Autopsy findings in a case of Lomentospora prolificans fungemia in myelodysplastic syndrome

Autopsy findings in a case of Lomentospora prolificans fungemia in myelodysplastic syndrome | 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 Autopsy findings in a case of Lomentospora prolificans fungemia in myelodysplastic syndrome Osamu Imataki, Yui Kawanaka, Tomoya Ishida, Haruyuki Fujita, Makiko Uemura This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3859425/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Lomentospora prolificans is a soil-, plant-, or animal-borne mold that can affect immunocompromised hosts. Most L. prolificans infections are identifieable in the bloodstream. L. prolificans fungemia has never been reported in an autopsy. Case report We treated a 79-year-old man with myelodysplastic syndrome (MDS), subtype MDS-EB-1. Due to a low MDS risk status, the patient was being monitored in an outpatient setting. He developed pneumonia and was hospitalized for treatment. He was treated empirically with meropenem and vancomycin, which did not improve the patient's symptoms or clinical data. We diagnosed the patient with bronchitis obliterans organizing pneumonia because the culture report of the lavage fluid obtained through bronchofiberscopy (BFS) was negative. We administered methylprednisolone (mPSL) at 500 mg/day for 3 days minipulse therapy on day 10, followed by high dose mPSL. The patient’s condition improved slightly but worsened again during the corticosteroid tapering process. A second BFS was performed on day 28, which detected L. prolificans on lavage culture. We treated the patient with voriconazole as per the literature, but it did not improve the condition, and on day 46, the patient died of multiple organ failure due to L. prolificans fungemia. An autopsy revealed macroscopically white nodules and foci of fungal mass abscess pathologically in systemic tissues, including the lung, heart, kidney, thyroid gland, and peritoneum. Discussion Diagnosing the rare invasive infection caused by L. prolificans in immunosuppressed patients with hematologic malignancies is difficult. We hope this case report contributes to understanding the pathogenesis of fatal L. prolificans fungemia. Lomentospora prolificans fungemia myelodysplastic syndrome autopsy Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Lomentospora prolificans (previously classified as Scedosporium prolificans ) is a mold fungus found in soil and contaminated water [ 1 ]. Individuals at risk for infection include cancer patients, including those with hematological malignancies; transplant recipients, including those receiving organs and hematopoietic stem cells; trauma victims, including those with burns; and those with uncontrolled diabetes [ 1 ]. Fungal infection in immunocompromised patients is difficult to diagnose and has a poor prognosis [ 1 – 3 ]. In the end stage of invasive fungal infections (IFIs), disseminated diseases or fungemia cause multiorgan failure, resulting in mortality. If the pathogenesis of fungemia could be determined, it would be helpful to treat and manage IFI. Unfortunately, IFI is on the rise in nosocomial settings, particularly among immunocompromised patients such as cancer patients and transplantation recipients [ 4 ]. Therefore, the clinical management of IFI is more important, especially in immunocompromised patients. Rare and critical IFIs other than Aspergillus spp. include Mucorales, Fusarium spp., and Scedosporium ( Lomentspora ) sp. Compared to yeasts, including Candida spp., mold infection does not generally result in fungemia. Nonetheless, fungemia caused by mold can develop as a final clinical stage of systemic infection if it disseminates to multiple organs. It is critical to understand the significance of blood culture-positive molds for the appropriate management of IFIs [ 5 ]. Among the many mold species, fusarium is a well-known cause of fungemia. Recently, pathogenic molds like S. apiospermum and L. prolificans have also emerged as leading causes of fungemia [ 5 ]. Here we treated an elderly man with myelodysplastic syndrome (MDS) who suffered from L. prolificans fungemia. After the patient’s death, an autopsy was performed to investigate the fungal multiorgan failure. Case presentation We treated a 79-year-old man diagnosed with MDS-EB-1 in low-risk status with complicated bronchopneumonia. On the first day of the outpatient clinic, he was hospitalized to treat pneumonia. On physical examination at admission, blood pressure was 94/56 mmHg, pulse was 93/min, and body temperature was 38.5℃. The patient was conscious and alert, but his activities of daily living were impaired by dyspnea. The oxygen saturation level was 94% in ambient air, and he required oxygen supplementation. Auscultation of the lung revealed clear respiratory sounds without rales, although the bilateral lower chest fields exhibited diminished respiratory sounds. The patient had a history of treatment for gastric ulcer (at 60 years of age), chronic atrial fibrillation (74 years old), adenocarcinoma on his left upper lung lobe (underwent surgery at 75 years old), and cerebral infarction without persistent paralysis (76 years old). He was administered apixaban at 2.5 mg/day for two days. He was a past smoker (30×40 pack years). He consumed 350 mL of beer every day. He engaged in gardening and cultivating chrysanthemums. The patient’s chest X-ray revealed nodular infiltration in the upper field of his lung (Fig. 1 a). A chest CT showed a massive consolidation in the right middle and lower lobes and a subpleural nodule on the left upper lobe. The laboratory data (Table 1 ) indicated increased CRP levels and leukocytosis. Arterial blood gas indicated type 1 respiratory failure, compensated with a low flow of oxygen inhalation (2.0 L/min through the nasal cannula). We began treating the patient for infectious bronchopneumonia, taking into account the possible pathogens including (1) Staphylococcus aureus , Streptococcus pneumonia , or Klebsiella pneumonia associated with lobar pneumonia, and (2) Aspergillus spp. or Mucor spp. that can cause fungal pneumonia. Table 1 The patient’s laboratory data (abbreviations; immature platelet fraction: IPF, reticulocyte: RET) Hemogram Biochemistry WBC 1870×10 2 /µL CRP 10.82 mg/dL Stab 0.5 % TP 6.9 g/dL Segmented 45.0 % ALB 2.7 g/dL Eosinophils 2.5 % BUN 17.9 mg/dL Basophils 2.0 % CRE 0.90 mg/dL Lymphocyte 48.0 % UA 3.5 mg/dL Monocyte 0.5 % T-BIL 1.0 mg/dL Blast 1.5 % AST 86 U/L RBC 348×10 4 /µL ALT 133 U/L HGB 10.8 g/dL ALP 448 U/L HCT 31.9 % LDH 284 U/L MCV 91.7 fL γGTP 190 U/L RET abs 2.19×10 4 /µL Na 125 