Burden of serious fungal in China Liping Zhu, Jiqin Wu. David S. Perlin, David W. Denning Huashan Hospital, Fudan University, Shanghai 200040 China; Public Health Research Institute, Newark, NJ, USA and The University of Manchester in association with the LIFE program at www.LIFE-worldwide.org Introduction The incidence of serous fungal infections has been increasing over the past several decades as a result of the expanding number of immunocompromised patients with risk factors such as HIV , transplantation, immunosuppressive therapy, corticosteroid therapy, and broad-spectrum , etc. Despite the availability of newer and potent agents, the morbidity and mortality of invasive fungal infections remain high. LIFE Understanding of the burden of fungal infections is crucial to both better disease prevention and treatment. In China, with the largest population in the LEADING world, population-based surveillance on various fungal infections is still lacking. However, data from specific high risk populations and some cities has INTERNATIONAL increasingly been reported. We have attempted to estimate the burden of serious fungal infection in China through literature review. FUNGAL Methods EDUCATION 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. , ABPA and CPA rates were from Denning, Bull WHO 2011, Med Mycol 2013 (ahead of print) and Ma, 2011. COPD admissions were from Tan, Respirology, 2009. 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, 2012. Pneumocystis jiroveci (PCP) rates were based in Hong Kong rates in HIV and in non-HIV on Wang, J Med Microbiol, 2011. Penicillium marneffei infection rate was based in HK data, adjusted for regional differences in HIV prevalence. 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 , 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 severe asthma with fungal sensitisation (SAFS). The rate of candidemia was estimated at 5/100,000 population (68,150 cases) and peritonitis at 19,982 cases. Invasive (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 transplantation and numerous other fungal diseases were not estimated.

Number of infections per underlying disorder per year Total Rate Infection None HIV/AIDS Respiratory Cancer/Tx ICU burden /100K Conclusion Oesophageal candidiasis - 50,834 --- 50.834 3.7 Without any national surveys of fungal disease in China, uncertainty Candidaemia --- 20,445 47,705 68,150 5.0 surrounds all these estimates. But the burden of fungal disease is Candida peritonitis - --- 19,082 19.082 1.4 almost certainly one of the greatest in the world. Epidemiological Recurrent vaginal candidiasis (4x/year +) 19.959k - - -- 19.959 2,929 studies are urgently required to validate or modify these estimates. Allergic bronchopulmonary aspergillosis (ABPA) - - 491.721 -- 491.721 36.1 Severe asthma with fungal sensitisation (SAFS) -- 648,300 648,300 47.6 Chronic pulmonary aspergillosis (CPA) -- 265.534 -- 265,534 19.5 Invasive aspergillosis --- 8.178 154,155 162,333 11.9 -- - 2.726 - 2,726 0.2 corresponding author: Cryptococcal meningitis 922 461 - 922 - 2306 0.17 Dr.Li-ping Zhu. Pneumocystis jiroveci pneumonia (PCP) - 16,140 ? 8.070 - 24,210 1.8 Email:zhulp@ fudan. edu.cn Penicillium marneffei infection ? 1,383 -- - 1,383 0.1 Fungal keratitis 17.038 -_ _ _ 17,038 1.3 Tinea capitis 34.075 -_-- 34,075 2.5 Total burden estimated 20.010k 151.822 1.405,555 37,615 221k 21,829k Belfast Health and Burden of Fungal Infection in Ireland Social Care Trust

Eileen Dorgan1, David W. Denning2, Ronan McMullan1 1. Department of Medical Microbiology, Royal Victoria Hospital, Belfast Health and Social Care Trust, Grosvenor Road, Belfast, BT12 6BA 2. The University of Manchester in association with the LIFE program at www.LIFE-worldwide.orq

