(1, 3)-Beta-D-Glucan in bronchoalveolar lavage fluid: a useful biomarker in diagnosis of invasive pulmonary infection caused by Hormographiella aspergillata?

(1, 3)-Beta-D-Glucan in bronchoalveolar lavage fluid: a useful biomarker in diagnosis of invasive pulmonary infection caused by Hormographiella aspergillata? | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report (1, 3)-Beta-D-Glucan in bronchoalveolar lavage fluid: a useful biomarker in diagnosis of invasive pulmonary infection caused by Hormographiella aspergillata? Haiyan Ye, Jinhui He, Jing Huang, Patrick Chu, Junru Liu, Fanfan Xing, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4481751/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 28 Dec, 2024 Read the published version in Diagnostic Pathology → Version 1 posted 10 You are reading this latest preprint version Abstract Hormographiella aspergillata is a rare hyaline mold causing invasive fungal infection in humans, until the frequent use of antifungal prophylaxis in immunocompromised hosts. Due to the high mortality of H. aspergillata infection, early recognition and treatment are crucial. Previous case reports suggested that serum (1,3)-beta-D-Glucan (BG) is one of the diagnostic aids for H. aspergillata infection. Here we report for the first time a case of pulmonary H. aspergillata infection with a negative serum BG but positive bronchoalveolar lavage fluid (BAL) BG. This may suggest that BAL BG is a useful and additional microbiological marker for prompt identification of this fatal invasive fungal infection (IFI). But it should be interpreted together with the clinical presentation, imaging, and other laboratory results. Hormographiella aspergillata (1 3)-beta-D-Glucan Invasive fungal infection amphotericin B Figures Figure 1 Figure 2 Figure 3 Introduction Invasive fungal infection (IFI) is a serious complication in patients with hematological malignancies. With the use of antifungal prophylaxis in immunocompromised hosts, there is a change in the etiology of fungal infection from Aspergillus and Candida to more resistant fungi such as Mucorales, Fusarium, Scedosporium , and Basidiomycetes [ 1 , 2 ]. Pulmonary infection due to Hormographiella aspergillata is rare but associated with a high mortality rate, leading to delays in diagnosis and treatment [ 3 ]. The diagnosis of invasive fungal infection is often difficult, because of risks associated with invasive procedures such as lung biopsy or bronchoalveolar lavage in patients with coagulopathies, low sensitivity of routine fungal culture, together with the long turn-around time in confirmation of fungal identity due to lack of expertise. Previous case reports have reported that serum BG levels were elevated in patients with H. aspergillata infection, suggesting it is an important marker of H. aspergillata infection [ 4 – 7 ]. Here we report the first case of pulmonary H. aspergillata infection with a negative serum but a positive BAL BG, suggesting that BAL BG may be a useful and additional tool for prompt diagnosis of this fatal IFI. Presentations A 34-year-old Chinese female, with newly diagnosed acute lymphoblastic leukemia, was admitted to our hospital for chemotherapy on 20th October 2016. Prior to admission, she experienced a dry cough and persistent neutropenic fever for 15 days, without improvement despite broad-spectrum antibiotics coverage with biapenem, amikacin, and itraconazole in another hospital. Chemotherapy was administered according to the GRAALL-2003 regimen [ 8 ] (Intravenous vincristine, daunorubicin, pegaspargase, and cyclophosphamide; oral prednisone; intrathecal methotrexate, cytarabine, and dexamethasone) from day 6 to day 34 of hospitalization. She enjoyed good past health with no known drug allergies. She had no personal history or contact history of pulmonary tuberculosis. She kept no pets at home and had never used any over-the-counter medication or traditional Chinese medicine. She was a non-smoker and a social drinker. Her body temperature was 38.7°C on admission, with a heart rate of 110 beats per minute, blood pressure of 112/69 mm Hg, respiratory rate of 28 breaths per minute, and oxygen saturation of 80% in room air. There were no palpable lymphadenopathies or finger clubbing. Abdominal, respiratory, and cardiovascular examinations were all unremarkable. On day 9 of admission, she remained neutropenic and febrile despite broad-spectrum antibiotics (imipenem, vancomycin, trimethoprim-sulfamethoxazole, doxycycline, and levofloxacin) and itraconazole prophylaxis. Computed tomography (CT) of the thorax showed no signs of pneumonia and pulmonary lesions (Fig. 1 A). In view of persistent fever, itraconazole was switched to micafungin for antifungal prophylaxis. However, fever still persisted despite adjustment of antifungal, with a repeated CT thorax (day 21) demonstrating two new pulmonary nodules in the right middle lobe with halo signs (Fig. 1 B). Blood culture, sputum for acid-fast bacilli (AFB) smear, and sputum for bacterial culture were unremarkable. Mycobacterium tuberculosis DNA was not detected in the sputum by PCR. Serum galactomannan and BG were negative on Day 22. Bronchoscopy with biopsy was not initially performed due to refusal by the patient and her family, therefore micafungin was empirically switched to caspofungin, with the subsequent addition of voriconazole. However, reassessment CT thorax (day 33) still showed a progression of the right middle lung mass with cavitation (Fig. 1 C). A bronchoscopy with lung biopsy was subsequently performed on the following day (day 34), and a mucous plug containing purulent secretions in the right posterior segmental bronchus was removed and sent for microbiological investigations. Both BAL and lung tissue bacterial cultures were negative, with Mycobacterium tuberculosis DNA not detected in the specimens. BAL galactomannan antigen was negative, but BAL BG was positive (> 600 pg/mL). Antifungal was subsequently switched to amphotericin B deoxycholate, escalating from 5mg daily to a treatment dose of 40mg daily (from day 34 to day 41) to reduce the chance of acute hypersensitivity reaction. Despite the recovery of her neutrophil level and the administration of amphotericin B deoxycholate, the lung lesions continued to progress (Fig. 1 D) with her clinical condition deteriorating rapidly, and the patient died from severe hemoptysis and respiratory failure on day 44. Mycology and histology After incubating the BAL and lung tissue on Sabouraud dextrose agar at 37℃ for 48 hours, white to cream-colored colonies and cottony aerial mycelium were observed. All inoculated media (Sabouraud dextrose agar, chocolate agar, and blood agar) yielded pure cultures of this fungus in the following days. Staining with lactophenol blue demonstrated septate conidiophores with clusters of smooth-walled, hyaline, and cylindrical arthroconidia (Fig. 2 ). Pan-fungal PCR and subsequent sequencing using the internal transcribed spacer (ITS) region of the rRNA gene of the isolates were performed. Based on the Basic Local Alignment Search Tool (BLAST) search of the sequence on the ITS region of the isolated fungus, the homology of Coprinopsis cinerea culture CBS 338.69 strain (GeneBank Accession No: MH878445.1) was 100.0% (365/ 365 bp), therefore the organism was identified as Coprinopsis cinerea (the teleomorph of Hormographiella aspergillata ). Histology of the lung tissue revealed hyaline, septate, and branched hyphae with evidence of angioinvasion (Fig. 3 ). Antifungal susceptibility testing was performed by the E-test method on Sabouraud dextrose agar, with the minimal inhibitory concentrations (MIC) of voriconazole and amphotericin B being 32µg/mL and 0.94 µg/mL, respectively. Discussion H. aspergillata belongs to the Basidiomycota division of fungi, and is the asexual form of Corprinopsis cinerea , an edible mushroom usually found in compost and other nutrient-rich substrates. H. aspergillata is a rare hyaline mold causing invasive fungal infection in humans, until the frequent use of echinocandin in patients with hematological malignancies. Twenty-seven cases were reported in the literature from 23 publications, with infection occurring mainly in patients with hematological malignancies [ 3 – 7 , 9 – 26 ]. The majority of the patients were diagnosed in Europe, with other cases documented in the United States, Japan, and India. Most cases of H. aspergillata infection have been reported as pulmonary and disseminated infections, but the involvement of the skin, central nervous system, eye, and spleen was also reported in immunocompromised patients [ 5 , 6 , 12 , 15 ]. Endocarditis and endophthalmitis have been described in immunocompetent patients [ 10 , 20 , 25 , 26 ]. The mortality rate of H. aspergillata infection was high (78%), likely related to the delay in diagnosis and initiation of effective antifungal agents [ 3 ]. Patients who survived were managed with prompt invasive diagnostic procedures such as bronchoscopy and lung biopsy for respiratory infection, adequate surgical debridement of involved areas, prompt initiation of broad-spectrum antifungal therapy, as well as recovery of neutrophils in patients with underlying hematological malignancies. Most cases of H. aspergillata infection were diagnosed by histology with confirmation by molecular techniques such as PCR and sequencing. Due to the high mortality of H. aspergillata infection, early recognition and treatment are crucial. We attempted to evaluate the value of galactomannan, BG, and glucuronoxylomannan (GXM) antigens from previous studies to facilitate the early diagnosis of H. aspergillata infection. GXM is the capsular antigen of Cryptococcus neoformans , that is widely used for the diagnosis of cryptococcosis. Cross-reactions with GXM have been described in the members of Basidiomycetes such as Trichosporon and Coprinopsis cinerea [ 27 ]. However, another study has demonstrated that the culture supernatants of H. aspergillata produce galactomannan and BG but not GXM [ 4 ]. This concurs with the two reported cases of H. aspergillata infection that the serum GXM antigens were negative [ 19 , 20 ]. Despite the in vitro result of positive galactomannan, the diagnostic utility of galactomannan is doubtful, as all documented cases of H. aspergillata infection have negative galactomannan assay. The situation of the use of BG for diagnosis is different, with an earlier study showing that BG is an important component of the cell wall of Coprinus cinereus [ 28 ]. In five reported cases of H. aspergillata infection with serum BG checked, four (80%) of them had positive serum BG (greater than 500pg/mL) [ 3 – 7 ]. Serum BG was also found to be positive seven days prior to the development of radiological changes and at least one month prior to the identification of H. aspergillata in one of the case reports [ 7 ]. In our case, serum BG was negative despite positive radiological findings, but the BAL BG was found to be strongly positive (> 600 pg/mL). Although Candida spp. colonization or overgrowth at the lower respiratory tract can lead to false positive BAL BG results, yeasts have never been cultured from the respiratory specimens in our case, which further supports H. aspergillata as the cause of positive BAL BG in this case. Although BAL BG has a similar sensitivity to BAL galactomannan in the diagnosis of invasive aspergillosis and fungal infection (71%), it exhibits inferior specificity [ 29 ]. A positive BAL BG should be interpreted together with the clinical presentation, imaging, and other laboratory results for the diagnosis of IFI [ 30 ]. Currently, there is no standardized antifungal susceptibility protocol, clinical breakpoints, and treatment guidelines for H. aspergillata . Based on previous in vitro data, Jonathan T et al. summarized the antifungal susceptibility profile of 16 H. aspergillata clinical isolates reported in the literature, most cases exhibited a relatively low MIC range of voriconazole (0.015 to 1 mg/L) and amphotericin B (0.03 to 2 mg/L), except one case of amphotericin B MIC was 32 mg/L, while the MIC range of caspofungin (0.5 to 32 mg/L) and micafungin (0.25 to 16 mg/L) were relatively higher, indicating that voriconazole and amphotericin B are important antifungal agents for the treatment of H. aspergillata infection [ 3 ]. Although the method of susceptibility testing used was not standardized, the voriconazole MIC of our H. aspergillata isolate was higher than the usual reported range in the literature, which concurs with the fact that our patient did not respond to voriconazole treatment. Breakthrough infection after empirical voriconazole treatment has been reported on three occasions for H. aspergillata infection [ 11 , 14 , 17 ]. Based on the above factors and experience, voriconazole may not be a reliable primary regimen for H. aspergillata infection. Amphotericin B should be considered as the first-line antifungal agent. Voriconazole or liposomal amphotericin B are preferred antifungal agents for the treatment