Lethal pulmonary fungal disease – ‘think fungus’ early David W. Denning National Aspergillosis Centre University Hospital of South Manchester The University of Manchester

Global Action Fund for Fungal Infections GAFFI Global Action Fund for Fungal Infections OUR VISION IS TO REDUCE ILLNESS AND DEATH ASSOCIATED WITH FUNGAL DISEASES WORLDWIDE.

LEAVE NO ONE BEHIND: Too many people have no access to life-saving fungal diagnostics and antifungal medicine. This has to change! Deaths from fungal infections need to fall

Fungal Infection TB (2015) Malaria (2015)

1,800,000 >1,660,000 (200,000 429,000 with HIV)

www.GAFFI.org Fungal infections

• Mucosal i.e. oral or vulvovaginal thrush • Cutaneous i.e. athlete’s foot, ringworm and onychomycosis • Chronic fungal infections such as chronic pulmonary aspergillosis • Allergic i.e. allergic fungal sinusitis and allergic bronchopulmonary aspergillosis (ABPA) • Invasive and life-threatening i.e. candidaemia, invasive aspergillosis and cryptococcal meningitis Fungal infections

• Mucosal i.e. oral or vulvovaginal thrush • Cutaneous i.e. athlete’s foot, ringworm and onychomycosis • Chronic fungal infections such as chronic pulmonary aspergillosis • Allergic i.e. allergic fungal sinusitis and allergic bronchopulmonary aspergillosis (ABPA) • Invasive and life-threatening i.e. candidaemia, invasive aspergillosis and cryptococcal meningitis Pegorie et al, J Infect 2017;74:60 Simple (single) aspergilloma

Patient NM

August 2006 May 2009 Positive Aspergillus antibodies in blood Community acquired New cough pneumonia requiring Lobectomy ICU care

Wythenshawe Hospital Irregular cavity walls – very characteristic of fungal growth in the cavity Chronic cavitary pulmonary aspergillosis

National Aspergillosis Centre 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 www.aspergillus.man.ac.uk Chronic cavitary pulmonary aspergillosis (CCPA) – coughing up blood (haemoptysis)

Wythenshawe Hospital Progression of CCPA to chronic fibrosing pulmonary aspergillosis

1992 1994 on no Rx 1997 still on no Rx Denning DW et al, Chronic pulmonary aspergillosis – Rationale and clinical guidelines for diagnosis and management. Eur Resp J 2016;47:45-68. Clinical phenotypes of chronic Aspergillus spp diseases

Single/simple aspergilloma

Aspergillus Subacute Invasive aspergillosis nodule(s) (SAIA) or chronic necrotizing pulmonary aspergillosis (CNPA)

Chronic cavitary pulmonary aspergillosis (CCPA)

Treat as for IA – 6 months

Chronic fibrosing pulmonary aspergillosis (CFPA)

Denning DW et al, Chronic pulmonary aspergillosis – Rationale and clinical guidelines for diagnosis and management. Eur Resp J 2016;47:45-68 Radiological diagnosis of CPA Population Intention Intervention SoR QoE Reference Comment Features of cavitation, Raise Radiological Roberts, 1987; CPA is often fungal ball, pleural suspicion of report must A II Kim, 2000; missed for years Franquet, and patients thickening and/or upper CPA for mention 2001; Denning, lobe fibrosis physicians possible CPA 2003; Greene, mismanaged. 2005; Kobashi, Microbiological 2006; Godet, testing required 2014 for confirmation High quality CT

with vessel visualisation

Denning et al, Eur Resp J 2016;47:45 Aspergillus nodule

Patients may have 1, 2 or more nodules Cough and dyspnoea are common, 30% weight loss, occcasional haemoptysis. 57% had positive IgG antibody

Muldoon E. BMC Pulm Med 2016 In press Spiculated nodule - aspergillosis

Figure 13 - Nodule of the right upper lobe with irregular and slightly spiculated borders that was surgically resected and proven to be an Aspergillus nodule.

