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How common are fungal diseases?
Prof. David W Denning, FRCP, FRCPath Professor of Infectious Diseases in Global Health The University of Manchester, UK
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Intended Learning Outcomes
To be aware of the vast clinical spectrum of fungal diseases To be aware of the global estimates of the burden of fungal diseases To be aware of the key risk factors of fungal diseases To present country-specific burden of fungal diseases
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Many clinical forms of fungal diseases
Skin, hair, nail, ear, eye infections Allergic bronchopulmonary aspergillosis Severe asthma with fungal sensitisation Allergic fungal rhinosinusitis Extrinsic allergic alveolitis Spectrum of Fungal Diseases Superficial infections Mucosal infections Acute invasive & life-threatening infections Chronic fungal diseases Allergic diseases Onychomycosis Tinea (capitis, pedis, corporis, cruris, manuum etc.) Otomycosis (otitis externa) Seborrheic dermatitis Fungal (mycotic) keratitis Oral candidiasis Oesophageal candidiasis Vulvovaginal candidiasis Chronic pulmonary aspergillosis Aspergillus bronchitis Coccidioidomycosis Blastomycosis Paracoccidioidomycosis ‘Neglected’ fungal diseases Mycetoma Chromoblastomycosis Sporotrichosis Histoplasmosis Cryptococcal meningitis Invasive candidiasis Invasive aspergillosis Pneumocystis pneumonia Mucormycosis Disseminated histoplasmosis Talaromycosis.
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Global Burden of Fungal Diseases
Fungal diseases often complicate other medical conditions like COPD, HIV, TB etc. Quantifying the global burden of fungal diseases is challenging Lack of routine surveillance for nearly all fungal diseases greatly limits the availability of data needed to compute an accurate global burden
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Cutaneous Fungal Diseases
Fungal infection of the skin, hair and nails affects ~1 billion people Tinea capitis Most common childhood infections Global prevalence ~200 million Prevalence: 0-20% in developed world, ~50% in developing world School going children are the most affected Onychomycosis (nail infections) Common in the general population Prevalence: 5-25% of the general population, higher in elderly people Tinea pedis (athlete’s foot) More common than onychomycosis More common in young men and sportsmen Vos et al. Lancet 2012; 380:2163–96. Abdel-Rahman et al. Paediatrics. 2010; 125: Adefemi et al. Niger J Clin Pract. 2011; 14:23-8.
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Country-specific burden of Tinea capitis
Algeria /100K Burkina Faso - 6,255 /100K Kenya - 4,302 /100K Tanzania – 663 /100K Mozambique - 4,472 /100K Nigeria - 10,070 /100K Malawi - 3,780 /100K Cameroon - 3,240 /100K Data from:
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Fungal (mycotic) Keratitis
Estimated global burden of ~1-12 million annual cases Fungal keratitis accounts for 10% of visual impairment worldwide ~1-6 million cases in Southeast Asia, India, Nepal, Sri Lanka Rates as low as 6.3/100,000 in Hong Kong to as high as ~800/100,000 in Kathmandu Rate of fungal keratitis in S. America and Africa are not known Due to implantation ocular injuries Usually farmers and labourers, occasionally contact lens wearers. How common are fungal diseases? Fungal Infection trust, updated August, 2017
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Burden of Fungal Keratitis
Germany, 0.03/100K Mexico, 10.4/100K Pakistan, 44/100K Nepal , 73/100K Egypt, 10.4/100K China, 1.3/100K Thailand, 15/100K Colombia, 0.3/100K Malawi, 10.3/100K Data from:
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Fungal Otitis Externa (otomycosis)
~10% of otitis are fungal in origin Almost always A. niger complex (~90% of cases) Acute otitis affects 1 in 250 persons annually Chronic otitis media affects 3-5% of the population ( million). The incidence is higher in hot climatic areas Risk factors include: Physical injury to the ear Excessive accumulation of cerumen in the auditory canal Secondary to bacterial otitis How common are fungal diseases? Fungal Infection Trust, updated August, 2017
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Chronic Fungal Diseases
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Chronic Pulmonary Aspergillosis
