Progression-free survival at 24 months (PFS24) and subsequent outcome for patients with diffuse large B-cell lymphoma (DLBCL) enrolled on randomized clinical trials.

Background: Patients with diffuse large B-cell lymphoma treated with first-line anthracycline-based immunochemotherapy and remaining in remission at 2 years have excellent outcomes. This study assessed overall survival (OS) stratified by progression-free survival (PFS) at 24 months (PFS24) using individual patient data from patients with DLBCL enrolled in multi-center, international randomized clinical trials as part of the Surrogate Endpoint for Aggressive Lymphoma (SEAL) Collaboration. Patients and methods: PFS24 was defined as being alive and PFS24 after study entry. OS from PFS24 was defined as time from identified PFS24 status until death due to any cause. OS was compared with each patient's age-, sex-, and country-matched general population using expected survival and standardized mortality ratios (SMRs). Results: A total of 5853 patients enrolled in trials in the SEAL database received rituximab as part of induction therapy and were included in this analysis. The median age was 62 years (range 18-92), and 56% were greater than 60 years of age. At a median follow-up of 4.4 years, 1337 patients (23%) had disease progression, 1489 (25%) had died, and 5101 had sufficient follow-up to evaluate PFS24. A total of 1423 assessable patients failed to achieve PFS24 with a median OS of 7.2 months (95% CI 6.8-8.1) after progression; 5-year OS after progression was 19% and SMR was 32.1 (95% CI 30.0-34.4). A total of 3678 patients achieved PFS24; SMR after achieving PFS24 was 1.22 (95% CI 1.09-1.37). The observed OS versus expected OS at 3, 5, and 7 years after achieving PFS24 was 93.1% versus 94.4%, 87.6% versus 89.5%, and 80.0% versus 83.7%, respectively. Conclusion: Patients treated with rituximab containing anthracycline-based immunochemotherapy on clinical trials who are alive without progression at 24 months from the onset of initial therapy have excellent outcomes with survival that is marginally lower but clinically indistinguishable from the age-, sex-, and country-matched background population for 7 years after achieving PFS24.

Characterization of efficacy and safety of pathogen inactivated and quarantine plasma in routine use for treatment of acquired immune thrombotic thrombocytopenic purpura.

BACKGROUND: Auto-immune thrombotic thrombocytopenic purpura (TTP) is a morbid multi-organ disorder. Cardiac involvement not recognized in initial disease descriptions is a major cause of morbidity. Therapeutic plasma exchange (TPE) requires exposure to multiple plasma donors with risk of transfusion-transmitted infection (TTI). Pathogen inactivation (PI) with amotosalen-UVA, the INTERCEPT Blood System for Plasma (IBSP) is licensed to reduce TTI risk. METHODS: An open-label, retrospective study evaluated the efficacy of quarantine plasma (QP) and IBSP in TTP and defined treatment emergent cardiac abnormalities. Medical record review of sequential patient cohorts treated with QP and IBSP characterized efficacy by remission at 30 and 60 days (d) of treatment, time to remission, and volume (L/kg) of plasma required. Safety outcomes focused on cardiac adverse events (AE), relapse rates, and mortality. RESULTS: Thirty-one patients (18 IBSP and 13 QP) met study criteria for auto-immune TTP. The proportions (%) of patients in remission at 30 d (IBSP = 61·1, QP = 46·2, P = 0·570) and 60 d (IBSP = 77·8, QP = 76·9, P = 1·00) were not different. Median days to remission were less for IBSP (15·0 vs. 24·0, P = 0·003). Relapse rates (%) 60 d after remission were not different between cohorts (IBSP = 7·1, QP = 40·0, P = 0·150). ECG abnormalities before and during TPE were frequent; however, cardiac AE and mortality were not different between treatment cohorts. CONCLUSIONS: Cardiac and a spectrum of ECG findings are common in TTP. In this study, IBSP and QP had similar therapeutic profiles for TPE.

Prospective pilot study of high-dose (10 mg/kg/day) liposomal amphotericin B (L-AMB) for the initial treatment of mucormycosis.

