on behalf of by fungal disease expects working with the LIFE program

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1 Burden of Fungal Infection abstracts presented at the 12rd European Congress on Clinical Microbiology and Infectious Diseases April 27 th 2013, Berlin on behalf of The Global Action Fund for Fungal Infections (GAFFI) by fungal disease expects working with the LIFE program In alphabetical order Austria, Brazil, China, India, Ireland, Israel, Kenya, Netherlands, Nigeria, Senegal, Singapore, Spain, Uganda Selected fungal infections estimated for a total population of 3.1 billion people

2 Burden of serious fungal infections in Austria Cornelia Lass Flörl, David W. Denning and The University of Manchester in association with the LIFE program at worldwide.org Introduction The number of fungal infections occurring each year in Austria is not known. We have estimated these based on populations at risk, supplemented with existing data. Methods All published epidemiology papers reporting fungal infection rates from Austria were identified. We also extracted reported data from the International Classification of Diseases (ICD) from Ministry of Health as comparators. Where no data existed, we used specific populations at risk and fungal infection frequencies in those populations to estimate national incidence or prevalence, depending on the condition. Asthma and COPD rates were from Statistik Austria, Gesundheitsbefragung 2006/2007 and OECD HIV data was from Ministry of Health transplantation numbers were from Gesundheit Osterreich. Results Of the 8.22M population, 14.5% are children (0-14 years) and 18% of population are >65 years old. We therefore estimate that 110,000 Austrian women get recurrent vaginal thrush (4+ times annually). 106 cases have been recorded in Tirol in 2011, a total of 1221 nationally. Of the 688 cases of pulmonary TB in 2011, 84% in HIV negative people, and that 25% of chronic pulmonary aspergillosis (CPA) cases are TB related we estimate a 5- year period prevalence of 382 CPA cases (assuming 15% annual mortality). Asthma prevalence in adults is 7% and assuming 2.5% of asthmatics have ABPA, 7,537 patients with ABPA are likely and 9,949 with severe asthma with fungal sensitisation (SAFS). Of the 15,000 estimated HIV positive patients, only 45 presented with AIDS in 2010 and 100% are taking ARVs. Only 5 cases of cryptococcal meningitis were identified and it is not possible to estimate the annual incidence of Pneumocystis pneumonia, or oesophageal candidiasis which is principally in non- AIDS patients. The rate of candidemia in Austria is low at 2.63/100,000 population consistent with 209 cases, although only 165 were actually documented. Candida peritonitis is estimated at 40% of the ICU candidaemia rate, based on French data. Most cases or oral and oesophageal candidiasis were probably in non- HIV infected people. Invasive aspergillosis in haematological and transplant patients is estimated at 96 cases [which contrasts with 158 from registry data (2007/8)] and 283 in COPD patients admitted to hospital. 28 mucormycosis and 2 histoplasmosis cases were recorded. Conclusion Substantial uncertainty surrounds these estimates except for invasive aspergillosis figures in immunocompromised patients and candidaemia, where

3 hospital- based surveillance studies have been done. Therefore, epidemiological studies are urgently required to validate or modify these estimates. Infection Number of infections per underlying disorder per year Total Rate None HIV/AIDS Respiratory Cancer/Tx ICU burden /100K Oesophageal candidiasis Oral candidiasis? ? Candidaemia Candida peritonitis Recurrent vaginal candidiasis (4x/year +) 110, ,000 2,616 ABPA - - 7, , SAFS - - 9,949 9, Chronic pulmonary aspergillosis Invasive aspergillosis Mucormycosis Cryptococcal meningitis Pneumocystis pneumonia -??? -? - Histoplasmosis? 2 -? Fungal keratitis? Tinea capitis Total burden estimated 111, ,976 1, ,964

4 The burden of human fungal infections in Brazil Lilian Carla Carneiro, UFCSPA Ludmila Fiorenzano Baethgen, UFCSPA Maria Adelaide Millington, SVS/MS David W Denning, National Aspergillosis Centre and University Hospital of South Manchester (Wythenshawe Hospital) Arnaldo L Colombo, UNIFESP Alessandro C Pasqualotto, ISCMPA and UFCSPA Objectives: to determine the burden of fungal infections in Brazil. Material and Methods: For inpatients, data was obtained from the Brazilian Ministry of Health Informatics Department System (DATASUS), based on patients' CID-10 discharge. Data was considered consistent only for fungal diseases for which there was a surveillance program in place. Cases of cryptococcosis and PCP were obtained from the Information System of Notifiable Diseases (SINAN). To other invasive mycoses, assumptions were made based on incidence rates reported in the Brazilian literature or - in the absence of such data - in the world literature. The denominator included the overall Brazilian population, number of patients with HIV/AIDS, respiratory diseases, cancer/immunocompromised and critical care/surgery, as reported in governmental publications. Results: Brazil has ~194 million inhabitants (75% adults, 51% women, and 33% are >40 years old). The current burden of serious fungal infections in Brazil was estimated in ~3.4 million (M) cases. Based on a TB incidence of 36/100,000 (2010), a prevalence of ~12 thousand (K) cases of chronic pulmonary aspergillosis (CPA) were estimated, not considering CPA cases due to other conditions. If 12.4% of Brazilian adults have asthma and assuming that at least 2.5% of asthmatics have ABPA, we estimated ~390K patients with ABPA. Only 392 cases of cryptococcal meningoencephalitis were documented per year (incidence 0.06% in the total HIV population) in official records. Cases of oral / oroesophageal candidosis in AIDS patients were estimated in ~164K and ~58K, respectively, whilst recurrent (>4 episodes/year) Candida vaginitis affected ~2.7M/year. The rate of candidaemia was 249/100,000 hospital admissions (~30K). Invasive aspergillosis in immunocompromised patients was estimated at ~9K patients including ~2K in critically ill/copd patients. For mucormycosis, the general rate of 2/1,000,000 suggests 243 cases based on hospital admissions annually. For

