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Infections Fongiques Invasives Révélant Un Déficit Immunitaire

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Infections Fongiques Invasives Révélant Un Déficit Immunitaire Infections fongiques invasives révélant un déficit immunitaire Fanny Lanternier Service de maladies infectieuses et tropicales Hôpital Necker Enfants malades IHU Imagine CNRMA, Unité de mycologie moléculaire, Institut Pasteur Primary immunodeficiencies Invasive fungal diseases • T cell deficiencies Severe combined immunodeficiencies, Combined immunodeficiencies, CD4 lymphopenia • Phagocytic cell deficiency Chronic granulomatous disease, severe congenital neutropenia and leukocyte adhesion deficiency: Invasive aspergillosis and candidiasis • IL-12/IFN-γ axis deficiency Dimorphic fungal infections, Cryptococcosis • STAT3 deficiency Aspergillosis, chronic mucocutaneous candidiasis • AD STAT1 gain of function mutations Dimorphic fungi, chronic mucocutaneous candidiasis +++, cryptococcosis, aspergillosis, pneumocystosis • AR CARD9 deficiency Central nervous system candidiasis+++, chronic mucocutaneous candidiasis+, phaeohyphomycosis dermatophytosis Comprehension of antifungal immunity Chronic Granulomatous Disease • Absence or dysfunction of • Recurrent infections NADPH complex – Catalase-positive organisms: • Inability of neutrophils to S. aureus and Burkholderia produce reactive oxygen cepacia species (phagocytosis, – Aspergillus sp. NETosis) • Inflammation • Neutrophils do not control A. fumigatus conidia growth • X-linked CGD: CYBB gp91phox 65% • AR CGD: CYBA p22phox, NCF1 p47phox, NCF2 p67phox, NCF4 p40phox Severe infections in CGD • 268 CGD patients 4 decades • Monocentric study • Aspergillus incidence 2.6 cases per 100 patient-years • 44% Aspergillus infection Most common pathogen • Median age of first infection lower gp91phox • Incidence higher in the lower superoxide production quartile • Fatality rate 9%, most common cause of death Marciano CID 2014 Epidemiology and outcome of Invasive Fungal Disease in patients with Chronic granulomatous diseases • Nationwide French study (CEREDIH) • 155 CGD 1976-2008 • 42.6% : 1 episode IFD • Median age at diagnosis: 6.5 years • Molds 65%: – Aspergillus (32) 65%, • A. fumigatus 14, A. nidulans 11 • 90% lung location Beaute J, PIDJ 2011 Search for cerebral location Survival IFD free After 1999 IFD Survival after IFD Beaute J, PIDJ 2011 Personnal data Salvatore, ERJ 2015 Antifungal • Prophylaxis – IFD incidence: 0.027 itraconazole prophylaxis vs 0.053 without prophylaxis IFD/patient-year – Guidelines: itraconazole 10 mg/kg/d • Curative treatment – Voriconazole – Slow response – Prolonged duration 307 days – Long term toxicity • Skin+++ Beaute J, PIDJ 2011 Geosmithia argillacea/ Rasamsonia argillacea • Mold • Mistaken identification with Penicillium or Paecilomyces • CF colonisation • Disseminated infection with CNS involvment in CGD • R LAmB, vori, itra • S echinoc (low MIC micafungine) • S terbinafine, variable posaconazole Machouart, JCM, 2011, Ravin, CID, 2011, Giraud 2013 Mold infections in STAT 3 deficient patients : national French study A. Dureault1, C. Tcherakian, S. Poiree, E. Catherinot, ME Bougnoux, H.Coignard, B. Sendid, M. Cornu, JF Bervar, A. Deschildre, L. Wemeau, C. Fieschi, A. Alanio, C. Menetrey, A. Senechal, P.Tattevin, P. Grosbois, C. Pison, L.Perez, C. Givel, G. Jouvion, D. Garcia Hermoso, C. Picard, O. Lortholary, MO Chansdesris, F. Lanternier. Presented at AAA, Manchester 2016 Autosomal dominant STAT 3 deficiency • Main etiology of hyper-IgE syndrome (SHIE) • Rare immune deficiency: 74 patients in France in 2015 • STAT 3 : Signal Transducer and Activator of Transcription 3 • Abnormal susceptibility to infections : Mucocutaneous candidiasis ENT : S. aureus, P. aeruginosa otitis Lower respiratory tract: S. Skin abcesses aureus, S. pneumoniae, H. S. aureus influenzae, P. aeruginosa Post-infectious lung complications • Bronchectasia or pneumatocele • Lung cavities: 67 % • Multiple, often large •Aspergillus infection or colonization : 22% Chandesris MO et al. Medicine (2012) Retrospective descriptive study Inclusion criteria •STAT 3 deficiency •Positive specimen for mold at infection site or positive Aspergillus serology •and CT image compatible with fungal infection Methods • Clinical, mycological and radiological data collection at time of infection (or colonisation) + follow up • Centralized data review comitee (pneumologist, radiologist, ID) files and CT: classification • Centralized pathology analysis Results : 23 episodes, 13 patients 18 patients – 28 episodes at least one positive sample (smear, culture, serology) 5 patients excluded : Aspergillus colonization 13 patients – 23 episodes TDM compatible with fungal infection Aspergilloma CPA-like ABPA-like Lung invasive Allergic sinusitis N = 6 N = 8 N = 5 infection with Aspergillus N=1 Rasamsonia N = 1 Mix forms