Introduction & Purpose The national figure on critical care beds was obtained form the critical care census Infection Number of infections per underlying disorder per year Total Burden Rate /100K and included just the level 3 beds. Abdominal surgery is used as a marker for None HIV/AIDS Respiratory Cancer/Tx ICU 601 peritoneal candidasis and candidaemia the results for Northern Ireland were Oesophageal candidiasis Fungal Infections are a growing global problem that are difficult to quantify in terms of 601 9.4 obtained from DHSSPSNI Statistics and Research records and the numbers were population affected, mortality, resources used and possible methods of prevention. Currently Candidaemia 275 128 403 6.3 then adjusted to include ROI population. 64 data available on fungal infections worldwide are crude estimates that have not been Candida peritonitis 64 1 standardized. This project attempts to compile data from several countries worldwide that Recurrent Candida Results (>4x/year) differ in terms of economic status, health care provision and ethnicity in order to form a better 94,974 94,974 1484 overall picture of the current state of fungal infection globally. Ireland has a population of 6,399,152. Of this, 22% are children under 16 and 8% Allergic 8,961 are women over 60. The rate of recurrent candida vaginitis is between 5-8% of adult bronchopulmonary aspergillosis (ABPA) Methods women; however in populations where a large percentage of women are over 50 this 8,961 140 11,675 may overcall the number of cases and a downward adjustment of 80% is Severe asthma with fungal For the purposes of creating a comparable data set for each country a template was provided sensitisation (SAFS) appropriate7. Therefore it is estimated that 94,974 women in Ireland have recurrent 11,675 182.4 that included demographic data and specific disease related information was gathered. 50 399 Candida vaginitis per year. Invasive aspergillosis 449 7 Relevant published epidemiology describing fungal infection in Ireland was identified. Data Current total HIV/AIDS 7374 Mucormycosis 13 13 0.2 were collected for 2010 from both Northern Ireland (NI) and the Republic of Ireland (ROI) and 3 Ireland has approximately 7,374 Cryptococcal meningitis 3 0 that combined data is presented here. This included some specific assumptions from Proportion of diagnosed cases on ARVs 0.79 people with HIV. There are few 12 38 published data that would allow the directly observed incidence of fungal infection to be used Number of diagnosed cases not receiving ARVS 1549 50 0.8 New cases of AIDS per year 50 AIDS-related opportunistic Chronic pulmonary 196 in conjunction with surrogate markers for fungal infection to estimate the total burden infections with only around 13 Proportion of AIDS cases presenting with PCP 25% aspergillosis 196 3.1 nationally. HIV-positive patients developing Fungal keratitis Proportion of AIDS cases presenting with 6% Pneumocystis pneumonia. Tinea capitis cryptococcal meningitis Population data were obtained from Northern Ireland Research and Statistics Agency and Total burden estimated 94,987 616 20,832 363 591 117,389 Central Statistic Office of Ireland, patients were categorized by age and gender. HIV/AIDS AIDS-related deaths in 2010 12 data for the Republic of Ireland was obtained from World Health Organization (WHO) “People Figure 1. HIV Data in Ireland Pulmonary TB (HIV positives) 20 Figure 4. Summary Table of Results for fungal infections in Ireland living with HIV” report and from the Health Service in Ireland 2011 HIV report. NI data was Among patients with chronic pulmonary Pulmonary TB (HIV negative) 225 gathered from the Public Health Agency (PHA) HIV & STI surveillance report 2011 and a Conclusions aspergillosis (CPA) it is estimated that 25% direct audit of HIV attendances at specialist clinics. It is assumed that 90% of patients with Pulmonary TB total 245 is attributable to TB. We infer an HIV who are not being treated with Anti-retrovirals (ARVs) will develop and it Most fungal infections are unreported and therefore are impossible to count in approximate prevalence of 196 cases of COPD prevalence (all GOLD stages) 10.1% absolute numbers. To have an impression of the overall fungal burden in Ireland it is is assumed that 20% of patients with HIV not on ARVs and 5% of those on ARVs develop CPA. oesophageal candidiasis. The assumptions for oral candidiasis and oesophageal candidiasis COPD admissions to hospital per 30720 necessary to make some assumptions about the population from known datasets and Using international data, indicating that may artificially elevate the numbers of these conditions in populations where patients are not year published literature. Based on available data approximately 1.9% of Ireland’s typically around 2.5% of adults with asthma receiving ARVs due to having a CD4 count >200 and not fitting clinical criteria that warrants Asthma rate in adults 7.1% population will have a serious fungal infection during one year. Since most of our have Allergic Bronchopulmonary ARV treatment as opposed to the unavailability of such interventions'1-2-3. Recent work has Numbers of adults with asthma 353,794 results are extrapolated from surrogate markers of fungal infection this model requires Aspergillosis (ABPA), we have estimated been published on Pneumocystis pneumonia in Northern Ireland and these results were validation; however, it provides a standardised means of estimating and comparing 8,691 cases per year among the estimated Number of Adults with Cystic 773 adjusted to include the ROI population4. the burden of disease across populations. 