Disseminated histoplasmosis diagnosed by mNGS in a middle-aged immunocompetent patient: a case report and literature review

Disseminated histoplasmosis diagnosed by mNGS in a middle-aged immunocompetent patient: a case report and literature review | 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 Disseminated histoplasmosis diagnosed by mNGS in a middle-aged immunocompetent patient: a case report and literature review Lianbao Li, Taigui Chen, Jing Li, Xianli Wu, Dalin Zheng, Hongxing Zhu, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8193535/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 03 Feb, 2026 Read the published version in BMC Infectious Diseases → Version 1 posted 9 You are reading this latest preprint version Abstract Histoplasmosis is a fungal infection caused by the dimorphic fungus Histoplasma capsulatum . Its clinical presentation is highly variable, ranging from asymptomatic cases to progressive disseminated infections. Disseminated histoplasmosis is the rarest form and is mostly found in immunocompromised patients, although rare cases have also been reported among immunocompetent individuals. In this study, we present a case of disseminated histoplasmosis in a middle-aged, immunocompetent patient from Sichuan Province, southwest China, diagnosed by mNGS. This condition is rarely documented in this region, and its diverse, non-specific clinical manifestations often lead to misdiagnosis. This atypical case highlights the challenges associated with the early recognition and diagnosis of disseminated histoplasmosis in immunocompetent patients presenting with non-specific symptoms. Additionally, we reviewed cases of histoplasmosis reported in immunocompetent individuals between 2021 and 2025. This information may serve as a reference for clinicians in the management of this uncommon disease. Histoplasmosis immunocompetent mNGS Figures Figure 1 Figure 2 Figure 3 Background Histoplasma capsulatum is a dimorphic fungus commonly found in soil and is the causal agent of histoplasmosis [1]. This organism grows as a mold in the environment but transforms into a yeast form in human hosts. H . capsulatum is distributed worldwide, and primarily infects humans through the inhalation of its spores (conidia) or mycelial particles[2]. Once inhaled, these microconidia transform into yeast forms within host tissues, facilitating infection and pathogenicity[3]. This transformation is a key pathogenic trait that enables the fungus to adapt to the intracellular host environment, evade immune responses, and infect a wide range of hosts[4]. While H . capsulatum can affect individuals across various immune statuses, immunosuppressed patients are disproportionately at risk for severe and disseminated disease. Among immunocompromised groups, particularly individuals with HIV[4], histoplasmosis remains a significant concern. In most immunocompetent hosts, the immune response is sufficient, and infected individuals seldom become symptomatic[5]. The most common symptoms in patients with disseminated histoplasmosis are fever, fatigue, loss of appetite, and weight loss[5]. For immunocompetent patients, the non-specific presentation, unrevealing initial infectious workup, and lack of typical risk factors for infectious processes delay further investigation, consequently hindering the diagnosis and treatment of this condition. Here, we report a rare case of disseminated histoplasmosis with non-specific presentation in a middle-aged, immunocompetent patient, diagnosed by metagenomic next-generation sequencing (mNGS). This atypical case highlights the challenges in the early identification and diagnosis of disseminated histoplasmosis in immunocompetent individuals presenting with nonspecific symptoms. Moreover, it underscores the importance of molecular diagnostic techniques, such as mNGS, in the diagnosis of infectious diseases. Additionally, we reviewed cases of histoplasmosis reported in immunocompetent individuals between 2021 and 2025. This information may serve as a reference for clinicians in the management of this uncommon disease. Case presentation One month before admission, a 38-year-old male presented with an unexplained fever, with a peak temperature of 39°C, accompanied by chills, rigors, occasional dizziness, and a mild cough with sputum production. He was admitted to a local county hospital, where he received anti-infective and antipyretic treatment with cefoperazone/sulbactam (approximately five days), piperacillin/tazobactam, and levofloxacin. However, the patient’s condition did not improve following treatment, and he continued to experience intermittent fever. The patient was subsequently transferred to our hospital for further management. At admission, the patient appeared well and was not in acute distress. His blood pressure was 112/67 mm Hg, he had a heart rate of 88 beats per minute, a respiratory rate of 20 breaths per minute, and a temperature of 37.8°C. The patient denied a history of diabetes mellitus, tuberculosis, typhoid fever, malaria, heart disease, cerebrovascular disease, or mental illness, had no comorbidities, and was not immunocompromised. An auxiliary examination at the time of admission yielded the following findings: white blood cell count, 7.51 × 10 9 /L (range 3.5 × 10 9 –9.5 × 10 9 /L); platelet count, 87 × 10 9 /L (range 125 × 10 9 –350 × 10 9 /L); sedimentation rate, 57 mm/h (range 0–20 mm/h); alanine aminotransferase, 45 U/L (range 9–50 U/L); aspartate aminotransferase, 26 U/L (range 15–40 U/L); alkaline phosphatase, 275 U/L (range 45–125 U/L); and total T-cell count (CD3 + ), 0.98 × 10 9 /L (range 0.52–2.86 × 10 9 /L). The autoimmune workup was negative. The tuberculosis infection T-cell assay (interferon-gamma release assay) and the HIV screen were also negative. To further determine the cause of the disease and refine the diagnostic procedures, imaging was performed. A chest CT scan revealed small nodules in both lungs, and an abdominal CT scan showed splenomegaly. The infection indicator procalcitonin was measured at 0.68 ng/mL (range 0.00–0.10 ng/mL). Meanwhile, the patient’s poor response to outpatient treatment and low platelet count indicated the possibility of an atypical pathogen infection. The physician