Cryptococcus gattii meningitis with a pulmonary cryptococcoma and cerebrospinal fluid epstein-barr virus reactivation: A diagnostic challenge

Abstract

This report describes a case of Cryptococcus gattii meningitis in an immunocompetent man that was initially misdiagnosed as Epstein–Barr virus meningitis and treated with steroids. The diagnostic challenges and radiographic findings are presented. It highlights the importance of maintaining a high index of suspicion for C. gattii meningitis in immunocompetent individuals presenting with subacute meningitis and pulmonary masses.

Background

Cryptococcus gattii is an emerging pathogen that can cause severe meningoencephalitis and pulmonary disease in immunocompetent individuals [1]. It is distinct from the more common Cryptococcus neoformans which typically affects immunocompromised individuals [2]. Pulmonary involvement, typically in the form of cryptococcomas or granulomatous lesions, occurs in up to 67% of C. gattii infections and may be completely asymptomatic, hindering clinical recognition [3]. Diagnosis is often delayed owing to its indolent and nonspecific presentation. The advent of advanced cerebrospinal fluid (CSF) diagnostics such as targeted next-generation sequencing (tNGS) has improved pathogen detection but introduces complexity in interpreting results, particularly when ubiquitous viruses such as Epstein–Barr virus (EBV) are present [4.], [5.]. Empirical corticosteroid use for suspected inflammatory conditions can transiently improve symptoms, while obscuring underlying subacute fungal infections [6].

We report a case of C. gattii meningitis accompanied by a pulmonary cryptococcoma and CSF EBV reactivation, to illustrate these diagnostic challenges.

Case report

A 54-year-old man was admitted to our hospital with a 10-day history of progressive global headache, fever (up to 38.5°C), nausea, and a single episode of vomiting. Ibuprofen provided partial relief of the fever. He had no focal neurological deficits or signs of altered consciousness but reported profound malaise and anorexia. The patient was a chronic smoker (20 cigarettes/day for 30 years) and reported being a long-term social drinker without daily or excessive alcohol use. The patient was a farmer residing in a rural area of Hebei Province, China-a region characterized by a temperate continental climate. His daily activities involved frequent outdoor agricultural work on forested hillsides. He did not have a history of immunosuppressive conditions, immunosuppressive medication use, connective tissue disease, recent travel, or significant environmental exposures. Initial evaluation at another hospital had shown no acute intracranial abnormalities on brain magnetic resonance imaging (MRI) but identified left lower lobe masses on chest computed tomography (CT).

On admission, the patient was febrile with meningeal signs. Laboratory investigations revealed chronic hepatitis B virus (HBV) infection (hepatitis B surface antigen positive, and HBV DNA load 4.02 × 10⁵ IU/mL). Tests for HIV, syphilis, thyroid dysfunction, and common tumor markers were negative. Abdominal ultrasound showed no cirrhosis or other abnormalities. No evidence of immunodeficiency was identified. Entecavir was initiated for HBV management. Enhanced MRI of the head showed focal leptomeningeal enhancement, suggestive of meningitis(Figure 1 A-B). A chest CT scan showed masses in the left lower lobe of the lung(Figure 1 C-D). Given the radiographic appearance of the pulmonary masses, malignancy could not be excluded. Percutaneous lung biopsy and bronchoscopy with bronchoalveolar lavage (BAL) were considered and discussed with the patient. However, the patient and his family declined these invasive procedures. Lumbar puncture revealed normal opening pressure (130 mmH₂O), lymphocytic pleocytosis (white blood cell count 343 × 10⁶ cells/L, 92% mononuclear), and elevated protein (64.4 mg/dL; reference range: 15–45 mg/dL) and low glucose (43.4 mg/dL; reference range: 50–80 mg/dL) and normal chloride (122.1 mmo/L; reference range:120–132 mmo/L) levels. At the first lumbar puncture, India ink, acid-fast, and Gram staining were all negative. CSF tNGS was sent as part of the diagnostic workup. Routine fungal culture, processed in parallel, ultimately returned negative as well. Initial CSF tNGS detected EBV DNA (46 sequences/100,000 reads), but no fungal, bacterial, or other viral pathogens. Unfortunately, no concurrent EBV viral load testing on blood was performed, as this was not part of our routine diagnostic protocol for suspected meningitis. The patient was provisionally diagnosed with viral meningitis and treated with intravenous acyclovir and dexamethasone (10 mg daily). The steroid was administered for only 5 days, resulting in transient symptom relief.

Figure1.