353,794 adults with asthma and 773 CF Fibrosis patients. Figure 2. in Ireland (CF) figures were extrapolated from the CF trust (NI) and CF registry (ROI). References COPD information from ROI was taken from the OECD library and asthma rates were The candidaemia rate is approximately 6.3/100,000, which gives us a total of 403 obtained from the Asthma Society IE. There was insufficient direct data for Northern Ireland 1. Matee MI, Scheutz F, Moshy J. Occurrence of oral lesions in relation to clinical and for COPD of Asthma numbers so this data was extrapolated using population figures. ABPA cases of candidaemia per year. Of these, an estimated 128 occur in critical care immunological status among HIV-infected adult Tanzanians. Oral Dis 2000;6:106-11. (Allergic Bronchopulmonary Aspergillosis) figures are determined by assuming rates of 15% each year, and an additional 64 cases of Candida peritonitis occur among 244,630 2. Smith E, Orholm M. Trends and patterns of opportunistic diseases in Danish AIDS patients 1980­ of adult CF patients and 2.5% of adult asthmatics. SAFS (Severe asthma with Fungal abdominal surgical procedures. 1990. Scand J Infect Dis. 1990;22(6):665-72. sensitisation) assumption is that this affects 33 % of the worst 10% of adult asthmatics. 1% 12% 3. Buchacz K, Baker RK, Palella FJ Jr, Chmiel JS, Lichtenstein KA, Novak RM, Wood KC, Brooks Pulmonary (TB) data for ROI was obtained from WHO and Northern Ireland 1% There are approximately 3 JT; HOPS Investigators. AIDS-defining opportunistic illnesses in US patients, 1994-2007: a Allogenic Stem Cell cohort study. AIDS. 2010 Jun 19;24(10):1549-59. information was obtained directly from PHA with supporting HIV audit data. In order to assess Transplant patients diagnosed with AML Renal Transplant per 100,000 population per 4. Coyle PV, et al. Rising incidence of Pneumocysitis jirovecii pneumonia suggests iatrogenic the total number of chronic pulmonary aspergillosis (CPA) the assumption is that 25% of CPA exposure of immuno-compromised patients may be becoming a significant problem. J Medical year in Ireland. In 2010 there is as a result of TB and therefore the figure for TB is multiplied by 4 to give the total Lung Transplant Microbiology 2012; 61: 1009-1015. prevalence. The prevalence of CPA in the TB population is assumed to be 20%5. were a total of 192 patients with 5. Denning DW, Cole DC, Pleuvry A. Global burden of chronic pulmonary aspergillosis as a sequel Myeloid Leukaemia in to pulmonary tuberculosis. Bull WHO 2011;89:864-872. doi: 10.2471/BLT.11.089441 The number of Acute Myeloid Leukaemia (AML) patients per year were obtained from the 61% Ireland. 6. Lortholary O, Gangneux JP, Sitbon K, Lebeau B, de Monbrison F, Le Strat Y, Coignard B, Dromer local cancer registry. It is assumed that non-AML haematological conditions in total have the Figure 3. Transplants in Ireland F, Bretagne S; French Study Group. Epidemiological trends in invasive aspergillosis in France: the SAIF network (2005-2007). Clin Microbiol Infect. 2011;17:1882-9. same rate of Invasive Aspergillosis as AML patients6. Some countries have high rates of hisoplasmosis, , tinea capitis 7. Sobel JD. Vulvovaginal candidosis. Lancet. 2007;369:1961-71. and fungal keratitis but there are few resources available in the literature to five a good ROI transplant data was obtained form 2011 Council of Europe report on organ transplant estimate of this for the Irish population and since these conditions are not always and NI data from the organ donation registry along with direct figures from the local clinically reported there was no resource for direct calculation of these numbers in Acknowledgements Haematology Transplant Co-ordinator to capture the Stem Cell Transplants It is assumed that Ireland. There is a general assumption that the rate of mucormycosis is approximately 0.5% of renal transplants, 4% lung, 6% heart 4% liver transplants also develop invasive 2 cases per million popluation. This and other fungal infection estimates are With Thanks to Michael Devine, Public Health Agency, Belfast, Susan Piggott , aspergillosis and other risks such as use cause negligible numbers of cases. summarised in the table. Haematology Transplant Co-ordinator Belfast Health and Social Care Trust and Yvonne Wilson Belfast Health and Social Care Trust for their help. 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 www.LIFE-worldwide.org