initiated empirical antimicrobial therapy with doxycycline and compound sulfamethoxazole-trimethoprim, and venous blood was collected for mNGS and fungal (1–3)- β -D-glucan (BDG) testing. The BDG level was 157 pg/mL (range < 60 pg/mL), suggestive of an invasive fungal infection, and mNGS of the venous blood confirmed histoplasmosis. Subsequently, Giemsa staining of bone marrow aspirate revealed oval yeast-like cells both scattered and in clusters within macrophages, further confirming histoplasmosis infection (Fig. 1 ). Once the infectious agent had been identified, and considering that the patient was immunocompetent, the extrapulmonary localization of the fungal infection, and the long duration of symptoms, the clinician immediately switched the treatment regimen to intravenous amphotericin B for antifungal therapy. After approximately three weeks of treatment, the patient’s vital signs had stabilized with no fever (Table 1, Fig. 2 ). Accordingly, the patient was discharged with continued amphotericin B therapy and was advised to return for a follow-up examination one week post-discharge. Literature Review A comprehensive literature search of the PubMed and Web of Science databases was conducted for articles published between 2021 and 2025, using the search terms “immunocompetent human” and “histoplasmosis”. Publications were restricted to English-language case reports. The inclusion criteria were 1) histoplasmosis confirmed by standard methods, and 2) immunocompetency. Articles detailing diseases with compromised immunity, immunosuppressive medication therapy, and autoimmune diseases were excluded. Based on these criteria, 39 articles describing 45 patients were identified. The features of the 45 patients are summarized in supplementary material 1. Eight of the patients were children, with the remainder being older than 16 years. Among the cohort, 9 were female, 35 were male, and one patient’s sex was unspecified. Infection involved various organs, including the skin, lymph nodes, adrenal glands, gastrointestinal tract, heart, liver, spleen, lungs, thyroid, and central nervous system. Lymph nodes, lungs, liver, spleen, and the gastrointestinal tract were the most frequently affected sites. Some patients exhibited multi-organ involvement, though no typical symptoms were present (Fig. 3 ). This indicates that histoplasmosis not only lacks typical symptoms in immunocompromised patients but also exhibits no characteristic features in immunocompetent individuals. In the reviewed cases, pathogen identification primarily relied on serum serology and histopathology. Owing to the difficulty in culturing the organism, fungal cultures were successfully obtained in only 8 (18%) cases, with 2 (4%) of these being supplemented by mass spectrometry. mNGS was less frequently used in clinical practice and was only applied for diagnosis in 3 (7%) patients. Histopathology, microscopy, and culture remain the cornerstone methods for histoplasmosis diagnosis. However, these conventional tools lack sensitivity, particularly during early phases of the disease[6]. In contrast, mNGS enables rapid and accurate pathogen identification without relying on microbial culture, and is especially suitable for detecting rare, novel, and atypical causes of complicated infectious diseases. In the near future, given its sensitivity, speed, and cost-effectiveness, mNGS has the potential to become part of routine diagnostic workups[7]. In non-endemic regions of China, clinicians often lack sufficient awareness of histoplasmosis, leading to frequent misdiagnosis or missed diagnosis. Currently, mNGS can serve as a complementary approach to traditional diagnostic methods, thereby enhancing the diagnostic accuracy for this disease. Discussion and conclusions Histoplasmosis is endemic to the Ohio and Mississippi River valleys, Central and South America, and microfoci in the Eastern United States, southern Europe, Africa, and southeastern Asia[8]. The overall epidemiology has evolved since the 1950s, involving changes in the distribution and proportion of symptomatic infections relative to the general population, which reflect shifts in environmental exposure and population immunity[9]. Within Asia, countries such as China, Thailand, and South Korea have been documented as endemic regions for histoplasmosis, particularly areas along the Yangtze River in China[10, 11]. Despite the presence of these endemic areas, histoplasmosis has historically been underrecognized in Asia, often leading to misdiagnosis as other invasive mycoses[12]. In this study, we present a case of histoplasmosis in a mountainous city in Sichuan Province, southwest China. Disseminated histoplasmosis is rarely reported in this region, potentially due to misdiagnosis arising from its diverse, non-specific clinical manifestations. This fungus thrives in environments contaminated with bat guano—especially from cave-dwelling species—or droppings from pigeons, starlings, or chickens[13]. Transmission is mainly environmental, with H . capsulatum spores released into the air during disturbance of contaminated soil or materials, making inhalation the primary route of infection[2, 8]. Contact with mucous membranes or non-intact skin may also serve as a secondary route, although this is less common than inhalation. Most patients diagnosed with histoplasmosis have usually reported exposure to caves and bat guano, often associated with travel to endemic areas. This highlights the need to comprehensively assess travel history and risk activities when histoplasmosis is suspected to avoid overlooking important information[14]. Our patient was born in a small village in Sichuan, China. Several months before symptom onset, the patient frequently ventured deep into remote forests to gather mushrooms, entering caves covered in bat droppings. We suspect the patient contracted H. capsulatum through exposure to bat feces. The spectrum of histoplasmosis ranges from asymptomatic infection or mild illness to deep pulmonary and/or systemic mycosis. Severe clinical manifestations are rare, occurring in less than 1% of patients[15]. Immunocompetent individuals typically contract the disease through activities such as tilling the soil, exploring caves, constructing