mmol/L RET% 0.60 % K 4.4 mmol/L IPF 6.5 % Cl 90 mmol/L Arterial blood gas (room air)/coagulation Immunology pH 7.508 βD glucan 10.0 U/mL Lactic acid 10.9 mg/dL S pneumonia Ag in urine (-) Fibrinogen 513 mg/dL Legionella Ag in urine (-) FDP 9.9 µg/mL SARS-CoV-2 PCR (-) During the treatment (Fig. 2 ), several antibiotics were administered as follows: (1) The initial empirical treatment was tazobactam/piperacillin (TAZ/PIPC) and micafungin (MCFG) from day 1 onwards. On day 4, MCFG was changed to voriconazole (VRCZ). On day 5, TAZ/PIPC was switched to meropenem (MEPM). On day 7, VRCZ switched to liposomal amphotericin B (L-AMB). The infection screening test was positive for Aspergillus antigen but negative for specific pathogen markers, including β-D-glucan. Intermittent fever persisted throughout the initial treatment, and empirical treatment was ineffective. Then, we performed bronchofiberscopy (BFS) to identify the pathogens of pneumonia. A respiratory therapist approached the first lesion of his right upper lung. The culture of bronchoalveolar lavage fluid (BALF) was negative. A biopsy was avoided due to hypoxia and thrombocytopenia. BFS detected no specific pathogens, including Mycobacterium tuberculosis. On day 7, CT findings revealed an exacerbated consolidation of the right known nodule (Fig. 1 b), and we diagnosed bronchitis obliterans organizing pneumonia based on the absence of pathogens in the patient’s BALF culture. We administered 500 mg/day of methylprednisolone (mPSL) minipulse therapy for 3 days, followed by 1.0 mg/kg/day of mPSL thereafter. The patient initially responded to mPSL therapy; however, his condition worsened again during the mPSL tapering phase. On day 20, a CT scan revealed that the pulmonary lesion had expanded to the dorsal portion of the right lower lobe. (Fig. 1 c). On day 28, BFS was performed again. Transbronchial lung biopsy (TBLB) confirmed organizing pneumonia; however, the culture of BALF identified mold (Fig. 3 a), which was subsequently identified as L. prolificans . We treated the patient with L-AMB followed by VRCZ again, but both were ineffective. On day 41, the consolidation involved the whole right lower lobe (Fig. 1 d). As L. prolificans was simultaneously isolated from his blood (Fig. 3 b), we determined that the invasive fungal infection of the lungs had progressed to fungemia. On day 46, he died of sepsis due to fungemia and multiple organ failure. After his death, an autopsy was approved by his family. The autopsy revealed fungal nodules in multiple organs, including the lung, heart, kidney (Fig. 4 ), thyroid gland, and peritoneum. The pathological findings illustrated the penetration of the blood vessel wall by Lomentospora hyphae and/or thrombosis of the blood vessel caused by fungal foci. Discussion The known risk factors of L. prolificans fungemia are solid organ and hematopoietic stem cell transplantations [ 2 ]. Additionally, the presence of cancer and prolonged neutropenia are risk factors. In this study, diseases underlying the immunocompromised state and predisposing to bacterial pneumonia (AMC) were considered powerful risks. Even the patient's habits could contribute to the infection from molds settled on plants. Muchmore, exogenous corticosteroids probably enhanced the progression of IFIs. Additional risk factors concerning host background are impaired bronchopulmonary anatomic characteristics, such as those encountered in cystic fibrosis, bronchiectasis, and lung transplantation, which increases susceptibility to chronic airway colonization [ 6 ]. Although there is no clear evidence that L. prolificans fungemia frequently occurs in MDS rather than in other hematological malignancies, the host immune response is impaired in Scedosporium/Lomentospora infection [ 7 ] in AML, and in other hematological malignancies [ 8 ]. Neutropenia is one of the poorest predictors [ 8 ]. Furthermore, transplant recipients, including those who underwent hematopoietic stem cell transplantation, are at high risk of L. prolificans infection [ 9 , 10 ]. L. prolificans infection manifested most commonly as disseminated infection in 44.4% of patients, followed by pneumonia in 29.0% and osteomyelitis or arthritis in 10.4% [ 8 ]. Dissemination of infection is the most commonly reported pattern of L. prolificans infection [ 11 ]. In addition, 87.3% of disseminated L. prolificans infection cases were associated with mortality [ 12 ]. This appears to be a worse outcome than those associated with underlying diseases such as hematological malignancies. The mechanism of the immune response in humans to fungi is still being investigated [ 7 ]. This mechanism may involve the invasion of human epithelial or membranous cells by fungi, leading to the production of cytokines. In particular, L. prolificans infiltrates the interzone of the epithelium and destroys the epithelial monolayer. Different molds share the same characteristics, making it impossible to identify the causative pathogen without a culture. The hyphae of L. prolificans are typically found in areas of inflammation, granuloma, or necrosis and appear septate. The microscopic distinctive features of L. prolificans are melanized hyphae and adventitious sporulation. Pathological findings of the infected tissue provide pathogenic virulence features of the hyphae, which are characterized by penetration of the blood vessel wall or thrombosis of the blood vessel. This is the reason why L. prolificans can easily extend to the bloodstream [ 11 ]. These features are strongly suggestive of L. prolificans infection but are not pathognomonic. In the present case, infected organs/tissues exhibited the common pathogenic features described above. Much more information was available from this case; the pathogenesis of local infection site due to L. prolificans appears to be vascular in origin; that is hemorrhage. This is not a pathognomic feature but is commonly seen in mold infection representative of Aspergillus infection. This indicates that L. prolificans infection makes blood vessels fragile and prone to bleeding and may induce hemorrhage. Then, in a critical case, hemoptic death or bleeding complications should be prepared to support by intensive intervention. Bleeding events should be avoided by every clinician. Although there is a lack of standardized treatment for L. prolificans , VRCZ is proposed to be used as an initial therapy. However, susceptibility to antifungal agents varies in each strain [ 13 ]. Indeed, our patient did not respond to VRCZ therapy. Some authorities in a review article recommend using multiple antifungal agents [ 3 ]. In refractory and