r r Abstract /lethods JI Conclusions L . -A L.

We estimated the adult burden of asthma by the GINA estimates. The Objective: India is the world’s second most populous country, with high rates of The total burden of antifungal-responsive chronic and allergic aspergillosis N prevalence of ABPA complicating asthma was estimated at 2.5% (0.7-3.5%) Time ABPA TB and HIV. Comprehensive baseline data is necessary for effective Year Population studie Comments Reference [Ref. 1]. The following factors were used in estimation of ABPA: in India is likely to exceed 860,000 patients. frame N prioritization of limited public health resources. Using scoping review d Epidemiological studies are required to better categorize the burden of Asthma cases Proportion with ABPA 1976 Secondary 3-4 367 17 IgE not measured, patients Khan et al % of asthma methodology and deterministic modelling, we have estimated the incidence per 100,000 X X among new referrals these diseases in India. and tertiary years (4.6%) had to have asthma and in adults population for asthma (2.5%) and 5yr period prevalence of chronic pulmonary aspergillosis (CPA) ? fungal periodic infiltrates, positive following TB and prevalence of allergic bronchopulmonary aspergillosis disease test, , A. fumigatus Asthma rate in adults was estimated from the prevalence of asthma from the (ABPA) complicating asthma in India. referrals grown from and References positive precipitins. GINA report applied to population estimates (mean prevalence of current Methods: The bases for the computations have been published (Denning et al, 2005 Sequential NS 105 8 12 patients excluded. Healthy Maurya et wheezing in children was 88% of adults in the countries which participated in Bull WHO 2011;89:864-72 and Denning et al, Med Mycol 2013. In press). referrals to (7.6%) control group also evaluated. al both studies). Additional modeling was done to accommodate several ABPA Denning DW, et al. Global burden of allergic bronchopulmonary Estimated pulmonary TB rates were updated from 2007 to 2011 using WHO a tertiary Patients also sensitized to non- studies in India. aspergillosis with asthma and its complication chronic pulmonary The burden of CPA complicating pulmonary TB was made on the following statistics, with deaths excluded. Asthma rate in adults was estimated from centre fumigatus Aspergilli aspergillosis in adults. Med Mycol 2013; IN PRESS 2007 Sequential 4.5 755 155 Full diagnostic details not Agarwal et assumptions [Ref. 2]: the country-specific prevalence of asthma from the GINA report applied to 2. Denning DW, et al. Global burden of chronic pulmonary aspergillosis as a referrals to years (20.5% provided for all ABPA patients. al Deaths from CPA in population estimates (mean prevalence of current wheezing in children was a tertiary ) subsequent CPA 5 -ye a r sequel to pulmonary tuberculosis. Bull World Heatlth Organ 2011;89:864- Total CPA y e a r(%) period 88% of adults in the countries which participated in both studies). Additional centre incidence to prevalence 872 2010 Tertiary 1 year 215 15 Excluded: those in receipt Ghosh et al following Surgeries for following modeling was done to accommodate several ABPA studies in India. PTB at CPA in PTBa Khan ZU, et al. Allergic bronchopulmonary aspergillosis: A study of 46 center (7%) of fo r 2 weeks in 1 year subsequent y e a r(%) Results: In 2011, the population of India was estimated at 1,241,000K. The referrals prior 6 months. 6 patients cases with special referecne to laboratory aspects. Scand J Respir Dis number of cases of pulmonary TB in India were 3,100K (249/100K) and the grew A. flavus. 1976; 57: 73-87 Estimated pulmonary TB rates were assessed for the year 2011 using WHO mortality was 300K (24/100K). The annual estimated incidence of new CPA fact sheet (http://www.who.int/tb/country/data/profiles/en/index.html), with 4. Maurya V, et al. Sensitization to Aspergillus antigens and occurrence of cases was 85,012 while 5 year period prevalence was 267,987. Rates of deaths excluded. allergic bronchopulmonary aspergillosis in patients with asthma. Chest ABPA complicating asthma with good denominators of referral populations Background & Objectives 2005; 127:1252-1259 L. -A (n=5 studies) vary from 0.7 to 3.5%, with the median being 2.5%. The Agarwal R, et al. Clinical significance of hyperattenuating mucoid Asthma of any severity may be complicated by allergic bronchopulmonary Results number of adult asthmatics is estimated at 23,709K and ABPA at 592,719. impaction in allergic bronchopulmonary aspergillosis: an analysis of 155 aspergillosis (ABPA). In 2011, the population of India was estimated at 1,241,000K. If rates of 5%, 7% and 20% are applied, the gross numbers of ABPA patients. Chest 2007; 132:1183-1190 Treated pulmonary tuberculosis (PTB) can lead to complications, including The number of cases of pulmonary TB in India has fallen slightly from patients estimated in India rises to 1,185K, 1,660K and 4,742K respectively. 6. Sarkar A, et al. Occurrence of allergic bronchopulmonary mycosis in progressive loss of lung function, persistent pulmonary symptoms and the 3,305K to 3,100K (2,100K - 4,300K) (249/100K) and the mortality also from All estimates (n=7) of Aspergillus sensitization rates in adult asthmatics in 331K to 300K (24/100K). patients with asthma: An Eastern India experience. Lung India 2010; most subtle, yet the most severe, chronic pulmonary aspergillosis (CPA), The annual estimated incidence of new CPA cases has risen from 83,000 India exceed 16% and are 50% in asthmatics admitted to ICU with asthma. 27:212-216 Both ABPA and CPA respond well to antifungal therapy. to 85,012 and 5 year period prevalence from 261,679 to 267,987. Conclusion: The total burden of antifungal-responsive chronic and allergic 7. Agarwal R, et al. Aspergillus hypersensitivity and allergic Using scoping review methodology and deterministic modelling, we Rates of ABPA complicating asthma with good denominators of referral aspergillosis in India is not known, but is likely to exceed 860,000 patients. populations (n=5 studies) vary from 0.7 to 3.5%, with the median being bronchopulmonary aspergillosis in patients with in a estimate the prevalence of ABPA complicating asthma; and the incidence CPA has many underlying conditions in addition to TB, which are not 2.5% [Ref. 1]. respiratory intensive care unit in North India. Mycoses 2010; 53:138-143 and 5yr period prevalence of CPA following PTB, in India. The number of adult asthmatics is estimated at 23,709K and ABPA at estimated. CPA carries an early mortality of 30% after diagnosis (Korea and 592,719. Japan), emphasizing the importance of antifungal therapy to minimize If rates of 5%, 7% and 20% are applied [Refs. 3-6], the gross numbers of death and morbidity. Epidemiological studies are required to better ABPA patients estimated in India rises to 1,185K, 1,660K and 4,742K respectively. categorize the burden of these diseases in India. All estimates (n=7) of Aspergillus sensitization rates in adult asthmatics in India exceed 16% and are 50% in asthmatics admitted to ICU with asthma [Ref. 7]. LEADINGLIFE INTERNATIONAL FUNGAL EDUCATION

Yong Loo Lin School of Medicine NUHNationaf University NUSNational University i f Hospital cf Singapore Burden of Serious Fungal Infections in Singapore 1Lionel Hon Wai LUM, 1 # Louis Yi Ann CHAI , Sophia ARCHULETA, 2David DENNING 1 Division of Infectious Diseases, National University Health System, Singapore 2 University of Manchester, United Kingdom, in association with the LIFE PROGRAM at www.LIFE-worldwide.org

