Aspergillosis Patients Support Outreach Meeting London June 2011 - David Denning

SECOND OUTREACH MEETING, LONDON LED BY GRAHAM ATHERTON SUPPORTED BY GEORGINA POWELL, MARIE KIRWAN & DEBBIE KENNEDY NAC CENTRE MANAGER CHRIS HARRIS TALKS GIVEN BY PHILIP LANGRIDGE & DAVID DENNING NATIONAL ASPERGILLOSIS CENTRE UHSM MANCHESTER Support Meeting for Aspergillosis Patients Fungal Research Trust

ABPA and SAFS David W. Denning National Aspergillosis Centre University Hospital of South Manchester The University of Manchester

Early descriptions of Aspergillus First descriptions: A. flavus – Link, 1809 A. fumigatus – Fresnius, 1863 A. niger - v. Tiegham, 1867 A. 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

Early reports of asthma exacerbated by fungi Denning et al Eur Resp J 2006:27:615
1698 - ‘asthmatic who fell into a violent fit, by going into a wine cellar where the must was fermenting’
1873 – Dr Charles Blackley self experimented with Penicillium glaucum which on inhalation of a large number of spores, induced hoarseness, aphonia and an attack of 'bronchial catarrh‘
1897 – Renon noted wheezing in pigeon-crammers and hair combers exposed to Aspergillus
1924 – Cadham attributed asthma to wheat rust ( Puccinia graminis ) exposure
1924 - Storm Van Leeuwen showed asthma was more prevalent in the humid parts of the Netherlands, and relief with the use of filtered air

Early reports of asthma exacerbated by fungi Denning et al Eur Resp J 2006:27:615
1925 – Van Leewen found 50% of Dutch asthmatics had mould skin sensitivity esp. to Mucor, Penicillium and A. fumigatus, niger, flavus and nidulans
1928 - Hansen found 15% of asthmatics had positive skin tests to Aspergillus or Penicillium grown from their environment and that inhalation challenge reproduced symptoms
1928 - Jimines-Diaz and Sanchez Cuenca demonstrated that ‘house dust’ sensitivity was often due to moulds
1930 - 3 separate case reports of asthma related to Alternaria , A. fumigatus and Trichopyton
1939 - Cohen showed that mattresses, pillows and furniture were potent sources of ‘house dust antigen’ which when removed abolished asthmatic symptoms in those with mould allergy

Fungal exposure in asthmatics is related to:
Life-threatening asthmatic attacks (ie thunderstorm asthma)
Severe asthma and hospital admission
O'Hollaren, N Engl J Med 1991; 324: 359; and many others

ABPA and severe asthma www.emphysema-copd.co.uk

Asthma – variable airflow obstruction Patient SY, Aspergillus Website Inhaled steroids

O’Driscoll, unpublished Skin prick testing – example of SAFS result Cladosporium +ve

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

ABPA - March – doing well FEV1 = 3.00 Aspergillus IgE = 31 IgE = 1900. No treatment

September – episode of pneumonia FEV1 = 1.6. IgE = 3000 Aspergillus IgE = 52.5. Exacerbation of ABPA

Sputum in ABPA www.aspergillus.org.uk

ABPA – bronchoscopy views showing mucous plugging www.aspergillus.org.uk

A. fumigatus in BAL and in bronchial tissue in ABPA

Charcot Leyden crystals

Eosinophilic Fungal Rhinosinusitis
Sinus opacification
Expansion
Bony erosion (extreme cases)
No tissue invasion
From Saleh

Central bronchiectasis as a complication of ABPA www.aspergillus.org.uk

Severe asthma with fungal sensitisation (SAFS) Denning et al, Eur Resp J 2006; 27;27:615
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
AND
Exclude ABPA (ie total IgE <1,000 iu/mL)

Hospital admission and sensitisation Allergen Asthma, no admission (n=82) Asthma, 2+ admissions (n=46) House dust mite 56 % 67 % Grass pollen 46 % 63 % Cat 37 % 59 % Dog 18 % 48 % Any non fungal allergen 70% 74% O’Driscoll et al, BMC Pulmonary Medicine 2005;5:4

Hospital admission and m ould a llergy Allergen Asthma, no admission (n=82) Asthma, 2+ admissions (n=46) Aspergillus 7 % 37 % Alternaria 5 % 26 % Cladosporium 1 % 41 % Penicillium 2 % 30 % Candida 10 % 33 % Any fungal allergen 16% 76% O’Driscoll et al, BMC Pulmonary Medicine 2005;5:4

0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 Mean sensitization score (mm) (Mean and 95% CI) O’Driscoll et al, BMC Pulmonary Medicine 2005;5:4 Non-Mould allergens No Hospital Admission Single Admission Multiple Admissions Mould allergens No Hospital Admission Single Admission Multiple Admissions P= <0.0001

Asthma and Aspergillus Fairs et al, Am J Respir Crit Care Med 2010; July 16 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).