life-threatening cases, combination therapy might be worth pursuing, but it may be expensive. Even with such an effort, disseminated IFI due to fungemia is fatal if not treated promptly [ 2 ]. In an in vitro assay, L.prolificans was found to be resistant to various antifungal agents, including amphotericin B, echinocandins, and many azoles [ 14 ]. Only to echinocandins does L. prolificans demonstrate varied responses, ranging from total susceptibility through intermediate susceptibility to resistance. However, this is an absolutely in vitro result. In clinical situations, in humans, the in vitro antifungal susceptibility patterns are not true. Many biological effects, such as tissue drug concentration, tissue permeability, tissue coagulation, local cytokine milieu, and immunologic responses, interfere with the effect of antifungals. In our patient, the administration of corticosteroids interfered with the antifungals. Antifungals seldom reach locally organizing pneumonia. The pathological findings of our patient indicated that the pulmonary lesions were necrotic and hemorrhagic, and the inflammation might spread to other sites. Some special situations seen in this study were precedent-organizing pneumonia and corticosteroid usage before the diagnosis of L. prolificans fungemia. We believe corticosteroids played a possible role in the L. prolificans infection. And he was a gardener; this may have been an additional factor in his inhalation and subsequent pulmonary colonization by the fungi. In conclusion, we hope this case report contributes to further investigation of the pathophysiology of Lomentospora infection in immunocompromised patients. Declarations Acknowledgement: NA Statement of Ethics: This research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. The study protocol was approved by the institute’s committee on human research. Consent to participate: The subject has given their written informed consent to participate the case study. Consent for publication: Written informed consent was obtained from the patient for publication of this study (including publication of images). Availability of data and materials: The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. Competing interests: The authors declare that they have no competing interests. Funding: The authors have no funding source to disclose concerning this report. This work was supported by JSPS KAKENHI Grant Numbers JP23K11850. Author Contributions: OI, YK, TI, and HF managed the patient’s case, contributed to the literature search, and wrote the manuscript. MU made substantial contributions to the concept and design of this report. YK and TI qualified the patient’s data, suggested important intellectual content. OI and MU took part in critical discussions. MU was involved in supervision of the manuscript and managed the research. All authors approved the final version of the manuscript. Conflict of interest: The authors have no conflicts of interest to disclose. 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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-3859425","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":267148613,"identity":"668777a2-7c19-4ecd-84cc-28b59f88c76d","order_by":0,"name":"Osamu Imataki","email":"data:image/png;base64,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","orcid":"","institution":"Kagawa University","correspondingAuthor":true,"prefix":"","firstName":"Osamu","middleName":"","lastName":"Imataki","suffix":""},{"id":267148614,"identity":"2d2bb76d-8124-42ca-9f30-8f07a891551e","order_by":1,"name":"Yui Kawanaka","email":"","orcid":"","institution":"Kagawa University","correspondingAuthor":false,"prefix":"","firstName":"Yui","middleName":"","lastName":"Kawanaka","suffix":""},{"id":267148615,"identity":"5442e828-610f-4c29-aa7b-19b3d819060a","order_by":2,"name":"Tomoya Ishida","email":"","orcid":"","institution":"Kagawa University","correspondingAuthor":false,"prefix":"","firstName":"Tomoya","middleName":"","lastName":"Ishida","suffix":""},{"id":267148616,"identity":"669de441-00bb-4203-898e-8e8773cee2d5","order_by":3,"name":"Haruyuki Fujita","email":"","orcid":"","institution":"Kagawa University","correspondingAuthor":false,"prefix":"","firstName":"Haruyuki","middleName":"","lastName":"Fujita","suffix":""},{"id":267148617,"identity":"18de0533-446b-402a-ba1b-420712d034c5","order_by":4,"name":"Makiko Uemura","email":"","orcid":"","institution":"Kagawa University","correspondingAuthor":false,"prefix":"","firstName":"Makiko","middleName":"","lastName":"Uemura","suffix":""}],"badges":[],"createdAt":"2024-01-13 07:59:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3859425/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3859425/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":49766031,"identity":"f9d76bf3-10ab-4555-a2d0-87059071113e","added_by":"auto","created_at":"2024-01-17 16:58:42","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1442796,"visible":true,"origin":"","legend":"\u003cp\u003ePatient pulmonary images and CT findings\u003c/p\u003e\n\u003cp\u003e(a) On the onset of bronchopneumonia\u003c/p\u003e\n\u003cp\u003e(b) On day 7, the consolidation shadow of the right lung worsened. Bronchofiberscopy was diagnosed as bronchitis obliterans organizing pneumonia.\u003c/p\u003e\n\u003cp\u003e(c) On day 20 the consolidation shadow remained. On day 28, bronchofiberscopy was performed again.\u003c/p\u003e\n\u003cp\u003e(d) On day 41, the infiltration shadow spread throughout the right lobe of the lung.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3859425/v1/04ee04a84172028fa1c8da75.jpg"},{"id":49766030,"identity":"5581ed24-f472-4609-b92e-c6aca983366a","added_by":"auto","created_at":"2024-01-17 16:58:42","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1061789,"visible":true,"origin":"","legend":"\u003cp\u003eThe patient's entire clinical course\u003c/p\u003e\n\u003cp\u003e(abbreviations: C-reactive protein; CRP, liposomal amphotericin B; L-AMB, micafungin; MCFG, multiorgan failure; MOF, methylprednisolone; mPSL, prednisolone; PSL, voriconazole; VRCZ)\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3859425/v1/98076bcf0daf5bd4981e694e.jpg"},{"id":49766032,"identity":"0083a1f3-9f77-4907-8596-d86dcd4b5174","added_by":"auto","created_at":"2024-01-17 16:58:42","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":2829344,"visible":true,"origin":"","legend":"\u003cp\u003eMold clinically isolated from the patient\u003c/p\u003e\n\u003cp\u003e(a) Isolated mold from bronchoalveolar lavage performed on day 28.\u003c/p\u003e\n\u003cp\u003e(b) Isolate mold from blood culture on day 41.