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1. Invasive mucormycosis in children: An epidemiologic study in European and non-European countries based on two registries

Author

Pana, Z.D. Seidel, D. Skiada, A. Groll, A.H. Petrikkos, G. Cornely, O.A. Roilides, E. Kindo, A. Núñez, A.A. Henrique, H. Carlesse, F. Chander, J. Lass-Flörl, C. Dupont, B. Heinz, W. Klimko, N. Khostelidi, S. Lagrou, K. Pagano, L. Racil, Z. Rolencova, M. Sedlacek, P. Chrenkova, V. Horakova, J. Mudry, P. Vehreschild, M.J.G.T. Zimmerli, S. Collaborators of Zygomyco.net and/or FungiScope™ Registries28

Abstract

Background: Mucormycosis has emerged as a rare but frequently fatal invasive fungal disease. Current knowledge on paediatric mucormycosis is based on case reports and small series reported over several decades. Contemporary data on a large cohort of patients is lacking. Methods: Two large international registries (Zygomyco.net and FungiScope™) were searched for mucormycosis cases in ≤19 year-old patients. Cases enrolled between 2005 and 2014 were extracted, and dual entries in the two databases merged. Epidemiology, clinical characteristics, diagnostic procedures, therapeutic management and final outcome were recorded and analysed with SPSS v.12. Results: Sixty-three unique cases (44 proven and 19 probable) were enrolled from 15 countries (54 in European and 9 in non-European countries). Median age was 13 years [Interquartile Range (IQR) 7.7] with a slight predominance (54.1 %) of females. Underlying conditions were haematological malignancies (46 %), other malignancies (6.3 %), haematopoietic stem cell transplantation (15.9 %), solid organ transplantation, trauma/surgery and diabetes mellitus (4.8 % each) and a variety of other diseases (7.9 %); in 9.5%, no underlying medical condition was found. Neutropenia was recorded in 46 % of the patients. The main sites of infection were lungs (19 %), skin and soft tissues (19 %), paranasal sinus/sino-orbital region (15.8 %) and rhino-cerebral region (7.9 %). Disseminated infection was present in 38.1 %. Mucormycosis diagnosis was based on several combinations of methods; culture combined with histology was performed in 31 cases (49.2 %). Fungal isolates included Rhizopus spp. (39.7 %), Lichtheimia spp. (17.5 %), Mucor spp. (12.7 %), Cunninghamella bertholletiae (6.3 %) and unspecified (23.8 %). Treatment comprised amphotericin B (AmB) monotherapy in 31.7 % or AmB in combination with other antifungals in 47.7 % of the cases, while 14.3 % received no antifungals. Surgery alone was performed in 6.3 %, and combined with antifungal therapy in 47.6 %. Crude mortality at last contact of follow-up was 33.3 %. In regression analysis, disseminated disease and prior haematopoietic stem cell transplantation were associated with increased odds of death, whereas the combination of systemic antifungal therapy with surgery was associated with improved survival. Conclusion: Paediatric mucormycosis mainly affects children with malignancies, presents as pulmonary, soft tissue, paranasal sinus or disseminated disease and is highly lethal. Outcome is improved when active antifungal therapy and surgery are combined. © 2016 The Author(s).

Published
2016

2. COMPARISON OF GALACTOMANNAN DETECTED IN SERUM/BRONCHOALVEOLAR LAVAGE FLUID AND TYPE OF ABNORMALITY ON PULMONARY HIGH RESOLUTION COMPUTER TOMOGRAPHY IN PATIENTS WITH PULMONARY INVASIVE ASPERGILLOSIS

Author

Weinbergerova, B., Racil, Z., Maluskova, D., Muzik, J., Kocmanova, I., Drgona, L., Kouba, M., Hricinova, M., Guman, T., Gabzdilova, J., Haber, J., Kristina Forsterova, Bojtarova, E., Ziakova, B., Novak, J., Chrenkova, V., Sedlacek, P., Vokurka, S., Mudry, P., Tkacikova, B., Zavrelova, A., Zak, P., Ostojic, A., Vrhovac, R., Sejnova, D., Zatezalo, V., Gredelj, N., Mallatova, N., Timr, P., Horakova, J., Chocholova, A., Navratil, M., Hajek, R., Rolencova, M., Mayer, J., Cetkovsky, P., Dusek, L., and Cools, Jan

