Introduction

The effectiveness of allergen immunotherapy (AIT) in the treatment of IgE-mediated inhalation allergies is undisputed. In the case of IgE-mediated mold allergies, the benefits of this therapy are sometimes controversially discussed among experts, especially when it comes to allergies by mold species which are mainly found in the indoor environment. Particularly in the case of indoor mold exposure, other health effects of mold exposure must be differentiated from common IgE-mediated reactions.

There are only reliable clinical studies on the effectiveness of AIT for IgE-mediated mold allergies for Alternaria alternata, which is predominantly found in outdoor air.

In the following, the outdoor and indoor air, the respective exposure to mold fungi and the therapeutic options of AIT are considered.

Outdoor molds

In studies and reviews on sensitization to molds in the general population, in children and adults, sensitization to Alternaria alternata and, albeit with a lower frequency, to Cladosporium herbarum, have been detected most frequently [2, 3]. The article by T. Gabrio and G. Fischer in this issue is dedicated to this topic.

Alternaria alternata is a potent allergen in outdoor air worldwide. Publications on this can be found, for example, from the USA, United Kingdom, Japan, Mexico, Australia, New Zealand, Poland and Spain. In a summary from 2022, the prevalence of sensitization to Alternaria is estimated at 23.5% in Greece, 20% in Spain and 13% in the USA [4]. Such figures are not available for Germany, but a prevalence in the order of 6–7% can be assumed.

Allergies to mold spores in the outside air are often underestimated, as the symptoms are often not attributed to mold allergy, but to sensitization to competing allergens such as grass and herb pollen.

The current 2023 update to the AWMF mold guideline [1] positions itself on this question as follows “The most common triggers of IgE-mediated rhinitis are allergens from molds that are predominantly found in the outside air, namely primarily Alternaria alternata, and much less frequently Cladosporium herbarum, Botrytis cinerea, Mucor spp., Penicillium spp. and Aspergillus spp.” [1]. In addition to spores, fragments of mycelium filaments also act as allergens, which, like spores, are found in the air as allergen carriers [5].

Alternaria alternata is particularly important for inhalation allergies in the outdoor air. In Germany, depending on the season and climatic conditions as well as vegetation and agricultural use, there are different levels of Alternaria alternata. The highest concentration of Alternaria spores or their fragments is found in rural areas with predominantly cereal cultivation, including maize, in regions with rapeseed cultivation, before the harvest, as the grains ripen, during the harvest (additional high concentration of spore fragments) and in the vicinity of pasture and meadow areas (hay mowing). Allergy symptoms can be expected from a threshold value of 100 spores/m3. The dependence of the concentration of Alternaria spores on weather conditions can be illustrated by evaluating the data from the Treuenbrietzen pollen trap over a period of ten years (Fig. 1).

Fig. 1
figure 1

Concentration of the number of Alternaria spores in the air in August 2007–2017 (data from the Treuenbrietzen pollen trap)

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June, July and August are the months with the highest concentration of airborne Alternaria spores. Competing allergens are grass pollen with a main load from June to mid-July and mugwort pollen with a main load from mid-July to the end of August. For this reason, allergy sufferers with symptoms during these periods often misinterpret the results of tests: Sensitization to pollen is assumed to be the trigger rather than Alternaria alternata being thought to be the cause. Figure 2 shows not only Alternaria spores but also fragments of Alternaria spores on 1 day in August in the pollen trap from Treuenbrietzen.

Fig. 2
figure 2

Microscopic image with Alternaria spores and spore fragments

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Increased allergen formation and increased allergen release has been described as a result of increasing CO2 exposure [6], as well as storms and thunderstorms and when frequent and heavy rain showers alternate with sunshine in summer. During extreme weather events, intact spores and fungal mycelium can be fragmented and are a major cause of asthma and exacerbation of pre-existing asthma [7,8,9,10,11,12,13,14].

A contribution by Pulimood et al. [15] should be mentioned as an example: The group gave an odds ratio for sensitization to Alternaria and asthma attacks during thunderstorms of 9.31 and defined the threshold concentration for triggering allergic symptoms as > 100 Alternaria alternata spores/m3, > 10 Alternaria alternata spore fragments/m3 and > 50 grass pollen/m3. The publication shows a higher number of stationary exposures with an increased number of spore fragments in the air (2.2-fold increase).

The current 2023 update to the AWMF mold guideline [1] positions itself as follows: “The genus Alternaria alternata (formerly A. tenuis), which is to be evaluated as an outdoor mu, appears to be a mold that is particularly important for the development and severity of asthma. A temporal relationship between asthma symptoms and Alternaria spore concentration could be shown, especially in patients with a high degree of sensitization and in patients with and without concomitant grass pollen allergy” [1].

At the Johanniter Hospital in Treuenbrietzen, the author of this article has been investigating the allergological significance of Alternaria alternata as an outdoor aeroallergen since the early 1990s. An evaluation of 1260 patients who were examined as outpatients for allergy complaints in 2020 showed that 6.1% (77 patients) were sensitized to Alternaria alternata (positive skin test and/or detection of allergen-specific IgE antibodies). 67 (87%) of these 77 have been challenged (nasal, conjunctival and/or bronchial challenge test). The challenge test was positive in 41 patients (61%). It can therefore be assumed that at least 3.2%, i.e. 41 of 1260 patients, suffered from a clinically relevant allergy Alternaria alternata, and had an indication for Alternaria alternata AIT. In 62 of the 77 sensitized patients a bronchial provocation with histamine was performed additionally, giving the diagnosis of non-specific bronchial hyperreactivity in 54 patients (87%). Some of these patients had previously not been diagnosed with asthma.

