Alternaria alternata

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Code: m6
Latin name: Alternaria alternata/Alternaria tenuis
Source material: Spores and mycelium
Family: Pleosporaceae
Common names: Alternaria
Mold
A mold, which may result in allergy symptoms in sensitised individuals.

Allergen Exposure

Geographical distribution
The number of fungal species (from a variety of classes and families) is estimated to be at least 1 million. Some genera of fungi with airborne spores, such as Alternaria, Aspergillus, Penicillium and Cladosporium, are found throughout the world (1). Approximately 80 fungus species have been reported to be connected with respiratory allergy (2).
 
A. alternata, growing commonly on vegetation, is a member of the imperfect fungi and is one of the most important among the allergenic fungi. Brown segmented mycelia give rise to simple or solitary conidiophores, which may produce solitary apical spores, or a string of spores. The spores produced by imperfect fungi vary in shape, size, texture, colour, number of cells, and thickness of the cell wall (1). Although other Alternaria species are probably also relevant clinically, in particular as a result of cross-reactivity of the species, most research has been directed toward A. alternata.
 
Alternaria is one of the main allergens affecting children. In temperate climates, airborne Alternaria spores are detectable from May to November, with peaks in late summer and autumn (3). Dispersion of Alternaria spores occurs during dry periods. These feature higher wind velocity and lower relative humidity, which result in peak dispersion during sunny afternoon periods (4).
 
Despite the large spore size, spore dispersal may be for hundreds of miles from the source. Counts of Alternaria on dry, windy days can be in the range of 500 to 1,000 spores per cubic metre in grass- or grain-growing areas. Outdoor spore counts of up to 7500 spores per cubic meter of air were associated with indoor spore counts between 0 and 280 per cubic meter (5). Significant concentrations of Alternaria allergens, between 3.0 and 1000 U/g of dust, have been found in house dust of allergic children, supporting the hypothesis that fungal allergen exposure is an important component in the pathogenesis of asthma (6-7). Alternaria has also been found in house dust samples in the absence of outdoor environmental mold spores (8).
 
Sensitised children display symptoms even in the absence of airborne Alternaria spores. Alternaria spore concentration, as well as pollen, is usually detected by a fixed device on the roof of a building at a height of 10-20 m. A recent study found that at ground-level (50 cm) Alternaria spore concentrations are significantly higher in the presence of vegetation, suggesting that the individual's exposure to Alternaria, especially in the case of children, is underestimated by samples taken at roof-top level by a fixed volumetric collector (9).
 
Environment
A. alternata occurs on many plants and other substrates, including foodstuffs and textiles. Favourite habitats are soils, corn silage, rotten wood, compost, bird nests, and various forest plants. Black spots on tomatoes may be caused by A. Alternata. It is frequently found on water condensed on window frames. It is one of the most common mold spores found in dwelling dust in both North America and Europe. But Alternaria is predominantly an outdoor allergen favouring damp spots, and most indoor concentrations may derive from outdoor primary sources.
 
Modern buildings may be conducive to the creation of an environment for Alternaria to grow. Alternaria, present in the drip pan of an air conditioner unit, was reported to result in allergic rhinitis and asthma in a sensitised individual (10).
 
Alternaria spores appear in the atmosphere of Sydney year-round, although they peak over spring, summer, and autumn. A number of meteorological factors, including mean, minimum, and maximum temperature, dew point temperature, and air pressure, are significantly correlated with the atmospheric concentration of Alternaria spores. Some of these meteorological variables (temperature and dew point temperature) show significant correlations with a 1-, 2-, and 3- day lag in changes of concentration, as well as for the same day (11).
 
Alternaria allergens may be found in high concentration in work environments, in particular during grain threshing, flax breaking and thyme cleaning, as described in a study which found that on 8 of 12 farms, mold concentration exceeded a proposed standard of 50,000 CFU/m3. Alternaria was found to be a very prevalent mold in facilities for the processing of cereals, flax and thyme (12).
 
Unexpected exposure
Due to the nature of this allergen being present almost every where, nearly all exposure is unexpected.
 
