R Herbrecht

Radboud University Medical Centre (Radboudumc), Nymegen, Gelderland, Netherlands

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Publications (271)1211.46 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: 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. 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. 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). 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.
    Journal of Antimicrobial Chemotherapy 12/2009; 65(2):296-302. · 5.34 Impact Factor
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    ABSTRACT: Caspofungin was evaluated as first-line monotherapy of invasive aspergillosis (IA) in patients with haematological malignancies and undergoing autologous transplants. 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. 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. 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.
    Journal of Antimicrobial Chemotherapy 12/2009; 64(6):1274-81. · 5.34 Impact Factor
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    ABSTRACT: 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. 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. 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. 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.
    Journal of Antimicrobial Chemotherapy 11/2009; 65(1):114-7. · 5.34 Impact Factor
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    ABSTRACT: Invasive aspergillosis is a devastating infection with attributable mortality of 40% despite antifungal therapy. In animal models of aspergillosis, deficiency of mannose-binding lectin (MBL), a pattern recognition receptor that activates complement, is a susceptibility factor. MBL deficiency occurs in 20%-30% of the population. We hypothesized that MBL deficiency may be a susceptibility factor for invasive aspergillosis in humans. Serum MBL concentrations were measured by enzyme-linked immunosorbent assay in 65 patients with proven or probable acute invasive aspergillosis and 78 febrile immunocompromised control subjects. MBL concentrations and the frequency of MBL deficiency were compared. The median serum MBL level was significantly lower in patients with aspergillosis than in control subjects (281 ng/mL vs 835 ng/mL; P = .007). MBL deficiency (MBL concentration, <500 ng/mL) was significantly more common in patients with aspergillosis than control subjects (62% vs 32%; P < .001). Frequency of MBL deficiency was similar among patients with aspergillosis irrespective of response to antifungal therapy (P = .10). This study is the first, to our knowledge, to show an association between MBL deficiency and acute invasive aspergillosis in humans. Further study is required to investigate the causal nature of this association and to define whether diagnosis of MBL deficiency may identify immunocompromised patients at increased risk of invasive aspergillosis.
    Clinical Infectious Diseases 11/2009; 49(10):1486-91. · 9.37 Impact Factor
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    ABSTRACT: The diagnosis of mature B-cell neoplasms (MBCN) remains difficult in a number of cases, especially leukemic phases of non-Hodgkin lymphoma, for which discriminating criteria or biomarker are often lacking. To identify new surface biomarkers, we developed an original proteomic approach based on mass spectrometry analysis of plasma membrane microparticles derived from chronic B-cell lymphoproliferations of single patients: chronic lymphocytic leukemia (CLL), small cell lymphoma (SLL) and mantle cell lymphoma (MCL). A straightforward selection process for proteomic-based candidate biomarker identification was further constructed in order to propose potentially useful and relevant biomarkers. Comparison of the lists of the proteins identified in each pathology combined to highly stringent MS validation criteria for protein identification allowed to propose CD148, a membrane receptor with phosphatase activity, as a discriminating biomarker candidate. Flow cytometry analyses, performed on 158 patients and 30 controls, showed that an anti-CD148 antibody stained significantly higher MCL than CLL and SLL circulating cells (p<0.0001), which validates CD148 overexpression in MCL. Our results indicate that a medium or high CD148 expression level may exclude the diagnosis of CLL and high CD148 expression levels (CD148 MFI equal or superior to 2 times the value obtained with CLL/SLL) allows MCL diagnosis to be suspected with 91% specificity (versus CLL and SLL) and 78% sensitivity. This study is one of the first where proteomic strategies allowed to identify a potentially useful biomarker.