Denning et al, Eur Resp J 2016;47:45 Aspergillosis in COPD

• There is an overlap between COPD and asthma, now referred to as ‘asthma- COPD overlap syndrome (ACOS)’ • Many COPD patients are ‘colonised’ by Aspergillus - ~30% by high volume culture • Aspergillus IgG antibody may be positive in COPD patients (~50%) – of uncertain clinical significance • The commonest underlying disease for CPA in high income countries includes COPD • Invasive aspergillosis complicates COPD in 1.3-3.9% of hospital admissions

www.GAFFI.org Multiple Aspergillus nodules

Figure 6 – Aspergillus nodules of variable size and borders and fungus ball filling a cavity with a wall of variable thickness in a patient with preexisting bronchiectasis and cicatricial atelectasis of the middle lobe. Successive axial views with lung windows.

Denning et al, Eur Resp J 2016;47:45 Differential diagnosis of patients with upper lobe disease, usually with cavitation • Pulmonary TB • Non-tuberculous mycobacterial infection (NTM) • Chronic pulmonary aspergillosis • Allergic bronchopulmonary aspergillosis (asthma) • Lung cancer (adeno, small cell or large cell) • Cavitating pneumonia – Pseudomonas, Staphylococcus, Rhodococcus, Nocardia etc • Actinomycosis

• Chronic cavitary pulmonary histoplasmosis • Pulmonary coccidioidomycosis • Pulmonary paracoccidioidomycosis

Interaction of Aspergillus with the host

A unique microbial-host interaction

Frequency Frequency aspergillosis of

ABPA Acute IA SAFS Allergic sinusitis Subacute IA

Aspergillus keratitis Aspergillus bronchitis Chronic pulmonary

Otitis externa Frequency of aspergillosis of Frequency Onychomycosis

Immune dysfunction Lung/tissue damage Immune hyperactivity After Casadevall & Pirofski, Infect. Immun 1999;67:3703 Important airborne fungi

Alternaria Cladosporium

Rhizopus Aspergillus Common allergen exposures by month

Twaroch et al, Allergy Asthma Immunol Res 2015:7:205 Skin prick testing for fungal asthma

Cladosporium +ve

O’Driscoll, unpublished

‘Fungal asthma’ ABPA versus SAFS

ABPA = allergic bronchopulmonary aspergillosis SAFS = severe asthma with fungal sensitisation

Denning et al, Med Mycol 2013:51:361

66% sensitised to one or more fungus: 45% to Aspergillus fumigatus

O’Driscoll R et al, Clin Exp All 2009;39:1677 The mycobiome of fungal asthma

Oral corticosteroid is strongly associated with higher Aspergillus fungal loads (p < 0.01) Fraczek et al, J Allergy Clin Immunol 2017;in press ‘Fungal asthma’ in the UK

Pegorie et al, J Infect 2017;74:60 Fungal disease of the lungs in outside the hospital

~200 million adult asthmatics

www.GAFFI.org 7,104 young adults in 13 countries (11 Europe) Questionnaires, sensitisation to Alternaria and Cladosporium, assessment of homes, asthma evaluation (metacholine challenge). New onset asthma (n=355) Correlation with water damage and mould in the house Follow up 8.7 (5.9-11.7) years.

Risk ratio for new asthma = 1.46 (water damage) and 1.3 (indoor moulds).

Norback D, Occup Environ Med 2013;70:325-31. Retrospective comparison of itraconazole antifungal treatment of SAFS with ABPA

22 patients with SAFS were compared with 11 with ABPA

Pasquallotto et al, Respirology 2009;14:1121 Proof of concept RCT of itraconazole in SAFS – outcomes at 32 weeks Quality of life outcome