5 histoplasmosis, incidence was estimated in 2/100,000 hospital admissions per year. Other endemic mycosis added ~2K cases. Conclusion: Based on local data and literature estimates of the frequency of mycoses in susceptible populations, 1.7% of Brazilians presents some form of severe fungal disease. Knowing that the mycoses are an internationally neglected health topic, we believe that if all fungal diseases could be officially notified the real number should be much higher than the estimated by this study. Keywords: Mycoses, epidemiology, aspergillosis, fungal infections.

6 Burden of serious fungal infections in China Liping Zhu, Jiqin Wu, David S. Perlin, David W. Denning Huashan Hospital, Fudan University, Shanghai China, Public Health Research Institute, Newark, NJ, USA and The University of Manchester in association with the LIFE program at worldwide.org Introduction We have attempted to estimate the burden of serious fungal infection in China. Methods All published epidemiology papers reporting fungal infection rates from China were identified. If few data existed, we used specific populations at risk and fungal infection frequencies in those populations to estimate national incidence or prevalence. Population (2009), HIV (2011) and TB (2011) data were from WHO. Asthma, ABPA and CPA rates were from Denning, Bull WHO 2011, Med Mycol 2013 (in press) and Ma, COPD admissions were from Tan, Respirology, Cryptococcal meningitis (CM) estimate in HIV was assumed to be 1% of late stage HIV patients, and the rate of CM in other cases on the ratios reported by Chen, Mycopathologia, Pneumocystis (PCP) rates were based in Hong Kong rates in HIV and in non- HIV on Wang, J Med Microbiol, Penicillium marneffei infection rate was based in HK data, adjusted for regional differences in HIV prevalence. Tinea capitis rate was on a report from Shanghai (Zhu, Mycopathologia, 2010). Keratitis rate was based on Xu in Qingdao (Chin Med J, 2012). Results Of the 1,363M population, 20% are children (0-14 years) and 12% are >60 years old. 20M chinese (age 15-50) women are estimated to get recurrent vaginal thrush (4+ times annually). Of the 740,000 estimated HIV positive patients in 2011, 92,227 are not on ARVs (CD4 <350). Of these an estimated 83,000 develop oral thrush, 50,000 oesophageal candidiasis, 461 CM, 16,140 PCP and 1,383 P. marneffei infection. We estimate a 5- year period prevalence of 256,534 CPA cases (assuming 15% annual mortality); 80% from 893,121 cases of pulmonary TB, 20% other conditions. Asthma prevalence in adults is estimated at nearly 20M and assuming 2.5% of asthmatics have ABPA, 491,721 patients with ABPA are likely and 648,300 have SAFS. The rate of candidemia was estimated at 5/100,000 population (68,150 cases) and Candida peritonitis at 19,982 cases. Invasive aspergillosis (IA) in >100,000 haematological patients is estimated at 8,178 cases and in the COPD 154,000 cases (11.9M admissions). IA numbers in renal and liver transplantation and numerous other fungal diseases were not estimated. Conclusion Without any national surveys of fungal disease in China, uncertainty surrounds all these estimates. But the burden of fungal disease is almost certainly one of the greatest in the world. Epidemiological studies are urgently required to validate or modify these estimates.

7 Infection Number of infections per underlying disorder per year Total Rate None HIV/AIDS Respiratory Cancer/Tx ICU burden /100K Oesophageal candidiasis - 50, , Candidaemia ,445 47,705 68, Candida peritonitis ,082 19, Recurrent vaginal candidiasis (4x/year +) 19,959k ,959 2,929 Allergic bronchopulmonary , , aspergillosis (ABPA) Severe asthma with fungal sensitisation (SAFS) , , Chronic pulmonary aspergillosis (CPA) , , Invasive aspergillosis , , , Mucormycosis ,726-2, Cryptococcal meningitis Pneumocystis pneumonia - 16,140? 8,070-24, Penicillium marneffei infection? 1, , Fungal keratitis 17, , Tinea capitis 34, , Total burden estimated 20,010k 151,822 1,405,555 37, k 21,829k