Furthermore, it was found that 37 of the patients sensitized to Alternaria alternata were simultaneously sensitized to grass pollen. 29 of these 37 patients were subjected to a provocation with grass pollen. In ten patients, both the provocation with Alternaria alternata and grass pollen were positive, which means that AIT with Alternaria alternata and grass pollen u.

AIT with Alternaria

As with all other mold extracts, Alternaria alternata extracts for AIT are obtained by extraction of molds kept in culture; the literature also reports on studies in which native, purified Alt a 1 [16] was used; animal experiments were also carried out with recombinantly produced Alt a 1 [17]. The problems associated with the production of allergen extracts from molds are discussed by M. Raulf and S. Kespohl in their article in this issue.

In contrast to other allergologically relevant molds, Alternaria alternata has one dominant major allergen, Alt a 1, with a sensitization frequency of 90% [4], comparable to Bet v 1 from birch (> 90%) and Fel d 1 from cat (> 90%). Alternaria alternata extracts for diagnostics and therapy are standardized for this major allergen; due to the dominance of this one allergen, studies on the efficacy of immunotherapy with Alt a 1 have also been conducted.

Another allergological relevant mold in the outdoor environment is Cladosporium herbarum. In contrast to Alternaria alternata, no dominant major allergen has been described for Cladosporium herbarum. Some allergen components in Cladosporium herbarum and Alternaria alternata extracts (Table 1) show a high degree of homology, which causes some cross-reactivity between different molds [18].

Table 1 Allergen components of Alternaria alternata and Cladosporium herbarum according to “Allergen Nomenclature WHO/IUIS Allergen Nomenclature Sub-Committee” (according to [18])
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The clinical efficacy and tolerability of Alternaria alternata AIT has been demonstrated in several clinical trials in children and adults [19,20,21,22,23,24]. Systemic side effects as treatment-related adverse events due to AIT with mold extracts occurred in 26.1% of treated patients in a meta-analysis of published studies, with a majority of side effects due to the treatment with Cladosporium extracts [24].

If there is evidence of relevant sensitization to Alternaria and grass pollen, AIT with two allergen extracts, in this case grass pollen and Alternaria alternata, can be considered for selected patients. In Germany, such allergen mixtures are not permitted under TAV; treatment is carried out using two separate extracts.

Indoor molds

The detection of relevant mold concentrations in the indoor environment is complicated. There are no reliable measurable parameters in the air or on surfaces that allow a valid evaluation. In this issue, T. Gabrio and G. Fischer have dealt with this problem in detail.

The diagnosis of IgE-mediated inhalation allergy caused by indoor molds is a challenge. In their article in this issue, M. Raulf and S. Kespohl discuss this problem. Aspergillus spp. frequently found indoor are contain a high number of allergen components. For Aspergillus fumigatus, 30 different allergen components have been described [18]. Five recombinant components (Asp f 1, 2, 3, 4, 6) are currently available for diagnostic purposes, but these are of little help in the diagnosis of clinically relevant inhalative allergies and in particular to decide on AIT. In contrast to a sensitization frequency of 90% against Alt a1 in Alternaria allergy sufferers, little is known about the prevalence of sensitization to the components of other molds.

The production of well-characterized and standardized extracts, particularly from Aspergillus species, is problematic as the allergen spectrum of the fungus changes relatively quickly in culture. However, a prerequisite for the efficacy of AIT is that all components to which a patient is sensitized are contained in the allergen extract. This requires an analysis of the sensitization spectrum of the patient and a molecular characterization of therapeutic extracts—further studies are essential. Currently, the indication for AIT in cases of allergy to indoor molds should be made with great caution.

The majority of proven mold sensitization cases have few therapeutic consequences, except for the detection of sensitization to Alternaria alternata. The possibilities of sound diagnostics depend on our scientific knowledge and in particular on the availability of high-quality diagnostics, as reported in the article in this issue by M. Raulf and S. Kespohl, who have a detailed diagnostic algorithm.

The differential diagnostic assessment of health impairments due to indoor molds has yet another facet. In addition to the allergen carriers spores and mycelium fragments, cell wall components such as β‑1,3‑glucans and chitins, mycotoxins and MVOC (“microbial volatile organic compounds”) are particularly relevant to the health of atopic patients [1]. Allergies to molds are only rarely the cause of the health impairment of atopic people due to moisture damage in indoor spaces. Inflammatory processes on the mucous membranes of the upper and lower respiratory tract as a result of moisture damage in indoor spaces can also be triggered in atopic patients by non-IgE-mediated mast cell activation. VOCs and proteases are candidates for this. Proteases also increase the activity of Th-2 cells, for example in the case of a concomitant mite allergy. Irritants (β‑1,3‑glucans, chitins, mycotoxins) can activate C‑nerve fibers and cough receptors in the inflamed mucous membrane. This results in symptoms such as dry cough, asthma, rhinitis, sneezing and conjunctivitis, which can be misinterpreted as an allergic reaction. J. Hurraß, B. Heinzow and G. Wiesmüller have published a detailed article on this topic in this issue.

Conclusion for practice

Molds, in particular Alternaria alternata and Cladosporium herbarum, are important outdoor allergens. Due to the frequent polysensitization of allergy sufferers and overlapping exposure times, test results must be critically evaluated. There is good evidence in the literature for the efficacy of AIT, particularly with Alternaria extracts.

Indoor mold is considered an important indoor problem by the general public, but the detection of relevant indoor mold contamination is problematic. The most important consequence of the detection of mold in indoor spaces is adequate remediation, which requires clarification of the cause of increased mold growth and, if necessary, structural measures.