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

OUR VISION IS TO REDUCE ILLNESS AND DEATH ASSOCIATED WITH FUNGAL DISEASES WORLDWIDE.

GAFFI Global Action Fund for Fungal Infections

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)

>1,660,000

1,800,000

(200,000

with HIV)

429,000

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

Positive Aspergillus antibodies in blood

Lobectomy

Wythenshawe Hospital

August 2006 May 2009

Community acquired New cough pneumonia requiring

ICU care

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’

Aspergillus growth on the surface of a pulmonary cavity

Severo on www.aspergillus.man.ac.uk

Orderly hyphal growth on the inside of the cavity

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.

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

nodule(s)

Chronic cavitary pulmonary

aspergillosis (CCPA)

Chronic fibrosing

pulmonary aspergillosis

(CFPA)

Subacute Invasive aspergillosis

(SAIA) or chronic necrotizing

pulmonary aspergillosis (CNPA)

Treat as for IA – 6 months

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

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

Aspergillus nodule

Muldoon E. BMC Pulm Med 2016 In press

Patients may have 1, 2 or more nodules

Cough and dyspnoea are common, 30% weight loss,

occcasional haemoptysis.

57% had positive IgG antibody

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.

Spiculated nodule - aspergillosis

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

Aspergillosis in COPD

www.GAFFI.org

• 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

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.

Multiple Aspergillus nodules

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

Immune dysfunction

Fre

quency of aspergillosis

Immune hyperactivity

Fre

quen

cy o

f as

perg

illo

sis

Acute IA

Subacute IA

Aspergillus keratitis Aspergillus bronchitis

Chronic pulmonary Otitis externa Onychomycosis

ABPA SAFS

Allergic sinusitis

. After Casadevall & Pirofski, Infect Immun 1999;67:3703

Lung/tissue damage

Important airborne fungi

Alternaria

Aspergillus

Cladosporium

Rhizopus

Common allergen exposures by month

Twaroch et al, Allergy Asthma Immunol Res 2015:7:205

O’Driscoll, unpublished

Skin prick testing for fungal asthma

Cladosporium +ve

‘Fungal asthma’

ABPA versus SAFS

Denning et al, Med Mycol 2013:51:361

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

66% sensitised to one or more fungus:

45% to Aspergillus fumigatus

O’Driscoll R et al, Clin Exp All 2009;39:1677

Fraczek et al, J Allergy Clin Immunol 2017;in press

The mycobiome of fungal asthma

Oral corticosteroid is strongly associated with higher Aspergillus fungal loads (p < 0.01)

‘Fungal asthma’ in the UK

Pegorie et al, J Infect 2017;74:60

www.GAFFI.org

Fungal disease of the lungs in outside the hospital

~200 million adult asthmatics

Norback D, Occup Environ Med 2013;70:325-31.

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).

Retrospective comparison of itraconazole antifungal treatment of SAFS with ABPA

Pasquallotto et al, Respirology 2009;14:1121

22 patients with SAFS

were compared

with 11 with ABPA

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 (0.28, 1.41)

-0.01 (-0.43, 0.42)

0.014

Improvement in AQLQ score of >0.75

54% (14) 18% (5) 0.013

Percentage change in total IgE (IU/L)

-27% (-14%, -38%)

+12% (-5%, +31%)

0.001

Change in FEV1 (L/min) -0.22 (-0.56, 0.11)

-0.02 (-0.16, 0.11)

NS

Change in FEV1 (% predicted) -3.66 (-9.39, 2.08)

0.13 (-3.67, 3.93)

NS

Change in average PEFR (am) 20.8 (3.5, 38.1)

-5.5 (-21.6, 10.7)

0.028

Change in average PEFR (pm) 16.8 (1.5, 35.2)

8.9 (-33.9, 51.8)

NS

Number needed to treat = 3.22

Denning et al, Am J Resp Crit 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)

www.GAFFI.org

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

Aspergillus, IPA and COPD

~ 22% of

Aspergillus in

COPD = invasive

aspergillosis

~ 1.3% of COPD

admissions have

invasive

aspergillosis by

culture

www.GAFFI.org

Guinea et al. Clin Microbiol Infect 2010;16:870.

72% mortality of IPA

IA in COPD

www.GAFFI.org

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

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

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)

Winters et al, BMJ Qual Saf doi:10.1136/bmjqs-2012-000803

Most common serious infectious diagnostic errors were pneumonia and invasive aspergillosis

Invasive aspergillosis linked to influenza

Schauwvlieghe et al, TIMM 2017

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

Diagnostic tests – GM = aspergillus antigen; G = glucan

Immune compromised

Fre

quency of aspergillosis

Allergy - atopy

Fre

quen

cy o

f as

perg

illo

sis

Acute invasive

Subacute IA

Aspergilloma Chronic pulmonary

Aspergillus bronchitis

ABPA Severe asthma with fungal sensitisation

Allergic sinusitis

. After Casadevall & Pirofski, Infect Immun 1999;67:3703

Lung damage

GM test G test

IgG antibody test G test

IgE antibody test IgG antibody test

GM and Aspergillus PCR in BAL & respiratory samples

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