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Clinical and radiological presentation and diagnosis
David W. Denning National Aspergillosis Centre University Hospital South Manchester [Wythenshawe Hospital] University of Manchester
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The National Aspergillosis Centre
new patients with aspergillosis referred annually
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CLASSIFICATION OF ASPERGILLOSIS
Invasive aspergillosis Acute (<1 month course) Subacute/chronic necrotising (1-3 months) Airways/nasal exposure to airborne Aspergillus Chronic aspergillosis (>3 months) Chronic cavitary pulmonary Aspergilloma of lung Chronic fibrosing pulmonary Chronic invasive sinusitis Maxillary (sinus) aspergilloma Persistence without disease - colonisation of the airways or nose/sinuses Allergic Allergic bronchopulmonary (ABPA) Extrinsic allergic (broncho)alveolitis (EAA) Asthma with fungal sensitisation Allergic Aspergillus sinusitis (eosinophilic fungal rhinosinusitis) Exposure to individual Aspergillus spores or conidia is almost constant. If eradicated immediately, as is usual in normal people, no disease results. If colonisation occurs, it may be short or long term. The pattern of disease is mostly determined by the host group (see next slide), with probably a component of the inoculum size contributing to invasive disease. However chronic disease if usually seen in patients with apparently normal immune systems. 3
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After Casadevall & Pirofski, Infect Immun 1999;67:3703
Interaction of Aspergillus with the host A unique microbial-host interaction Acute IA ABPA Severe asthma with fungal sensitisation Allergic sinusitis Subacute IA Frequency of aspergillosis Frequency of aspergillosis Aspergilloma Chronic pulmonary Immune dysfunction Immune hyperactivity . After Casadevall & Pirofski, Infect Immun 1999;67:3703
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Size of Aspergillus disease problem globally
Over 200,000 patients develop IA annually. Key groups include ~10% of acute leukaemia (30,000) and stem cell and other transplants (7,500) and 1.3% of COPD patients admitted to hospital (60,000 IA cases). Chronic pulmonary aspergillosis after TB – 1.1M cases prevalence Chronic pulmonary aspergillosis total - ~3M Asthma 197M in adults, of which ~10-20% severe, UK and USA have very high prevalence rates 5
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How common is ABPA in asthma?
10/1390 (0.72%) 9/255 (3.5%) 6/264 (2.3%) Donnelly, Irish J Med Sci 1991;160:288; Eaton, Chest 2000;118:66; Al-Mobeireek, Resp Med 2001;98:341
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Size of Aspergillus disease problem globally
Over 200,000 patients develop IA annually. Key groups include ~10% of acute leukaemia (30,000) and stem cell and other transplants (7,500) and 1.3% of COPD patients admitted to hospital (60,000 IA cases). Chronic pulmonary aspergillosis after TB – 1.1M cases prevalence Chronic pulmonary aspergillosis total - ~3M Asthma 197M in adults, of which ~10-20% severe, UK and USA have very high prevalence rates Allergic bronchopulmonary aspergillosis in asthma - ~4M worldwide (2.1% of adults referred with asthma) Severe asthma with fungal sensitisation - ~6M worldwide (33% of 10% (severe only)) 7
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Human genetic influence on disease expression
Interaction of Aspergillus with the host A unique microbial-host interaction Human genetic influence on disease expression Acute invasive aspergillosis ABPA Severe asthma with fungal sensitisation Allergic sinusitis Subacute invasive aspergillosis Frequency of aspergillosis Frequency of aspergillosis Aspergilloma Chronic pulmonary aspergillosis Immune dysfunction Immune hyperactivity . After Casadevall & Pirofski, Infect Immun 1999;67:3703
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Chronic Pulmonary Aspergillosis
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Common symptoms Common symptoms Cough, usually productive
Shortness of breath Weight loss Tiredness Coughing up blood Chest ache / discomfort Occasionally Fever Severe chest pain from rib fracture Additional chest infections Angina and heart attacks (chronic inflammation)
