A Case of Acute Cerebral Aspergillosis Complicating Influenza A/H1N1pdm 2009
In October 2009, a 24-year-old man was admitted to our hospital with decreased mental status. The patient had been diagnosed with type 1 diabetes mellitus 5 years before admission but was not followed-up. He was generally in good health until 5 days before admission, when cough and sore throat occured. He was tested for the influenza A/H1N1pdm 2009 by reverse transcription polymerase chain reaction (RT-PCR), and the result was positive 1 day before admission. Therefore, the patient was administered oseltamivir. The following day, his family reported him exhibiting mental confusion and unusual behavior including walking around naked and being unable to make eye contact during conversation.\nUpon examination, the patient's blood pressure was 151/97 mmHg, pulse was 122 beats per minute, temperature was 36.0℃, and respiratory rate was 28 breaths per minute. The patient exhibited labored breathing, and a coarse breathing sound with rales heard in both lung fields. A complete blood count showed a white cell count of 25,370/mm3 with 76.4% neutrophils. His C-reactive protein level was 43.8 mg/dL. Serum chemistry and arterial blood gas analysis showed high anion gap metabolic acidosis (pH, 6.864; pCO2, 19.9 mmHg; HCO3-, 3.5 mEq/L; and anion gap, 28), a glucose level of 532 mg/dL, and a serum creatinine level of 1.6 mg/dL. Chest radiography showed left lower lung field haziness (). Hemoglobin A1c was 16.2%.\nInitial fluid resuscitation and insulin therapy were started for diabetic ketoacidosis. The dose of oseltamivir was increased to 150 mg twice per day, and ampicillin, ceftriaxone and levofloxacin were administered as empirical antibiotics. The following day, the diabetic ketoacidosis improved, but his breathing was difficult and his mentality was drowsy. Respiratory oxygenation deteriorated, and mechanical ventilation was started. A nasopharyngeal swab tested positive for influenza A/H1N1pdm 2009 by RT-PCR on hospital day 2. Blood culture from day 1 and sputum culture from day 3 were positive for methicillin-sensitive Staphylococcus aureus(MSSA); therefore, the antibacterial agents were changed to nafcillin, ceftriaxone and levofloxacin still accompanied by oseltamivir. Corticosteroids were not administered. Over the next 4 days, the patient's renal function gradually worsened, resulting in pulmonary congestion and increased body weight. Therefore, continuous renal replacement therapy was started.\nThe patient's condition began improving with mechanical ventilation and continuous renal replacement therapy, but he did not regain consciousness. On hospital day 8, brain magnetic resonance imaging (MRI) showed diffuse leptomeningeal enhancement and multifocal infarction in the fronto-parietal cortical and subcortical white matter (). Therefore, lumbar puncture was performed. The opening pressure was 30 cmH2O, and cerebrospinal fluid (CSF) contained a white cell count of 207/mm3 (94% neutrophils), a protein concentration of 120.4 mg/dL, and a glucose concentration of 109 mg/dL (serum glucose: 110 mg/dL). Intravenous acyclovir and oral amantadine were added to his therapeutic regimen to treat possible combined viral encephalitis. The remaining antibacterial agents were changed to nafcillin and meropenem. The PCR results of the CSF were negative for cytomegalovirus, herpes simplex virus, varicella zoster virus, enterovirus, and influenza A/H1N1pdm 2009. The bacterial culture of the CSF was sterile. CSF analysis and MRI results were suggestive of meningitis and arterial infarction. Transthoracic echocardiography was normal. The antiviral agents oseltamivir, acyclovir, and amantadine and antibacterial agents nafcillin and meropenem were continued. On hospital day 10, the patient began regaining consciousness. He could answer questions by nodding but could not move his arms or legs. On hospital day 14, follow-up CSF analysis showed a white cell count of 310/mm3 (64% neutrophils and 2% lymphocytes) and a protein concentration of 316 mg/dL. The patient still had intermittent fever and chilling, but his general condition continued to improve. Mechanical ventilator and continuous renal replacement therapy were eventually ceased. His cognitive function improved but muscle strength in all 4 extremities showed limited improvement; on the basis of a 5-point muscle power scale, the right and left sides were assigned scores of 1 and 3 points, respectively.\nOn hospital day 27, the patient exhibited sleeping tendencies, and his motor power decreased further. MRI of the brain was repeated to evaluate the previous cerebral lesions. The results showed newly developed multiple rim-enhancing mass lesions in the cortical and subcortical white matter of fronto-pariental lobe, right cerebellum, and left upper medulla (). The level of diffusion restriction in the MRI was variable, suggestive of fungal origin. On hospital day 29, surgical drainage of the frontal cerebral abscess was performed. Gomori methenamine-silver stain and periodic acid-Schiff stain of the surgical specimen revealed a few degenerating fungal hyphae (). Culture of the aspirated abscess indicated the presence of A. fumigatus. Serum galactomannan assay result was negative. A single culture of transtracheal aspiration performed one month after admission was positive for A. fumigatus. Chest computed tomography scan showed multifocal bronchiectasis in the right middle lobe and lingular segment of the left upper lobe. Bronchoscopy was not performed.\nAfter an initial 2 days of amphotericin B deoxycholate, intravenous voriconazole 240 mg twice per day was started. After 4 weeks of therapy, voriconazole was changed to liposomal amphotericin B with 3 mg/kg/day owing to elevated liver enzymes. After 3 weeks, the antifungal agent was switched to oral voriconazole 200 mg twice per day, which was continued for 11 weeks. Voriconazole was subsequently discontinued because of recurrent Clostridium difficile-associated diarrhea, and the patient was followed-up without antifungal therapy. The patient's medical condition was stabilized with clear mental awareness and wheel chair ambulation. However, right hemiparesis persisted. He was followed-up for 2 years and showed no evidence of recurred aspergillosis by both clinical assessment and brain imaging during this period ().