BY 2025, ensure that 95% of people with serious fungal disease are diagnosed and 95% treated. 95-95 OVER A BILLION people are affected with fungal disease across the world IMPROVING OUTCOMES FOR PATIENTS WITH FUNGAL INFECTIONS ACROSS THE WORLD A ROAD MAP FOR THE NEXT DECADE 95B / 95 Y 2025 95B / 95 Y 2025 2 EXECUTIVE SUMMARY With over a billion people affected by fungal disease across the world resulting in approximately 11.5 million life- threatening infections and over 1.5 million deaths every year, we face a major challenge to improve this dismal situation. Recent advances in diagnostics, robust screening programs and improved access to low cost antifungal drugs provide an unprecedented opportunity to reduce the burdens of ill health and death, especially in those with HIV/AIDS. In this 10 year roadmap, we call upon By implementing these basic measures, governments, policy makers and GAFFI is confident that 95% of people international health agencies to: with serious fungal disease will be • Support the goal of reducing AIDS diagnosed and 95% will be treated. This deaths to under 500,000 by 2020, with constitutes GAFFI’s goal for the next 10 a determined focus on the commonest years encapsulated as ‘95-95 by 2025’. lethal fungal infections cryptococcal meningitis, Pneumocystis pneumonia, Who is at risk? About 30 fungal species cause 99% of disseminated histoplasmosis and human fungal disease. In decreasing chronic pulmonary aspergillosis after frequency, these are cutaneous (skin tuberculosis hair and nails) fungal diseases, mucosal Professor David Denning making a • Ensure that 95% of people with serious candidiasis, allergic fungal conditions point at the launch of GAFFI at the House fungal disease are diagnosed and 95% usually complicating asthma, chronic of Commons in London in 2013 treated by 2025 (95-95) skin, lung, sinus and bone infections To accomplish these goals, it is and the acute life or sight-threatening This 10 year Roadmap, an executive necessary in each country to: fungal infections. The vast majority of summary and all appendices may be • Ensure that affordable diagnostic tests infections are globally distributed, with downloaded from: for all common and uncommon fungal a few localized to continents, tropical www.gaffi.org/roadmap infections are made available, focused zones or even localized regions. This For all abbreviations see Appendix 2 on rapid, non-culture testing report addresses the current status of • Develop and maintain at least one diagnostics and diagnostic skills, clinical laboratory led by an expert in fungal practice and antifungal access, and disease diagnostics with a follows the first Global Forum of Fungal comprehensive diagnostic portfolio Infections in 2015 (Appendix 1). and critical mass of healthcare Fungal infections affect 6 main professionals per country groups of patients • Develop a network of expert clinicians • Cancer, leukaemia, transplantation and ‘train the trainer’ programs, and AIDS supported by clinical guidelines • Critical care - premature babies, • Ensure distribution of antifungal agents ICU, major surgery on the WHO Essential Medicine List to • Lung disease - severe asthma, reach all those who need them TB, COPD and cystic fibrosis • Establish ongoing surveillance of fungal • Injury - eye, burns, trauma, skin infections of high burden to inform especially in tropics clinical practice, training and research • Skin, hair and nails infection in needs normal people 95B / 95 • Develop local experts in public health • Sexual health - thrush, often recurrent, especially in pregnancy Y mycology 2025 3 ‘ Any efforts that are made to encourage the understanding and treatment of fungal infections, we definitely need to go as far as we can with that. What’s happened to me, I wouldn’t wish that on anybody.’ Robert Knowles, a patient with fungal keratitis. A. THE BURDEN OF FUNGAL DISEASES Understanding the global burden of fungal and other similar disease is critical to determine priorities. Only a small number of studies have estimated the global incidence and/or prevalence of different fungal diseases (1-9). Estimates involve major extrapolations, given the lack of high quality epidemiological data, and hence likely suffer from substantial errors (e.g. more than a 2-fold difference in burden estimate from the ‘truth’). Nonetheless, approximations of fungal disease burden and associated severity for the most common life-threatening fungal infections are possible and helpful (Appendix 3). Major AIDS associated Fungal Infections and their impact Collectively, fungal infections are by far the most common infections in AIDS DEATHS from fungal infections in AIDS (Table 1), numbering in excess of 11 million, and probably over 500,000 deaths are estimated at 700,000 annually, nearly annually. Pneumocystis pneumonia (PCP) occurs worldwide and is a leading initial half the total. Concrete steps to improve presentation of AIDS (see Appendix 3 for details). The frequency of other fungal diagnosis and access to therapy, including infections