Current trends in global fungal epidemiology and resistance Maiken Cavling Arendrup [email protected] Unit of Mycology Statens Serum Institute Denmark Disclosures: ESCMIDResearch Online grants & Speaker: Astellas Lecture, Basilea, Gilead, MSD & Pfizer; Library Advisory board: MSD, Pcovery, Pfizer; Acted as consultant for: Alcimed, Astellas, Gilead & Pfizer Chair(wo)man for EUCAST-AFST @ by author M Cavling ARENDRUP Agenda Types of Fungal infection Severe Fungal infections in numbers . in a global perspective Focus on . Cryptococcus infections . Acute and chronic Aspergillus infections . Invasive Candida infections Highlight the main challenges . in the high income countries . in the Resource limited countries ESCMID Online Lecture Library @ by author M Cavling ARENDRUP Fungal infections Mucosal . e.g. oral or vulvovaginal candidiasis Cutaneous . e.g. athlete’s foot, ringworm and onychomycosis Other non-invasive . e.g. fungal keratitis Chronic fungal infections . e.g. chronic pulmonary aspergillosis, chromoblastomycosis Allergic . e.g. allergic fungal sinusitis and allergic bronchopulmonary aspergillosis (ABPA) Invasive and life-threatening fungal infections . e.g. candidaemia, invasive aspergillosis and cryptococcal meningitis ESCMID Online Lecture Library @ by author M Cavling ARENDRUP Fungal infections Mucosal . e.g. oral or vulvovaginal candidiasis Cutaneous . e.g. athlete’s foot, ringworm and onychomycosis Other non-invasive Life threatening/ . e.g. fungal keratitis shortening Chronic fungal infections . e.g. chronic pulmonary aspergillosis, chromoblastomycosis Allergic . e.g. allergic fungal sinusitis and allergic bronchopulmonary aspergillosis (ABPA) Invasive and life-threatening fungal infections . e.g. candidaemia, invasive aspergillosis and cryptococcal meningitis ESCMID Online Lecture Library @ by author M Cavling ARENDRUP Global burden of common life threatening infections GAFFI: Global Action Fund for Fungal Infections Fungal infection Case fatality rate Estimated deaths Comments Cryptococcal meningitis 15-20% USA >50% developing world 600,000 CDC estimate ~50% in developed world if Many missed diagnoses Invasive Aspergillosis >100,000 treated globally Chronic pulmonary Under-diagnosed and ~15% in developed world >450,000 aspergillosis mistaken for tuberculosis Severe asthma with fungal ~100,000 asthma deaths – <1% but no good figures Uncertain sensitisation (SAFS) ~50% related to SAFS Candida bloodstream ~40% if treated >120,000 infection Most cases in Africa not ~15% in AIDS Pneumocystis pneumonia >80,000 diagnosed and 100% ~50% non-AIDS mortality Probably a significant Total >1,350,000 ESCMID Online Lecture Libraryunderestimate www.gaffi.org @ by author M Cavling ARENDRUP Global burden of common life threatening infections GAFFI: Global Action Fund for Fungal Infections Fungal infection Case fatality rate Estimated deaths Comments Cryptococcal meningitis 15-20% USA >50% developing world 600,000 CDC estimate ~50% in developed world if Many missed diagnoses Invasive Aspergillosis >100,000 treated globally Chronic pulmonary Under-diagnosed and ~15% in developed world >450,000 aspergillosis mistaken for tuberculosis Severe asthma with fungal ~100,000 asthma deaths – <1% but no good figures Uncertain sensitisation (SAFS) ~50% related to SAFS Candida bloodstream ~40% if treated >120,000 infection TB 2012 Malaria Most2013 cases in Africa not 1,420,000~15% in AIDS Pneumocystis pneumonia >80,000 584,000diagnosed and 100% ~50% non-AIDS mortality Probably a significant Total >1,350,000 ESCMID Online Lecture Libraryunderestimate www.gaffi.org; www.who.int@ by author M Cavling ARENDRUP Cryptococcus related deaths Worldwide ~ 600,000 deaths/year Deaths in Africa 800,000 sub-Saharan Arica sub-Saharan Africa only 700,000 . ≥ 500,000 deaths/year 600,000 ‒ ≥ possibly TB 500,000 . Case mortality 35%-65% 400,000 ‒ vs. 10%-20% in developed 300,000 200,000 countries 100,000 0 Malaria Cryptococcus TB Malaria Cryptococcus TB ESCMID Online Lecture Library WHO Rapid advice@ HIV/AIDS programmeby author Dec 2011, www.who.int reports for 2013 M Cavling ARENDRUP Cryptococcal meningitis in AIDS Impact of therapy Survival at 10 weeks 75% Best treatment with 50% amphotercin B and 5FC No treatment, Fluconazole always fatal 0% ESCMID Online Lecture Library www.gaffi.org; Nussbaum@ CID by 2010; Longley author CID 2008, Day NEJM 2013 M Cavling ARENDRUP Amphotericin B + 5FC superior! Crypto-meningitis. 