Infection Number of infections per underlying disorder per year Total Rate None HIV/AIDS Respirator Cancer/Tx ICU burden /100K INTRODUCTION/ PURPOSE y Oesophageal Singapore is a cosmopolitan South East Asian country with a Gross Domestic Product of USD 240 candidiasis 265 265 4.95 billion and a population of 5.35 million. However, the fungal burden is poorly recognized and Candidaemia --- 80 187 267 5 documented in Singapore. We aim to estimate the burden of fungal infections in the country as part of Candida a multi-national effort to quantify worldwide fungal infections peritonitis 37 37 0.7 Recurrent vaginal METHODS candidiasis Estimation of fungal disease burden was extrapolated from available epidemiological documents. (4x/year +) 106,000 106,000 1,981 Population statistics and respective disease distributions pertaining to HIV, malignancies, tuberculosis, ABPA -- unknown -- unknown chronic obstructive pulmonary disease (COPD) and asthma were extracted from Singapore SAFS -- unknown unknown Demographics Profile 2012 and Ministry of Health (MOH) releases. The total number with HIV/AIDS Chronic was estimated to be 5306 from the MOH statistics in 2011.The number of new AIDS patients per year pulmonary unknown was 183, with 47.7% presenting with Pneumocystis pneumonia and 9.2% presenting with aspergillosis Invasive cryptococcal meningitis ( taken from the Communicable Disease Surveillance Report in 1997). The aspergillosis 33 unknown 33 0.6 number of AML patients per year was estimated to be 161 per year, extrapolated from the data from Mucormycos is --- 10 - 10 0.2 ICD-10 C92.0. The annual incidence of pulmonary tuberculosis was 39.2 per 100000 as estimated Cryptococcal from MOH statistics. The prevalence of moderate to severe COPD and asthma were obtained from meningitis 17 unknown 17 0.3 World COPD day- The Singapore perspective from The College Mirror :Dec 2003: Vol 29(4) and The Pneumo cy s tis Health Promotion Board Singapore respectively. Transplant cases were estimated from Heart Lung pneumonia 87 unknown unknown 87 1.6 Registry, and from the Renal and Liver Transplant Lists in Singapore hospitals. The number of critical 2 2 - 2 - 6 0.1 care beds was obtained via a manual count of the hospitals countrywide. In cases whereby local Fungal keratitis 6 ---- 6 0.1 incidence of specific diseases was not known, this was reasonably extrapolated from that of Tinea capitis unknown ---- unknown unknown neighbouring Asian countries with similar population demographics. Total burden estimated 106,008 371 unknown 125 224 106,728 1.1 RESULTS Table : Summary of fungal burden in Singapore

13% of the population are younger than 15 years old, and 2.12 million are women older than 15 years of age, of which 106000 (5% of adult women) are estimated to have recurrent Candida vaginitis1. The CONCLUSIONS incidence of invasive aspergillosis in immunocompromised hosts is at least 33 cases annually (10% of The prevalence of medically-significant fungal infections in the population is under-recognised in AML, equal number of non AML hematological patients, 0.5% of renal transplant patients, 4% of lung Singapore. Increased awareness and surveillance will serve to enhance appropriate allocation of and liver transplant patients and 6% of heart transplant patients), but many more in COPD admissions healthcare resources in this disease spectrum. and ICU patients. On the other hand, the prevalence of chronic pulmonary aspergillosis (CPA) can, at best, be extrapolated from data in Taiwan and China. While asthma is relatively common in adults References Correspondence: (250,000 - 5% of population), ABPA and SAFS are rarely diagnosed. Based on 183 annual new AIDS Dr. Louis Chai 1. Sobel JD. Vulvovaginal candidosis. Lancet 2007; 369: 1961-71 patients in Singapore in 2011, 9.2% (17) of those with AIDS have cryptococcal meningitis , 47.7% (87) Division Of Infectious Diseases have Pneumocystis pneumonia, 460 patients per year have oral candidiasis, and 265 have 2. Chai et al Predominance of stream infections University Medicine Cluster . The annual incidence of candidemia is 268 per year ( 5 per 100000)2-3, with in a Singapore Teaching hospital Med Mycol 2007 Aug 45(5): 435-9 1E Kent Ridge Road NUHS Tower Block, Level 10 two thirds of the patients being in critical care or surgical care, and one thirds being cancer or 3. Tan TY et al. A retrospective analysis of antifungal susceptibilites of Singapore 119228 immunocompromised patients. Candida bloodstream isolates from Singapore hospitals. Ann Acad Email: Med Singapore. 2008 Oct 37 (10) : 835-40 [email protected] Burden of serious fungal infections in Austria, Abstract Nr. 757

Cornelia Lass Florl, V. Greil, David W. Denning and The University of Manchester in association with the LIFE program at www.LIFE-worldwide.org

Division of Hygiene and Medical Microbiology, Innsbruck Medical University, Austria Tiroler Landeskrankenanstalten, Innsbruck Medical University, Austria National Aspergillosis Centre, Education and Research Centre University Hospital of South Manchester (Wythenshawe Hospital), Manchester, UK

Abstract 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 Number of infections per underlying disorder per year Methods Rate All published epidemiology papers reporting fungal infection rates from Austria were identified /100 1999 2009 Results K 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+ Oesophageal candidiasis 100 418 518 7 992 323 8 363 040 times annually). 106 cases have been recorded Oral candidiasis 100 100 503 703 4 130 143 4290174 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 70 139 209 3 862 180 4072866 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 Candida peritonitis 70 70 Life expectancy at birth 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 Recurrent vaginal 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 110,000 2,616 candidiasis (&/year +) 74.8 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 Population mucormycosis and 2 histoplasmosis cases were recorded 7,537 7,537 1 231690 1 464 173 older than 65 years* 9,949 9,949 121 Conclusion Population 1 859 988 1 754082 Substantial uncertainty surrounds these estimates except for invasive aspergillosis figures in immunocompromised patients and candidaemia, where hospital-based surveillance studies have younger than 20 years’ been done. Therefore, epidemiological studies are urgently required to validate or modify these estimates 382 382

