Probable Pulmonary Aspergillosis Research Articles

Infections in children following chimeric antigen receptor T-cell therapy for B-cell acute lymphoblastic leukemia.

CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy is transforming care for pediatric patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL). There are limited pediatric-specific data concerning the infection risks associated with CD19 CAR-T therapy and the adequacy of current antimicrobial prophylaxis guidelines for these patients. We describe the antimicrobial prophylaxis used and the types of infectious occurring in the first 100 days following CAR-T therapy for relapsed or refractory B-cell ALL in children and adolescents (≤18 years) at our centre. Twenty-seven patients received their first CAR-T infusion (CTI) during the study period. Almost all patients (96%) had a comprehensive Infectious Diseases review prior to CTI, which informed a personalised prophylaxis or fever/sepsis plan in six (22%). Overall, six (22%) patients had one or more infections during the study period including five (19%, 0.9 per 100 days-at-risk) from days 0-30 and three (n = 20, 15%, 0.6 per 100 days-at-risk) from days 31-100. Bacterial blood stream infections were the most common type of infection encountered during both time periods, and one patient had probable pulmonary aspergillosis. There were no infection-related deaths. Our study contributes important information on the spectrum of infections encountered in pediatric patients with B-ALL post CAR-T therapy. Overall, the burden of infectious complications post CAR-T therapy in our cohort is lower than previously reported in the literature. Results suggest that our prophylaxis recommendations are effective in this population.

754. Olorofim for treatment of invasive fungal infections (IFI) due to moulds in patients with limited or no treatment options: Interim results from a Phase 2b open-label study (NCT03583164, Study 32)

Abstract Background Olorofim, the first orotomide antifungal, selectively inhibits fungal dihydroorotate dehydrogenase (DHODH), a key enzyme in fungal pyrimidine biosynthesis. Olorofim is active against Aspergillus (including azole-resistant and cryptic species), resistant moulds (e.g., Lomentospora prolificans, Scopulariopsis) and dimorphic fungi (e.g., Coccidioides). The drug is given orally and cleared by multiple CYP450 isoenzymes. Serial images via bronchoscope of Scopulariopsis infection at the anastamosis in a lung transplant patient, pre- and post-olorofim therapy. After lung transplant, airway obstruction at the anastomosis due to Scopulariopsis was unresponsive to available antifungal agents. The airway was clear by day 10 on olorofim monotherapy. Infection was cured with 84 days of olorofim. Methods Patients with limited or no treatment options for proven invasive mycoses or probable pulmonary invasive aspergillosis (IA, as per 2020 EORTC-MSGERC criteria) received olorofim (loading dose of 150mg BID on day 1, followed by 90mg BID) for up to 90 days, with extended therapy beyond day 90 allowed. The primary endpoint was DRC-adjudicated overall response rate by pathogen at day 42 using the EORTC-MSG response criteria. Results At database lock for the first 100 cases, infecting fungi were Aspergillus species (53, including 13 azole-resistant species), L. prolificans (17), Scedosporium (11), Coccidioides (11), and other fungi (8). Success (complete or partial response) was 44% at day 42 and 39% at day 84. When stable disease was counted as success, the success rate was 69% and 59% respectively. Response was seen in patients with highly active, uncontrolled infection (Figure). Overall all-cause mortality was 14% and 19% at day 42 and 84 respectively (IA: 23% and 30%; non-IA infections 4% and 6% respectively). Safety: Olorofim was well tolerated over the 84d median dosing duration (max 722 days). Altered hepatic biochemistry possibly due to olorofim was seen in 8% of study subjects and managed by dose reduction/pause and led to discontinuation in 2%. Mild, self-limiting GI intolerance was noted in 2%. Conclusion Olorofim is an oral, mechanistically novel anti-mould agent with activity against a range of mould infections which are difficult to treat. Olorofim has a positive risk-benefit profile in a well-defined population of patients with infections due to moulds including species considered resistant to all approved antifungals. Disclosures Johan A. Maertens, MD PhD, F2G Ltd: Advisor/Consultant|Gilead Sciences Ltd: Advisor/Consultant|Mundipharma: Advisor/Consultant|Pfizer Inc: Advisor/Consultant George R. Thompson, III, MD, Amplyx: Advisor/Consultant|Amplyx: Grant/Research Support|Astellas: Advisor/Consultant|Astellas: Grant/Research Support|Cidara: Advisor/Consultant|Cidara: Grant/Research Support|F2G: Advisor/Consultant|F2G: Grant/Research Support|Merck: Grant/Research Support|Pfizer: DSMB|Scynexis: Advisor/Consultant|Scynexis: Grant/Research Support Andrej Spec, MD, MSCI, Astellas: Grant/Research Support Sarah P. Hammond, MD, F2G: Advisor/Consultant|F2G: Grant/Research Support|GSK: Grant/Research Support|Merck: Grant/Research Support|pfizer: Advisor/Consultant|Scynexis: Grant/Research Support Bart Rijnders, MD, PhD, F2G: Advisor/Consultant P. Lewis White, PhD, Associates of Cape Cod: Honoraria|F2G: Advisor/Consultant|Gilead: Grant/Research Support|IMMY: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Honoraria Oliver A. Cornely, Prof. Dr., Abbott: Honoraria|Abbvie: Advisor/Consultant|Actelion: Board Member|Al-Jazeera Pharmaceuticals: Honoraria|Allecra Therapeutics: Board Member|Amplyx: Advisor/Consultant|Amplyx: Grant/Research Support|Astellas: Honoraria|Basilea: Advisor/Consultant|Basilea: Grant/Research Support|Biocon: Advisor/Consultant|Biosys: Advisor/Consultant|BMBF: Grant/Research Support|Cidara: Advisor/Consultant|Cidara: Board Member|Cidara: Expert Testimony|Cidara: Grant/Research Support|CoRe Consulting: Stocks/Bonds|Da Volterra: Advisor/Consultant|DLR: Grant/Research Support|DZIF: Grant/Research Support|Entasis: Board Member|EU Directorate-General for Resarch and Innovation: Grant/Research Support|F2G: Grant/Research Support|German Patent and Trade Mark Office: German patent (DE 10 2021 113 007.7)|Gilead: Advisor/Consultant|Gilead: Grant/Research Support|Grupo Biotoscana/United Medical/Knight: Honoraria|Hikma: Honoraria|IQVIA: Board Member|Janssen: Board Member|Matinas: Advisor/Consultant|Matinas: Grant/Research Support|MedPace: Advisor/Consultant|MedPace: Grant/Research Support|MedScape: Honoraria|MedUpdate: Honoraria|Menarini: Advisor/Consultant|Merck/MSD: Grant/Research Support|Merck/MSD: Honoraria|Molecular Partners: Advisor/Consultant|MSG-ERC: Advisor/Consultant|Mundipharma: Grant/Research Support|Mylan: Honoraria|Noxxon: Advisor/Consultant|Octapharma: Advisor/Consultant|Octapharma: Grant/Research Support|Paratek: Board Member|Pardes: Advisor/Consultant|Pfizer: Grant/Research Support|Pfizer: Honoraria|Projektträger Jülich: Grant/Research Support|PSI: Advisor/Consultant|PSI: Board Member|Pulmocide: Board Member|Scynexis: Advisor/Consultant|Scynexis: Grant/Research Support|Seres: Advisor/Consultant|Shionogi: Board Member|Wiley (Blackwell): Editor-in-Chief, Mycoses Lesley Fitton, BSc, F2G Ltd: Employee|F2G Ltd: Stocks/Bonds Aaron Dane, MSc, Amplyx: Advisor/Consultant|AN2 therapeutics: Advisor/Consultant|Artizan: Advisor/Consultant|Cidara: Advisor/Consultant|ContraFect: Advisor/Consultant|Correvio: Advisor/Consultant|Davolterra: Advisor/Consultant|Destiny Pharma: Advisor/Consultant|Entasis: Advisor/Consultant|F2G Limited: Advisor/Consultant|GSK: Advisor/Consultant|Humanigen: Advisor/Consultant|Kymab: Advisor/Consultant|Modis: Advisor/Consultant|Orca: Advisor/Consultant|Pfizer: Advisor/Consultant|Phico: Advisor/Consultant|Pled Pharma: Advisor/Consultant|Rare Thyroid: Advisor/Consultant|Roche: Advisor/Consultant|Scynexis: Advisor/Consultant|Sinovent: Advisor/Consultant|Spero Therapeutics: Advisor/Consultant|Transcrip: Advisor/Consultant|Venatorx: Advisor/Consultant John H. Rex, MD, Advent Life Sciences: Operating Partner|Advent Life Sciences: Ownership Interest|AMR Action Fund: Advisor/Consultant|AstraZeneca: Stocks/Bonds|Basilea Pharmaceutica: Advisor/Consultant|Bugworks Research, Inc.: Advisor/Consultant|F2G, Limited: Employee|F2G, Limited: Stocks/Bonds|Forge Therapeutics: Advisor/Consultant|GlaxoSmithKline: Advisor/Consultant|Pfizer Pharmaceuticals: Honoraria|Sumitovant: Advisor/Consultant Sharon C. Chen, PhD MBBS, F2G PTy Ltd: Grant/Research Support|MSD Australia: Grant/Research Support.

