aspergillosis in the usa, uk, and japan in the 20th century david w. denning wythenshawe hospital...
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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
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
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
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)
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
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
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
Yamashita. The first step to the identification of the Aspergilli. Japan J Med Mycol 1, 1960: 213.
Postgraduate education and
awareness
Increasing invasive aspergillosis in Japan in 1980’s
Yamazaki et al, J Clin Microbiol 1999;37:1732
Increase in aspergillosis in Japan 1969-1994
0
0.5
1
1.5
2
years
% c
as
es
am
on
g a
ll a
uto
ps
ies
1969 1980 1990 1994
Change from 1970 to 1976 in projected incidence (cases per 1 million per year) of
systemic mycoses requiring hospitalisation
+60
+20
-20
-80
-100
His
top
las
mo
sis
-60
-40
0
+40
+80
+100
+120
+140
+160
+180
23.0
19.7
% c
han
ge
Co
cc
idio
ido
my
co
sis
17.9
10.3
As
pe
rgil
los
is
4.8
1.9A
cti
no
my
co
sis
3.2
1.7
Cry
pto
co
cc
os
is
2.3
1.3
Ca
nd
idia
sis
1.8
1.7
Sp
oro
tric
ho
sis
0.5
0.6
Bla
sto
my
co
sis
0.2
0.9
1976 rate
1970 rate
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
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