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Fungus-associated asthma: overcoming challenges in diagnosis and treatment Expert Rev. Clin. Immunol. 10(5), 647–656 (2014)
Haruhiko Ogawa*1, Masaki Fujimura2, Noriyuki Ohkura3, Kazuo Satoh4 and Koichi Makimura4 1 Division of Pulmonary Medicine, Ishikawa-ken Saiseikai Kanazawa Hospital, Kanazawa 920-0353, Japan 2 Respiratory Medicine, National Hospital Organization Nanao Hospital, Nanao 926-8531, Japan 3 Respiratory Medicine, Ishikawa Prefectural Central Hospital, Kanazawa, Japan 4 Laboratory of Space and Environmental Medicine, Graduate School of Medicine and Graduate School of Medical Technology, Teikyo University, Itabashi-ku Tokyo, Japan *Author for correspondence: Tel.: +81 762 661 060 Fax: +81 762 661 070 [email protected]
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With regard to fungal colonization and fungal sensitization, the goals of fungus-associated asthma management are as follows: 1) to survey fungi colonizing the airways of patients repeatedly; 2) to evaluate the tendency of the colonizing fungi to sensitize patients and the influence on clinical manifestations of asthma; 3) to follow disease development to allergic bronchopulmonary mycosis or sinobronchial allergic mycosis; and 4) to determine whether fungal eradication from the airway of patients is beneficial from the viewpoints of future risk factors. Recent developments in molecular biological analyses have facilitated the identification of basidiomycetous fungi that were not previously thought to be of concern in fungal allergy. The total control of fungus-associated asthma will be accomplished by environmental management established from the viewpoint of both the ecology and life cycle of the responsible fungi. KEYWORDS: allergic bronchopulmonary mycosis • antifungal drugs • basidiomycetous fungi • Bjerkandera adusta • environmental control • fungus-associated asthma • fungus-colonized asthma • fungus-sensitized asthma • sinobronchial allergic mycosis
Association of environmental fungi & asthma
It has become important to assess the etiological and exacerbating agents as future risk factors of asthma, such as frequent exacerbations in the past year, admission to critical care for asthma and rapid decline in lung function, for both achieving and maintaining asthma control [1]. Fungi and molds are considered to be indoor or outdoor allergens, and fungal exposure is known to be associated with exacerbation of asthma [2]. Kennedy et al. [3] described three distinct forms of exposure to fungal allergens: fungal colonization of the lungs, inhalation of fungal allergens on spores or hyphae and fungal infection outside the respiratory tract. In contrast to other allergens, such as house dust mites or grass pollen, fungi have the ability to colonize the respiratory airway and to germinate on the respiratory mucosa. Some fungi may develop infection of the respiratory tract under conditions of impaired host defenses, while other fungi may merely colonize the airway as allergens [4]. Fungal colonization due to continuous exposure to fungal 10.1586/1744666X.2014.892829
allergens is considered to play a role in sensitizing asthmatic patients to the fungi or in enhancing clinical difficulty of treating asthma symptoms. Clarifying the causative allergens, eliminating the allergenic antigen and preventing exposure to the allergen are considered to be fundamental concepts in treating allergic disorders. When the responsible allergen is found to be environmental fungi, the treatment strategy is recommended to take into consideration the characteristics of the microbe, such as colonization or germination in the respiratory tract. Here, we reviewed the association between fungi and asthma, to reconsider the challenges in both diagnosis and treatment of fungusassociated asthma with regard to fungal colonization and fungal sensitization. Fungal sensitization & asthma
There is increasing interest in the association between severe asthma and fungal sensitization [5]. Fungal sensitization is generally defined as the presence of immediate cutaneous hyperreactivity or positive results for specific IgE antibodies to previously prepared fungal antigens [6]. Evaluating the results of
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skin tests and/or specific IgE antibodies would be significant for estimating the allergological background of asthma patients. Sensitization and exposure to fungal allergens, such as Aspergillus, Alternaria, Penicillium, Cladosporium and Trichophyton, have been reported to be associated with exacerbation and severity of asthma [7]. The frequency of exacerbations, treatment requirements and admission to intensive care for asthma are associated with skin test reactivity to one or more fungi [8]. Rapid decline in lung function is an important issue in assessment of future risk in asthma control [9–11]. Although the development of fixed airflow obstruction in asthma is believed to be due to the damaging effects of airway colonization by filamentous fungi, including Aspergillus fumigatus [12], Benghida et al. [13] reported that sensitization to Aspergillus does not have a deleterious effect on the decline of respiratory function in asthmatic patients. As lung function declines calculated based on changes in forced expiratory volume in 1 s (FEV1) at only two different points are easily influenced by the daily condition of asthma, for closer estimation, the annual decline in postbronchodilator FEV1 (delta FEV1 ml/year) should be calculated by single regression analysis using data from at least five evaluations over more than 5 years [14]. Impact of fungal colonization on fungal sensitization in asthma
The importance of fungal sensitization in severe asthma has been reported, but the significance of colonization by fungi remains unclear. Under conditions of continuous exposure to some fungi, chronic positive sputum culture may comprise an asthma phenotype, that is, ‘fungus colonization asthma’ [15]. The clinical course of such patients would likely depend on the characteristics of the colonizing fungi. Exposure of asthma patients to fungi to which they are sensitized would aggravate their asthma symptoms. The same individual would show different clinical manifestations in the presence or absence of the fungal allergen. However, the fungi to which the patients are sensitized do not always colonize the airways. In addition, it is also possible that unrelated fungi may colonize the airways of asthma patients who are sensitized to other fungi. Therefore, stratified analysis according to the presence of the respective fungus should be performed when planning clinical studies against fungal sensitization asthma. Agbetile et al. [15] reported that 48% of 126 asthma patients were IgE sensitized to one fungal allergen, while 22% were sensitized to more than two allergens. Twenty-seven different taxa of filamentous fungi were isolated from the sputa of 54% of these patients. Aspergillus species were most frequently cultured in isolation followed by Penicillium spp. Post-bronchodilator FEV1 was lowest in the culture- and sensitization-positive group. Patients with both positive culture and positive sensitization to some fungi may demonstrate particular clinical manifestations as a new phenotype of asthma under conditions of chronic exposure to such fungi. Thus, clinical concern regarding allergic fungal respiratory diseases may gradually shift from sensitization to colonization. 648
Difficulty in identification of colonizing fungi
