Talaromyces marneffei infection of central nervous system in an immunocompetent child in a nonendemic area: a case report and literature review

Abstract

Background Talaromyces marneffei

(T. marneffei, formerly Penicillium marneffei) is a rare fatal fungus endemic in Southeast Asia and southern China. T. marneffei infections mainly occur in HIV-infected adults, and commonly involves the skin, lung, and reticuloendothelial system. T. marneffei infections of isolated central nervous system (CNS) in immunocompetent pediatric patients in nonendemic areas have rarely been reported.

Case presentation

We report a rare case of T. marneffei-induced disseminated encephalomyelitis in an immunocompetent girl from a nonendemic area of Eastern China. The main clinical manifestations were abdominal pain with distension and abnormal gait. Contrast-enhanced magnetic resonance imaging (MRI) revealed both brain and spinal cord lesions. The infection status of T. marneffei was quickly determined via the metagenomic next-generation sequencing (mNGS) of spinal cord biopsy tissue. T. marneffei induced disseminated encephalomyelitis was diagnosed. Following successful antifungal treatment with amphotericin B liposomes and voriconazole, the child recovered gradually. To date, only 3 cases of T. marneffei infection of the central nervous system in non-HIV-infected pediatric patients have been reported in the literature. Among them, one child had inborn errors of immunity, and the other two children were from endemic areas. Moreover, the clinical manifestations of those 3 reported cases were disseminated with common infection sites in the lungs. our patient represents a unique case of an immunocompetent child from a nonendemic area with isolated CNS infection.

Conclusions

We report this rare case and aim to promote pediatric clinicians’ recognition of T. marneffei isolated CNS infection in immunocompetent pediatric patients from nonendemic regions. Furthermore, the early use of mNGS is recommended when non-HIV-infected pediatric patients present with unexplained clinical manifestations and poor response to conventional treatments. Timely diagnosis and appropriate antifungal therapy can improve patient prognosis.

Background

T. marneffei was first discovered in 1956 by Capponi et al. [1] at the Pasteur Institute in Vietnam from the liver of a Chinese bamboo rat that died of reticuloendotheliosis. The bamboo rat is its natural host. the first case of natural human infection with T. marneffei was reported in 1973 [2]. T. marneffei is prevalent in Southeast Asia, and Guangdong Province and Guangxi Province are the most common areas in China [3]. To date, infections have mainly been reported [4] in HIV infected or other immunocompromised adults, but rarely in immunocompetent adults let al.one in immunocompetent children. T. marneffei proliferates in macrophages and spreads through the reticuloendothelial system, causing multisystem damage, most commonly involving the skin, lung and reticuloendothelial system. Reports on isolated CNS infection are rare. Here, we describe an extremely rare case of disseminated encephalomyelitis caused by T. marneffei infection in an immunocompetent child from a nonendemic area. Besides, literatures of T. marneffei CNS infection in HIV-negative pediatric patients were reviewed to understand this rare disease better.

Case presentation

A 2-year and 11-month-old girl was admitted to our hospital due to abdominal pain with distension for half a year, abnormal gait for 5 months and aggravation for 1 week. The abnormal gait gradually became aggravated, manifested as buckling walking, the inability to stand upright, and worsening of the left leg compared with the right leg. One week before admission, the left lower limbs could not be moved horizontally. In addition, she could not control urination. She had no medical history, she was a previously healthy and lovely girl from Hangzhou, Zhejiang Province, China, who denied history of contact with bamboo rats or related epidemic areas. Despite multiple outpatient visits, her condition remained unresolved, so she was admitted to our department for further evaluation. Physical examination revealed abdominal distension, the meningeal stimulation sign was negative, the muscle strength of both upper limbs was grade V with normal muscle tension; the right lower limb was grade IV with normal muscle tension; the left lower limb was only grade 0 with reduced muscle tension, the knee and Achilles tendon reflexes were hyperactive, and both Babinski signs were positive. No skin lesions or abnormal lymph nodes were noted.