870. Olorofim for the treatment of invasive mould infections in patients with limited or no treatment options: Comparison of interim results from a Phase 2B open-label study with outcomes in historical control populations (NCT03583164, FORMULA-OLS, Study 32)

Abstract Background Olorofim is a novel antifungal agent active against Aspergillus spp (including azole-resistant strains), rare, resistant moulds (e.g., Lomentospora prolificans) and dimorphic moulds. Serial images of Lomentospora prolificans infection following breast enhancement surgery: progression of healing pre- and post-olorofim therapy. Post-surgical bone/ soft tissue Lomentospora prolificans infection of the chest wall in a healthy woman was uncontrolled with available agents (D -9 visible mould in wound base). At D42/84 overall response on olorofim monotherapy was stable; wound closure with complete resolution of IFI was achieved at D322 (case previously reported, ECCMID 2020 abstract #2585). Methods Patients with limited/no treatment options for proven invasive fungal infection (IFI) or probable pulmonary invasive aspergillosis (IA) using EORTC-MSGERC criteria1 received oral olorofim (150mg BID x1d loading dose then 90mg BID). Outcomes in the first 100 patients are compared with historical controls (HCs) as well as with expected outcomes in patients with baseline highly active, uncontrolled IFI (HAU-IFI). Results All-cause mortality in IA at month 3 (includes data to Day 100, the best-fit time point for IA HC data) was 17/53 (32%, 95 CI 20–46%) for olorofim vs. 40/46 (87%, 74–95%) in HCs given either no therapy or azole monotherapy for azole-resistant IA. Successful EORTC-MSGERC overall response2 (OR, complete or partial based on clinical + radiologic + mycologic improvement) was 47%/42% in IA (Day 42/D84, n = 53), 53%/53% (L. prolificans, n=17), 55%/36% (Scedosporium, n=11), and 50%/50% (other moulds, n=8). Stable response at D42/D84 predicted extended therapy responses, especially in HAU-IFI of brain and bone (Figure). For Coccidioides (n=11) OR was limited to stable due to very slow clearance of fungal serology but clinical response was rapid. Symptoms resolved completely in 18% (2/11) by D84 vs 3% (1/29) by D1523 in comparable HCs with poorly controlled extrapulmonary Coccidioides infection; similar trends were seen for other response measures. Conclusion Olorofim is a novel oral antifungal with activity against a wide range of mould infections which are difficult to treat. Compared with relevant HCs or expected outcomes for HAU-IFI, olorofim has a positive benefit-risk profile in a well-defined population of patients with limited/no treatment options. As noted previously3, considering stable in overall success if often appropriate when assessing responses in non-IA mould IFI.