of IFI. Amphotericin B is a polyene antifungal agent with activity in vitro against a wide variety of fungal pathogens [ 11 , 14 , 17 ], including most Candida spp, most hyaline and dematiaceous molds, and all dimorphic fungi. Liposomal amphotericin B has been introduced in the market to reduce the toxicities associated with amphotericin B deoxycholate. However, liposomal amphotericin B is not affordable for many patients in developing countries. According to FDA’s labeling resources for human prescription drugs, administration of amphotericin B deoxycholate should start with a test dose of 1 mg intravenously over 20 to 30 minutes, and healthcare workers should observe for any acute hypersensitivity reactions within 30 minutes. If no reactions were observed, then the remaining treatment dose can be administered. However, the practice in China is different. Amphotericin B deoxycholate is usually administered at a dosage of 1–5 mg for the first day, with a stepwise increase by 5 mg daily or alternate day based on the patient’s tolerance, until the treatment daily dosage of 0.6-1 mg/kg is reached. Further studies are required to compare the tolerance of patients with the two-dosing approach using the amphotericin B deoxycholate manufactured in China. The stepwise dosing approach delays the achievement of therapeutic concentration, leading to a delay in the management of invasive H. aspergillata infection in our patient. Therefore, we believe that in the treatment of severe and life-threatening fungal infection in neutropenic patients, the FDA recommendations of amphotericin B deoxycholate administration should be followed to ensure the timely administration of therapeutic concentrations of antifungal agents. Conclusion BAL BG is a useful microbiological investigation for the diagnosis of invasive fungal infection as demonstrated in our case of fatal pulmonary H. aspergillata infection, but it should be interpreted with an assessment with clinical presentation, imaging, and other laboratory results. Amphotericin B, instead of voriconazole, should be recommended as the first-line treatment for H. aspergillata infection. In the treatment of severe and life-threatening fungal infection in neutropenic patients, the FDA recommendations (test dose then treatment dose) should be followed to ensure the timely administration of therapeutic concentrations of antifungal agents. Abbreviations BAL: bronchoalveolar lavage fluid BG: (1,3)-beta-D-Glucan CT: computed tomography GXM: glucuronoxylomannan H. aspergillata : Hormographiella aspergillata IFI: Invasive fungal infection ITS ：Internal transcribed spacer Declarations Author contributions HY, KH-YC and SK-PL contributed to the design of the study. JH, JL, RWP, FX, SK-PL, and RW-TL participated in the acquisition and analysis of data. HY and KH-YC drafted the manuscript, PC and JF-WC revised the manuscript. All of the authors read and approved the final draft of the manuscript. D ata availability The data are available from the corresponding author upon reasonable request. The study was approved by the Ethics Committee of the University of Hong Kong-Shenzhen Hospital. Written informed consent was obtained from the patient’s husband. Competing interests None Funding This study was partly supported by funding from the Sanming Project of Medicine in Shenzhen, China (SZSM201911014) and the High Level-Hospital Program, Health Commission of Guangdong Province. The funding sources had no role in the study design, data collection, analysis, interpretation, or writing of the report. References Kontoyiannis DP, Marr KA, Park BJ, et al. Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients, 2001-2006: overview of the transplant-associated infection surveillance network (TRANSNET) database. Clin Infect Dis, 2010. 50(8):1091-100. Horn DL, Neofytos D, Anaissie EJ, et al. Epidemiology and outcomes of candidemia in 2019 patients: data from the prospective antifungal therapy alliance registry. Clin Infect Dis, 2009. 48(12):1695-703. Tschopp J, Perentes JY, Beigelman-Aubry C, et al. 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J Med Microbiol, 2005. 54(7): 685-688. Surmont I, Aelst FV, Verbanck J, et al. A pulmonary infection caused by Coprinus cinereus (Hormographiella aspergillata) diagnosed after a neutropenic episode. Med Mycol, 2002. 40(2):217-9. Verweij PE, Kasteren MV, Nes J, et al. Fatal pulmonary infection caused by the basidiomycete Hormographiella aspergillata. J Clin Microbiol, 1997. 35(10): 2675-8. Nenoff P, Friedrich T, Schwerke H, et al. Rare fatal simultaneous mould infection of the lung caused by Aspergillus flavus and the basidiomycete Coprinus sp. in a leukemic patient. J Med Vet Mycol. 1997, 35(1):65-9. Bartz-Schmidt KU, Tintelnot K, Steffen M, et al. Chronic basidiomycetous endophthalmitis after extracapsular cataract extraction and intraocular lens implantation. Graefes Arch Clin Exp Ophthalmol, 1996. 234(9): 591-3 Speller DE, Maclver AG. Endocarditis caused by a coprinus species a fungus of the toadstool group. J Med Microbiol, 1970. 4(3):370-4. Tone K, Umeda Y, Makimura K. 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Cite Share Download PDF Status: Published Journal Publication published 28 Dec, 2024 Read the published version in Diagnostic Pathology → Version 1 posted Editorial decision: Accepted 15 Dec, 2024 Reviews received at journal 15 Dec, 2024 Reviewers agreed at journal 04 Dec, 2024 Reviewers agreed at journal 08 Nov, 2024 Reviews received at journal 02 Oct, 2024 Reviewers agreed at journal 02 Oct, 2024 Reviewers invited by journal 02 Oct, 2024 Editor assigned by journal 27 May, 2024 Submission checks completed at journal 27 May, 2024 First submitted to journal 26 May, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4481751","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":308723318,"identity":"59474210-6d3e-4980-833d-3011a0790671","order_by":0,"name":"Haiyan Ye","email":"","orcid":"","institution":"University of Hong Kong - Shenzhen Hospital","correspondingAuthor":false,"prefix":"","firstName":"Haiyan","middleName":"","lastName":"Ye","suffix":""},{"id":308723319,"identity":"dbc2a31c-d654-490a-bd57-3e33f02bcdd3","order_by":1,"name":"Jinhui He","email":"","orcid":"","institution":"University of Hong Kong - Shenzhen 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Kong","correspondingAuthor":false,"prefix":"","firstName":"Susanna","middleName":"Kar-Pui","lastName":"Lau","suffix":""},{"id":308723329,"identity":"adf17905-496b-4b94-b265-5c15266af8ec","order_by":11,"name":"Kelvin