CPA + ABPA N = 2 No invasive aspergillosis according to EORTC/MSG criteria Chronic pulmonary aspergillosis October 2003 June 2004 ABPA-like 06/2012 Impactions Trapping 07/2012 Impactions resolution Remission Sd alvéolaire nécrose PNP d’inhalation Results : mycological criteria CPA-like Aspergilloma ABPA-like Total Mycological criteria N = 8 N = 6 N = 5 N = 23 positive/ available (%) Ag GM sérum (> 0.5) 2/6(33) 0/3 0/3 3/15 Ag GM LBA (>1) 3/3(100) 0/2 0/0 3/5 Sputum, culture 1/1(100) 0/0 3/3(100) 3/4 BAL, ED 3/5(60) 0/4 1/3(33) 4/14 BAL, culture 6/7(86) 3/4(75) 2/3(67) 12/17 Serology 6/6(100) 3/4(75) 4/4(100) 15/17 *: Aspergillus fumigatus **: précipitines: 8/15 Aspergillosis and STAT3 deficiency Mold infections, mainly Aspergillus fumigatus, 17.5% of STAT3 deficient patients. Only on pathological lung No invasive aspergillosis in French cohort. Contrast with other data with 28% iFI, including autopsic reports with angioinvasion Description of ABPA-like forms 50% relapse despite prolonged antifungal treatment Antifungal prophylaxis with itraconazole when lung cavities Surgery indication to be defined Vinh et al, J. Allergy Clin. Immunol., 2010 Avoid cavity drainage Freeman et al , J. Allergy Clin. Immunol., 2007 STAT3, endemic mycosis and cryptococcosis • 3 histoplasmosis • 1 disseminated coccidioidomycosis: CNS • 1 Crytpococcus gattii infection • Hyper IgE syndrome – 6 histoplasmosis – 4 cryptococcosis – 2 coccidioidomycosis: CNS • Frequence of GI location for histo, crypto – Role of Th17 Odio C, JACI, 2015 STAT 1 GOF mutation and fungal infections • STAT1 Gain-Of-Function mutation • Increased STAT1 phospohorylation • IL-17A IL17F producing T cell development impaired • 274 patients with confirmed STAT1 GOF mutations from 40 countries • Chronic mucocutaneous candidiasis (98%) – Median age first symptoms 1 year – Oral mucosae (93%), skin (57%), oesophagal/genital (56%), nail (56%) – Frequent azole resistance • Superficial dermatophytosis (16%) Toubiana J, … Puel A Blood 2016 STAT 1 GOF mutation and fungal infections • 10% IFI – 10 invasive candidiasis – 6 P. jirovecii pneumonia – 5 Aspergillus sp. pneumonia – 4 cryptococcosis ( 4 pneumonia, 2 meningitis) – Dimorphic fungal infection: 2 Histoplasma sp. pneumonia, 2 disseminated coccidioidomycosis – 1 disseminated mucormycosis • Bacterial infections (lung, skin, S. aureus) • Herpesviridae infections (skin) • Autoimmune diseases, cerebral aneurysms and carcinomas • 12% death (30 ans) (38% severe infections (2 fungal)) • Azole prophylaxis Toubiana J, … Puel A Blood 2016 Inborn errors in the IL12-IFNγ pathway and invasive fungal infections • Autosomal mutations IL12B, IL12RB1, IFNGR1, IFNGR2 • Associated with susceptibility to disseminated non-tuberculous mycobacterial infections and salmonellosis • Cryptococcosis (IL12RB1) • Dimorphic fungal infections: histoplasmosis (IFNGR), paracoccidioidomycosis (IL12RB1) disseminated coccidioidomycosis (IL12RB1, IFNGR1) • Lung and bone location Vinh D, CID, 2009, 2011, Zerbe CID 2005, de Moraes Vasconcelos CID 2005 CARD9 deficiency + One patient? • 37 years old man, from Morocco • « Maladie dermatophytique » • Long term history of recurrent, severe and treatment resistant dermatophytosis Dermatophytosis Dermatophytosis Superficial Invasive Stratum corneum Dermal invasion Deep dermatophytosis Superficial Majocchi granuloma Extensive dermal infection Benign Lymph node or organ invasion Perifollicular Tinea pedis, granuloma corporis, cruris Patients without and capitis known risk factors Risk “Maladie factors dermatophytique” No risk factor Risk factors North Africa Deep dermatophytosis: clinical characteristics of the 19 patients Male 12 (70) Median age at first symptoms [years] 8 [2-21] First symptoms Severe or recurrent tinea capitis 14 Severe or recurrent tinea corporis 10 Onychomycosis 6 Presentations in adulthood Lymph node involvement 10 Central nervous system invasion 1 Local organ invasion (bone, GI) 2 Associated infection: thrush 6 Death 5 Lanternier, NEJM, Jachiet, JAMA dermatol 2014, Grumach, J Clin Immunol 2015 Median age at death [years] 34 [28-91] Autosomal recessive CARD9 (Caspase recruitment domain containing protein 9) deficiency: first report NEJM 2009 - One large consanguineous Iranian family: 7 members affected CMC, dermatophytosis, Candida spp. CNS infection CARD9: Q295X/Q295X Q295X NH2 1 536 COOH CARD CC 6 98140 420 Deep dermatophytosis Homozygous mutations in CARD9 R101C Q289XQ295X NH2 1 536 COOH CARD CoilCoiled 6 98140 420 Lanternier, NEJM, 2013 Invasive Candida spp. CNS and gut infection CNS: 18 cases reported *meningitis *abcesses *no candidemia *relapses *hydrocephalus Gut: 2 cases reported Grimbacher, NEJM, 2009, Drewniak, Blood, 2012, Lanternier, NEJM, 2013, Gavino, CID, 2014, Lanternier JACI 2015, Herbst PIDJ 2015 UNUSUAL INVASIVE FUNGAL INFECTIONS REPORTED IN CARD9 DEFICIENCY Exophiala
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