Invasive fungal disease in patients treated for newly diagnosed acute leukemia.

Invasive fungal disease (IFD) is a significant cause of morbidity and mortality in patients undergoing treatment for acute leukemia (AL). Antifungal prophylactic strategies are associated with significant toxicities and cost. We performed a retrospective study of the incidence and risk factors for IFD among patients newly diagnosed with and treated for AL between January 1, 2004 and July 1, 2006. Patient follow up concluded January 1, 2007. Among 231 patients with newly diagnosed AL, 31 (13.4%) developed IFD by the end of follow up, 24 (10.4%) of whom developed IFD within the first 100 days after diagnosis of AL. The cumulative probability of developing IFD was 5.9% by 30 days and 11.1% at 100 days after AL diagnosis. Patients who had persistent leukemia after an initial course of induction chemotherapy were significantly more likely to develop IFD than those who did not have evidence of persistent leukemia (14/65 (21.5%) vs. 15/148 (10.1%), P = 0.03). In a time-dependent Cox model, the adjusted hazard ratio for developing IFD within the first 100 days of AL diagnosis based on the number of days of neutropenia in that period was 4.85 (95% confidence interval: 1.52, 15.4). Those patients with more days of neutropenia in the first 100 days after AL diagnosis, such as those who did not achieve remission after a first course of induction chemotherapy, were more likely to develop IFD.

Evaluation of caspofungin or micafungin as empiric antifungal therapy in adult patients with persistent febrile neutropenia: a retrospective, observational, sequential cohort analysis.

BACKGROUND: Caspofungin is approved in the United States for empiric antifungal therapy for persistent febrile neutropenia (FN). There are limited data about the use of other echinocandins in this setting. OBJECTIVE: After a formulary change, we retrospectively evaluated the safety and effectiveness of caspofungin and micafungin as empiric antifungal therapy for FN at Brigham and Women's Hospital (Boston, Massachusetts). METHODS: This was a retrospective, observational, sequential cohort study. We identified patients who had received >or=2 doses on concurrent days of either caspofungin (between November 2005 and October 2006) or micafungin (between November 2006 and October 2007) for empiric FN therapy. Patients were included for analysis if they were neutropenic (absolute neutrophil count <500 cells/microL) and febrile (temperature >or=100.5 degrees F [>or=38 degrees C]). Patients without previous exposure to an echinocandin were included; those included in the caspofungin cohort were excluded from the micafungin cohort. Those who had previously received another systemic antifungal agent for FN therapy (except fluconazole for mucosal candidiasis) were excluded. Patients were followed through hospital discharge. Outcomes analyzed were successful treatment of baseline invasive fungal disease (IFD), incidence of breakthrough IFD, overall mortality, and discontinuation because of adverse events (AEs). IFD was diagnosed and classified according to current 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 Consensus Group criteria. RESULTS: Three hundred twenty-three patients met inclusion criteria (caspofungin, n = 149; micafungin, n = 174). Median age was 49 years in both the caspofungin and micafungin groups; 80 (53.7%) and 99 (56.9%) patients in each group, respectively, were men. Fluconazole prophylaxis had been administered to 30 patients (20.1%) treated with caspofungin and 21 patients (12.1%) treated with micafungin. Caspofungin was administered at 70 mg for one dose, followed by 50 mg daily; micafungin was administered at 100 mg daily. The median duration of therapy and of hospitalization were 10 days and 29 days, respectively, with caspofungin, and 9 days and 28 days with micafungin (both, P = NS between groups). Twelve patients (8.1%) in the caspofungin cohort and 13 (7.5%) in the micafungin cohort died during the study period (P = NS). There were 3 cases (2.0%) of baseline IFD in the caspofungin cohort and 6 (3.4%) in the micafungin cohort (P = NS); 6 were successfully treated (caspofungin, 2 [1.3% of entire group]; micafungin, 4 [2.37% of entire group]; P = NS). Breakthrough IFD was diagnosed in 16 patients (10.7%) receiving caspofungin and 21 (12.1%) receiving micafungin (P = NS). AEs requiring echinocandin discontinuation were uncommon (caspofungin, 2 cases of rash and 1 anaphylactoid infusion reaction [2.0%]; mica-fungin, 1 liver function test elevation >or=5 times the upper limit of normal and 1 maculopapular rash [1.1%]; P = NS). CONCLUSION: Micafungin, as empiric antifungal therapy for persistent FN, did not appear to differ significantly from caspofungin in terms of safety profile or efficacy in the adult patients included in this sequential cohort analysis at one institution. ClinicalTrials.gov identifier: NCT00723073.

Diagnostic performance of the (1-->3)-beta-D-glucan assay for invasive fungal disease.