Contrast-enhanced MRI of the entire spinal cord revealed extensive abnormal signals, enhanced and thickened meninges, and multiple enhanced nodules of varying sizes (Fig. 1a–b). Intracranial contrast-enhanced MRI demonstrated hydrocephalus with interstitial edema, and enhanced, thickened meninges (Fig. 2a–b). On the fourth day of admission, a lumber puncture was performed, cerebrospinal fluid (CSF) revealed elevated protein levels (546.4 mg/L, normal range < 450 mg/L), but bacterial and fungal cultures were negative. To make a definitive diagnosis, a spinal cord biopsy was subsequently performed. mNGS of the biopsy samples revealed T. marneffei infection within one day (Fig. 3a). Histopathological examination of the biopsy tissue suggested granulomatous lesions; subsequent culture, Periodic Acid Schiff (PAS) staining and fungal fluorescence staining (FFS) (Fig. 3b-c) of the biopsy also suggested T. marneffei infection 14 days later.

Fig. 1.

Contrast-enhanced MRI of spinal cord. a–b T2-Flair-weighted images (T2-Flair) and contrast-enhanced T1-weighted images (T1WI + C) before antifungal therapy, showing extensive abnormal signals, enhanced and thickened meninges, and multiple significantly enhanced nodules. c–d T2-Flair and T1WI + C images after 41 days of antifungal therapy, demonstrating obvious improvement in abnormal signals and meningeal enhancement. e–f T2-Flair and T1WI + C images after 141 days of antifungal therapy, demonstrating a marked reduction in lesions

Fig. 2.

Intracranial contrast-enhanced MRI. a–b T2-Flair and T1WI + C images before antifungal therapy, showing hydrocephalus, interstitial edema, and enhanced, thickened meninges. c–d T2-Flair and T1WI + C images after 40 days of antifungal therapy, showing significant resolution of hydrocephalus and meningeal abnormalities

Fig. 3.

a mNGS of the biopsy samples revealing T. marneffei infection. b PAS staining of spinal cord biopsy samples, showing granulomatous lesions and inflammatory changes with diffuse macrophages infiltration. Red arrow shows yeast-like microorganisms (×200). c Fungal fluorescence staining of spinal cord biopsy samples revealing sausage-like cells with transverse septa(×200)

The evaluation of immune function was performed, with results as follows: Assessment of humoral immunity showed elevated serum IgE (162 IU/mL; normal range: 0–100 IU/mL), which is attributable to an allergic diathesis as evidenced by a history of penicillin allergy; IgG, IgA, and IgM levels were preserved, indicating intact antibody production. CD19 + B-cell counts were modestly elevated (33.55%; normal range: 19–29%), while a robust anti-hepatitis B surface antibody titer (> 1000 IU/L; normal range: <10 IU/L) confirmed preserved antigen-specific responsiveness. Comprehensive serologic screening, including tests for HIV, antinuclear antibodies, anti-neutrophil cytoplasmic antibodies, rheumatoid factor, (1,3)-β-D-glucan, and galactomannan was negative, effectively excluding associated autoimmune disorders and relevant chronic infections. Cellular immunity analysis revealed normal CD3 + T-cell counts, with a mildly elevated CD4 + proportion (41.45%; normal range: 30–40%) and a slightly decreased CD8 + proportion (18%; normal range: 20–27%), while the CD4/CD8 ratio remained normal. Natural killer cells (CD3 − CD16+CD56+) were moderately reduced (6.05%; normal range: 7–16%), though this isolated finding was deemed clinically insignificant in the context of overall immune competence. Evaluation of innate immunity demonstrated normal peripheral blood cell morphology and complement (C3, C4) levels. Whole-exome sequencing further identified no pathogenic mutations associated with primary immunodeficiency. Investigations, including blood and sputum cultures, tests for respiratory viruses, tuberculosis, HIV, serum EBV DNA, and procalcitonin, were all negative. Additionally, complete blood count, erythrocyte sedimentation rate, cytokine levels, thyroid and liver function tests, and tumor markers were all within normal limits. Chest radiography and abdominal ultrasound revealed no significant abnormalities. Testing for anti-interferon-γ autoantibodies (AIGAs) and serum protein electrophoresis results were within normal limits. Furthermore, no laboratory evidence supported a diagnosis of secondary immunodeficiency, as the workup revealed no hypogammaglobulinemia, complement deficiency, or hematologic abnormalities were observed. Critically, the patient was previously healthy, with a documented penicillin allergy as the only notable medical history, no risk factors for acquired immunodeficiency were identified, including prior B-cell targeted therapy, corticosteroid or other immunosuppressive therapy, chronic infections (e.g., HIV or EBV), malnutrition, protein-losing conditions, or hematologic malignancies.

