Case Report Allergic bronchopulmonary mycosis due to Schizophyllum commune in a patient with chronic hepatitis B

Introduction: Schizophyllum commune ( S. commune ) is an opportunistic pathogenic fungus and can cause infection of the respiratory system in immunocompromised hosts. Allergic bronchopulmonary mycosis (ABPM) is the major disease caused by S. commune . However, identification of S. commune using routine mycological diagnostic methods is difficult. It is easy to make mistakes in diagnosis and treatment, resulting in deterioration of the disease. We report the first case of ABPM due to S. commune in a Chinese patient with chronic hepatitis B. Case presentation: The patient presented cough, sputum and dyspnea for six months. The pathogen was missed during routine laboratory workup. We performed bronchoscopy examination and bronchoalveolar lavage. S. commune was identified by metagenomic next-generation sequencing (mNGS) of bronchial alveolar lavage fluid (BALF). Hence, the patient was immediately treated with 200 mg voriconazole twice daily (intravenous infusion) and 20 mg prednisone once a day (oral therapy), along with oral entecavir for hepatitis B. There was no recurrence of infection after the medication was discontinued. Conclusions: S. commune infection should be considered in the diagnosis of patients with refractory cough, sputum and dyspnea, especially in immunocompromised individuals. The mNGS technique is an effective supplementary technique for the diagnosis of S. commune infection, enabling precise clinical decision-making and appropriate treatment. Most patients have good prognosis with a combination of proper antifungal therapy and hormonal therapy.


Introduction
Schizophyllum commune (S. commune) is a type of filamentous basidiomycete fungus and is widely distributed in nature.It belongs to the Schizophyllaceae family, phylum Basidiomycota, class Agaricomycetes, and order Agaricales.S. commune is rarely involved in human disease because of its weak pathogenicity.Infections by S. commune in immunologically normal hosts is mostly manifested as colonization.However, in patients with immune insufficiency, local fungal colonizationcan can lead to local organ destruction and cause hypersensitivity reactions or even systemic dissemination.The main target of S. commune infection is the respiratory tract [1].Sinusitis and allergic bronchopulmonary mycosis (ABPM) are the two major diseases caused by S. commune.
ABPM is an immunologic disorder caused by hyperimmune response to the endobronchial growth of certain fungi.The most common pathogenic fungus is Aspergillus sp. ; S. commune (11%) is the third most important non-Aspergillus species causing ABPM [2,3].ABPM caused by S. commune was first reported by Kamei et al. in 1994 [4].S. commune is characterized by clamp connections, hyphal spicules, and formation of basidiocarps.Nevertheless, it often appears as a monokaryotic isolate in clinical samples and is unable to form the characteristic clamp connections [5].Therefore, S. commune cannot be identified with routine mycological diagnostic methods.Diagnosis is difficult and this can lead to treatment errors.
We experienced the first case of allergic bronchopulmonary mycosis due to S. commune in a patient with chronic hepatitis B. S. commune was missed during routine laboratory workup, but identified by metagenomic next-generation sequencing (mNGS) technique.Herein, we describe the successful treatment of the patient, and also review previous cases of ABPM caused by S. commune.

