Morena Caira

Invasive aspergillosis in patients with acute myeloid leukemia: a SEIFEM-2008 registry study.

Background The aim of this study was to evaluate prognostic factors, treatments and outcome of invasive aspergillosis in patients with acute myeloid leukemia based on data collected in a registry. Design and Methods The registry, which was activated in 2004 and closed in 2007, collected data on patients with acute myeloid leukemia, admitted to 21 hematologic divisions in tertiary care centers or university hospitals in Italy, who developed proven or probable invasive aspergillosis. Results One hundred and forty cases of invasive aspergillosis were collected, with most cases occurring during the period of post-induction aplasia, the highest risk phase in acute myeloid leukemia. The mortality rate attributable to invasive aspergillosis was 27%, confirming previous reports of a downward trend in this rate. Univariate and multivariate analyses revealed that the stage of acute myeloid leukemia and the duration of, and recovery from, neutropenia were independent prognostic factors. We analyzed outcomes after treatment with the three most frequently used drugs (liposomal amphotericin B, caspofungin, voriconazole). No differences emerged in survival at day 120 or in the overall response rate which was 71%, ranging from 61% with caspofungin to 84% with voriconazole. Conclusions Our series confirms the downward trend in mortality rates reported in previous series, with all new drugs providing similar survival and response rates. Recovery from neutropenia and disease stage are crucial prognostic factors. Efficacious antifungal drugs bridge the period of maximum risk due to poor hematologic and immunological reconstitution.

ESCMID and ECMM joint guidelines on diagnosis and management of hyalohyphomycosis: Fusarium spp., Scedosporium spp. and others

Mycoses summarized in the hyalohyphomycosis group are heterogeneous, defined by the presence of hyaline (non-dematiaceous) hyphae. The number of organisms implicated in hyalohyphomycosis is increasing and the most clinically important species belong to the genera Fusarium, Scedosporium, Acremonium, Scopulariopsis, Purpureocillium and Paecilomyces. Severely immunocompromised patients are particularly vulnerable to infection, and clinical manifestations range from colonization to chronic localized lesions to acute invasive and/or disseminated diseases. Diagnosis usually requires isolation and identification of the infecting pathogen. A poor prognosis is associated with fusariosis and early therapy of localized disease is important to prevent progression to a more aggressive or disseminated infection. Therapy should include voriconazole and surgical debridement where possible or posaconazole as salvage treatment. Voriconazole represents the first-line treatment of infections due to members of the genus Scedosporium. For Acremonium spp., Scopulariopsis spp., Purpureocillium spp. and Paecilomyces spp. the optimal antifungal treatment has not been established. Management usually consists of surgery and antifungal treatment, depending on the clinical presentation.

Genetic PTX3 Deficiency and Aspergillosis in Stem-Cell Transplantation

BACKGROUND The soluble pattern-recognition receptor known as long pentraxin 3 (PTX3) has a nonredundant role in antifungal immunity. The contribution of single-nucleotide polymorphisms (SNPs) in PTX3 to the development of invasive aspergillosis is unknown. METHODS We screened an initial cohort of 268 patients undergoing hematopoietic stem-cell transplantation (HSCT) and their donors for PTX3 SNPs modifying the risk of invasive aspergillosis. The analysis was also performed in a multicenter study involving 107 patients with invasive aspergillosis and 223 matched controls. The functional consequences of PTX3 SNPs were investigated in vitro and in lung specimens from transplant recipients. RESULTS Receipt of a transplant from a donor with a homozygous haplotype (h2/h2) in PTX3 was associated with an increased risk of infection, in both the discovery study (cumulative incidence, 37% vs. 15%; adjusted hazard ratio, 3.08; P=0.003) and the confirmation study (adjusted odds ratio, 2.78; P=0.03), as well as with defective expression of PTX3. Functionally, PTX3 deficiency in h2/h2 neutrophils, presumably due to messenger RNA instability, led to impaired phagocytosis and clearance of the fungus. CONCLUSIONS Genetic deficiency of PTX3 affects the antifungal capacity of neutrophils and may contribute to the risk of invasive aspergillosis in patients treated with HSCT. (Funded by the European Society of Clinical Microbiology and Infectious Diseases and others.).

Incidence and clinical impact of extended-spectrum-β-lactamase (ESBL) production and fluoroquinolone resistance in bloodstream infections caused by Escherichia coli in patients with hematological malignancies.