\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3859425/v1/86919cef73916bde70ce9297.jpg"},{"id":49766033,"identity":"1fc1124c-285b-453f-9d15-3d3ce6040b3e","added_by":"auto","created_at":"2024-01-17 16:58:42","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":5130486,"visible":true,"origin":"","legend":"\u003cp\u003eAutopsy pathology of the patient\u003c/p\u003e\n\u003cp\u003e(a) Right lung: Red arrowheads indicate the primary nodular site in the right lung. (Lower panel) Hemorrhagic abscesses were seen and solid hyphae aggregated in filamentous fungi.\u003c/p\u003e\n\u003cp\u003e(b) Heart: In the myocardium, plenty of white nodules were observed. (Lower panel) Branched hyphae invaded the intramyocardium with hemorrhage.\u003c/p\u003e\n\u003cp\u003e(c) Kidney (lower panel) Neutrophil infiltration, bleeding, and conidia formation were seen in interstitial tissues.\u003c/p\u003e\n\u003cp\u003eEach upper panel indicates a macroscopic picture.\u003c/p\u003e\n\u003cp\u003eIn each lower panel, the left column is HE stain and the right column is Grocott staining (×40).\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3859425/v1/abe675f40f4f6ac8c1ae8e69.jpg"},{"id":53127536,"identity":"387d7338-e261-49e9-b71a-8289962b7f76","added_by":"auto","created_at":"2024-03-21 01:26:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":755641,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3859425/v1/45019e23-ee15-49e2-9a55-93e231562cf4.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Autopsy findings in a case of Lomentospora prolificans fungemia in myelodysplastic syndrome","fulltext":[{"header":"Introduction","content":"\u003cp\u003e\u003cem\u003eLomentospora prolificans\u003c/em\u003e (previously classified as \u003cem\u003eScedosporium prolificans\u003c/em\u003e) is a mold fungus found in soil and contaminated water [\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e]. Individuals at risk for infection include cancer patients, including those with hematological malignancies; transplant recipients, including those receiving organs and hematopoietic stem cells; trauma victims, including those with burns; and those with uncontrolled diabetes [\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e]. Fungal infection in immunocompromised patients is difficult to diagnose and has a poor prognosis [\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e]. In the end stage of invasive fungal infections (IFIs), disseminated diseases or fungemia cause multiorgan failure, resulting in mortality. If the pathogenesis of fungemia could be determined, it would be helpful to treat and manage IFI.\u003c/p\u003e\n\u003cp\u003eUnfortunately, IFI is on the rise in nosocomial settings, particularly among immunocompromised patients such as cancer patients and transplantation recipients [\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e]. Therefore, the clinical management of IFI is more important, especially in immunocompromised patients. Rare and critical IFIs other than \u003cem\u003eAspergillus\u003c/em\u003e spp. include Mucorales, \u003cem\u003eFusarium\u003c/em\u003e spp., and \u003cem\u003eScedosporium\u003c/em\u003e (\u003cem\u003eLomentspora\u003c/em\u003e) sp. Compared to yeasts, including \u003cem\u003eCandida\u003c/em\u003e spp., mold infection does not generally result in fungemia. Nonetheless, fungemia caused by mold can develop as a final clinical stage of systemic infection if it disseminates to multiple organs. It is critical to understand the significance of blood culture-positive molds for the appropriate management of IFIs [\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e]. Among the many mold species, fusarium is a well-known cause of fungemia. Recently, pathogenic molds like \u003cem\u003eS. apiospermum\u003c/em\u003e and \u003cem\u003eL. prolificans\u003c/em\u003e have also emerged as leading causes of fungemia [\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e]. Here we treated an elderly man with myelodysplastic syndrome (MDS) who suffered from \u003cem\u003eL. prolificans\u003c/em\u003e fungemia. After the patient\u0026rsquo;s death, an autopsy was performed to investigate the fungal multiorgan failure.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eWe treated a 79-year-old man diagnosed with MDS-EB-1 in low-risk status with complicated bronchopneumonia. On the first day of the outpatient clinic, he was hospitalized to treat pneumonia. On physical examination at admission, blood pressure was 94/56 mmHg, pulse was 93/min, and body temperature was 38.5℃. The patient was conscious and alert, but his activities of daily living were impaired by dyspnea. The oxygen saturation level was 94% in ambient air, and he required oxygen supplementation. Auscultation of the lung revealed clear respiratory sounds without rales, although the bilateral lower chest fields exhibited diminished respiratory sounds. The patient had a history of treatment for gastric ulcer (at 60 years of age), chronic atrial fibrillation (74 years old), adenocarcinoma on his left upper lung lobe (underwent surgery at 75 years old), and cerebral infarction without persistent paralysis (76 years old). He was administered apixaban at 2.5 mg/day for two days. He was a past smoker (30\u0026times;40 pack years). He consumed 350 mL of beer every day. He engaged in gardening and cultivating chrysanthemums.\u003c/p\u003e\n\u003cp\u003eThe patient\u0026rsquo;s chest X-ray revealed nodular infiltration in the upper field of his lung (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ea). A chest CT showed a massive consolidation in the right middle and lower lobes and a subpleural nodule on the left upper lobe. The laboratory data (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e) indicated increased CRP levels and leukocytosis. Arterial blood gas indicated type 1 respiratory failure, compensated with a low flow of oxygen inhalation (2.0 L/min through the nasal cannula). We began treating the patient for infectious bronchopneumonia, taking into account the possible pathogens including (1) \u003cem\u003eStaphylococcus aureus\u003c/em\u003e, \u003cem\u003eStreptococcus pneumonia\u003c/em\u003e, or \u003cem\u003eKlebsiella pneumonia\u003c/em\u003e associated with lobar pneumonia, and (2) \u003cem\u003eAspergillus\u003c/em\u003e spp. or \u003cem\u003eMucor\u003c/em\u003e spp. that can cause fungal pneumonia.