1. Aspergillosis in the USA, UK, and Japan in the 20th Century David W. Denning Wythenshawe Hospital University of Manchester With many thanks to Aya Homei

2. In 1901 UK - Queen Victoria died, Boer war in South Africa, Boxer rebellion in China allowed an open door trade policy, Hong Kong 99 year lease, rise of socialism (Fabian Society).

3. In 1901 US – McKinley assassinated and succeeded by Roosevelt, rise of big business and anti-Trust sentiment, war with Spain forced Cuba to be independent, annexed Hawaii, Guam, Philippines and Puerto Rica

4. In 1901 Japan – under Emperor Matsuhito, post Sino- Japanese war controlled part of China (natural resources), Korea, Taiwan, transformation to an industrial economy with democratic parliament

5. And what did we know about Aspergillus in 1901? Many species had been described including: A. flavus – Link, 1809 A. fumigatus – Fresnius, 1863 A. niger - v. Tiegham, 1867 A. nidulans - (Eidam) Winter, 1884

6. Isolates obtained from human lung tissue. A. fumigatus by JB Georg W Fresnius Fresnius, Beiträge zur Mykologie, 1863 Isolates obtained from the bronchi and the lung of a bustard,

7. And what did we know about aspergillosis? Aspergillomas known (Bennett, 1842), but not described as such Wheezing and coughing in wig combers and pigeon crammers (Popoff, 1887; Renon 1897) Superficial aspergillosis described (otomycosis by Mayer, 1844; keratitis by Leber 1879) Sinus aspergillosis described (maxillary by Zarniko, 1891; sphenoid by Oppe, 1897) Few cases of invasive aspergillosis in normal hosts (pleural by Rayer, 1842 and renal by Ross in 1891)

8. Aspergillus tracheobronchitis - 1890 Autopsy drawing of a normal 3 year old who died over 10 days Wheaton Path Trans 1890; 41:34-37

9. Remarks upon a case of aspergillar mycosis - 1893 Boyce R, Journal of Pathology and Bacteriology 1893;1:163-6.

10. CLASSIFICATION OF ASPERGILLOSIS Airways/nasal exposure to airborne Aspergillus Invasive aspergillosis Acute (<1 month course) Subacute/chronic necrotising (1-3 months) Chronic aspergillosis (>3 months) Chronic cavitary pulmonary Aspergilloma of lung Chronic fibrosing pulmonary Chronic invasive sinusitis Maxillary (sinus) aspergilloma Allergic Allergic bronchopulmonary (ABPA) Extrinsic allergic (broncho)alveolitis (EAA) Asthma with fungal sensitisation (SAFS) Allergic Aspergillus sinusitis (eosinophilic fungal rhinosinusitis)

11. CLASSIFICATION OF ASPERGILLOSIS Airways/nasal exposure to airborne Aspergillus Invasive aspergillosis Acute (<1 month course) Subacute/chronic necrotising (1-3 months) Chronic aspergillosis (>3 months) Chronic cavitary pulmonary Aspergilloma of lung Chronic fibrosing pulmonary Chronic invasive sinusitis Maxillary (sinus) aspergilloma Allergic Allergic bronchopulmonary (ABPA) Extrinsic allergic (broncho)alveolitis (EAA) Asthma with fungal sensitisation (SAFS) Allergic Aspergillus sinusitis (eosinophilic fungal rhinosinusitis)

12. Asthma and airborne fungi 1870s - exacerbation of asthma by airborne fungi – Charles Blackley (Manchester physician) 1920s - Cadham reported exacerbation of asthma by wheat rust - van Leeuwen reported relief of asthma with filtered air and mould skin test +ves in >50% of asthmatics Denning et al, Eur Resp J 2006 In press

13. Fungi in housedust

14. Asthma and airborne fungi 1870s - exacerbation of asthma by airborne fungi – Charles Blackley (Manchester physician) 1920s - Cadham reported exacerbation of asthma by wheat rust - van Leeuwen reported relief of asthma with filtered air and mould skin test +ves in >50% of asthmatics - Jiminez- Diaz reported climatic asthma (mostly related to moulds) - Cohen showed removal of house dust antigen in furniture helped mould skin test +ve asthmatics Denning et al, Eur Resp J 2006 In press

15. Asthma and airborne fungi 1870s - exacerbation of asthma by airborne fungi – Charles Blackley (Manchester physician) 1920s - Cadham reported exacerbation of asthma by wheat rust - van Leeuwen reported relief of asthma with filtered air and mould skin test +ves in >50% of asthmatics - Jiminez- Diaz reported climatic asthma (mostly related to moulds) - Cohen showed removal of house dust antigen in furniture helped mould skin test +ve asthmatics 1930s – Asthma related to Alternaria, Trichophyton and A. fumigatus - sc A. fumigatus skin test (1:5000 extract) exacerbated asthma Denning et al, Eur Resp J 2006 In press

16. Experimental aspergillosis Henrici. J Immunol 1939;36:319 The mold, Aspergillus fumigatus, is a cause of spontaneous infections in man, domestic animals, and both domestic and wild birds. In man and the mammals such infections are so rare as to be of little practical importance......