Bacterial/fungal infection in hospitalized patients with COVID-19 in a tertiary hospital in the Community of Castilla y León, Spain

IntroductionBacterial/fungal coinfection and superinfections contribute to the increased morbi-mortality of viral respiratory infections (RIs). The main objective of this study was to determine the incidence of these infections in hospitalized patients with COVID-19. MethodRetrospective observational study of all patients admitted for COVID-19 and bacterial/fungal infections at the Hospital Clínico Universitario of Valladolid, Spain (March 1–May 31, 2020). Demographic, clinical and microbiological data were compared based on Intensive Care Unit (ICU) admission and predictors of mortality by were identified using multivariate logistic regression analyses. ResultsOf the 712 COVID-19 patients, 113 (16%) presented bacterial/fungal coinfections or superinfections. Their median age was 73 years (IQR 57−89) and 59% were men. The profiles of ICU patients (44%) included male, SARS-CoV-2 pneumonia, leukocytosis, elevated inteleukin-6, with interferon β-1b and tocilizumab and superinfection (p < 0.05). Coinfections were diagnosed in 5% (39/712) patients. Most common pathogens of respiratory coinfection (18) were Streptococcus pneumoniae (6) and Staphylococcus aureus (6). Superinfections were detected in 11% (80/712) patients. Urinary (53) and RI (39) constituted the majority of superinfections Acinetobacter baumannii multidrug-resistant was the main agent of IR and bacteremia. An outbreak of A. baumannii contributed to this result. Three patients were considered to have probable pulmonary aspergillosis. Mortality was higher in UCI patients (50% vs. 29%, p = 0.028). The predictive factors of mortality included being a male with various comorbidities, SARS-CoV-2 pneumonia, bacteremia and superinfections from A. baumannii. ConclusionThe outbreak of A. baumannii was a determining factor in the increases of the incidence of infection and the morbi-mortality of ICU patients.

INVASIVE FUNGAL INFECTIONS IN CHILDREN TREATED FOR HEMATOLOGIC MALIGNANCIES - A FIVE-YEAR SINGLE CENTER EXPERIENCE.

Invasive fungal infections (IFI) are life-threatening complications of intensive chemotherapy treatment, with the incidence in pediatric patients ranging from 2% to 21%. In this article, we describe our 5-year experience of IFI in pediatric oncology patients and its clinical manifestations with radiological findings, treatment and outcome. A retrospective and descriptive survey of IFI in children with hematologic neoplasms was conducted at the Department of Oncology and Hematology, Zagreb Children's Hospital. Medical charts of children 0-17 years of age, of both sexes, treated for leukemias and lymphomas from January 2016 to December 2020 were reviewed. In a 5-year period, 60 patients were treated for hematologic malignancy, acute lymphoblastic leukemia (ALL) being the most prevalent diagnosis. IFI was verified in 9 (15%) children, predominantly in patients with ALL (75%). The specific causative agent was detected in one child, whereas other infections were classified as probable pulmonary aspergillosis. All the patients received standard prophylaxis with fluconazole and treatment with liposomal amphotericin B and voriconazole. The majority of our patients achieved recovery. IFI prevention, diagnosis and treatment remain a challenge. Uniform prophylaxis and therapy protocols, as well as environmental control are of vital importance for the development of better strategies in the prevention, early detection and treatment of IFI in pediatric hematology patients.

Bortezomib-Thalidomide-Dexamethasone (VTD) As Salvage Treatment in Patients with Multiple Myeloma Candidates for Transplantation in the Real World