    Journal of Proteome Research 09/2009; · 5.06 Impact Factor
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    ABSTRACT: Temsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, has shown clinical activity in mantle cell lymphoma (MCL). We evaluated two dose regimens of temsirolimus in comparison with investigator's choice single-agent therapy in relapsed or refractory disease. In this multicenter, open-label, phase III study, 162 patients with relapsed or refractory MCL were randomly assigned (1:1:1) to receive one of two temsirolimus regimens: 175 mg weekly for 3 weeks followed by either 75 mg (175/75-mg) or 25 mg (175/25-mg) weekly, or investigator's choice therapy from prospectively approved options. The primary end point was progression-free survival (PFS) by independent assessment. Median PFS was 4.8, 3.4, and 1.9 months for the temsirolimus 175/75-mg, 175/25-mg, and investigator's choice groups, respectively. Patients treated with temsirolimus 175/75-mg had significantly longer PFS than those treated with investigator's choice therapy (P = .0009; hazard ratio = 0.44); those treated with temsirolimus 175/25-mg showed a trend toward longer PFS (P = .0618; hazard ratio = 0.65). Objective response rate was significantly higher in the 175/75-mg group (22%) compared with the investigator's choice group (2%; P = .0019). Median overall survival for the temsirolimus 175/75-mg group and the investigator's choice group was 12.8 months and 9.7 months, respectively (P = .3519). The most frequent grade 3 or 4 adverse events in the temsirolimus groups were thrombocytopenia, anemia, neutropenia, and asthenia. Temsirolimus 175 mg weekly for 3 weeks followed by 75 mg weekly significantly improved PFS and objective response rate compared with investigator's choice therapy in patients with relapsed or refractory MCL.
    Journal of Clinical Oncology 09/2009; 27(23):3822-9. · 18.04 Impact Factor
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    ABSTRACT: CASE DESCRIPTION: A French Caucasian man aged 39 with HIV infection was treated with abacavir/lamivudine and ritonavir/lopinavir. The patient (normal renal and liver functions) was diagnosed with a Burkitt lymphoma for which he was treated with cyclophosphamide day 1 to 5; doxorubicin day 1; methotrexate day 10; and vincristine day 1 and 8. At day 12, he suffered from abdominal pain associated with constipation. Paralytic ileus was diagnosed by study imaging. Ileus lasted 10 days necessitating parenteral feeding. Later on, a further cycle of chemotherapy with etoposide replacing vincristine was given and was well tolerated. CONCLUSION: We speculate that an interaction between ritonavir/lopinavir and vincristine was responsible for this severe toxicity. Vincristine is transported by P-gp and is metabolized via CYP3A5. Ritonavir is a potent CYP3A5 isoenzyme and P-gp inhibitor. Lopinavir is also a P-gp inhibitor. Ritonavir and lopinavir might have delayed vincristine elimination. Clinicians should be aware of this possible interaction.
    International Journal of Clinical Pharmacy 09/2009; 31(6):619-21. · 0.92 Impact Factor
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    ABSTRACT: The exact timing of the evolution of lesion volumes of invasive pulmonary aspergillosis (IPA) on CT scan images could be helpful in the management of hematological patients but has never been evaluated in a prospective study. We analyzed the CT scan data from the prospective Combistrat trial. Volumes of aspergillosis lesions from 30 patients (including 24 acute myeloid leukaemia) with probable (n=26) or proven (n=4) IPA according to the EORTC-MSG modified criteria, were measured prospectively on the thoracic CT scans at the enrolment in the study on day 0 (D0), D7, D14 and end of treatment (EOT). For the overall population, the volume of pulmonary aspergillosis lesions increased significantly from D0 to D7 (1.6 fold; p=0.003). Then this volume decreased significantly from D7 to D14 (1.36 fold at D14 with p=0.003 for D14 vs. D7, but with p=0.56 for D14 vs. D0). At EOT (= D17, median value), the volume of lesions was significantly lower than D14 (0.76 fold the initial volume; p<0.001) but it was not significantly different when compared to D0 (p=0.11). The results of this prospective study suggest that the sequential analysis of CT scan in neutropenic patients with IPA depicts more precisely the evolution of lesion volumes than comparison to baseline images. Moreover, the systematic use of chest CT appears to be a useful tool for diagnosis and outcome evaluation of IPA in clinical trials.