8 Estimating fungal infection burden in India using computational models: Mucromycosis burden as a case study. Arunaloke Chakrabarti, Prashant Sood, David W. Denning Department of Medical Microbiology, Postgraduate Institute of Medical Education & Research, Chandigarh, India; Department of Hematology, All India Institute of Medical Sciences, New Delhi, India; The University of Manchester, Manchester, UK, in association with the LIFE program at worldwide.org Objective: With a vulnerable population greater than 110 million and a stark absence of surveillance machinery, determining valid, comparable, evidence- based fungal burden estimates are of paramount importance in India. Comprehensive baseline data is pertinent for effective prioritization of already strained public health resources. We have developed contextual computational models for elucidating infection burden of all major fungi circulating in our country and present here our preliminary results using mucormycosis as a case study. Methods: Raw data spread across five decades ( ) of Indian literature was mined from time- scaled case series, hospitalization data, community studies and serological surveys. Each data set was assessed for accuracy and reliability based on the study design, study period, case definitions, diagnostic test efficacy and statistical denominators. Appropriate computational models were developed using multipliers, stratifications and corrections specific for each fungus' disease patterns and final statistical modelling was implemented using Monte Carlo algorithms. Results: Our computational model for mucormycosis reveals a prevalence of 0.14 cases per 1000 population in India. The cumulative burden ranges between 208,177 and 137,807 cases with a mean of 171,510 (SD: 12,365.6; 95% CI: 195, ,688) (Fig 1). Estimates specific for underlying risk factors reveal mean burden of 77,874 cases among diabetics, 18,625 cases among cancer and transplant patients, 8,566 cases among trauma and major surgery patients under intensive care, 794 cases among tuberculosis and COPD patients, 286 cases among HIV/AIDS patients and 44,949 cases among individuals with no apparent underlying disease. Conclusion: Our evidence- based computational estimates offer valuable fungal burden data so far unavailable with all national and international health authorities including the WHO. This comprehensive data is contextually relevant to our population, country's epidemiology, fungi distribution and underlying risk factors. Our computations assume steady state demographic and pathogen dynamics, a shortcoming we have partially circumvented using Monte Carlo probabilities. We are designing pathogen- specific outcome- trees linking exposure, infection and its outcomes for modelling dynamic burden of disease estimates.

9 Probability Density No. of Cases

10 Estimation of the burden of chronic and allergic aspergillosis in India Arunaloke Chakrabarti, Ritesh Agarwal, Donald C. Cole, Alex Pleuvry and David W. Denning Departments of Medical Microbiology and Pulmonary Medicine, Postgraduate Institute of Medical Education & Research, Chandigarh, India; Dalla Lana School of Public Health, University of Toronto, Toronto, Canada; Oncalex, High Peak, U.K The University of Manchester, Manchester, UK, in association with the LIFE program at worldwide.org. Objective: India is the world s second most populous country, with high rates of TB and HIV. Comprehensive baseline data is necessary for effective prioritization of limited public health resources. Using scoping review methodology and deterministic modelling, we have estimated the incidence and 5yr period prevalence of chronic pulmonary aspergillosis (CPA) following TB and prevalence of allergic bronchoplumonary aspergillosis (ABPA) complicating asthma in India. These long term conditions respond to antifungal therapy. Methods: The bases for the computations have been published (Denning et al, Bull WHO 2011;89: and Denning et al, Med Mycol In press). Estimated pulmonary TB rates were updated from 2007 to 2011 using WHO statistics, with deaths excluded. Asthma rate in adults was estimated from the country- specific prevalence of asthma from the GINA report applied to population estimates (mean prevalence of current wheezing in children was 88% of adults in the countries which participated in both studies). Additional modeling was done to accommodate several ABPA studies in India. Results: In 2011, the population of India was estimated at 1,241,000K. The number of cases of pulmonary TB in India has fallen slightly from 3,305K to 3,100K (2,100K 4,300K) (249/100K) and the mortality also from 331K to 300K (24/100K). The annual estimated incidence of new CPA cases has risen from 83,000 to 85,012 and 5 year period prevalence from 261,679 to 267,987. Rates of ABPA complicating asthma with good denominators of referral populations (n=5 studies) vary from 0.7 to 3.5%, with the median being 2.5%. The number of adult asthmatics is estimated at 23,709K and ABPA at 592,719. If rates of 5%, 7% and 20% are applied (Table), the gross numbers of ABPA patients estimated in India rises to 1,185K, 1,660K and 4,742K respectively. All estimates (n=7) of Aspergillus sensitisation rates in adult asthmatics in India exceed 16% and are 50% in asthmatics admitted to ICU with asthma. Conclusion: The total burden of antifungal- responsive chronic and allergic aspergillosis in India is not known, but is likely to exceed 860,000 patients. CPA has many underlying conditions in addition to TB, which are not estimated. CPA carries an early mortality of 30% after diagnosis (Korea and Japan), emphasising the importance of antifungal therapy to minimise death and morbidity. Epidemiological studies are required to better categorise the burden of these diseases in India. Year Population Time N frame studied ABPA N Comments Reference 1976 Cohort study IgE not measured, and Khan et al of secondary and tertiary? fungal disease referrals years (4.6%) patients had to have asthma and periodic infiltrates, positive skin test, eosinophilia, A. fumigatus grown from sputum and positive Aspergillus precipitins Sequential NS patients excluded. Maurya et

11 asthma referrals to a tertiary centre 2007 Sequential referrals to a tertiary centre 2010 Referrals to a tertiary centre 4.5 years (20.5%) (7.6%) Healthy control group also evaluated. Patients also sensitized to non- fumigatus Aspergilli Full diagnostic details not provided for all ABPA patients. 1 year (7%) Excluded: those in receipt of corticosteroids for 2 weeks in prior 6 months and allergic rhinitis or chronic sinusitis. 6 patients grew A. flavus. al Agarwal et al Ghosh et al

