Publications of Marie-Pierre HAYETTE
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See detailClinical course and challenging management of early COVID-19 infection after heart transplantation: case report of two patients
TCHANA-SATO, Vincent ULiege; ANCION, Arnaud ULiege; TRIDETTI, Julien ULiege et al

in BMC Infectious Diseases (2021)

Background: There are limited data on Coronavirus disease 2019 (COVID-19) in solid organ transplant patients, especially in heart transplant recipients, with only a few case reports and case series ... [more ▼]

Background: There are limited data on Coronavirus disease 2019 (COVID-19) in solid organ transplant patients, especially in heart transplant recipients, with only a few case reports and case series described so far. Heart transplant recipients may be at particular high risk due to their comorbidities and immunosuppressed state. Case presentation: This report describes the clinical course and the challenging management of early COVID-19infection in two heart transplant recipients who tested positive for the SARS-CoV-2 virus in the perioperative period of the transplant procedure. The two patients developed a severe form of the disease and ultimately died despite the initiation of an antiviral monotherapy with hydroxychloroquine coupled with the interruption of mycophenolate mofetil. Conclusions: These two cases illustrate the severity and poor prognosis of COVID-19 in the perioperative period of a heart transplant. Thorough screening of donors and recipients is mandatory, and the issue of asymptomatic carriers needs to be addressed. [less ▲]

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See detailEpidemiological, clinical and biological profile of neuromeningeal cryptococcosis among people living with HIV in Kinshasa, Democratic Republic of Congo
Zono, B.; Kamangu, E.; Situakibanza, H. et al

in Pan African Medical Journal (2020), 37(302), 1-9

Neuromeningeal cryptococcosis (NMC) is one of the most frequent opportunistic infections (OI) in Human Immunodeficiency Virus (HIV) infection. In Kinshasa, the latest data on cryptococcosis were published ... [more ▼]

Neuromeningeal cryptococcosis (NMC) is one of the most frequent opportunistic infections (OI) in Human Immunodeficiency Virus (HIV) infection. In Kinshasa, the latest data on cryptococcosis were published in 1996. The objective was to describe the epidemiological, clinical and biological profiles of NMC in HIV-infected people living in Kinshasa. This is a descriptive study based on the medical records of patients who attended three clinics in Kinshasa between January 1st 2011 and December 31st 2014. Only the medical records of HIV-infected people presenting the NMC were reviewed. During the 4 year-period of the study, 261 HIV-positive patients presented to the clinics for neuromeningeal syndrome, including 23 with NMC. The global prevalence of NMC was 8.8% for the three clinics. The mean age was 42.8 ± 9.5 years, with male predominance (65.2%). The main symptoms were headache (73.9%), neck stiffness (60.9%), fever (47.8%), and coma (47.8%). Biological records were as follows: median CD4 cell count was 79 cells/mm3; cerebrospinal fluid (CSF) was clear for 56.5% of the cases with predominance of neutrophils in 73.9%. The outcome was fatal in 34.8% of cases. The prevalence and therapeutic outcome of NMC show that it constitutes a non-negligible OI in Kinshasa, especially in HIV-infected people at the AIDS stage. As HIV-infected people with severe immunosuppression are the most affected by NMC, active preventive measures should benefit this vulnerable category of people. © Bive Zono et al. [less ▲]

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See detailComparison of practicability and effectiveness between unassisted HIV selftesting and directly assisted HIV self-testing in the Democratic Republic of the Congo: a randomized feasibility trial
Tonen-Wolyec, Serge; Kayembe Tshilumba, Charles; Batina-Agasa, Salomon et al

in BMC Infectious Diseases (2020)

Background: HIV self-testing (HIVST) can be performed using directly assisted and unassisted approaches in facilities or communities to reach different populations. The aim of this study was to compare ... [more ▼]

