Background

Fungi are eukaryotic non-chlorophyllous heterotrophic organisms with over 100,000 known species [1]. Molds are microfungi that are ubiquitous in the environment, with allergic implications due to production of airborne spores perennially. Allergies to mold can manifest in different conditions including but not limited to allergic rhinitis, allergic asthma, atopic dermatitis, allergic bronchopulmonary aspergillosis, allergic sinusitis, and hypersensitivity pneumonitis [1]. Mold allergies range from 6–24% in the general population, 44% in atopics, and 80% in asthmatics, and are responsible for the majority of fungal allergies [1]. Conversely, mushrooms are edible macrofungi which can rarely cause anaphylaxis when ingested with only a small number case reports described [2].

All edible fungi fall within the taxonomy divisions Basidiomycetes and Ascomycetes [3]. Given evolutionary similarity between all fungi, proteins produced by edible fungi can share immunological similarities to microfungi resulting in cross-reactivity. This cross-reactivity is akin to the pollen/fruit/vegetable cross-reactivity seen in pollen food allergy syndrome (PFAS) [1]. This is believed to be an immunoglobulin E (IgE) mediated phenomenon that typically presents with oropharyngeal pruritis, and in some cases angioedema due to homologous proteins present in the culprit food as well as the sensitizing aeroallergen [4]. In general, immunological similarity between epitopes occurs between closely related taxonomical species or between epitopes with similar function belonging to the same protein family [4, 5].

Exposure to epitopes of aeroallergens via the respiratory tract can cause sensitization that leads to symptoms with first exposure to similar epitopes within food. Cross-reactivity between several pollens and foods have been well reported [6]. Cross-reactivity between spore forming fungi and mushrooms has been suggested, however few case reports have ever been described in the literature [7]. Herein, we describe a case of a young male experiencing PFAS symptoms following mushroom ingestion who is able to tolerate mushroom in more extensively processed form.

Case presentation

A 15-year-old-male with a history of mild atopic dermatitis, peanut, and tree nut allergy previously diagnosed via skin prick testing (SPT) by another Allergist. He was referred to a hospital-based allergy clinic for asthma management. In addition to dyspnea and wheeze, he suffered from symptoms of seasonal and perennial allergic rhinoconjunctivitis. Skin prick testing to ALK allergen extracts was positive to grass, ragweed, Botrytis cinerea, Cephalosporium gramineum, and Aureobasidium pullulans with appropriate positive 1 mg/ml histamine and negative saline controls (Table 1); with positive testing defined as a wheal with largest diameter ≥ 3 mm larger than the negative control. He was prescribed ciclesonide nasal spray 50 mcg 1 spray twice daily to each nostril with proper technique reviewed.

Table 1 Summary of skin prick test (SPT) and serum specific immunoglobulin E (IgE) results
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Weeks following this assessment, the patient ingested a pizza with fresh mushrooms (Agaricus bisporus), and developed immediate throat pruritis and subjective throat tightness. He had ingested edible fungi previously without any issue or symptom. He was certain there was no cross-contamination with peanuts or tree nuts.

ImmunoCap serum specific IgE (from Phadia Laboratory Systems) were positive for Alternaria alternata (3.56 kU/l), Cladosporium herbarum (2.28 kU/l), and Penicillium notatum (19.45 kU/l); with a positive test defined as ≥ 0.35 kU/l. ImmunoCap serum specific IgE to whole mushroom (Agaricus hortensis) was negative with total IgE 764 kU/l (Table 1).

Subsequent SPT to fresh mushroom was positive for portobello mushroom (5 mm wheal), white cremini mushroom (6 mm wheal), and brown cremini mushroom (4 mm wheal). It was also negative to canned mushroom with an appropriate positive 1 mg/ml histamine and negative saline controls (Table 1, Fig. 1). Given these results, the patient underwent a 5-step graded oral challenge to canned mushrooms to a cumulative 3 g of mushroom protein as defined by the ingredient label. He successfully tolerated the challenge without any oral pruritis or other systemic symptoms suggestive of anaphylaxis. The patient declined an oral challenge to raw mushrooms to fully confirm PFAS as he did not want to experience recurrent clinical symptoms. He was already equipped with an epinephrine autoinjector due to pre-existing allergies and was advised to avoid consumption of raw or undercooked mushrooms as a precautionary measure.