Source: Statistics Austria 2( Introduction and Background Invasive aspergillosis 50 283 333 Invasive fungal diseases (IFDs) are an increasingly encountered threat among critically ill patients and are a significant cause of morbidity and mortality [1]. Worldwide, most infections are 28 28 caused by the genera Candida, Aspergillus and Cryptococcus. The incidence and severity of IFD are dependent on a variety of factors including increased use of immunosuppressive agents Cryptococcal meningitis antineoplastic agents, broad-spectrum , prosthetic devices and grafts and hyperalimentation. Improvements in medical care have resulted in critically ill patients surviving longer rendering them vulnerable to IFD. Populations at risk for IFD include haematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) recipients; patients with haematologica Pneumocystis pneumonia malignancy; patients with HIV / AIDS; and intensive care unit (ICU), surgical and burn patients [1, 2, 3] Candida species have historically been the most common causative organisms. However, the epidemiology of IFD has shifted in recent years as Aspergillus species and other moulds have become increasingly important pathogens [4, 5]. Most data available are mainly derived from single-institution reports or multiple sites within countries rather than from multi-national reports. 1221 1221 Fungi infect billions of people every year, yet their contribution to the global burden of disease is largely unrecognized. True rates are unknown because of a lack of good epidemiologica Total burden estimated 207 492 130,964 data and despite the high mortality rates of invasive fungal infections, they remain understudied and underdiagnosed as compared with other infectious diseases. Most serious fungal infections occur as a consequence of other health problems such as asthma, AIDS, cancer, transplantation and corticosteroid therapies Endemic mycoses, such as histoplasmosis, coccidioidomycosis, and penicilliosiss have a restricted geographic distribution and largely confined to areas of the world where the etiologic agents are found in nature. In recent years, however, increased domestic and international travel has led to an increase in the number of reported outbreaks and sporadic cases of mycotic DISCUSSION diseases. In Austria, for most fungal infections we lack any surveillance data, active or passive Austria is a landlocked country of roughly 8.22 million people in Central Europe. The Austrian health care system is characterised by a high density of easily accessible health care facilities. In 2008 a Herein, we have estimated fungal infections based on populations at risk, supplemented with existing data from several sources total of 267 hospitals with about 64 300 beds were available for in-patient care. The most common discharge diagnosis in Austria are malignant neoplasms (80% cancer) for women and diseases of Material and Methods the circulatory system in the case of men. The latter is also the most frequent cause of death in Austria, followed by cancer and respiratory diseases. In 2009 a newborn girl had a life expectancy of 82.9 years and a newborn boy of 77.4 years. Over the past 30 years life expectancy has increased by more than eight years whereas infant mortality has decreased by more than 75%. The infant 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 mortality rate corresponded to 3.8 deaths per 1 000 live births in 2009. In 2008 a 60-year- old man had a remaining life expectancy of 21.3 years, and in the same year a woman aged 60 could expect 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 to live for an additional 25.1 years. Many of the se individuals will have underlying chronic illnesses and consequently, are at greater risk of developing more serious infections prevalence, depending on the condition. Asthma and COPD rates were from Statistik Austria, Gesundheitsbefragung 2006/2007 and OECD. 2011 HIV data was from Ministry of Health. 2011 transplantation numbers were from Gesundheit Osterreich. Infections are grouped in invasive fungal infections (cryptococcal meningitis, invasive aspergillosis, candida bloodstream As shown by our study, we can conclude that several fungal infections are unreported and therefore are impossible to count in absolute numbers. To have an impression of the overall fungal burder infection, Pneumocystis pneumonia), chronic lung or deep tissue infection (chronic pulmonary aspergillosis), allergc fungal disease (allergic bronchopulmonary aspergillosis (ABPA), severe in Austria it is necessary to make some assumptions about population from known data sets and published literature. Based on available data approximately 1.59% of Austrian's population will have asthma with fungal sensitisation (SAFS)), mucosal infection (oral and oesophageal candidiasis, Candida vaginitis (thrush)) and skin, and infection (tinea capitis) serious fungal infections during one year. Recurrent vaginal candidiasis and severe asthma with fungal sensitisation (SAFS) are accounting for the most frequent infections, followed by ABPA From data available, most infections occur in immunocompromised and respiratory patients. We lack any data on Pneumocystis pneumonia and Fungal keratitis 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. 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 Underlying diseases [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

The rate of candidemia is lower when compared to Aspergillus [1,2] infections. This might be somewhat unusual when compared to other reports; however, we are of the opinion that intensive surveillance studies on infections done in the past contribute to this findings. No nation-wide studies on candidemia have been done so far. Overall, we notice an increase of infections due to mucormycetes [6], the reason are not yet fully understood. However, in Austria most of the centres treating patients with hematological malignancies use extensive treatment with and/or , drugs, which do not target mucormycetes. Since most of our data are extrapolated from surrogate markers this model requires validation. However, it provides a standardized means of estimating and comparing the burden of disease across population. Enhanced surveillance and reporting will be critical to improve our understanding of the importance of invasive fungal infections, to enable prioritization of research and prevention efforts , and to evaluate prevention strategies.