BackgroundTreatment for Multiple Myeloma (MM) has evolved greatly, ranging from corticosteroids to monoclonal antibodies. In low-resource countries, however, the first-choice treatment is still based on cyclophosphamide-thalidomide-dexamethasone (CTD) regimen, either in patients who are candidates or non-candidates for stem cell transplantation (SCT). In Peru, a few years ago, bortezomib has been introduced as salvage treatment. Bortezomib as salvage treatment has reported 6.22 months of time to progression and combined complete and partial response rates of 38% in pivotal study. 1ObjectivesTo determine the response to treatment to VTD in patients with multiple myeloma candidates to transplant. To determine progression-free survival (PFS) to VTD. To determine the percentage of transplant patients.MethodsWe retrospectively assessed the clinical efficacy and toxicity of VTD (bortezomib 1.3mg/m2 subcutaneously on days 1, 4, 8 and 11; thalidomide 100mg orally on days 1 through 21; dexamethasone 40mg orally on days 1, 2, 4, 5, 8, 9, 11, 12 for three-week cycles), as salvage treatment in patients with relapsed/refractory MM candidate to autologous stem cell transplantation treated at Instituto Nacional de Enfermedades Neoplasicas in Lima, Peru, between January 2014 and December 2016. Patients received only one prior treatment and at least 2 cycles of VTD. SPSS program was used for data analysis. Survival outcomes were estimated by Kaplan-Meier Method.ResultsSixteen patients were found to fulfill the selection criteria. The median age was 52 (39-62), fifty-six percent (n=9) were male. International Staging System III disease was present in 75%. ECOG 1-2 was present in 94%. Ig G and IgA MM were 62.5% and 12.5% respectively; lambda light chain was present in 56.3%. 37.5% of patient had renal impairment. B2µg was >3.5mg/dL in 57% of patients. CTD was the first-line in 94%, with overall response rate (ORR) of 62.5% (complete response (CR) 6.3%, very good partial response (VGPR) 12.5%, and partial response (PR) 43.8%). For VTD regimen the median number of treatment cycles delivered was three (range 2-5), totally 59 cycles. After a median of 14 months follow-up for VTD (range 4-34), the overall response rate was 75%, stringent complete response (SCR) was 18.8% (n= 3), complete response 37.5%, very good partial response 6.3%, and partial response 12.5%. Six out of 16 patients (37.5%) with VTD treatment who were candidates for transplantation finally were transplanted. Among the causes for not undergoing transplantation, infections was 40% (20% (two) of cases were pulmonary tuberculosis, one case (10%) was herpes simplex encephalitis, one case (10%) was probable pulmonary aspergillosis), relapsed disease 40%, renal failure 10%, failure of stem cell collection 10%. Median PFS was 14 months (4-33m). 2-years PFS was 37.5%. 5-years overall survival (OS) was 55%, the median was not reached (18-110m). The most common adverse events for all patients were grade 2 peripheral neuropathy and infections (four infections described above), both in 25%, deep venous thrombosis was not reported. Three deaths was reported (18.75%) all for progression disease.ConclusionVTD is an effective treatment in transplant candidates with multiple myeloma who have relapsed after one previous therapy including thalidomide. PFS is superior to Bortezomib pivotal study in relapsed disease. Infectious diseases represent 40% of cause for not undergoing transplantation.

Infección bacteriana/fúngica en pacientes con COVID-19 ingresados en un hospital de tercer nivel de Castilla y León, España

IntroductionBacterial/fungal coinfection and superinfections contribute to the increased morbi-mortality of viral respiratory infections (RIs). The main objective of this study was to determine the incidence of these infections in hospitalized patients with COVID-19. MethodRetrospective observational study of all patients admitted for COVID-19 and bacterial/fungal infections at the Hospital Clínico Universitario of Valladolid, Spain (March 1-May 31, 2020). Demographic, clinical and microbiological data were compared based on Intensive Care Unit (ICU) admission and predictors of mortality by were identified using multivariate logistic regression analyses. ResultsOf the 712 COVID-19 patients, 113 (16%) presented bacterial/fungal coinfections or superinfections. Their median age was 73 years (IQR 57-89) and 59% were men. The profiles of ICU patients (44%) included male, SARS-CoV-2 pneumonia, leukocytosis, elevated inteleukin-6, with interferon β-1b and tocilizumab and superinfection (p < 0.05). Coinfections were diagnosed in 5% (39/712) patients. Most common pathogens of respiratory coinfection (18) were Streptococcus pneumoniae (6) and Staphylococcus aureus (6). Superinfections were detected in 11% (80/712) patients. Urinary (53) and RIs (39) constituted the majority of superinfections Acinetobacter baumannii multidrug-resistant was the main agent of IR and bacteremia. An outbreak of A. baumannii contributed to this result. Three patients were considered to have probable pulmonary aspergillosis. Mortality was higher in UCI patients (50 vs. 29%; p = 0.028). The predictive factors of mortality included being a male with various comorbidities, SARS-CoV-2 pneumonia, bacteremia and superinfections from A. baumannii. ConclusionThe outbreak of A. baumannii was a determining factor in the increases of the incidence of infection and the morbi-mortality of ICU patients.

A case of cutaneous penicilliosis in a child with acute myeloid leukaemia

Introduction: We present a case of cutaneous penicilliosis in a paediatric patient with acute myeloid leukaemia (AML). Case report: A 2-year-old boy with AML first developed probable pulmonary aspergillosis during induction chemotherapy in an overseas centre in May 2013, and was treated with AmBisome and voriconazole. When he was admitted to our centre with relapsed AML in October 2013, he was given a fifth course of chemotherapy, and treated with AmBisome for probable pulmonary aspergillosis in view of pulmonary nodular opacities on computed tomography. He thereafter developed an erythematous skin lesion with central eschar on his right hand and left calf. Serum and bronchoalveolar lavage galactomannan antigen (GM Ag) indices increased to a value of &gt;10. AmBisome was changed to voriconazole, and caspofungin was added for 10 days. The left calf skin biopsy showed abundant fungal hyphae with septations. A skin culture grew Penicillium citrinum with MICs (μg ml− 1) of: caspofungin 0.016, itraconazole 0.5, amphotericin 1.5 and voriconazole &gt;256.Caspofungin and itraconazole were commenced, and voriconazole was discontinued. The skin lesions and serial GM Ag indices improved. The patient later developed increasing GM Ag indices to a value of &gt;10, which was attributed to Aspergillus flavus left pulmonary mycetoma, which was surgically resected. He eventually succumbed to relapsed AML after a bone-marrow transplant. Conclusion: To the best of our knowledge, this is the first paediatric case of P. citrinum infection. Rising GM Ag indices were attributed to cross-reactivity of Penicillium spp. with GM Ag enzyme immunoassays.

