Diagnosis of Alternaria alternata Allergy and Its Immunotherapy: History
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Subjects: Allergy
Contributor:
Eva Abel-Fernández
,
María José Martínez
,
Tania Galán
,
Fernando Pineda

Fungal allergy is the third most frequent cause of respiratory pathologies and the most related to a poor prognosis of asthma. The genera Alternaria and Cladosporium are the most frequently associated with allergic respiratory diseases, with Alternaria being the one with the highest prevalence of sensitization. Alternaria alternata is an outdoor fungus whose spores disseminate in warm and dry air, reaching peak levels in temperate summers. Alternaria can also be found in damp and insufficiently ventilated houses, causing what is known as sick building syndrome. Thus, exposure to fungal allergens can occur outdoors and indoors. However, not only spores but also fungal fragments contain detectable amounts of allergens and may function as aeroallergenic sources. Allergenic extracts of Alternaria hyphae and spores are still in use for the diagnosis and treatment of allergic diseases but are variable and insufficiently standardised, as they are often a random mixture of allergenic ingredients and casual impurities. Thus, diagnosis of fungal allergy has been difficult, and knowledge about new fungal allergens is stuck. 

  • fungal allergy
  • Alternaria alternata
  • molecular biology

1. Classification, Morphology and Distribution of Alternaria alternata

Fungi are heterotrophic eukaryotic organisms, and their reproduction can be sexual by spores (e.g., ascospores, basidiospores, zygospores), asexual by spores or mitospores (conidiospores and spores, created in sporangia), or by fragmentation of the mycelium, budding (in yeasts), and fission (vegetative reproduction).
Fungi are cosmopolitan organisms. They can be found in any region of the world. More than 100,000 species have been described so far. Nevertheless, it is estimated that there are at least one million and a half species [1]. Of these, only a few hundred have been described as opportunistic pathogens, producing disease in humans through three specific mechanisms: direct infection, induction of dysregulated immune responses and secondary metabolite toxicity. In general, exposure to fungi occurs by inhalation, skin contact or ingestion, although the inhalation route is the most important in terms of producing respiratory symptomatology.
Among the pathogenic fungal species described, about 80 genera produce type I allergy (IgE antibody-mediated), which usually manifests as allergic rhinitis and rhinosinusitis, allergic asthma and atopic dermatitis [2]. The most relevant allergenic fungi belong to the phylum Ascomycota, followed by the phyla Basidiomycota and Zygomycota. The genera Alternaria, Cladosporium, Aspergillus and Penicillium, belonging to the phylum Ascomycota, are considered the most relevant allergenic sources [2][3][4]. Other less relevant allergenic fungi are Candida, Fusarium or Curvularia (Ascomycota), Malassezia (Basidiomycota) or Rhizopus (Zygomycota), among others [2]. Alternaria alternata has a worldwide distribution and a high presence in the environment. The Alternaria spores are considered one of the most abundant and potent sources of sensitising airborne allergens [5].
The genus Alternaria belongs to the family Pleosporaceae, in the order Pleosporales, the largest of the class Dothideomycetes. A total of 275 Alternaria species were recognized according to the results of a study on Alternaria taxonomy based on morphological characteristics [6]. Alternaria is black-coloured due to melanin and forms fast-growing colonies. The surfaces of mature colonies may have a moist appearance due to the presence of numerous hyphae. The hyphae are septate and form conidiophores, also divided by septa. The conidia may be single or form chains. The A. alternata spores require dry air to be dispersed and relatively large, elongated and transversely septate [7]. Spores can separate from the conidiophore in dry air both passively and under the influence of strong winds. The similarity of the morphology and its variation according to the growth conditions makes it difficult the identification of the different Alternaria species [8].

