Cerebral and pulmonary aspergillosis, treatment and diagnostic challenges of mixed breakthrough invasive fungal infections: case report study.

BACKGROUND: Breakthrough invasive fungal infections (bIFIs) are an area of concern in the scarcity of new antifungals. The mixed form of bIFIs is a rare phenomenon but could be potentially a troublesome challenge when caused by azole-resistant strains or non-Aspergillus fumigatus. To raise awareness and emphasize diagnostic challenges, we present a case of mixed bIFIs in a child with acute lymphoblastic leukemia. CASE PRESENTATION: A newly diagnosed 18-month-old boy with acute lymphoblastic leukemia was complicated with prolonged severe neutropenia after induction chemotherapy. He experienced repeated episodes of fever due to extended-spectrum beta-lactamase-producing Escherichia coli bloodstream infection and pulmonary invasive fungal infection with Aspergillus fumigatus (early-type bIFIs) while receiving antifungal prophylaxis. Shortly after pulmonary involvement, his condition aggravated by abnormal focal movement, loss of consciousness and seizure. Cerebral aspergillosis with Aspergillus niger diagnosed after brain tissue biopsy. The patient finally died despite 108-day antifungal therapy. CONCLUSIONS: Mixed bIFIs is a rare condition with high morbidity and mortality in the patients receiving immunosuppressants for hematological malignancies. This case highlights the clinical importance of Aspergillus identification at the species level in invasive fungal infections with multiple site involvement in the patients on antifungal prophylaxis.

Invasive rhino-orbital-cerebral aspergillosis in an immunocompetent patient.

INTRODUCTION: Rhino-orbital-aspergillosis (ROA) is a rare but serious disease in immunocompetent patients. Diagnosis is often delayed due to the absence of specific clinical symptoms. We describe the case of a patient who presented initially with ROA which spread progressively to the right ethmoid-sphenoid sinuses and then to the brain. OBSERVATION: A 61-year-old patient with a history of well-controlled diabetes presented with a sudden severe decrease in right visual acuity. Cerebral MRI showed the presence of an infiltrate in the right orbital apex extending to the homolateral cavernous sinus without any cerebral involvement. A diagnosis of right orbital myositis was made and corticosteroid therapy was started. His symptoms worsened progressively leading to quasi-blindness. A new MRI showed the development of right sphenoid-ethmoid osteolytic lesions. A fungal aetiology was suspected and tests for fungal biomarkers found a ß-(1-3)-D-glucan level of 99pg/ml but negative galactomannan. An ethmoid biopsy was performed for histological and mycological investigations, including the detection of Aspergillus DNA by qPCR. qPCR was positive and culture resulted in the isolation of multi-sensitive Aspergillus fumigatus. Treatment was initiated with voriconazole. Due to persistence of blindness and the appearance of a lesion extending to the right frontal lobe, surgical excision was performed followed by antifungal treatment for a total duration of 1year. The patient is currently stable, but has persistence of blindness in the right eye. CONCLUSION: Invasive ROA is a rare but serious disease in immunocompetent patients which should be evoked in the differential diagnosis of a tumour or vasculitis. Early diagnosis is essential for optimal management.

Successful and safe long-term treatment of cerebral aspergillosis with high-dose voriconazole guided by therapeutic drug monitoring.

We report the case of a patient who had cerebral aspergillosis after otorhinolaryngologic surgery and who was successfully and safely treated with high-dose voriconazole (200 mg q6h) for more than 1 year thanks to a TDM-guided approach coupled with pharmacological review and with genotyping of CYP2C19 polymorphisms. The findings support the idea that personalized medicine based on TDM coupled with the need of avoiding drug-drug interactions may be helpful for maximizing the net benefit (probability of efficacy vs. probability of adverse events) of voriconazole in the management of long-term treatment of cerebral aspergillosis.

Acute Stroke as First Manifestation of Cerebral Aspergillosis.

OBJECTIVES: To describe the neurological manifestations of invasive aspergillosis presenting with a focal neurological deficit compatible with an acute stroke. MATERIALS AND METHODS: Retrospective analysis of a clinical series of patients between 2011 and 2017 with invasive aspergillosis and neurological symptoms compatible with an acute brain stroke. Clinical and epidemiological data, microbiological results, radiological findings, treatment, and course were recorded. RESULTS: Five patients were selected with a mean age of 55.4years. All patients were immunosuppressed. In 4, systemic infection was unknown. In every case, neurology on call was alerted because of acute focal neurological symptoms. None of the patients received revascularization procedures. Galactomannan antigen was positive in all of the patients and culture was positive in 3. Mortality was 100% despite specific antifungal treatment. CONCLUSIONS: Acute stroke can be the first manifestation of disseminated aspergillosis. This form of presentation was frequent in our series and should be suspected in immunocompromised patients with acute neurological deficits.