    European journal of radiology 08/2009; 74(3):e172-5. · 2.65 Impact Factor
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    ABSTRACT: 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. 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). 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. The type of induction therapy (ACVBP or ACE) did not significantly affect overall survival at a median 51 months' follow-up.
    Annals of Oncology 07/2009; 20(12):1985-92. · 7.38 Impact Factor
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    ABSTRACT: Drug interactions occur frequently with triazole antifungal agents because of their properties as inhibitors of 1 or more phase 1 (cytochrome P450) biotransformation enzymes and, possibly, as inhibitors or substrates of a phase 2 biotransformation enzyme or transporter protein. Multimorbid patients, including those with hematologic malignancies or other cancers, hematopoietic stem cell or organ transplant recipients, patients infected with the human immunodeficiency virus, and those in the intensive care unit, are at increased risk for drug interactions because they typically require several concomitant medications. They may also be extremely vulnerable to the clinical signs and symptoms of drug interactions. This review describes clinically significant drug interactions most frequently seen in multimorbid patients who receive systemic therapy with triazole antifungals for the prophylaxis or treatment of invasive fungal infections; including interactions with corticosteroids, immunosuppressants, anti-infective drugs, benzodiazepines, opioid analgesics, statins, anticoagulants, anticonvulsants, and drugs affecting gastric pH. The review also describes recommendations concerning contraindications and dose-modification strategies. The azoles differ markedly in their pharmacokinetic and antifungal properties, safety and tolerability, and drug-interaction profiles. Many drug interactions can be prevented if clinicians are thoroughly familiar with the pharmacokinetic profiles of different azoles, follow contraindications and dose-modification recommendations, and switch azoles when possible to achieve the best combination of clinical efficacy and safety. Therapeutic drug monitoring can help optimize treatment and prevent underdosing or overdosing of drugs. Education of patients and their families about signs and symptoms of possible drug interactions is also beneficial.
    Current Drug Metabolism 06/2009; 10(4):395-409. · 4.41 Impact Factor
  • La Revue de Médecine Interne 06/2009; 30. · 0.90 Impact Factor
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    ABSTRACT: The standard caspofungin treatment regimen (50 mg/day after a 70-mg dose on day 1) is effective and well tolerated for the treatment of invasive candidiasis, but experience with higher doses of caspofungin is limited. We evaluated the safety and efficacy of caspofungin at 3 times the standard dosing regimen. Patients with proven invasive candidiasis were randomized to receive a standard or high-dose (150 mg/day) caspofungin treatment regimen. Safety was assessed in all patients as treated. Efficacy was assessed as a secondary objective in a full-analysis-set population. A favorable overall response was defined as symptom resolution and microbiological clearance at the end of caspofungin therapy. A total of 204 patients were included in the safety analysis (104 received the standard regimen, and 100 received the high-dose regimen), and 197 were included in the efficacy analysis (102 and 95 in the standard and high-dose treatment groups, respectively). Patient demographic characteristics, neutropenia status (6.7% and 8.0% had neutropenia, respectively), and Acute Physiology and Chronic Health Evaluation II scores (mean, 16.5 and 17, respectively) were similar between treatment groups. Significant drug-related adverse events occurred in 1.9% of patients receiving the standard regimen and 3.0% of patients receiving the high-dose regimen (difference, 1.1%; 95% confidence interval, -4.1% to 6.8%). The most-common drug-related adverse events in the standard and high-dose treatment groups were phlebitis (3.8% and 2.0%, respectively), increased alkaline phosphatase level (6.9% and 2.0%, respectively), and increased aspartate transaminase level (4.0% and 2.0%, respectively). Overall, 71.6% of patients who received the standard regimen and 77.9% of patients who received the high-dose regimen had favorable overall responses (difference, 6.3%; 95% confidence interval, -5.9% to 18.4%; not statistically significant). Mortality at 8 weeks after therapy was similar between groups. Both caspofungin dosing regimens were effective and well tolerated in patients with invasive candidiasis. No safety concerns were found for caspofungin at a dosage of 150 mg/day.
