Aspergillosis in the USA, UK, and Japan in the 20th Century

David W. DenningWythenshawe Hospital

University of Manchester

With many thanks to Aya Homei

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).

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

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

And what did we know about Aspergillus in 1901?

Many species had been described including:A. flavus – Link, 1809A. fumigatus – Fresnius, 1863A. niger - v. Tiegham, 1867A. nidulans - (Eidam) Winter, 1884

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,

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)

Aspergillus tracheobronchitis - 1890

Autopsy drawing of a ‘normal’ 3 year old who died over 10 days

Wheaton Path Trans 1890; 41:34-37

Remarks upon a case of aspergillar

mycosis- 1893

Boyce R, Journal of Pathology and Bacteriology 1893;1:163-6.

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)

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)

Asthma and airborne fungi

1870’s - exacerbation of asthma by airborne fungi – Charles Blackley (Manchester physician)

1920’s - Cadham reported exacerbation of asthma by wheat rust

- van Leeuwen reported relief of asthma with filtered air

and mould skin test +ve’s in >50% of asthmatics

Denning et al, Eur Resp J 2006 In press

Fungi in housedust

Asthma and airborne fungi

1870’s - exacerbation of asthma by airborne fungi – Charles Blackley (Manchester physician)

1920’s - Cadham reported exacerbation of asthma by wheat rust

- van Leeuwen reported relief of asthma with filtered air

and mould skin test +ve’s 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

Asthma and airborne fungi

1870’s - exacerbation of asthma by airborne fungi – Charles Blackley (Manchester physician)

1920’s - Cadham reported exacerbation of asthma by wheat rust

- van Leeuwen reported relief of asthma with filtered air

and mould skin test +ve’s 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

1930’s – 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

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.. .. ..”

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

Aspergillus precipitins – early 1960’s

Longbottom, Pepys and Temple Clive. Lancet 1964;i:588

A. fumigatus

A. flavus

A. nidulans

Skin test and precipitin reactions to A. fumigatus

Pepys. Am Rev Resp Dis 1964;90:465-7

Patients Precipitins +ve (%)

Skin prick test +ve

(%)

Asthma 307 9 38Asthma + pulm eosinophilia

93 63 87

IgE testing and routine intradermal skin prick

testing

Open trial of itraconazole in ABPA - 1991

Before AfterPrednisone (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.

Randomised trial of itraconazole in ABPA - 2000

Itra PlaceboPhase 1Overall 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

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)

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

Radiology of aspergilloma

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

Pathology of aspergilloma

Aspergillus precipitins

Severo on www.aspergillus.man.ac.uk

Skin test and precipitin reactions to A. fumigatus

Pepys. Am Rev Resp Dis 1964;90:465-7

Patients Precipitins +ve (%)

Skin prick test +ve

(%)

Asthma 307 9 38Asthma + pulm eosinophilia

93 63 87

Mycetoma a) in situ 57 98 22 b) removed 9 55Miscellaneous 185 8 14

Simple (single) aspergilloma

Patient RTDecember 2002

Cough (mild) &tired

Wythenshawe Hospital

AspergillomaAspergilloma

Severo on www.aspergillus.man.ac.uk

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 = 7Space problems = 5 (+2 empyema)

thoracoplasty = 3

Death = 2 (resp failure)

Bilateral fibrocystic sarcoidosis with bilateral asperillomas

Wythenshawe Hospital

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).

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)

Invasive aspergillosis as an opportunistic infection - 1953

Rankin. Br Med J 1953;1(April 25th):918

Invasive aspergillosis as an opportunistic infection - 1953

Rankin. Br Med J 1953;1(April 25th):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’

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

Bikini atoll - Marshall Islands

2nd H bomb test 1st March 1954

Operation Castle at Bikini atoll - Bravo

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

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 23rd

1954.

Autopsy showed “A. fumigatus infection and

concomitant pneumonic lesion of the upper right and lower left pulmonary

lobes”

Professor Okudaira presented the case to senior mycologists at the

‘Research Committee of Hyphomycoses’

Aya Homei, taken on November 12, 2006

Sake manufacture

Ancient woodcut from Japan

Yamashita. The first step to the identification of the Aspergilli. Japan J Med Mycol 1, 1960: 213.

Postgraduate education and

awareness

Lucky Dragon (Daigo Fukuryumaru) Exhibition Hall

Aya Homei, personal collection

Foyer of the Lucky Dragon exhibition

Aya Homei, personal collection

The Lucky Dragon itself

Aya Homei, personal collection

The Lucky Dragon itself

Aya Homei, personal collection

Postcard from the Lucky Dragon

Exhibition Hall

Aya Homei, personal collection

Increasing invasive aspergillosis in Japan in 1980’s

Yamazaki et al, J Clin Microbiol 1999;37:1732

Increase in aspergillosis in Japan 1969-1994

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Fraser et al, JAMA 1979;242:1631

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

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 enrolled12 weeks End of Treatment

Complete 5% 26%

Partial 26% 13%

Stable 34% 4%

Failure 32%56% (30% other causes)

Deaths -- 31%

Denning et al, Am J Med 1994;97:135

New manifestations of aspergillosisUlcerative aspergillus tracheobronchitis

in lung transplant recipients

Kramer et al, Am Rev Resp Dis 1991;144:542.

New manifestations of aspergillosis Aspergillosis in AIDS

Denning et al, New Engl J Med 1991:324:654

Aspergillosis in AIDS

Denning et al, New Engl J Med 1991:324:654

including obstructing bronchial aspergillosis

Lipopeptide (cilofungin) activity in vivo against invasive aspergillosis

Denning & Stevens. Antimicrob Agents Chemother 1991;35:1329

Cilofungin alone

Clinical studies with voriconazole 1993-

Patient AB.First patient with aspergillosis treated with voriconazole. Sphenoid sinusitis and base of skullaspergillosisEnrolled 2 July 1993

Introduction of voriconazole

Swift J Otol Laryngol 1998;112:92. Denning & Griffiths J Exp Dermatol 2001;26:648

www.aspergillus.man.ac.uk launched in 1998

See history section