buildings, clearing old dwellings or bird habitats, or cutting down trees[16]. While much is known regarding the clinical spectrum of histoplasmosis in immunocompromised hosts, less information relating to disease presentation is available for non-immunocompromised individuals residing in endemic areas, a point explored by Leitão et al [4]. Their findings suggested that histoplasmosis can occur in immunocompetent individuals within endemic zones, often requiring a high index of clinical suspicion for diagnosis. The severity and form of the disease depend on the patient’s immune status. While primary infection can be asymptomatic and self-limiting, it can also progress to disseminated disease[17], the rarest form of histoplasmosis, and the form predominantly observed in immunocompromised individuals. Depending on the disease subtype, the patient usually presents with prolonged fever, rigors, anorexia, weight loss, cough, malaise, anemia, and hepatospleenomegaly[18]. Our case was a middle-aged immunocompetent patient with disseminated histoplasmosis who presented with pyrexia of unknown origin and other nonspecific symptoms. The patient was initially treated with various antibiotics by several physicians. After visiting three hospitals, the patient’s illness was finally diagnosed after nearly two months. In our review, the 45 immunocompetent patients ranged in age from four months to 85 years, with most occurring among young adults and middle-aged individuals between the ages of 20 and 60 years. Theoretically, this demographic exhibits relatively robust immunity, and infections in this population are primarily associated with occupational activities and travel. Therefore, regardless of the age group, the importance of monitoring such diseases in immunocompetent populations must not be overlooked. The diagnosis of histoplasmosis presents a significant challenge in clinical practice, stemming from the lack of specificity in its symptomatic presentation and the limitations of existing diagnostic methods. Microbiological culture remains the gold standard for confirming Histoplasma infection, relying on the demonstration of thermal dimorphism[19]. Serum or urinary antigen detection provides a rapid, non-invasive, and highly sensitive method for the identification of disseminated cases and treatment monitoring [20]. However, serology sensitivity can be very low in immunosuppressed patients, who may not mount an antibody response[6]. Serum BDG testing is a useful diagnostic tool, particularly in patients with histoplasmosis, but again, specificity is low. Nonetheless, molecular methods have significant potential to revolutionize the diagnosis of complex infectious diseases, including histoplasmosis. Assays with improved performance characteristics will likely play a larger role in this process in the future. Recently, the application of mNGS has emerged as a valuable diagnostic tool for histoplasmosis[21]. mNGS is a useful technique for detecting novel or rare microorganisms and also improves the analytical sensitivity required for the identification of fastidious microorganisms[7]. Its capacity for rapid and broad-spectrum pathogen detection is particularly advantageous in complex cases where traditional diagnostic methods may be insufficient. In the diagnosis of disseminated histoplasmosis, mNGS serves as a valuable adjunct to bone marrow aspiration, particularly for patients with unexplained fever[22]. In our case, the pathogen remained undetected during the initial phase, delaying appropriate treatment. Ultimately, Histoplasma was identified through mNGS analysis of the submitted blood sample. In summary, histoplasmosis remains a significant public health concern, given its diverse clinical presentations and significant diagnostic challenges. Disseminated histoplasmosis should be considered in patients from non-epidemic areas who present with the triad of fever, hepatosplenomegaly, and cytopenias, as timely treatment is essential for improving prognosis and reducing mortality from this disease. Ongoing research aimed at improving diagnostic methods, coupled with increased awareness of the epidemiology of histoplasmosis—particularly among immunocompetent populations—is essential for the effective management and control of this fungal disease. Declarations Acknowledgements We are grateful to our patients for giving consent and cooperating during management and to our resident doctors for helping in patient data collection and management. A uthor contribution s TG. C., and LB. L.: Writing – review & editing, Writing – original draft. J. L. and XL. W.: Supervision, Software, Methodology. DL. Z., and HX. Z.: Investigation, Data curation. J. W.: Supervision, Project administration. TG. C. and LB. L: Supervision, Data curation. All authors read and approved the final version. Funding No funding was available for this work. Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request. Ethics approval and consent to participate As a case report, our paper did not require any referral to our institutional clinical ethics committee. Consent for publication Written informed consent was obtained from the patient for publication of this report and any accompanying images. Competing interests The authors declare that they have no competing interests. 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Diao Z, Han D, Zhang R, Li J: Metagenomics next-generation sequencing tests take the stage in the diagnosis of lower respiratory tract infections. J Adv Res 2022, 38:201-212. http://doi.org/10.1016/j.jare.2021.09.012. Wang N, Zhao C, Tang C, Wang L: Case Report and Literature Review: Disseminated Histoplasmosis Infection Diagnosed by Metagenomic Next-Generation Sequencing. Infect Drug Resist 2022, 15:4507-4514. http://doi.org/10.2147/idr.S371740. Table 1 Table 1 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.xlsx Table 1 Biochemical parameters during hospitalization. Supplementarymaterial1.xlsx Cite Share Download PDF Status: Published Journal Publication published 03 Feb, 2026 Read the published version in BMC Infectious Diseases → Version 1 posted Editorial decision: Revision requested 29 Dec, 2025 Reviews received at journal 27 Dec, 2025 Reviewers agreed at journal 24 Dec, 