Multifocal periostitis as a complication of chronic use of voriconazole in a lung transplant recipient

Fungal infections are common in solid organ transplantation. An increasing number of transplant recipients receive antifungal therapy for prolonged duration owing to invasive fungal infections. Herein, we describe a diagnosis of periostitis as a complication of chronic use of voriconazole in a lung transplant recipient. The patient was diagnosed with probable pulmonary aspergillosis and was treated with oral voriconazole for a total of 9 months. Evidence of multifocal periostitis was observed in the axial and appendicular skeleton. Early recognition of this phenomenon is important to prevent unnecessary tests and procedures. Prompt discontinuation of voriconazole should result in improvement of symptoms.

Pharmacokinetic Profile of Voriconazole in a Critically Ill Patient on Therapeutic Plasma Exchange

Extracorporeal removal of drugs during therapeutic plasma exchange (TPE) can lead to decreased efficacy, as shown in several reports discussing altered pharmacokinetics (PKs) of antibiotics during TPE. In particular, drugs with a low volume of distribution or a high protein binding are susceptible to extracorporeal removal, as these drugs remain substantially within the intravascular space. No information is known about antifungal drug removal during TPE. We report the PKs of voriconazole in a critically ill patient undergoing TPE. A 61-year-old man, presenting with catastrophic antiphospholipid syndrome for which TPE was started, developed probable pulmonary invasive aspergillosis. Intravenous voriconazole was started. Blood samples were taken under steady state conditions to calculate PK parameters of voriconazole, both with and without TPE. PK parameters (area under the curve, Cl, Vd, and t1/2) were equivalent on both days. Voriconazole has a distribution volume of 4.5 L/kg and a protein binding of 58%, suggesting that drug removal during TPE would not be clinically significant. Our data support this assumption. Based on our findings, it seems that TPE does not alter the PK behavior of voriconazole. Voriconazole dosages should not be adjusted during TPE.

The Serum Galactomannan Index Predicts Mortality in Allogeneic Hematopoietic Stem Cell Transplant Recipients with Probable Pulmonary Invasive Aspergillosis

The Serum Galactomannan Index Predicts Mortality in Allogeneic Hematopoietic Stem Cell Transplant Recipients with Probable Pulmonary Invasive Aspergillosis

Molecular Epidemiology of Aspergillus fumigatus: an In-Depth Genotypic Analysis of Isolates Involved in an Outbreak of Invasive Aspergillosis

We recently reported an outbreak of invasive aspergillosis in the major heart surgery unit of Hospital Gregorio Marañón, Madrid, Spain (T. Peláez, P. Muñoz, J. Guinea, M. Valerio, M. Giannella, C. H. W. Klaassen, and E. Bouza, Clin. Infect. Dis., in press). Aspergillus fumigatus was isolated from clinical samples from 10 patients admitted to the unit during the outbreak period (surgical wound invasive aspergillosis, n = 2; probable pulmonary invasive aspergillosis, n = 4; colonization, n = 4). In the study described here, we have studied the genotypic diversity of the A. fumigatus isolates found in the air and clinical samples. We used short tandem repeats of A. fumigatus (STRAf) typing to analyze the genotypes found in the 168 available A. fumigatus isolates collected from the clinical samples (n = 109) from the patients and from the environmental samples taken from the air of the unit (n = 59). The genotypic variability of A. fumigatus was higher in environmental than in clinical samples. Intrasample variability was also higher in environmental than in clinical samples: 2 or more different genotypes were found in 26% and 89% of clinical and environmental samples, respectively. We found matches between environmental and clinical isolates in 3 of the 10 patients: 1 patient with postsurgical invasive aspergillosis and 2 patients with probable pulmonary invasive aspergillosis. A total of 7 genotypes from 3 different patients and the air grouped together in 2 clusters. Clonally related genotypes and microvariants were detected in both clinical and environmental samples. STRAf typing proved to be a valuable tool for identifying the source of invasive aspergillosis outbreaks and for studying the genotypic diversity of clinical and environmental A. fumigatus isolates.

Combination Antifungal Therapy and Surgery for the Treatment of Invasive Pulmonary Aspergillosis After Hematopoietic Stem Cell Transplantation

An 8-year old boy, affected by severe aplastic anemia, developed a probable pulmonary invasive aspergillosis (IA) early after a second unrelated allogeneic hematopoietic stem cell transplant (HSCT). He was treated promptly with the combination of liposomal amphotericin B and caspofungin. Despite the initial stabilization, the patient deteriorated and the antifungal therapy was switched to voriconazole and caspofungin. The patient gradually improved and was discharged home on day +29 post-HSCT on oral voriconazole. On day +119, a sudden episode of hemoptysis occurred and a right superior lobectomy was decided to remove the residual aspergilloma. The patient is now alive and well more than 24 months from HSCT. This case demonstrated that antifungal combination therapy and surgery are valid options to cure pulmonary IA even in patients at high-risk and severely immunosuppressed.

Oral Voriconazole for Neutropenia: A Leukemia Patient with Probable Pulmonary Aspergillosis and Scedosporidiosis

"Oral Voriconazole for Neutropenia: A Leukemia Patient with Probable Pulmonary Aspergillosis and Scedosporidiosis." Journal of Chemotherapy, 23(1), pp. 53–54

Infectious Complications After Unrelated Umbilical Cord Blood Transplantation (UCBT) in Adult Patients with Hematological Malignancies.