17. Allergic bronchopulmonary aspergillosis - 1952 Hinson, Moon & Plummer. Thorax 1952:7:317 First full description of ABPA complication of asthma coughing up casts episodes of pneumonia/ mucous impaction skin test positive for Aspergillus

18. Aspergillus precipitins – early 1960s Longbottom, Pepys and Temple Clive. Lancet 1964;i:588 A.fumigatus A. flavus A. nidulans

19. Skin test and precipitin reactions to A. fumigatus Pepys. Am Rev Resp Dis 1964;90:465-7 PatientsPrecipitins +ve (%) Skin prick test +ve (%) Asthma307938 Asthma + pulm eosinophilia 936387 IgE testing and routine intradermal skin prick testing

20. Open trial of itraconazole in ABPA - 1991 Before After Prednisone (mg/d) 43 24* Total IgE 2462 525* FEV1 1.48 1.79* FVC 2.3 2.9 *p=0.04 Denning et al, Chest 1991; 35:1329 Only 1 patient failed – he had low itraconazole levels.

21. Randomised trial of itraconazole in ABPA - 2000 Itra Placebo Phase 1 Overall response 13/28 (46%) 5/27 (19%) p=0.04 Age >50 8/12 (67%) 3/14 (21%) p=0.045 Stevens et al, New Engl J Med 2000; 342:756

22. CLASSIFICATION OF ASPERGILLOSIS Airways/nasal exposure to airborne Aspergillus Invasive aspergillosis Acute (<1 month course) Subacute/chronic necrotising (1-3 months) Chronic aspergillosis (>3 months) Chronic cavitary pulmonary Aspergilloma of lung Chronic fibrosing pulmonary Chronic invasive sinusitis Maxillary (sinus) aspergilloma Allergic Allergic bronchopulmonary (ABPA) Extrinsic allergic (broncho)alveolitis (EAA) Asthma with fungal sensitisation Allergic Aspergillus sinusitis (eosinophilic fungal rhinosinusitis)

23. Fukushima K & Sassa R. Clinical aspects of aspergillosis. Japan. J. Med. Mycol. 1, 1960: 19. Radiology of aspergilloma

24. Fukushima K & Sassa R. Clinical aspects of aspergillosis. Japan. J. Med. Mycol. 1, 1960: 19. Pathology of aspergilloma

25. Aspergillus precipitins Severo on www.aspergillus.man.ac.uk

26. Skin test and precipitin reactions to A. fumigatus Pepys. Am Rev Resp Dis 1964;90:465-7 PatientsPrecipitins +ve (%) Skin prick test +ve (%) Asthma307938 Asthma + pulm eosinophilia 936387 Mycetoma a) in situ579822 b) removed955 Miscellaneous185814

27. Simple (single) aspergilloma Patient RT December 2002 Cough (mild) & tired Wythenshawe Hospital

28. Aspergilloma Severo on www.aspergillus.man.ac.uk

29. Surgery for aspergilloma Kilman et al J Cardiovasc Surg 1969;57:642 Early experiences were: 14 resections: 8 lobectomies, 3 pneumonectomies and 4 segemental resections No problems = 7 Space problems = 5 (+2 empyema) thoracoplasty = 3 Death = 2 (resp failure)

30. Bilateral fibrocystic sarcoidosis with bilateral asperillomas Wythenshawe Hospital

31. Sarcoidosis and aspergilloma Winterbauer & Kraemer, Ar Intern Med 1976;136:1356. Wollschalger & Khan. Chest 1984;86:585 3 cases among 122 patients with sarcoid [Retrospective] [Prospective] 12 among 100 patients screened with Aspergillus precipitins, 10 had aspergillomas (10% rate) 19 had stage III (cystic parenchymal disease) and all 10 aspergillomas were in these patients (50% rate).

