Aspergillus flavus-Induced Brain Abscess in an Immunocompetent Child Case report

Intracranial aspergillosis is an extremely rare manifestation of invasive aspergillosis in immunocompetent children and is associated with high morbidity and mortality. We report a 12-year-old immunocompetent male child who was referred to the King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia, in May 2010 after a sudden-onset headache and loss of consciousness. Brain imaging revealed a large right space-occupying occipital lesion and the patient underwent a craniotomy and resection. Histopathology of the lesion revealed necrotising granulomatous fungal encephalitis with many hyphae engulfed by multinucleated giant histiocytes. Two days later, a computed tomography scan showed debulking of the fungal mass and the patient was discharged on oral voriconazole. However, imaging at a six-week follow-up showed progression of the abnormality. A residual or persistent fungal brain lesion was suspected. Further neurosurgical resection of the lesion was performed and cultures showed growth of Aspergillus flavus. The patient was treated successfully with antifungal therapy over the following two years.

At a six-week follow-up appointment, the patient underwent CT and MRI scans of the brain which showed a progression of the dense solid marginal tissue abnormality.The enhancement was consistent with a granulomatous tissue abnormality [Figure 2A].A residual or persistent fungal brain lesion was suspected and the patient subsequently underwent surgical exploration with further resection of the lesion.The histopathology remained consistent with that of the first resected brain lesion; however, cultures showed A. flavus growth.Oral administration of voriconazole was substituted for intravenous administration (6 mg/kg every 12 hours).Two days later, a postoperative CT scan showed a slight nonspecific enhancement in the periphery of the resected area.The patient was discharged with a prescription for oral voriconazole (6 mg/kg every 12 hours).This report describes an invasive Aspergillus-induced brain abscess in an immunocompetent patient with no history of trauma.

Case Report
A previously healthy 12-year-old male child was referred to the King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia, in May 2010 after a sudden-onset headache and loss of consciousness for 15 minutes.He had no convulsions, abnormal movements, eye abnormalities, vision impairment, fever, vomiting or skin rashes.In addition, he had no history of trauma.On examination, the patient was stable and interactive with no obvious neurological deficits.Computed tomography (CT) of the brain showed a right occipital space-occupying lesion, suspected to be a tumour.The nasal sinuses were clear.His complete blood count (haemoglobin: 135 g/L; white blood cell count: 6.4 x 10 9 /L; neutrophil count: 2.51 x 10 9 /L; eosinophils: 0.47 x 10 9 /L; platelet count: 333 x 10 9 /L) and erythrocyte sedimentation rate (3 mm/hour) were normal.Magnetic resonance imaging (MRI) of the brain revealed a large right occipital mass with heterogeneous enhancement and perifocal oedema in the right temporal and parietal lobes.The right occipital horn was compressed and there was a midline shift to the left [Figure 1A].A preoperative diagnosis of a brain tumour was made.
The patient underwent a craniotomy and resection of the brain lesion.Histopathology examination of the lesion revealed necrotising granulomatous fungal encephalitis with many hyphae engulfed by multinucleated giant histiocytes.No cultures  In the current case, the patient had invasive CNS aspergillosis without paranasal sinus involvement and with no identifiable immune defects.Although he had negative Aspergillus serum galactomannan antigens, this negative result does not exclude a diagnosis of invasive aspergillosis. 13Culture supernatants of A. flavus have demonstrated lower reactivity, with lower galactomannan concentrations. 14Negative results could be due to factors related to the host, the assay or the fungus itself.One of the blood investigations which can be used to detect Aspergillus is the enzyme-linked immunosorbent assay Platelia ™ Aspergillus EIA (Bio-Rad Laboratories, California, USA); this assay is most favourable in patients with haematological malignancies, especially those who have undergone a haematopoietic stem cell transplant and are neutropaenic. 15t is not clear how the patient in the present case developed the brain abscess.Although no immune defects were identified, he may nevertheless have been suffering from a rare form of immunodeficiency, such as an interleukin (IL)-4 or IL-6 deficiency; suppression of monocytes and T helper cells and interferon-gamma (IFN-γ) responses can lead to severe Aspergillus infections. 13,16A previous case report has indicated the beneficial role of IFN-γ treatment in combination with antifungal drugs in managing a patient with an A. fumigatus-induced brain abscess. 17

Conclusion
Persistent cerebral Aspergillus-induced abscesses in immunocompetent patients are extremely rare and the clinical and radiological features of these cases may be similar to primary or secondary neoplasms or other forms of infection.Health professionals should therefore be aware of the symptoms of Aspergillusinduced brain abscesses, as early detection and appropriate treatment is necessary to ensure positive patient outcomes.
A one-month follow-up MRI scan of the patient showed resolution of the solid enhancing parenchymal abnormality [Figure 2B].Subsequent MRI scans were performed at regular intervals, including four, six, 18 and 24 months after the second resection.After eight months of oral voriconazole treatment, (1,3)-beta-D-glucan levels were undetectable.Repeated assays for Aspergillus galactomannan also revealed undetectable levels.Antifungal treatment was discontinued after two years as there was on-going evidence of the complete resolution of the brain lesion by May 2013.

Discussion
In general, CNS aspergillosis-particularly invasive aspergillosis-is rarely observed in immunocompetent patients. 2The brain is remarkably resistant to fungal infections due to its abundant blood supply and the relatively impermeable blood-brain barrier.Nevertheless, despite the existence of anatomical and functional barriers which protect the brain and subarachnoid space, fungal pathogens can breach these barriers under certain conditions. 2 Persistent cerebral Aspergillus abscesses in immunocompetent patients may exhibit clinical and radiological features similar to primary or secondary neoplasms or other forms of infection. 10Only a few cases of invasive Aspergillus brain abscesses have been reported; of these, most involved adult rather than paediatric patients. 11e management of cerebral fungal abscesses remains controversial.Antifungal therapy alone reportedly has a poor outcome for patients with CNS aspergillosis, with a high mortality rate of >90%; this is likely due to the poor penetration of the CNS by the antifungal drugs. 2 Other research has indicated that surgical resection of focal CNS aspergillosis lesions reduces the mortality rate from 64% to 39%. 2 Overall, voriconazole seems to be the drug of choice for the treatment of aspergillosis. 2 In the current case, the patient showed clinical and radiological improvement with intravenous voriconazole administration and surgical resection.However, imaging scans at a six-week follow-up revealed that the lesion had progressed despite the continued administration of oral voriconazole; this is unusual due to the high bioavailability level (82.6%) of oral voriconazole. 12his uncommon occurrence may have been due to poor medication compliance on the part of the patient or incomplete resection which resulted in the slow progression of the remnant lesion.Unfortunately, no facilities were available to monitor the patient's exact voriconazole drug levels.

Figure
Figure 1A&B: A: Magnetic resonance imaging of brain of a 12-year-old immunocompetent child showing a large right occipital mass (arrow) with heterogeneous enhancement, perifocal oedema in the right temporal and parietal lobes and a midline shift to the left.The nasal sinuses were clear.B: Post-resection computed tomography showing debulking of the rightsided occipital fungal mass (arrow) two days later.Note the regression of the perilesional reactive changes with a persistent mild midline shift to the left and regression of the right trigone effacement.

Figure 2A&B :
Figure 2A&B: A: Magnetic resonance imaging (MRI) of the brain of a 12-year-old immunocompetent child six weeks after an initial resection of a right occipital fungal mass showing progression of the dense solid marginal tissue abnormality (arrow) and enhancement consistent with a granulomatous tissue abnormality.B: Brain MRI one month after the second resection showing partial resolution of the solid parenchymal abnormality (arrow).