The extraordinary spectrum of diseases caused by Aspergillus David W. Denning Wythenshawe Hospital...

The extraordinary spectrum of diseases caused by Aspergillus

David W. DenningWythenshawe Hospital

University of Manchester

The genus The genus AspergillusAspergillus - importance to - importance to humanityhumanity

www.aspergillus.org.uk

cause invasive and allergic diseasein humans and other animals:

A. fumigatus

cause plant and food spoilage and produce mycotoxins:

A. flavus and A. parasiticus

on the negative side:on the negative side:

The genus The genus AspergillusAspergillus - importance to - importance to humanityhumanity


on the positive side:on the positive side:

composting

well-established model organism in cell biology and genetics:A. nidulans

food production:enzymes and organic acids: A. niger East Asian foods: A. oryzae and A. sojae

pharmaceuticals:echinocandins: A. nidulans and A. sydowilovastatin: A. terreusfumagillin: A. fumigatus

Spores inhaled Germination

Mass of hyphae (plateau phase)

Hyphal elongation and branching

Aspergillus Life-cycle


A. nidulans – may be amphotericin B resistant

The genus The genus AspergillusAspergillus – – ~800 species, ~800 species,

~50 have caused disease (able to grow at 37C)~50 have caused disease (able to grow at 37C)

Common in the environmentCommon in the environment

A. nigerA. terreus – resistant to AmBA. flavus -sometimes amphotericin B resistant


A. fumigatus low frequency of azole resistance

Aspergillus fumigatus

conidial head

CLASSIFICATION OF ASPERGILLOSIS

Persistence without disease - colonisation of the airways or nose/sinuses

Airways/nasal exposure to airborne Aspergillus

Invasive aspergillosis• Acute (<1 month course)• Subacute/chronic necrotising (1-3 months)

Chronic aspergillosis (>3 months)• Chronic cavitary pulmonary• Aspergilloma of lung• Chronic fibrosing pulmonary• Chronic invasive sinusitis • Maxillary (sinus) aspergilloma

Allergic• Allergic bronchopulmonary (ABPA)• Extrinsic allergic (broncho)alveolitis (EAA)• Asthma with fungal sensitisation• Allergic Aspergillus sinusitis (eosinophilic fungal rhinosinusitis)

Immunosuppression and infection

• Inhalation of aspergillus spores is a common daily occurrence. A healthy immune system would normally remove the spores and no symptoms or infection would occur.

• In individuals whose immune system may be suppressed either because of illness eg AIDS, cancer patients or drugs, spores may germinate and resulting tissue or systemic aspergillus invasion can result.

• Individuals with allergies such as asthma, can also be vulnerable to allergic aspergillosis

Global opportunistic infections

DiseaseMost common species

LocationEstimated Life-ThreateningInfections / Year

Mortality Rates(% in infected populations)

Opportunistic Systemic Mycoses

Invasive aspergillosisAspergillus spp.

worldwide >200,000 30 - 95%

Invasive candidiasisCandida spp.

worldwide >400,000 46 - 75%

CryptococcosisCryptococcus neoformans

worldwide >1,000,000 20 - 70%

MucormycosisRhizopus oryzae

worldwide >10,000 30 – 90%

PneumocystisPneumocystis jirovecii

worldwide >400,000 20 - 80%

Brown et al, Sci Transl Med 2012;4:165rv13

Interaction of Aspergillus with the host

A unique microbial-host interaction

Immune dysfunction

Frequency

of a

sperg

illosis

Immune hyperactivity

Frequency

of

asp

erg

illosi

s

Acute IA

Subacute IA

Aspergillus keratitisAspergillus bronchitisChronic pulmonary

Otitis externaOnychomycosis

ABPASevere asthma with fungal sensitisation

Allergic sinusitis

. Lung/tissue

damagewww.aspergillus.org.uk

Aspergillosis burden in Europe

ECDC report published February 2013

Type of aspergillosis

Predominant risk groups

Risk population size (000’s)

Aspergillosis rate

Annual aspergillosis

burden (000’s)

ABPAAsthma 35,474 2.5%

887 (248 – 1,242)

Cystic fibrosis 29 15% 4.3SAFS

Severe asthmaa 3,547 33%1,170 (886 –

1,774) Chronic

pulmonary aspergillosis

COPD, TB, sarcoidosis, ABPA,

Pneumothorax>13,600 1-10% 240

Invasive aspergillosis

Myeloid leukaemia,

Other haematological

HSCT

4411.4

7%

3.13.1

0.8

COPD hospital admissions

3,600 1.2% 34

Solid organ transplantation

30 0.75% 0.25

Medical ICU 1,100 ( all ICU) 2% 22Total

aspergillosis annual burden

All - - 2,364.55

63,250

2,061,300

Invasive pulmonary aspergillosis


Normal lungIPA

IPA occurs in ~7% of acute

leukaemia patients, 10-15% allogeneic BMT

patients

Unequivocal ‘Halo sign’ surrounding a noduleUnequivocal ‘Halo sign’ surrounding a nodule

Herbrecht, Denning et al, NEJM 2002;347:408-15.