32. CLASSIFICATION OF ASPERGILLOSIS Airways/nasal exposure to airborne Aspergillus Invasive aspergillosis Acute (<1 month course) Subacute/chronic necrotising (1-3 months) Chronic aspergillosis (>3 months) Chronic cavitary pulmonary Aspergilloma of lung Chronic fibrosing pulmonary Chronic invasive sinusitis Maxillary (sinus) aspergilloma Allergic Allergic bronchopulmonary (ABPA) Extrinsic allergic (broncho)alveolitis (EAA) Asthma with fungal sensitisation Allergic Aspergillus sinusitis (eosinophilic fungal rhinosinusitis)

33. Invasive aspergillosis as an opportunistic infection - 1953 Rankin. Br Med J 1953;1(April 25 th ):918

34. Invasive aspergillosis as an opportunistic infection - 1953 Rankin. Br Med J 1953;1(April 25 th ):918 First description in Gloucester, UK 45 year window cleaner, thigh abscess complication of pancytopenia as a result of chloramphenicol toxicity autopsy diagnosis of disseminated aspergillosis, with vascular invasion, together with moniliasis

35. Eniwetok atoll in Marshall Islands 200 miles west of Bikini atoll –1 st H bomb test 1 st November 1952

36. Bikini atoll - Marshall Islands 2nd H bomb test 1st March 1954

37. Operation Castle at Bikini atoll - Bravo

38. Fishing boat Lucky Dragon was caught in the blast and it rained. All crew members were exposed Mr Aikichi Kuboyama, the radio operator was most affected by radiation sickness

39. Okudaira. Acta Pathologica Japonica 1955;5:117-24. Invasive aspergillosis complicating radiation sickness presented in 1st Tokyo National Hospital - 1954. Mr Aikichi Kuboyama died after 207 days in hospital on Sept 23 rd 1954. Autopsy showed A. fumigatus infection and concomitant pneumonic lesion of the upper right and lower left pulmonary lobes

40. Professor Okudaira presented the case to senior mycologists at the Research Committee of Hyphomycoses Aya Homei, taken on November 12, 2006

41. Sake manufacture Ancient woodcut from Japan

42. Yamashita. The first step to the identification of the Aspergilli. Japan J Med Mycol 1, 1960: 213. Postgraduate education and awareness

43. Lucky Dragon (Daigo Fukuryumaru) Exhibition Hall Aya Homei, personal collection

44. Foyer of the Lucky Dragon exhibition Aya Homei, personal collection

45. The Lucky Dragon itself Aya Homei, personal collection

46. The Lucky Dragon itself Aya Homei, personal collection

47. Postcard from the Lucky Dragon Exhibition Hall Aya Homei, personal collection

48. Increasing invasive aspergillosis in Japan in 1980s Yamazaki et al, J Clin Microbiol 1999;37:1732 1969 1980 1990 1994

49. Fraser et al, JAMA 1979;242:1631

50. Change from 1970 to 1976 in projected incidence (cases per 1 million per year) of systemic mycoses requiring hospitalisation +60 +20 -20 -80 -100 Histoplasmosis -60 -40 0 +40 +80 +100 +120 +140 +160 +180 23.0 19.7 % change Coccidioidomycosis 17.9 10.3 Aspergillosis 4.8 1.9 Actinomycosis 3.2 1.7 Cryptococcosis 2.3 1.3 Candidiasis 1.8 1.7 Sporotrichosis 0.5 0.6 Blastomycosis 0.2 0.9 1976 rate 1970 rate Fraser et al, JAMA 1979;242:1631

51. Early studies documenting efficacy of itraconazole in invasive aspergillosis Dupont & Drouhet Rev Infect Dis 1987;9(Suppl 1): S71 Ganer et al, Rev Infect Dis 1987;9(Suppl 1): S77 Phillips et al Rev Infect Dis 1987;9(Suppl 1): S87 Viviani et al, Mykosen 1987;30:233 Denning et al, Am J Med 1989; 86:791

52. First multicentre treatment study of invasive aspergillosis - 1988-90 [MSG] Open study of 600 mg/day for 4 days, then 400 mg/d. Treatment extended for >97 weeks, median 46 84 patients enrolled 12 weeksEnd of Treatment Complete5%26% Partial26%13% Stable34%4% Failure32% 56% (30% other causes) Deaths--31% Denning et al, Am J Med 1994;97:135

53. New manifestations of aspergillosis Ulcerative aspergillus tracheobronchitis in lung transplant recipients Kramer et al, Am Rev Resp Dis 1991;144:542.

54. New manifestations of aspergillosis Aspergillosis in AIDS Denning et al, New Engl J Med 1991:324:654

55. Aspergillosis in AIDS Denning et al, New Engl J Med 1991:324:654 including obstructing bronchial aspergillosis

56. Lipopeptide (cilofungin) activity in vivo against invasive aspergillosis Denning & Stevens. Antimicrob Agents Chemother 1991;35:1329 Cilofungin alone

57. Clinical studies with voriconazole 1993-

58. Patient AB. First patient with aspergillosis treated with voriconazole. Sphenoid sinusitis and base of skull aspergillosis Enrolled 2 July 1993 Introduction of voriconazole Swift J Otol Laryngol 1998;112:92. Denning & Griffiths J Exp Dermatol 2001;26:648

59. www.aspergillus.man.ac.ukwww.aspergillus.man.ac.uk launched in 1998 See history section