2025 Reviews received at journal 10 Dec, 2025 Reviewers agreed at journal 04 Dec, 2025 Reviewers invited by journal 27 Nov, 2025 Editor assigned by journal 25 Nov, 2025 Submission checks completed at journal 25 Nov, 2025 First submitted to journal 24 Nov, 2025 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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16:23:28","extension":"xml","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":42490,"visible":true,"origin":"","legend":"","description":"","filename":"80d5c7dcaffc4e24809d0858a06ce6661structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8193535/v1/0e1a9f26739af73db3be6557.xml"},{"id":97367816,"identity":"977d2542-6db2-4333-b741-cb6c7a4bbb20","added_by":"auto","created_at":"2025-12-03 16:20:49","extension":"html","order_by":15,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":48346,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8193535/v1/36d4986a041faf05f7f691f0.html"},{"id":97367163,"identity":"3e8415c0-db3a-4a11-9f0c-cc723d67148f","added_by":"auto","created_at":"2025-12-03 16:17:15","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1064629,"visible":true,"origin":"","legend":"\u003cp\u003eBone marrow smear (The arrows show the intracytoplasmic inclusions compatible with \u003cem\u003eH. capsulatum\u003c/em\u003e. Wright-Giemsa stain, 100× magnification (oil immersion).)\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8193535/v1/d0e9754c4e00aab549a91bf1.png"},{"id":97367026,"identity":"2a77b090-62f8-4c42-8932-9a3027788656","added_by":"auto","created_at":"2025-12-03 16:15:38","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":366600,"visible":true,"origin":"","legend":"\u003cp\u003eBody temperature during hospitalization.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8193535/v1/491a89eb12cd4e4ee51b3052.jpg"},{"id":97368995,"identity":"7e175e71-dfa4-4481-9f9e-d023f0139879","added_by":"auto","created_at":"2025-12-03 16:23:26","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":209668,"visible":true,"origin":"","legend":"\u003cp\u003eDistribution of Organ Involvement in 45 Patients.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-8193535/v1/f46b4e52a3debcaf546f7cab.png"},{"id":102234814,"identity":"7d948321-e6f1-4947-8d2d-a040f8f72831","added_by":"auto","created_at":"2026-02-09 16:13:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2494199,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8193535/v1/4ecfca78-8c0b-46ee-873c-3b21ad7fe01a.pdf"},{"id":97368967,"identity":"f8a1e7ca-7ebe-457a-a12e-30d0a1f0f3ce","added_by":"auto","created_at":"2025-12-03 16:23:22","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":10556,"visible":true,"origin":"","legend":"\u003cp\u003eTable 1 Biochemical parameters during hospitalization.\u003c/p\u003e","description":"","filename":"Table1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8193535/v1/dc795144e71584d81fb7a572.xlsx"},{"id":97265683,"identity":"bba59d07-2d2d-4ca0-8f93-66e76ba2a870","added_by":"auto","created_at":"2025-12-02 14:27:55","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":16704,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterial1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8193535/v1/ee04cf4d5f1fb112c2a6b197.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Disseminated histoplasmosis diagnosed by mNGS in a middle-aged immunocompetent patient: a case report and literature review","fulltext":[{"header":"Background","content":"\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003e\u003cem\u003eHistoplasma capsulatum\u003c/em\u003e is a dimorphic fungus commonly found in soil and is the causal agent of histoplasmosis [1]. This organism grows as a mold in the environment but transforms into a yeast form in human hosts. \u003cem\u003eH\u003c/em\u003e. \u003cem\u003ecapsulatum\u003c/em\u003e is distributed worldwide, and primarily infects humans through the inhalation of its spores (conidia) or mycelial particles[2]. Once inhaled, these microconidia transform into yeast forms within host tissues, facilitating infection and pathogenicity[3]. This transformation is a key pathogenic trait that enables the fungus to adapt to the intracellular host environment, evade immune responses, and infect a wide range of hosts[4].\u003c/p\u003e\u003cp\u003eWhile \u003cem\u003eH\u003c/em\u003e. \u003cem\u003ecapsulatum\u003c/em\u003e can affect individuals across various immune statuses, immunosuppressed patients are disproportionately at risk for severe and disseminated disease. Among immunocompromised groups, particularly individuals with HIV[4], histoplasmosis remains a significant concern. In most immunocompetent hosts, the immune response is sufficient, and infected individuals seldom become symptomatic[5]. The most common symptoms in patients with disseminated histoplasmosis are fever, fatigue, loss of appetite, and weight loss[5]. For immunocompetent patients, the non-specific presentation, unrevealing initial infectious workup, and lack of typical risk factors for infectious processes delay further investigation, consequently hindering the diagnosis and treatment of this condition.\u003c/p\u003e\u003cp\u003eHere, we report a rare case of disseminated histoplasmosis with non-specific presentation in a middle-aged, immunocompetent patient, diagnosed by metagenomic next-generation sequencing (mNGS). This atypical case highlights the challenges in the early identification and diagnosis of disseminated histoplasmosis in immunocompetent individuals presenting with nonspecific symptoms. Moreover, it underscores the importance of molecular diagnostic techniques, such as mNGS, in the diagnosis of infectious diseases. Additionally, we reviewed cases of histoplasmosis reported in immunocompetent individuals between 2021 and 2025. This information may serve as a reference for clinicians in the management of this uncommon disease.