Case presentation
A 49-year-old woman with chronic hepatitis B presented to our hospital for chronic cough, sputum and dyspnea on November 30, 2021.She had chronic cough since April 2021.She presented to the local physician who prescribed a cough mixture which was ineffective.Then in August 2021 she went to a tertiary hospital where chest computed tomography (CT) showed an abnormal shadow with a gloved finger sign in the middle lobe of the right lung (Figure 1A, B).The results of laboratory tests showed that whole blood eosinophils and serum IgE levels were 0.81 × 10 9 /L and 913 IU/mL, respectively.A bronchoscopy was performed but the cause was not found.She was treated with cephalosporins and azithromycin for two weeks and the symptoms improved.However, her cough recurred one month later with right chest pain and shortness of breath.
The patient was therefore referred to our hospital and re-evaluated.Chest CT showed consolidation in the right middle lung field (Figure 1C, D) and mucoid impaction of the bronchus (Figure 1E, F).She was then admitted to our hospital in November 2021 for further treatment.Her medical history revealed that she had a history of chronic hepatitis B and was not treated with anti-hepatitis B virus therapy.She denied any other chronic illnesses or surgical history.There was no history of dust or tuberculosis exposure, nor any family history, any pets, or any history of gardening or mountain hiking.
On examination, the patient appeared well.Her temperature was 36.8 °C, heart rate was 96 bpm and regular, blood pressure was 102/64 mmHg, and oxygen saturation was 98% in room air.Her breathing rate was 17 per minute.The sound of the right lung was lower than the left one, and no rales or wheezes were detected in both lungs.Laboratory investigations revealed the whole blood eosinophils count of 0.85 × 10 9 /L and serum IgE value had increased to 1280 IU/mL.Pulmonary function testing showed that the ratio of expiratory volume in the first second to forced lung capacity (FEV1/FVC) was 95.13%, and the level of fractional exhaled nitric oxide (FeNO) was 14 ppb.Chest contrast-enhanced CT showed no strengthening of lesions after enhancement.A bronchoscopy examination was performed again and several mucous plugs were found in the right middle bronchus (Figure 1G).We performed bronchoalveolar lavage in the right mid-lobe bronchus and completely removed the mucous plugs after bronchoscopic cryotherapy (Figure 1H).However, culture of sputum, bronchial alveolar lavage fluid (BALF) and mucous plugs was negative.The patient was further investigated because mucous plug is a feature of ABPM.Direct analysis of BALF samples using a next-generation sequencer revealed fungal DNA and S. commune was dominant.The gene coverage figure showed that 29 unique nucleotide sequences corresponded to the sequences of S. commune in the genome locus (Figure 2), and the relative abundance was 17.37%.Therefore, the patient was diagnosed with ABPM caused by S. commune based on the new diagnostic criteria proposed by Asano K et al. [19] and started intravenous 200 mg voriconazole twice a day and oral 20 mg prednisone once a day (0.5 mg/kg/d) from December 3, 2021.Meanwhile, the patient had a history of chronic hepatitis B. Despite normal liver function, the patient had elevated levels of HBV DNA at 2.16 × 10 6 IU/mL.Considering voriconazole's possible liver damage, the doctors of the infectious disease department suggested moving the anti-hepatitis B threshold forward; so entecavir was prescribed as an anti-hepatitis B virus drug in combination with a hepatoprotective drug.
Two weeks later, the patient's symptoms significantly relieved.She continued taking voriconazole (400 mg/day) and prednisone (10 mg/day) orally at discharge, tapering the dose of prednisone gradually.She was followed up on an outpatient basis and alanine aminotransferase and creatinine were reviewed once a month.The patient developed a rash on her hands with itching during the follow-up, which is considered as a side effect of voriconazole.So, we reduced the dose of voriconazole to 200 mg/day.A chest CT scan obtained in June 2022 showed only a little infiltration in the right middle lung and central bronchiectasis (Figure 1I, J).The treatment was evaluated as effective, and she stopped taking the pills.The patient's total course of treatment was six months.Her symptoms have not recurred through the most recent follow-up in January 2023 and chest CT showed no new lesions (Figure 1K, L).Laboratory results and treatment of the patient are listed in Table 1.

