alt a 12	11	Acid ribosomal protein P1	Minor allergen (5).
Alt a 13	26	Glutathione-S-transferase enzyme	Minor allergen (5). Positive skin test in 82% of 17 A. alternata sensitized patients (51)
Alt a 14	24	Manganese superoxide dismutase	Minor allergen (5). Positive immunoblot recognition by 11.5% of 61 A. alternata sensitized patients (52). Sensitization may be associated with allergic bronchopulmonary mycosis (5).
Alt a 15	58	Serine protease	Minor allergen (5). Positive immunoblot recognition by 10.2% of 59 A. alternata sensitized patients (53). Mostly observed in polysensitized individuals (5).

kDa: kilodaltons, IgE: Immunoglobulin E, YCP: Yeast Centromere Plasmids

Five other A. alternata allergens have been reported but have not yet been included in the WHO/IUIS approved list as of Feb 3^rd, 2021. These include Alt a TCTP (translationally controlled tumor protein), Alt a NTF2 (nuclear transport factor 2), Alt a 2, Alt a 9 and Alt a 70 kDa. The reported IgE reactivity of Alt a TCTP, Alt a NTF2, Alt a 2 and Alt a 9 in different studies was found as 4% (n=16), 0.8% (n=480), 0.0% (n=42) and 5% (n=98) respectively in A. alternata sensitized patients. Alt a 70 kDa triggered skin reactivity in 87% (n=16) of A. alternata sensitized individuals (5).

Biomarkers of severity

Alt a 1, recognized as a major A. alternata allergen and one of the primary elicitors of airborne allergies, is also considered a marker of genuine sensitization to A. alternata. It is specific for Alternaria genus and its related taxa like Pleosporaceae family species which has reported the presence of homologs of Alt a 1 (5). Further, Alt a 1 is found to be the protein that is formed before the germination of spores and related to the pathogenicity of the fungi (54). Alt a 1 level estimation in the environment could be used as a marker to predict the risk of development of respiratory reactions in patients allergic to A. alternata (55).

Furthermore, sensitization to other allergens like Alt a 3, Alt a 6, Alt a 10, and Alt a 13 may indicate co-sensitization as well as cross-reactivity with other allergens (3). Alt a 6 sensitization may be associated with cross-reactivity among members of different phyla like food, grass pollen and latex allergens (3, 32).

Cross-reactivity

Cross-reactivity is linked to the homology between allergens found in A. alternata and other allergenic molds, mainly Cladosporium, Penicillium, and Aspergillus. Less frequent cross-reactivity has been reported with foods: mushrooms and spinach (5).

Clinical cross-reactivity can occur without molecular homology, as reported for A. alternata and kiwifruit. Alt a 1 interacts with the thaumatin-like protein (PR-5) Act d 2 present in the pulp of kiwifruit and may be responsible for reactions to A. alternata caused by kiwifruit ingestion (54).

The table below provides the list of most common cross-reactive A. alternata allergens with other fungal allergens (5):

A. alternata allergen	Fungal Homologs IUIS allergens	Cross-reactive species
Alt a 3	Pen c 19 Mala s 10	Penicillium citrinum Malassezia sympodialis
Alt a 5	Fus c 1 Cla h 5 Asp f 8	Fusarium culmorum Cladosporium herbarum Aspergillus fumigatus
Alt a 6	Cla h 6 Asp f 22 Pen c 22 Cur l 2 Rho m 1	Fusarium culmorum Cladosporium herbarum Penicillium citrinum Curvularia lunata Rhodotorula mucilaginosa
Alt a 7	Cla h 7	Cladosporium herbarum
Alt a 8	Cla h 8	Cladosporium herbarum
Alt a 10	Cla h 10	Cladosporium herbarum
Alt a 12	Cla h 12 Pen cr 26 Pen b 26	Cladosporium herbarum Penicillium crustosum Penicillium brevicompactum
Alt a 14	Asp f 6 Mala s 11	Aspergillus fumigatus Malassezia sympodialis
Alt a 15	Cur l 4 Cla h 9 Cla c 9 Asp f 18, Asp f 13 Asp v 13 Asp o 13 Asp fl 13 Pen ch 13, Pen ch 18 Pen c 13 Rho h 2 Tri r 2	Curvularia lunata Cladosporium herbarum Cladosporium cladosporioides Aspergillus fumigatus Aspergillus versicolor Aspergillus oryzae Aspergillus flavus Penicillium chrysogenum Penicillium citrinum Rhodotorula mucilaginosa Trichophyton rubrum

Compiled By

Author: Turacoz Healthcare Solutions

Reviewer: Dr. Christian Fischer

Last reviewed: March 2021

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