Intracranial Fungal Infection After Solid-Organ Transplant.

Neurologic complications after solid-organ transplant reveal a great spectrum of pathologies. Intracranial hemorrhages, cerebral ischemic lesions, infarctions, lymphoproliferative disorders, and infections, including aspergillosis, have been observed after liver transplant. Fungi constitute nearly 5% of all central nervous system infections, mainly occurring in immunocompromised patients. The most common causative agent is Aspergillus species. It presents either as maxillary sinusitis or pulmonary infection. Brain involvement of Aspergillus carries a high rate of mortality. Aspergillosis presents in the forms of meningitis, mycotic aneurysms, infarctions, and mass lesions. Aspergillosis does not have a specific radiologic appearance. Parenchymal aspergillosis has heterogenous signal intensity (hypointense on T1-weighted and hyperintense on T2-weighted images). Here, we present 3 patients who underwent solid-organ transplant and developed central nervous system aspergillosis. Different modalities of neurosurgical intervention were performed in combination with chemotherapy as part of their fungal therapy.

Successful Treatment of Combined Aspergillus and Cytomegalovirus Abscess in Brain and Lung After Liver Transplant for Toxic Fulminant Hepatitis.

Invasive aspergillosis is one of the most important and fatal complications after liver transplant, especially in patients with involvement of the central nervous system. We present a case of a patient who developed cerebral and pulmonary aspergillosis, coinfected with cytomegalovirus, after liver transplant for toxic fulminant hepatitis. The patient was treated successfully with neurosurgical intervention and voriconazole. Voriconazole is considered more effective in cerebral aspergillosis than other anti-fungal agents due to the greater penetration into central nervous system and higher cerebrospinal fluid and brain tissue levels.

Chronic Invasive Aspergillus Sinusitis and Otitis with Meningeal Extension Successfully Treated with Voriconazole.

Invasive aspergillosis (IA) is a severe disseminated fungal disease that occurs mostly in immunocompromised patients. However, central nervous system IA, combining meningitis and skull base involvement, does not occur only in groups with classic risk factors for IA; patients with chronic renal failure and diabetes mellitus are also at risk for more chronic forms. In both of our proven IA cases, voriconazole monotherapy was effective without surgery, and cerebrospinal fluid and serum 1,3-ß-d-glucan test results were initially positive, in contrast to galactomannan antigen results.

Thoracic spinal cord intramedullary aspergillus invasion and abscess.

Invasive central nervous system aspergillosis is a rare form of fungal infection that presents most commonly in immunocompromised individuals. There have been multiple previous reports of aspergillus vertebral osteomyelitis and spinal epidural aspergillus abscess; however to our knowledge there are no reports of intramedullary aspergillus infection. We present a 19-year-old woman with active acute lymphoblastic leukemia who presented with several weeks of fevers and bilateral lower extremity weakness. She was found to have an intramedullary aspergillus abscess at T12-L1 resulting from adjacent vertebral osteomyelitis and underwent surgical debridement with ultra-sound guided aspiration and aggressive intravenous voriconazole therapy. To our knowledge this is the first reported case of spinal aspergillosis invading the intramedullary cavity. Though rare, this entity should be included in the differential for immunocompromised patients presenting with fevers and neurologic deficit. Early recognition with aggressive neurosurgical intervention and antifungal therapy may improve outcomes in future cases.

Cerebral aspergillosis in a patient with leprosy and diabetes: a case report.

BACKGROUND: Opportunistic fungi are dispersed as airborne, ground and decaying matter. The second most frequent extra-pulmonary disease by Aspergillus is in the central nervous system. CASE PRESENTATION: The case subject was 55 years old, male, mulatto, and an assistant surveyor residing in Teresina, Piauí. He presented with headache, seizures, confusion, fever and left hemiparesis upon hospitalization in 2006 at Hospital São Marcos. Five years previously, he was diagnosed with diabetes mellitus, and 17 months previously he had acne margined by hyperpigmented areas and was diagnosed with leprosy. Laboratory tests indicated leukocytosis and magnetic resonance imaging showed an infarction in the right cerebral hemisphere. Cerebrospinal fluid examination showed 120 cells/mm(3) and was alcohol-resistant bacilli negative. Trans-sphenoidal surgery with biopsy showed inflammation was caused by infection with Aspergillus fumigatus. We initiated use of parenteral amphotericin B, but his condition worsened. He underwent another surgery to implant a reservoir of Ommaya-Hickmann, a subcutaneous catheter. We started liposomal amphotericin B 5 mg/kg in the reservoir on alternate days. He was discharged with a prescription of tegretol and fluconazole. CONCLUSION: This report has scientific interest because of the occurrence of angioinvasive cerebral aspergillosis in a diabetic patient, which is rarely reported. In conclusion, we suggest a definitive diagnosis of cerebral aspergillosis should not postpone quick effective treatment.