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Underlying diseases 9 patients with chronic cavitary pulmonary aspergillosis 15 with chronic necrotising pulmonary aspergillosis Camuset et al, Chest 2007:131:1435
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Underlying diseases - CPA
Classical tuberculosis * Atypical tuberculosis * Allergic bronchopulmonary aspergillosis * Lung cancer survivor * Pneumothorax * COPD/emphysema * Sarcoidosis (stage II/III) * Rheumatoid arthritis Thoracic surgery Asthma Chest radiotherapy None * Common Smith, ISHAM 2009 12
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Chronic pulmonary aspergillosis – pre-existing disease
Prior pulmonary disease esp: Atypical mycobacteria pulmonary infection Sarcoidosis Tuberculosis Recurrent pneumothorax Prior pulmonary surgery ABPA Denning DW et al, Clin Infect Dis 2003; 37:S265
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Frequency of chronic pulmonary aspergillosis after TB
~10% of all cases of pulmonary TB get CPA Anonymous. Tubercle 1970;51:227
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Before After treatment
Acute tuberculosis Cavities Cavities Before After treatment Cavities No cavities Lee, Eur J Radiol 2008; 67:100;
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Chronic pulmonary aspergillosis
Infection of the lung by Aspergillus Single fungal ball or aspergilloma in a pre-existing cavity Exposure to individual Aspergillus spores or conidia is almost constant. If eradicated immediately, as is usual in normal people, no disease results. If colonisation occurs, it may be short or long term. The pattern of disease is mostly determined by the host group (see next slide), with probably a component of the inoculum size contributing to invasive disease. However chronic disease if usually seen in patients with apparently normal immune systems.
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Simple (single) aspergilloma
Patient RK Haempotysis, nil else Positive Aspergillus antibodies in blood Lobectomy Wythenshawe Hospital
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Aspergillomas from 2 patients
Wythenshawe Hospital; Severo on
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Histology of an aspergilloma
Severo on
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Aspergillus fumigatus
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Aspergilloma due to A. niger and oxalosis
Renal oxalosis Oxalate crystals in wall of the aspergilloma Severo on
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Early Aspergillus infection of a pulmonary cavity – ‘pre-aspergilloma’
Orderly hyphal growth on the inside of the cavity Aspergillus growth on the surface of a pulmonary cavity Severo on
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‘Multicavity’ disease is the hallmark of chronic cavitary pulmonary aspergillosis (CCPA)
Wythenshawe Hospital
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Aspergilloma #3 – spatially ordered isolates from multiple cavities
Bowyer et al, unpublished
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Aspergillus precipitins (Aspergillus antibody (IgG) ) in blood
Patient 2 blood Patient 3 blood Patient 1 blood Aspergillus extract Patient 6 blood Patient 4 blood Patient 5 blood Severo on
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Aspergillus IgG serology
Baxter, AAA 2010;Abstr 51 26
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Chronic pulmonary aspergillosis - serology
All 18 patients had positive Aspergillus precipitins (1+-4+) All 18 patients had elevated inflammatory markers, CRP, PV and / or ESR May have elevated total IgE and Aspergillus specific IgE (RAST) Only 40% have a positive sputum culture Denning DW et al, Clin Infect Dis 2003; 37:S265
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Chronic pulmonary aspergillosis
Infection of the lung by Aspergillus Single fungal ball or aspergilloma in a pre-existing cavity Chronic cavitary pulmonary aspergillosis +/- fungal ball Exposure to individual Aspergillus spores or conidia is almost constant. If eradicated immediately, as is usual in normal people, no disease results. If colonisation occurs, it may be short or long term. The pattern of disease is mostly determined by the host group (see next slide), with probably a component of the inoculum size contributing to invasive disease. However chronic disease if usually seen in patients with apparently normal immune systems.