12 Burden of serious fungal infections in Ireland Eileen Dorgan 1, David W. Denning 2, Ronan McMullan 1 1 Royal Victoria Hospital, Belfast and 2 The University of Manchester in association with the LIFE program at worldwide.org Objective To estimate the annual burden of serious fungal infection on the island of Ireland Method Relevant published epidemiology describing fungal infection in Ireland was identified. Data were collected for Population data were obtained from Northern Ireland Research and Statistics Agency and Central Statistic Office of Ireland. HIV/AIDS data obtained from World Health Organization (WHO), Health in Ireland HIV report and HIV and STI surveillance report for NI. Data for respiratory disease were taken from WHO, Organisation for Economic Co- operation and Development (OECD) library and asthma society. Transplant data were extracted from transplant registries. Results Of Ireland s 6.4M population, 22% are children under 16 and 8% are women over 60. Population data was used to estimate rates of age- related fungal infection; therefore, we estimate that 94,974 women have recurrent Candida vaginitis per year. This and other fungal infection estimates are summarised in the table. Ireland has approximately 7,374 people with HIV. There are few AIDS- related opportunistic infections with only around 13 HIV- positive patients developing Pneumocystis pneumonia. Among patients with chronic pulmonary aspergillosis (CPA) it is estimated that 25% is attributable to TB. We infer an approximate prevalence of 196 cases of CPA. Using international data, indicating that typically around 2.5% of adults with asthma have Allergic Bronchopulmonary Aspergillosis (ABPA), we have estimated 8,691 cases per year among the estimated 353,794 adults with asthma and 773 CF patients. The candidaemia rate is approximately 6.3/100,000, which gives us a total of 403 cases of candidaemia per year. Of these, an estimated 128 occur in critical care each year, and an additional 64 cases of Candida peritonitis occur among 244,630 abdominal surgical procedures.

13 Conclusions Most fungal infections are unreported and therefore are impossible to count in absolute numbers. To have an impression of the overall fungal burden in Ireland it is necessary to make some assumptions about the population from known datasets and published literature. Based on available data approximately 1.9% of Ireland s population will have a serious fungal infection during one year. Since most of our results are extrapolated from surrogate markers of fungal infection this model requires validation; however, it provides a standardised means of estimating and comparing the burden of disease across populations. Infection Number of infections per underlying disorder per year None HIV/AIDS Respiratory Cancer/Tx ICU Total Burden Rate /100K Oesophageal candidiasis Candidaemia Candida peritonitis Recurrent Candida vaginitis (>4x/year) 94,974 94, Allergic 8,961 bronchopulmonary aspergillosis (ABPA) 8, Severe asthma with fungal 11,675 sensitisation (SAFS) 11, Invasive aspergillosis Mucormycosis Cryptococcal meningitis Pneumocystis pneumonia Chronic pulmonary 196 aspergillosis Total burden estimated 94, , ,389

14 The burden of serious fungal infection in Israel Ronen Ben-Ami, David Denning Tel Aviv Sourasky Medical Center, Tel Aviv, Israel, and The University of Manchester, UK, in association with the LIFE program ( Objectives Estimates of fungal infection caseloads are required to plan and implement healthcare policies. In Israel, healthcare is universal, and specialized medical care is centralized in 5 tertiary-level medical centers. A growing medical tourism industry and immigration from Africa have contributed to an increase in the population of patients cared at tertiary hospitals, as well as newly diagnosed TB and HIV/AIDS. We aimed to estimate national fungal infection caseloads from epidemiological datasets. Methods We searched national data available from the Israeli ministry of health, WHO and OECD reports, as well as surveillance studies published by us and other authors for relevant disease terms. Locally collected incidence data were available for candidaemia, HIV/AIDS, solid organ and stem cell transplantation, TB, asthma, COPD and CF. Generally, disease estimates were conservative as they assumed the lowest incidence rates reported in the literature and focused only on well-defined risk populations. Results Israel s population in 2011 was 7.8 M (50% female, median age 29 yrs, 34% <=18 yrs, 10% =>65 yrs). Twenty percent of Israelis were smokers, 20% of whom (312,000) had COPD. 375,000 people were living with asthma, and 468 persons had CF. 6,579 persons were living with HIV/AIDS, and 70% of those were receiving antiretroviral treatment. Nationwide surveillance detected a candidaemia rate of 5.5/100,000 population/yr (429/yr), with a crude in-hospital mortality rate of 49%. Conservative estimates of oral and oesophageal candidiasis incidence were 1,776 and 625 cases/yr, respectively. Recurrent vulvovaginal candidiasis (=>4 episodes/yr) occurred at a conservative estimate in 130,000 women/yr. Cases of invasive aspergillosis were estimated at 130/yr, and mucormycosis at 20/yr. ABPA was estimated in 7,945 persons, and SAFS in 12,375 persons. Based on TB statistics, the incidence of chronic pulmonary aspergillosis was estimated at 9-75/yr. PCP was diagnosed in ~17 HIVinfected patients/yr. Endemic fungi were reported only sporadically, and were imported in all cases. Conclusion The candidaemia rate in Israel is among the highest reported in the literature. Our estimates point to candidaemia and invasive aspergillosis as the leading causes of fungal-associated death, whereas fungal-related morbidity is mainly due to recurrent vulvovaginal candidiasis, SAFS and ABPA. More precise, prospectively reported data are needed to support informed healthcare policymaking.