Subjects
carbohydrates (lipids), respiratory system, Invasive aspergillosis, Galactomannan, HRCT, bacterial infections and mycoses, skin and connective tissue diseases, respiratory tract diseases
Abstract

Background: Up to now there have been missing data in the literature concerning relationship of galactomannan (GM) detected in bronchoalveolar lavage (BAL) fluid and type of abnormality on pulmonary high resolution computer tomography (HRCT) in patients (pts.) with pulmonary invasive aspergillosis (IPA). Aims: To evaluate relationship between sensitivity of GM detected in BAL fluid and serum (S-GM) and type of abnormality on pulmonary HRCT in pts. with IPA. Methods: We retrospectively analyzed mentioned relationship in pts. with IPA entered in „Fungal InfectioN Database (FIND)“ aspergillus between 2001 and 2012.

Published
2014

3. Invasive aspergillosis in patients with hematological malignancies in Czech and Slovak Republics: fungal infection database (find) analysis (2001-2011) - an update

Author

Weinbergerova, B., Racil, Z., Kocmanova, I., Muzik, J., Kouba, M., Vydra, J., Drgona, L., Masarova, L., Gabzdilova, J., Guman, T., Ziakova, B., Bojtarova, E., Forsterova, K., Haber, J., Chrenkova, V., Sedlacek, P., Novak, J., Heklova, R., Mudry, P., Sejnova, D., SAMUEL VOKURKA, Karas, M., Mallatova, N., Chocholova, A., Horakova, J., Ligova, A., Ostojic, A., Vrhovac, R., Timr, P., Gredelj, N., Rolencova, M., Kandrnal, V., Cetkovsky, P., Mayer, J., Cornely, O. A., Meis, J. F. G. M., and Schaller, M.

Subjects
Invasive aspergillosis, Hematologic malignancies
Abstract

Objectives: “Fungal InfectioN Database” (FIND) represents international database of invasive fungal infections in Czech and Slovak hematooncological departments. FIND - aspergillus covers all case of invasive aspergillosis (IA) in participating centers since 2001. Methods: The goal of our retrospective analysis was to evaluate incidence, early diagnostic procedures and effect of antifungal therapy in proven and probable IA that occurred in 16 institutions participating in FIND database between 2001–2011. Till 2009 we followed EORTC/MSG 2002 and from 2010 EORTC/MSG 2008 criteria in evaluation of IA diagnosis and therapy response. Results: 256 probable and 58 proven IA (91% isolated pulmonary IA, IPA) have been documented. Prolonged and profound neutropenia (61%) and long-term use of corticosteroids (28%) were identified as the major risk factors of IA. 68% pts. had consecutive positivity of serum-galactomannan (S-GM) (OD index >0.5). 83% pts. with IPA and bronchoalveolar lavage (BAL) had positive GM in BAL fluid (OD index >0.5). In pts. with IPA only 7.6% BAL fluids and 8.4% sputum samples had positive microscopic result for filamentous fungi and 2.2% BAL fluids and 1.8% sputum samples had positive culture for Aspergillus spp. The primary antifungal therapy of IA was used in 89% pts. - 41% voriconazole (VORI), 7% echinocandins (ECHINO), 23% VORI+ECHINO, 7% amphotericine B deoxycholate (C-AMB) and 9% lipid- based AMB (LBA). Overall RR to primary therapy of IA was 46% - VORI 55%, VORI+ECHINO 54%, C-AMB 35%, LBA 39%, ECHINO 25%. There was a statistically significant difference in overall RR to targeted therapy in pts. with neutrophil count 1.0x10e9/L at the end of therapy (21% vs. 71%). The overall mortality rate was 61%, with 39% attributable to IA. Conclusion: On the basis of our analysis we confirm typical risk factors for IA and critical role of S-GM and CT for early diagnosis and prompt start of antifungal therapy of IA. A reasonable treatment response was achieved using VORI, VORI+ECHINO or LBA in primary therapy of IA. We have confirmed neutropenia at the end of antifungal therapy as the major predictive factor for therapeutic response. On behalf of CELL - The Czech leukemia study group for life.