There have been many attempts to detect colonizing fungi in bronchial specimens from patients with allergic fungal respiratory diseases, such as allergic bronchopulmonary mycosis (ABPM) [16], eosinophilic pneumonia [17], hypersensitive pneumonitis [18], chronic cough [19] and bronchial asthma [20]. When unknown eumycetes are cultured from bronchial materials of patients with bronchial asthma [21], a great deal of care will be necessary to determine the clinical significance of the detected fungi on the disease. It is reasonable to carry out bronchial washing to exclude contamination and to obtain relevant fungi. However, with regard to patient safety, the essential purpose may be accomplished by obtaining samples of repeated induced sputum instead of bronchial washing as a routine part of asthma management [22]. The fact that same species of fungi are repeatedly cultured from the same patients is one of the key points to decide to commence investigation of the correlation between asthma and the fungi. There are limitations for the identification of fungi. In the slide culture method (30˚C for 2–3 weeks), fungi obtained from respiratory specimens have been identified mainly based on the morphological features of the conidial head (conidia). Therefore, it has not been possible to identify non-sporulating molds (NSM) that do not have conidia or fruiting bodies, and such filamentous fungi may have been classified as belonging to either the category of ‘hyphae’ or ‘unknown’ [23]. Recent developments in molecular biological analyses have facilitated the identification of NSM, and have increased the list of environmental fungi that were not previously thought to be of concern as pathogenic agents [24]. It should be noted that although it requires only 2 days to detect the common fungal allergen Aspergillus in cultured sputum samples, a period of approximately 10 days is required to culture white colonies of NSM on either potato dextrose agar or Sabouraud’s dextrose agar containing chloramphenicol. However, culture medium has often been discarded after approximately 2 days, and white-rot fungi may have been diagnosed as mere contaminating fungi in previous studies [23]. Implications of basidiomycetous fungi for bronchial asthma
Singh et al. [24] isolated NSM from 4948 respiratory specimens, and they concluded that basidiomycetous (BM) fungi were the predominant NSM based on the internal transcribed spacer region and D1/D2 domain of the large subunit region. BM fungi consist of approximately 31,000 species and include mushrooms, puffballs, rusts, smuts and bracket fungi [25]. Although only a limited number of reports have documented infectious diseases caused by BM fungi, they are well known to act as airborne allergens [26]. Positive results of intradermal testing for BM were reported in 42–68% of patients with atopic asthma [27]. To clarify the prevalence of BM fungi in sputum from patients with bronchial asthma, the medical records of 92 patients with asthma, who were referred to Saiseikai Kanazawa Hospital Expert Rev. Clin. Immunol. 10(5), (2014)
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Fungus-associated asthma
between August and October 2009, were collected and reviewed retrospectively. Fungal culture of sputum was successfully obtained from 67 patients in this study. The results of the identification of fungal culture were A. fumigatus in 31 patients (46.3%), BM fungi in 30 patients (44.8%), Candida albicans in 27 patients (40.3%), Penicillium spp. in 15 patients (22.4%) and Aspergillus niger in 7 patients (10.4%). BM fungi were among the most predominant fungi detected in the sputum of bronchial asthma. Therefore, it is becoming increasingly important to pay attention to BM fungi in addition to classical environmental fungi in fungus-associated asthma. The influence of these fungi on the clinical manifestations of asthma should be elucidated in the near future.
Review
Millien et al. reported that Toll-like receptor 4 (TLR4) is activated by airway proteinase activity to initiate both allergic airway disease and antifungal immunity. Allergic airway inflammation represents an antifungal defensive strategy that is driven by fibrinogen cleavage products and TLR4 activation. Future studies to determine the usefulness of interrupting fibrinogen cleavage product-TLR4 signaling may lead to new therapeutic strategies [36]. He et al. [37] reported that the bronchial lavage fluid of mice stimulated with B. adusta showed marked eosinophil accumulation, the influence of B. adusta colonization itself on patients with asthma will be investigated in the near future. Peculiar fungal asthma
Schizophyllum commune & Bjerkandera adusta in patients with asthma
Although the importance of BM allergy in asthma has been known for a long time, detailed investigations were difficult due to limitations of conventional identification for filamentous BM fungi [28]. Especially Schizophyllum commune and Bjerkandera adusta are correlated with common diseases, that is, bronchial asthma and chronic cough, respectively [29]. S. commune is a very common species of mushroom belonging to the genus Schizophyllum. It is the most widely distributed mushroom around the world, occurring on every continent except Antarctica. S. commune is a filamentous pathogenic BM fungus, which causes both allergic and invasive respiratory diseases. Our recent studies suggested that S. commune, which can cause ABPM [30], is an important causative fungal antigen and is a candidate organism influencing the clinical manifestations of asthma via sensitization to this fungus [31]. B. adusta is a species of fungus in the Meruliaceae family and is a well-known mushroom in the field of agricultural science, because it secretes multiple lignin peroxidase isozymes [32]. In another series of studies in our laboratory, the wood decay BM fungus B. adusta attracted attention because of its potential role in enhancing the severity of cough symptoms by sensitization to this fungus [33]. In a preliminary study, we found S. commune and B. adusta in samples from only 2 (7.4%) and 14 (51.9%) of 27 patients with asthma whose sputum yielded BM fungi, respectively (TABLE 1). The predominance of B. adusta rather than of S. commune in asthma patients is noteworthy. Thus, among the approximately 31,000 species in the BM phylum, these additional two fungi should be taken into consideration when managing fungus-associated asthma. Possible mechanisms of action of fungi in patients with asthma
Kheradmand et al. reported that intrinsic protease activity in allergenic preparations of A. fumigatus gives rise to eosinophildriven allergic airway disease in mice [34]. Matsuwaki et al. demonstrated that Alternaria alternata produces aspartate proteases and that human peripheral blood eosinophils degranulate in response to the cell-free extract of A. alternata [35]. informahealthcare.com
Historically, Candida asthma has been reported and considered as a peculiar condition. Sensitization to C. albicans, which is not an aeroallergen but is present in the human gut flora, is demonstrated in up to 10% of individuals with mild stable asthma and 33% of patients with severe asthma [38]. C. albicans is correlated with intrinsic severe asthma. An association between thunderstorms and increased rate of acute asthma attacks has been reported. Thunderstorm asthma is positively correlated with a doubling of ambient fungal spores, especially those of Alternaria spp. [39]. Sensitization to Trichophyton, which causes superficial skin or nail infection, has been reported to be correlated with the severity of asthma [40]. As infection by this fungus occurs outside the respiratory tract, Trichophyton is not always detected in the airways of such patients. Recent studies demonstrated that Aspergillus restrictus aggravates the clinical manifestations of patients with asthma sensitized to Trichophyton; cross-reactivity should be investigated in such cases [41]. Schizophyllum asthma has been reported as a new clinical entity [42]. Sensitization to S. commune is one of the risk factors involved in the severity of asthma [31], as well as the exacerbation frequency and lung function decline in asthmatic patients [43]. As S. commune is a mushroom spore that generally grows in fields or forests, consideration of its ecology and life cycle may provide insights to prevent sensitization to this fungus [44]. Fungus-associated asthma & ABPM
It is noteworthy that S. commune is predominant not only in ABPM and pulmonary fungal balls, but also in asymptomatic colonization of the lung as colonizers in 12/22 cases (54.5%) with varied clinical diagnosis of chronic obstructive pulmonary disease, interstitial lung disease, post-tubercular sequelae and asthma [24]. We have rarely experienced mucoid impaction of bronchi (MIB) in patients with chronic cough whose sputum yields A. fumigatus. The inferior environment, such as impaired mucociliary clearance or airway epithelial barrier damage [45], caused by eosinophilic airway inflammation may be necessary for the development of MIB by A. fumigatus. By contrast, S. commune colonization may also cause production of mucus plugs in the 649
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Table 1. Details of identification of the 27 basidiomycetous fungi isolated from patients with asthma by D1/D2 sequencing. Identification by D1/D2
DDBJ/EMBL/GenBank accession numbers of closely related strain
Identity (%)
Bjerkandera adusta
AB096738.1
99
B. adusta
AB096738.1
99
Schizophyllum commune
AM269871.1
100
Ceraceomyces violascens
EU118612.1
100
Mycoaciella bispora
AY586692.1
98
B. adusta
AB096738.1
100
Phanerochaete sordida
EU118653.1
98
B. adusta
GQ470629.1
100
B. adusta
GQ470629.1
99
B. adusta
GQ470629.1
100
Pycnoporus spp.