    Clinical Infectious Diseases 06/2009; 48(12):1676-84. · 9.37 Impact Factor
  • Revue De Medecine Interne - REV MED INTERNE. 01/2009; 30.
  • Mycoses 01/2009; 52(5):391-391. · 1.28 Impact Factor
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    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 11/2008; 23(3):617-9. · 10.16 Impact Factor
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    ABSTRACT: Background: C at standard dose was evaluated as 1st-line monotherapy of probable/proven (strict EORTC/MSG criteria) IA in allogeneic HSCT pts. Methods: Pts with possible IA were included if upgraded to probable/proven based on tests performed within 48 h after registration. Diagnosis and efficacy were assessed by a Data Review Board. The primary efficacy endpoint was complete (CR) or partial response (PR) at the end of C treatment (EOT). Other endpoints included response and survival at day 84, and safety. Thirty seven evaluable pts were needed to test the null hypothesis of a true response rate (RR) ≤ 13% with a power of 95% in case of a true RR of ≥ 33%, using a significance level of 10%. Trial had to be stopped prematurely because of low accrual. Results: 42 patients were enrolled; 24 were eligible. Median age was 50 y (range: 19-65). Transplant was unrelated in 16 pts; acute/chronic GVHD was present in 10 and 7 pts, respectively. 12 pts were neutropenic (<500/µL), 12 received steroids and 12 a calcineurin inhibitor. 9 pts had a +ve culture and 22 had +ve antigen in BAL or serum. Median duration of C treatment was 24 d (range: 2 -85). At EOT, 10 of 24 (42%) pts had a favorable (CR + PR) outcome (95% CI 22%-63%), while 1 (4%) and 12 (50%) had stable and worsening disease, respectively, allowing to reject the null hypothesis of a true RR ≤ 13%. At d 84, 7 out of 23 assessable pts (30%) had CR or PR. Survival rate at d 84 was 48%. None of the pts had a drug-related serious adverse event or discontinued treatment because of toxicity. Conclusions: C was effective as first-line therapy of IA in allogeneic HSCT pts.
    Infectious Diseases Society of America 2008 Annual Meeting; 10/2008
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    ABSTRACT: Background: sCAS (70 mg x 1, then 50 mg/day) for IC is effective & well tolerated. Yet, CAS data at higher doses is limited. Methods: Patients (pts) with proven IC within 4 days of entry were randomized to sCAS vs hCAS (150 mg/day). The primary objective was the incidence of significant drug-related adverse events (SDRAE), defined as a serious DRAE or CAS discontinuation due to DRAE. The noninferiority margin for difference in SDRAE (hCAS - sCAS) was 15% (95% CI upper bound). Safety was assessed in all-pts-as-treated (APaT). Efficacy was assessed as a secondary objective in pts with proven IC & >1 day of CAS Rx (full analysis set [FAS]). Success required symptom resolution & microbiological clearance at end of CAS Rx (EOCT). Results: 204 pts were in APaT (100 & 104 in hCAS & sCAS, respectively) & 197 were in FAS (95 & 102). Pt demographics in the 2 Rx arms, including neutropenia status (9% & 7%) & APACHE II scores (mean 17 & 16.5), were similar. The incidence of SDRAE in the 2 Rx arms was comparable (hCAS 3% vs sCAS 2%); Rx difference 1.1% (-4.1%, 6.8%). Most common DRAE (>2%) were phlebitis (2 vs 4%), ↑ alkaline phosphatase (2 vs 7%), & ↑AST (2 vs 4%). Success at EOCT in the 2 Rx arms was similar: sCAS 78% vs hCAS 72% (Rx difference 6.3% [-5.9%, 18.4%]). Rx success by infection site, neutropenic status, & APACHE II score was similar. Mortality at 8 weeks postRx was similar (38% vs 34%). Conclusions: In this study, the safety profiles of hCAS & sCAS were comparable. No significant efficacy differences were seen in the 2 Rx arms.