Background: HIV self-testing (HIVST) can be performed using directly assisted and unassisted approaches in facilities or communities to reach different populations. The aim of this study was to compare the practicability andeffectiveness of the two delivery approaches for HIVST, unassisted HIVST (UH) and directly assisted HIVST (DAH), in the field setting of Kisangani, the Democratic Republic of the Congo (DRC). Methods: A randomized (1:1), non-blinded, non-inferiority trial using a blood-based and facility-based HIVST method was carried out in four facilities in Kisangani, the DRC, targeting populations at high risk for HIV infection. The primary outcome was the difference in the practicability of the HIV self-test between the two arms. Practicability was defined as successfully performing the test and correctly interpreting the result. Requests for assistance, positivity rate, linkage to care, and willingness to buy an HIV self-test kit constituted the secondary outcomes for HIVST effectiveness. The adjusted risk ratios (aRRs) were calculated using Poisson regression. Results: The rate of successfully performing the test was same (93.2%) in the UH and DAH arms. The rate of correctly interpreting the results was 86.9% in the UH arm versus 93.2% in the DAH arm, for a difference of − 6.3%. After the follow-up 72 h later, participants in the UH arm had a significantly lower chance of correctly interpreting the test results than those in the DAH arm (aRR: 0.60; P = 0.019). Although the positivity rate was 3.4% among the participants in the DAH arm and 1.7% among those in the UH arm, no significant differences were found between the two arms in the positivity rate, requests for assistance, and linkage to care. Willingness to buy an HIV self-test was higher in the UH arm than in the DAH arm (92.3% versus 74.1%; aRR: 4.20; P < 0.001).Conclusion: The results of this study indicate that UH is as practicable and effective as DAH among individuals at high risk for HIV infection in Kisangani, the DRC. However, additional support tools need to be assessed to improve the interpretation of the self-test results when using the UH approach. [less ▲]

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See detailCapillary whole-blood IgG-IgM COVID-19 selftest as a serological screening tool for SARSCoV-2 infection adapted to the general public
Tonen-Wolyec, Serge; Dupont, Raphael; Batina-Agasa, Salomon et al

in PLoS ONE (2020)

The practicability of a prototype capillary whole-blood IgG-IgM COVID-19 self-test (Exacto® COVID-19 self-test, Biosynex Swiss SA, Freiburg, Switzerland) as a serological screening tool for SARS-CoV-2 ... [more ▼]

The practicability of a prototype capillary whole-blood IgG-IgM COVID-19 self-test (Exacto® COVID-19 self-test, Biosynex Swiss SA, Freiburg, Switzerland) as a serological screening tool for SARS-CoV-2 infection adapted to the general public was evaluated in across-sectional, general adult population study performed between April and May 2020 in Strasbourg, France, consisting of face-to-face, paper-based, semi-structured, and selfadministrated questionnaires. Practicability was defined as the correct use of the self-test and the correct interpretation of the result. The correct use of self-test was conditioned by the presence of the control band after 15-min of migration. The correct interpretation of the tests was defined by the percent agreement between the tests results read and interpret by the participants compared to the expected results coded by the numbers and verified by trained observers. A total of 167 participants (52.7% female; median age, 35.8 years; 82% with post-graduate level) were enrolled, including 83 and 84 for usability and test results interpretation substudies, respectively. All participants (100%; 95% CI: 95.6– 100) correctly used the self-test. However, 12 (14.5%; 95% CI: 8.5–23.6) asked for verbal help. The percent agreement between the tests results read and interpret by the participants compared to the expected results was 98.5% (95% CI: 96.5–99.4). However, misinterpretation occurred in only 2.3% of positive and 1.2% of invalid test results. Finally, all (100%) participants found that performing the COVID-19 self-test was easy; and 98.8% found the interpretation of the self-test results easy. Taken together, these pilot observations demonstrated for the first-time, high practicability and satisfaction of COVID-19 selftesting for serological IgG and IgM immune status, indicating its potential for use by the general public to complete the arsenal of available SARS-CoV-2 serological assays in the urgent context of the COVID-19 epidemic. [less ▲]

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See detailEpidemiology of Cryptosporidiosis in France from 2017 to 2019
Costa, Damien; Razakandrainibe, Romy; Valot, Stéphane et al

in Proceedings (2020), 8

Cryptosporidiosis is currently recognized worldwide as a leading cause of moderate to severe diarrhea. In Europe, large water- and foodborne outbreaks have been reported, highlighting the widespread ... [more ▼]