DQ327661.1
99
B. adusta
GQ470629.1
100
B. adusta
GQ470629.1
99
Termitomyces albuminosus
AF079072.1
100
Oxyporus corticola
DQ873641.1
99
B. adusta
GQ470629.1
100
B. adusta
GQ470629.1
100
B. adusta
FN298244.1
99
Ceriporiopsis subvermispora
FN298246.1
99
B. adusta
FN298244.1
99
Trametes versicolor
JF416687.1
100
B. adusta
AB733334.1
99
Phanerochaete subglobosa
GQ470662.1
98
Fomitopsis palustris
AB733302.1
100
B. adusta
AB733334.1
100
Ceriporia lacerata
AB566280.1
100
S. commune
AM269871.1
100
PCR was performed with the primers for the 28 SrDNA partial sequences (D1/D2 region). The DDBJ/EMBL/GenBank nucleotide sequence databases were searched for matches of the confirmed sequences by using basic local alignment search tool programs. Sequence-based species identification was defined by >99% similarity.
airways of healthy non-asthmatic subjects and subsequently result in MIB or ABPM. This hypothesis may support the observation that the presence of bronchial asthma in ABPM was much lower than in allergic bronchopulmonary 650
aspergillosis (ABPA), as described by Chowdhary et al. [46]. It is believed that fungus-associated asthma is not always a precursor of ABPM [47]. ‘One airway, one disease’ in allergic fungal respiratory disease
Based on the concept of ‘one airway, one disease’ in fungal allergy, we assume that one fungal antigen causes both allergic fungal rhinosinusitis (AFRS) [48] and ABPM. Historically, the term ‘sinobronchial allergic mycosis’ (SAM) [49] coined by Venarske and deShazo is close to this concept. Patients with SAM have chronic sinusitis involving multiple sinuses, asthma, immediate cutaneous reactivity to fungal allergens, peripheral eosinophilia and radiographic evidence of bronchiectasis. Total serum IgE levels are also usually elevated, and a variety of chest radiographic abnormalities may occur, ranging from mass lesions to diffuse pulmonary infiltrates and even normal findings on chest radiography. Theoretically, fungus-associated asthma, ABPM and AFRS may overlap. SAM includes AFRS and ABPM. The width of each area of overlap would depend on the characteristics of the colonizing fungi, such as eosinophil accumulation and mucus production. Thus, SAM is reasonable as a theoretical concept, but there is often difficulty in separately investigating the allergological reactions that arise in the upper and lower airways in clinical practice [50]. It is not realistic to prepare antigenic solutions of all detected fungi for allergological testing. Despite the development of methods to identify the fungi, obstacles preventing acquisition of the antigenic solution in allergological investigations have remained. Chowdhary et al. [51] reported that S. commune was the third most common major causative antigen (11%) in 143 cases of ABPM due to fungi other than Aspergillus. A. fumigatus and S. commune are the most important candidate organisms as causative fungal antigens of SAM. Considering both the high prevalence of this fungus in ABPM and the fundamental similarity in therapy for both disorders occurring in the same individual [52], it will be helpful to develop simplified guidance for S. commune-associated SAM from the viewpoint of Schizophyllum allergy. We tentatively propose the following guidance for S. commune-associated SAM [53]. Fundamental condition of the patient: eosinophilic MIB with/without asthma and/or eosinophilic mucin involved in multiple sinuses with/without nasal polyposis; major criteria: positive fungal culture of S. commune from bronchial specimens or sinus contents and positive results for S. commune-specific IgE and/or S. commune-specific IgG; supplemental findings: elevated peripheral eosinophils and/or total serum IgE levels and radiographic evidence of ABPM and/or AFRS. Are antifungal drugs planned against fungus-sensitized asthma?