Fig. 1
figure 1

Skin prick test to Portobello mushroom (PO), White Cremini mushroom (W), Brown Cremini mushroom (Br), and canned mushroom (CM) with appropriate positive histamine (+) and negative saline (−) controls

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Discussion and conclusion

Wide-spread cross-reactivity between the phyla Basidiomycetes and Ascomycetes has been well established [1]. However, only a few cases of PFAS-like reaction from mushroom cross-reactivity have ever been reported [4]. Dauby et al. (2002) described the first case of PFAS with uncooked mushroom in a patient allergic to molds. They showed a cross-reactivity between raw heat labile mushroom proteins of 43 kilodaltons (kD) and 67 kD and molds Horodendrum cladosporioides, Alternaria tenuis, Fusarium vasinfectum, and Helminthosporium interseminatum [8]. Another case report with PFAS to mushroom and anaphylaxis to spinach showed cross-reactivity between epitopes from the mold species Alternaria alternata and Cladosporium herbarum, and epitopes from the mushroom Agaricus bisporus and spinach [9]. Glabriel et al. [7] reported a patient who suffered anaphylaxis postulated to be secondary to cross-reactive IgE between mold aeroallergens and thermostable proteins found in Agaricus bisporus. The proteins were identified to be a 24 kD manganese-dependent superoxide dismutase (MnSOD) and 27 kD NADP-dependent mannitol dehydrogenase [7]. Most recently, Betancor et al. [10] identified a heat stabile cross-reactive protein between Agaricus bisporus and A. alternata identified to be a 36 kD member of the porin family.

Our case adds to the developing body of knowledge by describing a patient with a history of allergic rhinitis to microfungi aeroallergens who developed PFAS-like reaction with mushroom ingestion. Despite this reaction, they were able to pass a graded oral challenge to canned mushrooms. Mushroom canning entails temperatures from 115–130 °C from 2 to 97 min, which has been thought to denature any heat labile proteins [11]. Passing an oral challenge to canned mushrooms with a positive raw mushroom skin test implies there is a possible reaction to a heat labile protein akin to PFAS patients tolerating cooked but not raw fruit/vegetables [6]. Positive SPT and IgE to well-known spore forming fungi and edible fungi of the phyla Basidiomycetes (Agaricus bisporus) and Ascomycetes (Cladosporium herbarum, Alternaria alternata, Penicillium notatum, Botrytis, Cephalosporium, and Pullaria) suggests there is cross-reactivity occurring between these species causing sensitization and PFAS-like reaction with ingestion. Thus, we hypothesize the culprit protein to be a current unidentified heat-labile protein in the 47 kD or 67 kD range as suggested by Dauby et al. [8]. Future research utilizing the techniques of sodium dodecyl sulfate polyacrylamide gel electrophoresis with serum specific IgE immunoblotting followed by immunoblotting-inhibition testing to Agaricus bisporus and the patient’s mold sensitizations (B. cinerea, C. gramineum, A. pullulans, A. alternata, C. herbarum, and P. notatum) is required to verify cross reactivity.

It is plausible to postulate that the patient’s reaction could have been triggered by the presence of environmental aeroallergen spores on the outer surface of the mushroom pizza, considering that the conditions favorable for cultivating macrofungi are likely to support the growth of microfungi as well. However, we propose this explanation to be less probable, considering the patient’s medical history of experiencing seasonal and perennial rhinoconjunctivitis upon exposure to microfungi spores as well as positive SPT to multiple fresh mushrooms from different sources. It is noteworthy that the initial reaction occurred following the ingestion of mushroom-topped pizza, which theoretically would have led to the denaturation of heat-labile proteins. We hypothesize that the heterogeneous nature of vegetable thickness, cooking duration, and the presence of other food items that could disperse heat unevenly may account for this case; potentially allowing for the preservation of these heat labile cross-reactive proteins. Unfortunately, the canned mushroom species used for the oral challenge was not explicitly delineated. Nevertheless, Agaricus bisporus is the most widely cultivated and canned species in North America, while other varieties are generally identified with distinct labeling [12]. Given the prevalence of Agaricus bisporus and the observed morphological similarities between the canned mushrooms and Agaricus bisporus, we inferred the oral challenge was conducted with the same mushroom species employed in the SPT.

In conclusion, this case adds to the existing body of evidence supporting the relationship between sensitization to mold aeroallergens and allergy to edible fungi ingestion. However, knowledge of specific allergenic proteins that cause clinically relevant cross-reactions between molds and mushrooms is still limited. More research is required to understand the allergenic components that are involved and the specific species of mold and mushroom that are at risk of cross-reactivity.