1-Jean-Philippe Bouchara - ISHAM

1 st Meeting of theISHAM Working group onFungal respiratory infections in Cystic FibrosisFaculty of Pharmaceutical Sciences, Angers2009, June 7-8

Fungal respiratory infections in CFThe most common genetic inhereted disease in the EuropeanCaucasian populationThe third orphan disease in FranceDue to mutations in the gene CFTR(Cystic Fibrosis Transmembrane Conductance Regulator)Modifications of the electrolytic exchangesDefect in the mucociliairy clearanceand thickening of the bronchial mucusEntrapment of the inhaled bacteria and fungal spores

Fungal respiratory infections in CFBeside bacteria, several fungal species may also colonizethe respiratory tract, sometimes leading to true respiratory infections,the frequency of which is increasing.The prevalence of these fungi in the context of CF is certainlyunderestimated and the clinical significance of their isolation stillremains to be defined.Basic research on the ecology of these fungi, their biochemistry, andtheir pathogenic mechanisms should be promoted.

Fungal respiratory infections in CFWorking group approved by the ISHAM council on October 2006Clinicians and mycologists involved in the follow-up of CF patients, aswell as scientists working on basic research on CF-associated fungiThis WG would take advantage of and form a bridge between otherexisting ISHAM working groups such as the ISHAM Working groupson Pseudallescheria / Scedosporium infections or on Black yeasts.Working together, it would be possible to improve our knowledgeon the epidemiology, the physiopathology and clinical relevanceof the colonization of the airways by fungi in CF patients,and thus to contribute to improve the follow-up of the patients.

Clinical surveillanceAspergillus fumigatus : the main causativeagent of colonization of the airways9 to 57% of the patientsBecker et al., Chest, 1996 : 16% - USAMilla et al., Pediatr Pulmonol, 1996 : 21.2% - USABurns et al., Clin Infect Dis, 1998 : 24.5% - USACimon et al., Eur J Med Microbiol Infect Dis, 2000 : 46.1% - FranceBakare et al., Mycoses, 2003 : 45.7% - GermanyResponsible for various diseases in the context of CFAsthma, bronchiitis and aspergillomaInvasive pulmonary aspergillosis (after lung transplantation)Allergic broncho-pulmonary aspergillosis or ABPA

Clinical surveillanceOther filamentous fungi are increasingly reported, such as Scedosporiumapiospermum and some Aspergillus species, particularly A. terreus,but little is knownabout the prevalence of these fungiand the allergic diseases that they cause.Exophiala dermatitidisHigh prevalence in Germany, but very lowin other countriesClimatic differences ? differences in the way of life ? …

Clinical surveillanceRecent description of new fungal species (new Scedosporium speciessuch as S. aurantiacum), and some thermophilic fungiSome of these fungi seem to be closely associated with CFMarkers of a CF-related disease ? A large-scale study should beperformed to determine the frequency of CF-related diseases in case ofrepeated isolation of some fungal species in patients with proximalbronchiectasis.

Clinical surveillance - specific tasks- to determine the prevalence of the different fungi associated with CF- to determine the real prevalence of the different clinical entitiesrelated to A. fumigatus, and of allergic diseases due to other species- to determine the frequency of CF-related diseases in patients withchronic respiratory infections and proximal bronchiectasis- to create a web-base database for declaration of cases of fungalcolonization/infection, and a dedicated website to make allinformation available- to promote direct information of clinicians and microbiologists

Biological diagnosis No standardization of mycological examination of sputum samplesfrom CF patients (culture media, incubation time or temperature) Need for simple and reliable methods allowing an accurate andeasy identification of the newly described Scedosporium species Molecular methods allowing the detection of all fungi that may beencountered in sputum samples Serological tests for differentiation between colonization of theairways and true respiratory infection, or for diagnosis of allergicdiseases Development of ELISA-based kits using recombinant proteins fordiagnosis of allergic diseases caused by non-A. fumigatus fungi