To prevent fungal sensitization, which is correlated with a decline in lung function [54], it is reasonable to plan some interventions, such as antifungal therapy. Ward et al. reported that Expert Rev. Clin. Immunol. 10(5), (2014)
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the use of fluconazole (100 mg/day for 5 months) was associated with decreased bronchial hyperresponsiveness to Trichophyton inhalation, reduced oral steroid dose and increased peak expiratory flow rate [55]. Denning et al. reported the results of a randomized controlled trial [56] that showed a significant quality of life benefit, a decrease in IgE and modest improvements in rhinitis and morning peak expiratory flow, but not the FEV1, after oral antifungal therapy in patients with severe asthma sensitized to one of several common fungi. In their report, information on the association with fungal colonization and efficacy of antifungal drug was not presented in detail. Although there may be room to reconsider the appropriate dose and duration of antifungal drug administration in such studies, other effects such as decreasing the frequency of exacerbation of asthma or improvement of laryngeal sensations [57] should be estimated appropriately. It has recently been demonstrated that colonization by B. adusta is necessary in the process of sensitization to this fungus in allergic fungal cough patients [19]. On the other hand, it has recently been clarified that colonization by S. commune is not necessary for sensitization to this fungus in asthma [22], but it is necessary in ABPM caused by this fungus [47]. Various components, such as conidia, spores, hyphae, hyphal fragments, cell wall constituents and voltaic organic compounds, may act as antigens in fungal sensitization [56]. The efficacy of antifungal drugs against fungus-sensitized asthma is an important issue [58], but the routine use of these agents in such cases requires further evaluation [20]. Without considering the role of fungal colonization for sensitization in patients with fungus-associated asthma, it would not be possible to achieve successful treatment with antifungal drugs [59]. Antifungal therapy for reduction & eradication of fungus-colonized asthma
Kennedy et al. reported that the use of antifungal agents is generally only considered for patients with fungal colonization [60]. Antifungal therapy is expected to have advantages for reducing or eradicating the colonizing antigen burden [61] and thus preventing the sensitization process. Gonzalez et al. [62] reported that B. adusta was susceptible to itraconazole, amphotericin B and voriconazole in vitro, with MIC values of 0.125, 0.5 and 0.5 mg/ml, respectively. Although we reported that sensitization to S. commune may be one of the risk factors involved in lung function decline in asthmatic patients [43], the efficacy of antifungal drugs on pulmonary function in S. commune-sensitized asthma has not been sufficiently demonstrated. S. commune colonization in the airway of patients with asthma may be important in the progression to ABPM rather than in clinical manifestations of asthma itself. In S. commune-sensitized asthma, fungal exposure to a degree at which the fungus is able to colonize the airway would result in exacerbation of asthma or in prelude of ABPM. Therefore, it may be significant to eradicate S. commune-colonization from the viewpoint of prevention of subsequent disease progression even in S. commune-sensitized asthma. informahealthcare.com
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The previously proposed four-step treatment strategy for ABPM [47] would be applicable for fungus-colonized asthma: prevention and eradication of fungal colonization in the airway; control of eosinophilic bronchitis caused by fungal exposure; removal of any mucus plugs from the airway (if present); and effective management of environmental fungi. However, further investigations are required to clarify whether full doses of antifungal drugs are actually necessary to eradicate fungal colonization in the airways in such cases. Due to the low susceptibility to antifungal drugs against BM fungi [62,63], there is wide clinical significance of identifying NSM obtained from respiratory specimens [24]; however, sufficient attention should be paid to the phenomenon of antifungal resistance as well as adverse effects [64]. Anti-IgE therapy
Omalizumab is a recombinant, monoclonal antibody that binds IgE and inhibits interaction of IgE with IgE receptors on inflammatory cells. The use of omalizumab was shown to be an effective add-on therapy in patients with severe asthma [65] and to decrease the requirement of inhaled corticosteroids and reduce the number of exacerbations [66]. Although omalizumab has been shown to be beneficial in ABPA [67], the routine use of this drug in fungus-associated asthma requires further evaluation. Environmental management from the viewpoint of both the ecology & life cycle of the fungi
ABPA is widely understood to progress into chronic pleuropulmonary fibrosis [68] based on exposure to Aspergillus throughout the year in the chronic desquamative condition of eosinophilic bronchitis. However, S. commune exposure is believed to be limited to the mushroom overgrowth season in the field [44]. It has not been reported that ABPM caused by S. commune shows progression to the clinical stage of ‘fibrosis’ similar to ABPA. A literature search [63] did not reveal any peculiar seasonality of either disease onset or the first visit to hospital. However, disease recrudescence seemed to be concentrated in September to November (6 of 8 [75%] patients described). It remains to be determined whether this trend can be explained by coincidence of the mushroom overgrowth season in the field [44]. Periodic surveys of S. commune and the appropriate use of antifungal drugs may be useful for establishing strategies to prevent disease recurrence [49]. Such a consideration of both the ecology and life cycle of the fungi may also be applicable to the management of fungus-associated asthma. Environmental management
Dampness and mold growth in the home have been shown to be associated with wheezing and asthma in many geographical settings [69]. In such studies, the discussion mainly concerns the association with damp housing conditions and/or visible molds [70]. Further studies are required to investigate the correlation and fungal culture obtained from bronchial specimens and environmental fungi collected by air samplers. 651
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The importance of sensitization against airborne basidiomycetes, ascomycetes and fungal fragments to exacerbation of respiratory allergies in tropical environments has already been reported [71]. Despite the availability of antifungal drugs [62,63], our case reports suggested that disease recurrence in both allergic fungal cough [23] and ABPM [47] was influenced by the presence of related fungi in the patients’ environments. Dealing with this fungus as a mushroom spore and considering the ecology and life cycle of the fungus may provide insights to prevent disease recrudescence. Indoor and outdoor aspects of human responses to climate change are becoming important issues [72]; however, the question remains regarding how best to deal with such mushroom spores to prevent sensitization to this fungus. Are air filter systems recommended to reduce mushroom spores in the indoor environment? Should we open or shut the windows? [73]. Sautour et al. reported that in outdoor samples, B. adusta (8%) was the third most frequent species, especially in summer, and was the third and fourth most common species in the adult hematology unit (13%) and the pediatric hematology unit (11%), respectively, at a French hospital. They also mentioned that the concentration of this fungus was particularly high during the winter 2006/07, with a prevalence close to 30% in indoor samples [74]. Environmental management & prevention strategies for fungus-associated asthma
Mushrooms help in both the rotting of fallen trees and in returning their organic material back into the soil. The normal state of the forest is considered to be maintained in this way. However, attention should also be paid to other aspects of mushroom spores, including their enhancing effects on the clinical manifestations of allergic respiratory disorders. The control of the recurrence of fungus-associated asthma, which seemed to be influenced by the presence of the respective fungi in the environment, will be accomplished by environmental management [75]. Yellow sand dust with the long-range transport of atmospheric pollutants originating from the Taklamakan and Gobi Deserts was shown to reach not only Asia but also North America and Europe [76]. Recently, Kobayashi et al. [77] reported that direct sampling of Asian sand dust indicated the presence of Nocardiopsis spp., Bacillus spp., Streptomyces spp. and Bjerkandera spp. Thus, this mushroom spore is assumed to influence not only chronic cough patients but also patients with asthma, from the viewpoint of Bjerkandera allergy [78]. Although occupational-related mushroom allergy is recognized as hypersensitivity pneumonitis and is often limited to workers in certain industries [79], B. adusta is a wood decay BM fungus with a worldwide distribution, and therefore this fungal antigen may be a matter of clinical concern. Therefore, when discussing the influence of yellow sand dust on human health [80], we should not overlook exposure to particulate matter