15 BURDEN OF SERIOUS FUNGAL INFECTIONS IN KENYA John Abuga Guto, Christine Bii and David W. Denning Kenya Medical Research Institute, The University of Manchester in association with the LIFE program at worldwide.org Introduction Kenya is a developing East African Country with a high rate of TB and a moderate HIV infection burden. The main fungal infections are respiratory, eye and dermatological. Research reports show increased incidence of cryptococcal meningitis (CM), Pneumocystis pneumonia (PCP), Keratitis and skin infections.we have attempted a preliminary estimate of serious fungal infections in Kenya. Methods A full literature search was done to identify all epidemiology papers reporting fungal infection rates from Kenya. We used specific populations at risk and fungal infection frequencies in the population to estimate national incidence or prevalence. WHO population statistics of 2010, the 2010 WHO HIV infection and ARV treatment rates; Kenya AIDS Epidemic Update 2012, Kenya Facts and figures 2012, Kenya Demographic and Health Survey, WHO 2010 TB statistics, ISAAC estimate of asthma prevalence are some of the databases used and the GINA Report. Results Kenya population is about 39.8 million with 43% under 15 years of age and 4% over the age of 60. Estimates are: Kenyan women get (5%) of 4 episodes or more of Candida vaginitis per year, a total of 566,271. HIV/AIDS population estimated at 710,000 with 61% on ARV therapy so population at risk of OIs 277,000. Estimates are: oral thrush 249,210, oesophageal candidiasis 77,035, CM rate of 7% in all HIV patients with < CD4 count in Kenya, so 7,810 cases, PCP 27,690 cases (10% not treated with ARVs), with a high mortality. Pulmonary TB cases resulting in prevalence of 10,848 cases of chronic pulmonary aspergillosis, using a 15% annual mortality rate, perhaps 67% of the total CPA caseload. The adult asthma population prevalence is 7% (4% of GP consultations) and assuming 2.5% have ABPA 39,702 cases would be expected. Severe asthma with fungal sensitisation (SAFS) is estimated to affect 54,407 people. Invasive aspergillosis, candidaemia and candida peritonitis are probably uncommon. Tinea capitis is common 9.6% in Kenya a prevalence of 1,712,267. Fungal keratitis is difficult to estimate. Conclusion At any one time, 6.25% of the Kenyan population suffers from a fungal infection, with recurrent vaginitis and tinea capitis accounting for 88% of the infections. These basic estimates require epidemiological studies to validate or modify the substantial burden estimates.

16 Infection Number of infections per underlying disorder per year Total Rate None HIV/AIDS Respiratory Cancer/Tx ICU burden /100K Oesophageal candidiasis - 77, , Candidaemia ,990 1,990 5 Candida peritonitis Recurrent vaginal candidiasis (4x/year +) 566, , ABPA - 39, , SAFS - 54,407 54, Chronic pulmonary aspergillosis , , Invasive aspergillosis ? Mucormycosis Cryptococcal meningitis 7, , Pneumocystis pneumonia - 27,690?? - 27, Histoplasmosis??? - -?? Fungal keratitis? ? Tinea capitis 1,712, ,712, Total burden estimated 2,278, , , ,786 2,502,560

17 The burden of serious fungal infections in the Netherlands Jacques F. Meis*, David W. Denning, Paul E. Verweij Canisius Wilhelmina Hospital, and Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands, and The University of Manchester in association with the LIFE program at worldwide.org. Objective: The healthcare system in the Netherlands is advanced, but the number of fungal infections (FIs) nationally is not known. Using different populations at risk we have estimated numbers of serious FIs. Methods: Published papers reporting FI rates from the Netherlands and population data were extracted from monitoring.nl, Results: Amongst a population of M, 17.3% are children (0-14 years) and 21% of population are >60 years old. Recurrent vaginal thrush (4+ times annually) affects 5% of women under 50, an estimated total of 219,588. Of the 1073 cases of pulmonary TB in 2011, 96% HIV negative, 45 new cases of chronic pulmonary aspergillosis (CPA) cases are estimated, a 5- year period prevalence of 142 CPA cases, 25% of all cases (assuming 15% annual mortality). Asthma prevalence in adults is 7.2% (997,378 cases) although 2003 figures suggest 519,800. Assuming that 2.5% of the lower number have ABPA, 13,085 patients with ABPA are likely and 17,153 have severe asthma with fungal sensitisation (SAFS). Of the 16,555 estimated HIV positive patients, only 812 presented with AIDS in 2011 and none developed Pneumocystis pneumonia or cryptococcal meningitis. Estimating the annual incidence of Pneumocystis pneumonia or oesophageal candidosis in other patient groups was not possible. The rate of candidemia was estimated at 5/100,000 population consistent with 838 cases. Candida peritonitis is estimated at 50% of the ICU candidaemia rate, itself estimated to be 70% of all candidaemia. Among haematological/transplant and COPD patients, invasive aspergillosis is estimated at 336 and 240 respectively. Conclusion: Most serious fungal infections in the Netherlands occur in immunocompromised and respiratory patients. Both community and hospital- based surveillance studies are urgently required to validate or modify these estimates. Infection Number of infections per underlying disorder per year Total Rate None HIV/AIDS Respiratory Cancer/Tx ICU burden /100K Oesophageal candidosis ? Candidaemia Candida peritonitis Recurrent vaginal candidiasis (4x/year +) 219, , ABPA , , SAFS ,153 17, Invasive aspergillosis Mucormycosis Cryptococcal meningitis Pneumocystis pneumonia - 0???? - Total burden estimated 219, , ,010

