interaction of aspergillus with the host a unique microbial-host interaction immune dysfunction...

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

AspergillomaChronic pulmonary

ABPASevere asthma with fungal sensitisationAllergic sinusitis

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

Size of fungal disease problem globally

1. Invasive aspergillosis - ? 70,000 cases/year in EU, >5M at risk; new problems COPD, ICU etc - ~50% mortality

2. Candidaemia in UK – 2,000 cases, rising, many more at risk, ~40% mortality

3. Cryptococcal meningitis - ~1M worldwide annually

4. Chronic pulmonary aspergillosis after TB – 1.1M cases prevalence

5. Chronic pulmonary aspergillosis total - ~3M

6. Asthma 197M in adults, of which ~10-20% severe, UK and USA have very high prevalence rates

7. Allergic bronchopulmonary aspergillosis in asthma - ~3M worldwide (2.1% of adults with asthma)

8. Severe asthma with fungal sensitisation - ~13M worldwide (33% of 20% (severe only))

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)

Risk factors for invasive aspergillosis

Major• Neutropenia (+ monocytopenia)• Corticosteroid treatmentMinor• CD4penia• Inherited immunodeficiency (ie CGD)• Lung or sinus damage/disease• Severe liver disease• Exposure to high inocula

Examples of at-risk patients and pace of progression

Degree of immunocompromise

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Where in the hospital does invasive aspergillosis occur?

Cornillet et al, Clin Infect Dis 2006;43:577

Risk factors for invasive aspergillosis in AIDS

Stage of AIDS CDC Group II 4 (1%) CDC Group IV 289 (72%)

Neutropenia <1000 x 106/L 92/202 (46%)

Corticosteroid therapy 79/202 (39%)Prior pulmonary infection 124/169

(73%)

Khoo & Denning, Clin Infect Dis 1994; 19 (S1) 541

Lymphoma and corticosteroids

www.aspergillus.org.uk

4 days later

CT scan showing nodules with halo – lung cancer and neutropenia

Aspergillus, IPA and COPD

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

~ 22% of Aspergillus in COPD = invasive aspergillosis



Clues to the diagnosis of IA

• GOLD stage 3 or 4.

• Excess wheezing (consider tracheobronchitis)

• Worsening infiltrates in an ‘exacerbation’ (66%)

• Bilateral infiltrates (55%)

• Culture of Aspergillus

• High corticosteroid exposure recently

• Do NOT expect fever (38%), chest pain or haemoptysis

Invasive aspergillosis in COPD

Bulpa, Clin Infect Dis 2007;30:782

Invasive aspergillosis in ICU

127 of 1850 (6.9%) consecutive medical ICU admissions with IA or colonisation (micro/histol).

89/127 (70%) did not have haematological malignancy

67/89 proven/probable IA, 33 of 67 (50%) COPD

Meersemann et al, Am J Resp Med Crit Care 2004;170:621.

Radiology completely unhelpful in suspecting the diagnosis

Meersseman, Clin Infect Dis 2007;45:205

Risk factors for invasive aspergillosis in ICU

Meersseman, Clin Infect Dis 2007;45:205

Invasive aspergillosis in ICU

Vandewoude et al, Critical Care 2006;10:R31.

Aspergillus detected,

no infectionN = 89Invasive

aspergillosis + treatment

N = 73Invasive aspergillosis no treatment

N = 12

Invasive Aspergillosis in Invasive Aspergillosis in ChildrenChildren in the USA in 2000in the USA in 2000

Incidence of 437 cases per 100,000 immunocompromised children

MORTALITY RATES

Disease

Patients without Invasive Aspergillosis (151,537 children)

Patients with Invasive Aspergillosis(666 children)

Relative Risk of Death

Acute Leukemia (ALL)