Biological diagnosis - specific tasks- to develop molecular tools for detection and direct identification ofthe fungal biota from clinical samples- to develop selective or semi-selective media for detectionof these fungi from respiratory secretions- to defne guidelines for mycological examinationof respiratory secretions through multicenter studies- to develop well-standardized serological tests for diagnosisof respiratory infections or allergic diseases- to preserve the isolates for future studies

Physiopathology and treatment Airway colonization due to the defect in the mucociliaryclearance, the thickening of the bronchial mucus and therepeated use of antibiotics and corticosteroidsAlways succeed to bacterial respiratory infections (priorbronchopulmonary epithelial tissue damage are required for theestablishment of fungi ?)- The sequence of events needs to be confirmed- Interactions between bacteria and fungi also should beinvestigated.

Fungal respiratory infections in CF Genetic studies of the hostIdentification of genetic risk factors for ABPA and airwaycolonization by A. fumigatus.Genetic risk factors for the other fungi associated with CF ? Genotype studies of the isolates collected from CF patientsRegarding A. fumigatus, particular genotypes are selected with theageing colonization.Mechanisms of this genotype selection ?

Fungal respiratory infections in CF What effects for fungal colonization of the airways on theevolution of the pulmonary disease ?The colonization of the airways could contribute to theinflammatory reaction and therefore to the deterioration of the lungfunction How and when to treat ?Progress are needed in prophylaxis of fungal infections after lungtransplantation for colonized patients, most of the causative fungalspecies being capable of dissemination

Ecology of these fungiWhat could be the origin of the contamination of the patients ? Identification of the niches of Scedosporium apiospermum shouldallow us to define prophylactic measures Methods facilitating the detection of the fungus from environmentalsamples should be developed to identify the potential sources ofcontamination of the patients, especially in the indoor environment. Epidemiological studies dealing with identification of the niches ofthe other filamentous fungi associated with CF should be promoted.

Fungal respiratory infections in CFA lot of works have to be done (and certainly others not listed here)Our working group is still in infancyPoor knowledge of the research teams involved in fungalrespiratory infections in cystic fibrosis, of their research topicand their field of experienceVery few collaborative works performed until now1 st Meeting, Faculty of Pharmaceutical Sciences,Angers, 2009, June 7-8

Fungal respiratory infections in CF65 attendants (14 countries)Angers UniversityGEIHP, UPRES-EA 3142 (epidemiology, diagnosis andphysiopathology of fungal respiratory infections in CF)SONAS, UPRES-EA 921 (Natural Products and SyntheticAnalogs)

Fungal respiratory infections in CFDunkerqueLilleRouenRennesParisPoitiersDijonBordeauxLyonGrenobleToulouseMarseilleGiens

Fungal respiratory infections in CFStuart ElbornCaroline BaxterKen BruceGeraint RogersChris Thornton

Fungal respiratory infections in CFKlaus MortensenJan-Bart YntemaCorné KlaassenLies VanheeFrançoise SymoensTom CoenyePatrick Lebecque

Fungal respiratory infections in CFRegine HorréKathrin TintelnotGerhard HaaseMarc SeidlerAmparo SoléJavier PemanEnrique CalderonVicente FriazaMaria SimitsopoulouGraziana Manno

Fungal respiratory infections in CFCarlos MillaFrancisca HernandezLaila ZougaghiRachid ZouhairMarina BuarqueIlma PaschoalGisele YonezawaWieland Meyer

Fungal respiratory infections in CF

Fungal respiratory infections in CFSunday, June 7th : Musée des Beaux Arts

Fungal respiratory infections in CF

Fungal respiratory infections in CFMonday, June 8th : Castle of Plessis-Bourré (XVth century)

Fungal respiratory infections in CFThanks to:Angers University and Institut Fédératif de Recherche 132, CellInteractions and Therapeutic ApplicationsAngers Agglomération and Conseil Général de Maine et LoirePharmaceutical laboratories : MSD, Shering-Plough,Pfizer Laboratories and GileadIn vitro Diagnosis : Bio-Rad, SR2B, SERFIB and Fumouze DiagnosticInternational Society for Human and Animal Mycology