BACKGROUND: Mucormycosis incidence is increasing and is associated with a high rate of mortality. Although lipid-based formulations of amphotericin B are the recommended first-line treatment, only one prospective trial in a limited number of patients has been performed to evaluate this regimen. METHODS: Patients with proven or probable mucormycosis were included between June 2007 and March 2011. Patients were scheduled to receive 10 mg/kg/day liposomal amphotericin B (L-AMB) monotherapy for 1 month and surgery was performed when appropriate. The primary outcome was response rate at week 4 or at the end of treatment (EOT) if before week 4, evaluated by an independent committee. ClinicalTrials.gov Identifier: NCT00467883. RESULTS: Forty patients were enrolled. Response was analysed in 33 patients at week 4. Most patients had a haematological malignancy as their primary underlying disease (53%). Seventy-one percent of patients underwent therapeutic surgery. The response rate at week 4 or at EOT was 36%, with 18% partial responses and 18% complete responses. The response rate at week 12 was 45%, with 13% partial responses and 32% complete responses. Overall mortality was 38% at week 12 and 53% at week 24. Serum creatinine doubled in 16 (40%) patients and returned to normal levels within 12 weeks in 10/16 (63%). CONCLUSIONS: High-dose L-AMB for mucormycosis, in combination with surgery in 71% of cases, was associated with an overall response rate of 36% at week 4 and 45% at week 12 and creatinine level doubling in 40% of patients (transient in 63%). These results may serve as the basis for future clinical trials.

[Medication adverse events: Impact of pharmaceutical consultations during the hospitalization of patients]. / Évènements iatrogènes médicamenteux : impact des consultations pharmaceutiques en cours d'hospitalisation.

The medication iatrogenic events are responsible for nearly one iatrogenic event in five. The main purpose of this prospective multicenter study is to determine the effect of pharmaceutical consultations on the occurrence of medication adverse events during hospitalization (MAE). The other objectives are to study the impact of age, of the number of medications and pharmaceutical consultations on the risk of MAE. The pharmaceutical consultation is associated to a complete reassessment done by both a physician and a pharmacist for the home medication, the hospital treatment (3days after admission), the treatment during chemotherapy, and/or, the treatment when the patient goes back home. All MAE are subject to an advice for the patient, additional clinical-biological monitoring and/or prescription changes. Among the 318 patients, 217 (68%) had 1 or more clinically important MAE (89% drug-drug interaction, 8% dosing error, 2% indication error, 1% risk behavior). The patients have had 1121 pharmaceutical consultations (3.2±1.4/patient). Thus, the pharmaceutical consultations divided by 2.34 the risk of MAE (unadjusted incidence ratio, P≤0.05). Each consultation decreased by 24% the risk of MAE. Moreover, adding one medication increases from 14 to 30% as a risk of MAE on the population. Pharmaceutical consultations during the hospital stay could reduce significantly the number of medication adverse effects.

Comparison of pixantrone-based regimen (CPOP-R) with doxorubicin-based therapy (CHOP-R) for treatment of diffuse large B-cell lymphoma.

BACKGROUND: Pixantrone is an aza-anthracenedione with enhanced, preclinical antitumor activity and reduced cardiotoxicity compared with doxorubicin. PATIENTS AND METHODS: We compared the efficacy and toxic effect of CPOP-R (substituting pixantrone for doxorubicin) against CHOP-R in untreated, diffuse large B-cell lymphoma (DLBCL) patients. The primary objective was to demonstrate non-inferiority of CPOP-R by complete response/complete response unconfirmed (CR/CRu) rate. RESULTS: The CR/CRu rate for CPOP-R was 75% versus 84% for CHOP-R. Three-year overall survival was lower for CPOP-R (69% versus 85%) (P = 0.029). Median progression-free survival (PFS) was not reached for CPOP-R and was 40 months for CHOP-R [HR 95% confidence interval (CI) = 1.02 (0.60, 1.76), P = 0.934]. Fewer CPOP-R patients developed congestive heart failure (CHF) (0% versus 6%, P = 0.120), ≥ 20% declines in ejection fraction (2% versus 17%, P = 0.004), or elevations in troponin-T (P = 0.003). CONCLUSIONS: CPOP-R is an active regimen with modestly lower response rates than CHOP-R but similar PFS and event-free survival. This study demonstrates a substantially lower cardiotoxicity of pixantrone compared with doxorubicin when used as first-line therapy in DLBCL.

High incidence but low burden of coronaviruses and preferential associations between respiratory viruses.