Hei-Yeung Chiu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyklEQVRIiWNgGAWjYBACAwYGNoYEBgk5fhAvoYB4LTbGkg0gLQbEamFgSEvccADKJQjMJZKfPXjYdjhx8/nViR8eGDDI84sdwK/FckaauUFi22HjbTfebpYAOsxw5uwEAg67kcMmAdQiu+3G2Q0gLQkGt4nUwrh5xtnNP0jRkqa4gb93G5G2nHlmJpFwzsZY4gbvNosEAwki/HI8+ZnkjzJgVPaf3XzzR4WNPL80AS0MAjAFEmCGBAHlIMB/AJ0xCkbBKBgFowANAADE6EfVgGhYDQAAAABJRU5ErkJggg==","orcid":"","institution":"Queen Mary Hospital","correspondingAuthor":true,"prefix":"","firstName":"Kelvin","middleName":"Hei-Yeung","lastName":"Chiu","suffix":""}],"badges":[],"createdAt":"2024-05-27 02:00:45","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4481751/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4481751/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13000-024-01589-9","type":"published","date":"2024-12-28T15:57:14+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":58170774,"identity":"f5fa15dc-b8a9-41bc-86b3-d18737aa5783","added_by":"auto","created_at":"2024-06-12 03:39:12","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1342352,"visible":true,"origin":"","legend":"\u003cp\u003eCT thorax (sagittal view) showing the progression of the lung lesions (arrows). \u003cstrong\u003eA:\u003c/strong\u003e No signs of pneumonia and pulmonary lesions on day 9;\u003cstrong\u003e B:\u003c/strong\u003e Two new pulmonary nodules (the biggest one is 1.9×1.5cm) located in the right middle lobe surrounded by a halo of ground-glass opacity on day 21; \u003cstrong\u003eC:\u003c/strong\u003e Progression of the right middle lung mass (the biggest one is 3.5×5.2cm) with cavitation on day 33; \u003cstrong\u003eD: \u003c/strong\u003eProgression of the right middle lung mass（3.6×5.2cm) with cavitation on day\u003cstrong\u003e \u003c/strong\u003e41.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4481751/v1/49015f7db63e62741a3d3354.png"},{"id":58171409,"identity":"ebb550db-3d43-4885-807e-7b1741b5cd24","added_by":"auto","created_at":"2024-06-12 03:47:12","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1116785,"visible":true,"origin":"","legend":"\u003cp\u003eStaining with lactophenol blue demonstrating septate conidiophores with clusters of smooth-walled, hyaline, and cylindrical arthroconidia (10×100).\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-4481751/v1/13fc51a1a03b42d3f3cd6dd3.png"},{"id":58172835,"identity":"f62e61ea-2e72-4ebd-bcf3-1895059b1817","added_by":"auto","created_at":"2024-06-12 03:55:12","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":8167966,"visible":true,"origin":"","legend":"\u003cp\u003eHistology of lung biopsy showing septate (red arrow) and branched hyphae with the formation of clews (white arrow); \u003cstrong\u003eA\u003c/strong\u003e: Hematoxylin and Eosin stain (10×40); \u0026nbsp;\u003cstrong\u003eB\u003c/strong\u003e: Gomori-Grocott stain (10×40); \u003cstrong\u003eC\u003c/strong\u003e: Periodic Acid-Schiff stain (10×40).\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4481751/v1/438e277f1b32d6c607899250.png"},{"id":72640773,"identity":"58258e99-b793-4d04-9b78-5ce923021547","added_by":"auto","created_at":"2024-12-30 16:09:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":19900591,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4481751/v1/23ba2f83-a8dc-420a-be0d-eeddc6c22275.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"(1, 3)-Beta-D-Glucan in bronchoalveolar lavage fluid: a useful biomarker in diagnosis of invasive pulmonary infection caused by Hormographiella aspergillata?","fulltext":[{"header":"Introduction","content":"\u003cp\u003eInvasive fungal infection (IFI) is a serious complication in patients with hematological malignancies. With the use of antifungal prophylaxis in immunocompromised hosts, there is a change in the etiology of fungal infection from \u003cem\u003eAspergillus\u003c/em\u003e and \u003cem\u003eCandida\u003c/em\u003e to more resistant fungi such as \u003cem\u003eMucorales, Fusarium, Scedosporium\u003c/em\u003e, and \u003cem\u003eBasidiomycetes\u003c/em\u003e [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Pulmonary infection due to \u003cem\u003eHormographiella aspergillata\u003c/em\u003e is rare but associated with a high mortality rate, leading to delays in diagnosis and treatment [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The diagnosis of invasive fungal infection is often difficult, because of risks associated with invasive procedures such as lung biopsy or bronchoalveolar lavage in patients with coagulopathies, low sensitivity of routine fungal culture, together with the long turn-around time in confirmation of fungal identity due to lack of expertise. Previous case reports have reported that serum BG levels were elevated in patients with \u003cem\u003eH. aspergillata\u003c/em\u003e infection, suggesting it is an important marker of \u003cem\u003eH. aspergillata\u003c/em\u003e infection [\u003cspan additionalcitationids=\"CR5 CR6\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e–\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Here we report the first case of pulmonary \u003cem\u003eH. aspergillata\u003c/em\u003e infection with a negative serum but a positive BAL BG, suggesting that BAL BG may be a useful and additional tool for prompt diagnosis of this fatal IFI.\u003c/p\u003e \u003cdiv id=\"Sec2\" class=\"Section2\"\u003e \u003ch2\u003ePresentations\u003c/h2\u003e \u003cp\u003eA 34-year-old Chinese female, with newly diagnosed acute lymphoblastic leukemia, was admitted to our hospital for chemotherapy on 20th October 2016. Prior to admission, she experienced a dry cough and persistent neutropenic fever for 15 days, without improvement despite broad-spectrum antibiotics coverage with biapenem, amikacin, and itraconazole in another hospital. Chemotherapy was administered according to the GRAALL-2003 regimen [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] (Intravenous vincristine, daunorubicin, pegaspargase, and cyclophosphamide; oral prednisone; intrathecal methotrexate, cytarabine, and dexamethasone) from day 6 to day 34 of hospitalization. She enjoyed good past health with no known drug allergies. She had no personal history or contact history of pulmonary tuberculosis. She kept no pets at home and had never used any over-the-counter medication or traditional Chinese medicine. She was a non-smoker and a social drinker. Her body temperature was 38.7°C on admission, with a heart rate of 110 beats per minute, blood pressure of 112/69 mm Hg, respiratory rate of 28 breaths per minute, and oxygen saturation of 80% in room air. There were no palpable lymphadenopathies or finger clubbing. Abdominal, respiratory, and cardiovascular examinations were all unremarkable.