Repeat lumbar puncture on hospital day 10 demonstrated a rising leukocyte count (48*10^⁶/L) compared with the initial study, markedly elevated protein levels (30178.2 mg/L, normal range < 450 mg/L), decreased glucose concentrations (1.03 mmol/L, normal range 2.8–4.5 mmol/L) and chloride concentrations (106.6 mmol/L, normal range 120–132 mmol/L). Following the mNGS results, the CSF culture medium and incubation conditions were adjusted to meet the needs of T. marneffei, which confirmed the infection one week later.

Finally, the child was diagnosed with disseminated encephalomyelitis caused by T. marneffei infection. On the twelfth day after admission, amphotericin B liposomes was given intravenously for 4 weeks as the initial antifungal treatment, and the consolidation therapy was then switched to oral voriconazole. No adverse events occurred during the course of antifungal treatment. The patient’s clinical symptoms gradually improved, and follow up contrast-enhanced MRI (Figs. 1 and 2 and c–d) showed significant resolution of the lesions. The CSF culture subsequently turned negative. After 2 months of hospitalization, the patient was discharged and transferred to the rehabilitation department for further recovery while continuing oral voriconazole therapy. At the time of discharge, the patient was asymptomatic with a normal gait and no urinary dysfunction. Neurological examination showed near-normal muscle strength (grade V-) and normal tension in the right lower limb, with significant improvement in the left lower limb (grade IV-) accompanied by slightly reduced tension. Deep tendon reflexes had returned to normal, whereas a left Babinski sign remained positive. The patient subsequently underwent rehabilitation at an external institution and was lost to follow-up at our center. However, Contrast-enhanced MRI of the entire spinal cord performed in February 2023(Fig. 1, e–f) showed a marked reduction in lesions compared to the October 2022 images. A one-year post-discharge telephone follow-up confirmed that the child remained clinically asymptomatic. (The complete clinical timeline was summarized in Fig. 4).

Fig. 4.

The clinical timeline

Discussion

T. marneffei is a rare fungus that is reported mainly in Southeast Asia and southern China. T. marneffei is spread by infected bamboo rats and their feces, contaminated soil or water. The patient in this case was born in Hangzhou, Eastern China. and had no history of travel to endemic areas. Previous reports [3, 4] have shown that T. marneffei infections occur mostly in adults. Our patient was 2 years and 11 months old, and the age of onset was rare. T. marneffei is known as an opportunistic infection and predominantly occurs in immunocompromised individuals, such as those with HIV positivity, organ transplant recipients, autoimmune diseases and malignant tumors, and it is rarely observed in immunocompetent hosts. No evidence of an immunocompromised condition was identified in the present case, a conclusion collectively supported by normal core immune parameters, a robust vaccine response, and the absence of any laboratory or historical evidence of secondary immunodeficiency. T. marneffei can cause general multisystem damage, involving skin, lung, lymph node, bone, bone marrow, joint, pericardium, liver and spleen damage. The skin, lung and lymph node are commonly affected. There are few reports [5, 6] on CNS damage. A study in Vietnam [7] revealed that only 21 (3%) of the 677 adult patients with HIV-related T. marneffei had CNS involvement. In childhood, a report [8] of 28 HIV-related T. marneffei pediatric cases in China found no CNS involvement. According to our literature review (Table 1), only 3 cases of T. marneffei CNS infection in HIV-negative pediatric patients have been reported [9–11]; among them one child had inborn errors of immunity with STAT3 gene mutation, and the other two children were from Guangdong Province, a place where T. marneffei infection is prevalent. Our patient represents a unique case of an immunocompetent child from a nonendemic area with isolated CNS infection.