Halo sign

Recent examples of the frequency of invasive aspergillosis

Underlying condition Incidence Reference/yearAcute myeloid leukaemia

8% Cornet, 2002

Acute lymphatic leukaemia

6.3% Cornet, 2002

Allogeneic HSCT 11-15% Grow, 2002; Marr, 2002

Lung transplantation 6.2-12.8% Minari, 2002; Singh,2003

Heart-lung transplantation

11% Duchini, 2002

Small bowel tranplantation

11% Duchini, 2002

AIDS 2.9% Libanore, 2002

Gillies & Campbell, www.aspergillus.org.uk

Bleeding as an aspect of disseminated invasive aspergillosis

Fumagillin is anti-angiogenic

A haemolysin described from Aspergillus fumigatus

Other factors that contribute to thrombosis or a coagulopathy?

How does Aspergillus fumigatus cause thrombosis (clotting of vessels) and also bleeding?

Filler et al, Blood 2004;103:2134; Paris et al, Infect Immun 1997;65:1510.

Interaction of conidia and

endothelial cell projections

Internalisation of conidia (and hyphae) by

endothelial cells with injury

apparent at 4 hours


Cerebral aspergillosis (abscess) in chronic lymphocytic leukaemia

Dissemination via the blood stream

to the brain occurs in ~5% of cases of

invasive aspergillosis, and

in ~40% of allogeneic bone marrow (HSCT)

recipients

Early diagnosis of invasive aspergillosis is important

Treatment started <10d >11dMortality 40% 90%

Von Eiff et al, Respiration 1995;62:241-7.

Sputum Cultures for Fungus

Bacteriological media inferior to fungal media – 32% higher yield on fungal

media

A four day A. fumigatus culture on malt extract agar (above). Light microscopy

pictures are taken at 1000x, stained with lacto-phenol cotton blue.

Aspergillus Antigen Test

• Diagnosis or surveillance? • Only blood, or BAL, CSF etc• Best OD cut-off - 0.7• False positives in kids / antibiotics• False negative with antifungal

prophylaxis• Not as useful for non-hematology• Not useful if pre-existing antibody

Herbrecht et al, J Clin Microbiol 2002;20:1898-906; and others

Use of serology, PCR, and GM to establish patient groups

• 130 patients not on azoles• Total IgE, specific IgE aspergillus, specific

IgG aspergillus, sputum galactomannan, sputum PCR

• Cluster analysis – software Mplus version 6.1

Baxter, J Allerg Clin Immunol 2013;132:560

Outcome from invasive aspergillosis – amphotericin B therapy

Survival Functions by Site of Infection

Days

3603303002702402101801501209060300

Cu

mu

lative

Su

rviv

al R

ate

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

CNS or Disseminated

Pulmonary (n=83)

Aspergilloma (n=10)

Multi-site (n=11)

Sinusitis (n=17)

(n=35)

Lin et al, Clin Infect Dis 2001;32:358

Risk groups and frequencies of invasive aspergillosis – different test performances

Herbrecht, Ann NY Acad Sci 2012;1271:23

Sub-acute invasive aspergillosis in AIDSSub-acute invasive aspergillosis in AIDS


Sub-acute invasive aspergillosisSub-acute invasive aspergillosis

• Less immunocompromised patients• Slower progression of disease (> 1 month)• Cavitary or nodular pulmonary disease typical • Vascular invasion less common• Dissemination less common• Antigen testing less useful• Antibody testing may be helpful in diagnosis


Aspergillus otitis externa

• Almost always A. niger• Acute otitis affects 1 in 250

persons annually • Chronic otitis affects 3-5%

of the population (200-350 million)

• ~10% are fungal in origin

Aspergillus onychomycosis

• Almost always toenails• 0.5-3% of all cases of

onychomycosis• 10’s to 100’s millions with

onychomycosis worldwide• ? 1 million cases

Aspergillus keratitis• Usually A. flavus or A.

fumigatus• ~50% of keratitis fungal,

and ~50% of these are due to Aspergillus.

• 1-12 million affected worldwide, especially in India, Nepal, Sri Lanka, Myanmar.

