Special scenarios in the management of central nervous system aspergillosis: a case series and review of literature.

Aspergillus is a rare but important opportunistic pathogen to invade the central nervous system (CNS). It is a significant pathogen of not only immunocompromised but also immunocompetent patients. Its manifestations are pleiotropic, reflecting multiple mechanisms of pathogenesis and host interactions. Despite significant advances in diagnostic methods and therapeutic options, the mortality remains high. Several advances have been made in medications and surgical management, yet, current treatment practices lack uniformity. Patient woes are further heightened by the high costs of treatment and prolonged duration of therapy. In view of the challenging aspects of this disease, we present a short review of four challenging cases touching on the varied aspects of management of CNS aspergillosis covering pathogenesis, diagnostic pitfalls, surgical and medical options and evidence-based guidelines for the management of the same.

Molecular diagnosis of invasive mycoses of the central nervous system.

INTRODUCTION: In September 2012, the Centers for Disease Control and Prevention (CDC) began investigating an outbreak of fungal meningitis among patients who had received contaminated preservative-free methyl prednisolone acetate injections from the New England Compounding Center in Framingham, Massachusetts. Thousands of patients were potentially exposed to tainted corticosteroids, but establishing the diagnosis of fungal meningitis during the nationwide outbreak was difficult because little was known about the natural history of the disease. Areas covered: The challenges associated with this outbreak highlighted the need for rapid and reliable methodologies to assist in the diagnosis of invasive mycoses of the central nervous system (IMCNS), which may be devastating and difficult to treat. In this paper, we review the causative agents of these potentially-lethal infections, which include cryptococcal meningitis, cerebral aspergillosis, and hematogenous Candida meningoencephalitis. Expert commentary: While microscopy, culture, and histopathologic identification of fungal pathogens remain the gold standard for diagnosis, new platforms and species-specific assays have recently emerged, including lateral flow immunoassays (LFA), matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS), and multiplex PCR in conjunction with magnetic resonance (MR) to potentially aid in the diagnosis of IMCNS.

Cerebral aspergillosis in adult critically ill patients: a descriptive report of 10 patients from the AspICU cohort.

An unexpectedly high incidence of invasive pulmonary aspergillosis (IPA) has been reported in non-neutropenic intensive care unit (ICU) patients. After the respiratory tract, the brain is most often affected by invasive aspergillosis. However, little is known about brain involvement by Aspergillus in critically ill patients. In this study, demographics, risk profile, diagnosis, treatment and outcome of proven cases of invasive cerebral aspergillosis (ICA) taken from a cohort of 563 adult patients with evidenced Aspergillus involvement during their ICU stay were reviewed. Ten patients with central nervous system aspergillosis were identified. All had one or more host factors predisposing for invasive aspergillosis. The clinical and radiological presentation was non-specific and exclusively pulmonary-related. All but one patient had proven or probable/putative IPA. On cerebral computed tomography, lesions appeared as either solitary and hyperdense or were multiple and randomly distributed throughout the brain. One patient presented with sole meningeal infestation. Aspergillus infection was confirmed by brain biopsy in three subjects. Voriconazole was used as primary treatment in only one-half of the patients. Mortality was 90%. ICA is not frequently observed in adult ICU patients. Diagnosis must be considered in patients at risk presenting with proven or probable/putative IPA in association with suggestive neuroradiological findings. The brain is most likely affected through haematogenous dissemination from the lungs. Current treatment recommendations are not always applied and outcome remains dismal.

[Aspergillosis. Clinical forms and treatment]. / Aspergilosis. Formas clínicas y tratamiento.

Invasive aspergillosis, chronic pulmonary aspergillosis and allergic bronchopulmonary aspergillosis are the clinical forms of aspergillosis. Although there is a great number of Aspergillus species, Aspergillus fumigatus-complex is the more frequent aetiological agent, regardless of clinical form or baseline condition. The increase in immunosuppressive agents and the higher use of corticosteroids in chronic obstructive pulmonary disease have led to aspergillosis becoming more prominent in recent years. Galactomannan detection and radiological diagnostic images complement the limitations of microbiology cultures in these patients. Voriconazole and liposomal amphotericin B are the gold standard in patients requiring therapy, and posaconazole, itraconazole, caspofungin and other echinocandins are effective alternatives. The prognosis depends of clinical forms and characteristics of the host, but it is particularly poor in the disseminated invasive forms.