\u003c/p\u003e \u003cp\u003eOn day 9 of admission, she remained neutropenic and febrile despite broad-spectrum antibiotics (imipenem, vancomycin, trimethoprim-sulfamethoxazole, doxycycline, and levofloxacin) and itraconazole prophylaxis. Computed tomography (CT) of the thorax showed no signs of pneumonia and pulmonary lesions (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). In view of persistent fever, itraconazole was switched to micafungin for antifungal prophylaxis. However, fever still persisted despite adjustment of antifungal, with a repeated CT thorax (day 21) demonstrating two new pulmonary nodules in the right middle lobe with halo signs (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). Blood culture, sputum for acid-fast bacilli (AFB) smear, and sputum for bacterial culture were unremarkable. \u003cem\u003eMycobacterium tuberculosis\u003c/em\u003e DNA was not detected in the sputum by PCR. Serum galactomannan and BG were negative on Day 22. Bronchoscopy with biopsy was not initially performed due to refusal by the patient and her family, therefore micafungin was empirically switched to caspofungin, with the subsequent addition of voriconazole. However, reassessment CT thorax (day 33) still showed a progression of the right middle lung mass with cavitation (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC). A bronchoscopy with lung biopsy was subsequently performed on the following day (day 34), and a mucous plug containing purulent secretions in the right posterior segmental bronchus was removed and sent for microbiological investigations. Both BAL and lung tissue bacterial cultures were negative, with \u003cem\u003eMycobacterium tuberculosis\u003c/em\u003e DNA not detected in the specimens. BAL galactomannan antigen was negative, but BAL BG was positive (\u0026gt; 600 pg/mL). Antifungal was subsequently switched to amphotericin B deoxycholate, escalating from 5mg daily to a treatment dose of 40mg daily (from day 34 to day 41) to reduce the chance of acute hypersensitivity reaction. Despite the recovery of her neutrophil level and the administration of amphotericin B deoxycholate, the lung lesions continued to progress (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eD) with her clinical condition deteriorating rapidly, and the patient died from severe hemoptysis and respiratory failure on day 44.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Mycology and histology","content":"\u003cp\u003eAfter incubating the BAL and lung tissue on Sabouraud dextrose agar at 37℃ for 48 hours, white to cream-colored colonies and cottony aerial mycelium were observed. All inoculated media (Sabouraud dextrose agar, chocolate agar, and blood agar) yielded pure cultures of this fungus in the following days. Staining with lactophenol blue demonstrated septate conidiophores with clusters of smooth-walled, hyaline, and cylindrical arthroconidia (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Pan-fungal PCR and subsequent sequencing using the internal transcribed spacer (ITS) region of the rRNA gene of the isolates were performed. Based on the Basic Local Alignment Search Tool (BLAST) search of the sequence on the ITS region of the isolated fungus, the homology of \u003cem\u003eCoprinopsis cinerea\u003c/em\u003e culture CBS 338.69 strain (GeneBank Accession No: MH878445.1) was 100.0% (365/ 365 bp), therefore the organism was identified as \u003cem\u003eCoprinopsis cinerea\u003c/em\u003e (the teleomorph of \u003cem\u003eHormographiella aspergillata\u003c/em\u003e). Histology of the lung tissue revealed hyaline, septate, and branched hyphae with evidence of angioinvasion (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Antifungal susceptibility testing was performed by the E-test method on Sabouraud dextrose agar, with the minimal inhibitory concentrations (MIC) of voriconazole and amphotericin B being 32µg/mL and 0.94 µg/mL, respectively.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003e \u003cem\u003eH. aspergillata\u003c/em\u003e belongs to the Basidiomycota division of fungi, and is the asexual form of \u003cem\u003eCorprinopsis cinerea\u003c/em\u003e, an edible mushroom usually found in compost and other nutrient-rich substrates. \u003cem\u003eH. aspergillata\u003c/em\u003e is a rare hyaline mold causing invasive fungal infection in humans, until the frequent use of echinocandin in patients with hematological malignancies. Twenty-seven cases were reported in the literature from 23 publications, with infection occurring mainly in patients with hematological malignancies [\u003cspan additionalcitationids=\"CR4 CR5 CR6\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan additionalcitationids=\"CR10 CR11 CR12 CR13 CR14 CR15 CR16 CR17 CR18 CR19 CR20 CR21 CR22 CR23 CR24 CR25\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. The majority of the patients were diagnosed in Europe, with other cases documented in the United States, Japan, and India. Most cases of \u003cem\u003eH. aspergillata\u003c/em\u003e infection have been reported as pulmonary and disseminated infections, but the involvement of the skin, central nervous system, eye, and spleen was also reported in immunocompromised patients [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Endocarditis and endophthalmitis have been described in immunocompetent patients [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. The mortality rate of \u003cem\u003eH. aspergillata\u003c/em\u003e infection was high (78%), likely related to the delay in diagnosis and initiation of effective antifungal agents [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Patients who survived were managed with prompt invasive diagnostic procedures such as bronchoscopy and lung biopsy for respiratory infection, adequate surgical debridement of involved areas, prompt initiation of broad-spectrum antifungal therapy, as well as recovery of neutrophils in patients with underlying hematological malignancies.