18 BURDEN OF SERIOUS FUNGAL INFECTION IN NIGERIA Rita Oladele, Obianuju Ozoh. David W. Denning, College of Medicine of University of Lagos, Lagos, Nigeria; The University of Manchester and the LIFE program at Corresponding author: Rita Oladele Introduction Nigeria is the most populous country in Africa with a high rate of tuberculosis and a moderate HIV infection burden. Some reports of cutaneous and mucosal fungal infections have emerged from Nigeria. We have estimated the total number of serious fungal infections in Nigeria. Methods A full literature search was done to identify all epidemiology papers reporting fungal infection rates from Nigeria. We used specific populations at risk and fungal infection frequencies in the population to estimate national incidence or prevalence. WHO population statistics of 2009, the 2010 WHO HIV infection and ARV treatment rates; National Agency for the Control of AIDS child/adult HIV split 2011, WHO 2010 TB statistics, ISAAC estimate of asthma prevalence are some of the databases used for estimating population at risk. Results 50% of the nearly 155M Nigerian population are children and 38M are women between the age of 15 and 50 yrs. 1.5M Nigerian women get recurrent vaginal thrush. Local estimates of tinea capitis exceed 20% of school age children, suggesting that over 15.5M children have tinea capitis. There were 78,032 cases of pulmonary TB in 2010, most in HIV negative people and based on cavity frequency and Aspergillus IgG serology, we expect 19,000 new cases of chronic pulmonary aspergillosis (CPA) with a 5 year period prevalence of 60,377 cases (Denning, 2011) probably 50% of the total CPA caseload. Asthma is also common in Nigeria and a population prevalence of 15.2% has been reported. (Desalu, 2009), Therefore we expect about 3.7M adult asthmatics of which 2.5% will have ABPA (94,000 with ABPA are likely and 124,00 with SAFS). Based on the 3,459,363 cases of HIV infection reported, (55% children), 1,449,166 on ARV therapy, and 281,180 new AIDS cases, an estimated 32,000 cases of cryptococcal meningitis is estimated. 75,000 of the AIDS cases are expected to develop Pneumocystis pneumonia (40% rate in children), 253,000 oral candidiasis and 144,000 oesophageal candidiasis based on the WHO prevalence rate. Rates of candidaemia, invasive aspergillosis, mucormycosis and histoplasmosis were estimated on a population basis, without supporting data and are probably uncommon or rare. Conclusion Our estimates indicate that over 11.8% of the Nigerian population is estimated to suffer from a serious fungal infection each year. If tinea capitis and recurrent vaginal thrush are excluded, over 800,000 are estimated to be affected, with substantial mortality. Epidemiological studies are urgently required to validate or modify these estimates.

19 Infection Number of infections per underlying disorder per year Total Rate None HIV/AIDS Respiratory Cancer/Tx ICU burden /100K Oesophageal - 144,195??? 144, candidiasis Candidaemia -?? 3,095 6,189 9, Candida peritonitis ,321 2, Recurrent vaginal 1,521, ,521, candidiasis (4x/year ) ABPA , ,649 6 SAFS , ,617 7 Chronic pulmonary , ,753 8 aspergillosis Invasive aspergillosis -?? 928? Mucormycosis Cryptococcal? 16,034?? - 16,034 1 meningitis Pneumocystis - 74,594??? 74, pneumonia Histoplasmosis??? - -? 5 Fungal keratitis? ? Tinea capitis 15,581400???? 15,581, Total burden estimated 17,941,657

20 Burden of Serious Fungal Infections in Singapore Lionel Hon Wai LUM, Louis Yi Ann CHAI, Sophia ARCHULETA, David DENNING Division of Infectious Diseases, University Medicine Cluster, National University Health System, Singapore University of Manchester, UK in association with the LIFE program at worldwide.org Objectives: Singapore is a cosmopolitan South East Asian country with a Gross Domestic Product of USD 240 billion and an estimated population of 5.35 million. We aim to estimate the burden of fungal infections in the country as part of a multi- national effort to quantify worldwide fungal infections. Methods: Estimation of fungal disease burden was extrapolated from available epidemiological documents. Population statistics and respective disease distributions pertaining to HIV, malignancies, tuberculosis, chronic obstructive pulmonary disease (COPD) and asthma were extracted from Singapore Demographics Profile 2012 and Ministry of Health (MOH) releases. Transplant cases were estimated from Heart Lung Registry, and from the renal and liver transplant lists in Singapore hospitals. The number of critical care beds was obtained via a manual count of the hospitals countrywide. In cases whereby local incidence of specific diseases was not known, this was reasonably extrapolated from that of neighbouring Asian countries with similar population demographics. Results: 13% of the population are younger than 15 years old, and 2.12 million are women older than 15 years of age, of which are estimated to have recurrent Candida vaginitis. The incidence of invasive aspergillosis in immunocompromised hosts is at least 37 cases annually, but many more in COPD admissions and ICU patients. On the other hand, the prevalence of chronic pulmonary aspergillosis (CPA) after tuberculosis (TB) figures at 182 cases, based on calculation of annual cavitary pulmonary TB cases and established CPA incidence, with further extrapolated data from Taiwan and China. This is possibly 33% of the total CPA caseload. While asthma is relatively common in adults (250,000-5%), allergic bronchopulmonary aspergillosis (ABPA) and severe asthma with fungal sensitisation (SAFS) are rarely diagnosed. Based on 183 cases of AIDS in Singapore in 2011, 9.2% (17) present with cryptococcal meningitis, 47.7% (87) have Pneumocystis pneumonia. 460 patients per year have oral candidiasis, and 265 have esophageal candidiasis. The annual incidence of candidemia is 268 per year, with two thirds of the patients being in critical care or surgical care, and one third being cancer or immunocompromised patients. Conclusions: The prevalence of medically- significant fungal infections in the population is under- recognised in Singapore. Increased awareness and surveillance will serve to enhance appropriate allocation of healthcare resources in this disease spectrum.