    Infectious Diseases Society of America 2008 Annual Meeting; 10/2008
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    ABSTRACT: Background: Delays in therapy for IC are associated with increased mortality. We sought to validate a CPR to identify critically-ill pts at risk of IC for empirical antifungal therapy. Methods: Review of contemporary pts in their first ICU stay who were age ≥18 yrs and were in ICU ≥ 4 days. Pts were excluded for the following: Fungal infection on admission, neutropenia, HIV/AIDS, CGD, stem cell or organ transplant, antifungals from day -7 to ICU day +3, and antifungal prophylaxis. The CPR consisted of: a) Any of: Fever, hypothermia, hypotension, or leukocytosis, b) Other infections excluded or treated, c) Central venous catheter, mechanical ventilation and antibiotics on days 1-3 of ICU stay, and d) Any of: Parenteral nutrition on days 1-3, dialysis on days 1-3, major surgery on days -7 to 0, pancreatitis on days -7 to 0, or systemic steroids/other immunosuppressants on days -7 to 0 of ICU stay. Results: We analyzed 649 cases from sites in Switzerland, France, US, and Australia. Mean APACHE II score was 16 and mortality was13%. 13% of pts received at least 1 antifungal. Mean hospital stay was 30 days. Mean ICU stay was 12 days. 66% of pts had Candida colonization identified from routine clinical cultures of non-sterile sites. Median time to colonization was 4 days. 12 pts had proven IC (incidence 1.8%). Median time to IC was 16 days. Performance of the CPR is shown below. Conclusion: The proposed CPR + colonization identify ICU pts at high risk for IC who may benefit from empirical antifungal therapy. CPR CPR + colonization Sensitivity 0.83 0.67 Specificity 0.68 0.87 PPV 0.04 0.09 NPV 0.99 0.99 Accuracy 0.68 0.87 RR (95%CI) 10.4 (2.6, 42.3) 13 (4.2, 40.4) % of patients with IC 4.7% 9.3% NNT 23 12 % of ICU patients that would be treated 32% 13% % of unit IC cases that would be captured 83% 67%
    Infectious Diseases Society of America 2008 Annual Meeting; 10/2008
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    ABSTRACT: Background: Acute myeloblastic leukemia (AML) patients experience prolonged neutropenia during treatment with intensive chemotherapy, leading to a high risk of invasive fungal infections (IFI). Methods: We performed a retrospective chart review on AML patients presenting with probable or proven IFI to study the type of infections, resources consumed and costs associated with these infections. Costing was performed according to French guidelines. Results: Fifty consecutive IFI cases (80% of aspergillosis) from 6 French centers were included between. Main locations of IFI were chest (76%), blood (18%) and sinus (8%). Among the 50 patients, 32 were followed until death. The average follow-up duration from IFI occurrence was 297 days. Length of stay of index hospitalization was 45 days on average of which 82% were due to malignancy treatment. Mean duration of antifungal treatments was 198 days (11 to 613 days; median 154 days). An average of 3.7 lines of treatment were prescribed of which 1.1 was a combination of two or more agents. The most widely used antifungal agent was voriconazole (59.9% of the total cumulative consumption), then caspofungin (14.8%), itraconazole (7.1%), posaconazole (5.4%), amphotericin B (4.6%), fluconazole (4.2%) and liposomal amphotericin B (3.9%). The mean total cost of IFI episodes was estimated at 51,033 euros including 35,967 euros for antifungal treatments plus 13,721 euros for additional charge for index hospitalizations plus 1,345 euros for additional hospitalizations. Conclusions: The costs of IFI in AML patients after intensive chemotherapy in France was higher than 50,000 euros when they were followed on average for one year. The cost estimate was used to study the cost-effectiveness of prophylaxis.