Allergens
It is almost impossible to grow 2 consecutive cultures with exactly the same antigenic profiles (13). Thus, the number of allergens in A. alternata extracts may range from 10 to 30, and few allergens are present in nearly all extracts studied (14). The presence of specific allergens, including the major allergens, depends very much on the growth conditions, and may vary during the growth cycle, being higher one day than another (15-16). Furthermore, the major allergens are secreted proteins, whereas the other allergens are intracellular proteins, and these are presented to the immune system in the spores of this mold, which are too large to reach the alveoli of the lung (15). Furthermore, germination of spores significantly increases allergen release (but not all spores release allergens). For example, Alt a 1, the major allergen, may be a minor contributor to the total allergen released from spores, except when spores have germinated (17). How the phenomena revealed in these results reflect the allergen content of spores in the air that we breathe has, however, not been fully elucidated. Nevertheless, advances in molecular biology have led to a better understanding of these allergens and their relationship to allergic disease (18-19).
 
Allergens:
  • Alt a 1, a 29.2-31 kDa a major allergen, a heat-stable protein (1, 15, 20-37)
     
  • Alt a 2, a 25 kDa protein, a major allergen, an aldehyde dehydrogenase (1, 33-38)
     
  • Alt a 3, a heat shock protein (1, 15, 33-34, 36)
     
  • Alt a 4 (1, 15, 33-35)
     
  • Alt a 5, a 47 kDa protein, an enolase (formerly Alt a 11) (1, 33, 34, 39-44)
     
  • Alt a 6, a 11 kDa protein, an acid ribosomal protein P2 (1, 14, 33-34, 36, 45)
     
  • Alt a 7, a 22 kDa protein, a YCP4 Protein (1, 33-34, 36)
     
  • Alt a 8 (33, 35).
     
  • Alt a 9 (33, 35)
     
  • Alt a 10, a 53 kDa protein, an aldehyde dehydrogenase (1, 33-34, 36, 46)
     
  • Alt a 11, now reclassified as Alt a 5
     
  • Alt a 12, a 12, an acid ribosomal protein P1 (1, 34)
     
  • Alt a 70kD, a 70 kDa protein (47-48)
     
  • Alt a NTF2, a nuclear transport factor 2 protein (49)
     
  • rAlt a 1 (50)
     
  • rAlt a 2 (38-50)
     
  • rAlt a 5 (50).
     
  • rAlt a 7 (50)
Alt a 1 is the major Alternaria allergen causing sensitisation in asthmatics. Of 43 asthma/rhinitis patients having an Alternaria > 0.7 kUA/l, 93% of the asthmatics had IgE to Alt a 1, whereas only 47% of the atopic dermatitis patients had antibody to Alt a 1, and their levels were low when compared to the asthmatics. This particular study also found that other Alternaria allergens may be important in atopic dermatitis (51). Other studies have concurred in finding high rates of sensitisation to Alt a 1 in A. alternata-sensitised individuals, from 85.7% to rAlt a 1 (50) to >90% to natural Alt a 1 (23). However, studies indicate that this allergen may have several conformational or structural isoforms, which may be responsible for the allergen appearing to have a number of molecular sizes (25, 30).
 
Alt a 2 appears to be a major allergen, as indicated in a study in which rAlt a 2 bound to IgE antibodies in the sera of 16 of 26 (61%) individuals allergic to A. alternata (38).
 
Alt a 3 is recognised by approx. 5% of allergic subjects (14).
 
Alt a 5, an enolase, is recognised by approximately 20% to 50% of Alternaria-sensitised individuals (15, 44). However, skin-specific IgE testing with recombinant enolase in 7 Alternaria-allergic individuals produced positive results in only 2 individuals, indicating that rAlt a 5 may not have the same reactivity as the natural allergen (50).
 
Alt a 6 bound IgE from the sera of 7% of Alternaria-sensitive individuals (33).
 
Alt a 7 bound IgE in 7% of Alternaria-sensitive individuals (33). However, skin testing with recombinant Alt a 7 failed to elicit a positive result in 7 Alternaria-sensitive individuals (50).
 
Alt a 10 bound IgE in 2% of Alternaria-sensitised individuals (46).
 