2. Diagnosis of Alternaria alternata Allergy and Its Immunotherapy

Allergic symptoms usually correlate to the presence of the allergenic source in the environment (pollen grains, mites and derivates, etc.). Regarding fungal allergy, patients who are allergic to A. alternata are frequently sensitized to other allergens such as grass and olive pollen, which are present in the atmosphere at the same time of the year, difficulting the diagnosis of Alternaria allergy. Traditional methods used to elaborate aerobiological calendars are based on pollen and spore detection. Nevertheless, it has been shown that Alternaria allergic symptoms do not correlate with the atmosphere spore counts, while a positive correlation has been observed between symptomatology and Alt a 1 levels [9]. Further studies relating symptoms and the detection of different allergens in the environment should be developed to improve the diagnosis of Alternaria allergy and help to predict the prognosis of the disease [10].
Allergen extracts are complex biological products used for the diagnosis and treatment of allergic diseases. They are obtained from the natural source (raw material) by extraction of its components. The biological composition of allergen extracts may change depending on the raw material origin, the time of collection and/or the production method, as well as the allergen elution methods and times, together with the purification processes used [11]. These factors will determine the final composition and quality of diagnostic products and vaccines and standardised products should be used as far as possible to ensure their efficacy and safety.
Since the 1990s, the development of recombinant allergen molecules has offered new diagnostic and therapeutic possibilities at a molecular level, allowing the identification of allergens to which a patient is sensitised, using purified natural or recombinant allergens in singleplex or multiplex measurement platforms [12][13][13]. Currently, the use of individual allergens for allergy testing in patients, known as Component Resolved Diagnosis (CRD), has improved allergy diagnostic accuracy and efficacy. The application of CRD has made it possible to minimise the problems of standardisation of allergen extracts, such as variability between fungal strains and between batches, the type of culture and technology used to prepare allergen extracts, as well as the stability of the extract once obtained. In recent decades, the application of molecular diagnostic procedures using individualised allergens has been helpful in the treatment of atopic individuals and allergic patients [14].
From the point of view of their composition, in most cases, allergy vaccines are safe, and their effectiveness is 80–90%, depending on the allergen or allergens involved. This efficacy has been proven in controlled studies in asthma and allergic rhinitis caused by mites, pollens and some fungi and animal epithelia [15]. However, the administration of allergenic extracts, whether subcutaneously or sublingually, is not exempt from risk. Generally, the most frequent reactions are local, with swelling or itching at the site of application, and although more severe reactions are rare, they occur within minutes of administration and can be life-threatening [16].
The efficacy of subcutaneous immunotherapy with allergenic extracts of Alternaria spp. and Cladosporium spp. has been demonstrated in adults and children; prospective, double-blind studies conducted so far have shown a symptomatological improvement in treated patients, as well as a decrease in IgE antibody levels and an increase in serum IgG levels [16][17][18][19][20][21][22][23][24].  However, fungal allergenic extracts have a complex composition of proteins, cbohydrates and other components that do not contribute to allergenicity but may produce adverse effects during treatment, so the safety of subcutaneous immunotherapy has been questioned [25]. It has been observed that treatment of asthmatic patients with extracts of Alternaria spp. and Cladosporium spp. produced a greater number of severe anaphylactic reactions than those produced by grass pollen, mites, or animal epithelia [26][27]. Thus, fungal extracts have been found to be less well tolerated than other allergenic extracts.
Different strategies have been developed to shorten allergy treatments and reduce the risk of developing adverse reactions. These are based on the modification of allergens or their adsorption to insoluble carriers (aluminium hydroxide, calcium phosphate, etc.). One of the most widely used methods, which has been shown to reduce allergenicity without compromising immunogenicity, is the use of glutaraldehyde (GA). GA is an aliphatic dialdehyde that binds to the free amino groups of amino acids such as lysine and arginine. Its addition to the allergenic extracts produces a chemical cross-linking between the proteins, obtaining allergen polymers or allergoids, which have altered immunological characteristics and a larger average molecular size much (100 to 1000 times larger) [28].
Another immunotherapy strategy is the isolation and characterisation of purified allergenic molecules from natural sources of allergens using classical biochemical methods [29][30] However, single-allergen immunotherapy might not be successful in the total allergic population. Rodriguez et al. observed in 64 patients from a clinical trial that the percentage of recognition for Alt a 3, Alt a 4, and/or Alt a 6, Alt a 7, Alt a 8, Alt a 10 and/or Alt a 15 was 1.6%, 21.9%, 12.5%, 12.5%, and 12.5%, respectively, and 70.3% of the patients only recognized Alt a 1 [31]. In addition, these preparation methods are labour-intensive, and their efficiency is limited, making them less suitable for obtaining pure allergens in sufficient quantities for diagnostic and immunotherapy purposes [32][33].

This entry is adapted from the peer-reviewed paper 10.3390/jof9050582

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