Discussion
S. commune is an opportunistic pathogenic fungus.The development of S. commune infection is closely related to age of the host, host immunity and the number of fungal agents.As the number of patients with hematopathy, diabetes, acquired immune deficiency syndrome (AIDS), chemotherapy, dialysis, organ transplantation, and other diseases is increasing, the incidence of rare fungal infections is on the rise.S. commune infection can be categorized into allergic, saprophytic, chronic, and invasive forms.ABPM is one of the major diseases caused by S. commune.
However, data on clinical features, diagnostic methods and treatment options of ABPM caused by S. commune are currently not sufficient, especially in patients with immune insufficiency.We reported the first case of ABPM due to S. commune in a patient with  We summarized 13 cases of ABPM caused by S. commune that were reported globally (Table 2).Out of these, 11 cases were from Japan (84%), which may be related to the high awareness of the disease among Japanese clinicians and microbiologists.The age of onset ranged from 35 to 80 years, and females made up the majority (84%, n = 11).
Among the 13 reported cases (Table 2), four patients had underlying diseases, including pulmonary tuberculosis (n = 3) and diabetes mellitus (n = 1).However, there have been no previous cases of ABPM due to S. commune, secondary to chronic hepatitis B. Hepatitis B virus infection is the major cause of hepatic failure in China, and hepatic failure is considered to be one possible cause of immune insufficiency.
Visvanathan et al. [15] pointed out that patients with chronic hepatitis B are characterized by downregulation of a number of Toll-like receptor 2, Kuff's cells, dendritic cells, and natural killer cells.We suspect that the patient in our case had a history of chronic hepatitis B and elevated levels of HBV DNA, resulting in impaired innate and acquired immunity.The pathogenic process may be inhalation of spores from the environment.The spores colonize the lungs and germinate to form hyphae.The hyphae have protease antigens that stimulate the body to release cytokines to initiate an immune response, including elevated IgE and increased eosinophils [16].A persistent inflammatory response leads to disruption of the bronchial wall, mucus obstruction, and characteristic bronchiectasis.
Correct pathogenic diagnosis is the prerequisite for treatment.The identification of S. commune mostly uses traditional microbial methods including sputum, BALF and mucous plugs culture (n = 9).But S. commune may be missed by routine laboratory workup because it generally does not form spores and grows woolly, whitish, and sterile colonies.The analysis of the internal transcriptional interval regional sequence (ITS) and D1/D2 large subunit (LSU) region sequencing of ribosomal DNA (rDNA) is the most accurate method for identifying haploid S. commune [17].In our case, sputum and BALF culture did not yield any significant pathogen.S. commune was identified via analysis of BALF samples using a next-generation sequencer, and the gene coverage figure revealed 29 unique nucleotide sequences corresponding to the sequences of S. commune in the genome locus (Figure 2).The mNGS technique can quickly and accurately target the nucleic acid in samples to unbiasedly detect pathogens.It is increasingly being used for the clinical diagnosis of bacterial or fungal infection in infectious diseases, due to its higher sensitivity and faster identification of the pathogen and is less affected by antibiotics.
Diagnosis of allergic bronchopulmonary mycosis is a complex process that requires a combination of clinical presentation, mycology, and imaging features.The criteria proposed by Rosenberg and Patterson et al. [18] are classical diagnostic criteria.However, the criteria are highly specific, and less sensitive.In 2021, Asano et al. developed new diagnostic criteria for ABPM in patients who do not have cystic fibrosis [19].The new diagnostic criteria have higher sensitivity and reasonable specificity.The female patient of our case had asthma symptoms, elevated peripheral blood eosinophils and total IgE, lung infiltrates and atelectasis, central bronchiectasis, and tracheoscopic mucus plugs.The pathogen was identified as S. commune and antifungal therapy combined with corticosteroids was effective.She met seven components of the new diagnostic criteria, and was diagnosed as ABPM due to S. commune.
The clinical symptoms of allergic bronchopulmonary mycosis due to S. commune are nonspecific and can be manifested as cough, sputum, dyspnea, fever and hemoptysis.The most common manifestation is cough.Some patients present with an elevated peripheral eosinophil count and total IgE, mildly elevated or normal peripheral leukocytes, as well as normal erythrocyte sedimentation Rate (ESR) and Creactive protein (CRP).Evaluation of serum specific IgE/IgG against S. commune has certain diagnostic value.Lung imaging can be presented as bronchial mucus plugs, atelectasis, central bronchiectasis, infiltrates, gloved finger signs, etc.It is worth noting that bronchial mucus plugs and central bronchiectasis are the most common manifestations and have important value in the diagnosis of ABPM.The bronchoscopic manifestations are mostly white or yellow jelly-like mucus plugs that can be seen in the bronchial lumen, and in severe cases, completely block the lumen, resulting in local or total atelectasis.S. commune infections should be considered in the diagnosis of patients with chronic cough, sputum and dyspnea, especially in immunocompromised hosts.But the final pathogen diagnosis still depends on the identification of S. commune.
There are currently no guidelines for the treatment of ABPM caused by S. commune, but guidelines for treatment of allergic bronchopulmonary mycosis due to Aspergillus sp (ABPA) recommends a combination of antifungal therapy and hormonal therapy [20].Among the previous 13 patients with ABPM due to S. commune (Table 2), six patients were treated with combination therapies of antifungal agents with systemic and/or inhaled hormone, four patients were treated with only antifungal therapy, and one patient was treated with bromhexine.The efficacy of antifungal therapy combined with hormonal therapy reached 100%.In terms of the choice of antifungal drugs, Chowdhary et al. reported in vitro susceptibility tests of 30 strains of common S. commune to different antifungal drugs, and the low minimum inhibitory concentration (MIC) group with better clinical efficacy was: itraconazole 0.20 mg/mL, voriconazole 0.24 mg/mL, and amphotericin B 0.29 mg/mL [21].Ishiguro et al. reported a patient with ABPM due to S. commune who did not improve when treated with itraconazole for 16 weeks and then the treatment was changed to oral voriconazole effectively for two years without recurrence [12].In our case, although drug susceptibility testing was not performed, the patient was treated with combination of voriconazole and prednisone.Her symptoms and the lung CT lesion were improved and there was no recurrence six months after stopping medication.As a result, we recommend a combination of antifungal and hormonal therapy in patients with ABPM caused by S. commune.Besides medication therapy, we can remove the mucus plug in the bronchi by repeated lavage or freeze-thaw under bronchoscopy.Amitani et al. [6] and Ogawa et al. [9] reported cases of tracheoscopic removal of mucus plug alone, and the patients recovered, but the follow-up data were not available.Surgical operation is limited to pulmonary fungal ball and colonization status, and video-assisted thoracoscopic surgery is available in patients with empyema [22].

Figure 1 .
Figure 1.A to F and I to L: chest CT images; G and H: bronchoscopic images.A, B: red arrow shows a gloved finger sign in the middle lobe of the right lung; C, D: red arrow shows consolidation in the right middle lung field and mucoid impaction of the bronchus; E, F: red arrow shows mucous plugs in the right middle bronchus and blocking the lumen; G: white arrow shows mucous plugs in the right middle bronchus; H: white arrow indicates that mucous plugs were completely removed after bronchoscopic cryotherapy; I, J: red arrow shows a little infiltration in the right middle lung and central bronchiectasis; K, L: red arrow shows that no new lesions can be seen on CT images.

Figure 2 .
Figure 2. Gene coverage figure of Schizophyllum commune in the BALF sample.Twenty-nine unique nucleotide sequences corresponded to the sequences of S. commune in the genome locus.

Table 1 .
Laboratory results and treatment of the patient.bloodcell count; E: eosinophils; E%: eosinophils/white blood cell count; CRP: C-reactive protein.chronichepatitis B. We also reviewed global literature focused on ABPM caused by S. commune.Our literature search through PubMed and Web of Science covered the period up to December 2022.

Table 2 .
Literature review of case reports on ABPM due to Schizophyllum commune.