Respiratory viruses are the leading cause of acute infections in humans. However, the burden of certain respiratory viruses, such as coronaviruses, and the relevance of viral coinfections remain unclear. In this study, we investigated the distribution and seasonal occurrences of respiratory viruses detected by multiplex molecular assay in 6,014 samples from 2008 to 2011 in a French hospital. We assessed the detection frequencies of 14 respiratory viruses and their clinical impact in immunosuppressed and nonimmunosuppressed patients. Furthermore, we explored the preferential association patterns between respiratory viruses in multiple infections. Our results indicated that human rhinovirus/enterovirus (HRV/EV) and coronavirus (HCoV) were frequently detected in respiratory samples (48.81% and 11.74% of infected samples, respectively), and the detection frequencies of these viruses were further increased in immunosuppressed patients. The most common subtypes of HCoV were HCoV-229E (33.80%) and HCoV-HKU1 (32.39%). A sharp increase in the detection frequencies of HCoV-229E and HCoV-HKU1 over several months suggested that these subtypes were epidemic in our population. In immunosuppressed patients, HCoV contributed to upper respiratory tract infections (52%). Evidence did not support lower respiratory tract infections exclusive to a unique HCoV infection. In multiply infected individuals, determined in 6.3% of samples, HRV/EV and HCoV were detected in 33.29% and 22.90% of samples, respectively. Interestingly, nearly 50% of HCoV infections were detected in association with another virus. Since the distributions of respiratory viruses in multiply infected patients were subject to preferential association patterns between viruses, we propose complex interactions between different respiratory viruses and host factors.

Cerebral aspergillosis in the era of new antifungals: The CEREALS national cohort study Nationwide CEREbral Aspergillosis Lesional study (CEREALS).

BACKGROUND: Cerebral aspergillosis (CA) is a life-threatening disease for which diagnosis and management remain challenging. Detailed analyses from large cohorts are lacking. METHODS: We included 119 cases of proven (n = 54) or probable (n = 65) CA diagnosed between 2006 and 2018 at 20 French hospitals. Data were collected at baseline and during follow-up. Cerebral imaging was reviewed centrally by two neuroradiologists. RESULTS: The most frequent underlying conditions were hematological malignancy (40%) and solid organ transplantation (29%). Galactomannan was detected in the serum of 64% of patients. In 75% of cases, at least one of galactomannan, Aspergillus PCR, and ß-d-glucan was positive in the cerebrospinal fluid. Six-week mortality was 45%. Two distinct patterns of disease were identified according to presumed route of dissemination. Presumed haematogenous dissemination (n = 88) was associated with a higher frequency of impaired consciousness (64%), shorter time to diagnosis, the presence of multiple abscesses (70%), microangiopathy (52%), detection of serum galactomannan (69%) and Aspergillus PCR (68%), and higher six-week mortality (54%). By contrast, contiguous dissemination from the paranasal sinuses (n = 31) was associated with a higher frequency of cranial nerve palsy (65%), evidence of meningitis on cerebral imaging (83%), macrovascular lesions (61%), delayed diagnosis, and lower six-week mortality (30%). In multivariate analysis and in a risk prediction model, haematogenous dissemination, hematological malignancy and the detection of serum galactomannan were associated with higher six-week mortality. CONCLUSION: Distinguishing between hematogenous and contiguous dissemination patterns appears to be critical in the workup for CA, as they are associated with significant differences in clinical presentation and outcome.

Treatment outcome of invasive mould disease after sequential exposure to azoles and liposomal amphotericin B.

OBJECTIVES: To analyse the potential antagonism between azoles, which inhibit ergosterol synthesis, and polyenes, which bind directly to ergosterol in cell membranes, in patients receiving sequential azole-polyene treatment. METHODS: In an earlier randomized, double blind study of liposomal amphotericin as initial therapy for invasive filamentous fungal infection (IFFI), a 3 mg/kg/day dose had a favourable overall response rate of 50% and 12 week survival rate of 72%. No improved outcome was seen with 10 mg/kg/day for the first 14 days. The study population was further analysed for the effect of prior azole exposure on treatment responses to liposomal amphotericin B. The protocol allowed prior treatment with azoles for prophylaxis or empirical therapy, and for up to 4 days for the confirmed IFFI before starting liposomal amphotericin B. Outcomes were compared for subsets of patients based on receipt of any azole and receipt of voriconazole during the 30 day screening period prior to study treatment. RESULTS: Of 201 patients with data review board-confirmed IFFI, 116 (57.7%) received prior azoles and 36 (17.9%) received prior voriconazole. Favourable responses were achieved in 57 (49.1%) patients with prior azole exposure, in 39 (45.9%) without prior azole and in 13 (36.1%) with prior voriconazole. Numbers of patients alive at 12 weeks were 74 (63.8%) with any prior azole, 56 (65.9%) without prior azole and 26 (72.2%) after prior voriconazole. No differences were statistically significant. CONCLUSIONS: Prior treatment with any azole or specifically with voriconazole did not seem to impact on overall response or survival in patients treated with liposomal amphotericin B for confirmed IFFI.