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Chronic cavitary pulmonary aspergillosis – CT reconstruction
Wythenshawe Hospital
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Chronic cavitary pulmonary aspergillosis (CCPA) – sputum production
Aspergillus cultures positive in CCPA in 10-40% of cases only Wythenshawe Hospital
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‘Multicavity’ disease is the hallmark of chronic cavitary pulmonary aspergillosis (CCPA)
Wythenshawe Hospital
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Chronic cavitary pulmonary aspergillosis (CCPA) – haemoptysis
Wythenshawe Hospital
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Chronic Cavitary Pulmonary Aspergillosis Normal 30 year female smoker
Patient JA Jan 2001
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Chronic Cavitary Pulmonary Aspergillosis
Patient JA April 2003
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Multifocal cavities with aspergillomas – unrecognised phenotype
Wythenshawe Hospital
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18F-FDG PET positive pulmonary nodules in aspergillosis – a differential diagnosis of lung cancer
10 patients Presentations like lung cancer 1 subacute IPA 1 ABPA 1 aspergilloma 7 CPA Aspergillus IgG 28 ->200 mg/L All positive on histology Baxter, Thorax 2011
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CLASSIFICATION OF ASPERGILLOSIS
Invasive aspergillosis Acute (<1 month course) Subacute/chronic necrotising (1-3 months) Airways/nasal exposure to airborne Aspergillus Chronic aspergillosis (>3 months) Chronic cavitary pulmonary Aspergilloma of lung Chronic fibrosing pulmonary Chronic invasive sinusitis Maxillary (sinus) aspergilloma Persistence without disease - colonisation of the airways or nose/sinuses Allergic Allergic bronchopulmonary (ABPA) Extrinsic allergic (broncho)alveolitis (EAA) Asthma with fungal sensitisation Allergic Aspergillus sinusitis (eosinophilic fungal rhinosinusitis) Exposure to individual Aspergillus spores or conidia is almost constant. If eradicated immediately, as is usual in normal people, no disease results. If colonisation occurs, it may be short or long term. The pattern of disease is mostly determined by the host group (see next slide), with probably a component of the inoculum size contributing to invasive disease. However chronic disease if usually seen in patients with apparently normal immune systems. 37
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Allergic Bronchopulmonary Aspergillosis
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ABPA – Diagnostic clues
Asthma/CF not well controlled History of ‘pneumonia’ History of coughing up plugs, or paroxysms of coughing that clear when chest clears Central bronchiectasis on CT scan, or mucoid impaction Eosinophilia Rare cases in non-asthmatics, non-CF patients
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Asthma – variable airflow obstruction
Inhaled steroids Patient SY, Aspergillus Website
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Proposed new criteria for ABPA
Serum IgE >1000 IU/mL Asthma OR CF Airway obstruction (ie CT scan/bronchoscopy) by or production of mucus plugs containing hyphae Which fungus? Fungal sensitisation (IgE or SPT) and/or fungus detected in respiratory secretions Knutsen et al, AAAAI Task Force on Fungus and Asthma 41
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ABPA - March – doing well
FEV1 = 3.00 Aspergillus IgE = 31 IgE = 1900. No treatment
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September – episode of pneumonia
FEV1 = 1.6. IgE = 3000 Aspergillus IgE = 52.5. Exacerbation of ABPA
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Exacerbation of ABPA Patient AL
January 2011 June 2011 May 2010
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Exacerbation of ABPA Patient AL
September 2011
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Mucoid impaction due to ABPA
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Mucoid impaction due to ABPA