299 pts. Treatment doses Treatment strategy Amphotericin B 1 mg/kg 5-FC 100 mg/kg/day Combo: 2 weeks fluconazole 400 mg/d 8 weeks Fluconazole 800 mg/day Mono: 4 weeks fluconazole 400 mg/d 6 weeks ESCMID Online Lecture Library Day NEJM 2013 @ by author M Cavling ARENDRUP Drug availability Amphotericin B Flucytosine Fluconazole ESCMID Online Lecture Library www.gaffi.org @ by author M Cavling ARENDRUP Cryptococcal meningitis in AIDS Common cause of death in many communities Excellent antigen test Can identify disease before symptoms Takes 10 mins and costs $2 ESCMID OnlineHighly Lecture cost effective Library www.gaffi.org; Lourens@ JCM 2014by author M Cavling ARENDRUP Agenda Types of Fungal infection Severe Fungal infections in numbers40 -50% of the 1,350,000 IFI deaths/y . in a global perspective Drug availability & cost challenges Rapid bed-side test available Focus on Huge potential to save lives . Cryptococcus infections . Acute and chronic Aspergillus infections . Invasive Candida infections Highlight the main challenges . in the high income countries . in the Resource limited countries ESCMID Online Lecture Library @ by author M Cavling ARENDRUP Aspergillus: Host interaction & spectrum of disease Aspergillus inoculum Colonisation Disease Normal Host Overreacting immune Impaired (lung) tissue Compromised immune system architecture system Transient ABPA TB Haematological disease colonisation Sinusitis Sarcoidosis HSCT, GVHD Asthma w fungal COPD Wegeners granulomatosis sensitisation etc Aspergilloma Steroids Chronic forms of aspergillosis Influenza… Semi acute invasive ESCMID Online Lecture Libraryaspergillosis @ by author M Cavling ARENDRUP Aspergillus disease in Europe Type of Predominant risk Risk Aspergillosis Annual aspergillosis aspergillosis groups population rate burden size (000’s) (000’s) ABPA Asthma 42,500 2.1% (0.7-3.5%) 893 (298 – 1,488) 2.65 Cystic fibrosis 29 15% 4.3 Mill SAFS Severe asthma 2,450 – 6,380 33% 1,457 (765 – 2,125) CPA COPD, TB, Sarcoidosis, >13,600 1-10% 240 0.24 ABPA, Pneumothorax Mill IA Myeloid leukaemia, 46 7% 3.2 Other haematological 3.2 HSCT 11.4 0.8 63.43 COPD hospital 2,830 1.2% 34.0 Thou- admissions sand Solid organ 30 (SOT) 0.75% 0.23 transplantation ESCMIDMedical ICU Online1,100 ( all ICU ) Lecture2% Library22 Denning, Personal communication: Beasley 2004; Denning 2010, 2011 & In press; Stevens 2003; Mehta 2010; Sant 2010; Pagano M Cavling ARENDRUP 2006; Perkhofer 2010;@ Baldomero by2011; Bulpa 2007;author NHS 2010; Pappas 2010; Trick 2002; Lortholary 2012. Chronic Pulmonary Aspergillosis 3 mill people worldwide (of whom 1,2 mill has TB); >450,000 deaths South-Africa Denmark 5-y prevalence rate W-Europe 1.2/100,000 ~65 cases 5-year EU prevalences Lithuania: 8.8/100,000 Portugal: 3.3/100,000 The NL: 0.65/100,000 5-y prevalence rate 128/100,000 ESCMID Online Lecture Library~64 094 cases www.gaffi.org @ by author M Cavling ARENDRUP Chronic Aspergillosis after TB Frequency of Aspergillus antibodies after TB . UK 1970: 34% . India 2001: 27% . Brazil 1988: 21% . Japan 1989: 20% 1992 1994 1997 ESCMID Onlinenot on antifungal Lecture tx still Library not on antifungal tx Iwata Kekkaku 1989, Shahid Indian J Med Microbiol 2001, Kurhade Indian J. Med Microbiol 2002, Ferreira-da-Cruz et al. Memórias do M Cavling ARENDRUP Instituto Oswaldo Cruz@ 1988; Courtesy by David Denning,author www.gaffi.org; Prognosis of chronic pulmonary aspergillosis Study summary 1.0 p<0.0001 Retrospective observational study Study period: 2001-9 0.8 129 Aspergillus cult+ Colonization - 42 CPA (32.6%) 0.6 - 87 colonisation (67.4%) BMI was an independent 0.4 predictor of prognosis (Odds Ratio, 1.973; p = 0.0223) 0.2 Probability of survival Probability CPA 0 0 10 20 30 40 50 60 70 80 ESCMID OnlineMonths Lecture Library Ohba et al. Resp Med@ 2012;106:724; by www.gaffi.org author M Cavling ARENDRUP Itraconazole for chronic pulmonary aspergillosis India: Post TB chronic aspergillosis Clinical response Prospective, randomised controlled Oral trial Control Itraconazole CPA patients ±6 months oral therapy 80% 60% 40% 31 patients (mean age, 37 years) 20% . itraconazole (n = 17) Improved . control (n = 14) group. 0% Stable Worsened -20% Overall response -40% . Itraconazole 75.5% -60% . Control 35.7 (P 0.02) -80% ESCMID Online Lecture Library Agarwal R et al, Mycoses@ 2013; by 56:559 author M Cavling ARENDRUP Drug availability ESCMID Online Lecture Library www.gaffi.org @ by author M Cavling ARENDRUP Agenda Types of Fungal infection Chronic pulm aspergillosis Severe Fungal infections in numbers 500,000 IFI deaths/y . in a global perspective global infection but Huge variation High income >< Focus on Resource limited countries . Cryptococcus infections Under-/ misdiagnosed cases . Acute and chronic Aspergillus infections . Invasive Candida infections Highlight the main challenges . in the high income countries . in the Resource limited countries ESCMID Online Lecture Library @ by author M Cavling ARENDRUP IPA - Patient groups and Host Factors Haematological malignancy - anti-IA-antifungals Cancer & chemotherapy ≥ the last 3 months SOT recipient