Allergic Bronchopulmonary Mycosis due to fungi other than Aspergillus.

Summary: Allergic bronchopulmonary mycosis (ABPM) is a clinical syndrome associated with immune sensitivity to various fungi that colonize the airways. Early diagnosis and treatment with systemic corticosteroids is the key in preventing the progression of the disease to irreversible lung fibrosis. Although Aspergillus has progressively gained recognition as a causative agent in past few decades, other fungi, that have been reported to cause ABPM, are not yet widely evaluated. We studied hundred and two patients with asthma for occurrence of ABPM. Patients were tested for cutaneous hypersensitivity and serum precipitin to 12 common fungal antigens. The positive cases were further evaluated for ABPM using standard criteria. Out of 102 asthma patients screened, 18 patients had either skin prick test (SPT) and/or serum precipitin positive. While 14 patients were SPT positive for one or more fungal antigen, two patients were serum precipitin positive for one or more fungi. Two patients had both serum precipitin positive as well as SPT positive. Six (5.8%) patients were diagnosed as ABPM as they fulfilled the criteria. Three of these were because of Aspergillus sp. Two were because of fungi other than Aspergillus namely Schizophyllum and Curvularia. One patient had ABPM because of both Aspergillus and Curvularia. In our study absolute eosinophil count (AEC), total IgE, serum precipitin and SPT had sensitivity of 100%, 100% 50% and 83.3% respectively for diagnosing ABPM. The specificity of these tests was 44.79%, 64.58% 98.96% and 88.54% respectively. Specfic IgE was positive in 50% of patients with either serum precipitin or SPT positivity. SPT or serum precipitin followed by specific IgE had sensitivity of 100% and specificity of 96.88% for diagnosing ABPM. SPT alone followed by Specific IgE had a sensitivity of 83.33% and specificity of 96.88% for diagnosing ABPM. We found that fungi other than Aspergillus such as schizophyllum, and curvularia, can be implicated in ABPM. Multiple fungal agents may be responsible for ABPM in an individual. There is a subset of patients of BA who have fungal sensitization but do not fulfil the criteria for ABPM. SPT was the single most sensitive and specific test, AEC >350 and total IgE more than 417IU were most sensitive tests and SPT followed by specific IgE was most effective strategy for diagnosing ABPM.

The role of fungal sensitisation in clinical presentation in patients with chronic obstructive pulmonary disease.

Atopic patients with chronic obstructive pulmonary disease (COPD) demonstrate more severe symptoms than their non-atopic counterparts. Also, Aspergillus hypersensitivity is known in COPD. However, allergic sensitisation to non-Aspergillus fungi has never been studied in COPD patients. To evaluate the prevalence of fungal sensitisation and its impact on the clinical presentation and outcome of COPD patients. Sensitisation to 17 fungi was studied in 55 COPD patients through skin prick tests, fungus-specific IgE, precipitating antibodies, total IgE and eosinophil counts. The clinical symptoms of patients were monitored thorough a patient-administered questionnaire. Overall, 5.4% (n = 3) of COPD patients were fungus sensitive. The sensitisation was noted to Alternaria alternata and Schizophyllum commune in two patients each, whereas another was sensitive to A. tamarii, Rhizopus spp. and Aspergillus fumigatus. Eosinophils were higher in fungus-sensitised patients (P = 0.001 vs. 0.003). No differences were noted in the clinical presentation of patients sensitised to fungi compared to those not sensitised to fungi or non-atopic. Although low, fungal sensitisation occurs in COPD but it is not limited to Aspergilli alone. Fungus-sensitised patients exhibit greater eosinophilia, implying more severe inflammation. Thus, such patients should be followed up regularly to recognise clinical worsening or development of ABPM.

Glucoamylase is a major allergen of Schizophyllum commune.

BACKGROUND: Schizophyllum commune is one of the causative agents of basidiomycosis including disorders such as allergic bronchopulmonary mycosis, allergic fungal sinusitis, and mucoid impaction of bronchi, the incidence of those of which has been increasing. These mycoses are difficult to diagnose because only a limited number of diagnostic tools are currently available. The biggest problem is that no specific antigens of S. commune have been identified to enable serodiagnosis of the disease. OBJECTIVE: In this study, we attempted to identify a major antigen of S. commune to establish a reliable serodiagnostic method. METHODS: We used mass spectrometry to identify an antigen that reacted with the serum of a patient with allergic bronchopulmonary mycosis caused by S. commune. The protein was expressed in Escherichia coli, highly purified, and the patient sera IgG and IgE titres against the protein were determined by enzyme-linked immunosorbent assay. RESULTS: The protein identified as a major antigen of S. commune was named Sch c 1; it was a homolog of glucoamylase. The IgG and IgE titres against Sch c 1 in patient sera were significantly higher than those in healthy volunteer sera (P < 0.01). CONCLUSIONS AND CLINICAL RELEVANCE: Sch c 1 is recognized by the host immune system of patients as an antigen/allergen. The purified glucoamylase Sch c 1 is a promising candidate antigen for the serodiagnosis of S. commune-induced mycosis.