Global burden of ~3 million cases 1.2 million cases following tuberculosis ~0.07 million cases in pulmonary sarcoidosis Other respiratory disorders commonly associated e.g. COPD, NTM etc. Often mis-diagnosed as ‘smear negative’ non-HIV patients Oladele et al. Int J Tuberc Lung Dis; 2017; 21: Denning et al. Eur Resp J 2013; 41:621-6. Denning et al. Bull WHO 2011;89:
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Country burden of Chronic Pulmonary Aspergillosis
Rate/100,000 Russia 52,311 126 Nigeria 120,747 78 Philippines 77,172 Pakistan 72,438 70 Vietnam 55,509 61 Dominican Republic 1374 55 Uganda 18,000 46 Bangladesh 20,720 41 Kenya 12,927 32 Thailand 19,044 29 Belgium 662 28 Qatar 176 27 Nepal 6611 24 India 209,147 Tanzania 10,437 Korea 10,754 22 Ukraine 10,054 Senegal 2700 19 Mexico 18,246 16 Sri Lanka 2886 14 Egypt 3015 Peru 3593 11 Guatemala 1484 9.6 Spain 4318 9.2 Country Burden Rate/100,000 Trinidad and Tobago 110 8.2 Chile 1212 6.9 Uzbekistan 1941 6.3 Brazil 12,032 6.2 Hungary 504 6.0 United Kingdom 3600 5.7 France 3450 5.2 Denmark 270 4.8 Austria 328 4.7 Greece 386 3.7 Czech Republic 365 3.5 Ecuador 2100 3.3 Ireland 196 3.1 Portugal 776 Jamaica 82 3.0 Germany 2320 2.9 Israel 200 2.5 Algeria 897 2.2 Canada 492 1.4 Table from Bongomin et al J. Fungi 2017, 3(4), 57
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Neglected tropical fungal diseases
No global estimates for these diseases ~9,000 cases of mycetoma ~3,500-6,200 in endemic areas (Madagascar , Brazil) Sporotrichosis is probably more common: hyper-endemic in Peru and Mexico ~10,000 cases of chromoblastomycosis Few data on subcutaneous zygomycosis, and phaeohyphomycosis Van de Sande PLoS Negl Trop Dis, 2013; 7(11): e2550. Queiroz-Telles et al. Clin Microbiol Rev, 2017; 30: Chakrabarti A. Medical Mycology, 2015, 53, 3–14
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Allergic fungal diseases
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Allergic Bronchopulmonary Aspergillosis
Key risk factors Asthma Cystic fibrosis Burden ~4.8 million cases in asthmatics ~2.5% adult asthmatics ~6,675 cases in cystic fibrosis ~15% of adults with cystic fibrosis Uncommon in children <4 years of age Burden in selected countries UK~ 372 per 100,000 people 2.5% asthma, 12.5% adult CF and 7.5% children with CF India~114 per 100,000 2.5% of adult asthmatics Tanzania~44 per 100,000
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Country burden of ABPA Country Burden Rate/100,000 United Kingdom 235,070 372 Trinidad and Tobago 3491 260 Dominican Republic 25,149 249 Belgium 23,119 208 Brazil 390,486 201 Greece 20,843 193 Jamaica 5116 188 Ecuador 26,642 185 Canada 61,854 174 Egypt 133,834 162 Spain 59,210 156 Germany 123,960 154 France 95,331 145 Ireland 8960 140 Hungary 13129 133 Denmark 7328 131 Philippines 121,113 123 Russia 175,082 Portugal 12,600 119 India 1,380,000 114 Israel 8297 101 Chile 17,183 98 Austria 7537 92 Algeria 31,310 77 Country Burden Rate/100,000 Peru 22,453 72 Senegal 9976 71 Ukranie 28,447 62 Nigeria 93,649 61 Qatar 1126 60 Mexico 47,855 Thailand 38,009 58 Korea 27,312 57 Bangladesh 90,262 56 Pakistan 94,358 51 Sri Lanka 10,344 49 Uganda 18,700 Czech Republic 4739 45 Kenya 17,696 44 Tanzania 18,987 Guatemala 5568 36 Nepal 9546 35 Vietnam 23,607 23 Uzbekistan 879 2.9 Table from Bongomin et al J. Fungi 2017, 3(4), 57
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Severe asthma with fungal sensitisation
Burden depends on the frequency of severe asthma British Thoracic Society step 4 or worse 5-20% of Asthmatics have severe asthma Predicted burden of ~6.5 million cases (range : million) cases ~30% overlap between ABPA and SAFS Collectively termed “fungal asthma” All ABPA patients are sensitised to fungi (Aspergillus) ~0.5 million asthma-related deaths worldwide ~50% attributable to SAFS (needs confirmation) Burden in selected countries Brazil. ~288/100,000 Denmark. ~139/100,000 Vietnam. ~34/100,000
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66% sensitised to one or more fungus: 45% to Aspergillus fumigatus
O’Driscoll R et al, Clin Exp All 2009;39:1677
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Fungal sensitisation data by country
Twaroch et al, Allergy Asthma Immunol Res.2015:7:205
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Allergic Fungal Rhino-Sinusitis (AFRS)