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eOne month before admission, a 38-year-old male presented with an unexplained fever, with a peak temperature of 39\u0026deg;C, accompanied by chills, rigors, occasional dizziness, and a mild cough with sputum production. He was admitted to a local county hospital, where he received anti-infective and antipyretic treatment with cefoperazone/sulbactam (approximately five days), piperacillin/tazobactam, and levofloxacin. However, the patient\u0026rsquo;s condition did not improve following treatment, and he continued to experience intermittent fever. The patient was subsequently transferred to our hospital for further management. At admission, the patient appeared well and was not in acute distress. His blood pressure was 112/67 mm Hg, he had a heart rate of 88 beats per minute, a respiratory rate of 20 breaths per minute, and a temperature of 37.8\u0026deg;C. The patient denied a history of diabetes mellitus, tuberculosis, typhoid fever, malaria, heart disease, cerebrovascular disease, or mental illness, had no comorbidities, and was not immunocompromised. An auxiliary examination at the time of admission yielded the following findings: white blood cell count, 7.51 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L (range 3.5 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e\u0026ndash;9.5 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L); platelet count, 87 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L (range 125 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e\u0026ndash;350 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L); sedimentation rate, 57 mm/h (range 0\u0026ndash;20 mm/h); alanine aminotransferase, 45 U/L (range 9\u0026ndash;50 U/L); aspartate aminotransferase, 26 U/L (range 15\u0026ndash;40 U/L); alkaline phosphatase, 275 U/L (range 45\u0026ndash;125 U/L); and total T-cell count (CD3\u003csup\u003e+\u003c/sup\u003e), 0.98 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L (range 0.52\u0026ndash;2.86 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L). The autoimmune workup was negative. The tuberculosis infection T-cell assay (interferon-gamma release assay) and the HIV screen were also negative. To further determine the cause of the disease and refine the diagnostic procedures, imaging was performed. A chest CT scan revealed small nodules in both lungs, and an abdominal CT scan showed splenomegaly. The infection indicator procalcitonin was measured at 0.68 ng/mL (range 0.00\u0026ndash;0.10 ng/mL). Meanwhile, the patient\u0026rsquo;s poor response to outpatient treatment and low platelet count indicated the possibility of an atypical pathogen infection. The physician initiated empirical antimicrobial therapy with doxycycline and compound sulfamethoxazole-trimethoprim, and venous blood was collected for mNGS and fungal (1\u0026ndash;3)-\u003cem\u003eβ\u003c/em\u003e-D-glucan (BDG) testing. The BDG level was 157 pg/mL (range\u0026thinsp;\u0026lt;\u0026thinsp;60 pg/mL), suggestive of an invasive fungal infection, and mNGS of the venous blood confirmed histoplasmosis. Subsequently, Giemsa staining of bone marrow aspirate revealed oval yeast-like cells both scattered and in clusters within macrophages, further confirming histoplasmosis infection (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Once the infectious agent had been identified, and considering that the patient was immunocompetent, the extrapulmonary localization of the fungal infection, and the long duration of symptoms, the clinician immediately switched the treatment regimen to intravenous amphotericin B for antifungal therapy. After approximately three weeks of treatment, the patient\u0026rsquo;s vital signs had stabilized with no fever (Table\u0026nbsp;1, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Accordingly, the patient was discharged with continued amphotericin B therapy and was advised to return for a follow-up examination one week post-discharge.\u003c/p\u003e\u003c/div\u003e"},{"header":"Literature Review","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003cp\u003eA comprehensive literature search of the PubMed and Web of Science databases was conducted for articles published between 2021 and 2025, using the search terms \u0026ldquo;immunocompetent human\u0026rdquo; and \u0026ldquo;histoplasmosis\u0026rdquo;. Publications were restricted to English-language case reports. The inclusion criteria were 1) histoplasmosis confirmed by standard methods, and 2) immunocompetency. Articles detailing diseases with compromised immunity, immunosuppressive medication therapy, and autoimmune diseases were excluded. Based on these criteria, 39 articles describing 45 patients were identified. The features of the 45 patients are summarized in supplementary material 1. Eight of the patients were children, with the remainder being older than 16 years. Among the cohort, 9 were female, 35 were male, and one patient\u0026rsquo;s sex was unspecified. Infection involved various organs, including the skin, lymph nodes, adrenal glands, gastrointestinal tract, heart, liver, spleen, lungs, thyroid, and central nervous system. Lymph nodes, lungs, liver, spleen, and the gastrointestinal tract were the most frequently affected sites. Some patients exhibited multi-organ involvement, though no typical symptoms were present (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). This indicates that histoplasmosis not only lacks typical symptoms in immunocompromised patients but also exhibits no characteristic features in immunocompetent individuals.\u003c/p\u003e\u003cp\u003eIn the reviewed cases, pathogen identification primarily relied on serum serology and histopathology. Owing to the difficulty in culturing the organism, fungal cultures were successfully obtained in only 8 (18%) cases, with 2 (4%) of these being supplemented by mass spectrometry. mNGS was less frequently used in clinical practice and was only applied for diagnosis in 3 (7%) patients. Histopathology, microscopy, and culture remain the cornerstone methods for histoplasmosis diagnosis. However, these conventional tools lack sensitivity, particularly during early phases of the disease[6]. In contrast, mNGS enables rapid and accurate pathogen identification without relying on microbial culture, and is especially suitable for detecting rare, novel, and atypical causes of complicated infectious diseases. In the near future, given its sensitivity, speed, and cost-effectiveness, mNGS has the potential to become part of routine diagnostic workups[7]. In non-endemic regions of China, clinicians often lack sufficient awareness of histoplasmosis, leading to frequent misdiagnosis or missed diagnosis. Currently, mNGS can serve as a complementary approach to traditional diagnostic methods, thereby enhancing the diagnostic accuracy for this disease.