Brain MRI and Chest CT Findings of the Patient. (A-B) Axial post-contrast FLAIR MRI shows focal leptomeningeal enhancement in the occipital (A) and parietal (B) lobes. (C-D) Initial chest CT reveals two spiculated masses (cryptococcomas) in the left lower lobe. (E-F) Follow-up chest CT after two months of antifungal therapy demonstrates marked resolution of the pulmonary lesions. (G-H) Follow-up chest CT after six months of therapy shows further reduction of the lesions. FLAIR = fluid-attenuated inversion recovery.

Three days after steroid discontinuation, his symptoms recurred. A second lumbar puncture was performed (opening pressure 170 mmH₂O). CSF analysis showed persistent inflammation with persistent lymphocyte pleocytosis (white blood cell count 115 × 10⁶ cells/L, 77% mononuclear),a mildly elevated protein level (47.4 mg/dL), a normal glucose level (71.0 mg/dL), and a decreased chloride level (117 mmol/L). India ink staining was positive on the same day, raising suspicion of cryptococcal infection. Cryptococcal antigen testing and tNGS were promptly performed. Repeat tNGS detected C. gattii (273 sequences/100,000 reads) and persistent EBV (65 sequences). A cryptococcal antigen test was positive(>100 μg/L) in both CSF and serum, and the presence of C. gattii in the CSF was confirmed by culture and Alcian blue staining. Acyclovir was discontinued, and no specific anti-EBV treatment (e.g., ganciclovir) was given. Aggressive antifungal therapy was initiated with intravenous amphotericin B deoxycholate (35 mg daily, 0.8 mg/kg/day) and oral flucytosine (1 g every 6 h) for 6 weeks, followed by consolidation therapy with oral fluconazole (600 mg/day).The patient tolerated the induction therapy well with no signs of clinically significant kidney or liver injury.

The patient's clinical condition steadily improved. Serial CSF analyses showed normalization of pressure, decreasing cell counts, and declining cryptococcal antigen titers, CSF cultures remained negative during follow-up (Table 1). The patient recovered fully with no neurological sequelae at discharge. Two months after antifungal therapy, the pulmonary lesions showed significant reduction (Fig. 1 E-F); after six months of treatment, the lesions further diminished but did not completely resolve, thereby confirming them as cryptococcomas (Fig. 1 G-H).

Table 1.

Evolution of key cerebrospinal fluid parameters following the initiation of antifungal therapy.

Date	Opening Pressure (mmH₂O)	White Cell Count (×10⁶/L)	Mononuclear Cells (%)	Protein (mg/dL)	Glucose (mg/dL)	Chloride (mmol/L)	CSF Culture	CSF CrAg*(μg/L)	Serum CrAg*(μg/L)
Day1 (On admission)	130	343	92	64.4	43.4	122.1	Negative	N/A†	N/A†
Day 15	170	115	77	47.4	71.0	117.0	Positive (C. gattii)	> 100	> 100
Day 56	130	79	89	56.2	35.7	122.2	Negative	71.56	> 100
Day 66	130	90	95	73.5	34.6	119.4	Negative	47.93	> 100

N/A†:Not available. Test was not performed at this time point.

^*CrAg: Cryptococcal capsular antigen. Reference range: 0–8 μg/L.

Discussion

This case presents a multifaceted diagnostic challenge. The initial detection of EBV DNA by tNGS, coupled with a transient response to antivirals and steroids, led to a mistaken initial presumptive diagnosis of viral meningitis. The relapse on steroid withdrawal was the critical clue prompting further investigation, which revealed C. gattii as the true pathogen. This highlights a key lesson that a therapeutic response, especially to anti-inflammatory agents, does not confirm the etiology and can mask occult infections. Clinicians should exercise caution when using corticosteroids for suspected viral meningitis, especially when initial diagnostics are inconclusive or the clinical response is inconsistent.

The interpretation of EBV detection in CSF was another key challenge. EBV is latent in over 90% of adults worldwide, and reactivation can occur during systemic inflammation, infection, or immunosuppression [7.], [8.]. In this case, persistent EBV DNA in the CSF, without clinical or laboratory features of primary EBV encephalitis (e.g., encephalopathy, focal neurological deficits, elevated EBV viral load), suggests that EBV reactivation was triggered by C. gattii-induced systemic inflammation. This bystander role of EBV highlights the need to consider molecular findings according to the clinical context, traditional diagnostics (e.g., antigen testing, culture), and response to therapy. Unlike tNGS, cryptococcal antigen testing is highly sensitive and specific for cryptococcal infection（sensitivity: 97.7%–100%; specificity: 99.1%–99.9% in serum and CSF, respectively, and provided rapid confirmation of the primary pathogen [9]. The initial failure of tNGS to detect C. gattii may be attributable to a low fungal burden in the first CSF sample or technical limitations of the assay, highlighting the value of combining molecular and traditional diagnostic tests. An alternative possibility is that EBV was the initial pathogen, and corticosteroids triggered dissemination of pre-existing pulmonary cryptococcosis. However, this is less likely because: (1) the patient was immunocompetent and received only a short course of steroids; (2) EBV was detected at low abundance (46 and 65 reads/100 K) compared to C. gattii (273 reads); and (3) antifungal therapy alone achieved complete resolution. While EBV as an initial trigger cannot be entirely excluded, the available evidence favors C. gattii as the primary pathogen.