\u003c/p\u003e \u003cp\u003eMost cases of \u003cem\u003eH. aspergillata\u003c/em\u003e infection were diagnosed by histology with confirmation by molecular techniques such as PCR and sequencing. Due to the high mortality of \u003cem\u003eH. aspergillata\u003c/em\u003e infection, early recognition and treatment are crucial. We attempted to evaluate the value of galactomannan, BG, and glucuronoxylomannan (GXM) antigens from previous studies to facilitate the early diagnosis of \u003cem\u003eH. aspergillata\u003c/em\u003e infection. GXM is the capsular antigen of \u003cem\u003eCryptococcus neoformans\u003c/em\u003e, that is widely used for the diagnosis of cryptococcosis. Cross-reactions with GXM have been described in the members of \u003cem\u003eBasidiomycetes\u003c/em\u003e such as \u003cem\u003eTrichosporon\u003c/em\u003e and \u003cem\u003eCoprinopsis cinerea\u003c/em\u003e [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. However, another study has demonstrated that the culture supernatants of \u003cem\u003eH. aspergillata\u003c/em\u003e produce galactomannan and BG but not GXM [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. This concurs with the two reported cases of \u003cem\u003eH. aspergillata\u003c/em\u003e infection that the serum GXM antigens were negative [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Despite the \u003cem\u003ein vitro\u003c/em\u003e result of positive galactomannan, the diagnostic utility of galactomannan is doubtful, as all documented cases of \u003cem\u003eH. aspergillata\u003c/em\u003e infection have negative galactomannan assay. The situation of the use of BG for diagnosis is different, with an earlier study showing that BG is an important component of the cell wall of \u003cem\u003eCoprinus cinereus\u003c/em\u003e [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. In five reported cases of \u003cem\u003eH. aspergillata\u003c/em\u003e infection with serum BG checked, four (80%) of them had positive serum BG (greater than 500pg/mL) [\u003cspan additionalcitationids=\"CR4 CR5 CR6\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Serum BG was also found to be positive seven days prior to the development of radiological changes and at least one month prior to the identification of \u003cem\u003eH. aspergillata\u003c/em\u003e in one of the case reports [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In our case, serum BG was negative despite positive radiological findings, but the BAL BG was found to be strongly positive (\u0026gt;\u0026thinsp;600 pg/mL). Although \u003cem\u003eCandida spp.\u003c/em\u003e colonization or overgrowth at the lower respiratory tract can lead to false positive BAL BG results, yeasts have never been cultured from the respiratory specimens in our case, which further supports \u003cem\u003eH. aspergillata\u003c/em\u003e as the cause of positive BAL BG in this case. Although BAL BG has a similar sensitivity to BAL galactomannan in the diagnosis of invasive aspergillosis and fungal infection (71%), it exhibits inferior specificity [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. A positive BAL BG should be interpreted together with the clinical presentation, imaging, and other laboratory results for the diagnosis of IFI [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCurrently, there is no standardized antifungal susceptibility protocol, clinical breakpoints, and treatment guidelines for \u003cem\u003eH. aspergillata\u003c/em\u003e. Based on previous \u003cem\u003ein vitro\u003c/em\u003e data, Jonathan T et al. summarized the antifungal susceptibility profile of 16 \u003cem\u003eH. aspergillata\u003c/em\u003e clinical isolates reported in the literature, most cases exhibited a relatively low MIC range of voriconazole (0.015 to 1 mg/L) and amphotericin B (0.03 to 2 mg/L), except one case of amphotericin B MIC was 32 mg/L, while the MIC range of caspofungin (0.5 to 32 mg/L) and micafungin (0.25 to 16 mg/L) were relatively higher, indicating that voriconazole and amphotericin B are important antifungal agents for the treatment of \u003cem\u003eH. aspergillata\u003c/em\u003e infection [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Although the method of susceptibility testing used was not standardized, the voriconazole MIC of our \u003cem\u003eH. aspergillata\u003c/em\u003e isolate was higher than the usual reported range in the literature, which concurs with the fact that our patient did not respond to voriconazole treatment. Breakthrough infection after empirical voriconazole treatment has been reported on three occasions for \u003cem\u003eH. aspergillata\u003c/em\u003e infection [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Based on the above factors and experience, voriconazole may not be a reliable primary regimen for \u003cem\u003eH. aspergillata\u003c/em\u003e infection. Amphotericin B should be considered as the first-line antifungal agent.\u003c/p\u003e \u003cp\u003eVoriconazole or liposomal amphotericin B are preferred antifungal agents for the treatment of IFI. Amphotericin B is a polyene antifungal agent with activity \u003cem\u003ein vitro\u003c/em\u003e against a wide variety of fungal pathogens [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], including most \u003cem\u003eCandida\u003c/em\u003e spp, most hyaline and dematiaceous molds, and all dimorphic fungi. Liposomal amphotericin B has been introduced in the market to reduce the toxicities associated with amphotericin B deoxycholate. However, liposomal amphotericin B is not affordable for many patients in developing countries. According to FDA\u0026rsquo;s labeling resources for human prescription drugs, administration of amphotericin B deoxycholate should start with a test dose of 1 mg intravenously over 20 to 30 minutes, and healthcare workers should observe for any acute hypersensitivity reactions within 30 minutes. If no reactions were observed, then the remaining treatment dose can be administered. However, the practice in China is different. Amphotericin B deoxycholate is usually administered at a dosage of 1\u0026ndash;5 mg for the first day, with a stepwise increase by 5 mg daily or alternate day based on the patient\u0026rsquo;s tolerance, until the treatment daily dosage of 0.6-1 mg/kg is reached. Further studies are required to compare the tolerance of patients with the two-dosing approach using the amphotericin B deoxycholate manufactured in China. The stepwise dosing approach delays the achievement of therapeutic concentration, leading to a delay in the management of invasive \u003cem\u003eH. aspergillata\u003c/em\u003e infection in our patient. Therefore, we believe that in the treatment of severe and life-threatening fungal infection in neutropenic patients, the FDA recommendations of amphotericin B deoxycholate administration should be followed to ensure the timely administration of therapeutic concentrations of antifungal agents.