BACKGROUND: Diagnosis of invasive fungal disease (IFD) is challenging, and it remains a significant cause of morbidity and mortality in immunocompromised patients. The (1-->3)-beta-D-glucan (BG) assay may be a useful adjunct, but its diagnostic performance is not well characterized. METHODS: We retrospectively assessed the diagnostic indices of the BG assay in patients at risk of IFD who had a compatible clinical syndrome for the diagnosis of IFD a week after initial BG testing and at the end of the hospitalization associated with the first BG value. Patients with IFD were classified according to current European Organization for Research and Treatment of Cancer-Mycoses Study Group criteria, independent of BG results. RESULTS: A total of 1308 BG assays were performed for 871 patients. One hundred twelve proven or probable IFD cases were diagnosed within 1 week after initial testing, and 116 cases were diagnosed by the end of hospitalization. Sensitivity of an initial BG level 80 pg/mL for IFD at 1 week was 0.64 (95% confidence interval [CI], 0.55-0.73), specificity was 0.84 (95% CI, 0.81-0.86), the positive likelihood ratio was 3.93 (95% CI, 2.94-5.26), and the negative likelihood ratio was 0.43 (95% CI, 0.31-0.59). Albumin, intravenous immunoglobulin, and hemodialysis were associated with elevated BG levels in patients without IFD (odds ratio, 4.78; 95% CI, 2.59-8.80). After excluding patients with these factors, specificity and the positive likelihood ratio of an initial BG level 80 pg/mL increased slightly. Empirical systemic antifungal treatment did not reduce overall BG sensitivity. Sensitivity was slightly lower among patients with hematologic malignancy or stem cell transplantation. Consideration of BG results would have increased the diagnostic certainty to probable in 54% of possible IFD cases. CONCLUSIONS: BG level appears to be a fair diagnostic adjunct for IFD in patients with appropriate pretest probability and a suggestive clinical syndrome, especially when checked serially in patients not receiving factors associated with an elevated BG level in the absence of IFD.

Diagnostic efficacy and safety of computed tomography-guided transthoracic needle biopsy in patients with hematologic malignancies.

RATIONALE AND OBJECTIVES: The role of transthoracic needle biopsy (TTNB) in patients with hematologic malignancies, particularly in discriminating between malignant and benign etiologies, has not been well studied. Hence, the diagnostic efficacy and safety of computed tomography-guided TTNB were retrospectively evaluated in this population. MATERIALS AND METHODS: The records of 53 patients with hematologic malignancies who underwent TTNB from August 1, 1999, to July 31, 2007, were reviewed. Potential factors for increased diagnostic yield and risk for complications were collected and analyzed, including the status of neutropenia, thrombocytopenia, chemotherapy, and transplant as well as lesion size and location. Both cytopathologic and microbiologic results were assessed. RESULTS: The most common underlying hematologic malignancy was non-Hodgkin lymphoma, in 20 patients (37.7%). Lesions were most frequently located in the left upper lobe (16 [30.2%]); 33 lesions were pleural based (63.5%), and nine had cavitation (17.0%). TTNB established specific diagnoses in 22 patients (41.5%): malignancies was found in 12 (22.6%) and infections in 10 (18.9%). Sensitivity for detecting malignancy was 50.0%, and sensitivity for the detection of a specific infection was 40.0%. There were no false-positive results. Complications occurred in nine patients (17.0%): self-limited small-volume hemoptysis in one patient (1.9%) and pneumothorax in eight patients (15.1%), one requiring chest tube placement. The results of TTNB led to changes in antimicrobial therapy for eight of the 22 patients with specific diagnoses (36.4%). CONCLUSIONS: TTNB is a safe diagnostic procedure in patients with hematologic malignancies and has the potential of making specific diagnoses with minimal morbidity.

Sirolimus-based graft-versus-host disease prophylaxis protects against cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation: a cohort analysis.

Sirolimus-based immunosuppressive regimens in organ transplantation have been associated with a lower than expected incidence of cytomegalovirus (CMV) disease. Whether sirolimus has a similar effect on CMV reactivation after allogeneic hematopoietic stem cell transplantation (HSCT) is not known. We evaluated 606 patients who underwent HSCT between April 2000 and June 2004 to identify risk factors for CMV reactivation 100 days after transplantation. The cohort included 252 patients who received sirolimus-tacrolimus for graft-versus-host disease (GVHD) prophylaxis; the rest received non-sirolimus-based regimens. An initial positive CMV DNA hybrid capture assay was observed in 225 patients (37.1%) at a median 39 days after HSCT for an incidence rate of 0.50 cases/100 patient-days (95% confidence interval [CI], 0.44-0.57). Multivariable Cox modeling adjusting for CMV donor-recipient serostatus pairs, incident acute GVHD, as well as other important covariates, confirmed a significant reduction in CMV reactivation associated with sirolimus-tacrolimus-based GVHD prophylaxis, with an adjusted HR of 0.46 (95% CI, 0.27-0.78; P = .004). The adjusted HR was 0.22 (95% CI, 0.09-0.55; P = .001) when persistent CMV viremia was modeled. Tacrolimus use without sirolimus was not significantly protective in either model (adjusted HR, 0.66; P = .14 and P = .35, respectively). The protective effect of sirolimus-containing GVHD prophylaxis regimens on CMV reactivation should be confirmed in randomized trials.