Forty-one recent cases of invasive zygomycosis from a global clinical registry.

BACKGROUND: Invasive zygomycosis accounts for a significant proportion of all invasive fungal diseases (IFD), but clinical data on the clinical course and treatment response are limited. PATIENTS AND METHODS: Fungiscope-A Global Rare Fungal Infection Registry is an international university-based case registry that collects data of patients with rare IFD, using a web-based electronic case form at www.fungiscope.net. RESULTS: Forty-one patients with invasive zygomycosis from central Europe and Asia were registered. The most common underlying conditions were malignancies (n = 26; 63.4%), diabetes mellitus (n = 7; 17.1%) and solid organ transplantation (n = 4; 9.8%). Diagnosis was made by culture in 28 patients (68.3%) and by histology in 26 patients (63.4%). The main sites of infection were the lungs (n = 24; 58.5%), soft tissues (n = 8; 19.5%), rhino-sinu-orbital region (n = 8; 19.5%) and brain (n = 6; 14.6%). Disseminated infection of more than one non-contiguous site was seen in six patients (14.6%). Mycocladus corymbifer was the most frequently identified species (n = 10, 24.4%). A favourable response was observed in 23 patients (56.1%). Overall survival was 51.2% (n = 21). At diagnosis, four patients (9.8%) were on continuous antifungal prophylaxis with itraconazole (n = 1; 2.4%) or posaconazole (n = 3; 7.3%). Initial targeted treatment with activity against zygomycetes was administered to 34 patients (82.9%). Liposomal amphotericin B was associated with improved response (P = 0.012) and survival rates (P = 0.004). CONCLUSIONS: Pathogen distribution and, consequently, drug susceptibility seem to vary across different geographic regions. Furthermore, protection from invasive zygomycosis for patients on posaconazole prophylaxis is not absolute. Our findings indicate that the use of liposomal amphotericin B as first-line treatment for patients diagnosed with zygomycoses merits further investigation, preferably in the form of a clinical trial.

Using routine blood parameters to anticipate clinical outcomes in invasive aspergillosis.

OBJECTIVE: In invasive aspergillosis (IA), monitoring response to antifungal treatment is challenging. We aimed to explore if routine blood parameters help to anticipate outcomes following IA. METHODS: Post hoc secondary analysis of two multicenter randomized trials was performed. The Global Comparative Aspergillosis Study (GCA, n = 123) and the Combination Antifungal Study (CAS, n = 251) constituted the discovery and validation cohorts respectively. The outcome measures were response to treatment and survival to 12 weeks. Interval platelet, galactomannan index (GMI) and C-reactive protein (CRP) levels prior and during antifungal treatment were analysed using logistic regression, Kaplan-Meier survival and receiver operating characteristic (ROC) analyses. RESULTS: The 12-week survival was 70.7% and 63.7% for the GCA and CAS cohorts respectively. In the GCA cohort, every 10 × 109/L platelet count increase at week 2 and 4 improved 12-week survival odds by 6-18% (odds ratio (OR) 1.06-1.18, 95% confidence interval (CI) 1.02-1.33). Survival odds also improved 13% with every 10 mg/dL CRP drop at week 1 and 2 (OR 0.87, 95% CI 0.78-0.97). In the CAS cohort, week 2 platelet count was also associated with 12-week survival with 10% improved odds for every 10 × 109/L platelet increase (OR, 1.10, 95% CI 1.04-1.15). A GMI drop of 0.1 unit was additionally found to increase the odds of treatment response by 3% at the baseline of week 0 (OR 0.97, 95% CI 0.95-0.99). Week 2 platelet and CRP levels performed better than GMI on ROC analyses for survival (area under ROC curve 0.76, 0.87 and 0.67 respectively). A baseline platelet count higher than 30 × 109/L clearly identified patients with >75% survival probability. CONCLUSIONS: Higher serial platelets were associated with overall survival while GMI trends were linked to IA treatment response. Routine and simple laboratory indices may aid follow-up of response in IA patients.