Cryptosporidiosis is currently recognized worldwide as a leading cause of moderate to severe diarrhea. In Europe, large water- and foodborne outbreaks have been reported, highlighting the widespread distribution of the parasite and its important health impact. Surveillance networks have been progressively set up and the aim of this study was to present recent epidemiological data obtained in France from 2017 to 2019 by the National Reference Center—Expert Laboratory of cryptosporidiosis (Centre National de Référence–Laboratoire Expert cryptosporidioses CNR-LE). Data were obtained from online reports of volunteer network participants and stools were sent to the CNR-LE for species identification and GP60 genotyping. During this period, data from 750 online reports were available. Cryptosporidiosis occurred predominantly in young children (<5 years old) and in young adults, especially during late summer. Most patients were immunocompetent (60%), and deaths were reported only in immunocompromised patients. Cryptosporidium parvum was largely predominant (72% of cases) over C. hominis (24%) and some other uncommon species. C. parvum GP60 subtypes IIa and IId were the most represented, which suggests frequent zoonotic transmission. For C. hominis, subtypes IbA10G2 and IaA22R2 were predominant. [less ▲]

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See detailLa déferlante COVID-19 : la PCR à la rescousse ! : Chronique d’une gestion de crise au Laboratoire de Microbiologie clinique du CHU de Liège
Hayette, Marie-Pierre ULiege; MEEX, Cécile ULiege; BONTEMS, Sébastien ULiege et al

in Revue Médicale de Liège (2020), 75(S55-S61), 55-61

The SARS-CoV-2 outbreak in December 2019 in China and its expansion across the world and Europe have requested the participation of clinical laboratories as major players in the diagnosis of COVID-19, to ... [more ▼]

The SARS-CoV-2 outbreak in December 2019 in China and its expansion across the world and Europe have requested the participation of clinical laboratories as major players in the diagnosis of COVID-19, to perform PCR tests mainly on nasopharyngeal swabs. In Belgium, the first confirmed COVID-19 patient was diagnosed in early February, the first of many, especially travelers returning from winter sports. In order to meet the ever-increasing demands for testing, the Clinical Microbiology Laboratory of the CHU of Liege had to adapt to this situation: firstly, by developing manual PCR tests and then automated solutions, permitting to increase the number of analyzes by ensuring a short turnaround time of results. Then, a system for the communication of results on a large scale has been set up, and finally solutions to deal with the lack of sampling devices have been found. This first wave of the pandemic has also highlighted an unprecedented solidarity within the institution. In this article, we recount the chronology of the management of this unprecedented health crisis within the Clinical Microbiology Laboratory of the CHU of Liege. [less ▲]

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See detailThe lack of K13-propeller mutations associated with artemisinin resistance in Plasmodium falciparum in Democratic Republic of Congo (DRC)
Yobi, Doudou; Kayiba, Nadine; Mvumbi, Dieudonné et al

in PLoS ONE (2020), 15(8),

Artemisinin-based combination therapies (ACTs) have been recommended by the World Health Organization (WHO) as first-line treatment of uncomplicated Plasmodium falciparum (P. falciparum) malaria since ... [more ▼]

Artemisinin-based combination therapies (ACTs) have been recommended by the World Health Organization (WHO) as first-line treatment of uncomplicated Plasmodium falciparum (P. falciparum) malaria since 2005 in Democratic Republic of Congo (DRC) and a regular surveillance of the ACT efficacy is required to ensure the treatment effectiveness. Mutations in the propeller domain of the pfk13 gene were identified as molecular markers of artemisinin resistance (ART-R). This study investigated the pfk13-propeller gene polymorphism in clinical isolates of P. falciparum collected in the DRC. In 2017, ten geographical sites across DRC were selected for a cross-sectional study that was conducted first in Kinshasa from January to March, then in the nine other sites from September to December. Dried blood samples were collected from patients attending health centers for fever where diagnosis of Malaria was first made by rapid diagnostic test (RDT) available on site (SD Bioline malaria Ag Pf or CareStart Malaria Pf) or by thick blood smear and then confirmed by a P. falciparum real-time PCR assay. A pfk13-propeller segment containing a fragment that codes for amino acids at positions 427-595 was amplified by conventional PCR before sequencing. In total, 1070 patients were enrolled in the study. Real-time PCR performed confirmed the initial diagnosis of P. falciparum infection in 806 samples (75.3%; 95% CI: 72.6%- 77.9%). Of the 717 successfully sequenced P. falciparum isolates, 710 (99.0%; 95% CI: 97.9% - 99.6) were wild-type genotypes and 7 (1.0%; 95% CI: 0.4% - 2.1%) carried non-synonymous (NS) mutations in pfk13-propeller including 2 mutations (A578S and V534A) previously detected and 2 other (M472I and A569T) not yet detected in the DRC. Mutations associated with ART-R in Southeast Asia were not observed in DRC. However, the presence of other mutations in pfk13-propeller gene calls for further investigations to assess their implication in drug resistance. [less ▲]