References m 1.Richardson C, Lass- Florl C. Changing epidemiology of systemic fungal infections. Clin Microbiol Infect 2008; Suppl 4:5-24 2. Presterl E, et al. Changing pattern of candidaemia 2001-2006 and use of antifungal therapy at the University Hospitalof Vienna,Austria . Clin Microbiol Infect 2007; 13:1072-6. 3. Martino R, Subira M. Invasive fungal infections in hematology: new trends. Ann Hematol 2002; 81:233-43. 4. Auberger J, et al. Invasive fungal breakthrough infections, fungal colonization and emergence of resistant strains in high-risk patients receiving antifungal prophylaxis with : real-life data from a single-centre institutional retrospective observational study. Antimicrob Chemother 2012; 67: 2268-2273 5. Perkhofer S et al. The Nationwide Austrian Aspergillus Registry: a prospective data collection on epidemiology, therapy and outcome of invasive mould infections in immunocompromised and/or // immunosuppressed patients. Int J Antimicrob Agents 2010; 36:531-6 I 6. Auberger J, et al. Significant alterations in the epidemiology and treatment outcome of invasive fungal infections in patients with hematological malignancies. Int J Hematol 2008;88:508-15 J i_ V The burden of severe human fungal infections in Brazil UFCSPA I SANTA CASA I univcrsidade Federal dc Cicncias da Saude dc Porto Alegrc I d e misericOrdia! P O R T O ALEGRE Ludmila F. Baethgen,1 Lilian C. Carneiro,1 Maria Adelaide Millington,2 David W. Denning,3 Arnaldo L. Colombo,4 Alessandro C. Pasqualotto1-5* in association with the LIFE program (www.LIFE-worldwide.org)

1Universidade Federal de Ciencias da Saude de Porto Alegre, Brazil; 2Brazilian Ministry of Health, Brazil; 3University of Manchester, UK; 4Universidade Federal de Sao Paulo, Brazil; 5Santa Casa de Misericordia d rto Alegre, Brazil. * Corresponding author: Alessandro C. Pasqualotto MD PhD. Av Independencia 155, HDVS, Molecular Biology Laboratory, 90075150, Porto Alegre, Brazil. E-mail: [email protected]; Phone: +55 51 99951614 r ^ r ^ r ^ r I Introduction Assumptions Results Contrast with official data L. -J

S Serious human fungal infections (SHFI) are worldwide S Invasive aspergilosis: 13.4% of AML + 2.3% allo HSCT + 0.5% Brazilian scenario: Brazil has ~194 million inhabitants (76% adults, S The official hospitalization data for aspergillosis presented 442 associated with high morbidity and mortality rates despite some renal Tx (Nucci, 2012) + 13.3% lung Tx (Pasqualotto, 2010). Not 51% women, and 33% are >40 years old). Knowing that almost cases while in our estimative we have more than 400,000 effective treatment options; available data for aspergillosis in renal, heart and liver Tx in all fungal diseases occurs as a consequence of other health aspergillosis cases. Most are in the community - allergic and Brazil. World: 6% Heart Tx and 1.3% liver Tx. Other steroid problems; we used official Ministry Health as follows: chronic, but there are an estimated 8,664 invasive cases; S Patients with SHFI often require hospital care, as a consequence patients ignored. Added to: COPD admissions to hospital per of a difficult diagnosis and treatment - almost all fungal diseases year *0,013; S HIV/AIDS: the current total of HIV/AIDS cases is 608,230 which S For all kinds of Candida infections the official data in 2011 were occurs as a consequence of other health problems. Despite this, 30% are not receiving antiretroviral (ARVs). Each year are 1,242 hospitalizations, differing absurdly of our estimation S Chronic pulmonary aspergillosis (CPA) post tuberculosis: 64,825 it is an internationally neglected health topic; reported 34,218 annual new AIDS cases (at risk of opportunistic study that we should have almost 30,000 hospitalizations. TB pulmonary cases, and 59,639 alive pulmonary cases (WHO, infections). In 2010, about 12,000 deaths were related to AIDS; S This situation is also a problem in Brazil where none of the SHFI 2011); S It is important to note that we exclude for our analysis all cases are official reportable disease (except for cryptococcal S Respiratory diseases: pulmonary TB annual incidence is of severe asthma with fungal sensitization (SAFS), that could S Allergic bronchopulmonary aspergillosis (ABPA) in cystic fibrosis meningitis). This situation hampers epidemiological survey data 36/100,000 (2010). The chronic obstructive pulmonary disease be as many as 600,000 cases. and masks the tragic reality of the many fungal diseases in our patients: frequencies ranging from 22-23% (Carneiro, 2008; (COPD) prevalence all GOLD stages is 15.8% with 142,421 country. Paschoal, 2007). ABPA affects 2.15% of asmathics; COPD admissions to hospital per year. We have an asthma rate S The dermatomycoses were excluded for our study since the S Candidaemia in hospitalized patients: 2,49*Critical care + in adults estimated in 12.4% (To, 2012). About 200 adults are minority of the cases are treated in public health centers or in surgery. (2,49/1,000 hospital admissions (Nucci, 2010; Colombo, reported with cystic fibrosis. private clinics, making the official data collection unreliable. 2006); S Cancer, leukaemia, transplant and other S Candidaemia in outpatients: 3% of all cases (Colombo, 2006) - immunocompromised patients: the AML population frequency Purpose conservative assumption, since another publication (Pasqualotto, is estimated in 5/100,000 with 25,244 AML patients reported per Graph 2. Candida infections estimated cases 2005) revealed 9%; year. In 2011, about 700 patients had undergone allogeneic S To estimate the total burden (incidence and/or prevalence) of hematopoietic stem cell transplantation (HSCT) and 6,658 were S Oral candidosis: 90% of patients with HIV not on ARVs [possible SHFIs in Brazil so that new decision making for monitoring, submitted to solid organ Tx (renal, lung, heart and liver); 897 (0%) over-estimation if a large % not on ARVs have CD4 >200 cells]; 164,222(6%) □ Candidaemia (hospital) prevention and fungal disease control becomes possible. S Critical care and surgery cases: Brazil has 35,403 critical care 28,991 (1%) 57,782 (2%) S Oesophageal candidosis: 20% of patients not on ARVs, and beds and ~11,6 million (M) of hospital admissions per year. A tota □ Candidaemia (outpatients) 0.5% of those on ARVs; of 5,609 peritoneal dialysis were done in 2011. S Recurrent Candida vaginitis (>4x/year): 5% of woman □ Oral candidosis Methods (childbearing age) (75% of woman 10-49 years). Literature estimate is 5-8%; □ Oesophageal candidosis S Historical data was collected from the Ministry of Health S Fungal keratitis: 9.01/million of inhabitants per year (based on 2,729,525 (91%) □ Recurrent Candida vaginitis Informatics Department System (DATASUS), from year 2011, for sales distribution of antifungal eye drops; Ibrahim, 2012). Table 1. Estimated burden of serious fungal diseases in Brazil. (>4x/year) hospitalization admissions and/or notification cases of:

No underlying 0 . 4 Cancer + Respiratory Critical care + Incidence cryptococcal meningitis, mucormycosis, histoplasmosis, disease/ HIV/AIDS .. 3 immuno- disease surgery (100,000) coccidioidomycosis, and ; Fungal disease Total other compromised Cryptococcal meningitis in AIDS 392 138 392 0.20 S Official country data was considered consistent only for fungal Pneumocystis pneumonia 18,820 18,820 39.60 Graph 1. Aspergillosis estimated cases Invasive aspergillosis 8,664 6,813 1,851 4.47 diseases for which there was a surveillance program in place; CPA post TB 12,032 6.20 ABPA 390,486 390,486 201.31 S Cases of meningitis and PCP (for AIDS patients) Total Aspergillosis 411,183 211.98 were obtained from the Information System of Notifiable Diseases 8,664 12,032 2% 3% Candidaemia in hospitalized patients 28,991 11,654 870 3,131 13,336 249.00 S Based on local data and literature estimates of the frequency of (SINAN). □ Invasive aspergillosis Candidaemia in outpatients 897 Oral candidosis 164,222 164,222 84.66 mycoses in susceptible populations, 1.7% of Brazilians Oesophageal candidosis 57,782 57,782 29.79 S For aspergillosis, candidosis and fungal keratitis we conducted Recurrent Candida vaginitis (>4x/year) 2,729,525 2,729,525 presents some form of serious fungal disease; multiple electronic bibliographic database searches. Assumptions □ CPA post TB Total Candida 2,981,416 S Knowing that the mycoses are an internationally neglected health were derived using the frequency of these diseases from the Fungal keratitis 1,696 0.87 topic, we believe that if all fungal diseases could be officially literature and as denominator we used official data (population, notified the real number should be much higher than the respiratory diseases, cancer and immunocompromised, and □ ABPA Mucormycosis* 243*** 2.09** Histoplasmosis* 255 2.19** estimated by this study; critical care beds) as reported in official governmental Coccidioidomycosis* 829 •j ^ * * publications; Paracoccidioidomycosis* 930 7.99** S Additional epidemiological estimates are required to validate the Total serious fungal infection burden modelling estimates presented here. S All data were entered into a Microsoft Excel spreadsheet for (per year) 3,415,764 Total Prevalence 1,76

statistical analysis. *Numbers of cases reported to the Ministry of Health in 2011, based on hospital admission’s codes (CID10); **Incidence in 100,000 hospital admissions. For all other incidences are related to the general population; *** Adjusted value. One Brazilian state is overestimating the mucormycosis cases attended in hospitals.

(1) Brasil. Ministerio da Saude. Secretaria de Atengao a Saude. Departamento de Regulagao Avaliagao e Controle. Coordenagao Geral de Sistemas de Informagao. Fonte: Base de Dados do SIHSUS-Sistema de Informagoes Hospitalares - fornecido pelo DATASUS (tabulados pela CGSI em 17/08/2012). (2) Nucci M, et al. Clin Microbiol Infect 2012 (in press). (3) Pasqualotto AC, et al. Transplantation 2010; 90: 306-11. (4) Carneiro AC, et al. J Bras Pneumol 2008; 34: 900-6. (5) Paschoal IA, et al. Lung, 2007;185:81-87. (6) Colombo AL, et al. J Clin Microbiol 2006; 44: 2816-23. (7) Pasqualotto AC, et al. J Hosp Infect 2005; 60: 129-34. (8) Matee Ml, et al. Oral Dis 2000; 6: 106-11. (9) Smith E, et al. Scand J Infect Dis 1990; 22: 665-72. (10) Sobel JD. Lancet 2007; 369: 1961-71. (11) Ibrahim MM, et al. Plos One 2012; 7: e33775. (12) To T, et al. BMC Public Health 2012; 12: 204. (13) ABTO. Associagao brasileira de References transplante de orgaos. 2011. http://tabnet.datasus.gov.br (14) http://www.gbefc.org.br/gbefc/REBRAFC_EN_2009.pdf (15) http://www.inca.gov.br/estimativa/2012/tabelaestados.asp?UF=BR (16) http://www.aids.gov.br/sites/default/files/anexos/publicacao/2011/50652/boletim_aids_2011_final_m_pdf_26659.pdf (17) http://www.who.int/hiv/pub/progress_report2011/en/index.html (18) http://www.fungalinfectiontrust.org/fungaldis.html