Voriconazole plus terbinafine combination antifungal therapy for invasive Lomentospora prolificans infections: analysis of 41 patients from the FungiScope® registry 2008-2019.

OBJECTIVES: Lomentospora prolificans is an emerging cause of serious invasive fungal infections. Optimal treatment of these infections is unknown, although voriconazole-containing treatment regimens are considered the treatment of choice. The objective of this study was to evaluate the role of combination antifungal therapy for L. prolificans infections. METHODS: We performed a retrospective review of medical records of patients with invasive L. prolificans infection diagnosed between 1 January 2008 and 9 September 2019 that were documented in the FungiScope® registry of rare invasive fungal infections. We compared clinical outcomes between antifungal treatment strategies. RESULTS: Over the study period, 41 individuals with invasive L. prolificans infection from eight different countries were documented in the FungiScope® registry. Overall, 17/40 (43%) had treatment response/stable disease and 21/40 (53%) had a fatal outcome attributed to invasive fungal infection. Combination antifungal therapy was associated with increased 28-day survival (15/24 survived versus 4/16 receiving monotherapy; p 0.027) and the combination voriconazole plus terbinafine trended to be associated with higher rates of treatment success (10/16, 63%, 95% CI 35%-85%) compared with other antifungal treatment regimens (7/24, 29%, 95% CI 13%-51%, p 0.053). In Kaplan-Meier survival analysis there was a higher survival probability in individuals receiving the voriconazole/terbinafine combination compared with other antifungal regimens (median survival 150 days versus 17 days). CONCLUSIONS: While overall mortality was high, combination antifungal treatment, and in particular combination therapy with voriconazole plus terbinafine may be associated with improved treatment outcomes compared with other antifungal regimens for the treatment of invasive L. prolificans infections.

Rituximab versus observation after high-dose consolidative first-line chemotherapy with autologous stem-cell transplantation in patients with poor-risk diffuse large B-cell lymphoma.

BACKGROUND: This study compared the induction regimens doxorubicin, cyclophosphamide and etoposide (ACE) with doxorubicin, cyclophosphamide, vincristine, bleomycin and prednisone (ACVBP) before high-dose therapy (HDT) followed by autologous stem-cell transplantation (ASCT) for patients with poor-risk diffuse large B-cell lymphoma (DLBCL). A second randomisation compared rituximab with observation post-ASCT. MATERIALS AND METHODS: Four hundred and seventy-six patients <60 years old with newly diagnosed CD20+ DLBCL were randomised to induction with ACE or ACVBP. Three hundred and thirty responders received HDT followed by ASCT. After ASCT, 269 patients were re-randomised to receive either maintenance rituximab or observation alone. Randomisation was stratified by the quality of response to ASCT. The primary end point of this study was event-free survival (EFS). RESULTS: At a median of 4 years' follow-up from the second randomisation, there was a trend (P = 0.1) towards increased EFS for patients who received rituximab compared with observation. CONCLUSION: The type of induction therapy (ACVBP or ACE) did not significantly affect overall survival at a median 51 months' follow-up.

An EORTC Phase II study of caspofungin as first-line therapy of invasive aspergillosis in haematological patients.