21 Infection Number of infections per underlying disorder per year Total None HIV/AIDS Respiratory Cancer/Tx ICU burden Rate /100K Oesophageal candidiasis Candidaemia Candida peritonitis Invasive aspergillosis Mucormycosis Cryptococcal meningitis Pneumocystis pneumonia - 87?? Histoplasmosis? 2 -? Fungal keratitis Total burden estimated Indicate POSTER Add 3 Keywords : Singapore, fungal, burden

22 Burden of serious fungal infection in Senegal Aida Sadikh Badiane, David W. Denning Cheikh Anta Diop University, Dakar, Senegal and The University of Manchester in association with the LIFE program at worldwide.org Introduction Senegal is a West African country with a high rate of tuberculosis and a relatively low HIV seropositivity rate. Surgical series of aspergilloma resection reports of serious and life- threatening fungal infections have been reported. We have estimated the number of serious fungal infections, partly to assess diagnostic and treatment deficiencies nationally. Methods All published epidemiology papers reporting fungal infection rates from Senegal were identified. Where no data existed, we used specific populations at risk and fungal infection frequencies in those populations to estimate national incidence or prevalence, depending on the condition population statistics were derived from the Statistics National Institute; HIV cases and AIDS deaths from the US World Factbook (2012); TB cases from Rapport CNLS (2012); and COPD cases from Thèse UCAD (Chirurgie dentaire). Results 43% of the nearly 13M population are children and 3.5M are women between the age of 15 and 64. Estimates are: 175,000 Sengalese women get recurrent vaginal thrush; as tinea capitis exceed 40% of school age children, over 2M children have tinea capitis. Of the 11,408 cases of TB in 2011, most in HIV negative people, it is estimated that 740 new cases of chronic pulmonary aspergillosis (CPA) occurred and that the 5 year period prevalence is 2300 cases, perhaps 50% of total CPA cases as COPD etc are frequent in Senegal. Estimates of asthma prevalence in adults are 3.2% (2011) and 8.2% (2001) (mean 5%) and assuming 2.5% of asthmatics have ABPA, 92,000 patients with ABPA are likely and 122,00 with SAFS. Of the 59,000 estimated HIV positive patients, 160 (2.9%) of 5544 new AIDS cases each year have cryptococcal meningitis and as many as 1220 (22%) Pneumocystis pneumonia. Oral candidiasis (53%) and dermatophytosis (16%) is common in advanced HIV infection. Burden of candidaemia, invasive aspergillosis, mucormycosis and histoplasmosis were not estimated (? rare or undiagnosed). 113 cases of mycetoma were diagnosed ( ) [Ndiaye et al 2011]. Eumycetoma (70%) were more frequent than actinomyceta. Conclusion Using local data and literature estimates of the incidence or prevalence of fungal infections, over 17% of the sengalese population is estimated to suffer from a fungal infection each year. These figures are dominated by tinea capitis. Substantial uncertainty surrounds these estimates and epidemiological studies are urgently required to validate or modify these estimates.

23 Infection Number of infections per underlying disorder per year Total Rate None HIV/AIDS Respiratory Cancer/Tx ICU burden /100K Oesophageal candidiasis ??? Candidaemia -?????? Candida peritonitis ??? Recurrent vaginal candidiasis (4x/year +) 175, ,000 1,346 ABPA , , SAFS , , Chronic pulmonary aspergillosis Invasive aspergillosis -?????? Mucormycosis Cryptococcal meningitis? 160?? Pneumocystis pneumonia ??? Histoplasmosis??? - -?? Fungal keratitis? ? Tinea capitis 2,000,000???? 2,000,000 Total burden estimated 2,396,321

24 Burden of serious fungal infections in Spain Juan Luis Rodriguez Tudela 1, Manuel Cuenca- Estrella 1, Jose María Miro 2, Asunción Nuñez Boluda 3, Isabel Ruiz Camps 4, Amparo Sole 5, David W. Denning 6 and The University of Manchester in association with the LIFE program at worldwide.org Introduction Spain is a South European country with an estimated population of 47 millions of people. We have estimated the number of serious fungal infections in order to define the burden of these diseases in Spain. Methods All published epidemiology papers reporting fungal infection rates from Spain were identified. Where no data existed, we used specific populations at risk and fungal infection frequencies in those populations to estimate national incidence or prevalence, depending on the condition population statistics were derived from the Statistics National Institute. HIV/AIDS cases and deaths (2010) were obtained from the Spanish National registry. Tuberculosis cases from National Tuberculosis Registry (2010). COPD cases from Miratvilles et al. Thorax; 64: Transplant cases (2010) from the Spanish National Organization for Transplantation. Cystic fibrosis cases from the European Registry of ECFs And Spanish Scientific Society of Cystic Fibrosis. Number of critical beds from the Spanish Health Ministry (2010). Results 40.5% of the 47 M population are adults, 21% women and 14% children below 14 years. 22% of population are >60 years old. Estimates are: 822,094 Spanish women get recurrent vaginal thrush. Of the 5351 cases of TB in 2010, most in HIV negative people, it is estimated that 342 new cases of chronic pulmonary aspergillosis (CPA) occurred and that the 5- year period prevalence is 1,079 cases (assuming 15% annual mortality). As total CPA cases as COPD etc., are more frequent, 4,318 total CPA cases are estimated. Estimates of asthma prevalence in adults are between 5-8% and assuming 2.5% of asthmatics have ABPA, 59,210 patients with ABPA are likely and 93,044 with SAFS. Of the 150,000 estimated HIV positive patients, 15 (1%) of 1,500 new AIDS cases each year develop cryptococcal meningitis. Annual incidence of Pneumocystis pneumonia is 3.4 cases/100,000 consistent with 1,598 cases (87% in HIV + patients). In HIV infection, oral candidiasis is estimated to occur at least once in 90% of those with low CD4 counts (33,750 cases), and oesophageal candidiasis in 20%. The rate of candidemia in Spain is 10.7/100,000 habitants consistent with 5,029 cases. There is one case of candida peritonitis for every 2 ICU patients with