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Fungus-associated asthma: overcoming challenges in diagnosis and treatment Expert Rev. Clin. Immunol. 10(5), 647–656 (2014)
Haruhiko Ogawa*1, Masaki Fujimura2, Noriyuki Ohkura3, Kazuo Satoh4 and Koichi Makimura4 1 Division of Pulmonary Medicine, Ishikawa-ken Saiseikai Kanazawa Hospital, Kanazawa 920-0353, Japan 2 Respiratory Medicine, National Hospital Organization Nanao Hospital, Nanao 926-8531, Japan 3 Respiratory Medicine, Ishikawa Prefectural Central Hospital, Kanazawa, Japan 4 Laboratory of Space and Environmental Medicine, Graduate School of Medicine and Graduate School of Medical Technology, Teikyo University, Itabashi-ku Tokyo, Japan *Author for correspondence: Tel.: +81 762 661 060 Fax: +81 762 661 070 [email protected]
informahealthcare.com
With regard to fungal colonization and fungal sensitization, the goals of fungus-associated asthma management are as follows: 1) to survey fungi colonizing the airways of patients repeatedly; 2) to evaluate the tendency of the colonizing fungi to sensitize patients and the influence on clinical manifestations of asthma; 3) to follow disease development to allergic bronchopulmonary mycosis or sinobronchial allergic mycosis; and 4) to determine whether fungal eradication from the airway of patients is beneficial from the viewpoints of future risk factors. Recent developments in molecular biological analyses have facilitated the identification of basidiomycetous fungi that were not previously thought to be of concern in fungal allergy. The total control of fungus-associated asthma will be accomplished by environmental management established from the viewpoint of both the ecology and life cycle of the responsible fungi. KEYWORDS: allergic bronchopulmonary mycosis • antifungal drugs • basidiomycetous fungi • Bjerkandera adusta • environmental control • fungus-associated asthma • fungus-colonized asthma • fungus-sensitized asthma • sinobronchial allergic mycosis
Association of environmental fungi & asthma
It has become important to assess the etiological and exacerbating agents as future risk factors of asthma, such as frequent exacerbations in the past year, admission to critical care for asthma and rapid decline in lung function, for both achieving and maintaining asthma control [1]. Fungi and molds are considered to be indoor or outdoor allergens, and fungal exposure is known to be associated with exacerbation of asthma [2]. Kennedy et al. [3] described three distinct forms of exposure to fungal allergens: fungal colonization of the lungs, inhalation of fungal allergens on spores or hyphae and fungal infection outside the respiratory tract. In contrast to other allergens, such as house dust mites or grass pollen, fungi have the ability to colonize the respiratory airway and to germinate on the respiratory mucosa. Some fungi may develop infection of the respiratory tract under conditions of impaired host defenses, while other fungi may merely colonize the airway as allergens [4]. Fungal colonization due to continuous exposure to fungal 10.1586/1744666X.2014.892829
allergens is considered to play a role in sensitizing asthmatic patients to the fungi or in enhancing clinical difficulty of treating asthma symptoms. Clarifying the causative allergens, eliminating the allergenic antigen and preventing exposure to the allergen are considered to be fundamental concepts in treating allergic disorders. When the responsible allergen is found to be environmental fungi, the treatment strategy is recommended to take into consideration the characteristics of the microbe, such as colonization or germination in the respiratory tract. Here, we reviewed the association between fungi and asthma, to reconsider the challenges in both diagnosis and treatment of fungusassociated asthma with regard to fungal colonization and fungal sensitization. Fungal sensitization & asthma
There is increasing interest in the association between severe asthma and fungal sensitization [5]. Fungal sensitization is generally defined as the presence of immediate cutaneous hyperreactivity or positive results for specific IgE antibodies to previously prepared fungal antigens [6]. Evaluating the results of
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skin tests and/or specific IgE antibodies would be significant for estimating the allergological background of asthma patients. Sensitization and exposure to fungal allergens, such as Aspergillus, Alternaria, Penicillium, Cladosporium and Trichophyton, have been reported to be associated with exacerbation and severity of asthma [7]. The frequency of exacerbations, treatment requirements and admission to intensive care for asthma are associated with skin test reactivity to one or more fungi [8]. Rapid decline in lung function is an important issue in assessment of future risk in asthma control [9–11]. Although the development of fixed airflow obstruction in asthma is believed to be due to the damaging effects of airway colonization by filamentous fungi, including Aspergillus fumigatus [12], Benghida et al. [13] reported that sensitization to Aspergillus does not have a deleterious effect on the decline of respiratory function in asthmatic patients. As lung function declines calculated based on changes in forced expiratory volume in 1 s (FEV1) at only two different points are easily influenced by the daily condition of asthma, for closer estimation, the annual decline in postbronchodilator FEV1 (delta FEV1 ml/year) should be calculated by single regression analysis using data from at least five evaluations over more than 5 years [14]. Impact of fungal colonization on fungal sensitization in asthma
The importance of fungal sensitization in severe asthma has been reported, but the significance of colonization by fungi remains unclear. Under conditions of continuous exposure to some fungi, chronic positive sputum culture may comprise an asthma phenotype, that is, ‘fungus colonization asthma’ [15]. The clinical course of such patients would likely depend on the characteristics of the colonizing fungi. Exposure of asthma patients to fungi to which they are sensitized would aggravate their asthma symptoms. The same individual would show different clinical manifestations in the presence or absence of the fungal allergen. However, the fungi to which the patients are sensitized do not always colonize the airways. In addition, it is also possible that unrelated fungi may colonize the airways of asthma patients who are sensitized to other fungi. Therefore, stratified analysis according to the presence of the respective fungus should be performed when planning clinical studies against fungal sensitization asthma. Agbetile et al. [15] reported that 48% of 126 asthma patients were IgE sensitized to one fungal allergen, while 22% were sensitized to more than two allergens. Twenty-seven different taxa of filamentous fungi were isolated from the sputa of 54% of these patients. Aspergillus species were most frequently cultured in isolation followed by Penicillium spp. Post-bronchodilator FEV1 was lowest in the culture- and sensitization-positive group. Patients with both positive culture and positive sensitization to some fungi may demonstrate particular clinical manifestations as a new phenotype of asthma under conditions of chronic exposure to such fungi. Thus, clinical concern regarding allergic fungal respiratory diseases may gradually shift from sensitization to colonization. 648
Difficulty in identification of colonizing fungi