\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion and conclusions","content":"\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eHistoplasmosis is endemic to the Ohio and Mississippi River valleys, Central and South America, and microfoci in the Eastern United States, southern Europe, Africa, and southeastern Asia[8]. The overall epidemiology has evolved since the 1950s, involving changes in the distribution and proportion of symptomatic infections relative to the general population, which reflect shifts in environmental exposure and population immunity[9]. Within Asia, countries such as China, Thailand, and South Korea have been documented as endemic regions for histoplasmosis, particularly areas along the Yangtze River in China[10, 11]. Despite the presence of these endemic areas, histoplasmosis has historically been underrecognized in Asia, often leading to misdiagnosis as other invasive mycoses[12]. In this study, we present a case of histoplasmosis in a mountainous city in Sichuan Province, southwest China. Disseminated histoplasmosis is rarely reported in this region, potentially due to misdiagnosis arising from its diverse, non-specific clinical manifestations.\u003c/p\u003e\u003cp\u003eThis fungus thrives in environments contaminated with bat guano\u0026mdash;especially from cave-dwelling species\u0026mdash;or droppings from pigeons, starlings, or chickens[13]. Transmission is mainly environmental, with \u003cem\u003eH\u003c/em\u003e. \u003cem\u003ecapsulatum\u003c/em\u003e spores released into the air during disturbance of contaminated soil or materials, making inhalation the primary route of infection[2, 8]. Contact with mucous membranes or non-intact skin may also serve as a secondary route, although this is less common than inhalation. Most patients diagnosed with histoplasmosis have usually reported exposure to caves and bat guano, often associated with travel to endemic areas. This highlights the need to comprehensively assess travel history and risk activities when histoplasmosis is suspected to avoid overlooking important information[14]. Our patient was born in a small village in Sichuan, China. Several months before symptom onset, the patient frequently ventured deep into remote forests to gather mushrooms, entering caves covered in bat droppings. We suspect the patient contracted \u003cem\u003eH. capsulatum\u003c/em\u003e through exposure to bat feces.\u003c/p\u003e\u003cp\u003eThe spectrum of histoplasmosis ranges from asymptomatic infection or mild illness to deep pulmonary and/or systemic mycosis. Severe clinical manifestations are rare, occurring in less than 1% of patients[15]. Immunocompetent individuals typically contract the disease through activities such as tilling the soil, exploring caves, constructing buildings, clearing old dwellings or bird habitats, or cutting down trees[16]. While much is known regarding the clinical spectrum of histoplasmosis in immunocompromised hosts, less information relating to disease presentation is available for non-immunocompromised individuals residing in endemic areas, a point explored by Leit\u0026atilde;o \u003cem\u003eet al\u003c/em\u003e[4]. Their findings suggested that histoplasmosis can occur in immunocompetent individuals within endemic zones, often requiring a high index of clinical suspicion for diagnosis. The severity and form of the disease depend on the patient\u0026rsquo;s immune status. While primary infection can be asymptomatic and self-limiting, it can also progress to disseminated disease[17], the rarest form of histoplasmosis, and the form predominantly observed in immunocompromised individuals. Depending on the disease subtype, the patient usually presents with prolonged fever, rigors, anorexia, weight loss, cough, malaise, anemia, and hepatospleenomegaly[18]. Our case was a middle-aged immunocompetent patient with disseminated histoplasmosis who presented with pyrexia of unknown origin and other nonspecific symptoms. The patient was initially treated with various antibiotics by several physicians. After visiting three hospitals, the patient\u0026rsquo;s illness was finally diagnosed after nearly two months. In our review, the 45 immunocompetent patients ranged in age from four months to 85 years, with most occurring among young adults and middle-aged individuals between the ages of 20 and 60 years. Theoretically, this demographic exhibits relatively robust immunity, and infections in this population are primarily associated with occupational activities and travel. Therefore, regardless of the age group, the importance of monitoring such diseases in immunocompetent populations must not be overlooked.\u003c/p\u003e\u003cp\u003eThe diagnosis of histoplasmosis presents a significant challenge in clinical practice, stemming from the lack of specificity in its symptomatic presentation and the limitations of existing diagnostic methods. Microbiological culture remains the gold standard for confirming \u003cem\u003eHistoplasma\u003c/em\u003e infection, relying on the demonstration of thermal dimorphism[19]. Serum or urinary antigen detection provides a rapid, non-invasive, and highly sensitive method for the identification of disseminated cases and treatment monitoring [20]. However, serology sensitivity can be very low in immunosuppressed patients, who may not mount an antibody response[6]. Serum BDG testing is a useful diagnostic tool, particularly in patients with histoplasmosis, but again, specificity is low. Nonetheless, molecular methods have significant potential to revolutionize the diagnosis of complex infectious diseases, including histoplasmosis. Assays with improved performance characteristics will likely play a larger role in this process in the future. Recently, the application of mNGS has emerged as a valuable diagnostic tool for histoplasmosis[21]. mNGS is a useful technique for detecting novel or rare microorganisms and also improves the analytical sensitivity required for the identification of fastidious microorganisms[7]. Its capacity for rapid and broad-spectrum pathogen detection is particularly advantageous in complex cases where traditional diagnostic methods may be insufficient. In the diagnosis of disseminated histoplasmosis, mNGS serves as a valuable adjunct to bone marrow aspiration, particularly for patients with unexplained fever[22]. In our case, the pathogen remained undetected during the initial phase, delaying appropriate treatment. Ultimately, \u003cem\u003eHistoplasma\u003c/em\u003e was identified through mNGS analysis of the submitted blood sample.