25 candidaemia. Invasive aspergillosis in immunocompromised patients is estimated at 1,346 patients annually including 874 cases in critical, many with COPD. For mucormycosis, the general rate of 1/1,000,000 suggests nearly 100 cases annually. For Histoplasmosis, incidence can be estimated in 10 new cases per year. Conclusion Using local data and literature estimates of the incidence or prevalence of fungal infections, almost 1 M (2,12%) people in Spain suffer from a fungal infection each year. These figures are dominated by recurrent vaginitis. Substantial uncertainty surrounds these estimates except for candidaemia figures where a population based surveillance study has been recently made. Therefore, epidemiological studies are urgently required to validate or modify these estimates. Infection Number of infections per underlying disorder per year Total Rate None HIV/AIDS Respiratory Cancer/Tx ICU burden /100K Oesophageal candidiasis - 11, , Candidaemia ,886 3,143 5, Candida peritonitis Recurrent vaginal candidiasis (4x/year +) 822, , ABPA , , SAFS ,044 93, Chronic pulmonary aspergillosis - - 4, , Invasive aspergillosis , Mucormycosis Cryptococcal meningitis Pneumocystis pneumonia - 1, Histoplasmosis??? 10 0,02 Fungal keratitis? Tinea capitis? Total burden estimated 822,188 12, ,572 2,566 4, ,596

26 Estimated Burden of Fungal Disease in Uganda Rosalind Parkes- Ratanshi, Beatrice Achan, Andrew Kambugu, David Meya, David W. Denning Background In Uganda, as elsewhere in Sub Saharan Africa, the HIV epidemic has highlighted cryptococcal and Candida infections as important opportunistic fungal infections. However, the burden of other fungal diseases is not well described. Estimating the burden of these infections in Uganda is an important first step in highlight gaps in diagnosis, care and treatment for fungal illnesses. Methods All epidemiological papers of fungal diseases in Uganda were reviewed. For infections where there is no Ugandan data, global data or data from East Africa were used. Population statistics were obtained from World Bank, HIV statistics from the Uganda AIDS Indicator survey (UAIS), pregnancy rates from the UNFPA, and TB rates from WHO statistics (all 2011). Results Of 35 million Ugandans, 1.1million have HIV and an estimated 9.2% (101,000) have a CD4 count <200 cells/µl. The cryptococcal antigen positivity rate is well defined (Leitchy 2010, Meya 2010, Parkes- Ratanshi 2011), an estimated 2,834 cryptococcal cases per year. PCP rates in hospitalized HIV patients suggest around 748 cases per year (Worodria 2012). HIV related oral and vaginal Candida rates have been described pre- ART and post- ART, which gives an estimate of 41,329 cases/year (Parkes- Ratanshi, 2011). Recurrent vaginal candidiasis is estimated to be 5-8% worldwide in women (=312,950 Uganda women/ year). Prevalence of Candida in pregnant Ugandan women is 60% = 651,600 cases/year (Tann 2006). In 2011 Uganda had 38,444 cases of pulmonary TB (estimated 5,000 deaths). Using previously described calculations (Denning 2011) this gives an estimate of between 497 to 3816/year of chronic pulmonary aspergillosis post TB. Asthma affects 4.4% adults in East Africa (GINA, 2004), contributing 40,392 asthma- related fungal infections. There are no data on tinea capitis or fungal keratitis in Uganda, but in Kenya Tinea affects up to 10% of all school children per year (Uganda= approximately 1,300,000/year.) Summary There are an estimated 1 million fungal infections per year in Uganda, excluding tinea capitis.. Cryptococcus and PCP alone may cause around 30,000 deaths per year. Despite cryptococcal research in Uganda, overall fungal disease burden in Africa is not well described. As chronic diseases such as asthma increase, and cancer treatments is more widely available, it will be important to improve diagnostics and research, as well as to educate medical staff on the prevention, care and treatment of a wider range of fungal diseases.

27 Infection Incidence /rate in specific population Special population Total number affected in Uganda Cryptococcal 5.8% CD4 count < PCP 36.8% HIV +ve hospital admissions CD4<100 Oral/ vaginal candidiasis 61.4 HIV +ve pre ART 24,290 NA /100PYO 11.6 /100PYO <200CD4 HIV +ve on ART <200 CD Oesophageal candidiasis 21.3 /100PYO pre ART <200CD NA 2.39 /100PYO on ART <200 CD Invasive aspergillosis 10% AML patients Chronic pulmonary 12-22% with cavities 280 to aspergillosis post TB 1-4% without cavities 217 to 1244 Allergic bronchopulmonary aspergillosis (ABPA) 2.2% Adult asthmatics 15,708? Severe asthma with fungal sensitisation (SAFS) 3.3% Adult asthmatics 24,684? Candida vaginitis (pregnancy) 60% Pregnant women 651,600 NA Recurrent Candida vaginitis 5% Women yr 312,950 (>4x/year) NA Fungal keratitis??? NA Tinea capitis School children?1,000,000 NA NA NA Histoplasmosis, Mucormycosis, Coccidioidomycosis, Paracoccidioidomycosis TOTAL No data available 1,089,680 to 2,000,000 Estimated deaths from condition in Uganda Upto 30,000