Table 1.

Clinical characteristics of HIV-negative pediatric patients with T. marneffei CNS infection

	Case 1[9]	Case 2[10]	Case 3[11]	Our case
Age	2y	2y5m	2y5m	2y11m
Gender	F	F	F	F
Residence	Guangdong, China	Southeast of China	Guangdong, China	Zhejiang, China
Underlying diseases	Immunocompetent	Inborn Errors of Immunity	Immunocompetent	Immunocompetent
CNS symptoms	Fever, lethargy, rapid neurological deterioration	Fever, disturbance of consciousness	Fever, drowsiness, decreased consciousness	Abnormal gait
Other sites of infection	Skin, lung	Skin, lung, lymph node	Lung	None
CSF analysis	Elevated protein, decreased glucose	NA	Elevated protein	First: Elevated protein. Second: elevated leucocyte and protein, decreased glucose and chloride
CNS Imaging	Multiple intracranial calcifications	Cerebral infarction, cerebral hernia,	Cerebral infarction; multiple abnormal signals, diffuse pial mater enhancement	Hydrocephalus, enhanced nodules in spine, enhanced and thickened meninges
Positive clinical specimens	Cultures of CSF, BALF and BM	Cultures of CSF, BALF, and sputum	mNGS of CSF, cultures of BALF, CSF and blood	mNGS, culture and FFS of spinal tissue, culture of CSF
Duration of illness	0.5 m	NA	0.5 m	6 m
Clinical outcomes	Died	Died	Died	Improved

NA Not available, BALF Bronchoalveolar lavage fluid, BM Bone marrow, FFS Fungal fluorescence staining

In our literature review, all 3 non-HIV-infected children with T. marneffei CNS infection exhibited multisystem damage, involving not only the nervous system, but also the skin, lung and lymph node. Headache, dizziness, vomiting, fever, dyskinesia, diplopia or altered consciousness with seizures are the common symptoms of T. marneffei CNS infection. This patient had an elevated leukocyte count, high protein levels, low glucose and chloride levels in the CSF, consistent with other fungal CNS infections. Imaging findings in adults HIV-related T. marneffei CNS infections typically include ventricular dilatation or intracranial infectious lesions [12]. In the three pediatric cases reviewed, cerebral infarction, multiple abnormal signals with diffuse pial mater enhancement, and cerebral hernia were observed. In contrast, our patient exhibited isolated CNS involvement, with both brain and spinal cord lesions causing dyskinesia but no other disseminated damage.

Patients infected with T. marneffei initiate an immune response in which cytokines, such as interleukin-12, interferon-γ and tumor necrosis factor are released to clear the fungus. AIGAs have been implicated in adult immunodeficiency syndromes and are associated with T. marneffei infections in some studies [13, 14]. However, AIGAs were negative in our patient, consistent with the findings of Guo et al. [15], who reported that AIGAs were negative in all 11 HIV-negative T. marneffei infected pediatric patients. Additionally, there were no abnormalities in medical history or other micro infections, cytokines, immunoglobulins, CD4 + T lymphocytes, HIV-related tests or immunodeficiency-related gene mutations in our patient. Based on the available evidence, no immunodeficiency was found, although limitations in current diagnostic technologies cannot be entirely ruled out.

The occurrence of isolated CNS infection caused by T.marneffei in immunocompetent hosts represents a rare clinical presentation. To date, only one such case has been reported in an adult [16]. The pathogenesis of this localized form of CNS infection may be explained by the following hypotheses: (1) Underlying and focal immunodeficiency: The host’s apparent immunocompetence may mask a localized or specific immunodeficiency undetectable by standard assessments. Such a defect could allow local CNS invasion by T. marneffei without triggering widespread dissemination. (2) Distinct form of localized infection: Following a transient fungemia, systemic immunity may clear the pathogen from circulation, but a compromised local immune milieu in the CNS could allow a persistent infection to establish. (3) Advancements in diagnostics: The recent application of highly sensitive techniques like NGS has improved the detection of cases that were previously undiagnosed, thereby expanding the recognized clinical spectrum to include isolated CNS infection.