OBJECTIVES To identify risk factors for mortality in patients suffering from hematological malignancies with concurrent bacteremia caused by Escherichia coli. Particular attention was focused on defining the impact of extended-spectrum-beta-lactamase (ESBL) production and fluoroquinolone resistance by the bacterial isolates on mortality. MATERIALS AND METHODS A retrospective eight-year cohort study design was employed. The outcome measured was death within 30 days of the first positive blood culture. Survivor and non-survivor subgroups were compared to identify predictors of mortality. RESULTS A total of 62 episodes of bacteremia caused by E. coli were analyzed. The overall incidences of ESBL production and fluoroquinolone resistance were 41.9% and 62.9%, respectively. The overall 30-day mortality rate was 20.9% (13/62). In a multivariate analysis, significant predictors of mortality were inadequate initial antimicrobial therapy (OR=14.96, 95% CI 1.95-114.51; P=0.009), infection caused by ESBL-producing isolates (OR=8.84, 95% CI 1.48-52.91; P=0.01), and prolonged neutropenia (OR=8.10, 95% CI 1.29-50.57; P=0.02). CONCLUSIONS Sound knowledge of the local distribution of pathogens and their susceptibility patterns and prompt initiation of effective antimicrobial treatment are essential in patients suffering from hematological malignancies with BSIs caused by E. coli.

Diagnosis of Invasive Aspergillosis by a Commercial Real-Time PCR Assay for Aspergillus DNA in Bronchoalveolar Lavage Fluid Samples from High-Risk Patients Compared to a Galactomannan Enzyme Immunoassay

ABSTRACT Culture-independent molecular techniques such as real-time PCRs offer the potential for early diagnosis of invasive aspergillosis (IA), thereby reducing the disease-associated mortality rate. PCR-based testing is presently excluded from disease-defining consensus criteria due to lack of standardization and clinical validation. A single-center prospective study was conducted to investigate the performance of the commercially available MycAssay Aspergillus test for detecting Aspergillus DNA in patients with suspicion of IA. To this end, a total of 158 bronchoalveolar lavage (BAL) fluid specimens that were consecutively collected from hematology (n = 68) and intensive care unit (n = 90) patients were examined. Sixteen of 17 (94.1%) specimens from patients with proven/probable IA were MycAssay positive, and 15 of these 16 patients were also positive by an “in-house” PCR assay. A total of 139 of 141 (98.6%) specimens from patients without proven/probable IA were MycAssay negative. Fifteen of 16 (94.1%) MycAssay-positive patients were also positive for BAL fluid galactomannan (GM) at an index cutoff of ≥1.0 (index range, 1.1 to 8.3), as were 3 patients without IA but with pulmonary fusariosis. Interestingly, in seven of the PCR-positive BAL specimens that tested culture positive for Aspergillus species, cycle threshold values were earlier than those of specimens with a culture-negative result. In conclusion, the MycAssay Aspergillus PCR appears to be a sensitive and specific molecular test for the diagnosis of IA, and its performance is comparable to that of the GM assay. However, more large studies are necessary to firmly establish its clinical utility in high-risk settings.

The role of Gemtuzumab Ozogamicin in the treatment of acute myeloid leukemia patients.

Gemtuzumab Ozogamicin (GO) is an antibody-targeted chemotherapy agent consisting of the humanized murine CD33 antibody (clone P67.6) to which the calicheamicin-g1 derivative is attached via a hydrolysable bifunctional linker. GO is able to induce apoptosis in vitro in CD33-expressing cells and it has been approved in USA and in Europe as monotherapy for the treatment of elderly patients (older than 60 years) with relapsed acute myeloid leukemia (AML). GO administered as a single agent has resulted in overall response rates of about 30% in previously relapsed adults AML patients (including also with incomplete platelet recovery). Preliminary data indicate a potential role for GO also as a component of induction or consolidation regimens in adults and children. As for adverse events, veno-occlusive syndrome characterizes its tolerability profile, but GO is comparatively well tolerated by most patients.

Characterization of Specific Immune Responses to Different Aspergillus Antigens during the Course of Invasive Aspergillosis in Hematologic Patients

Several studies in mouse model of invasive aspergillosis (IA) and in healthy donors have shown that different Aspergillus antigens may stimulate different adaptive immune responses. However, the occurrence of Aspergillus-specific T cells have not yet been reported in patients with the disease. In patients with IA, we have investigated during the infection: a) whether and how specific T-cell responses to different Aspergillus antigens occur and develop; b) which antigens elicit the highest frequencies of protective immune responses and, c) whether such protective T cells could be expanded ex-vivo. Forty hematologic patients have been studied, including 22 patients with IA and 18 controls. Specific T cells producing IL-10, IFN-γ, IL-4 and IL-17A have been characterized through enzyme linked immunospot and cytokine secretion assays on 88 peripheral blood (PB) samples, by using the following recombinant antigens: GEL1p, CRF1p, PEP1p, SOD1p, α1–3glucan, β1–3glucan, galactomannan. Specific T cells were expanded through short term culture. Aspergillus-specific T cells producing non-protective interleukin-10 (IL-10) and protective interferon-gamma (IFN-γ) have been detected to all the antigens only in IA patients. Lower numbers of specific T cells producing IL-4 and IL-17A have also been shown. Protective T cells targeted predominantly Aspergillus cell wall antigens, tended to increase during the IA course and to be associated with a better clinical outcome. Aspergillus-specific T cells could be successfully generated from the PB of 8 out of 8 patients with IA and included cytotoxic subsets able to lyse Aspergillus hyphae. Aspergillus specific T-cell responses contribute to the clearance of the pathogen in immunosuppressed patients with IA and Aspergillus cell wall antigens are those mainly targeted by protective immune responses. Cytotoxic specific T cells can be expanded from immunosuppressed patients even during the infection by using the above mentioned antigens. These findings may be exploited for immunotherapeutic purposes in patients with IA.