Alt a 70kD accounts for 13% of the dry weight of Alternaria extracts and elicited positive skin test results in 87% (14/16) of patients with Alternaria sensitivity (47). This protein is thought to be distinct from Alt a 1, because substantial discrepancies were observed over time when the allergens were measured in air samples, which suggests that these glycoproteins are released under different conditions (18).
 
In a study evaluating the sera of a large cohort of monozygotic and dizygotic twins, researchers concluded that there was a strong genetic influence on IgE response to the mixture of Alternaria allergens and a weaker effect on IgE response to individual allergens (52).
 
Furthermore, it has been demonstrated that exposure to Alternaria allergens can be substantial, but still highly variable between individuals, and that the amount of mold particles inhaled relates both to location of the individual and activity being performed. The variation was found to be independent of age group (53).

Potential Cross-Reactivity

An extensive cross-reactivity among the different individual species of the genus could be expected (1). An Alt a 2 homologue has been found in 6 other Alternaria strains (38, 54).
 
Enolase is a common allergen found in many species of mold, and has been shown to exhibit high cross-reactivity to other fungal enolases (39). In particular, enolase from Alternaria alternata and Cladosporium herbarum are major allergens, and about 50% of the sera from patients have been reported to be reactive to each Cladosporium and Alternaria (44). IgE cross-reactivity has also been reported to occur between enolase from A. fumigatus, P. citrinum and A. alternata (40). Extensive cross-reactivity has been reported to occur between the enolases of C. herbarum, A. alternata, S. cerevisiae, C. albicans and A. fumigatus (15). The enolase from R. mucilaginosa shares high sequence identity with enolase allergens from Candida albicans (85%), Saccharomyces cerevisiae (76%), Penicillium citrinum (76%), Aspergillus fumigatus (76%), Cladosporium herbarum (76.5%), and Alternaria alternata (74%). Although enolases are highly conserved allergens among different fungal species, most of the allergic patients examined in this study differed in their IgE reactivity to the 5 different fungal enolases tested (41). The Latex allergen Hev b 9 is an enolase and has been shown to be cross-reactive with enolases from Cladosporium herbarum and Alternaria alternata (42, 55).
 
The nuclear transport factor 2 (NTF2) allergen from A. alternata has sequence homology with allergens from Cladosporium herbarum and Aspergillus fumigatus (49).
 
Without identifying comparable allergens, other studies have reported cross-reactivity with Alternaria.
 
Epi p 1 allergen from Epicoccum purpurascens has been reported to exhibit dose-dependent inhibition with Aspergillus fumigatus, Alternaria alternata, Curvularia lunata,Cladosporium herbarum and Fusarium solani, confirming cross-reactivity of this allergen. Other laboratory methods confirmed that Epi p 1 shares common epitopes with the fungi tested (56).
 
A 45 kDa protein isolated from Fusarium solani demonstrated cross-reactivity with Epicoccum nigrum, Curvularia lunata, Cladosporium herbarum and Alternaria alternata. The allergen involved did not show homology to enolase or other known fungal proteins (57). Marked cross-reactivity has also been reported between Epicoccum nigrum and A. alternata, with less by C. lunata, C. herbarum, and P. citrinum (58).
 
A report was published of a patient with oral allergy symptoms to raw, but not cooked, mushrooms, who also had positive skin testing to 4 types of molds. The immunoblot assay revealed immunoglobulin E antibodies directed against similar-molecular-weight proteins in the raw mushroom and 3 of the 4 molds: A. alternata, Fusarium vasinfectum, and Hormodendrum cladosporioides. These proteins were absent in the cooked mushrooms. The authors concluded that they had documented cross-reactivity between mushroom and molds in a patient with oral allergy syndrome to raw mushroom and allergic rhinitis as a result of hypersensititivy to molds (59).

Clinical Experience

IgE-mediated reactions
Sensitivity to Alternaria, a potent allergen, has been increasingly recognised as a risk factor for the development, persistence, and exacerbation of asthma (18, 31, 60-63, 51).
 
Studies have suggested that sensitivity to Alternaria may be a risk factor for life-threatening asthma (62, 64-65). In a study of 11 children and young adults aged 11 to 25 years with asthma who had sudden respiratory arrest, exposure to this aeroallergen was reported to be a significant risk factor (4). A 9-year-old boy with IgE-mediated sensitivity to Alternaria has been described as developing an acute, life-threatening asthma attack during the peak Alternaria season (18). The influence of ambient Alternaria spores on emergency department visits for children with acute asthma exacerbations has also been demonstrated (66-67).
 
