Dengue-associated invasive central nervous system aspergillosis in an immunocompetent host

INTRODUCTION

Invasive fungal infections have been well described in immunodeficient individuals. Recently, published reports have described fungal infections following dengue infection.^[1] We present a case of dengue-associated Aspergillus brain abscesses in a previously immunocompetent host.

CASE REPORT

A 35-year-old woman presented with high-grade fever accompanied by chills, rigors, and headache to a local hospital on the 3^rd day of illness. She was found to have thrombocytopenia and tested positive for dengue NS1 antigen. She responded to parenteral antipyretic agents but developed acute-onset hemiparesis on day 7 of her illness.

Non-contrast computed tomography (NCCT) brain revealed a right fronto-parietal hypodensity, while computed tomography angiogram of the head-and-neck vessels was unremarkable. Contrast-enhanced magnetic resonance imaging (CE-MRI) brain revealed a T2/fluid-attenuated inversion recovery heterogeneously hyperintense lesion in the bilateral centrum semiovale (right >left) with foci of diffusion restriction, microhemorrhages, and patchy contrast enhancement [Figure 1]. Her cerebrospinal fluid (CSF) analysis showed 8 cells (L100), protein 51 mg/dL, and glucose 69 mg/dL. She was diagnosed with acute disseminated encephalomyelitis and was treated with intravenous methylprednisolone 1 g once daily. However, after 3 days of therapy, her sensorium worsened, and she was referred to our center.

She was comatose upon admission (Glasgow Coma Scale: E4V1M2), had spasticity of all limbs (left > right), bilateral extensor plantars with neck rigidity. She was intubated and a repeat CE-MRI (6 days after her first) revealed a significant increase in lesion size with mass-effect with microhemorrhages [Figure 2]. She had lymphopenia (minimum count - 608/mL) with raised triglyceride and ferritin levels, suggestive of cytokine storm. CSF showed 15 cells (L100), protein 65 mg/dL, and sugar 76 mg/dL (corresponding blood sugar: 118 mg/dL). CSF Gram’s stain, bacterial culture, India ink, cryptococcal antigen, ZN staining, GeneXpert, VDRL, panviral polymerase chain reaction (PCR), malignant cytology, wet mount for parasites, and fungal culture were negative [Supplementary Table 1]. An atypical neuro-infection was considered (parasitic, fungal, or atypical bacterial), and she was started on a cocktail of liposomal amphotericin B, cotrimoxazole, rifampicin, meropenem, and azithromycin. She tested positive for both serum (0.8, normal value <0.5) and CSF galactomannan (4.674, normal value <0.5), but her fungal culture was negative.

Close

Figure 1:

(a) Axial T1-weighted imaging (T1-WI) shows ill-defined iso-to hypointense lesions in the bilateral centrum semiovale, with more pronounced involvement on the right side (arrow). (b) On T2-weighted imaging (T2-WI), the lesions appear heterogeneously hyperintense (arrows). (c) Diffusion-weighted imaging reveals areas of diffusion restriction (arrows) within the lesions. (d) Coronal T2-WI demonstrates lesion extension into the subcortical, deep, and periventricular white matter, along with a central cavity (arrow). (e) Axial susceptibility-weighted angiography shows multiple susceptibility foci, including some arranged around the central cavity (arrow). (f) Contrast-enhanced T1-WI highlights patchy, heterogeneous enhancement (arrows), with prominent enhancement of the central cavity wall.

Export to PPT

Close

Figure 2:

Follow-up magnetic resonance imaging demonstrates interval changes. (a) Axial T1-weighted imaging (T1-WI) shows well-defined iso-to hypointense lesions in the bilateral centrum semiovale, with significant enlargement. (b) On T2-weighted imaging, the lesions remain heterogeneously hyperintense. (c) Coronal fluid-attenuated inversion recovery reveals lesion extension into the subcortical, deep, and periventricular white matter, with additional involvement of the basal ganglia and a midline shift. (d) Diffusion-weighted imaging and (e) apparent diffusion coefficient maps show persistent diffusion restriction (arrows) within the lesions. (f) Axial susceptibility-weighted imaging SWI reveals multiple susceptibility foci, some encircling the central cavity (arrows). (g) Contrast-enhanced axial and (h) coronal T1-WI demonstrate patchy, heterogeneous enhancement, including areas of ring-like enhancement (arrows).

Export to PPT

On day 4 of her admission with us, her sensorium dropped to E1VTM1 with anisocoria (right pupil > left). The NCCT head revealed an increase in edema and midline shift, following which a decompressive hemicraniectomy with dural brain biopsy was performed. KOH-calcofluor white fluorescent staining of the brain biopsy showed septate hyphae, and histopathology showed a lymphoplasmacytic infiltrate [Supplementary Figures 1 and 2, respectively]. Further identification was done using the AsperGenius^TM multiplex real-time PCR assay (Pathonostics, Netherlands) on the brain biopsy, which came positive for Aspergillus fumigatus. Despite our best efforts, she succumbed to septic shock a day later.

DISCUSSION

Neurological complications of dengue can be due to neurotropism of the virus (encephalitis, meningitis, myelitis, or myositis), systemic complications of infections, or post-infectious complications.^[2] Invasive fungal infections can mimic these common complications and delay antifungal agent initiation, resulting in poorer outcomes.

Singhal et al. reported three cases of invasive fungal rhinosinusitis due to Aspergillus and Mucormycosis in immunocompetent hosts recovering from dengue virus infection.^[3] Sushmitha et al.^[4] and Verma et al.^[1] described one case each of post-dengue mucormycosis in an immunocompetent host. Lin et al. found two patients to be serum galactomannan positive among 10 dengue patients, both of whom were ultimately diagnosed with invasive pulmonary aspergillosis coexistent with dengue.^[5] Altaf et al. described atypical neuroimaging of fungal infections in an immunocompetent host.^[6]

Dengue virus affects macrophages, neutrophils, and dendritic cells, altering the milieu of the host’s innate immune system. Dengue-related cytokine release leads to lymphopenia. Moreover, raised interleukin-8 levels cause thrombocytopenia and neutrophil degranulation, leading to complement and coagulation pathway activation, resulting in endothelial barrier breakdown, allowing fungal spread.^[7]

CONCLUSION

Post-dengue invasive central nervous system fungal infections are being recognized in clinical practice. A high index of clinical suspicion should be considered for fungal infections in dengue patients with cytokine storm, even in immunocompetent hosts.