• Usually farmers and labourers, occasionally contact lens wearers

Aspergillus bronchitis• Complicates cystic fibrosis

and bronchiectasis• Recurrent infection and/or

mucus plugging• Superficial invasion of the

bronchial wall.• 8600 UK CF patients, 5000

adults.• Aspergilus bronchitis

affects ~1,500• Non-CF patients unclear

Chronic necrotizing aspergillosis(CNPA)

Chronic necrotizing pulmonary aspergillosis (CNPA) is a subacute process usually found in patients with some degree of immunosuppression.

Usually it is associated with underlying lung disease, alcoholism, or chronic corticosteroid therapy. Because it is uncommon, CNPA often remains unrecognized for weeks or months and causes a progressive cavitary pulmonary infiltrate.

Chronic necrotising pulmonary aspergillosis

Denning, Clin Microbiol Infect 2001;7(Suppl 2):25-31.

Right upper lobe. Patient has diabetes and pulmonary

mycobacterium avium- shows small cavitary lesion PT MS 1995.

Right upper lobe showing circular shadow partly filled by a mass. PT

MS 1997

Same lobe shows expansion of the shadow, still partially

filled with a mass. Pt MS 1998

Right lobe shows huge cavity containing some

debris, with +ve aspergillus precipitins.Pt

MS 2000

Aspergillus and airways

Langley, ATS 2004

Types of aspergillosis of the airways• Colonisation (no disease – could be at risk)• Obstructing Aspergillus tracheobronchitis /Mucus

impaction (non-invasive)• Aspergillus bronchitis/tracheobronchitis (superficially invasive only)• Ulcerative Aspergillus tracheobroncitis (locally

invasive) (lung transplants – at anastomosis)• Pseudomembranous Aspergillus tracheobronchitis

(Extensive disease, locally invasive, associated with IPA and may disseminate)

Aspergillus tracheobronchitis

Autopsy drawing of a ‘normal’ 3 year old who died over 10 days

Wheaton, Path Trans 1890; 41:34-37

Aspergillus bronchitis

Young et al. Medicine (Balt) 1970;49:147

Aspergillus tracheobronchitis

Review of 58 patients in literature for normal and immuno compromised patients - risk factors

%None (ie normal) 25Heart / Lung transplant 18Solid tumour 15BMT 13Leukaemia 13HIV/AIDS 8Other 8

Kemper et al, Clin Infect Dis 1993; 17: 344

Spectrum of pulmonary aspergillosis

Hope. Med Mycol 2005:43 (Suppl 1) S207

Different patterns of CPA

Radiological response varies by subtype of CPA

AspergillomaAspergilloma

Patient RTDecember 2002

Fungus ball

http://www.aspergillus.man.ac.uk/secure/image_library/agillom/brazil6.htm

Chronic pulmonary aspergillosis – pre-Chronic pulmonary aspergillosis – pre-existing diseaseexisting disease

All 18 patients had prior pulmonary disease

9 TB, 5 with atypical mycobacteria

13 smokers or ex-smokers

All 18 non-immunocompromised

3 excess alcohol

Denning DW et al, Clin Infect Dis 2003; 37:S265

Chronic pulmonary aspergillosis - Chronic pulmonary aspergillosis - presentationpresentation

Weight loss 16 / 18 (89%)Cough 15 / 18 (83%)Shortness of breath 9 / 18 (50%)Haemoptysis 9 / 18 (50%)Fatigue / malaise 5 / 18 (28%)Chest pain 3 / 18 (17%)Sputum production ++ 3 / 18 (17%)Fever 2 / 18 (11%)


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

14 of 18 (78%) had elevated total IgE (>20), 13 >200 and 7 >400

9 of 14 (67%) had Aspergillus specific IgE (RAST)


Chronic cavitary pulmonary aspergillosis Chronic cavitary pulmonary aspergillosis (CCPA)(CCPA)

Patient RWSeptember 1992 Relapse in normal lung


Patient RWDecember 1991 Pre surgical resection

Chronic cavitary pulmonary Chronic cavitary pulmonary aspergillosisaspergillosis

Patient RWJuly 1993


Chronic Cavitary Pulmonary Chronic Cavitary Pulmonary AspergillosisAspergillosis

Patient JAJan 2001


Patient JAFeb 2002


Patient JAApril 2003


Patient JAJuly 2003

Chronic cavitary pulmonary Chronic cavitary pulmonary aspergillosisaspergillosis

Patient JP June 1999


Chronic Cavitary Pulmonary Aspergillosis, Chronic Cavitary Pulmonary Aspergillosis, with aspergillomawith aspergilloma