Furthermore, asthma in children with Alternaria sensitivity was reported to persist beyond age 11 years, compared to asthma in individuals who were negative (68).
 
Alternaria-sensitised patients may also be at risk for allergic rhinitis (69). Most severe cases of rhinitis may be attributable to Alternaria sensitivity (70). According to a study to determine whether natural exposure to Alternaria induces rhinoconjuctivitis symptoms, among 132 alternaria-sensitised children (aged 7-12 years) in inland New South Wales, Australia, the proportion of children atopic to Alternaria, reporting symptoms of rhinitis and using anti-allergic medication was significantly higher in the summer, when airborne concentrations of Alternaria were high, than in the winter, when airborne concentrations were low. A strong correlation between airborne concentrations of grass pollen and Alternaria was found. However, when all children atopic to Rye grass were excluded from the analyses, significant associations between symptoms and season remained (71). Similarly, in the USA, where chronic rhinosinusitis is reported to be one of the most common long-term illnesses, patients with this disease were shown to have exaggerated humoural and cellular responses, both T(H)1 and T(H)2 types, to common airborne fungi, particularly Alternaria. Researchers concluded that the anomalous immune and inflammatory responses to ubiquitous fungi may explain the chronic nature of airway inflammation in chronic rhinosinusitis (72).
 
Fungal components may upon skin contact cause eczema or trigger inflammatory skin eruptions in a subgroup of patients with atopic eczema (73). Infrequently, hypersensitivity pneumonitis has also been attributed to this organism (74).
 
Although it is clear from a number of epidemiologic studies that sensitisation to indoor allergens and the spores of the outdoor seasonal fungus Alternaria are risk factors for the development of asthma in both children and adults (75), detailed investigation is problematic. Many studies have utilised serum-specific IgE and skin-specific IgE determination, but there are inherent difficulties with the manufacturing and standardising of fungal extracts (76), and variability in epidemiologic studies inevitably results (18). Un-standardised mold extracts may also result in poor outcomes in specific immunotherapy (77). It has furthermore been suggested that skin-specific IgE evaluation with either epicutaneous or intradermal testing may not be an accurate or sufficient technique for the assessment of Alternaria reactivity, as mold allergies may involve more complex immune mechanisms than an immunoglobulin (Ig)E-mediated type I immediate hypersensitivity response alone (78).
 
Indeed, where routine diagnostic tests were unhelpful in determining the causal allergens of asthma, aerobiological sampling using a battery-powered portable device allowed identification of the responsible allergen, Alternaria in one case and thuja pollen in the other. This suggests that in selected cases of difficult diagnosis, aerobiological sampling with a portable device should be considered (79).
 
Nonetheless, widespread sensitisation to Alternaria indicates that this is a common allergen, particularly for asthmatics, and especially for younger patients (18). Therefore, although the prevalence of sensitisation to commercial fungal extracts has been reported to be approximately 3% in epidemiologic studies, in selected groups of patients, particularly those with asthma, the sensitisation rate might be as high as 30% (2).
 
North America
A. alternata is considered one of the most important allergenic molds in the United States, and is one of the most widely studied. In the USA, up to 80% of subjects with confirmed asthma have demonstrated positive reactions to 1 or more fungi (46, 80). And up to 70% of patients with fungal allergy have skin sensitisation to Alternaria (18). The highest concentrations of spores are in grain-growing areas such as the Midwest (4). Nevertheless, in a study of 12,086 asthmatic children with asthma residing in US inner cities, 38.3% had positive skin test reactions to Alternaria species (81).
 
In a 1987 study of more than 17,000 US citizens, positive skin-specific IgE test responses to Alternaria occurred in 3.6% (82). In a later study, asthma was reported to be associated with sensitisation to house dust and Alternaria in a sample of 4295 individuals aged 6 to 24 years, and allergic rhinitis was associated with reactivity to Ragweed, Rye grass, house dust, and Alternaria (83). In a cross-sectional survey of a representative sample of 4164 United States children aged 6 to 16 years (the Third National Health and Nutrition Examination Survey from 1988 to 1994), it was concluded that African American children had significantly higher odds of sensitivity to A. alternata (84). In a study in Pennsylvania, sensitivity to Cockroach antigens and Alternaria was significantly greater in the urban population than in the pooled rural group (85).
 