Impact of Schizophyllum sensitization on decline of lung function in asthma.

OBJECTIVE: There is increasing interest in the association between the severity of asthma and fungal sensitization, and lung function decline in relation to mold and dampness in the home has recently been reported. This study was performed to determine the correlation between sensitization to Schizophyllum commune and decline of lung function, and to elucidate the outcomes and risk factors, especially from Schizophyllum allergy. METHODS: The medical records of 50 patients with asthma who satisfied the following inclusion criteria were collected and reviewed retrospectively: (1) at least 5 years of follow-up with five evaluations; (2) intradermal skin tests including S. commune performed at the initial assessment; and (3) severity ranging from mild-to-moderate. Lung function decline (evaluated as adjusted delta FEV1/year) was compared in a cross-sectional manner with regard to gender, age, BMI, smoking habit, allergological characteristics and exacerbation frequency. RESULTS AND CONCLUSIONS: There were significant differences in lung function decline between females and males (p < 0.05), positive and negative results of late-phase skin reaction to S. commune (p < 0.001), and positive and negative late-phase skin reaction to Aspergillus (p < 0.05). Lung function decline was correlated with exacerbation frequency (r = 0.428, p = 0.002). On multiple regression analysis, the probability of lung function decline in asthma was found to be significantly associated with female gender and positive late-phase skin reaction against S. commune. Our results suggested that sensitization to S. commune may be one of the risk factors involved in lung function decline in asthmatic patients.

The definitive diagnostic process and successful treatment for ABPM caused by Schizophyllum commune: a report of two cases.

BACKGROUND: Although mucoid impaction of the bronchi (MIB) is a well-known manifestation in allergic bronchopulmonary mycosis (ABPM), when unknown samples or plural eumycetes are cultured from bronchial materials, several problems are encountered which can affect the definitive diagnostic process or successful treatment. CASE SUMMARY: The definitive diagnostic process of two patients [a 58-(Case 1) and a 70-(Case 2) year-old female] with MIB was: 1) to identify the existence of any allergic respiratory disorder, 2) to detect the fungi obtained from bronchial materials, with use of the 28S rDNA sequencing and analysis, 3) to investigate whether the detected fungus was a probable etiologic antigen, and 4) to make the final diagnosis based on the results of the inhalation examinations using the antigenic solution of the fungi. As a treatment strategy, bronchial toilet and low dose itraconazole therapy were planned according to the clinical manifestations of each patient. DISCUSSION: The two patients with MIB were successfully diagnosed as ABPM caused by Schizophyllum commune (Sc-ABPM) accompanied with hyperattenuating mucoid impaction. The reliability of some allergological makers as a substitution for the bronchoprovocation test should be clarified in near future. Clinical manifestations demonstrated in our cases suggested that the allergic reaction such as eosinophilic bronchoalveolitis spreading around the mucus plug was a primary lesion underlying the Sc-ABPM. The success of the treatment for Sc-ABPM will be achieved by the strategy targeting to fundamental condition and by the control of the disease recurrence by means of effective environmental management.

Two cases of Schizophyllum asthma: is this a new clinical entity or a precursor of ABPM?

BACKGROUND: There is a close link between fungal sensitization and asthma severity. Although Schizophyllum commune (S. commune, "suehirotake" in Japanese), one of the basidiomycetous (BM) fungi, is a fungus that can cause allergic bronchopulmonary mycosis (ABPM) and allergic fungal sinusitis (AFS), whether the fungus causes or sensitizes subjects to asthma is unclear. METHODS: The bronchial provocation test using S. commune antigen was performed in two asthmatics who had demonstrated positive skin reactions to the S. commune antigen, and low dose of itraconazole (50 mg/day) was prescribed as an adjunctive therapy for 2 weeks. The allergological features and clinical manifestations of these patients are herein evaluated and discussed. RESULTS: Case 1 was a 71-year-old female, and case 2 was a 69-year-old male. Both patients demonstrated positive reactions to the inhalation test. A diagnosis of AFS or ABPM was excluded in both patients because of the lack of a history of pulmonary infiltrates, central bronchiectasis, a history of expectoration of brown plugs or flecks, or sinusoidal findings. Although the efficacy of itraconazole in our cases was unclear, the elevated titer of the specific IgG-for S. commune in case 2 gradually decreased during the period of antifungal therapy. CONCLUSIONS: The two patients described herein were diagnosed to have bronchial asthma caused by S. commune; so-called Schizophyllum asthma. S. commune may also be a causative fungal antigen of bronchial asthma.