Abstract 1142Poster Board I-164Unrelated umbilical cord blood is being increasingly used as an alternative stem cell source for allogeneic stem cell transplantation. This retrospective study assessed infectious complications occurring in adult patients after UCBT.Thrity-one patients received a single (n=4) or double UCBT (n=27) with a median dose of 4.7×107 nucleated cells/kg (range, 2.4-7.7). Patients received either a reduced-intensity conditioning (n=23) or a standard myeloablative regimen (n=8). The cumulative incidence of neutrophil recovery was 90%. Neutrophil recovery was achieved at a median time of 24 (range, 8-60) days after UCBT.With a median follow up of 10 (range, 3-30) months in surviving patients, the OS was 57% (95%CI, 38-84). At last follow-up, 10 patients have died. Relapse (n=5) and TRM (n=5) were the primary causes of death. In the 5 patients who died from NRM, the causes of death were secondary graft failure (n=1), refractory GVHD (n=2) and infectious-related mortality (n=2; cumulative incidence, 8%). The two patients who died from infectious causes had an EBV-related lymphoproliferative disorder and adenovirus infection respectively. Overall, 7 documented bacteremia were observed in 5 patients, at a median time of 7 (range, 3-277) days after UCBT. The cumulative incidence of first bacteremia was 16% in the whole study population and 21% (n=4/20) when excluding patients with graft failure. Recurrent CMV infection was detected in 6 patients at a median time of 36 (range, 26-89) days. No CMV disease developed after preemptive CMV therapy. The cumulative incidence of recurrent CMV infection was 21%. Of note, 4 of these 6 cases of CMV recurrences were diagnosed in patients with primary graft failure. Therefore, the cumulative incidence was only 11% when focusing on patients without graft failure. EBV reactivation occurred in 6 patients with a median time of 101 (range, 28-438) days after UCBT. Except for one patient who developed a fatal EBV-related lymphoproliferative disorder refractory to Rituximab, all other 5 cases of EBV infections were asymptomatic. Other isolated viruses included: BK-virus with hemorrhagic cystitis (n=6), adenovirus (detected in the blood, n=3), Varicella-Zoster Virus (n=1), Respiratory Syncitial Virus (rhinitis, n=1) and parainfluenzae 3 virus (rhinitis, n=1). Of note, HHV6 was systematically detected in recipient blood samples.In all, 5 cases of fungal or parasitic infections were documented. Two cases of Toxoplasmosis gondii encephalitis were diagnosed in one patient with a primary graft failure and in another patient with a secondary graft failure (cumulative incidence of parasitic infections, 6%). Three probable pulmonary invasive aspergillosis were also diagnosed, two of which occurred in patients with refractory acute leukemias. The cumulative incidence of invasive fungal infections (IFI) was 10%. None of these fungal or parasitic infections was the primary cause of death. Overall, the cumulative incidence of infectious-related mortality (IRM) was 8%.In conclusion, this data suggests that UCBT can be performed in adult patients with hematological malignancies with an acceptable incidence of IRM provided a sufficient dose of nucleated cells is infused to the patient. DisclosuresNo relevant conflicts of interest to declare.

Iron Overload in Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation: Quantification of Iron Burden by a Superconducting Quantum Interference Device (SQUID) and Therapeutic Effectiveness of Phlebotomy

Iron overload (IO) is a known adverse prognostic factor in patients who undergo allogeneic hematopoietic stem cell transplantation (HSCT) for thalassemia and appears to play a similar role in patients with other hematologic disorders. The estimation of IO is based primarily on serum ferritin level; however, many confounding factors can result in ferritin overestimation, especially in HSCT recipients. The aim of the present study was to quantify IO after HSCT using a superconducting quantum interference device (SQUID), and to evaluate the impact of IO on hepatic function and infections. In addition, the feasibility of iron depletion was investigated. A total of 102 consecutive allogeneic HSCT recipients admitted to our outpatient department between December 2005, and December 2007, were analyzed. Primary diagnosis included acute leukemia/myelodysplastic syndrome in 61% of cases. Assessment of IO after HSCT included serum ferritin; in those with hyperferritinemia (ferritin>1000 ng/mL), liver iron concentration (LIC) was evaluated by SQUID magnetic susceptometry. Iron removal therapy was offered to patients with moderate IO (LIC 1000-2000 microg Fe/g wet weight [ww]) or severe IO (LIC >2,000 microg Fe/g ww). Fifty-seven patients had a ferritin level <1000 ng/mL: the median time between HSCT and assessment of ferritin level was 1006 days (range, 93-5239 days), significantly different from the median time of 183 days (range, 78-2957 days) in the 45 patients with a ferritin level >1000 ng/mL. Out of 42 patients evaluated by SQUID, 29 had moderate to severe IO (median LIC value, 1493 microg Fe/g ww [range, 1030-3253]). In a multivariate analysis, a significant correlation was found between a ferritin level >1000 ng/mL and the presence of at least one abnormal liver function test (LFT) ORo=6.8; 95% CI=2.2-20.6). In addition, the rate of proven/probable invasive fungal disease was significantly higher in the patients with hyperferritinemia (13% vs 0%; P=.006). Nineteen of the 24 patients considered eligible for iron-depletion therapy underwent regular phlebotomy; 13 completed the program in a median of 287 days (range, 92-779 days), reaching the target of a ferritin level<500 ng/mL; LIC was significantly reduced (median, 1419 microg Fe/g ww to 625 microg Fe/g ww; P < .001) in 8 of the 9 patients who were revaluated by SQUID at the end of the iron-depletion program. In conclusion, the measurement of LIC obtained by SQUID documented the presence of moderate/severe IO in 69% of the patients with a high ferritin level. Our data showed that in HSCT recipients, high ferritin level is an independent risk factor for abnormal LFTs, and IO may be considered a potential risk factor for fungal infections. A phlebotomy program may be feasible in two-thirds of the patients who might benefit from iron depletion.