4. Invasive aspergillosis in patients with hematological malignancies in Czech, Slovak and Croatian hematooncological departments: Fungal INfection Database (FIND) analysis (2001-2014) - an update

Author

Weinbergerova, B., Racil, Z., Kocmanova, I., Lengerova, M., Janousova, E., Drgona, L., Kouba, M., Hricinova, M., Ostojic, A., Vrhovac, R., Gabzdilova, J., Guman, T., Petecukova, V., Novak, J., Forsterova, K., Haber, J., Ziakova, B., Bojtarova, E., Zavrelova, A., Vokurka, S., Chrenkova, V., Sedlacek, P., Tkacikova, B., Mudry, P., Zatezalo, V., Gredelj, N., Mallatova, N., Timr, P., Sejnova, D., Tanuskova, D., Chocholova, A., Horakova, J., Navratil, M., Roman Hajek, Chudej, J., Sokol, J., Rolencova, M., Zak, P., Cetkovsky, P., and Mayer, J.

Subjects
invasive aspergillosis, education, population characteristics, health care economics and organizations, geographic locations, humanities
Abstract

Invasive aspergillosis in patients with hematological malignancies in Czech, Slovak and Croatian hematooncological departments: Fungal INfection Database (FIND) analysis (2001-2014) - an update

5. Micafungin as empirical antifungal therapy in hematological patients: a retrospective, multicenter study in the Czech and Slovak Republics.

Author

Racil Z, Toskova M, Kocmanova I, Buresova L, Kouba M, Drgona L, Masarova L, Guman T, Tothova E, Gabzdilova J, Forsterova K, Haber J, Ziakova B, Bojtarova E, Rolencova M, Timilsina S, Cetkovsky P, and Mayer J

Subjects
Adult, Aged, Antifungal Agents adverse effects, Antineoplastic Agents adverse effects, Antineoplastic Agents therapeutic use, Czech Republic, Echinocandins adverse effects, Female, Fever etiology, Hematologic Neoplasms drug therapy, Humans, Lipopeptides adverse effects, Male, Micafungin, Middle Aged, Neutropenia chemically induced, Retrospective Studies, Slovakia, Treatment Outcome, Young Adult, Antifungal Agents therapeutic use, Echinocandins therapeutic use, Fever drug therapy, Hematologic Neoplasms complications, Lipopeptides therapeutic use, Neutropenia drug therapy
Abstract

The objective of this retrospective, multicenter study was to evaluate the efficacy and safety of micafungin as empirical antifungal therapy during febrile neutropenia (FN) in 73 hematological patients from six centers in two countries. All patients received 100 mg of micafungin/day. The overall favorable response rate (RR) was 64.8% when the resolution of fever during neutropenia was included in the response criteria and 84.5% when excluded. A significantly lower favorable RR in patients with persistent fever and non-specific pulmonary infiltrates compared to patients with persistent fever only (82.8 vs. 52.4%, respectively; p = 0.011) was not found when resolution of fever was not included in the composite endpoint criteria (93.1 vs. 78.6%, respectively; p = 0.180). Breakthrough fungal disease developed in 2.7% of patients. Treatment was discontinued in 16.4% of cases. Only one patient (1.4%) discontinued therapy due to an adverse event. Posaconazole prophylaxis improved favorable RR when defervescence was included as composite endpoint criterion (p = 0.047), but not when it was excluded (p = 0.485). However, neutrophil recovery did not influence favorable RR (p = 0.803 and p = 0.112, respectively). These data suggest that micafungin is safe and effective as an empirical therapy in patients with FN.

Published
2013
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6. Monitoring trough voriconazole plasma concentrations in haematological patients: real life multicentre experience.

Author

Racil Z, Winterova J, Kouba M, Zak P, Malaskova L, Buresova L, Toskova M, Lengerova M, Kocmanova I, Weinbergerova B, Timilsina S, Rolencova M, Cetkovsky P, and Mayer J

Subjects
Adolescent, Adult, Aged, Antifungal Agents adverse effects, Aryl Hydrocarbon Hydroxylases genetics, Aspergillosis complications, Aspergillosis genetics, Cytochrome P-450 CYP2C19, Dose-Response Relationship, Drug, Female, Hematologic Diseases complications, Hematologic Diseases genetics, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Pyrimidines adverse effects, Retrospective Studies, Treatment Outcome, Triazoles adverse effects, Voriconazole, Young Adult, Antifungal Agents administration & dosage, Antifungal Agents blood, Aspergillosis drug therapy, Drug Monitoring, Hematologic Diseases drug therapy, Pyrimidines administration & dosage, Pyrimidines blood, Triazoles administration & dosage, Triazoles blood
Abstract