The incidence of C. gattii infection is higher in tropical and subtropical regions, but has increasingly been reported in temperate regions [1]. The patient’s rural residence and frequent outdoor activities in mountainous areas may have exposed him to environmental reservoirs of C. gattii such as decaying woody material and soil. Additionally, he had a smoking history, which is a known risk factor for C. gattii infection, as smoking impairs pulmonary mucosal immunity and mucociliary clearance, facilitating fungal colonization and dissemination [10]. Although Chronic HBV infection does not cause overt immunosuppression, it may have altered his immune surveillance, as chronic viral infections can modulate host immune response to other pathogens [11].

Pulmonary involvement is a hallmark of C. gattii infection, occurring in up to 67% of cases [3]. Unlike the more common C. neoformans, which typically causes ill-defined nodular or infiltrative lesions, C. gattii often forms distinct, well-circumscribed cryptococcomas that may be misdiagnosed as primary or metastatic tumors [1.], [2.], [3.]. We acknowledge the lack of histopathological confirmation of the pulmonary lesions as a limitation. However, in the context of confirmed cryptococcal meningitis and the patient‘s favorable clinical and radiographic response to antifungal therapy, the diagnosis of pulmonary cryptococcomas remains the most plausible explanation. The absence of respiratory symptoms and signs in this case highlights the importance of chest imaging in patients with C. gattii meningitis, even in the absence of respiratory signs.

Global guidelines for managing cryptococcosis recommend extended induction therapy (4–6 weeks) with amphotericin B plus flucytosine for CNS C. gattii infection, followed by consolidation and maintenance therapy with fluconazole [12]. This patient received 6 weeks of induction therapy, consistent with guidelines, and had a satisfactory therapeutic response. Notably, the CSF protein and glucose abnormalities persisted longer than clinical symptoms, reflecting the slow resolution of meningeal inflammation in cryptococcal meningitis [13]. In this patient, despite persistent positivity of serum and CSF cryptococcal antigen and ongoing CSF biochemical abnormalities, clinical improvement and negative CSF cultures indicated successful treatment. Therefore, decisions to adjust antifungal therapy should be guided by clinical response and CSF culture results rather than by persistently positive antigen titers or abnormal CSF parameters [12].

Conclusion

This case highlights the importance of maintaining a high index of suspicion for C. gattii meningitis in immunocompetent individuals presenting with subacute meningitis and pulmonary masses. Host factors such as smoking and chronic viral hepatitis may provide additional clues that the patient is at risk and should not be overlooked. Empiric corticosteroid use should be avoided in cases of meningitis unless the diagnosis is definitive, because it may mask fungal infections. EBV detection in the CSF should be interpreted cautiously. Integrated use of tNGS, cryptococcal antigen testing, and culture is critical for accurate and timely diagnosis, enabling targeted therapy and improved outcomes.

Author contributions

QXH was responsible for literature collection and sorting, study conceptualization, data curation, initial manuscript drafting, critical revision, MLN and CSP made substantial contributions to study conceptualization, data curation, initial manuscript drafting. LJC contributed to the organization and preparation of imaging and table data. LHL provided critical review and editing of the manuscript with academic and clinical logic suggestions and served as the corresponding author for all journal communication. JYL completed literature collection and sorting, and collaborated in drafting partial content of the initial manuscript. All authors read and approved the final version of the manuscript.

CRediT authorship contribution statement

Hongli Liu: Writing – review & editing, Writing – original draft. Jincheng Li: Data curation. Shanpeng Chen: Writing – original draft, Data curation, Conceptualization. Lina Ma: Writing – original draft, Data curation, Conceptualization. Xuehui Qin: Writing – review & editing, Writing – original draft, Investigation, Data curation, Conceptualization. Yali Ji: Writing – original draft, Investigation.

Patient consent statement

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. The study was conducted in accordance with institutional guidelines.

Ethical approval

Ethical approval was not required for this single retrospective case report.

Declaration of Generative AI and AI-assisted technologies in the writing process

The authors used Language Tool for grammar checking during manuscript revision. The authors take full responsibility for the final content.

Funding

None.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data availability

The data in this case report are derived from the clinical records of a single patient. Due to requirements for patient privacy and confidentiality protection, these data are not publicly disclosed. Upon reasonable request, anonymized data may be obtained from the corresponding author.