Allergic sinusitis and chronic rhinitis ~15% (900 million) people worldwide ~1.3% is predominantly fungal allergy Estimated global burden of AFRS ~12 million cases Probably an underestimate Country rates Israel ~ 0.5% of the population affected 40,000 cases India –community survey Population prevalence ~0.11% Allergic FRS in 41 (56.1%), Chronic granulomatous FRS in 13 (17.8%), Eosinophilic FRS in 11 (15.0%), Fungal ball in 7 (9.5%) and Chronic invasive FRS in one (1.3%)
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Invasive Fungal Diseases
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Acute Invasive Aspergillosis
>10 million patients in Europe, USA and Japan are at risk >300,000 annual cases – probably an underestimate ~50% mortality, even with treatment Key groups include: Acute leukaemia ~10% Stem cell and solid organ transplant COPD ~ % Lung cancer ~3% AIDS ~4% (at autopsy) Liver failure ~5% Severe influenza ~16% Brown et al. Sci Transl Med 2012:4: 165rv13 How common are fungal diseases? Fungal Infection trust, updated August, 2017
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Invasive Aspergillosis-Risk Factors
Chronic granulomatous disease AML/MDS (esp. Induction chemo and in relapse Allogeneic HSCT with GvHD Severe influenza High risk Allogeneic HSCT without GvHD Solid organ trsnplantation Acute leukaemias Chronic lymphocytic leukaemia Myelodysplastic syndrome Intermediate risk Multiple myeloma COPD with acute exacerbation AIDS NHL Autologous HSCT Kidney transplant Solid tumour Autoimmune diseases Low risk Herbrecht. et al. Ann. N.Y. Acad. Sci. 2012; 1272: 23–30
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Country burden of invasive aspergillosis
Rate/100,000 Vietnam 14,523 16 Egypt 9001 11 Greece 1125 10 Algeria 2865 7.1 Ireland 445 7.0 Israel 574 6.8 Belgium 675 6.1 Pakistan 10,949 5.9 Ecuador 748 5.5 Denmark 294 5.3 Bangladesh 5166 5.1 Germany 4280 Peru 1621 5.0 Uzbekistan 1521 4.8 United Kingdom 2912 4.6 Brazil 1854 4.5 Korea 2150 Guatemala 671 4.3 Austria 333 4.1 Mexico 4510 4.0 Nepal 1119 Uganda 389 3.8 Hungary 319 3.2 Philippines 3085 3.0 Czech Republic 297 2.8 Spain 1293 Ukraine 1233 2.7 Country Burden Rate/100,000 Portugal 243 2.3 Russia 3238 France 1185 1.8 Chile 296 1.7 Canada 566 1.6 Thailand 941 1.4 Sri Lanka 229 1.1 Dominican Republic 61 0.8 Kenya 239 0.6 Nigeria 928 Qatar 11 Trinidad and Tobago 8 Tanzania 20 0.1 Table from Bongomin et al J. Fungi 2017, 3(4), 57
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Invasive Candidiasis Candida peritonitis Main risk factors
~750,000 annual cases of candidaemia Blood culture ~40% sensitive Likely that ~1 million episodes each year ~30-50% of candidaemia in ICU patients Mortality ~30-55% Candida peritonitis ~60,000 – 100,000 episodes each year Main risk factors Post-surgical patients Long-term peritoneal dialysis Mortality ~30-60% Brown et al. Sci Transl Med. 2012:4: 165rv13 Cleveland et al. PLoS One. 2015; 10(3):e Arendrup et al. J Clin Microbiol. 2011; 49:
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Risk factors for invasive candidiasis
Haematological malignancies Solid-organ transplantation (esp. liver) Solid-organ tumours Acute necrotizing pancreatitis Use of broad-spectrum antibiotics Neonates: low birth & preterm infants Presence of central vascular catheter Total parenteral nutrition Intravenous drug use Critical illness: Long-term ICU stay ~50% of episodes of candidaemia Haemodialysis Glucocorticoid use or anticancer chemotherapy Candida colonisation Abdominal surgery: repeated laparotomies & anastomotic leakage Brown et al. Sci Transl Med. 2012:4: 165rv13 Cleveland et al. PLoS One. 2015; 10(3):e Arendrup et al. J Clin Microbiol. 2011; 49:
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Country burden of invasive candidiasis
Rate/100,000 Pakistan 38,795 21 Qatar 288 15 Brazil 28,991 Thailand 8650 13 Hungary 1110 11 Israel 664 Denmark 527 9.4 Russia 11,840 8.3 Spain 3807 8.1 United Kingdom 5142 Ireland 403 6.3 Nigeria 9284 6.0 Uzbekistan 1825 5.9 Algeria 2020 5.0 Bangladesh 8100 Belgium 555 Chile 878 Czech Republic 526 Dominican Republic 504 Ecuador 1037 Country Burden Rate/100,000 Egypt 4127 5.0 Greece 541 Guatemala 772 Jamaica 136 Kenya 1990 Mexico 5617 Peru 1557 Tanzania 2181 Trinidad and Tobago 87 Ukraine 752 Vietnam 4540 Germany 3712 4.6 Korea 1976 4.1 France 2370 3.6 Canada 1034 2.9 Austria 209 2.6 Sri Lanka 507 2.5 Portugal 231 2.2 Philippines 1968 2.0 Table from Bongomin et al J. Fungi 2017, 3(4), 57