There have been many attempts to detect colonizing fungi in bronchial specimens from patients with allergic fungal respiratory diseases, such as allergic bronchopulmonary mycosis (ABPM) [16], eosinophilic pneumonia [17], hypersensitive pneumonitis [18], chronic cough [19] and bronchial asthma [20]. When unknown eumycetes are cultured from bronchial materials of patients with bronchial asthma [21], a great deal of care will be necessary to determine the clinical significance of the detected fungi on the disease. It is reasonable to carry out bronchial washing to exclude contamination and to obtain relevant fungi. However, with regard to patient safety, the essential purpose may be accomplished by obtaining samples of repeated induced sputum instead of bronchial washing as a routine part of asthma management [22]. The fact that same species of fungi are repeatedly cultured from the same patients is one of the key points to decide to commence investigation of the correlation between asthma and the fungi. There are limitations for the identification of fungi. In the slide culture method (30˚C for 2–3 weeks), fungi obtained from respiratory specimens have been identified mainly based on the morphological features of the conidial head (conidia). Therefore, it has not been possible to identify non-sporulating molds (NSM) that do not have conidia or fruiting bodies, and such filamentous fungi may have been classified as belonging to either the category of ‘hyphae’ or ‘unknown’ [23]. Recent developments in molecular biological analyses have facilitated the identification of NSM, and have increased the list of environmental fungi that were not previously thought to be of concern as pathogenic agents [24]. It should be noted that although it requires only 2 days to detect the common fungal allergen Aspergillus in cultured sputum samples, a period of approximately 10 days is required to culture white colonies of NSM on either potato dextrose agar or Sabouraud’s dextrose agar containing chloramphenicol. However, culture medium has often been discarded after approximately 2 days, and white-rot fungi may have been diagnosed as mere contaminating fungi in previous studies [23]. Implications of basidiomycetous fungi for bronchial asthma
Singh et al. [24] isolated NSM from 4948 respiratory specimens, and they concluded that basidiomycetous (BM) fungi were the predominant NSM based on the internal transcribed spacer region and D1/D2 domain of the large subunit region. BM fungi consist of approximately 31,000 species and include mushrooms, puffballs, rusts, smuts and bracket fungi [25]. Although only a limited number of reports have documented infectious diseases caused by BM fungi, they are well known to act as airborne allergens [26]. Positive results of intradermal testing for BM were reported in 42–68% of patients with atopic asthma [27]. To clarify the prevalence of BM fungi in sputum from patients with bronchial asthma, the medical records of 92 patients with asthma, who were referred to Saiseikai Kanazawa Hospital Expert Rev. Clin. Immunol. 10(5), (2014)
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Fungus-associated asthma
between August and October 2009, were collected and reviewed retrospectively. Fungal culture of sputum was successfully obtained from 67 patients in this study. The results of the identification of fungal culture were A. fumigatus in 31 patients (46.3%), BM fungi in 30 patients (44.8%), Candida albicans in 27 patients (40.3%), Penicillium spp. in 15 patients (22.4%) and Aspergillus niger in 7 patients (10.4%). BM fungi were among the most predominant fungi detected in the sputum of bronchial asthma. Therefore, it is becoming increasingly important to pay attention to BM fungi in addition to classical environmental fungi in fungus-associated asthma. The influence of these fungi on the clinical manifestations of asthma should be elucidated in the near future.
Review
Millien et al. reported that Toll-like receptor 4 (TLR4) is activated by airway proteinase activity to initiate both allergic airway disease and antifungal immunity. Allergic airway inflammation represents an antifungal defensive strategy that is driven by fibrinogen cleavage products and TLR4 activation. Future studies to determine the usefulness of interrupting fibrinogen cleavage product-TLR4 signaling may lead to new therapeutic strategies [36]. He et al. [37] reported that the bronchial lavage fluid of mice stimulated with B. adusta showed marked eosinophil accumulation, the influence of B. adusta colonization itself on patients with asthma will be investigated in the near future. Peculiar fungal asthma
Schizophyllum commune & Bjerkandera adusta in patients with asthma
Although the importance of BM allergy in asthma has been known for a long time, detailed investigations were difficult due to limitations of conventional identification for filamentous BM fungi [28]. Especially Schizophyllum commune and Bjerkandera adusta are correlated with common diseases, that is, bronchial asthma and chronic cough, respectively [29]. S. commune is a very common species of mushroom belonging to the genus Schizophyllum. It is the most widely distributed mushroom around the world, occurring on every continent except Antarctica. S. commune is a filamentous pathogenic BM fungus, which causes both allergic and invasive respiratory diseases. Our recent studies suggested that S. commune, which can cause ABPM [30], is an important causative fungal antigen and is a candidate organism influencing the clinical manifestations of asthma via sensitization to this fungus [31]. B. adusta is a species of fungus in the Meruliaceae family and is a well-known mushroom in the field of agricultural science, because it secretes multiple lignin peroxidase isozymes [32]. In another series of studies in our laboratory, the wood decay BM fungus B. adusta attracted attention because of its potential role in enhancing the severity of cough symptoms by sensitization to this fungus [33]. In a preliminary study, we found S. commune and B. adusta in samples from only 2 (7.4%) and 14 (51.9%) of 27 patients with asthma whose sputum yielded BM fungi, respectively (TABLE 1). The predominance of B. adusta rather than of S. commune in asthma patients is noteworthy. Thus, among the approximately 31,000 species in the BM phylum, these additional two fungi should be taken into consideration when managing fungus-associated asthma. Possible mechanisms of action of fungi in patients with asthma
Kheradmand et al. reported that intrinsic protease activity in allergenic preparations of A. fumigatus gives rise to eosinophildriven allergic airway disease in mice [34]. Matsuwaki et al. demonstrated that Alternaria alternata produces aspartate proteases and that human peripheral blood eosinophils degranulate in response to the cell-free extract of A. alternata [35]. informahealthcare.com
Historically, Candida asthma has been reported and considered as a peculiar condition. Sensitization to C. albicans, which is not an aeroallergen but is present in the human gut flora, is demonstrated in up to 10% of individuals with mild stable asthma and 33% of patients with severe asthma [38]. C. albicans is correlated with intrinsic severe asthma. An association between thunderstorms and increased rate of acute asthma attacks has been reported. Thunderstorm asthma is positively correlated with a doubling of ambient fungal spores, especially those of Alternaria spp. [39]. Sensitization to Trichophyton, which causes superficial skin or nail infection, has been reported to be correlated with the severity of asthma [40]. As infection by this fungus occurs outside the respiratory tract, Trichophyton is not always detected in the airways of such patients. Recent studies demonstrated that Aspergillus restrictus aggravates the clinical manifestations of patients with asthma sensitized to Trichophyton; cross-reactivity should be investigated in such cases [41]. Schizophyllum asthma has been reported as a new clinical entity [42]. Sensitization to S. commune is one of the risk factors involved in the severity of asthma [31], as well as the exacerbation frequency and lung function decline in asthmatic patients [43]. As S. commune is a mushroom spore that generally grows in fields or forests, consideration of its ecology and life cycle may provide insights to prevent sensitization to this fungus [44]. Fungus-associated asthma & ABPM
It is noteworthy that S. commune is predominant not only in ABPM and pulmonary fungal balls, but also in asymptomatic colonization of the lung as colonizers in 12/22 cases (54.5%) with varied clinical diagnosis of chronic obstructive pulmonary disease, interstitial lung disease, post-tubercular sequelae and asthma [24]. We have rarely experienced mucoid impaction of bronchi (MIB) in patients with chronic cough whose sputum yields A. fumigatus. The inferior environment, such as impaired mucociliary clearance or airway epithelial barrier damage [45], caused by eosinophilic airway inflammation may be necessary for the development of MIB by A. fumigatus. By contrast, S. commune colonization may also cause production of mucus plugs in the 649
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Table 1. Details of identification of the 27 basidiomycetous fungi isolated from patients with asthma by D1/D2 sequencing. Identification by D1/D2
DDBJ/EMBL/GenBank accession numbers of closely related strain
Identity (%)
Bjerkandera adusta
AB096738.1
99
B. adusta
AB096738.1
99
Schizophyllum commune
AM269871.1
100
Ceraceomyces violascens
EU118612.1
100
Mycoaciella bispora
AY586692.1
98
B. adusta
AB096738.1
100
Phanerochaete sordida
EU118653.1
98
B. adusta
GQ470629.1
100
B. adusta
GQ470629.1
99
B. adusta
GQ470629.1
100
Pycnoporus spp.