Owing to its nonspecific and diverse clinical manifestations, T.marneffei is often misdiagnosed as tuberculosis, cryptococcosis, viral or bacterial infections, or hematological diseases. Delayed diagnosis is more common in non-HIV-infected patients, leading to higher mortality rates compared to HIV-infected individuals. In our literature review, all 3 non-HIV infected children with T. marneffei infection died due to rapid neurological deterioration and severe systemic damage. Early diagnosis is highly important for preventing disease aggravation and improving patient prognosis. However, traditional culture-based diagnosis takes up to 7–14 days for identification, which is slow and insensitive. Mp1p antigen detection has emerged as a promising method for rapid diagnosis, particularly in HIV/AIDS patients with low CD4 + counts [17]. It has been shown to be superior to blood and urine culture in sensitivity. Although CSF Mp1p antigen detection was not performed in our case, a report by Li et al. [18] in 2024 demonstrated its utility in diagnosing T. marneffei CNS infection in an HIV-positive woman, offering valuable insights for future cases. Further studies are needed to validate the role of Mp1p in CNS T. marneffei infection. mNGS of pathological tissue has proven to be a rapid and effective diagnosis tool, especially in non-HIV-infected patients [19]. In our patient, the blood and initial CSF culture were negative, while culture of the spinal cord took 14 days to yield positive results. In contrast, mNGS provided a diagnosis within 1 day, highlighting its potential as a rapid and accurate diagnostic method compared to traditional microbial cultures. We recommend the early use of mNGS in non-HIV-infected patients presenting with unexplained clinical manifestations and poor response to conventional treatments. Early etiological diagnosis can mitigate the life-threatening consequences of disseminated T. marneffei infection.

Timely and appropriate antifungal therapy is also crucial for improving prognosis. Currently, there are no g standardized treatment guidelines for T. marneffei infection in pediatric patients. Successful treatment typically requires long-term antifungal therapy. Studies [20, 21] suggest that amphotericin is effective for treating T. marneffei infection, and that amphotericin liposomes have greater permeability of the blood-brain barrier and are more effective for treating the CNS infection. Voriconazole, with its lower nephrotoxicity and oral administration option, is a suitable choice for consolidation therapy. In our case, treatment with amphotericin B liposomes and voriconazole led to substantially improvement in the patient’s clinical symptoms, physical examination and CNS imagines. And the parents expressed great gratitude for our prompt diagnosis and effective treatment.

Conclusion

T. marneffei infection should be considered in immunocompetent pediatric patients with isolated CNS symptoms even in nonendemic areas, particularly when unexplained syndromes and poor treatment are observed. Increased awareness of T. marneffei isolated CNS infection in HIV negative pediatric patients from nonendemic area by pediatricians can facilitate timely diagnosis and treatment. Furthermore, mNGS is a valuable tool for rapid diagnosis of T. marneffei infection, potentially reducing mortality and improving prognosis.

Abbreviations

T. marneffei

Talaromyces marneffei

HIV

Human immunodeficiency virus

CNS

Central nervous system

CSF

Cerebrospinal fluid

mNGS

Metagenomic next-generation sequencing

MRI

Magnetic resonance imaging

AIGA

Anti-interferon-γ autoantibodies

PAS

Periodic Acid Schiff

T2-Flair

T2-Flair-weighted

T1WI+C

Contrast-enhanced T1-weighted

Authors’ contributions

GXS wrote the manuscript, and CYZ, LHJ, XZ and FG provided revisions of the manuscript, all authors approved the final version of the manuscript.

Funding

Not applicable.

Data availability

The data used during the current study available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

This case report was conducted in accordance with the Helsinki Declaration. This study was approved by the Ethics Committee of Children′s Hospital, Zhejiang University School of Medicine (2025-IRB-0177-P-01). Written informed consent to participate in the study was obtained from the parents of the patient.

Consent for publication

Written informed consent for publication of this case report was obtained from parents of the patient.

Competing interests

The authors declare no competing interests.