Antifungal therapy of aspergillosis of the central nervous system and aspergillus endophthalmitis.

Cerebral Aspergillosis is the most lethal manifestation of infection due to Aspergillus species arising most commonly as hematogenous dissemination from a pulmonary focus, direct extension from paranasal sinus infection or direct inoculation through trauma and surgery of the central nervous system (CNS). Voriconazole is currently considered the standard of treatment of CNS aspergillosis with liposomal amphotericin B being the next best alternative. Neurosurgical resection of infected cerebral tissue in addition to antifungal therapy is frequently performed in patients with CNS aspergillosis to prevent neurological deficits and improve outcome. Aspergillus endophthalmitis may occur endogenously mostly from a pulmonary focus or exogenously following eye surgery or trauma. Although amphotericin B is still described as the primary therapy, voriconazole is increasingly considered the first line treatment of Aspergillus endophthalmitis. Vitrectomy is recommended in most cases of Aspergillus endophthalmitis.

Experimental central nervous system aspergillosis therapy: efficacy, drug levels and localization, immunohistopathology, and toxicity.

We have shown previously that high-dose lipid amphotericin preparations are not more efficacious than lower doses in aspergillosis. We studied toxicity, drug concentrations and localization, and quantitative infection concurrently, using a 4-day model of central nervous system (CNS) aspergillosis to assess early events. Mice given Aspergillus fumigatus conidia intracerebrally, under a cyclophosphamide immunosuppressive regimen, were treated for 3 days (AmBisome at 3 or 10 mg/kg of body weight, Abelcet at 10 mg/kg, amphotericin B deoxycholate at 1 mg/kg, caspofungin at 5 mg/kg, or voriconazole at 40 mg/kg). Sampling 24 h after the last treatment showed that AmBisome at 3 but not at 10 mg/kg, as well as Abelcet, caspofungin, and voriconazole, reduced brain CFU. All regimens reduced renal infection. Minor renal tubular changes occurred with AmBisome or Abelcet therapy, whereas heart, lung, and brain showed no drug toxicity. Amphotericin B tissue and serum concentrations did not correlate with efficacy. Endothelial cell activation (ICAM-1 and P-selectin in cerebral capillaries) occurred during infection. Amphotericin B derived from AmBisome and Abelcet localized in activated endothelium and from Abelcet in intravascular monocytes. In 10-day studies dosing uninfected mice, minor renal tubular changes occurred after AmBisome or Abelcet at 1, 5, or 10 mg/kg with or without cyclophosphamide treatment; nephrosis occurred only with Abelcet in cyclophosphamide-treated mice. Hepatotoxicity occurred with AmBisome and Abelcet but was reduced in cyclophosphamide-treated mice. Marked CFU reduction by AmBisome at 3 mg/kg occurred in association with relatively more intense inflammation. Abelcet renal localization appears to be a precursor to late nephrotoxicity. Hepatotoxicity may contribute to high-dose Abelcet and AmBisome failures. Our novel observation of endothelial amphotericin localization during infection may contribute to amphotericin mechanism of efficacy.

Resistance to voriconazole due to a G448S substitution in Aspergillus fumigatus in a patient with cerebral aspergillosis.

A voriconazole-resistant isolate of Aspergillus fumigatus was recovered from an immunocompetent patient receiving long-term antifungal therapy for cerebral aspergillosis. A G448S amino acid substitution in the azole target (Cyp51A) was identified as the cause of the resistance phenotype. This article describes the first isolation of a voriconazole-resistant A. fumigatus isolate from an immunocompetent patient in Spain.

Invasive intracranial aspergillosis spread by the pterygopalatine fossa in an immunocompetent patient.

Aspergillosis of the central nervous system (CNS) is an uncommon infection, mainly found in immunocompromised patients but rarely seen among immunocompetent patients. Herein we describe a 57 year-old immunocompetent man who suffered intracranial aspergillosis spread by the pterygopalatine fossa (PPF) following a tooth extraction. Based on magnetic resonance imaging (MRI) characteristics, in this report we focus on the spreading routes of CNS aspergillosis via communicative structures of the PPF, the relationship between clinical manifestations and the locations of the lesion, and propose a therapeutic strategy to improve the prognosis.

Invasive intracranial aspergillosis spread by the pterygopalatine fossa in an immunocompetent patient

Aspergillosis of the central nervous system (CNS) is an uncommon infection, mainly found in immunocompromised patients but rarely seen among immunocompetent patients. Herein we describe a 57 year-old immunocompetent man who suffered intracranial aspergillosis spread by the pterygopalatine fossa (PPF) following a tooth extraction. Based on magnetic resonance imaging (MRI) characteristics, in this report we focus on the spreading routes of CNS aspergillosis via communicative structures of the PPF, the relationship between clinical manifestations and the locations of the lesion, and propose a therapeutic strategy to improve the prognosis.