Twenty-nine cases of invasive aspergillosis in neutropenic patients.

INTRODUCTION: Invasive aspergillosis is a life-threatening infectious complication in hematological patients undergoing immunosuppressive chemotherapy. PATIENTS AND METHODS: We report 29 cases of invasive aspergillosis diagnosed in the Sousse Farhat Hached hospital Hematology unit, Tunisia, between 2002 and 2010. RESULTS: The most frequent disease (65.5%) was acute myeloid leukemia. All patients were severely neutropenic (<500/mm(3), mean duration=27 days). Pulmonary invasive aspergillosis was suggested in 28 (96.5%) cases. The most frequent respiratory signs were cough (64.3%), chest pain (53.6%), and hemoptysis (50%). The chest X-ray showed suggestive lesions in 60.7% of cases. CT scans revealed nodules with cavitation in 65% of cases, a halo sign in 20% of cases, and nodules in 15% of cases. Galactomannan antigenemia was positive in 88%, mycological examination positive in 51.6%, and seroconversion was noted in 35.7% of the cases. Invasive pulmonary aspergillosis was classified, according to EORTC/MSG criteria, as probable in 26 cases, possible in one case, and proven in one case. Aspergillus flavus was the dominant species in pulmonary invasive aspergillosis accounting for 73.7% of isolates. Extrapulmonary involvement was suggested in 39.3% of cases, the most frequent were sinusitis and brain abscess. Primary cutaneous aspergillosis was observed in one case. The overall mortality rate was 64.2%; the 12-week survival rate was 71.4%. CONCLUSION: Our results are correlated to published data. A. flavus was the most frequent species in our region.

Infectious and non-infectious neurologic complications in heart transplant recipients.

Neurologic complications are important causes of morbidity and mortality in heart transplant (HT) recipients. New immunomodulating agents have improved survival rates, although some have been associated with a high rate of neurologic complications (infectious and non-infectious). We conducted this study to analyze the frequency of these complications, before and after the use of daclizumab induction therapy. We reviewed all neurologic complications in our HT cohort, comparing infectious with non-infectious complications over 2 periods of time in which different induction therapies were used (316 patients with OKT3 or antithymocyte globulin from 1988 to 2002, and 68 patients with daclizumab from 2003 to 2006). Neurologic complications were found in 75/384 patients (19.5%) with a total of 78 episodes. Non-infectious complications accounted for 68% of the 78 episodes of neurologic complications. A total of 51 patients and 53 episodes were detailed as follows: 25 episodes of stroke (25 of 78 total episodes, 32%; 19 ischemic, 6 hemorrhagic); 7 neuropathies; 6 seizures; 4 episodes of transient ischemic attack (TIA); 3 anoxic encephalopathy; 2 each brachial plexus palsy and metabolic encephalopathy; and 1 each myoclonia, central nervous system (CNS) lymphoma, subdural hematoma, and Cotard syndrome. Mean time to presentation of stroke, TIA, and encephalopathy was 1 day (range, 1-19 d) posttransplant. Mortality rate among non-infectious complications was 12/53 (22.6%). Infectious complications accounted for 32% of the 78 total episodes. We found 25 episodes in 24 patients: 17 herpes zoster (median, 268 d after HT), 3 CNS aspergillosis (median, 90 d after HT), 1 CNS toxoplasmosis and tuberculosis (51 d after HT), 1 pneumococcal meningitis (402 d after HT), and 2 Listeria meningitis (median, 108 d after HT). The 3 patients with CNS aspergillosis died. The mortality rate among patients with infectious neurologic complications was 12% (42.8% if the CNS was involved). When we compared the OKT3-ATG and daclizumab groups, we found that the incidence of non-infectious complications was 15.1% vs. 7.3%, respectively, and the incidence of infectious complications was 7.5% vs. 1.4%, respectively. All but 1 opportunistic infection occurred in the OKT3-ATG time period. In conclusion, a wide variety of neurologic complications affected 19.5% of HT recipients. Non-infectious causes clearly predominated, but infections still accounted for 32% of the episodes. New monoclonal induction therapies have contributed to diminished CNS opportunistic infections in our program.

