No abstract

The European Society for Clinical Microbiology and Infectious Diseases, the European Confederation of Medical Mycology and the European Respiratory Society Joint Clinical Guidelines focus on diagnosis and management of aspergillosis. Of the numerous recommendations, a few are summarized here. Chest computed tomography as well as bronchoscopy with bronchoalveolar lavage (BAL) in patients with suspicion of pulmonary invasive aspergillosis (IA) are strongly recommended. For diagnosis, direct microscopy, preferably using optical brighteners, histopathology and culture are strongly recommended. Serum and BAL galactomannan measures are recommended as markers for the diagnosis of IA. PCR should be considered in conjunction with other diagnostic tests. Pathogen identification to species complex level is strongly recommended for all clinically relevant Aspergillus isolates; antifungal susceptibility testing should be performed in patients with invasive disease in regions with resistance found in contemporary surveillance programmes. Isavuconazole and voriconazole are the preferred agents for first-line treatment of pulmonary IA, whereas liposomal amphotericin B is moderately supported. Combinations of antifungals as primary treatment options are not recommended. Therapeutic drug monitoring is strongly recommended for patients receiving posaconazole suspension or any form of voriconazole for IA treatment, and in refractory disease, where a personalized approach considering reversal of predisposing factors, switching drug class and surgical intervention is also strongly recommended. Primary prophylaxis with posaconazole is strongly recommended in patients with acute myelogenous leukaemia or myelodysplastic syndrome receiving induction chemotherapy. Secondary prophylaxis is strongly recommended in high-risk patients. We strongly recommend treatment duration based on clinical improvement, degree of immunosuppression and response on imaging.

Invasive mycoses are pre-eminent causes of morbidity and mortality in the allogeneic stem cell transplant setting. In spite of novel diagnostic modalities, the timely and specific identification of invasive mycoses still remains challenging. We analyzed the case history of 97 consecutive patients receiving 103 allogeneic stem cell transplants between January 2003 and October 2006 performed by a single team at 2 transplant centers in Budapest, Hungary. All patients with febrile neutropenia not responding to broad-spectrum antibacterial therapy received amphotericin B deoxycholate empirically. In cases of proven or probable invasive aspergillosis, intravenous voriconazole was instituted. Patients who failed to improve on initial therapy were treated with an antifungal combination, while responders were switched to oral voriconazole. A total of 38 patients died following allografting. Both centers had an autopsy rate of 100% due to central health care regulations. An infectious cause of death could be identified in 15 cases, invasive fungal disease being the most prevalent and accounting for 10 fatalities. Six patients died of invasive aspergillosis, while invasive candidiasis and mucormycosis led to a fatal outcome in 2 cases each. Despite the regular use of galactomannan antigen detections and imaging, an ante mortem diagnosis of proven/probable invasive fungal disease could only be established in 4 of 10 autopsy-verified cases (aspergillosis: 3, candidiasis: 1, mucormycosis: 0). In the remaining 6 patients, deep mycoses were missed clinically and were revealed only by postmortem histology. Present diagnostic and therapeutic strategies still seem to be suboptimal for the management of invasive fungal diseases in the high-risk allogeneic stem cell transplant population.

Viral reactivation is a frequent complication of allogeneic hematopoietic stem cell transplantation especially in children. For refractory cases, rapid virus-specific T-cell therapy would be ideally implemented within a few days. Over the course of a year in our pediatric cohort of 43 allogeneic transplantation, 9 patients fulfilled criteria for virus-specific T-cell therapy. Viral infections were due to cytomegalovirus (CMV) in 3, Epstein-Barr virus (EBV) in 2, and adenovirus (AdV) in 1 case, whereas >1 virus was detected in 3 cases. Viral diseases necessitating a T-cell therapy were CMV pneumonitis and colitis, AdV enteritis and cystitis, and EBV-induced posttransplantation lymphoproliferative disease. Cells were produced by the CliniMACS Prodigy CCS (IFN-gamma) System within 24 hours after mononuclear leukapheresis. Eight patients became completely asymptomatic, whereas 7 also cleared the virus. Six patients are alive without viral illness or sequelae demonstrating viral DNA clearance in peripheral blood with a median follow-up of 535 (350-786) days. One patient with CMV pneumonitis died of respiratory insufficiency. In 2 cases the viral illness improved or cleared, however, the patients died of invasive aspergillosis. No cases of graft-versus-host disease, rejection, organ toxicity, or recurrent infection were noticed. Virus-specific T-cell therapy implemented by the CliniMACS Prodigy CCS (IFN-gamma) System is an automated, fast, safe, and probably effective way to control resistant viral diseases after pediatric hematopoietic stem cell transplantation.