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eBAL BG is a useful microbiological investigation for the diagnosis of invasive fungal infection as demonstrated in our case of fatal pulmonary \u003cem\u003eH. aspergillata\u003c/em\u003e infection, but it should be interpreted with an assessment with clinical presentation, imaging, and other laboratory results. Amphotericin B, instead of voriconazole, should be recommended as the first-line treatment for \u003cem\u003eH. aspergillata\u003c/em\u003e infection. In the treatment of severe and life-threatening fungal infection in neutropenic patients, the FDA recommendations (test dose then treatment dose) should be followed to ensure the timely administration of therapeutic concentrations of antifungal agents.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eBAL: bronchoalveolar lavage fluid\u003c/p\u003e\n\u003cp\u003eBG: (1,3)-beta-D-Glucan\u003c/p\u003e\n\u003cp\u003eCT:\u0026nbsp;computed tomography\u003c/p\u003e\n\u003cp\u003eGXM: glucuronoxylomannan\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eH. aspergillata\u003c/em\u003e: \u003cem\u003eHormographiella aspergillata\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eIFI: Invasive fungal infection\u003c/p\u003e\n\u003cp\u003eITS ：Internal transcribed spacer\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAuthor contributions\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHY, KH-YC and SK-PL contributed to the design of the study. JH, JL, RWP, FX, SK-PL, and RW-TL participated in the acquisition and analysis of data. HY and KH-YC drafted the manuscript, PC and JF-WC revised the manuscript. All of the authors read and approved the final draft of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eD\u003c/strong\u003e\u003cstrong\u003eata availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;The study was approved by the Ethics Committee of the University of Hong Kong-Shenzhen Hospital. Written informed consent was obtained from the patient\u0026rsquo;s husband.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was partly supported by funding from the Sanming Project of Medicine in Shenzhen, China (SZSM201911014) and the High Level-Hospital Program, Health Commission of Guangdong Province. The funding sources had no role in the study design, data collection, analysis, interpretation, or writing of the report.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKontoyiannis DP, Marr KA, Park BJ, et al. Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients, 2001-2006: overview of the transplant-associated infection surveillance network (TRANSNET) database. Clin Infect Dis, 2010. 50(8):1091-100.\u003c/li\u003e\n\u003cli\u003eHorn DL, Neofytos D, Anaissie EJ, et al. Epidemiology and outcomes of candidemia in 2019 patients: data from the prospective antifungal therapy alliance registry. Clin Infect Dis, 2009. 48(12):1695-703.\u003c/li\u003e\n\u003cli\u003eTschopp J, Perentes JY, Beigelman-Aubry C, et al. Invasive Hormographiella aspergillata infection in patients with acute myeloid leukemia: Report of two cases successfully treated and review of the literature. Med Mycol Case Rep, 2021. 32: 68-72.\u003c/li\u003e\n\u003cli\u003eMoniot M, Lavergne RA, Morel T, et al. Hormographiella aspergillata: an emerging basidiomycete in the clinical setting? A case report and literature review. BMC Infect Dis, 2020. 20(1):945.\u003c/li\u003e\n\u003cli\u003eChauhan A, Gruenberg J, Arbefeville S, et al. Disseminated Hormographiella aspergillata Infection with Lung and Brain Involvement after Allogenic Hematopoietic Stem-Cell Transplantation in a 54-Year-Old Man. Lab Med, 2019. 50(4):426-431.\u003c/li\u003e\n\u003cli\u003eNanno S, Nakane T, Okamura H, et al. Disseminated Hormographiella aspergillata infection with involvement of the lung, brain, and small intestine following allogeneic hematopoietic stem cell transplantation: case report and literature review. Transpl Infect Dis, 2016. 18(4):611-6.\u003c/li\u003e\n\u003cli\u003eKoncan R, Nadali G, Favuzzi V, et al. Invasive Fungal Infection by Hormographyella aspergillata: A Tricky Diagnosis Triggered by (1,3)-Beta-D-Glucan Assay. J Microb Biochem Technol, 2016. 8:4.\u003c/li\u003e\n\u003cli\u003eHuguet F, Leguay T, Raffoux E, et al. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol, 2009. 27: 911\u003c/li\u003e\n\u003cli\u003eIsabel Cristina, R, Diana A, Karen A, et al. Breakthrough Hormographiella aspergillata Infection in a Patient with Acute Myeloid Leukemia Receiving Posaconazole Prophylaxis: A Case Report and Review. Mycopathologia, 2020. 185(6): 1069-1076.\u003c/li\u003e\n\u003cli\u003eJain N, Jinagal J, Ghosh A, et al. Ocular infection caused by Hormographiella aspergillata: A case report and review of literature. J Mycol Med, 2019. 29(1): 71-74.\u003c/li\u003e\n\u003cli\u003eGodet C, Cateau E, Rammaert B, et al. Nebulized Liposomal Amphotericin B for Treatment of Pulmonary Infection Caused by Hormographiella aspergillata: Case Report and Literature Review. Mycopathologia, 2017. 182(7-8): 709-713.\u003c/li\u003e\n\u003cli\u003eCorrea-Martinez C, Brentrup A, Hess K, et al. First description of a local Coprinopsis cinerea skin and soft tissue infection. New Microbes New Infect, 2017. 21: 102-104.\u003c/li\u003e\n\u003cli\u003eHeiblig M, Bozzoli V, Saison J, et al. Combined medico-surgical strategy for invasive sino-orbito-cerebral breakthrough fungal infection with Hormographiella aspergillata in an acute leukaemia patient. Mycoses, 2015. 58(5): 308-312.\u003c/li\u003e\n\u003cli\u003eCorzo-Leon DE, Satlin MJ, Soave R, et al. Epidemiology and outcomes of invasive fungal infections in allogeneic haematopoietic stem cell transplant recipients in the era of antifungal prophylaxis: a single-centre study with focus on emerging pathogens. Mycoses, 2015. 58(6):325-36.\u003c/li\u003e\n\u003cli\u003eBojic M, Willinger B, Rath T, et al. Fatal skin and pulmonary infection caused by Hormographiella aspergillata in a leukaemic patient: case report and literature overview. Mycoses, 2013. 56(6): 687-689.\u003c/li\u003e\n\u003cli\u003ePang KP, Godet C, Fekkar A, et al. Breakthrough invasive mould infections in patients treated with caspofungin. J Infect, 2012. 64(4):424-9.\u003c/li\u003e\n\u003cli\u003eConen A, Weisser M, Hohler D, et al. Hormographiella aspergillata: an emerging mould in acute leukaemia patients? Clin Microbiol Infect, 2011. 17(2): 273-7.