Clinical, laboratory, radiologic characteristics and outcomes of probable and proven pulmonary invasive fungal disease in hemato-oncologic patients — single center study

The Therapeutic Efficacy and Blood Drug Concentration of Posaconazole Enteric-Coated Tablets in Preventing Pulmonary Invasive Fungal Disease after HSCT

Children, adolescents, and young adults with acute myeloid leukemia are at high risk of life-threatening invasive fungal disease with both yeasts and molds. To compare the efficacy of caspofungin vs fluconazole prophylaxis against proven or probable invasive fungal disease and invasive aspergillosis during neutropenia following acute myeloid leukemia chemotherapy. This multicenter, randomized, open-label, clinical trial enrolled patients aged 3 months to 30 years with newly diagnosed de novo, relapsed, or secondary acute myeloid leukemia being treated at 115 US and Canadian institutions (April 2011-November 2016; last follow-up June 30, 2018). Participants were randomly assigned during the first chemotherapy cycle to prophylaxis with caspofungin (n = 257) or fluconazole (n = 260). Prophylaxis was administered during the neutropenic period following each chemotherapy cycle. The primary outcome was proven or probable invasive fungal disease as adjudicated by blinded central review. Secondary outcomes were invasive aspergillosis, empirical antifungal therapy, and overall survival. The second interim efficacy analysis and an unplanned futility analysis based on 394 patients appeared to have suggested futility, so the study was closed to accrual. Among the 517 participants who were randomized (median age, 9 years [range, 0-26 years]; 44% female), 508 (98%) completed the trial. The 23 proven or probable invasive fungal disease events (6 caspofungin vs 17 fluconazole) included 14 molds, 7 yeasts, and 2 fungi not further categorized. The 5-month cumulative incidence of proven or probable invasive fungal disease was 3.1% (95% CI, 1.3%-7.0%) in the caspofungin group vs 7.2% (95% CI, 4.4%-11.8%) in the fluconazole group (overall P = .03 by log-rank test) and for cumulative incidence of proven or probable invasive aspergillosis was 0.5% (95% CI, 0.1%-3.5%) with caspofungin vs 3.1% (95% CI, 1.4%-6.9%) with fluconazole (overall P = .046 by log-rank test). No statistically significant differences in empirical antifungal therapy (71.9% caspofungin vs 69.5% fluconazole, overall P = .78 by log-rank test) or 2-year overall survival (68.8% caspofungin vs 70.8% fluconazole, overall P = .66 by log-rank test) were observed. The most common toxicities were hypokalemia (22 caspofungin vs 13 fluconazole), respiratory failure (6 caspofungin vs 9 fluconazole), and elevated alanine transaminase (4 caspofungin vs 8 fluconazole). Among children, adolescents, and young adults with acute myeloid leukemia, prophylaxis with caspofungin compared with fluconazole resulted in significantly lower incidence of invasive fungal disease. The findings suggest that caspofungin may be considered for prophylaxis against invasive fungal disease, although study interpretation is limited by early termination due to an unplanned interim analysis that appeared to have suggested futility. ClinicalTrials.gov Identifier: NCT01307579.

The increase of invasive fungal disease (IFD) in immunocompromised patients has led to the frequent prescription of highly active antifungal drugs but with a high economic cost. To characterize the use of antifungals drugs, evaluate its prescription and determine consumption and associated costs. Retrospective descriptive study from January 2015 to April 2016. Audit of prescriptions and review of clinical files. Each prescription was classified according to whether it corresponded to a possible, probable or proven invasive fungal disease (IFD). Consumptions and treatment costs were calculated. 152 antifungal prescriptions were audited in 79 patients. The total cost of antifungal medications was US $ 714,413. 52.1% of the expenditure (US $ 372,319) corresponded to indications in proven IFD, 10.7% (US $ 76,377) probable IFD, 0.8% (US $ 5,638) non-IFI, 12.2% (US $ 87,459) IFD possible and 1.5% (US $ 10,896) non-IFD and 22.6% (US $ 161,723) was prophylaxis. The highest consumption was in indications related to IFD tested with a proven DOT of 10.54 days, with liposomal amphotericin B and iv voriconazole the drugs with the highest consumption with a DOT probable_AnBL of 3.15 and DOT proven voriconazole iv of 3.01. The consumption of antifungal drug medications generates high costs at 12% of the total pharmacy budget of our institution. The expense was associated mainly with the indications in IFI tested the voriconazole and amphotericin B liposomal with the highest consumption which added to its high cost and prolonged days of general therapy a big impact in the budget.