OBJECTIVES: Caspofungin was evaluated as first-line monotherapy of invasive aspergillosis (IA) in patients with haematological malignancies and undergoing autologous transplants. METHODS: Adults with proven or probable IA, defined strictly according to EORTC-MSG criteria, were eligible. Those with possible IA were enrolled, but were not evaluable for efficacy unless upgraded to proven/probable disease within 7 days of registration based on investigations performed within 48 h after enrolment. Caspofungin dosage was 70 mg (day 1) followed by 50 mg/day. The primary endpoint was the proportion of patients with complete or partial response at the end of caspofungin therapy in the modified intention to treat (MITT) group; secondary endpoints were response and survival at day 84 and safety. RESULTS: In the MITT group (n = 61), 75% of patients had cancer not in remission (relapsing or refractory), 85% were neutropenic at enrolment and 49% had a Karnofsky score of < or =50. At end of treatment, 1 and 19 patients had complete and partial response, respectively [success rate 33% (20/61)], 9 (15%) achieved stabilization and 31 (51%) had disease progression. One patient was not evaluable. The 6 and 12 week survival rates were 66% (40/61) and 53% (32/60), respectively. Baseline characteristics associated with survival at day 84 were an underlying disease in remission (not relapsing or refractory) and Karnofsky score. Recovery from neutropenia at the end of treatment was also significantly associated with survival. No serious drug-related adverse events or discontinuations due to drug-related adverse events were observed. CONCLUSIONS: Caspofungin provided an observed response rate compatible with the null hypothesis of a true response rate of < or =35%. Underlying disease-related factors had a major impact on results.

Isavuconazole: A new broad-spectrum azole. Part 2: pharmacokinetics and clinical activity.

Isavuconazole, the active moiety of its prodrug isavuconazonium, is a new extended-spectrum triazole whose activity against yeasts, molds, including Aspergillus and mucorales, and dimorphic fungi has been shown in vitro and in preclinical models. The most relevant pharmacokinetics features are water-solubility of the prodrug, rapid cleavage of the prodrug into active moiety and cleavage product by plasmatic esterases, high oral bioavailability of isavuconazole with an extensive penetration into most tissues and a good safety profile even in case of renal impairment. The results of two main clinical studies have led to an approval by FDA and EMA in the treatment of invasive aspergillosis and invasive mucormycosis. Isavuconazole is non-inferior to voriconazole in terms of response and survival in invasive aspergillosis and has shown improved safety and tolerability. Importantly, less hepatobiliary, skin and eye disorders have been reported in isavuconazole-treated patients. Isavuconazole has therefore been granted a grade A-I recommendation by the European Conference on Infections in Leukemia (ECIL) for the treatment of invasive aspergillosis. Efficacy has also been demonstrated in mucormycosis in an open-label study. Survival was similar to the survival of matched patients from the international Fungiscope registry and treated with an amphotericin B formulation. Isavuconazole failed to show non-inferiority to caspofungin in a large double-blind candidemia trial. The aim of this review is to give the reader an overview of the data available so far to support inclusion of isavuconazole in the anti-mold therapeutic arsenal.

Isavuconazole: A new broad-spectrum azole. Part 1: In vitro activity.

Triazoles compounds are first-line agents for the treatment of invasive fungal diseases. Isavuconazole is the most recent triazole compound, approved in 2015 by the FDA and the EMA to treat invasive aspergillosis and mucormycosis. We reviewed here the in vitro activity of isavuconazole against a vast spectrum of species. Isavuconazole MICs were evaluated using CLSI, EUCAST or Etest methods, with no significant differences between the technics. Low MIC50 and MIC90 (<1µg/mL) were described for isavuconazole against the majority of Candida spp., except for C. glabrata and C. krusei. In vitro activity against Aspergillus spp. varied according to the species with an overall MIC90 of 1µg/mL ranging from 0.125µg/mL (A. fumigatus) to 16µg/mL (A. niger, A. tubingiensis). As for Aspergillus, the activity of isavuconazole against agents of mucormycosis varies upon genus and species, with an overall MIC90 from 4 (Rhizopus spp.) to 16µg/mL (Rhizomucor spp. and Mucor spp.). Recently, to help detecting non-wild-type isolates, EUCAST committee has proposed ECOFFs values for C. albicans, C. parapsilosis and C. tropicalis (0.03µg/mL), for Aspergillus fumigatus (2µg/mL), A. nidulans (0.25µg/mL), A. terreus (1µg/mL), A. flavus (2µg/mL) and A. niger (4µg/mL). Moreover, clinical breakpoints (susceptible/resistant) were defined for Aspergillus fumigatus (1µg/mL), A. nidulans (0.25µg/mL) and A. terreus (1µg/mL). Using these breakpoints, isavuconazole showed activity against the vast majority of fungi.

18F-FDG PET/CT for invasive fungal infection in immunocompromised patients.