The association between mold hypersensitivity and asthma was assessed in a large group of ambulatory patients for the years 1993 through 2001 at a single medical centre in New York, showing that the presence of hypersensitivity to either A. alternata or C. herbarum had a significant independent association with asthma after adjustment for Cat/Dust mite hypersensitivity, and after adjustment for other clinical factors. The authors concluded that it was conceivable that mold hypersensitivity plays a contributing and independent role in initiating or perpetuating the allergic response in patients with asthma in the New York area (86).
 
Europe and the UK
Studies in Europe have also evaluated Alternaria sensitisation. In an epidemiological survey in 30 centres across Europe, the frequency of sensitisation to molds (Alternaria alternata, Cladosporium herbarum, or both) increased significantly with increasing asthma severity in all of the regions studied, although there were differences in the frequency of sensitisation. Researchers concluded that sensitisation to molds is a powerful risk factor for severe asthma in adults (87).
 
In a 1996 study of 981 children on the Isle of Wight, United Kingdom, examined for atopy at age 4 years, and assessed by skin-specific IgE to a battery of allergens, 61 (6%) were shown to be sensitised to Alternaria alternata and Cladosporium herbarum (88). In a 2001 report on the same group, allergic disorders (asthma, rhinitis, and eczema) were present in 276 (28.1%) of 981. Atopy was found in 19.6% of the children, and 50% of children sensitised to House dust mite had asthma, as opposed to 44% of those sensitised to Cat, 42% of those sensitised to grass pollen, and 32% of those sensitised to A alternata. Overall, 57.4% of children sensitised to A. alternata had asthma, eczema, and/or rhinitis. The respective figures for grass pollen, Cat, and House dust mite were 64.9%, 66.7%, and 68.4% (89).
 
In Italy, a study evaluated the frequency of respiratory allergies in different age groups of asthmatic atopic children in the Chieti-Pescara area. Among 507 children aged between 1 to 17 years examined using skin-specific IgE determination for 12 common aeroallergens, it was found that 13% were sensitised to Alternaria (90). In a study evaluating a group of patients monosensitised to Alternaria, of 37 subjects, 20 were asthmatic and 22 experienced perennial symptoms. Serum-specific IgE carried out on 34 monosensitised subjects was positive in 11. The study concluded that Alternaria sensitisation is characterised by a perennial periodicity, with severe respiratory symptoms (asthma) occurring primarily in children (91). In a study north of Milan, sensitisation to airborne allergens was assessed in 726 patients. It was reported that the prevalence of new sensitisations was 11% in Alternaria-allergic subjects (92). In a cohort of 4962 respiratory subjects aged 3-80 years examined using skin-specific IgE tests to fungal extracts from Alternaria, Aspergillus, Candida, Cladosporium, Penicillium, Saccharomyces, and Trichophyton, 19% of the allergic population reacted to at least 1 fungal extract. Alternaria and Candida accounted for the largest number of positive tests, and along with Trichophyton they were the main sensitisers in the subset of patients with an isolated sensitisation (93).
 
In a Polish study assessing allergy to mold in 460 adults with perennial rhinitis and asthma, the most frequent allergy was to Alternaria (47.1%) and Cladosporium (30.8%) (94).
 
In Thessaloniki, Greece, of 1311 asthmatics with atopy, positive skin reaction to fungal spores was observed in 421 (32%). Positive skin-specific IgE was found to Alternaria species in 177 patients (13.5%), in 98 (7.4%) to Cladosporium, in 65 (5%) to Aspergillus, in 45 (3.4%) to Fusarium and in 36 (2.7%) to Rhizopus. Mold hypersensitivity was found to be more frequent in younger men (95).
 
In Finland, from skin-specific IgE tests performed with C. herbarum in 6,376 Finnish patients and also with A. alternata in 1,504 of this group, it was found that the prevalence of positive tests to A. alternata and C. herbarum was low (2.8% and 2.7%, respectively). Most of the patients were also positive to several other fungal allergens. Four patients had a positive reaction to A. alternata and 6 to C. herbarum in conjunctival challenges (96).
 