Invasive fungal diseases, in particular those due to Aspergillus spp., are increasing in incidence and constitute an important cause for morbidity and mortality in children and adolescents with hematologic malignancies and those undergoing allogeneic hematopoietic stem cell transplantation (HSCT) [1]. A contemporary retrospective analysis demonstrated that corticosteroid therapy, neutropenia, immunosuppressive therapy, malignancy, and allogeneic HSCT are the most common risk factors for invasive aspergillosis in pediatric age groups [2]. The overall case fatality rate of invasive aspergillosis in this study was 53%, which is similar to that seen in adult patients. Invasive aspergillosis significantly contributes to the in-house mortality of children with acute lymphoblastic and myeloid leukemia, lymphoma, allogeneic HSCT, and solid organ transplantation. In a retrospective cohort study using a national database of hospital inpatient stays during 2000, 18% (122 of 666) of children with invasive aspergillosis died in the hospital, compared with 1% (1736 of 151 537) of similarly immunocompromised children without invasive aspergillosis [3]. Despite substantial achievements over the past 2 decades, diagnosis and treatment of invasive fungal diseases in children and adolescents are still limited by a number of factors. As a matter of fact, not all antifungal agents are approved in the pediatric population, the appropriate dosage of several drugs has not been established for all age groups, and postmarketing data providing information on safety and efficacy of approved agents under real-life circumstances are scant. Similarly, the value of newer diagnostic tools is not defined in the pediatric population, although they are of major impact for establishing preventive and treatment strategies of invasive aspergillosis [4]. Whereas both the halo sign and the air-crescent sign revealed by pulmonary computed tomography scan are common and highly suggestive for invasive mold infection in adult patients and are included as clinical criteria in the revised definitions of invasive fungal disease set forth by the European Organization for Research and Treatment of Cancer and the Mycosis Study Group (EORTC/MSG) [5], radiographic findings in immunocompromised children with proven pulmonary invasive fungal disease are often nonspecific. In younger children (aged <5 years) in particular, typical signs of pulmonary invasive fungal disease are not seen in the majority of patients. In contrast, multiple nodules or fluffy masses and infiltrates that look like mass lesions are frequently reported [2]. Testing galactomannan (GM), a polysaccharide cell-wall component that is released by all Aspergillus spp. during cell growth, has been evaluated in multiple studies in adults and is included as a microbiological criterion in the revised definitions of invasive fungal disease by the EORTC/MSG consensus group and in a number of Editorial Commentary

There is limited information concerning the overall epidemiology of invasive fungal disease (IFD) in children. The aim of this study was to clarify the clinical features of IFD in a tertiary pediatric care hospital. Patients diagnosed with proven or probable IFD at our hospital between 2011 and 2015 were retrospectively reviewed. Proven and probable IFD were defined according to the European Organization for Research and Treatment of Cancer/Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group consensus. Patients with possible IFD were excluded. The incidence of proven or probable IFD was 26 of 20,079 hospitalized patients (0.13%). The predominant underlying disease was malignancy (54%) and congenital anomaly (27%). The most common diagnosis was candidemia among the patients with proven IFD (8 of 13, 62%). All the isolated pathogens in the candidemia patients were non-albicans Candida spp. The most common site of infection was the lungs in patients with probable IFD (11 of 13 patients, 85%). In probable IFD episodes, positive β-D-glucan and galactomannan were found in 12 of 13 (92%) and 5 of 13 (38%) patients, respectively. All but one patient (96%) received empirical antifungal therapy. No patients underwent surgical resection of residual lesions. The overall mortality was 23% and the attributable mortality of IFD was 12%. Our results suggest the emergence of non-albicans Candida species as important pathogens in childhood IFD.

Outcome in Pediatric Patients with a History of Fungal Disease Prior to Allogeneic Stem Cell Transplant

ObjectivesBiomarkers for invasive fungal disease (IFD) have been shown to reduce antifungal prescriptions in neutropaenic haemato-oncology patients. Our study aimed to assess the real-life impacts of introducing a novel biomarker-based pathway, incorporating serum galactomannan and Aspergillus PCR, for pyrexial haemato-oncology admissions.MethodsPatients with neutropaenic fever were identified prospectively after introduction of the new pathway from 2013-2015. A historical group of neutropaenic patients who had blood cultures taken from 2009-2012 was generated for comparison. Clinical details including demographics, underlying diagnosis, investigations, radiology and antimicrobial treatment were obtained.ResultsProspective data from 308 patients was compared to retrospective data from 302 patients. The proportion of patients prescribed an antifungal medication was unchanged by the pathway (p=0.79), but the pattern was different with more patients receiving targeted antifungals (p=0.04). A negative serum galactomannan test was not sufficient evidence to withhold therapy with 17.2% of those episodes felt to have possible or probable IFD by EORTC/MSG criteria. There was no difference in 30-day mortality (p=0.21) or 1-year mortality (p=0.57) following introduction of the pathway.ConclusionsBiomarkers can be used safely as part of a multidisciplinary approach to the diagnosis of IFD in neutropaenic haemato-oncology patients. Whilst they do not necessarily result in antifungal therapy being withheld, they can allow more confident diagnosis of IFD and more specific antifungal therapy in selected cases.