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See detailA recurrent mutation at position 1 26,340 of SARS-CoV-2 is associated with failure of the E-gene qRT-PCR utilized in a commercial dual-target diagnostic assay
Artesi, Maria ULiege; Bontems, Sébastien ULiege; Göbbels, Paul et al

in Journal of Clinical Microbiology (2020)

Control of the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic requires accurate laboratory testing to identify infected individuals, while also clearing essential staff to ... [more ▼]

Control of the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic requires accurate laboratory testing to identify infected individuals, while also clearing essential staff to continue work. At the current time a number of qRT-PCR assays have been developed to identify SARS-CoV-2, targeting multiple positions in the viral genome. While the mutation rate of SARS-CoV-2 is moderate, given the large number of transmission chains it is prudent to monitor circulating viruses for variants that might compromise these assays. Here we report the identification of a C-to-U transition at position 26,340 of the SARS-CoV-2 genome which is associated with failure of the cobas® SARS-CoV-2 E-gene qRT-PCR in eight patients. As the cobas® SARS-CoV-2 assay targets two positions in the genome, the individuals carrying this variant were still called as SARS-CoV-2 positive. Whole genome sequencing of SARS-CoV-2 showed all to carry closely related viruses. Examination of viral genomes deposited on GISAID showed this mutation has arisen independently at least four times. This work highlights the necessity of monitoring SARS-CoV-2 for the emergence of SNPs which might adversely affect RT PCRs used in diagnostics. Additionally, it argues that two regions in SARS-CoV-2 should be targeted to avoid false negatives. [less ▲]

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See detailEvaluation of the new Id-Fungi plates from Conidia for MALDI-TOF MS identification of filamentous fungi and comparison with conventional methods as identification tool for dermatophytes from nails, hair and skin samples
SACHELI, Rosalie ULiege; Henri, Anne-Sophie ULiege; SEIDEL, Laurence ULiege et al

in Mycoses (2020)

Objectives: We first compare the efficiency of mould/dermatophytes identification by MALDI-TOF MS using a new medium called Id-Fungi plates (IDFP) from Conidia® and two different databases. For the second ... [more ▼]

Objectives: We first compare the efficiency of mould/dermatophytes identification by MALDI-TOF MS using a new medium called Id-Fungi plates (IDFP) from Conidia® and two different databases. For the second purpose, we evaluated a new version of the medium supplemented with cycloheximide, Id-Fungi plates Plus (IDFPC) for the direct inoculation of nails, hair and skin samples and compared the efficiency of MALDI-TOF MS identification of dermatophytes to classical methods based on culture and microscopy. Methods: A total of 71 strains have been cultured IDFP and Sabouraud gentamicin plates (SGC2) and were identified by MALDI-TOF MS. For the evaluation of the combination IDFPC/ MALDI-TOF MS as a method of identification for dermatophytes, 428 samples of hair nails and skin were cultivated in parallel on IDFPC and Sabouraud + cycloheximide medium (SAB-ACTI ). Results: For Aspergillus sp. and non-Aspergillus moulds, the best performances were obtained on IDFP after maximum 48h growth, following protein extraction. For dermatophytes, the best condition was using the IDFP at 72h, after extended direct deposit. Regarding the direct inoculation of nails, hair skin on IDFPC, 129/428 (30.1%) showed a positive culture against 150/428 (35%) on SAB-ACTI medium. Among the 129 positive strains the identification by MALDI-TOF MS was correct for 92/129 (71.4%). Conclusion: The IDFP allows the generation of better spectra by MALDI-TOF MS compared to SGC2. It facilitates sampling and deposit. Regarding the use of IDFPC, this medium seems less sensitive than SAB-ACTI but among positive strains, the rate of correct identification, by MALDI-TOF MS is satisfactory. [less ▲]

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See detailA phylodynamic workflow to rapidly gain insights into the dispersal history and dynamics of SARS-CoV-2 lineages
Dellicour, Simon; Durkin, Keith ULiege; Hong, Samuel et al

E-print/Working paper (2020)

Since the start of the COVID-19 pandemic, an unprecedented number of genomic sequences of the causative virus (SARS-CoV-2) have been publicly released. The resulting volume of available genetic data ... [more ▼]