Posaconazole as Prophylaxis in Immunocompromised Patients: A Single Center Experience

Efficacy of posaconazole was recently demonstrated in the prevention of invasive fungal infections (IFI) in recipients of allogeneic hematopoietic stem cell transplantation (Allo-HSCT) with GVHD and in patients undergoing intensive chemotherapy for acute myelogenous leukemia or myelodysplastic syndromes.Between Jan 2007 and April 2008, 54 patients had received posaconazole prophylaxis (200 mg t.i.d orally) either during induction chemotherapy (33 pts) or because of GVHD (25 pts). Four patients belong to the two subgroups. We analyze these two subgroups separately. IFI were defined as possible/probable/proven according to EORTC/MSG criteria. Prophylaxis with posaconazole was performed to 33 patients undergoing induction chemotherapy (29 AML, 3 MDS, 1 aplastic anemia), (19F/14M), median age 67 years ( range 21 – 81). The median duration of neutropenia (ANC< 500 cells/mm3 ) was 39 days (range10 – 278 days). Median duration of posaconazole prophylaxis was 27 days (range 4 – 203 days), early discontinuation of prophylaxis was observed in 20 patients because of progression to IFI in 5 cases, empirical antifungal therapy for persistent fever (11 cases), mucositis (3 cases) and hepatic toxicity (1 case). Possible or probable IFI was diagnosed in 5/33 (14%) patients (3 possible and 2 probable pulmonary aspergillosis). Five deaths were occurred, only one was related to the IFI, other causes of death were intercurrent disease in 3 patients and one septic choc. Twenty five patients with GVHD treated with intensive immunosuppressive therapy had received posaconazole prophylaxis (13F/12M), median age 52 years (range21– 70), one patient had a prior diagnosis of IFI and was in complete resolution. RIC allo-HSCT was performed to 12 patients,10 sibling donors,14 MUD, one patient received umbilical cord blood transplantation. Acute GVHD grade II to IV and chronic extensive GVHD were reported in 16 and 9 patients respectively. All patients had received high dose corticosteroids (0.5 to 2 mg/Kg/d), the majority of them (21) had two or more immunosuppressive agents. The median duration of posaconazole prophylaxis was 110 days (range 19 days - 10 months), 6 patients are still receiving prophylaxis, 4 premature discontinuations due to hepatic toxicity in one case, progression to IFI in 2 cases and diet because of severe digestive GVHD in one case. Two patients (8%) developed IFI ( 1 possible and 1 probable pulmonary aspergillosis) during prophylaxis period. One patient died from IFI. IFI-unrelated death occurred in 5/25 (20%) patients.Conclusions: We observed 6% (2/33) probable/proven IFI in AML patients undergoing intensive chemotherapy and 4% (1/25) in GVHD patients witch is comparable to the incidence reported in recent studies (Oliver et al., NEJM 2007; 356:348–59/Andrew et al., NEJM 2007; 356:335–47). These results suggest that posaconazole prophylaxis is effective in reducing the incidence of IFI in this high risk population.

Voriconazole Is Safe and Effective as a Prophylactic Regimen of Invasive Fungal Infections for High Risk Patients after Reduced-Intensity Umbilical Cord Blood Transplantation

Invasive fungal infections (IFI) are significant complications after allogeneic hematopoietic stem cell transplantation. We previously reported that 3-year cumulative incidence of IFI was 10.2 % and median onset of IFI was day 20 post reduced-intensity umbilical cord blood transplantation (RI-CBT) under the prophylaxis by fluconazole or micafungin (Biol Bone Marrow Transplant 2007; 13:771). In recent years, voriconazole (VOR) has been employed in IFI prophylactic regimens during bone marrow or peripheral blood stem cell transplantation in several clinical trials and reports, but the safety and efficacy during umbilical cord blood transplantation is unclear. In order to address this issue, we prospectively administered VOR to 46 high risk recipients of RI-CBT for IFI prophylaxis, between August 2007 and May 2008. All of the patients had no prior episode of IFI and were treated in reverse isolation in laminar airflow-equipped rooms. The plasma trough concentration of VOR and serum galactomannan index was obtained once a week. Chest CT scan was performed for persistent fever under the administration of broad antibiotics. Proven and probable IFI were defined according to revised EORTC/MSG criteria. Median age was 58 years old (range, 21–82). Twenty-three were AML, 10 were non-Hodgkin lymphoma, 6 were aplastic anemia, 5 were ALL, 1 was CML, and 1 was multiple myeloma. All patients were at high risk of IFI, except one patient with lymphoma in CR; 22 had high risk underlying diseases, 17 had prior transplantation, and 6 were very severe aplastic anemia. All patients received fludarabine-based preparative regimens. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus & mycophenolate mofetil in 30, tacrolimus alone in 15, and cyclosporine alone in 1. Additional immune suppressive therapy against pre-engfraftment immune reactions (Transplant 2005; 80:34) or GVHD were administered in 35 patients; 19 received corticosteroid (CS), 7 beclomethasone (BDP), 5 CS & BDP, 1 CS & BDP & infliximab, 1 CS & infliximab, 1 CS & BDP & etanercept, and 1 CS & methotrexate. Forty-two patients achieved neutrophil recovery > 500/uL on day 21 post-transplant at medium (range, 11–38). The median length of VOR prophylaxis from transplantation was 85 days (range, 6–422) for patients who survived longer than 100 days. The total number of patient-days on VOR was 4241 days. There were no proven IFI. Two patients developed probable pulmonary aspergillosis during VOR administration (at day 71 and 75; 1-year cumulative incidence 4.3 %.) No breakthrough infections by candida or zygomycetes were detected. VOR was well tolerated, except in 2 patients who discontinued VOR due to abnormal liver test and severe visual disturbance. Two patients developed probable pulmonary aspergillosis after switching from VOR to other antifungals (at day 80 and 263 under the administration of micafungin and itraconazole, respectively). Thus, VOR can be safely administered, and have reduced the incidence of IFI, with no breakthrough infections by candida or zygomycetes, indicating possible superiority of incorporating this drug as an IFI prophylactic regimen in RI-CBT.