Factors associated with mortality in bacteremic patients with hematologic malignancies

We conducted a retrospective cohort study to identify risk factors for mortality in a large cohort of hematologic patients with bacteremia. From 2000 through 2005, bacteremia was diagnosed in 217 patients with hematologic malignancies. The infections were caused only by Gram-positive organisms in 57.1% (124/217) cases and only by Gram-negative bacteria in 37.8% (82/217); the remaining 5.1% (11/217) were polymicrobial. The overall 30-day mortality rate was 20.3% (44/217). In multivariate analysis, significant predictors of mortality were prolonged neutropenia (P < 0.001), acute renal failure (P = 0.002), nosocomial bacteremia (P = 0.009), age >55 years (P = 0.007), and monomicrobial bacteremia due to antibiotic-resistant Gram-negative bacteria (P = 0.009). Reducing fatal outcomes associated with bacteremia in patients with hematologic malignancies is a challenge, and the emergence of resistance to the antimicrobials widely used in this setting is of great concern. Future infection trends must be carefully monitored and treatment guidelines adjusted accordingly.

Evaluation of the Practice of Antifungal Prophylaxis Use in Patients With Newly Diagnosed Acute Myeloid Leukemia: Results From the SEIFEM 2010-B Registry

BACKGROUND To analyze the efficacy of antifungal prophylaxis (AFP) with posaconazole and itraconazole in a real-life setting of patients with acute myeloid leukemia (AML) during the first induction of remission. METHODS From January 2010 to June 2011, all patients with newly diagnosed AML were consecutively registered and prospectively monitored at 30 Italian hematological centers. Our analysis focused on adult patients who received intensive chemotherapy and a mold-active AFP for at least 5 days. To determine the efficacy of prophylaxis, invasive fungal disease (IFD) incidence, IFD-attributable mortality, and overall survival were evaluated. RESULTS In total, 515 patients were included in the present analysis. Posaconazole was the most frequently prescribed drug (260 patients [50%]) followed by fluconazole (148 [29%]) and itraconazole (93 [18%]). When comparing the groups taking posaconazole and itraconazole, there were no significant differences in the baseline clinical characteristics, whereas there were significant differences in the percentage of breakthrough IFDs (18.9% with posaconazole and 38.7% with itraconazole, P< .001). The same trend was observed when only proven/probable mold infections were considered (posaconazole, 2.7% vs itraconazole, 10.7%, P= .02). There were no significant differences in the IFD-associated mortality rate, while posaconazole prophylaxis had a significant impact on overall survival at day 90 (P= .002). CONCLUSIONS During the last years, the use of posaconazole prophylaxis in high-risk patients has significantly increased. Although our study was not randomized, it demonstrates in a real-life setting that posaconazole prophylaxis confers an advantage in terms of both breakthrough IFDs and overall survival compared to itraconazole prophylaxis. CLINICAL TRIALS REGISTRATION NCT01315925.

The use and efficacy of empirical versus pre-emptive therapy in the management of fungal infections: the HEMA e-Chart Project

Background Neutropenic patients with persistent fever despite antibiotic therapy are managed with empirical or pre-emptive antifungal therapy. The aim of the present study was to evaluate the current clinical use and efficacy of these two approaches in patients with high risk hematologic conditions. Design and Methods An electronic medical record system, the “Hema e-Chart”, was designed and implemented to collect information prospectively on infectious complications, particularly on invasive fungal diseases, in patients with hematologic malignancies treated with chemotherapy and/or autologous or allogenic hemopoietic stem cell transplantation. The patients were enrolled from Hematology units distributed widely across Italy. Results Three hundred and ninety-seven adults with hematologic malignancies treated with chemotherapy with persistent fever and suspected invasive fungal disease were evaluable for the study (190 treated had been treated with empirical antifungal therapy and 207 with preemptive antifungal therapy). There was a significantly lower incidence of proven/probable invasive fungal diseases in patients treated with empirical antifungal therapy (n=14, 7.4%) than in patients treated with pre-emptive therapy (n=49, 23.7%) (P<0.001). The rate of deaths attributable to invasive fungal diseases was significantly lower in subjects treated with empirical antifungal therapy (1 case; 7.1%) than in subjects treated with pre-emptive therapy (11 cases; 22.5%) (P=0.002). Conclusions These data indicate that empirical antifungal treatment decreased the incidence of invasive fungal disease and of attributable mortality with respect to a pre-emptive antifungal approach in neutropenic febrile patients with hematologic malignancies. (ClinicalTrials.gov Identifier: NCT01069887)