in AIDS, notably cryptococcal meningitis, disseminated histoplasmosis and a screen and treat program for pre- rarer infections, vary by geography, and risk factors such as Talaromyces marneffei symptomatic cryptococcal, disease, could infection in SE Asia and invasive aspergillosis. Histoplasmosis has a high incidence in realistically reduce deaths by 457,000 per certain places in Central and South America, but is worldwide in tropical and semi- year by 2020, if 60-90% of patients are tropical countries. Oral and oesophageal candidiasis are extremely common, and reached. worldwide. In Bangladesh, the top disease associations with death in hospital were oesophageal candidiasis (odds ratio 27.5) and PCP (OR 18.5), ahead of a CD4 cell 90-90-90 = 90% of HIV infected patients count of <200 (OR 16.6) or cancer (OR 15.2) (10). know their infection status, 90% of all HIV patients receiving ART and 90% viral load AIDS deaths remain too high because of opportunistic infections. Many people suppression. present with advanced HIV infection and very damaged immune systems and/or are not responsive to ARVs because of antiviral resistance. The incidence of PCP, For all abbreviations see Appendix 2 cryptococccal meningitis and oesophageal candidiasis will fall as 90-90-90 (Appendix 7) rolls out, but histoplasmosis and skin and nail infections are likely to remain static. Even after starting ARVs, patients are dying of fungal disease and undiagnosed infection in the first year (Table 2). Some deaths are due to immune reconstitution, but most are probably related to continuing immune suppression, which has not yet recovered. Left. The cryptococcal antigen LFA which has excellent performance in many specimen types for both diagnosis and surveillance for cryptococcal disease, in AIDS and others. Right. Young chinese woman with cryptococcal meningitis being treated with a lumbar drain to reduce intracranial pressure. 4 Table 1. Global estimates and related deaths of fungal infections per year among people with AIDS. Fungal infection Annual burden Case fatality rate if treated Estimated annual deaths Cryptococcal meningitis 371,700 – 957,900 15-20% USA >50% in LMICs 125,000 – 624,700 Pneumocystis pneumonia >400,000 15% with best treatment >200,000 Disseminated histoplasmosis >100,000 15-30%, if diagnosed and treated >80,000 Chronic pulmonary aspergillosis >185,000 15-40% mortality in HIC >100,000 Invasive aspergillosis >45,000 30% mortality if treated in HIC >30,000 T. marneffei infection >8,000 18-33% >2,000 Mucosal and skin fungal infection >10,120,000 <1% <1,000 Total >11.22 million >535,000 Table 2. Deaths from key infections in the first year of ART in 5 studies. Deaths in first year of ART by therapy (%) C o u n t r y Years Total Cryptococcal meningitis TB Undiagnosed infections Senegal (11) 47/404 (12%) 5/47 (11%) 8/47 (16%) 9/47 (18%) 98-02 Morocco (12) 57/1243 (4.6%) 7/57 (12%) 20/57 (35%) Not described 99-10 Zimbabwe and 179/3316 (5.4%) 20/179 (11%) 14/179 (8%) 33/179 (18%) 03-04 Uganda (13) Malawi (14) 190/1584 (12%) 7/190 (4%) 10/190 (5%) 35/190 (18%) 03-05 India (15) 56/759 (7%) 5/56 (9%) 27/56 (48%) 10/56 (18%) 09-10 Below. Diagnoses of histoplasmosis in Colombia, showing increase Below. Mycology reference laboratory in Cayenne, French Guiana, since implementation of rapid testing with antigen detection (16) and transforms the outcome of disseminated histoplasmosis in AIDS with PCR (17) (Caceres et al, unpublished data). rapid PCR testing (18). Early deaths Histoplasmosis cases 140 100 140 120 120 80 100 100 60 80 80 60 60 40 40 40 Number of patients 20 39 20 20 Proportion of early deaths (%) Proportion 41 18 0 0 8 0 Incident histoplasmosis cases (%) 1992-1997 1992-1997 1992-1997 1988 1990 1992 1994 1997 1998 2000 2002 2004 2007 2008 2010 2012 2014 5 ‘If the medicine is out there, I don’t understand why everyone can’t get it. It just doesn’t make sense to not get those drugs out here.’ Woodrow Maitland-Brown, a patient with fungal disease. Hospital-associated infection, including cancer-associated fungal infection For the hospitalized patient, the most common life-threatening infections are invasive candidiasis (including Candida bloodstream infection) and invasive aspergillosis. Less commonly PCP, mucormycosis and a large number of rarer fungi may cause infection, usually acquired in the community prior to hospitalization (Appendix 3.2). Mortality from fungal infections in hospital is unknown in LMICs but approaching 100% because many countries do not have diagnostic tools and antifungals for these diseases. Table 3. Global estimates of fungal infections and related deaths per year in immunocompromised and/or hospitalized patients without HIV infection. Fungal infection Annual burden Case fatality rate if treated Estimated deaths Invasive candidiasis >750,000 ~45% mortality in HIC >350,000 Invasive aspergillosis >250,000 ~50% mortality in HIC >125,000 Pneumocystis pneumonia >100,000 ~50% non-AIDS, in HIC >50,000 Total >1.1 million >425,000 1992 1994 No RX 1997 Still no RX Above.