Risk factors for invasive aspergillosis and related mortality in recipients of allogeneic SCT from alternative donors: an analysis of 306 patients.

Invasive aspergillosis (IA) is a serious complication in patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT), particularly from donors other than HLA-identical sibling. All 306 patients who underwent alternative donor HSCT between 01 January 1999 and 31 December 2006 were studied. Late IA was defined as occurring >or=40 days after HSCT. The median follow-up was 284 days (range, 1-2709). Donors were matched unrelated (n=185), mismatched related (n=69), mismatched unrelated (n=35) and unrelated cord blood (n=17). According to European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria, 2 patients already had IA at HSCT, 23 had early IA and 20 had late IA (IA incidence 15%). Eight patients had proven and 37 probable IA. Multivariate analyses showed that significant predictors of IA were delayed neutrophil engraftment, extensive chronic GVHD (cGVHD), secondary neutropenia and relapse after transplant. Early IA was associated with active malignancy at HSCT, CMV reactivation and delayed lymphocyte engraftment. Late IA was predicted by cGVHD, steroid therapy, secondary neutropenia and relapse after HSCT. IA-related mortality among IA patients was 67% and was influenced by use of anti-thymocyte globulin, steroids, higher levels of creatinine, and lower levels of IgA and platelets. The outcome of IA depends on the severity of immunodeficiency and the status of the underlying disease.

Aspergillosis of the central nervous system: a catastrophic opportunistic infection.

The clinical features and outcome of the treatment of aspergillosis of the central nervous system (CNS) in Thai patients are presented. The patients who were diagnosed as having CNS aspergillosis by tissue biopsy or culture from January 1, 1991 to December 31, 2000 were retrospectively reviewed. The study variables including age, sex, underlying disease, symptoms and signs, neuro-imaging studies, pathological findings and outcome of treatment, are described. There were seven cases of aspergillosis of the central nervous system. Four patients were male. The median age was 65 years (range 36-78 years). The most common underlying disease was diabetes mellitus (4/7; 57.1%). Two patients (28.6%) had no underlying disease. The most common primary site of infection was the paranasal sinuses (6/7; 85.7%). The most common clinical presentation was headache (6/7; 85.7%). Common neurological signs included multiple cranial nerve palsies (5/7; 71.4%) and alteration of consciousness (3/7; 42.9%). The median duration of the symptoms prior to admission was 60 days (range 8-180 days). All patients were treated with intravenous antifungal agents at high doses. Extensive surgery was performed in 6 patients. The mortality rate was very high (6/7; 85.7%). The median time from diagnosis and treatment to death was 53 days (22-720 days). Aspergillosis of the CNS should be considered in those with clinical features of headache, multiple cranial nerve palsies and alteration of consciousness accompanied by sinusitis, especially in elderly and diabetic patients. It remains a catastrophic opportunistic infection in spite of the current intensive and aggressive treatment.

Fungal colonization and invasive fungal infections following allogeneic BMT using metronidazole, ciprofloxacin and fluconazole or ciprofloxacin and fluconazole as intestinal decontamination.

Invasive fungal infections (IFI) are increasingly diagnosed in patients undergoing allogeneic BMT. We have previously shown that the addition of metronidazole to ciprofloxacin for gastrointestinal bacterial decontamination significantly reduces the incidence of grades II-IV aGVHD by reduction of the anaerobic intestinal bacterial flora. Here, we found that the combined use of ciprofloxacin, metronidazole and fluconazole as antifungal prophylaxis increased intestinal yeast colonization when compared to ciprofloxacin and fluconazole alone (P < 0.01). Based on the EORTC criteria, a total of 18 out of 134 study patients developed IFI: seven of 68 (10%) patients who received metronidazole compared to 11 of the 66 (17%) patients decontaminated without metronidazole developed IFI (log-rank P = 0.36). Lethal IFI occurred in two of seven patients receiving metronidazole and in four of 11 patients without anaerobic decontamination. In conclusion, bacterial intestinal decontamination using metronidazole as an antibiotic with activity against most anaerobic intestinal bacteria significantly increases the intestinal yeast burden without influencing the incidence of IFI in patients undergoing allogeneic BMT.