Lethal pulmonary fungal disease think fungus early

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1 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

2 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!

3 Deaths from fungal infections need to fall Fungal Infection TB (2015) Malaria (2015) >1,660,000 1,800,000 (200,000 with HIV) 429,000

4 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

5 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

6 Pegorie et al, J Infect 2017;74:60

7 Simple (single) aspergilloma Patient NM August 2006 May 2009 Community acquired New cough pneumonia requiring ICU care Positive Aspergillus antibodies in blood Lobectomy Wythenshawe Hospital

8 Irregular cavity walls very characteristic of fungal growth in the cavity

9 Chronic cavitary pulmonary aspergillosis National Aspergillosis Centre

10 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

11 Chronic cavitary pulmonary aspergillosis (CCPA) coughing up blood (haemoptysis) Wythenshawe Hospital

12 Progression of CCPA to chronic fibrosing pulmonary aspergillosis on no Rx 1997 still on no Rx

13 Denning DW et al, Chronic pulmonary aspergillosis Rationale and clinical guidelines for diagnosis and management. Eur Resp J

14 Clinical phenotypes of chronic Aspergillus spp diseases Single/simple aspergilloma Aspergillus nodule(s) Subacute Invasive aspergillosis (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

15 Denning et al, Eur Resp J Radiological diagnosis of CPA Population Intention Intervention SoR QoE Reference Comment Features of cavitation, fungal ball, pleural thickening and/or upper lobe fibrosis Raise suspicion of CPA for physicians Radiological report must mention possible CPA A II Roberts, 1987; Kim, 2000; Franquet, 2001; Denning, 2003; Greene, 2005; Kobashi, 2006; Godet, 2014 CPA is often missed for years and patients mismanaged. Microbiological testing required for confirmation High quality CT with vessel visualisation

16 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

17 Denning et al, Eur Resp J 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.

18 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 % of hospital admissions

19 Denning et al, Eur Resp J 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.

20 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

21 Frequency of aspergillosis Interaction of Aspergillus with the host A unique microbial-host interaction Acute IA Subacute IA Aspergillus keratitis Aspergillus bronchitis Chronic pulmonary Otitis externa Onychomycosis ABPA SAFS Allergic sinusitis Frequency of aspergillosis Immune dysfunction Lung/tissue damage Immune hyperactivity After Casadevall & Pirofski, Infect. Immun 1999;67:3703

22 Important airborne fungi Alternaria Cladosporium Rhizopus Aspergillus

23 Common allergen exposures by month Twaroch et al, Allergy Asthma Immunol Res 2015:7:205

24 O Driscoll, unpublished Skin prick testing for fungal asthma Cladosporium +ve

25 Denning et al, Med Mycol 2013:51:361 Fungal asthma ABPA versus SAFS ABPA = allergic bronchopulmonary aspergillosis SAFS = severe asthma with fungal sensitisation

26 66% sensitised to one or more fungus: 45% to Aspergillus fumigatus O Driscoll R et al, Clin Exp All 2009;39:1677

27 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

28 Fungal asthma in the UK Pegorie et al, J Infect 2017;74:60

29 Fungal disease of the lungs in outside the hospital ~200 million adult asthmatics

30 Norback D, Occup Environ Med 2013;70: ,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 ( ) years. Risk ratio for new asthma = 1.46 (water damage) and 1.3 (indoor moulds).

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

32 Proof of concept RCT of itraconazole in SAFS outcomes at 32 weeks Quality of life outcome Mean (95% CI) or % (n) Itraconazole Change in AQLQ score (0.28, 1.41) Improvement in AQLQ score of >0.75 Percentage change in total IgE -27% (IU/L) (-14%, -38%) Change in FEV1 (L/min) (-0.56, 0.11) Placebo (-0.43, 0.42) P-value % (14) 18% (5) Number needed to treat = 3.22 Change in FEV1 (% predicted) (-9.39, 2.08) Change in average PEFR (am) 20.8 (3.5, 38.1) +12% (-5%, +31%) (-0.16, 0.11) 0.13 (-3.67, 3.93) -5.5 (-21.6, 10.7) NS NS Change in average PEFR (pm) NS Denning et al, Am J Resp Crit Care Med 2009; 179:11

33 Risk groups and frequencies of invasive aspergillosis different test performances Herbrecht, Ann NY Acad Sci 2012;1271:23

34 Invasive aspergillosis by finished consultant episodes - UK

35 IA in immunocompromised patients Pegorie et al, J Infect 2017;74:60

36 COPD admissions (rate per 40+ years old) OECD Health Statistics 2013, ttp://dx.doi.org/ /health-data-en.

37 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.

38 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.

39 IA in lung disease patients - most probably being missed Pegorie et al, J Infect 2017;74:60

40 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: /bmjqs

41 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 patients with influenza 23 (16%) had IA 14/23 (61%) died Schauwvlieghe et al, TIMM 2017

42 Frequency of aspergillosis Diagnostic tests GM = aspergillus antigen; G = glucan GM test G test IgG antibody test G test IgE antibody test IgG antibody test Acute invasive Subacute IA Aspergilloma Chronic pulmonary Aspergillus bronchitis ABPA Severe asthma with fungal sensitisation Allergic sinusitis GM and Aspergillus PCR in BAL & respiratory samples Frequency of aspergillosis Immune compromised Lung damage Allergy - atopy After Casadevall & Pirofski, Infect. Immun 1999;67:3703

43 Pneumocystis pneumonia in the UK all underlying diseases Maini et al, Emerg Infect Dis 2013;10:386

44 Serious fungal disease in the UK Pegorie et al, J Infect 2017;74:60

45 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

46 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