Since the start of the COVID-19 pandemic, an unprecedented number of genomic sequences of the causative virus (SARS-CoV-2) have been publicly released. The resulting volume of available genetic data presents a unique opportunity to gain real-time insights into the pandemic, but also a daunting computational hurdle if analysed with gold-standard phylogeographic methods. We here describe and apply an analytical pipeline that is a compromise between fast and rigorous analytical steps. As a proof of concept, we focus on Belgium, one of the countries with the highest spatial density of sequenced SARS-CoV-2 genomes. At the global scale, our analyses confirm the importance of external introduction events in establishing transmission chains in the country. At the country scale, our spatially-explicit phylogeographic analyses highlight an impact of the national lockdown of mid-March on the dispersal velocity of viral lineages. Our pipeline has the potential to be quickly applied to other countries or regions, with key benefits in complementing epidemiological analyses in assessing the impact of intervention measures or their progressive easement. [less ▲]

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See detailVariability and target attainment of fluconazole in critically ill patients
Van Daele, Ruth; Wauters, Joost; Brüggemann, Roger J. et al

Poster (2020, April 21)

Background: Fluconazole is an antifungal drug frequently used in the intensive care unit (ICU) but few data are available regarding its exposure in this population. A subanalysis of the DALI-study raised ... [more ▼]

Background: Fluconazole is an antifungal drug frequently used in the intensive care unit (ICU) but few data are available regarding its exposure in this population. A subanalysis of the DALI-study raised some concerns considering variability in exposure and inadequate target attainment in critically ill patients. We aimed to determine fluconazole variability and target attainment at the ICU. Materials/methods: All adult, critically ill patients treated with intravenous fluconazole between May and September 2019 were included, provided that the DNR code was <2 and written informed consent was obtained. The administered dose was left at the discretion of the treating clinician. Trough samples were collected during a maximum period of 15 days. Samples were analysed using an UPLC-DAD analytic method. The intra-and intersubject variability of fluconazole trough concentrations was calculated by dividing the standard deviation by the mean*100. Moreover, the difference between the maximum and minimum fluconazole concentration within each patients was determined. For target attainment, the fAUC/MIC from clinical data amounts to 100 corresponding with trough levels >10-15 mg/L, as recommended by EUCAST and ECIL-6. The limit for toxicity was set on 50 mg/L. Results: Seventeen patients were included, resulting in 95 fluconazole trough levels. Patients had a median APACHE-II score of 18 [16-23] and administered dose of 5.1 [4.1-7.5] mg/kg/day. The median fluconazole trough level was 26.6 [19.7-35.3] mg/L. In Figure 1, fluconazole trough concentrations are depicted in function of the dose. The mean intra-and intersubject variability (CV%) were 18,4% and 34,5%, respectively. The median difference between the maximum and minimum concentration for the 14 patients with >1 measured fluconazole level, was 14,8 [6,6-18,9] mg/L. In two patients, this difference was more than 2-fold. All trough levels were >10mg/L and 85/95 (89%) samples were >15mg/L. None of the levels exceeded the upper limit of 50 mg/L. Conclusions: As shown in the DALI-study, a considerable intra-and intersubject variability in fluconazole levels was observed at the ICU. Despite this variability, all fluconazole trough levels were above the lower limit of 10 mg/L and most of them >15 mg/L. No toxic concentrations were observed. [less ▲]

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See detailEconomic costs analysis of uncomplicated malaria case management in the Peruvian Amazon
Moreno-Gutierrez, Diamantina; Rosas-Aguirre, Angel; Llanos-Cuentas, Alejandro et al

in Malaria Journal (2020), 19(1), 161

Background Case management is one of the principal strategies for malaria control. This study aimed to estimate the economic costs of uncomplicated malaria case management and explore the influence of ... [more ▼]