Patient JP July 2001


Chronic Fibrosing Pulmonary Chronic Fibrosing Pulmonary AspergillosisAspergillosis

Patient JPApril 2002


Prognosis

CPA + subacute IAKorea (1995-2007)

CPA Japan (2001-9)

75% mortality

80% mortality

Nam Int J Infect Dis 2010;14:e479; Ohba et al, Resp Med 2012; 106:724

ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS – Key diagnostic criteria

• Asthma• Blood eosinophilia (>1,000 / cu

mm)• History of pulmonary infiltrates• Central bronchiectasis

Rickett et al. Arch Intern Med 1983; 143: 1553; Patterson, Chest 2000;118:7

ABPA possibleABPA possibleABPA probable

ABPA almost certain

• Precipitins against A. fumigatus positive• Aspergillus IgE antibody >2x asthma control• Aspergillus IgG antibody >2x asthma control• Total serum IgE concentration, >1000 iu/mL

If 3 tests +ve, then ABPA very likely, If all 4 +ve the diagnosis established

ABPA versus SAFS

Denning et al, Med Mycol 2013:51:361

How common is ABPA in asthma?

13/500 (2.6%)

10/1390 (0.72%)

9/255 (3.5%)

6/264 (2.3%)+ 5/200 (2.5%) China

Donnelly, Irish J Med Sci 1991;160:288; Eaton, Chest 2000;118:66; Al-Mobeireek, Resp Med 2001;98:341

ABPA


Before bronchoscopy

After bronchoscopy

ABPA mucous plugging


ABPA - CT showing central bronchiectasis


ABPA and surfactant

5 surfactant proteins in man, SPA1, SPA2, SPB, SPC and SPD – all ‘collectin’ family

Mason et al, Am J Physiol 1998;275:L1-13.

ABPA – surfactant defects

2 exonic polymorphisms, and 2 intronic polymorphisms in SP-A2 associated with ABPA

A1660G = OR of 4.78; or if combined with G1649C = OR 10.4

Also associated with higher peripheral eosinophilia

Saxena et al, J Allergy Clin Immunol 2003;111:1001-7.

Eosinophilic fungal rhinosinusitis or allergic fungal sinusitis

Patient with chronic symptoms of nasal obstruction, loss of smell and nasal polyps

Ponikau et al, Mayo Clinic Proc 1999;74:877 & www.aspergillus.org.uk

Eosinophilic fungal rhinosinusitis(link with airborne fungi - ?which most important

= Myelin basic protein, highly toxic to local epithelium

Ponikau et al, Mayo Clinic Proc 1999;74:877

A link between Aspergillus and asthma?

Fungal-associated asthma – evidence

Fungal-associated asthma

ABPA

Treatment of ABPAand pilot data

Severe asthma linked with fungal

sensitisation

Frequency of fungal sensitisation

High spore counts and asthmatic attacks

Spore counts and asthma attacks and admission to hospital

All circumstantial evidence

• Thunderstorm asthma – linked to Alternaria

• Asthma deaths (Chicago) linked to high ambient spores counts and season (summer autumn) when spore counts highest

• Asthma hospital admission linked to high ambient spore counts (Derby, New Orleans, Ottawa

• Asthma hospital attendance linked to high spore counts , but not pollen counts (Canada)

• Asthma symptoms increased on days of high spore counts (California, Pennsylvania)

O'Hollaren, N Engl J Med 1991; 324: 359; Newson, Occup Environ Med 2000; 57: 786-92.

Fungus at homeEnvironmental data

• Mouldy housing associated with worse asthma, with a correlation between asthma severity and degree of dampness in the home and separately with visible mould growth

• In Germany bronchial reactivity in children was associated with damp housing

• Mouldy and damp school associated with asthma symptoms and emergency room visits

• Highest concentration of Aspergillus fumigatus is at home

Williamson, Thorax 1997;52:229. Taskinen, Acta Paediatr 1999; 88:1373.

Severe asthma and moulds

Mild asthma – 564 (50%)

Moderate asthma – 333 (29%)

Severe asthma – 235 (21%) – linked with fungus skin test positivity

Zureik et al, Br Med J 2002;325:411

Asthma severity, house dust mites, cats and moulds

Langley, ATS 2004

Allergen No asthman= 111

Mild asthma FEV1 >75%

<90%n= 67

Moderate asthma FEV1

>60% <75%n= 42

Severe asthma FEV1

>60% n= 42

House dust mite

61% 71% 45% 77%

Cats* 49% 51% 38% 35%

Moulds# 17% 19% 36% 31%

* P = 0.05# p = 0.01

The extraordinary spectrum of diseases caused by Aspergillus David W. Denning Wythenshawe Hospital...

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