DQ327661.1
99
B. adusta
GQ470629.1
100
B. adusta
GQ470629.1
99
Termitomyces albuminosus
AF079072.1
100
Oxyporus corticola
DQ873641.1
99
B. adusta
GQ470629.1
100
B. adusta
GQ470629.1
100
B. adusta
FN298244.1
99
Ceriporiopsis subvermispora
FN298246.1
99
B. adusta
FN298244.1
99
Trametes versicolor
JF416687.1
100
B. adusta
AB733334.1
99
Phanerochaete subglobosa
GQ470662.1
98
Fomitopsis palustris
AB733302.1
100
B. adusta
AB733334.1
100
Ceriporia lacerata
AB566280.1
100
S. commune
AM269871.1
100
PCR was performed with the primers for the 28 SrDNA partial sequences (D1/D2 region). The DDBJ/EMBL/GenBank nucleotide sequence databases were searched for matches of the confirmed sequences by using basic local alignment search tool programs. Sequence-based species identification was defined by >99% similarity.
airways of healthy non-asthmatic subjects and subsequently result in MIB or ABPM. This hypothesis may support the observation that the presence of bronchial asthma in ABPM was much lower than in allergic bronchopulmonary 650
aspergillosis (ABPA), as described by Chowdhary et al. [46]. It is believed that fungus-associated asthma is not always a precursor of ABPM [47]. ‘One airway, one disease’ in allergic fungal respiratory disease
Based on the concept of ‘one airway, one disease’ in fungal allergy, we assume that one fungal antigen causes both allergic fungal rhinosinusitis (AFRS) [48] and ABPM. Historically, the term ‘sinobronchial allergic mycosis’ (SAM) [49] coined by Venarske and deShazo is close to this concept. Patients with SAM have chronic sinusitis involving multiple sinuses, asthma, immediate cutaneous reactivity to fungal allergens, peripheral eosinophilia and radiographic evidence of bronchiectasis. Total serum IgE levels are also usually elevated, and a variety of chest radiographic abnormalities may occur, ranging from mass lesions to diffuse pulmonary infiltrates and even normal findings on chest radiography. Theoretically, fungus-associated asthma, ABPM and AFRS may overlap. SAM includes AFRS and ABPM. The width of each area of overlap would depend on the characteristics of the colonizing fungi, such as eosinophil accumulation and mucus production. Thus, SAM is reasonable as a theoretical concept, but there is often difficulty in separately investigating the allergological reactions that arise in the upper and lower airways in clinical practice [50]. It is not realistic to prepare antigenic solutions of all detected fungi for allergological testing. Despite the development of methods to identify the fungi, obstacles preventing acquisition of the antigenic solution in allergological investigations have remained. Chowdhary et al. [51] reported that S. commune was the third most common major causative antigen (11%) in 143 cases of ABPM due to fungi other than Aspergillus. A. fumigatus and S. commune are the most important candidate organisms as causative fungal antigens of SAM. Considering both the high prevalence of this fungus in ABPM and the fundamental similarity in therapy for both disorders occurring in the same individual [52], it will be helpful to develop simplified guidance for S. commune-associated SAM from the viewpoint of Schizophyllum allergy. We tentatively propose the following guidance for S. commune-associated SAM [53]. Fundamental condition of the patient: eosinophilic MIB with/without asthma and/or eosinophilic mucin involved in multiple sinuses with/without nasal polyposis; major criteria: positive fungal culture of S. commune from bronchial specimens or sinus contents and positive results for S. commune-specific IgE and/or S. commune-specific IgG; supplemental findings: elevated peripheral eosinophils and/or total serum IgE levels and radiographic evidence of ABPM and/or AFRS. Are antifungal drugs planned against fungus-sensitized asthma?