The influence of Schizophyllum commune on asthma severity.

BACKGROUND: The sensitization and exposure to fungal allergens have been reported to be associated with asthma. The aim of this study was to clarify the impact of sensitization to Schizophyllum commune (S. commune) on the severity and exacerbations of asthma. METHODS: Ninety-two patients with asthma of various levels of severity [mild (n = 18), moderate (28), and severe (46)] and exacerbation severity [moderate (n = 43) and severe (6)] were retrospectively examined with regard to fungal sensitization such as specific IgE or intradermal skin reactions against S. commune and other common allergens. We also classified the patients into three groups: (1) three or more asthma attacks during the past year (F-BA) (n = 29),(2) one or two asthma attacks (NF-BA) (n = 20), and (3) no asthma attack (C-BA) (n = 43). RESULTS: The positive rate of late cutaneous reactions to S. commune was higher in patients with severe asthma (41.2%) than with moderate (26.1%) or mild asthma (6.7%), and was significantly different among the three groups (P < 0.05). Although the ratio did not show a significant difference between the patients with severe (83.3%) or moderate (36.1%) exacerbation, it was higher in F-BA (60.9%) than in NF-BA (21.1%) and C-BA patients (10.0%), and it was significantly different among the three groups (P = 0.0002). Multivariate analysis identified positive results for late-phase skin reactions to S. commune and the age of the patients as an independent determinant of asthma severity, and the skin results and %FVC an independent determinant of exacerbation frequency. CONCLUSION: This study demonstrated that S. commune is an environmental fungus that appears to enhance both the severity of asthma and the exacerbation frequency.

[Allergic bronchopulmonary mycosis induced by Schizophyllum commune--case report and review of the literature].

A 55-year-old man was admitted to our hospital because of pyrexia, cough and sputum. He suffered from bronchial asthma. Chest X-ray showed infiltrates in the left upper and right lower lung fields. Chest CT scans showed mucoid impaction and consolidation predominantly in the left upper lobe. Laboratory tests showed peripheral eosinophilia, elevated level of serum IgE, and the increased eosinophils in his sputum. Schizophyllum commune was isolated from the bronchoscopically-removed mucous plug. A diagnosis of allergic bronchopulmonary mycosis (ABPM) due to S. commune was made. Simultaneous daily administration of 400 mg itraconazole (ITCZ) and corticosteroid (prednisolone; 30 mg daily) provided sufficient improvement. However recurrence was recognized on chest CT scan findings one year later. There are not enough case reports concerning S. commune-induced ABPM to establish a therapeutic approach to the condition.

Mucoid impaction caused by monokaryotic mycelium of Schizophyllum commune in association with bronchiectasis.

A 51-year-old female was admitted to our hospital because of fever, cough, and hemoptysis. A chest radiograph showed a partial collapse of the left upper division and infected bullae in the left upper lobe. Bronchoscopic examination showed thick mucous plugs in the left upper bronchus. The isolates of the plugs proved to be Schizophyllum commune. Neither accumulation of eosinophils nor Charcot-Leyden crystals were present in the plugs. Mild ectatic changes of the left upper bronchus had been observed 17 years previously. We describe the first case of mucoid impaction, which was independent of the immunological reactions, caused by S. commune in association with bronchiectasis.

[Analysis of the cases in which Schizophyllum commune was isolated].

Infections caused by Schizophyllum commune have recently been on the increase. We analyzed cases in which this fungus was isolated from clinical samples from 1991 to 1995. Regular morphological methods were first employed in the identification of S. commune, and when necessary, mating was made with a known S. commune isolate. IgG antibodies against S. commune in the patients' serum were determined by the ELISA method. Profiles of the cases were analyzed and the English-language medical literature was reviewed. S. commune was isolated from 12 patients. Eighty three percent of the patients were female, most of which presented with allergy-related pulmonary diseases, i. e. allergic bronchopulmonary mycosis or mucoid impaction of bronchi. IgG antibodies were detectable in nine of eleven patients examined (82%). Fifty eight percent of the isolates were monokaryotic, and therefore, unidentifiable by regular morphological methods. In contrast, analysis of the English literature disclosed that sinusitis is the most common form of infection, and that hyphal invasion into the tissue was seen in 50% of reported cases. Our study shows that S. commune should be regarded as a pathogenic fungus, and is infecting humans much more frequently than previously assumed. Further investigation is warranted.

Allergic fungal sinusitis caused by Bipolaris spicifera and Schizophyllum commune.