Background Case management is one of the principal strategies for malaria control. This study aimed to estimate the economic costs of uncomplicated malaria case management and explore the influence of healthseeking behaviours on those costs. Methods A knowledge, attitudes and practices (KAP) survey was applied to 680 households of fifteen communities in Mazan-Loreto in March 2017, then a socio-economic survey was conducted in September 2017 among 161 individuals with confirmed uncomplicated malaria in the past three months. Total costs per episode were estimated from both provider (Ministry of Health, MoH) and patient perspectives. Direct costs were estimated using a standard costing estimation procedure, while the indirect costs considered the loss of incomes among patients, substitute labourers and companions due to illness in terms of the monthly minimum wage. Sensitivity analysis evaluated the uncertainty of the average cost per episode. Results The KAP survey showed that most individuals (79.3%) that had malaria went to a health facility for a diagnosis and treatment, 2.7% received those services from community health workers, and 8% went to a drugstore or were self-treated at home. The average total cost per episode in the Mazan district was US$161. The cost from the provider’s perspective was US$30.85 per episode while from the patient’s perspective the estimated cost was US$ 131 per episode. The average costs per Plasmodium falciparum episode (US$180) were higher than those per Plasmodium vivax episode (US$156) due to longer time lost from work by patients with P. falciparum infections (22.2 days) than by patients with P. vivax infections (17.0 days). The delayed malaria diagnosis (after 48 hours of the onset of symptoms) was associated with the time lost from work due to illness (adjusted mean ratio 1.8; 95%CI 1.3, 2.6). The average cost per malaria episode was most sensitive to the uncertainty around the lost productivity cost due to malaria. Conclusions: Despite the provision of free malaria case management by MoH, there is delay in seeking care and the costs of uncomplicated malaria are mainly borne by the families. These costs are not well perceived by the society and the substantial financial impact of the disease can be frequently undervalued in public policy planning [less ▲]

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See detailMulticentre validation of a EUCAST method for the antifungal susceptibility testing of microconidia-forming dermatophytes
Arendrup, Maiken; Jorgensen, Karin Mainike; Guinea, Jesus et al

in Journal of Antimicrobial Chemotherapy (2020)

OBJECTIVES: Terbinafine resistance is increasingly reported in Trichophyton, rendering susceptibility testing particularly important in non-responding cases. We performed a multicentre evaluation of six ... [more ▼]

OBJECTIVES: Terbinafine resistance is increasingly reported in Trichophyton, rendering susceptibility testing particularly important in non-responding cases. We performed a multicentre evaluation of six EUCAST-based methods. METHODS: Ten laboratories susceptibility tested terbinafine, itraconazole, voriconazole and amorolfine against a blinded panel of 38 terbinafine WT and target gene mutant isolates. E.Def 9.3.1 modifications included: medium with/without addition of chloramphenicol and cycloheximide (CC), incubation at 25°C to 28°C for 5-7 days and three MIC endpoints [visually and spectrophotometrically (90%/50% inhibition)], generating 7829 MICs. Quality control (QC) strains were Aspergillus flavus ATCC 204304 and CNM-CM1813. Eyeball, ECOFFinder (where ECOFF stands for epidemiological cut-off) and derivatization WT upper limits (WT-ULs), very major errors (VMEs; mutants with MICs ≤WT-ULs) and major errors (MEs; WT isolates with MICs >WT-ULs) were determined. RESULTS: MICs fell within the QC ranges for ATCC 204304/CNM-CM1813 for 100%/96% (voriconazole) and 84%/84% (itraconazole), respectively. Terbinafine MICs fell within 0.25-1 mg/L for 96%/92%, suggesting high reproducibility. Across the six methods, the number of terbinafine MEs varied from 2 to 4 (2.6%-5.2%) for Trichophyton rubrum and from 0 to 2 (0%-2.0%) for Trichophyton interdigitale. Modes for WT and mutant populations were at least seven 2-fold dilutions apart in all cases. Excluding one I121M/V237I T. rubrum mutant and two mixed WT/mutant T. interdigitale specimens, the numbers of VMEs were as follows: T. rubrum: CC visual, 1/67 (1.5%); CC spectrophotometric 90% inhibition, 3/59 (5.1%); and CC spectrophotometric 50% inhibition, 1/67 (1.5%); and T. interdigitale: none. Voriconazole and amorolfine MICs were quite uniform, but trailing growth complicated determination of itraconazole visual and spectrophotometric 90% inhibition MIC. CONCLUSIONS: Although none of the laboratories was experienced in dermatophyte testing, error rates were low. We recommend the CC spectrophotometric 50% inhibition method and provide QC ranges and WT-ULs for WT/non-WT classification. [less ▲]

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See detailMulticentre validation of a EUCAST method for the antifungal susceptibility testing of microconidia-forming dermatophytes
Arendrup, Maiken; Jorgensen, Karin; Guinea, Jesus et al

Poster (2020, April)

Background: Terbinafine resistance is increasingly reported in Trichophyton rubrum and Trichophyton interdigitale rendering susceptibility testing important particularly in non-responding cases. We ... [more ▼]