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Sputum in ABPA
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ABPA – bronchoscopy views showing mucous plugging
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A. fumigatus in BAL and in bronchial tissue in ABPA
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Severe Asthma and Fungal Sensitisation
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Fungal exposure in asthmatics is related to:
Life-threatening asthmatic attacks (ie thunderstorm asthma) Severe asthma and hospital admission Increased wheezing and symptoms Loss of medication control Allergic bronchopulmonary mycosis Eosinophilic fungal rhinosinusitis O'Hollaren, N Engl J Med 1991; 324: 359; and many others
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Airborne fungal fragments
Diffusing allergen leeching out of fungus in contact with liquid Green et al, J Allergy Clin Immunol 2005;115:1043
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Genomic analysis of allergens
Bowyer et al, BMC Genomics 2006;7:251
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Severe asthma and mould senstivity – Alternaria and Cladosporium
Mild asthma – 564 (50%) Moderate asthma – 333 (29%) Severe asthma – 235 (21%) Zureik et al, Br Med J 2002;325:411
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Mean sensitization score (mm)
Non-Mould allergens No Hospital Admission Single Multiple Admissions 20.0 Mould allergens No Hospital Admission Single Multiple Admissions P= <0.0001 17.5 15.0 12.5 Mean sensitization score (mm) (Mean and 95% CI) 10.0 7.5 5.0 2.5 0.0 O’Driscoll et al, BMC Pulmonary Medicine 2005;5:4
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Colonisation in ‘normal’ lungs
22 of 30 (73%) grew a fungus in both lung samples taken 10/30 (33%) grew >1 species Lass-Florl et al, Br J Haematol 1999;104:745
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Asthma and Aspergillus
79 adult asthmatics and 14 controls Patients sensitised to A. fumigatus compared with non-sensitised asthmatics had: lower lung function (% pred. FEV1 68% vs 88% p < 0.05), more bronchiectasis (68% versus 35% p < 0.05) and more sputum neutrophils (80.9% vs 49.5% p < 0.01). Fairs et al, Am J Respir Crit Care Med 2010; July 16
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Severe asthma and aspergillosis in ICU
57 of 357 (16%) admitted ICU with acute asthma Compared with 755 outpatients with asthma Aspergillus skin prick test used to screen for aspergillus hypersensitivity, if positive IgE etc for ABPA checked Aspergillus positive ABPA Asthma in ICU /57 (51%) /57 (39%) Outpatient asthma 90/755 (39%) /755 (21%) P value Agarwal et al, Mycoses 2009 Jan 24th
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Severe asthma with invasive aspergillosis
Felton et al Chest 2010;137:724
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Severe asthma with fungal sensitisation (SAFS)
Criteria for diagnosis Severe asthma (BTS step 4 or 5) AND RAST (IgE) positive for any fungus OR Skin prick test positive for any fungus Exclude ABPA (ie total IgE <1,000 iu/mL) Denning et al, Eur Resp J 2006; 27;27:615
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Comparison of ABPA and SAFS serology
ABPA results normal range date 1 date 2 Patient 1 2 SAFS results
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Skin prick testing – example of SAFS result
Cladosporium +ve O’Driscoll, unpublished
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>23% discordant results
Fungal sensitisation in severe asthma – skin prick test or RAST for diagnosis? N= 121 patients screened 100% } >23% discordant results 50% 43 34 10 13 SPT + RAST both positive SPT positive RAST negative SPT negative RAST positive SPT negative RAST negative O’Driscoll et al, Clin Exp Allergy. In press
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Sensitisation to one or more fungi