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Cryptococcal meningitis
~233,100 annual cases in AIDS patients Declining incidence in HAART era ~70% mortality in Sub-Saharan Africa Late diagnosis Sub-optimal therapy Accounts for 15% AIDS-related deaths Rajasingham et al. Lancet Infect Dis. 2017;17:
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Deaths from Cryptococcal meningitis by region
Global: ,100 (119, ,300) Sub-Saharan Africa: ,900 (75%) Asia and Pacific: 39, (22%) Latin America: , (1.3%) North Africa & Middle East: 1, (1.1%) Europe: , (1.0%) Caribbean: (0.4%) North America: (0.4%) Rajasingham et al. Lancet Infect Dis. 2017;17:
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Pneumocystis pneumonia
~500,000 annual cases in AIDs and non- AIDS ~2.2 million at risk patients PCP as an AIDS indicator In children: 5-50% In adults : 10-40% Mortality 10-30% in developed countries 20-80% globally Mortality is higher in non-AIDS patients Brown et al. Sci Transl Med. 2012;4: 165rv13 Teshale et al. Clin Infect Dis. 2007; 44:879-83 Walzer et al. Clin Infect Dis. 2008;46:625-33
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Country burden of PCP Country Burden Rate/100,000 Nigeria 74,595 48
Kenya 17,000 43 Trinidad and Tobago 400 30 Tanzania 9600 22 Ukraine 6152 14 Jamaica 350 13 Senegal 1149 8.2 Uzbekistan 165 5.4 Guatemala 722 4.7 Peru 1447 4.6 Mexico 5130 4.5 Chile 766 4.3 Nepal 990 3.6 Spain 305 3.4 Ecuador 535 3.3 Thailand 1708 2.6 Dominican Republic 234 2.3 Brazil 4115 2.1 Germany 1013 1.3 Pakistan 2200 1.2 Belgium 120 1.1 Country Burden Rate/100,000 France 658 1.0 Greece 112 Uganda 412 Ireland 50 0.8 Qatar 15 Canada 252 0.7 Czech Republic 72 Vietnam 608 Portugal 65 0.6 Korea 245 0.5 Philippines 391 0.4 United Kingdom 207 0.3 Israel 26 Algeria 74 0.2 Russia 1414 Egypt 125 Hungary 5 0.1 Bangladesh 58 0.04 Denmark 2 Table from Bongomin et al J. Fungi 2017, 3(4), 57
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Mucormycosis ~>10,000 annual incidence Major risk factors
Three population analyses have been conducted USA study 2 cases per 1,000,000 people French study 0.6 cases per 1,000,000 Indian Study 130 cases per 1,000,000 High rates of diabetes in India Major risk factors Uncontrolled diabetes mellitus in ketoacidosis Deferoxamine therapy Burns Other risk factors Organ or bone marrow transplantation Neutropenia Trauma Rees et al. Clin Infect Dis. 1998; 27: Bitar et al. Rev Epidemiol Sante Publique. 2012; 60:383-7.
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Histoplasmosis Brown et al. Sci Transl Med. 2012;4:165rv13
Highly variable rates from one locality to another Endemic in many parts of South and Central America, North America, Africa and SE Asia. ~25,000 symptomatic cases are estimated in the USA annually. ~500,000 new infections each year globally Mainly in endemic areas Disseminated histoplasmosis in AIDS AIDS-defining illness ~100,000 cases annually Very high case-fatality rates Difficult to diagnose rapidly enough to save the patients, even with either rapid antigen or PCR testing Brown et al. Sci Transl Med. 2012;4:165rv13
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Estimate methodology Challenges
A worldwide increase in the frequency of fungal diseases has been reported in the last couple of decades. Knowing each country’s burden and epidemiologic trends of fungal diseases is necessary to prioritise prevention, diagnostics and therapeutic strategies Estimate data is based on: Registries (e.g. data from reference laboratories ) High quality epidemiological studies Eg Cryptococcal antigen surveys Tinea capitis studies in school Modelling Based on best available evidence for each fungal disease, population at risk and country population Challenges Non existence of fungal disease surveillance for most fungal diseases, for most countries across the world- hence lack of data Fungal blood cultures are not done in low income countries Lack of data on many of the underlying medical conditions predisposing to fungal diseases e,g COPD High degree of uncertainity due to limited data
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Global Burden of Fungal Diseases
Bongomin et al J. Fungi 2017, 3(4), 57
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Thank You
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