To prevent fungal sensitization, which is correlated with a decline in lung function [54], it is reasonable to plan some interventions, such as antifungal therapy. Ward et al. reported that Expert Rev. Clin. Immunol. 10(5), (2014)
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Fungus-associated asthma
the use of fluconazole (100 mg/day for 5 months) was associated with decreased bronchial hyperresponsiveness to Trichophyton inhalation, reduced oral steroid dose and increased peak expiratory flow rate [55]. Denning et al. reported the results of a randomized controlled trial [56] that showed a significant quality of life benefit, a decrease in IgE and modest improvements in rhinitis and morning peak expiratory flow, but not the FEV1, after oral antifungal therapy in patients with severe asthma sensitized to one of several common fungi. In their report, information on the association with fungal colonization and efficacy of antifungal drug was not presented in detail. Although there may be room to reconsider the appropriate dose and duration of antifungal drug administration in such studies, other effects such as decreasing the frequency of exacerbation of asthma or improvement of laryngeal sensations [57] should be estimated appropriately. It has recently been demonstrated that colonization by B. adusta is necessary in the process of sensitization to this fungus in allergic fungal cough patients [19]. On the other hand, it has recently been clarified that colonization by S. commune is not necessary for sensitization to this fungus in asthma [22], but it is necessary in ABPM caused by this fungus [47]. Various components, such as conidia, spores, hyphae, hyphal fragments, cell wall constituents and voltaic organic compounds, may act as antigens in fungal sensitization [56]. The efficacy of antifungal drugs against fungus-sensitized asthma is an important issue [58], but the routine use of these agents in such cases requires further evaluation [20]. Without considering the role of fungal colonization for sensitization in patients with fungus-associated asthma, it would not be possible to achieve successful treatment with antifungal drugs [59]. Antifungal therapy for reduction & eradication of fungus-colonized asthma
Kennedy et al. reported that the use of antifungal agents is generally only considered for patients with fungal colonization [60]. Antifungal therapy is expected to have advantages for reducing or eradicating the colonizing antigen burden [61] and thus preventing the sensitization process. Gonzalez et al. [62] reported that B. adusta was susceptible to itraconazole, amphotericin B and voriconazole in vitro, with MIC values of 0.125, 0.5 and 0.5 mg/ml, respectively. Although we reported that sensitization to S. commune may be one of the risk factors involved in lung function decline in asthmatic patients [43], the efficacy of antifungal drugs on pulmonary function in S. commune-sensitized asthma has not been sufficiently demonstrated. S. commune colonization in the airway of patients with asthma may be important in the progression to ABPM rather than in clinical manifestations of asthma itself. In S. commune-sensitized asthma, fungal exposure to a degree at which the fungus is able to colonize the airway would result in exacerbation of asthma or in prelude of ABPM. Therefore, it may be significant to eradicate S. commune-colonization from the viewpoint of prevention of subsequent disease progression even in S. commune-sensitized asthma. informahealthcare.com
Review
The previously proposed four-step treatment strategy for ABPM [47] would be applicable for fungus-colonized asthma: prevention and eradication of fungal colonization in the airway; control of eosinophilic bronchitis caused by fungal exposure; removal of any mucus plugs from the airway (if present); and effective management of environmental fungi. However, further investigations are required to clarify whether full doses of antifungal drugs are actually necessary to eradicate fungal colonization in the airways in such cases. Due to the low susceptibility to antifungal drugs against BM fungi [62,63], there is wide clinical significance of identifying NSM obtained from respiratory specimens [24]; however, sufficient attention should be paid to the phenomenon of antifungal resistance as well as adverse effects [64]. Anti-IgE therapy
Omalizumab is a recombinant, monoclonal antibody that binds IgE and inhibits interaction of IgE with IgE receptors on inflammatory cells. The use of omalizumab was shown to be an effective add-on therapy in patients with severe asthma [65] and to decrease the requirement of inhaled corticosteroids and reduce the number of exacerbations [66]. Although omalizumab has been shown to be beneficial in ABPA [67], the routine use of this drug in fungus-associated asthma requires further evaluation. Environmental management from the viewpoint of both the ecology & life cycle of the fungi
ABPA is widely understood to progress into chronic pleuropulmonary fibrosis [68] based on exposure to Aspergillus throughout the year in the chronic desquamative condition of eosinophilic bronchitis. However, S. commune exposure is believed to be limited to the mushroom overgrowth season in the field [44]. It has not been reported that ABPM caused by S. commune shows progression to the clinical stage of ‘fibrosis’ similar to ABPA. A literature search [63] did not reveal any peculiar seasonality of either disease onset or the first visit to hospital. However, disease recrudescence seemed to be concentrated in September to November (6 of 8 [75%] patients described). It remains to be determined whether this trend can be explained by coincidence of the mushroom overgrowth season in the field [44]. Periodic surveys of S. commune and the appropriate use of antifungal drugs may be useful for establishing strategies to prevent disease recurrence [49]. Such a consideration of both the ecology and life cycle of the fungi may also be applicable to the management of fungus-associated asthma. Environmental management
Dampness and mold growth in the home have been shown to be associated with wheezing and asthma in many geographical settings [69]. In such studies, the discussion mainly concerns the association with damp housing conditions and/or visible molds [70]. Further studies are required to investigate the correlation and fungal culture obtained from bronchial specimens and environmental fungi collected by air samplers. 651
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The importance of sensitization against airborne basidiomycetes, ascomycetes and fungal fragments to exacerbation of respiratory allergies in tropical environments has already been reported [71]. Despite the availability of antifungal drugs [62,63], our case reports suggested that disease recurrence in both allergic fungal cough [23] and ABPM [47] was influenced by the presence of related fungi in the patients’ environments. Dealing with this fungus as a mushroom spore and considering the ecology and life cycle of the fungus may provide insights to prevent disease recrudescence. Indoor and outdoor aspects of human responses to climate change are becoming important issues [72]; however, the question remains regarding how best to deal with such mushroom spores to prevent sensitization to this fungus. Are air filter systems recommended to reduce mushroom spores in the indoor environment? Should we open or shut the windows? [73]. Sautour et al. reported that in outdoor samples, B. adusta (8%) was the third most frequent species, especially in summer, and was the third and fourth most common species in the adult hematology unit (13%) and the pediatric hematology unit (11%), respectively, at a French hospital. They also mentioned that the concentration of this fungus was particularly high during the winter 2006/07, with a prevalence close to 30% in indoor samples [74]. Environmental management & prevention strategies for fungus-associated asthma
Mushrooms help in both the rotting of fallen trees and in returning their organic material back into the soil. The normal state of the forest is considered to be maintained in this way. However, attention should also be paid to other aspects of mushroom spores, including their enhancing effects on the clinical manifestations of allergic respiratory disorders. The control of the recurrence of fungus-associated asthma, which seemed to be influenced by the presence of the respective fungi in the environment, will be accomplished by environmental management [75]. Yellow sand dust with the long-range transport of atmospheric pollutants originating from the Taklamakan and Gobi Deserts was shown to reach not only Asia but also North America and Europe [76]. Recently, Kobayashi et al. [77] reported that direct sampling of Asian sand dust indicated the presence of Nocardiopsis spp., Bacillus spp., Streptomyces spp. and Bjerkandera spp. Thus, this mushroom spore is assumed to influence not only chronic cough patients but also patients with asthma, from the viewpoint of Bjerkandera allergy [78]. Although occupational-related mushroom allergy is recognized as hypersensitivity pneumonitis and is often limited to workers in certain industries [79], B. adusta is a wood decay BM fungus with a worldwide distribution, and therefore this fungal antigen may be a matter of clinical concern. Therefore, when discussing the influence of yellow sand dust on human health [80], we should not overlook exposure to particulate matter