    Infectious Diseases Society of America 2008 Annual Meeting; 10/2008
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    ABSTRACT: Invasive aspergillosis is associated with high death rates. Factors associated with increased mortality have not yet been identified in a large population of patients with various underlying conditions. We retrospectively reviewed 385 cases of suspected or documented aspergillosis that occurred during a 9-year period. We identified 289 episodes that fulfilled the criteria for possible, probable, or proven invasive aspergillosis according to the international definition criteria and that was treated with an anti-Aspergillus active antifungal drug. Clinical and microbiological variables were analyzed for their effects on overall and attributable mortality. Significant variables in univariate analysis were introduced into a multivariate Cox model. Twelve-week overall and disease-specific survival rates were 52.2% (95% confidence interval, 46.5%-57.9%) and 59.8% (95% confidence interval, 54.0%-65.4%), respectively. Receipt of allogeneic hematopoietic stem cell or solid-organ transplant, progression of underlying malignancy, prior respiratory disease, receipt of corticosteroid therapy, renal impairment, low monocyte counts, disseminated aspergillosis, diffuse pulmonary lesions, pleural effusion, and proven or probable (as opposed to possible) aspergillosis are predictors of increased overall mortality. Similar factors are also predictors of increased attributable mortality, with the following exceptions: pleural effusion and low monocyte counts have no impact, whereas neutropenia is associated with a higher attributable mortality. Identification of predictors of death helps in the identification of patients who could benefit from more-aggressive therapeutic strategies. Initiation of therapy at the stage of possible infection improves outcome, and this finding calls for the development of efficient preemptive strategies to fill the gap between empirical and directed therapy.
    Clinical Infectious Diseases 10/2008; 47(9):1176-84. · 9.37 Impact Factor

Publication Stats

12k Citations
1,211.46 Total Impact Points


  • 2012
    • Radboud University Medical Centre (Radboudumc)
      • Department of Human Genetics
      Nymegen, Gelderland, Netherlands
  • 1989–2012
    • University of Strasbourg
      Strasburg, Alsace, France
  • 2011
    • University of Birmingham
      • School of Health and Population Sciences
      Birmingham, ENG, United Kingdom
    • Assistance Publique – Hôpitaux de Paris
      Lutetia Parisorum, Île-de-France, France
    • Universitair Ziekenhuis Leuven
      Louvain, Flanders, Belgium
  • 2000–2010
    • CHRU de Strasbourg
      • Pôle Pharmacie-pharmacologie
      Strasburg, Alsace, France
    • Centre Henri Becquerel
      Rouen, Upper Normandy, France
  • 2007–2009
    • University of Cologne
      • Department of Internal Medicine
      Köln, North Rhine-Westphalia, Germany
  • 2008
    • Hopitaux Civils De Colmar
      Kolmar, Alsace, France
    • University of Florida
      • Department of Medicine
      Gainesville, FL, United States
  • 2006
    • Haematology Oncology Practice Altona
      Hamburg, Hamburg, Germany
  • 2004
    • CHU de Lyon - Institut d'hématologie et d'oncologie pédiatrique
      Lyons, Rhône-Alpes, France
  • 2003
    • CHU de Lyon - Hôpital Gériatrique Pierre Garraud
      Lyons, Rhône-Alpes, France
  • 1998
    • Institut Curie
      Lutetia Parisorum, Île-de-France, France
  • 1997
    • Hospices Civils de Lyon
      Lyons, Rhône-Alpes, France
  • 1996
    • Centre Hospitalier Universitaire de Nancy
      Nancy, Lorraine, France
  • 1991
    • Centre Hospitalier Lyon Sud
      Lyons, Rhône-Alpes, France