Australia
In an Australian study examining sensitisation to Alternaria in different climatic regions, in the less humid interior, sensitivity to Alternaria was more likely to be associated with asthma than sensitivity to house dust mites. In the study group, 15.2% of 770 subjects were sensitised to Alternaria (97). In a study investigating the extent to which exposure to Alternaria increases the severity of asthma, a prospective cohort study was done of 399 school children who had positive skin tests to 1 or more aeroallergens. Airway responsiveness, wheeze, and bronchodilator use increased significantly in association with increased spore concentrations, and the increase in airway responsiveness was greater in children sensitised to Alternaria than in other children. The results suggested that Alternaria allergens contribute to severe asthma in regions where exposure to the fungus is high (62).
 
Asia
Alternaria sensitivity has also been evaluated in desert environments. In 810 patients from Kuwait, with extrinsic asthma or allergic rhinitis, sera were assessed for specific IgE to 6 fungi. Overall, 20.9% had serum-specific IgE to at least 1 mold. Asthmatic children had the highest sensitisation rate (66.0% in the 7- to 12-year age group). Among asthmatics, Candida and Aspergillus had the highest sensitisation rates (23.1 and 21.3%, respectively), followed by Helminthosporium (18.8%), Cladosporium (15.9%), Alternaria (14.6%) and Penicillium (13.9%). Researchers concluded that even in a desert environment, sensitisation to molds is quite common among patients with allergic respiratory diseases (98). Similarly in Saudi Arabia, 13% of patients were found to be sensitised to fungal extracts (99). A study reported that Alternaria is a major allergen associated with the development of asthma in children raised in a semiarid environment and that skin test responses at age 6 are more closely linked to asthma than those at age 11 (61).
 
Alternaria has also been reported to be an important aeroallergen in the East, including Taiwan (100). In a Japanese study using both skin- and serum-specific IgE determination on 94 asthmatic patients (mean age 12 years), Aspergillus restrictus, Aspergillus fumigatus, Alternaria alternata and house dust elicited positive reactions in 8 (8.5%), 8 (8.5%), 15 (16.0%) and 69 (73.4%) patients, respectively. Serum-specific IgE was found in 27 (28.7%) subjects for A. restrictus, 22 (23.4%) for A. fumigatus, 35 (37.2%) for A. alternata, and 75 (79.8%) for house dust (101).
 
Occupational allergy
Alternaria sensitisation may occur in occupational settings, including gardens, bakeries, forests and farms. Occupational asthma may be precipitated by fungal spores of Alternaria, Macrosporium and Stemphylium during Asparagus and Strawberry harvesting times year-round. Alternaria is associated with baker's asthma and wood pulp worker's lung. In a study evaluating 3 types of farming activities, including animal feeding on a hog farm, cleaning and animal handling on a dairy farm, and soybean unloading and handling on a grain farm, grain unloading and handling activity generated the highest concentrations of airborne fungi, compared to the other 2 activities. Prevalent airborne fungi belonged to Cladosporium, Aspergillus/Penicillium, Ascospores, smut spores, Epicoccum, Alternaria, and Basidiospores (102).
 
Cladosporium and Alternaria have also been shown to be the leading strains of fungi encountered in fur processing procedures, resulting in cough, sputum, chest tightness, dyspnoea, and fever. Antibodies to Cladosporium and Alternaria (44.2%, 42.8%) were significantly higher than those in the control workers (103).
 
Air contamination inside greenhouses is mainly related to molds, and is facilitated by the high indoor temperature and humidity. Cladosporium, Penicillium, Aspergillus, and Alternaria and a wide range of flower pollens can sensitise greenhouse workers and cause occupational asthma (104).
 
Other reactions
Pulmonary fungal infections (105) and localised skin infections, in particular in patients receiving long-term glucocorticoid therapy, and especially in immune-compromised patients, may also be encountered (106).
 
Compiled by Dr Harris Steinman, harris@zingsolutions.com 

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As in all diagnostic testing, the diagnosis is made by the physican based on both test results and the patient history.