Next-Generation Sequencing Confirmed the Diagnosis of Isolated Central Nervous System Infection Caused by Talaromyces marneffei in an Immunocompetent Patient

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Next-Generation Sequencing Confirmed the Diagnosis of Isolated Central Nervous System Infection Caused by Talaromyces marneffei in an Immunocompetent Patient

Talaromyces marneffei (formerly Penicillium marneffei), a thermally dimorphic fungus, was first identified in 1956 from a wild Chinese bamboo rat in Vietnam. Historically associated with immunocompromised individuals, particularly those with HIV, this pathogen has recently emerged as a rare but life-threatening cause of infection in immunocompetent hosts. This case report details the diagnostic challenges, clinical course, and successful management of a 33-year-old immunocompetent woman in Guangdong, China, who developed isolated central nervous system (CNS) infection due to T. marneffei. The case underscores the critical role of next-generation sequencing (NGS) in identifying elusive pathogens and highlights the expanding geographic and clinical spectrum of this fungal infection.

Case Presentation

A previously healthy 33-year-old woman presented with a 4-day history of bilateral temporal headaches and dizziness on February 19, 2018. Initial symptoms progressed rapidly: by February 23, she experienced blurred vision, vomiting, and altered consciousness. Admission to a local hospital revealed elevated intracranial pressure (240 mmH 2O) via lumbar puncture, with cerebrospinal fluid (CSF) analysis showing pleocytosis (176 cells/µL, predominantly lymphocytes), hypoglycorrhachia (1.1 mmol/L; normal: 2.8–4.5 mmol/L), and elevated protein (0.87 g/L; normal: 0.15–0.45 g/L). Cranial magnetic resonance imaging (MRI) with contrast demonstrated diffuse meningeal enhancement and T2-weighted hyperintensities in white matter. Suspecting tuberculous meningoencephalitis, empiric antitubercular therapy (isoniazid, rifampicin, pyrazinamide, ethambutol) was initiated.

Despite treatment, her condition deteriorated over the next week. She developed recurrent seizures, fever (39°C), and a Glasgow Coma Scale (GCS) score of 5 (E1V1M3). Transfer to Nanfang Hospital revealed worsening intracranial pressure (330 mmH 2O on repeat lumbar puncture) and persistent CSF abnormalities: glucose 0.58 mmol/L, protein normalization, and 150 cells/µL. Repeat MRI (Figure 1) showed multifocal lesions in bilateral basal ganglia, paraventricular regions, and frontotemporal lobes, alongside acute ischemic infarcts, hemorrhagic transformation, hydrocephalus, and meningeal enhancement. Magnetic resonance angiography (MRA) revealed intracranial vasculopathy characterized by luminal narrowing and wall irregularity, suggestive of vasculitis or edema-related compression.

Diagnostic Challenges

Extensive laboratory investigations excluded autoimmune disorders, HIV, syphilis, and common pathogens (herpes simplex virus, cytomegalovirus, influenza, tuberculosis, mycoplasma). Serum biomarkers for fungal infection (1,3-β-D-glucan, galactomannan) were negative. Chest CT identified bilateral pulmonary infiltrates, while abdominal imaging was unremarkable. Traditional microbiological methods—including CSF, sputum, blood, and bone marrow cultures—failed to isolate pathogens.

The patient’s clinical trajectory defied empirical antitubercular therapy, prompting suspicion of an atypical or fungal etiology. Given the endemicity of T. marneffei in Southern China and the patient’s residence in Guangdong, NGS was deployed as a diagnostic rescue.

Next-Generation Sequencing in Diagnosis

CSF samples underwent NGS (Beijing Genome Institute) using the TIANamp Micro DNA Kit (Tiangen Biotech). To enhance fungal DNA yield, CSF was pretreated with glass beads (Sigma) prior to extraction. Sequencing identified 49 reads aligning to T. marneffei, confirming the diagnosis on the seventh hospital day. Repeat NGS one month later detected six residual reads, validating the pathogen’s persistence despite therapy.

Clinical Management and Outcome

Antitubercular drugs were discontinued, and voriconazole (a broad-spectrum triazole antifungal) was initiated. Within three weeks, CSF parameters normalized: opening pressure decreased to 230 mmH 2O, glucose rose to 2.86 mmol/L, and cell count stabilized at 7 cells/µL. Neurological improvement followed gradually, with GCS improving to 8 (E4VTM3) after 2.5 months. The patient was transferred to rehabilitation with sustained clinical stability.

Discussion on Talaromyces marneffei Infections

T. marneffei predominantly infects immunocompromised hosts, particularly HIV-positive individuals in Southeast Asia. Disseminated disease typically involves the reticuloendothelial system, lungs, and skin. Isolated CNS infection, as seen here, is exceptionally rare—only 5% of non-HIV-infected patients exhibit neurological involvement. This case represents the first documented instance of isolated CNS T. marneffei infection in an immunocompetent host, expanding the clinical phenotype of this pathogen.

The route of transmission remains enigmatic. While bamboo rat exposure is theorized as a zoonotic reservoir, this patient denied such contact. Environmental acquisition via inhaled conidia is plausible, with subsequent hematogenous dissemination to the CNS. The absence of pulmonary lesions on initial imaging suggests either rapid CNS seeding or resolution of primary pulmonary foci before hospitalization.

Implications for Clinical Practice

  1. Diagnostic Pitfalls: T. marneffei’s mimicry of tuberculous meningitis—both presenting with chronic meningitis, vasculitis, and basal ganglia involvement—underscores the need for heightened suspicion in endemic regions. Traditional diagnostics (culture, serology) exhibit poor sensitivity in CNS infections, necessitating advanced techniques like NGS.
  2. Role of NGS: This case highlights NGS as a paradigm-shifting tool for pathogen detection. Unlike targeted PCR, NGS provides unbiased sequencing of all nucleic acids in a sample, enabling diagnosis within 24 hours. Its utility is amplified in culture-negative, antibody-negative, or rare infections.
  3. Therapeutic Considerations: Voriconazole’s success aligns with its superior CNS penetration compared to amphotericin B. Early antifungal escalation, guided by NGS, was pivotal in reversing disease progression.

Conclusion

The rising incidence of T. marneffei infections in non-endemic regions and immunocompetent populations necessitates global awareness. This case illustrates the lethal potential of CNS involvement and the indispensable role of NGS in diagnosing occult fungal pathogens. Clinicians must integrate molecular diagnostics into routine practice when facing atypical neurological presentations, particularly in regions where T. marneffei is endemic.

doi.org/10.1097/CM9.0000000000000593

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