Risk factors for invasive fungal disease in heart transplant recipients

Low Incidence of Fungal Infections after Chimeric Antigen Receptor T-Cell Therapy for Non-Hodgkin Lymphoma in an Endemic Region for Coccidioidomycosis

Breakthrough invasive fungal disease in patients receiving posaconazole primary prophylaxis: a 4-year study

Evidence on risk factors for Clostridium difficile infection (CDI) in hemato-oncologic patients is conflicting. We studied risk factors for CDI in a large, well-characterized cohort of hemato-oncological patients. 144 hemato-oncological patients were identified in this retrospective, single center study with a microbiologically confirmed CDI-associated diarrhea. Patients were compared with 144 age and sex matched hemato-oncologic patients with CDI negative diarrhea. Risk factors such as prior antimicrobial therapy, type of disease, chemotherapy and survival were evaluated. CDI-positive patients received more frequently any antimicrobial agent and antimicrobial combination therapy than CDI-negative patients (79% vs. 67%; OR = 2.26, p = 0.038 and OR = 2.62, p = 0.003, respectively). CDI positive patients were treated more frequently with antimicrobial agents active against C. difficile than CDI negative ones (25% vs. 13%; OR = 2.2, p = 0.039). The interval between last chemotherapy and onset of diarrhea was significantly shorter in patients without CDI (median, 17 days vs 36 days; p < 0.001). Our study demonstrates that chemotherapy is not a significant risk factor for CDI but for early onset CDI negative diarrhea. The predominant modifiable risk factor for CDI is in hemato-oncological patients antimicrobial treatment. These findings should be taken into account in the daily clinical practice to avoid CDI associated complications and excess health care costs.

This study aimed to assess whether genetic variants of dendritic cell-associated C-type lectine-1 (Dectin-1), Toll-like receptor 2 (TLR2), Toll-like receptor 4 (TLR4), and myeloid differentiation primary response 88 (MyD88) influence the susceptibility to pulmonary invasive fungal disease (IFD) in patients with acute myeloid leukemia (AML) from a Chinese Han population. Eight single nucleotide polymorphisms (SNPs) of Dectin-1 (rs16910526, rs3901533, and rs7309123), TLR2 (rs5743708), TLR4 (rs4986790 and rs4986791) and MyD88 (rs4988453 and rs4988457) in the genomic DNA of 172 adult AML patients were genotyped. Pulmonary IFD was diagnosed as proven or probable according to the 2008 European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) consensus guidelines. SNPs that were significant in the univariate analysis were further analyzed using the multiple logistic regression analysis to determine their association with the occurrence of pulmonary IFD. The mRNA expression of Dectin-1 was detected according to the genotype by quantitative realtime PCR (qRT-PCR), and the correlation of this expression with the occurrence of pulmonary IFD in AML patients was analyzed. Two Dectin-1 intron SNPs (rs3901533 and rs7309123) were found to be significantly associated with the susceptibility to pulmonary IFD in AML patients in a Chinese Han population. Significant associations were noted between pulmonary IFD and Dectin-1 rs3901533 dominant model (G/T+G/G vs. T/T, OR: 2.158; 95% CI: 1.109-4.2, P=0.02), Dectin-1 rs3901533 G allele (OR: 2.201; 95% CI: 1.206-4.019, P=0.01), or Dectin-1 rs7309123 C allele (OR: 1.919; 95% CI: 1.047-3.518, P=0.03). There were no significant associations between pulmonary IFD and the remaining Dectin-1 SNPs (rs16910526), TLR2 (rs5743708), TLR4 (rs4986790 and rs4986791) or MyD88 (rs4988453 and rs4988457). In conclusion, two Dectin-1 SNPs (rs3901533 and rs7309123) are associated with increased susceptibility to pulmonary IFD in AML patients in a Chinese Han population.

Lung and sinus fungal infection imaging in immunocompromised patients

Clinical charts from 63 consecutive highly immunocompromised haematologic patients presenting with pulmonary nodular lesions on CT scan, classified as either probable or possible invasive fungal disease (IFD) according to the revised EORTC/MSG classification, were retrospectively studied. Histopathological analysis of lung tissues, available for 23 patients, demonstrated proven IFD in 17 cases (14 invasive aspergillosis and 3 invasive zygomycosis), diffuse alveolar damage in one and organising pneumonia (OP) in five cases. In the OP cases, three of which have been defined as probable IFD according to EORTC/MSG classification, extensive immunohistochemical, molecular and immunological analyses for fungi were negative. Our case descriptions extend the notion that OP may be encountered as a distinct histopathological entity in pulmonary nodular lesions in patients with leukaemia with probable/possible IFD.

Lung Resection in Hematologic Patients With Pulmonary Invasive Fungal Disease