Background: Terbinafine resistance is increasingly reported in Trichophyton rubrum and Trichophyton interdigitale rendering susceptibility testing important particularly in non-responding cases. We performed a multicentre evaluation of a recently proposed modified EUCAST method implementing medium supplemented with chloramphenicol and cycloheximide (CC) to avoid contamination. Materials/methods: A blinded panel of wild-type and squalene epoxidase (SQLE) target gene mutant T. rubrum and T. interdigitale strains were distributed to 10 European laboratories. Susceptibility to terbinafine, itraconazole, voriconazole and amorolfine) were performed according to the E.Def 9.3.1 method with and without addition of chloramphenicol and cycloheximide (final concentrations 50 mg/L and 300 mg/L, respectively). Plates were incubated at 25 °C (one laboratory used 30 °C) for 5-7 days until sufficient growth. MICs were determined visually (ignoring trailing growth for itraconazole) and spectrophotometrically with 90% and 50% endpoints yielding a total of 7,829 MICs. A. flavus ATCC 204304 and A. flavus CNM-CM1813 were included as controls. Results: 100%/96% (voriconazole) and 84%/84% (itraconazole) MIC determinations fell within the QC ranges for the two QC strains, respectively, and 96%/92% terbinafine MICs fell in a 0.25-1 mg/L 3 two-fold-dilution range suggesting a high interlaboratory reproducibility. Across the six methods, the number of terbinafine MEs varied from 2 (2.6%) to 5 (6.6%) for T. rubrum and between 0 and 2 (2.0%) for T. interdigitale (lowest for the CC-method (2.6%-4.4%/ 0-1% for T. rubrum/T. interdigitale). The difference between the modes for the wt and mutant population were ≥7 two-fold-dilutions in all cases (Table). If excluding a I121M/V237I T. rubrum mutant, and two mixed T. interdigitale strains, the number of VMEs were CC visual: T. rubrum: 1/77 (1.3%), CC spec-90%: 3/68 (4.4%) and CC spec-50%: 1/76 (1.3%), and none for T. interdigitale. The activity of voriconazole, itraconazole and amorolfine were quite uniform against T. rubrum and T. interdigitale, but unacceptably wide MIC ranges were found for the visual and spec-90% inhibition methods for itraconazole (data not shown). Conclusions: Although none of the laboratories perform dermatophyte testing at a regular basis an acceptable interlaboratory agreement and good separation between SQLE wt and mutants were found, suggesting a robust performance of the proposed method. [less ▲]

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See detailSpatial and molecular mapping of PfKelch13 gene polymorphism in Africa in the era of emerging Plasmodium falciparum resistance to artemisinin: A systematic review
Kayiba, Nadine; Yobi, Doudou; Tshibangu-Kabamba, Evariste et al

in Lancet Infectious Diseases (2020)

The spread of Plasmodium falciparum (Pf) isolates carrying mutations in the kelch 13 (PfK13) gene associated with artemisinin resistance (PfART-R) in Southeast Asia (SEA) threatens malaria control and ... [more ▼]

The spread of Plasmodium falciparum (Pf) isolates carrying mutations in the kelch 13 (PfK13) gene associated with artemisinin resistance (PfART-R) in Southeast Asia (SEA) threatens malaria control and elimination efforts. An eventual emergence of PfART-R in Africa would result in a major public health problem. We conducted a systematic review to investigate the frequency and spatial distribution of PfK13 mutants in Africa, including mutants linked to PfART-R in SEA. Seven databases were searched for relevant articles published before January, 2019 following PRISMA guidelines, identifying 53 studies that sequenced the PfK13 gene of 23100 sample isolates in 41 Sub-Saharan African countries. The PfK13 sequence was highly polymorphic (292 alleles, including 255 in the PfK13-propeller domain) but with mutations occurring at very low relative frequencies. Nonsynonymous mutations were found in only 626 isolates (2·7%) from Western, Central, and Eastern Africa. Nine different mutations linked to PfART-R in SEA according to the WHO (F446I, C469Y, M476I, R515K, S522C, P553L, V568G, P574L, and A675V) were detected, mainly in Eastern Africa. Several other PfK13 mutations such as those structurally mimicking SEA PfART-R mutations were also identified, but their relevance for drug resistance is still unknown. This review shows that Africa, thought to be spared from PfART-R, has reported resistance-related mutants in recent years. Surveillance using PfART-R molecular markers can provide valuable decision-making information to sustain the effectiveness of ART in the continent. [less ▲]