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eThe patient\u0026rsquo;s laboratory data (abbreviations; immature platelet fraction: IPF, reticulocyte: RET)\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth colspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eHemogram\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eBiochemistry\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eWBC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1870\u0026times;10\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e/\u0026micro;L\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCRP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10.82\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emg/dL\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eStab\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eg/dL\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSegmented\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e45.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eALB\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eg/dL\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEosinophils\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBUN\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emg/dL\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBasophils\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCRE\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.90\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emg/dL\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLymphocyte\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e48.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emg/dL\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMonocyte\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT-BIL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emg/dL\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBlast\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAST\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e86\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eU/L\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRBC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e348\u0026times;10\u003csup\u003e4\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e/\u0026micro;L\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eALT\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e133\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eU/L\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHGB\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eg/dL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eALP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e448\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eU/L\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHCT\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e31.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLDH\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e284\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eU/L\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMCV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e91.7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003efL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026gamma;GTP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e190\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eU/L\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRET abs\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.19\u0026times;10\u003csup\u003e4\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e/\u0026micro;L\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNa\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e125\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emmol/L\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRET%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.60\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eK\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emmol/L\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIPF\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCl\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e90\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emmol/L\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eArterial blood gas (room air)/coagulation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eImmunology\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003epH\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7.508\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026beta;D glucan\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;6.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003epg/mL\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePaO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e68.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTorr\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eProcalcitonin\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.40\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eng/mL\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePaCO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30.7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTorr\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAspergillus Ag\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(+)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHCO\u003csub\u003e3\u003c/sub\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e23.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emmol/L\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCrypococcus Ag\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(-)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBE\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emmol/L\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT-SPOT\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(-)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eO\u003csub\u003e2\u003c/sub\u003e Sat\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e95.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMAC Ab\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026gt;\u0026thinsp;10.