Mean (95% CI) or % (n) P-value Itraconazole Placebo Change in AQLQ score +0.85 -0.01 0.014 (0.28, 1.41) (-0.43, 0.42) Improvement in AQLQ score 54% (14) 18% (5) 0.013 of >0.75 Percentage change in total IgE -27% +12% 0.001 (IU/L) (-14%, -38%) (-5%, +31%) Change in FEV1 (L/min) -0.22 -0.02 NS Number needed(-0.56, to 0.11) treat = 3.22(-0.16, 0.11) Change in FEV1 (% predicted) -3.66 0.13 NS (-9.39, 2.08) (-3.67, 3.93) Change in average PEFR (am) 20.8 -5.5 0.028 (3.5, 38.1) (-21.6, 10.7) Change in average PEFR (pm) 16.8 8.9 NS (1.5, 35.2)Denning et al, Am(- J33.9, Resp Crit51.8) Care Med 2009; 179:11 Risk groups and frequencies of invasive aspergillosis – different test performances

Herbrecht, Ann NY Acad Sci 2012;1271:23 Invasive aspergillosis by finished consultant episodes - UK

www.aspergillus.org.uk IA in immunocompromised patients

Pegorie et al, J Infect 2017;74:60 COPD admissions (rate per 40+ years old)

OECD Health Statistics 2013, ttp://dx.doi.org/10.1787/health-data-en.

www.GAFFI.org Aspergillus, IPA and COPD

~ 1.3% of COPD admissions have invasive aspergillosis by culture

~ 22% of Aspergillus in COPD = invasive aspergillosis

72% mortality of IPA

Guinea et al. Clin Microbiol Infect 2010;16:870. www.GAFFI.org IA in COPD

58 of the 298 COPD admissions with a lower respiratory tract sample processed grew Aspergillus spp.

39 (3.9%) had probable IA. Only 13% had oral corticosteroids 43% died

Xu H et al. Clin Microbiol Infect 2012;18:403.

www.GAFFI.org IA in lung disease patients - most probably being missed

Pegorie et al, J Infect 2017;74:60 Missed diagnoses in multiple intensive care units (31 studies, 5863 autopsies)

Most common serious infectious diagnostic errors were pneumonia and invasive aspergillosis

Winters et al, BMJ Qual Saf doi:10.1136/bmjqs-2012-000803 Invasive aspergillosis linked to influenza

Literature review – 68 cases of influenza-associated IA – 47% mortality.

Severe influenza admitted to 8 tertiary ICUs in Netherlands Dec 2015 to April 2016

144 patients with influenza 23 (16%) had IA 14/23 (61%) died

Schauwvlieghe et al, TIMM 2017 Diagnostic tests – GM = aspergillus antigen; G = glucan

GM test IgG antibody test IgE antibody test

G test G test IgG antibody test

Frequency Frequency aspergillosis of

ABPA Acute invasive Severe asthma with fungal sensitisation GM and AspergillusSubacute PCR IA in BAL & respiratoryAllergic sinusitis samples

Aspergilloma Chronic pulmonary

Aspergillus bronchitis

Frequency of aspergillosis of Frequency

Immune compromised Lung damage Allergy - atopy After Casadevall & Pirofski, Infect. Immun 1999;67:3703 Pneumocystis pneumonia in the UK – all underlying diseases

Maini et al, Emerg Infect Dis 2013;10:386 Serious fungal disease in the UK

Pegorie et al, J Infect 2017;74:60 Conclusions All forms of aspergillosis of the lungs are underdiagnosed, untreated and probably contribute to unnecessary morbidity, death and inappropriate antibiotic use. In some populations, fungal disease is common, notably severe asthma, CF, COPD in hospital with an infiltrate, influenza and complex patients Early diagnosis is ideal, and may necessary for survival We have good diagnostic tools and drugs – they need to be utilised The global problem of fungal disease is huge www.aspergillus.org.uk 17 years Over 1M pages read monthly in >125 countries Supported by the Fungal Infection Trust – 20 year anniversary in 2011

New section on drug interactions which you can search very quickly + app for iphones and android (search antifungal interaction)

691 interactions were rated as minor, 919 moderate and 381 severe, = 2216 recorded interactions