Liposomal Amphotericin B IV (LIPO AB) Once Per Week Is Effective in the Prevention of Invasive Fungal Infections (IFI) in Patients (Pts) with Acute Leukemia: Preliminary Analysis of a Randomized Trial.

Background: IFI remain an important cause of morbidity and mortality in pts with acute myelogenous leukemia or high risk myelodysplastic syndrome (AML/HR-MDS). We have previously shown that voriconazole (VORI) or LIPO AB 3 mg/kg/day TIW were effective prophylactic regimens in AML/HR-MDS. LIPO AB given once every week achieves tissue levels expected to prevent IFI, decreases the risk for infusion-related adverse events (IRE) and would simplify prophylaxis.Materials and Methods: We conducted a 3-arm randomized trial comparing LIPO AB, 3 mg/kg/d TIW (LIPO AB 3); versus LIPO AB 9 mg/kg/d, 1/week (LIPO AB 9); versus VORI 200 mg PO 2/day among pts with AML/MDS undergoing induction or salvage chemotherapy (CHEMO). Pts were stratified by age and disease status and randomized to receive any of the 3 regimens 24 hours after completion of CHEMO. Serum Galactomannan Index (GMI) was obtained 2/week while CT scan of chest (CT) was performed for persistent fever after 3 days of broad spectrum antibiotics. Proven and probable IFI were defined according to EORTC/MSG criteria. The results of the first 59 pts (of 150 planned) enrolled between Dec 06 -July 07 are presented.Results: Pts characteristics and response are shown in Table 1. All pts had Zubrod performance status ≤ 2 and most underwent remission induction chemo (90% in each group). No significant differences were observed on key baseline characteristics. Three of the 59 pts did not receive study drug (AMBI 9=2; VORI=1) and were excluded from efficacy and safety analysis. There were no proven IFI; 3 pts developed probable pulmonary Aspergillosis [GMI(+); CT (+), cultures (−) ], while 10 pts received additional empirical antifungal therapy (AFT) because of FUO [ 7 pts; GMI (−), CT (−), cultures (−)] or pneumonia [ 3 pts; GMI (−), cultures (−)]. None of these 10 pts developed proven/probable IFI. Two pts in each study arm developed reversible side effects that lead to drug discontinuation [AMBI 3: Grade 2 hyperbilirubinemia (1); Grade 3 infusion related events (1); AMBI 9: Grade 3 infusion related event (2); VORI: Grade 2 hyperbilirubinemia (1), visual hallucinations (1)]. Overall mortality was 5% (1 pt/arm). There were no IFI-related deaths.Conclusion: Intermittent LIPO AB (3 mg/kg/d TIW or 9 mg/kg/d, 1/week) and VORI 200 mg PO 2/day prophylaxis appear to be effective and well-tolerated regimens. Enrollment of additional pts is ongoing.Table 1LIPO AB 3 (n=20)LIPO AB 9 (n=20)VORI (n=19)Median age* (range)60 (40–79)60 (23–69)58 (31–77)Pts in protected environment* (%)806579Diabetes mellitus**, n(%)1 (5)1 (5)5 (26)Median days on prophylaxis* (range)17 (1–34)14 (1–37)17 (1–37)Efficacy and adverse eventsLIPO AB 3 (n=20)LIPO AB 9 (n=18)VORI (n=18)No IFI*, n(%)14 (70)14 (78)15 (83)Proven/Probable IFI*, n(%)2 (10)1 (5)0Empiric AFT*, n(%)4 (10)3 (17)3 (17)Adverse events*, n443All drug-related*, n(%)2 (10)2 (11)2 (11)*p=ns; **p=0.061

Successful treatment of tongue aspergillosis caused byAspergillus flavuswith liposomal amphotericin B in a child with acute lymphoblastic leukemia

A 5-year-old boy with acute lymphoblastic leukemia and probable pulmonary aspergillosis developed a hard, protuberant, white-yellow and aggressive elongated lesion on the left side of his tongue during a febrile agranulocytopenic episode. Despite the use of broad-spectrum antibiotics and other supportive therapies, the lesion increased to about 2x4 cm in size within two days and became grey-black with an erythemateous, irregular line. Partial excision of the tongue was performed and isolates recovered from the tongue biopsy specimen were identified as Aspergillus flavus. An increase in the systemic dose (7 mg/kg/day) and local intraoral delivery of liposomal amphotericin B was successful in treating the patient and resulted in improved clinical and laboratory findings. Herein, we document the observation of tongue aspergillosis in a leukemic child with probable pulmonary aspergillosis receiving liposomal amphotericin B therapy and the successful treatment of tongue aspergillosis with an increased dose (7mg/kg) of liposomal amphotericin B. To the best of our knowledge, this is the youngest patient with documented intraoral aspergillosis and only the second case of tongue aspergillosis caused by Aspergillus flavus.