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eU/mL\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLactic acid\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emg/dL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eS pneumonia Ag\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ein urine\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(-)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFibrinogen\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e513\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emg/dL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLegionella Ag\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ein urine\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(-)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFDP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026micro;g/mL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSARS-CoV-2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePCR\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(-)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eDuring the treatment (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e), several antibiotics were administered as follows: (1) The initial empirical treatment was tazobactam/piperacillin (TAZ/PIPC) and micafungin (MCFG) from day 1 onwards. On day 4, MCFG was changed to voriconazole (VRCZ). On day 5, TAZ/PIPC was switched to meropenem (MEPM). On day 7, VRCZ switched to liposomal amphotericin B (L-AMB). The infection screening test was positive for Aspergillus antigen but negative for specific pathogen markers, including \u0026beta;-D-glucan. Intermittent fever persisted throughout the initial treatment, and empirical treatment was ineffective.\u003c/p\u003e\n\u003cp\u003eThen, we performed bronchofiberscopy (BFS) to identify the pathogens of pneumonia. A respiratory therapist approached the first lesion of his right upper lung. The culture of bronchoalveolar lavage fluid (BALF) was negative. A biopsy was avoided due to hypoxia and thrombocytopenia. BFS detected no specific pathogens, including Mycobacterium tuberculosis. On day 7, CT findings revealed an exacerbated consolidation of the right known nodule (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eb), and we diagnosed bronchitis obliterans organizing pneumonia based on the absence of pathogens in the patient\u0026rsquo;s BALF culture. We administered 500 mg/day of methylprednisolone (mPSL) minipulse therapy for 3 days, followed by 1.0 mg/kg/day of mPSL thereafter. The patient initially responded to mPSL therapy; however, his condition worsened again during the mPSL tapering phase. On day 20, a CT scan revealed that the pulmonary lesion had expanded to the dorsal portion of the right lower lobe. (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ec). On day 28, BFS was performed again. Transbronchial lung biopsy (TBLB) confirmed organizing pneumonia; however, the culture of BALF identified mold (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003ea), which was subsequently identified as \u003cem\u003eL. prolificans\u003c/em\u003e. We treated the patient with L-AMB followed by VRCZ again, but both were ineffective. On day 41, the consolidation involved the whole right lower lobe (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ed). As \u003cem\u003eL. prolificans\u003c/em\u003e was simultaneously isolated from his blood (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eb), we determined that the invasive fungal infection of the lungs had progressed to fungemia. On day 46, he died of sepsis due to fungemia and multiple organ failure.\u003c/p\u003e\n\u003cp\u003eAfter his death, an autopsy was approved by his family. The autopsy revealed fungal nodules in multiple organs, including the lung, heart, kidney (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e), thyroid gland, and peritoneum. The pathological findings illustrated the penetration of the blood vessel wall by \u003cem\u003eLomentospora\u003c/em\u003e hyphae and/or thrombosis of the blood vessel caused by fungal foci.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe known risk factors of \u003cem\u003eL. prolificans\u003c/em\u003e fungemia are solid organ and hematopoietic stem cell transplantations [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Additionally, the presence of cancer and prolonged neutropenia are risk factors. In this study, diseases underlying the immunocompromised state and predisposing to bacterial pneumonia (AMC) were considered powerful risks. Even the patient's habits could contribute to the infection from molds settled on plants. Muchmore, exogenous corticosteroids probably enhanced the progression of IFIs. Additional risk factors concerning host background are impaired bronchopulmonary anatomic characteristics, such as those encountered in cystic fibrosis, bronchiectasis, and lung transplantation, which increases susceptibility to chronic airway colonization [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlthough there is no clear evidence that \u003cem\u003eL. prolificans\u003c/em\u003e fungemia frequently occurs in MDS rather than in other hematological malignancies, the host immune response is impaired in \u003cem\u003eScedosporium/Lomentospora\u003c/em\u003e infection [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] in AML, and in other hematological malignancies [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Neutropenia is one of the poorest predictors [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Furthermore, transplant recipients, including those who underwent hematopoietic stem cell transplantation, are at high risk of \u003cem\u003eL. prolificans\u003c/em\u003e infection [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. \u003cem\u003eL. prolificans\u003c/em\u003e infection manifested most commonly as disseminated infection in 44.4% of patients, followed by pneumonia in 29.0% and osteomyelitis or arthritis in 10.4% [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Dissemination of infection is the most commonly reported pattern of \u003cem\u003eL. prolificans\u003c/em\u003e infection [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In addition, 87.3% of disseminated \u003cem\u003eL. prolificans\u003c/em\u003e infection cases were associated with mortality [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. This appears to be a worse outcome than those associated with underlying diseases such as hematological malignancies. The mechanism of the immune response in humans to fungi is still being investigated [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. This mechanism may involve the invasion of human epithelial or membranous cells by fungi, leading to the production of cytokines. In particular, \u003cem\u003eL. prolificans\u003c/em\u003e infiltrates the interzone of the epithelium and destroys the epithelial monolayer.