\u003c/p\u003e\u003cp\u003eIn summary, histoplasmosis remains a significant public health concern, given its diverse clinical presentations and significant diagnostic challenges. Disseminated histoplasmosis should be considered in patients from non-epidemic areas who present with the triad of fever, hepatosplenomegaly, and cytopenias, as timely treatment is essential for improving prognosis and reducing mortality from this disease. Ongoing research aimed at improving diagnostic methods, coupled with increased awareness of the epidemiology of histoplasmosis\u0026mdash;particularly among immunocompetent populations\u0026mdash;is essential for the effective management and control of this fungal disease.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe are grateful to our patients for giving consent and cooperating during management and to our resident doctors for helping in patient data collection and management.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eA\u003c/strong\u003e\u003cstrong\u003euthor contribution\u003c/strong\u003e\u003cstrong\u003es\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTG. C., and LB. L.: Writing \u0026ndash; review \u0026amp; editing, Writing \u0026ndash; original draft. J. L. and XL. W.: Supervision, Software, Methodology. DL. Z., and HX. Z.: Investigation, Data curation. J. W.: Supervision, Project administration. TG. C. and LB. L: Supervision, Data curation. All authors read and approved the final version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding was available for this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs a case report, our paper did not require any referral to our institutional clinical ethics committee.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient for publication of this report and any accompanying images.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSilva DL, Peres NTA, Santos DA: Key fungal coinfections: epidemiology, mechanisms of pathogenesis, and beyond. \u003cem\u003emBio \u003c/em\u003e2025, 16(5):e0056225. http://doi.org/10.1128/mbio.00562-25. \u003c/li\u003e\n\u003cli\u003eSchmidt TE, Vieceli T, Damasceno LS, Kimuda S, Pasqualotto AC, Bahr NC: Evolving Epidemiology, Improving Diagnostic Tests and Their Importance for the Correct Diagnosis of Histoplasmosis. \u003cem\u003eJ Fungi (Basel) \u003c/em\u003e2025, 11(3). http://doi.org/10.3390/jof11030196. \u003c/li\u003e\n\u003cli\u003eBarros N, Wheat JL, Hage C: Pulmonary Histoplasmosis: A Clinical Update. \u003cem\u003eJ Fungi (Basel) \u003c/em\u003e2023, 9(2). http://doi.org/10.3390/jof9020236. \u003c/li\u003e\n\u003cli\u003eSep\u0026uacute;lveda VE, Rader JA, Li JJ, Goldman WE, Matute DR: Phenotypic characterization of cryptic species in the fungal pathogen Histoplasma. \u003cem\u003ebioRxiv \u003c/em\u003e2024. http://doi.org/10.1101/2024.01.08.574719. \u003c/li\u003e\n\u003cli\u003eRichter YS, Kenny DX, Semon SB, Meiklejohn KM, Bays DJ, Damon LE: Hidden Histoplasmosis: Adrenal and Central Nervous System Mycosis in an Immunocompetent Patient. \u003cem\u003eCureus \u003c/em\u003e2025, 17(8):e90831. http://doi.org/10.7759/cureus.90831. \u003c/li\u003e\n\u003cli\u003eHage CA, Ribes JA, Wengenack NL, Baddour LM, Assi M, McKinsey DS, Hammoud K, Alapat D, Babady NE, Parker M\u003cem\u003e et al\u003c/em\u003e: A multicenter evaluation of tests for diagnosis of histoplasmosis. \u003cem\u003eClin Infect Dis \u003c/em\u003e2011, 53(5):448-454. http://doi.org/10.1093/cid/cir435. \u003c/li\u003e\n\u003cli\u003eMiao Q, Ma Y, Wang Q, Pan J, Zhang Y, Jin W, Yao Y, Su Y, Huang Y, Wang M\u003cem\u003e et al\u003c/em\u003e: Microbiological Diagnostic Performance of Metagenomic Next-generation Sequencing When Applied to Clinical Practice. \u003cem\u003eClin Infect Dis \u003c/em\u003e2018, 67(suppl_2):S231-s240. http://doi.org/10.1093/cid/ciy693. \u003c/li\u003e\n\u003cli\u003eKauffman CA: Histoplasmosis. \u003cem\u003eClin Chest Med \u003c/em\u003e2009, 30(2):217-225, v. http://doi.org/10.1016/j.ccm.2009.02.002. \u003c/li\u003e\n\u003cli\u003eBenedict K, Toda M, Jackson BR: Revising Conventional Wisdom About Histoplasmosis in the United States. \u003cem\u003eOpen Forum Infect Dis \u003c/em\u003e2021, 8(7):ofab306. http://doi.org/10.1093/ofid/ofab306. \u003c/li\u003e\n\u003cli\u003ePan B, Chen M, Pan W, Liao W: Histoplasmosis: a new endemic fungal infection in China? Review and analysis of cases. \u003cem\u003eMycoses \u003c/em\u003e2013, 56(3):212-221. http://doi.org/10.1111/myc.12029. \u003c/li\u003e\n\u003cli\u003eValdez AF, Miranda DZ, Guimar\u0026atilde;es AJ, Nimrichter L, Nosanchuk JD: Pathogenicity \u0026amp; virulence of \u003cem\u003eHistoplasma capsulatum\u003c/em\u003e - A multifaceted organism adapted to intracellular environments. \u003cem\u003eVirulence \u003c/em\u003e2022, 13(1):1900-1919. http://doi.org/10.1080/21505594.2022.2137987. \u003c/li\u003e\n\u003cli\u003eNacher M, Marshall E, Bani-Sadr F, Peugny S, Denis B, Ouedraogo E, Gallien S, Meybeck A, Fran\u0026ccedil;oise U, Adenis A\u003cem\u003e et al\u003c/em\u003e: Disseminated Histoplasmosis in Persons Living with HIV, France and Overseas Territories,1992-2021. \u003cem\u003eEmerg Infect Dis \u003c/em\u003e2025, 31(7):1377-1385. http://doi.org/10.3201/eid3107.241931. \u003c/li\u003e\n\u003cli\u003eMora-Jaramillo N, Orlando SA, Rivera M, Echevarr\u0026iacute;a J, Carvajal E, Rodr\u0026iacute;guez-Pazmi\u0026ntilde;o S, Paredes DS, Arcos Alcivar F, Rebolledo V, Fuentes T\u003cem\u003e et al\u003c/em\u003e: High prevalence of \u003cem\u003eHistoplasma capsulatum\u003c/em\u003e in bats and pigeons is linked to human histoplasmosis in an endemic area of Ecuador. \u003cem\u003eFront Vet Sci \u003c/em\u003e2025, 