BACKGROUND: Opportunistic invasive fungal infections (IFIs) comprise a heterogeneous spectrum of pathogens, whose early diagnosis remains challenging. Candida spp. and Aspergillus spp, the most frequent pathogens in immunocompromised patients, frequently affect lungs, liver, bone and skin. AIM: To evaluate the impact of 18F-FDG PET/CT in the management of immunocompromised patients with IFI. DESIGN: A single-center retrospective study included 51 immunocompromised patients with IFI diagnosis undergoing 83 18F-FDG PET/CTs. METHODS: Twenty-nine 18F-FDG PET/CTs were performed for primary work-up in 29 treatment-naïve patients. Fifty-four PET/CTs were performed during follow-up to confirm IFI suspicion in 22 patients who had anti-fungal drug therapy before PET/CT. When available, histological and/or microbiological criteria were used to assess IFI diagnosis. RESULTS: Aspergillus spp. and Candida spp. were the most frequent microorganisms responsible for IFI in our population. 18F-FDG PET/CT sensitivity, specificity, positive and negative predictive values, and global accuracy were 93%, 81%, 95%, 72% and 90%, respectively. 18F-FDG PET/CT influenced the diagnostic work-up at primary staging in 16/29 patients (55%) by assessing the extent of infection and targeting the diagnostic procedure. 18F-FDG PET/CT results during treatment induced anti-fungal drugs dosage increase and/or new drugs addition in 8/54 cases (15%) and contributed to the reduction of anti-fungal drugs dosage or treatment withdraws in 17 cases (31%). CONCLUSIONS: We recommend the utilization of 18F-FDG PET/CT to improve the primary staging work-up of immunocompromised patients with IFI and to assess treatment effectiveness or disease relapse. Both 18F-FDG PET/CT and conventional imaging should be integrated into a well-defined imaging diagnostic algorithm considering the clinical context and both strengths and limitations of each diagnostic modality.

Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline.

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.

Assessment of high-priced systemic antifungal prescriptions.

OBJECTIVES: To assess compliance with international guidelines for costly antifungal prescriptions and to compare these results with a first study performed in 2007. METHODS: Retrospective study including all costly antifungal prescriptions made in surgical and medical intensive care units and in a hepatobiliary, pancreatic, and digestive surgery unit. Prescriptions were assessed in terms of indication, dosage, and antifungal de-escalation. RESULTS: Seventy-four treatments were analyzed. Treatments were prescribed for prophylactic (1%), empirical (22%), pre-emptive (16%), or targeted therapy (61%). Caspofungin accounted for 68% of prescriptions, followed by voriconazole (20%) and liposomal amphotericin B (12%). Indication was appropriate in 91%, debatable in 1%, and inappropriate in 8%. Dosage was appropriate in 69%, debatable in 8%, and inappropriate in 23%. Prescriptions were inappropriate for the following reasons: lack of dosage adjustment in light of the hepatic function (10 cases), underdosage or excessive dosage by>25% of the recommended dose in seven cases. De-escalation to fluconazole was implemented in 40% of patients presenting with a fluconazole-susceptible candidiasis. CONCLUSION: The overall incidence of appropriate use was higher in 2012 compared with 2007 (62% and 37% respectively, P=0.004). Nevertheless, costly antifungal prescriptions need to be optimized in particular for empirical therapy, dosage adjustment, and potential de-escalation to fluconazole.

Clinical antifungal efficacy trials in invasive aspergillosis: Consensus standards for trial design and room for improvement.

Despite recent improvements in outcome of invasive aspergillosis there are still high failure and fatality rates. The trial comparing voriconazole to amphotericin B deoxycholate has become a reference for clinical trials in invasive aspergillosis due to the large number of patients included, the use of definition criteria close to the international consensus criteria, the inclusion of the halo sign on chest computed tomography for the definition of probable cases, the extensive review of the data by a panel of experts including radiologists, and most important, the successful efficacy results. Similar strict methodology for eligibility and assessment of outcome has been applied in the recently completed liposomal amphotericin B trial. This study compared a standard daily dose of liposomal amphotericin B (3 mg/kg) versus a high loading dose (10 mg/kg/d). The option to include possible cases in this trial and to give the investigators a few days to upgrade the diagnosis to a probable or definite level proved to be an effective strategy, saving four months in the duration of the recruitment period. Additional progress can be expected in future trials with the use of a standardized cutoff for the galactomannan detection test and a stratification at randomization on the most critical prognostic factor such as progressive underlying malignancy or allogeneic stem cell transplantation.