\u003c/li\u003e\n\u003cli\u003eSuarez F, Olivier G, Garcia-Hermoso D, Randriamalala E, et al. Breakthrough Hormographiella aspergillata Infections Arising in Neutropenic Patients Treated Empirically with Caspofungin. J Clin Microbiol, 2011. 49(1): 461-465.\u003c/li\u003e\n\u003cli\u003eAbuali MM, Posada R, Toro GD, et al. Rhizomucor variabilis var.regularior and Hormographiella aspergillata Infections in a Leukemic Bone Marrow Transplant Recipient with Refractory Neutropenia. J Clin Microbiol, 2009. 47(12): 4176-4179.\u003c/li\u003e\n\u003cli\u003eGreer EL, Kowalski TJ, Cole ML, et al. Truffles revenge a pig-eating fungus. Cardiol Path, 2008. 342-343.\u003c/li\u003e\n\u003cli\u003eLagrou K, Massonet C, Theunissen K, et al. Fatal pulmonary infection in a leukaemic patient caused by Hormographiella aspergillata. J Med Microbiol, 2005. 54(7): 685-688.\u003c/li\u003e\n\u003cli\u003eSurmont I, Aelst FV, Verbanck J, et al. A pulmonary infection caused by Coprinus cinereus (Hormographiella aspergillata) diagnosed after a neutropenic episode. Med Mycol, 2002. 40(2):217-9.\u003c/li\u003e\n\u003cli\u003eVerweij PE, Kasteren MV, Nes J, et al. Fatal pulmonary infection caused by the basidiomycete Hormographiella aspergillata. J Clin Microbiol, 1997. 35(10): 2675-8.\u003c/li\u003e\n\u003cli\u003eNenoff P, Friedrich T, Schwerke H, et al. Rare fatal simultaneous mould infection of the lung caused by Aspergillus flavus and the basidiomycete Coprinus sp. in a leukemic patient. J Med Vet Mycol. 1997, 35(1):65-9.\u003c/li\u003e\n\u003cli\u003eBartz-Schmidt KU, Tintelnot K, Steffen M, et al. Chronic basidiomycetous endophthalmitis after extracapsular cataract extraction and intraocular lens implantation. Graefes Arch Clin Exp Ophthalmol, 1996. 234(9): 591-3\u003c/li\u003e\n\u003cli\u003eSpeller DE, Maclver AG. Endocarditis caused by a coprinus species a fungus of the toadstool group. J Med Microbiol, 1970. 4(3):370-4.\u003c/li\u003e\n\u003cli\u003eTone K, Umeda Y, Makimura K. Cross reactivity in Cryptococcus antigen latex agglutination test in two commercial kits. Med Mycol, 54(4):439-43.\u003c/li\u003e\n\u003cli\u003eSietsma JH, Wessels JG. Solubility of (1 leads to 3)-beta-D/(1leads to 6)-beta-D-glucan in fungal walls: importance of presumed linkage between glucan and chitin. J Gen Microbiol, 1981. 125 (1): 209\u0026ndash;212.\u003c/li\u003e\n\u003cli\u003eReischies FMJ, Prattes J, Pruller F, et al. Prognostic potential of 1,3-beta-d-glucan levels in bronchoalveolar lavage fluid samples. J Infect, 2016, 72(1): 29-35.\u003c/li\u003e\n\u003cli\u003eShi X, Liu Y, Gu XM, et al. Diagnostic value of (1 \u0026rarr; 3)-\u0026beta;-D-glucan in bronchoalveolar lavage fluid for invasive fungal disease: A meta-analysis. Respir Med, 2016. 117: 48-53.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"diagnostic-pathology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"dpat","sideBox":"Learn more about [Diagnostic Pathology](http://diagnosticpathology.biomedcentral.com)","snPcode":"13000","submissionUrl":"https://submission.nature.com/new-submission/13000/3","title":"Diagnostic Pathology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Hormographiella aspergillata, (1,3)-beta-D-Glucan, Invasive fungal infection, amphotericin B","lastPublishedDoi":"10.21203/rs.3.rs-4481751/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4481751/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eHormographiella aspergillata is a rare hyaline mold causing invasive fungal infection in humans, until the frequent use of antifungal prophylaxis in immunocompromised hosts. Due to the high mortality of H. aspergillata infection, early recognition and treatment are crucial. Previous case reports suggested that serum (1,3)-beta-D-Glucan (BG) is one of the diagnostic aids for H. aspergillata infection. Here we report for the first time a case of pulmonary H. aspergillata infection with a negative serum BG but positive bronchoalveolar lavage fluid (BAL) BG. This may suggest that BAL BG is a useful and additional microbiological marker for prompt identification of this fatal invasive fungal infection (IFI). But it should be interpreted together with the clinical presentation, imaging, and other laboratory results.\u003c/p\u003e","manuscriptTitle":"(1, 3)-Beta-D-Glucan in bronchoalveolar lavage fluid: a useful biomarker in diagnosis of invasive pulmonary infection caused by Hormographiella aspergillata?","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-12 03:39:08","doi":"10.21203/rs.3.rs-4481751/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accepted","date":"2024-12-15T12:21:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-12-15T09:01:21+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"86681950119965819843036148128704570708","date":"2024-12-04T09:55:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"178287975217532916423628160702913224177","date":"2024-11-08T14:09:16+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-02T20:10:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"115273528065467028980991624510721379527","date":"2024-10-02T17:58:19+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-10-02T14:35:57+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-05-28T01:32:23+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-05-27T10:20:56+00:00","index":"","fulltext":""},{"type":"submitted","content":"Diagnostic Pathology","date":"2024-05-27T01:59:26+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"diagnostic-pathology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"dpat","sideBox":"Learn more about [Diagnostic Pathology](http://diagnosticpathology.biomedcentral.com)","snPcode":"13000","submissionUrl":"https://submission.nature.com/new-submission/13000/3","title":"Diagnostic Pathology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0d7afacd-ebef-4445-a348-82dbbe371a89","owner":[],"postedDate":"June 12th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-12-30T16:04:20+00:00","versionOfRecord":{"articleIdentity":"rs-4481751","link":"https://doi.org/10.1186/s13000-024-01589-9","journal":{"identity":"diagnostic-pathology","isVorOnly":false,"title":"Diagnostic Pathology"},"publishedOn":"2024-12-28 15:57:14","publishedOnDateReadable":"December 28th, 2024"},"versionCreatedAt":"2024-06-12 03:39:08","video":"","vorDoi":"10.1186/s13000-024-01589-9","vorDoiUrl":"https://doi.org/10.1186/s13000-024-01589-9","workflowStages":[]},"version":"v1","identity":"rs-4481751","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4481751","identity":"rs-4481751","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}