Comparison of ABPA and SAFS serology ABPA results normal range date 1 date 2 SAFS results Patient 1 2

Fungal sensitisation in severe asthma – skin prick test or RAST for diagnosis? N= 121 patients screened O’Driscoll et al, Clin Exp Allergy 2009;39:1677-83. SPT + RAST both positive 100% 50% 43 10 13 34 SPT positive RAST negative SPT negative RAST positive SPT negative RAST negative } > 23% discordant results

Fungal sensitisation in severe asthma – number sensitised to one or more fungi O’Driscoll et al, Clin Exp Allergy 2009;39:1677-83. 1 2 3 4 5 6 7 N = 40 N = 20 29 11 11 12 3 7 7 Sensitisation to one or more fungi 13 sensitised to only Aspergillus 8 to Candida 3 to Trichophyton 3 to Penicillium 1 to Alternaria 1 to Cladosporium

Chronic cavitary pulmonary aspergillosis as a complication of ABPA www.aspergillus.org.uk

ABPA and development of CPA www.aspergillus.org.uk 1981 1985 1993 1995 2002

Morphology of Aspergillus Weichel et al, Clin Exp Allergy 2003;33:72, www.aspergillus.org.uk

Airborne fungal fragments Green et al, J Allergy Clin Immunol 2005; 115:1043 Fungal fragment Diffusing allergen leeching out of fungus in contact with liquid

Effect of A. fumigatus proteases on airways Kauffmann et al

Surfactant A and D Kishore et al Mol Immunol 2006;43:1293

Immune roles of surfactant Wright JR Nat Rev Immunol 2005;5:58.

ABPA and surfactant defects
ABPA patients have a higher frequency of SP-A2 A1660G SNP compared with with control subjects (OR = 4.78). In combination with SP-A2 G1649C more significant (OR = 10.4)
(P=0.016 and p=0.008)
Vaid et al, Clin Chem Lab Med 2007;45:183; Saxena et al, J All Clin Immunol 2003;111:1001

Toll-like Receptor genetic differences and ABPA vs. SAFS Carvalho, J Infect Dis 2008;197:618

Randomised studies of antifungals and ABPA and/or asthma Disease Antifungal, duration Benefit? Author, year ABPA Natamycin inh, 52 wks No Currie, 1990 ABPA Itraconazole, 32 wks Yes Stevens, 2000 ABPA Itraconazole, 16 wks Yes Wark, 2003 “ Trichophyton” asthma Fluconazole, 20 wks Yes Ward, 1999 SAFS Itraconazole, 32 wks Yes Denning, 2009

Chishimba et al, unpublished data Second and third line antifungal therapy for ABPA and/or asthma
26 patients, ABPA (n = 21) or SAFS (n = 5).
All patients had failed itraconazole (n=14) or developed adverse events (AEs) (n=12)
34 courses of therapy, 25 with voriconazole and 9 with posaconazole.
Voriconazole responses: 17/25 (68%) at 3 months, 15/20 (75%) at 6 months and 12/16 (75%) at 12 months,
Posaconazole responses: 7/9 (78%) at 3, 6 and 12 months for posaconazole.
18/24 (75%) discontinued oral corticosteroids, 12 of them within 3 months of starting antifungal therapy.
6/23 (26%) patients on voriconazole had AEs requiring discontinuation before 6 months compared to none on posaconazole (p=0.15).
4 relapsed (57%), 1 at 3 months and 3 at 12 months after discontinuation.

Denning et al, unpublished data How common is ABPA?

Conclusions
ABPA and SAFS are more common than diagnosed
Neither blood allergy or skin allergy tests are 100% sensitive, so both may be necessary to identify SAFS
Genetic risk factors are the most likely difference between different patients – probably several genes
Current treatments are partially successful - better results can be obtained with monitoring levels in blood
We need more antifungals, and we need to learn better how to minimise steroid usage
Antifungal resistance is an increasing problem
Opportunities for immune therapies going forward

Aspergillosis Patients Support Outreach Meeting London June 2011 - David Denning

by Graham Atherton on Jul 27, 2011

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