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See detailMolecular surveillance of anti-malarial drug resistance in Democratic Republic of Congo: high variability of chloroquinoresistance and lack of amodiaquinoresistance
Yobi, Doudou; Kayiba, Nadine; Mvumbi, Dieudonné et al

in Malaria Journal (2020), 19(121),

Background: The loss of chloroquine (CQ) efectiveness has led to its withdrawal from national policies as a frst-line treatment for uncomplicated malaria in several endemic countries, such as the ... [more ▼]

Background: The loss of chloroquine (CQ) efectiveness has led to its withdrawal from national policies as a frst-line treatment for uncomplicated malaria in several endemic countries, such as the Democratic Republic of Congo (DRC). The K76T mutation on the pfcrt gene has been identifed as a marker of CQ resistance and the SVMNT haplotype in codons 72–76 on the same gene has been associated with resistance to amodiaquine (AQ). In the DRC, the prevalence of K76T has decreased from 100% in 2000 to 63.9% in 2014. The purpose of this study was to determine the prevalence of K76T mutations in circulating strains of Plasmodium falciparum, 16 years after CQ withdrawal in the DRC and to investigate the presence of the SVMNT haplotype. Methods: In 2017, ten geographical sites across the DRC were selected. Dried blood samples were collected from patients attending health centres. Malaria was frst detected by a rapid diagnostic test (RDT) available on site (SD Bioline Malaria Ag Pf or CareStart Malaria Pf) or thick blood smear and then confrmed by a P. falciparum species-specifc real-time PCR assay. A pfcrt gene segment containing a fragment that encodes amino acids at positions 72–76 was amplifed by conventional PCR before sequencing. Results: A total of 1070 patients were enrolled. Of the 806 PCR-confrmed P. falciparum positive samples, 764 were successfully sequenced. The K76T mutation was detected in 218 samples (28.5%; 95% CI 25.4%–31.9%), mainly (96%) with the CVIET haplotype. Prevalence of CQ resistance marker was unequally distributed across the country, ranging from 1.5% in Fungurume to 89.5% in Katana. The SVMNT haplotype, related to AQ resistance, was not detected. Conclusion: Overall, the frequency of the P. falciparum CQ resistance marker has decreased signifcantly and no resistance marker to AQ was detected in the DRC in 2017. However, the between regions variability of CQ resistance remains high in the country. Further studies are needed for continuous monitoring of the CQ resistance level for its prospective re-use in malaria management. The absence of the AQ resistance marker is in line with the use of this drug in the current DRC malaria treatment policy. [less ▲]

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See detailBelgian national survey on tinea capitis: epidemiological considerations and highlight of terbinafine resistant T. mentagrophytes with a mutation on SQLE gene
SACHELI, Rosalie ULiege; Harag, Saadia; Dehavay, Florence et al

in Journal of Fungi (2020)

Background: In this last decade, a huge increase in African anthropophilic strains causing tinea capitis has been observed in Europe. The Belgian National Reference Center for Mycosis (NRC) conducted a ... [more ▼]

Background: In this last decade, a huge increase in African anthropophilic strains causing tinea capitis has been observed in Europe. The Belgian National Reference Center for Mycosis (NRC) conducted a surveillance study on tinea capitis in 2018 to learn the profile of circulating dermatophytes. Methods: Belgian laboratories were invited to send all dermatophyte strains isolated from the scalp with epidemiological information. Strain identification was confirmed by ITS (Iinternal Ttranscribed Sspacer) sequencing. Mutation in the squalene epoxidase (SQLE) gene was screened by PCR. Results: The main population affected by tinea capitis was children from 5–9 years. Males were more affected than females. The majority of the strains were collected in the Brussels area followed by the Liege area. Among known ethnic origins, African people were more affected by tinea capitis than European people. The major aetiological agent was Microsporum audouinii, followed by Trichophyton soudanense. One strain of Trichophyton mentagrophytes has been characterized to have a mutation on the squalene epoxidase gene and to be resistant to terbinafine. Conclusions: African anthropophilic dermatophytes are mainly responsible for tinea capitis in Belgium. People of African origin are most affected by tinea capitis. The monitoring of terbinafine resistance among dermatophytes seems necessary as we have demonstrated the emergence of resistance in T. mentagrophytes. [less ▲]

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