\u003c/p\u003e \u003cp\u003eDifferent molds share the same characteristics, making it impossible to identify the causative pathogen without a culture. The hyphae of \u003cem\u003eL. prolificans\u003c/em\u003e are typically found in areas of inflammation, granuloma, or necrosis and appear septate. The microscopic distinctive features of \u003cem\u003eL. prolificans\u003c/em\u003e are melanized hyphae and adventitious sporulation. Pathological findings of the infected tissue provide pathogenic virulence features of the hyphae, which are characterized by penetration of the blood vessel wall or thrombosis of the blood vessel. This is the reason why \u003cem\u003eL. prolificans\u003c/em\u003e can easily extend to the bloodstream [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. These features are strongly suggestive of \u003cem\u003eL. prolificans\u003c/em\u003e infection but are not pathognomonic. In the present case, infected organs/tissues exhibited the common pathogenic features described above. Much more information was available from this case; the pathogenesis of local infection site due to \u003cem\u003eL. prolificans\u003c/em\u003e appears to be vascular in origin; that is hemorrhage. This is not a pathognomic feature but is commonly seen in mold infection representative of Aspergillus infection. This indicates that \u003cem\u003eL. prolificans\u003c/em\u003e infection makes blood vessels fragile and prone to bleeding and may induce hemorrhage. Then, in a critical case, hemoptic death or bleeding complications should be prepared to support by intensive intervention. Bleeding events should be avoided by every clinician.\u003c/p\u003e \u003cp\u003eAlthough there is a lack of standardized treatment for \u003cem\u003eL. prolificans\u003c/em\u003e, VRCZ is proposed to be used as an initial therapy. However, susceptibility to antifungal agents varies in each strain [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Indeed, our patient did not respond to VRCZ therapy. Some authorities in a review article recommend using multiple antifungal agents [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In refractory and life-threatening cases, combination therapy might be worth pursuing, but it may be expensive. Even with such an effort, disseminated IFI due to fungemia is fatal if not treated promptly [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. In an in vitro assay, \u003cem\u003eL.prolificans\u003c/em\u003e was found to be resistant to various antifungal agents, including amphotericin B, echinocandins, and many azoles [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Only to echinocandins does \u003cem\u003eL. prolificans\u003c/em\u003e demonstrate varied responses, ranging from total susceptibility through intermediate susceptibility to resistance. However, this is an absolutely \u003cem\u003ein vitro\u003c/em\u003e result. In clinical situations, in humans, the in vitro antifungal susceptibility patterns are not true. Many biological effects, such as tissue drug concentration, tissue permeability, tissue coagulation, local cytokine milieu, and immunologic responses, interfere with the effect of antifungals. In our patient, the administration of corticosteroids interfered with the antifungals. Antifungals seldom reach locally organizing pneumonia. The pathological findings of our patient indicated that the pulmonary lesions were necrotic and hemorrhagic, and the inflammation might spread to other sites.\u003c/p\u003e \u003cp\u003eSome special situations seen in this study were precedent-organizing pneumonia and corticosteroid usage before the diagnosis of \u003cem\u003eL. prolificans\u003c/em\u003e fungemia. We believe corticosteroids played a possible role in the \u003cem\u003eL. prolificans\u003c/em\u003e infection. And he was a gardener; this may have been an additional factor in his inhalation and subsequent pulmonary colonization by the fungi. In conclusion, we hope this case report contributes to further investigation of the pathophysiology of Lomentospora infection in immunocompromised patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAcknowledgement: NA\u003c/p\u003e\n\u003cp\u003eStatement of Ethics: This research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. The study protocol was approved by the institute\u0026rsquo;s committee on human research.\u003c/p\u003e\n\u003cp\u003eConsent to participate: The subject has given their written informed consent to participate the case study.\u003c/p\u003e\n\u003cp\u003eConsent for publication: Written informed consent was obtained from the patient for publication of this study (including publication of images).\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials: The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003eCompeting interests: The authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003eFunding: The authors have no funding source to disclose concerning this report. This work was supported by JSPS KAKENHI Grant Numbers JP23K11850.\u003c/p\u003e\n\u003cp\u003eAuthor Contributions: OI, YK, TI, and HF managed the patient\u0026rsquo;s case, contributed to the literature search, and wrote the manuscript. MU made substantial contributions to the concept and design of this report. YK and TI qualified the patient\u0026rsquo;s data, suggested important intellectual content. OI and MU took part in critical discussions. MU was involved in supervision of the manuscript and managed the research. All authors approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003eConflict of interest: The authors have no conflicts of interest to disclose.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eJenks JD, Seidel D, Cornely OA, Chen S, van Hal S, Kauffman C, Miceli MH, Heinemann M, Christner M, Jover S\u0026aacute;enz A, Burchardt A, Kemmerling B, Herbrecht R, Steinmann J, Shoham S, Gr\u0026auml;ber S, Pagano L, Deeren D, Slavin MA, Hoenigl M. Clinical characteristics and outcomes of invasive Lomentospora prolificans infections: Analysis of patients in the FungiScope\u0026reg; registry. Mycoses. 2020 May;63(5):437-442. doi: 10.1111/myc.13067. Epub 2020 Apr 15. PMID: 32080902. \u003c/li\u003e\n\u003cli\u003eSeidel D, Mei\u0026szlig;ner A, Lackner M, Piepenbrock E, Salmanton-Garc\u0026iacute;a J, Stecher M, Mellinghoff S, Hamprecht A, Dur\u0026aacute;n Graeff L, K\u0026ouml;hler P, Cheng MP, Denis J, Chedotal I, Chander J, Pakstis DL, Los-Arcos I, Slavin M, Montagna MT, Caggiano G, Mares M, Trauth J, Aurbach U, Vehreschild MJGT, Vehreschild JJ, Duarte RF, Herbrecht R, Wisplinghoff H, Cornely OA. Prognostic factors in 264 adults with invasive Scedosporium spp. and Lomentospora prolificans infection reported in the literature and FungiScope\u0026reg;. Crit Rev Microbiol. 2019 Feb;45(1):1-21. doi: 10.1080/1040841X.2018.1514366. Epub 2019 Jan 10. Erratum in: Crit Rev Microbiol. 2019 Feb 18;:1. PMID: 30628529.