12:1613841. http://doi.org/10.3389/fvets.2025.1613841. \u003c/li\u003e\n\u003cli\u003eIde S, Kutsuna S, Yamada G, Hashimoto K, Abe M, Nagi M, Ujiie M, Hayakawa K, Ohmagari N: Pulmonary histoplasmosis diagnosed in a Japanese woman after traveling to central and South America: A case report. \u003cem\u003eJ Infect Chemother \u003c/em\u003e2021, 27(11):1658-1661. http://doi.org/10.1016/j.jiac.2021.06.015. \u003c/li\u003e\n\u003cli\u003eTeixeira Mde M, Patan\u0026eacute; JS, Taylor ML, G\u0026oacute;mez BL, Theodoro RC, de Hoog S, Engelthaler DM, Zancop\u0026eacute;-Oliveira RM, Felipe MS, Barker BM: Worldwide Phylogenetic Distributions and Population Dynamics of the Genus Histoplasma. \u003cem\u003ePLoS Negl Trop Dis \u003c/em\u003e2016, 10(6):e0004732. http://doi.org/10.1371/journal.pntd.0004732. \u003c/li\u003e\n\u003cli\u003eFaiolla RC, Coelho MC, Santana Rde C, Martinez R: Histoplasmosis in immunocompetent individuals living in an endemic area in the Brazilian Southeast. \u003cem\u003eRev Soc Bras Med Trop \u003c/em\u003e2013, 46(4):461-465. http://doi.org/10.1590/0037-8682-0124-2013. \u003c/li\u003e\n\u003cli\u003eKumar B, Agarwal D, Meena DS, Vaswani S, Sri DS, Kumar D, Purohit A, Garg P: CNS histoplasmosis coexisting with pulmonary tuberculosis in a HIV negative patient: case report. \u003cem\u003eBMC Infect Dis \u003c/em\u003e2024, 24(1):1297. http://doi.org/10.1186/s12879-024-10068-x. \u003c/li\u003e\n\u003cli\u003eBardia PC, Detroja KN, Maniar RC, Dharsandia HK: A case of disseminated histoplasmosis diagnosed by bone marrow aspiration in immunocompetent patient from nonendemic area, Rajkot, Gujarat. \u003cem\u003eIndian J Pathol Microbiol \u003c/em\u003e2024, 67(1):230-232. http://doi.org/10.4103/ijpm.ijpm_200_22. \u003c/li\u003e\n\u003cli\u003eVen\u0026acirc;ncio de Barros A, Sousa Gon\u0026ccedil;alves F, Mendon\u0026ccedil;a L, Carvalho D, Melo Cristino J: \u003cem\u003eHistoplasma capsulatum\u003c/em\u003e var. duboisii: A Case of Histoplasmosis 50 Years After the Exposure. \u003cem\u003eCureus \u003c/em\u003e2025, 17(1):e77854. http://doi.org/10.7759/cureus.77854. \u003c/li\u003e\n\u003cli\u003eAzar MM, Hage CA: Laboratory Diagnostics for Histoplasmosis. \u003cem\u003eJ Clin Microbiol \u003c/em\u003e2017, 55(6):1612-1620. http://doi.org/10.1128/jcm.02430-16. \u003c/li\u003e\n\u003cli\u003eDiao Z, Han D, Zhang R, Li J: Metagenomics next-generation sequencing tests take the stage in the diagnosis of lower respiratory tract infections. \u003cem\u003eJ Adv Res \u003c/em\u003e2022, 38:201-212. http://doi.org/10.1016/j.jare.2021.09.012. \u003c/li\u003e\n\u003cli\u003eWang N, Zhao C, Tang C, Wang L: Case Report and Literature Review: Disseminated Histoplasmosis Infection Diagnosed by Metagenomic Next-Generation Sequencing. \u003cem\u003eInfect Drug Resist \u003c/em\u003e2022, 15:4507-4514. http://doi.org/10.2147/idr.S371740. \u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table 1","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\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":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Histoplasmosis, immunocompetent, mNGS","lastPublishedDoi":"10.21203/rs.3.rs-8193535/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8193535/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eHistoplasmosis is a fungal infection caused by the dimorphic fungus \u003cem\u003eHistoplasma capsulatum\u003c/em\u003e. Its clinical presentation is highly variable, ranging from asymptomatic cases to progressive disseminated infections. Disseminated histoplasmosis is the rarest form and is mostly found in immunocompromised patients, although rare cases have also been reported among immunocompetent individuals. In this study, we present a case of disseminated histoplasmosis in a middle-aged, immunocompetent patient from Sichuan Province, southwest China, diagnosed by mNGS. This condition is rarely documented in this region, and its diverse, non-specific clinical manifestations often lead to misdiagnosis. This atypical case highlights the challenges associated with the early recognition and diagnosis of disseminated histoplasmosis in immunocompetent patients presenting with non-specific symptoms. Additionally, we reviewed cases of histoplasmosis reported in immunocompetent individuals between 2021 and 2025. This information may serve as a reference for clinicians in the management of this uncommon disease.\u003c/p\u003e","manuscriptTitle":"Disseminated histoplasmosis diagnosed by mNGS in a middle-aged immunocompetent patient: a case report and literature review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-02 14:27:50","doi":"10.21203/rs.3.rs-8193535/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-29T08:34:48+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-27T15:51:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"214715331832722783234414019299327642047","date":"2025-12-24T16:22:21+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-10T18:33:00+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"320051717780951865081441863953377914930","date":"2025-12-04T18:22:38+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-27T14:40:52+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-25T07:29:49+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-11-25T07:28:27+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Infectious Diseases","date":"2025-11-24T12:31:36+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3b840132-4b6c-4bf4-ad5e-aef646794792","owner":[],"postedDate":"December 2nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-02-09T16:06:10+00:00","versionOfRecord":{"articleIdentity":"rs-8193535","link":"https://doi.org/10.1186/s12879-026-12692-1","journal":{"identity":"bmc-infectious-diseases","isVorOnly":false,"title":"BMC Infectious Diseases"},"publishedOn":"2026-02-03 15:58:13","publishedOnDateReadable":"February 3rd, 2026"},"versionCreatedAt":"2025-12-02 14:27:50","video":"","vorDoi":"10.1186/s12879-026-12692-1","vorDoiUrl":"https://doi.org/10.1186/s12879-026-12692-1","workflowStages":[]},"version":"v1","identity":"rs-8193535","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8193535","identity":"rs-8193535","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}