The objective of this retrospective study was to evaluate results from voriconazole therapeutic drug monitoring (TDM) in haematological patients in routine clinical practice. Between 2005 and 2010, 1228 blood samples were obtained from 264 haematological patients (median 3 samples/patient; range 1-27) receiving voriconazole for targeted/preemptive treatment of invasive aspergillosis (IA) (46.3% of samples), empirical therapy (12.9%) or prophylaxis (40.8%). A high-pressure liquid chromatography assay was used to analyse voriconazole concentrations. Clinical and laboratory data were analysed retrospectively. The median of the detected voriconazole plasma concentration was 1.00 μg ml(-1) (range <0.20-13.47 μg ml(-1)). Significant inter- and intra-patients variability of measured concentrations (81.9% and 50.5%) were identified. With the exception of omeprazole administration, there was no relevant relationship between measured voriconazole concentrations and drug dose, route administration, age, gender, CYP2C19*2 genotype, gastrointestinal tract abnormality, administration via nasogastric tube, serum creatinine, and liver enzymes. However, per patient analysis identified significant role of individual voriconazole dose and drug form change on measured plasma concentration. Measured voriconazole concentrations did not correlate with the treatment outcome of patients with IA. We only identified a limited number of adverse events related to voriconazole therapy; however, the median plasma concentration was not different from concentrations measured in samples without reported toxicity. Our retrospective study has suggested that routine monitoring of voriconazole plasma concentrations has probably only a limited role in daily haematological practice., (© 2012 Blackwell Verlag GmbH.)

Published
2012
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7. Galactomannan detection in bronchoalveolar lavage fluid for the diagnosis of invasive aspergillosis in patients with hematological diseases-the role of factors affecting assay performance.

Author

Racil Z, Kocmanova I, Toskova M, Buresova L, Weinbergerova B, Lengerova M, Rolencova M, Winterova J, Hrncirova K, Volfova P, Skrickova J, and Mayer J

Subjects
Adolescent, Adult, Aged, Antifungal Agents adverse effects, Antifungal Agents therapeutic use, Aspergillus chemistry, Aspergillus isolation & purification, Bronchoscopy, Cohort Studies, Female, Galactose analogs & derivatives, Hematologic Neoplasms complications, Humans, Invasive Pulmonary Aspergillosis drug therapy, Invasive Pulmonary Aspergillosis microbiology, Male, Mannans blood, Middle Aged, Neutropenia complications, Predictive Value of Tests, Retrospective Studies, Sensitivity and Specificity, Young Adult, Bronchoalveolar Lavage Fluid chemistry, Hematologic Diseases complications, Invasive Pulmonary Aspergillosis diagnosis, Mannans analysis
Abstract

Background: We evaluated the performance of a galactomannan (GM) assay in bronchoalveolar lavage (BAL) fluid compared to serum samples for the diagnosis of invasive pulmonary aspergillosis (IPA) in patients with hematological diseases., Methods: Two hundred and fifty-five bronchoscopies were performed on 230 patients. Bronchial and alveolar samples from BAL fluid as well as serum samples were analyzed in the GM assay., Results: Twenty-eight cases of IPA (11%) were diagnosed. The sensitivity, specificity, positive predictive value, and negative predictive value of the GM assay using a cut-off of 0.5 were 57.1%, 99.3%, 94.1%, and 92.5%, respectively, for the alveolar sample; 44.0%, 99.3%, 91.7%, and 91.4%, respectively, for the bronchial sample; and 60.7%, 100%, 100%, and 92.9%, respectively, for serum. The highest sensitivity (78.6%) with good specificity (98.6%) was obtained with a 'triple detection' of GM in bronchial, alveolar, and serum samples. Neutropenia and antifungal therapy for only 24h increased the sensitivity, while antifungal treatment for ≥ 2 days decreased assay performance. Moreover, a trend towards a higher volume of aspirated fluid in GM-negative BAL (p=0.092) was observed., Conclusions: In contrast to recently published data, we found only moderate sensitivity, but high specificity and high positive predictive value of the detection of GM in BAL fluid. In addition, neutropenia, antifungal therapy, and BAL standardization affected GM assay performance., (Copyright © 2011 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Published
2011
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