There have been very few reports in Japan of patients with allergic fungal sinusitis (AFS). We describe two cases caused by Bipolaris spicifera and Schizophyllum commune. The patients were a 70-year-old male (Case 1) and a 55-year-old female (Case 2). Both presented with nasal obstruction and purulent nasal discharge. CT scans revealed each to have a soft tissue mass extending from the ethmoid sinus to the sphenoid sinus. In addition, pathological studies on the contents of the paranasal sinuses of both patients revealed the presence of fungal elements in the allergic mucin. Microbiological studies resulted in the recovery of Bipolaris spicifera from Case 1 and Schizophyllum commune from Case 2. To date there have been no reports of AFS due to these two fungi in Japan. It is very important in the diagnosis of AFS to demonstrate the presence of fungal elements in the allergic mucin. Squash cytology of the paranasal sinus contents was especially useful for proving the presence of fungi.

Allergic bronchopulmonary mycosis caused by the basidiomycetous fungus Schizophyllum commune.

We describe, to our knowledge, the first case of allergic bronchopulmonary mycosis (ABPM) caused by the basidiomycetous fungus Schizophyllum commune in an otherwise healthy woman. Bronchoscopic analysis repeatedly disclosed S. commune hyphae in the bronchi of the lingular lobe; these hyphae were originally misidentified as Aspergillus because the presence of clamp connections was overlooked. A lingular infiltrate with ectatic proximal bronchi, eosinophilia, an elevated serum level of IgE, and antibodies to S. commune supported the diagnosis. It is sometimes difficult to isolate and identify S. commune in clinical specimens, and hence only a limited number of cases of ABPM might have been correctly diagnosed in the past. We suspect, therefore, that some cases of ABPM caused by an allergic reaction to S. commune may be misdiagnosed as allergic bronchopulmonary aspergillosis or eosinophilic pneumonia of unknown origin. The significance of S. commune in allergic bronchopulmonary diseases is discussed.

Bronchial mucoid impaction due to the monokaryotic mycelium of Schizophyllum commune.

We report, to our knowledge, the first case of mucoid impaction of the bronchi due to a hypersensitivity reaction to the monokaryotic mycelium of Schizophyllum commune. The patient was hospitalized because of mild asthma attacks, persistent cough, peripheral eosinophilia, and "gloved finger" shadows on a chest roentgenogram. Bronchoscopic examination disclosed mucoid impactions that consisted of accumulations of eosinophils, Charcot-Leyden crystals, and nondichotomously branched hyphae in B3, B9, and B10 of the left lung. Cultures of the mucous plugs and sputum samples yielded white, felt-like mycelial colonies that were later identified as the monokaryotic mycelium of S. commune by use of mating tests with established monokaryotic and dikaryotic strains of S. commune. The results of tests for serum antibody to S. commune cytosol antigen were positive. Repeated bronchoscopies for performing bronchial toilet were effective in removing the mucous plugs and relieving the patient's symptoms. We suggest that the monokaryotic mycelium of S. commune should be considered as one of the fungi that can cause hypersensitivity-related lung diseases.

Characterization of beta-glucan recognition site on C-type lectin, dectin 1.

Dectin 1 is a mammalian cell surface receptor for (1-->3)-beta-d-glucans. Since (1-->3)-beta-d-glucans are commonly present on fungal cell walls, it has been suggested that dectin 1 is important for recognizing fungal invasion. In this study we tried to deduce the amino acid residues in dectin 1 responsible for beta-glucan recognition. HEK293 cells transfected with mouse dectin 1 cDNA could bind to a gel-forming (1-->3)-beta-d-glucan, schizophyllan (SPG). The binding of SPG to a dectin 1 transfectant was inhibited by pretreatment with other beta-glucans having a (1-->3)-beta-d-glucosyl linkage but not by pretreatment with alpha-glucans. Dectin 1 has a carbohydrate recognition domain (CRD) consisting of six cysteine residues that are highly conserved in C-type lectins. We prepared 32 point mutants with mutations in the CRD and analyzed their binding to SPG. Mutations at Trp(221) and His(223) resulted in decreased binding to beta-glucan. Monoclonal antibody 4B2, a dectin- 1 monoclonal antibody which had a blocking effect on the beta-glucan interaction, completely failed to bind the dectin-1 mutant W221A. A mutant with mutations in Trp(221) and His(223) did not have a collaborative effect on Toll-like receptor 2-mediated cellular activation in response to zymosan. These amino acid residues are distinct from residues in other sugar-recognizing peptide sequences of typical C-type lectins. These results suggest that the amino acid sequence W221-I222-H223 is critical for formation of a beta-glucan binding site in the CRD of dectin 1.