Fungal sensitisation in severe asthma – number sensitised to one or more fungi N = 40 13 sensitised to only Aspergillus 8 to Candida 3 to Trichophyton 3 to Penicillium 1 to Alternaria 1 to Cladosporium N = 20 29 11 11 12 7 7 3 Sensitisation to one or more fungi O’Driscoll et al, Clin Exp Allergy. In press
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Distinguishing different forms of aspergillosis
Disease group CCPA ABPA + CCPA ABPA SAFS n 116 16 98 52 Median serum IgE level (IQR) 99.8 ( ) (n=107) 2739 ( ) (n=16) 2300 ( ) (n=97) 370 ( ) (n=52) Aspergillus specific IgG 93.6% (103/110) 81.3% (13/16) 65.4% (53/81) 35.9% (14/39) Positive fungal culture 25% (29/116) 25.0% (4/16) 23.5% (23/98) 21.2% (11/52) Positive specific IgE Positive SPT Mixed mould N/T 88.9% (8/9) 90.9% (20/30) 100% (2/2) A. fumigatus 37.7% (40/106) 93.8% (15/16) 96.9% (94/97) 78.8% (41/52) Alternaria alternata 10.0% (1/10) 100% (10/10) 77.5% (55/71) 32.5% (13/40) 47.4% (9/19) C. albicans 33.3% (3/9) 90.0% (9/10) 81.4% (57/70) 37.5% (15/25) 52.6% (10/19) Cladosporium herbarum 20.0% (2/10) 80.0% (8/10) 70.4% (50/71) 24.4% (10/41) 35.5% (6/17) Penicillium chrysogenum 27.3% (3/11) 85.3% (58/68) 30.0% (12/40) 43.8% (7/16) Trichophyton mentagrophyte 33.3% (2/6) 100% (3/3) 65.2% (30/46) 25.0% (9/36) 23.1% (3/13)
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Distinguishing different forms of aspergillosis
Disease group CCPA ABPA + CCPA ABPA SAFS n 116 16 98 52 Median serum IgE level (IQR) 99.8 ( ) (n=107) 2739 ( ) (n=16) 2300 ( ) (n=97) 370 ( ) (n=52) Aspergillus specific IgG 93.6% (103/110) 81.3% (13/16) 65.4% (53/81) 35.9% (14/39) Positive fungal culture 25% (29/116) 25.0% (4/16) 23.5% (23/98) 21.2% (11/52) Positive specific IgE Positive SPT Mixed mould N/T 88.9% (8/9) 90.9% (20/30) 100% (2/2) A. fumigatus 37.7% (40/106) 93.8% (15/16) 96.9% (94/97) 78.8% (41/52) Alternaria alternata 10.0% (1/10) 100% (10/10) 77.5% (55/71) 32.5% (13/40) 47.4% (9/19) C. albicans 33.3% (3/9) 90.0% (9/10) 81.4% (57/70) 37.5% (15/25) 52.6% (10/19) Cladosporium herbarum 20.0% (2/10) 80.0% (8/10) 70.4% (50/71) 24.4% (10/41) 35.5% (6/17) Penicillium chrysogenum 27.3% (3/11) 85.3% (58/68) 30.0% (12/40) 43.8% (7/16) Trichophyton mentagrophyte 33.3% (2/6) 100% (3/3) 65.2% (30/46) 25.0% (9/36) 23.1% (3/13)
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Conceptual framework for CPA and IA
Immune function Hyphal load in tissue Normal Massive Chronic inflammation and fibrosis Vascular invasion, necrosis, dissemination Granulomas, acute inflammation, central necrosis Aspergilloma - CCPA - CNPA/subacute IPA - acute IPA
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Alternative Aspergillus diagnoses
Aspergillus bronchitis Obstructing bronchial aspergillosis Invasive Aspergillus tracheobronchitis Community acquired Aspergillus pneumonia Sub-acute invasive pulmonary aspergillosis (often called chronic necrotising pulmonary aspergillosis or CNPA) Extrinsic allergic (bronchiol)alveolitis (EAA) Aspergillus empyema
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6th Jan 24th Feb Arendrup, Scand J Infect Dis 2006:38:945
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Obstructing bronchial aspergillosis
Patient ML Pre-bronchscopy Patient ML After bronchoscopy Denning et al, New Engl J Med 1991;324: 654
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Subacute invasive pulmonary aspergillosis in AIDS
Patient HB Day +14, CD4 cells 84/uL Biopsy positive for Aspergillus Sambatakou, Eur J Clin Microbiol Infect Dis 2005;24:628
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Conclusions CPA = 3 months of pulmonary cavitation or nodule +/- aspergilloma, with symptoms + Aspergillus IgG or precipitins positive CPA patients almost all have an underlying diagnosis ABPA = asthma (any severity) or cystic fibrosis + total IgE >1,000 + SPT or Aspergillus IgE positive. SAFS = severe asthma + fungal SPT or IgE positive + total IgE <1,000 Some patients have overlap syndromes and more than 1 Aspergillus diagnosis
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