\u003c/li\u003e\n\u003cli\u003eRamirez-Garcia A, Pellon A, Rementeria A, Buldain I, Barreto-Bergter E, Rollin-Pinheiro R, de Meirelles JV, Xisto MIDS, Ranque S, Havlicek V, Vandeputte P, Govic YL, Bouchara JP, Giraud S, Chen S, Rainer J, Alastruey-Izquierdo A, Martin-Gomez MT, L\u0026oacute;pez-Soria LM, Peman J, Schwarz C, Bernhardt A, Tintelnot K, Capilla J, Martin-Vicente A, Cano-Lira J, Nagl M, Lackner M, Irinyi L, Meyer W, de Hoog S, Hernando FL. Scedosporium and Lomentospora: an updated overview of underrated opportunists. Med Mycol. 2018 Apr 1;56(suppl_1):102-125. doi: 10.1093/mmy/myx113. PMID: 29538735.\u003c/li\u003e\n\u003cli\u003eRichardson M, Lass-Fl\u0026ouml;rl C. Changing epidemiology of systemic fungal infections. Clin Microbiol Infect. 2008 May;14 Suppl 4:5-24. doi: 10.1111/j.1469-0691.2008.01978.x. PMID: 18430126.\u003c/li\u003e\n\u003cli\u003eLionakis MS, Bodey GP, Tarrand JJ, Raad II, Kontoyiannis DP. The significance of blood cultures positive for emerging saprophytic moulds in cancerpatients. Clin Microbiol Infect. 2004 Oct;10(10):922-5. doi: 10.1111/j.1469-0691.2004.00933.x.\u003c/li\u003e\n\u003cli\u003eRichardson M, Lass-Fl\u0026ouml;rl C. Changing epidemiology of systemic fungal infections. Clin Microbiol Infect. 2008 May;14 Suppl 4:5-24. doi: 10.1111/j.1469-0691.2008.01978.x.\u003c/li\u003e\n\u003cli\u003eBuldain I, Martin-Souto L, Antoran A, Areitio M, Aparicio-Fernandez L, Rementeria A, Hernando FL, Ramirez-Garcia A. The Host Immune Response to Scedosporium/Lomentospora. J Fungi (Basel). 2021 Jan 22;7(2):75. doi: 10.3390/jof7020075. PMID: 33499053; PMCID: PMC7912657.\u003c/li\u003e\n\u003cli\u003eRodriguez-Tudela JL, Berenguer J, Guarro J, Kantarcioglu AS, Horre R, de Hoog GS, Cuenca-Estrella M. Epidemiology and outcome of Scedosporium prolificans infection, a review of 162 cases. Med Mycol. 2009 Jun;47(4):359-70. doi: 10.1080/13693780802524506. PMID: 19031336.\u003c/li\u003e\n\u003cli\u003eHusain S, Mu\u0026ntilde;oz P, Forrest G, Alexander BD, Somani J, Brennan K, Wagener MM, Singh N. Infections due to Scedosporium apiospermum and Scedosporium prolificans intransplant recipients: clinical characteristics and impact of antifungal agent therapy on outcome. Clin Infect Dis. 2005 Jan 1;40(1):89-99. doi: 10.1086/426445. Epub 2004 Dec 8.\u003c/li\u003e\n\u003cli\u003eJohnson LS, Shields RK, Clancy CJ. Epidemiology, clinical manifestations, and outcomes of Scedosporium infections among solid organ transplant recipients. Transpl Infect Dis. 2014 Aug;16(4):578-87. doi: 10.1111/tid.12244. Epub 2014 Jun 24.\u003c/li\u003e\n\u003cli\u003eKonsoula A, Tsioutis C, Markaki I, Papadakis M, Agouridis AP, Spernovasilis N. Lomentospora prolificans: An Emerging Opportunistic Fungal Pathogen. Microorganisms. 2022 Jun 29;10(7):1317. doi: 10.3390/microorganisms10071317. 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Semin Oncol. 2004 Apr;31(2 Suppl 4):91-8. doi: 10.1053/j.seminoncol.2004.02.020.\u003c/li\u003e\n\u003cli\u003eTortorano AM, Richardson M, Roilides E, van Diepeningen A, Caira M, Munoz P, Johnson E, Meletiadis J, Pana ZD, Lackner M, Verweij P, Freiberger T, Cornely OA, Arikan-Akdagli S, Dannaoui E, Groll AH, Lagrou K, Chakrabarti A, Lanternier F, Pagano L, Skiada A, Akova M, Arendrup MC, Boekhout T, Chowdhary A, Cuenca-Estrella M, Guinea J, Guarro J, de Hoog S, Hope W, Kathuria S, Lortholary O, Meis JF, Ullmann AJ, Petrikkos G, Lass-Fl\u0026ouml;rl C; European Society of Clinical Microbiology and Infectious Diseases Fungal Infection Study Group; European Confederation of Medical Mycology. ESCMID and ECMM joint guidelines on diagnosis and management of hyalohyphomycosis: Fusarium spp., Scedosporium spp. and others. Clin Microbiol Infect. 2014 Apr;20 Suppl 3:27-46. doi: 10.1111/1469-0691.12465. PMID: 24548001.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Lomentospora prolificans, fungemia, myelodysplastic syndrome, autopsy","lastPublishedDoi":"10.21203/rs.3.rs-3859425/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3859425/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eLomentospora prolificans\u003c/em\u003e is a soil-, plant-, or animal-borne mold that can affect immunocompromised hosts. Most \u003cem\u003eL. prolificans\u003c/em\u003e infections are identifieable in the bloodstream. \u003cem\u003eL. prolificans\u003c/em\u003e fungemia has never been reported in an autopsy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase report\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe treated a 79-year-old man with myelodysplastic syndrome (MDS), subtype MDS-EB-1. Due to a low MDS risk status, the patient was being monitored in an outpatient setting. He developed pneumonia and was hospitalized for treatment. He was treated empirically with meropenem and vancomycin, which did not improve the patient's symptoms or clinical data. We diagnosed the patient with bronchitis obliterans organizing pneumonia because the culture report of the lavage fluid obtained through bronchofiberscopy (BFS) was negative. We administered methylprednisolone (mPSL) at 500 mg/day for 3 days minipulse therapy on day 10, followed by high dose mPSL. The patient’s condition improved slightly but worsened again during the corticosteroid tapering process. A second BFS was performed on day 28, which detected \u003cem\u003eL. prolificans\u003c/em\u003e on lavage culture. We treated the patient with voriconazole as per the literature, but it did not improve the condition, and on day 46, the patient died of multiple organ failure due to \u003cem\u003eL. prolificans\u003c/em\u003e fungemia. An autopsy revealed macroscopically white nodules and foci of fungal mass abscess pathologically in systemic tissues, including the lung, heart, kidney, thyroid gland, and peritoneum.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDiagnosing the rare invasive infection caused by \u003cem\u003eL. prolificans\u003c/em\u003e in immunosuppressed patients with hematologic malignancies is difficult. We hope this case report contributes to understanding the pathogenesis of fatal \u003cem\u003eL. prolificans\u003c/em\u003e fungemia.\u003c/p\u003e","manuscriptTitle":"Autopsy findings in a case of Lomentospora prolificans fungemia in myelodysplastic syndrome","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-17 16:58:37","doi":"10.21203/rs.3.rs-3859425/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"11331a92-93c1-430a-bcc4-adb7692e75ba","owner":[],"postedDate":"January 17th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-03-21T01:18:15+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-17 16:58:37","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3859425","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3859425","identity":"rs-3859425","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}