1% 21% 14.9Acute Leukemia (AML) 3% 20% 5.0

Brain Tumor 2% 69% 21.6Bone Marrow Transplant 8% 44% 3.8

Zaoutis TE, et al. Pediatrics 2006;117:e711

Tait, Thorax 1993;48: 1285

Pseudomembranous Aspergillus tracheobronchitis

Wheezing 4 days before death,immunocompromised

Pseudomembranous Aspergillus tracheobronchitis

Bulpa Eur Resp J 2007;30:782

Pseudomembranous Aspergillus tracheobronchitis with IPA in

COPD


Myelodysplasia with clinical evidence of acute invasive fungal rhinosinusitis

after chemotherapy – biopsy showed hyphal invasion of bone

Pre-treatment 6 months later after initial caspofungin then voriconazole

Cultures for Aspergillus from sputum and BAL

Horvath & Dummer, Am J Med 1996;100:171

Bacteriological media inferior to fungal media –

32% higher yield on fungal media

Yield in IA from BAL and sputum ~30%Cultures take 1-10 days to grow + time to

identification

Modalities for early diagnosis of invasive aspergillosis

• CT scanning• Microscopy• Antigen (blood or respiratory fluid)• [PCR (blood or respiratory fluid)]

Pediatric Galactomannan

• Prospective study from 1995-1998 – 450 adult allogeneic HSCT patients (3883 samples)– 347 children with hematologic malignancies (2376

samples)

• GM > 1.5 in at least two sequential samplesAdult Pediatric

– Sensitivity 88.6% 100%– Specificity 97.5% 89.9%

• False-positive antigenemia

– Adult patients 2.5% (10/406) – Pediatric patients 10.1% (34/338)

Sulahian Cancer 2001;91:311.

Pediatric GM in Oncology Patients

• St. Jude & NCI– 56 pediatric oncology patients – 39 pts without IA; 17 pts with proven/probable IA– Most done retrospectively (frozen samples)

• At least one GM positive in 11/17 patients with IA (sensitivity 65.7%)

• False-positive rate 1% (all ≤ 0.8) (per sample)• At least one false-positive in 12.8% patients• Piperacillin-tazobactam was not used in any

patients in this study

• No association with accuracy and patient age

Hayden R Pediatr Infect Dis J 2008;27:815

Unequivocal ‘Halo sign’ surrounding a nodule

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

Small vessel angioinvasion

Halo

IPA


Pulmonary nodules a useful feature if invasive pulmonary aspergillosis

CT features in 48 CTs of which 17 IPA

IPA OtherHalo 13/17 0/31Nodules 14/1711/31Masses 6/17 2/31

Kami, Mycoses 2002;45:287-94.

Microscopy

Ruchel R, www.aspergillus.org.uk/images

Fluorescent brighteners such as Calcufluor white,

Blankophor increase sensitivity and speed

Cultures for Aspergillus from sputum and BAL

Horvath & Dummer, Am J Med 1996;100:171-8.

Bacteriological media inferior to fungal media –

32% higher yield on fungal media

Yield in IA from BAL and sputum ~30%

• 13/17 (76%) in acute leukaemia with CT abnormality

• 20/20 (100%) in haem-onc pts with IPA

• 37/49 (76%) in HSCT & haem-onc with IPA

• 6 of 11 (55%) immunocompromised (8 of 11 +ve by PCR)

• 5/20 (25%) in suspected IFIs

Becker, Br J Haem 2003;121:448; Sanguinetti, JCM 2003;41:3922; Musher, JCM 2004;42:5517.

Aspergillus Antigen in BAL

• 17/17 (100%) in neutropenic patients before antifungal Rx, 0% after 3d antifungal therapy

Diagnosis of IPA in leukaemia using blood PCR

Barnes et al, J Clin Pathol 2009;62:64

130 haematology patientsItraconazole prophylaxis for AML and HSCTFluconazole prophylaxis for others (ALL,

lymphoma etc)EORTC/MSG criteria applied2x weekly sampling

Diagnosis of IPA in leukaemia using blood PCR and Aspergillus antigen (EIA)

Barnes et al, J Clin Pathol 2009;62:64

Chronic pulmonary aspergillosis

Single fungal ball or

aspergillomain a pre-

existing cavity

Infection of the lung by Aspergillus

Simple (single) aspergilloma

Patient RK

Haempotysis, nil else

Positive Aspergillus antibodies in blood

Lobectomy

Wythenshawe Hospital

Simple (single) aspergilloma

Patient NM

Positive Aspergillus antibodies in blood

Lobectomy


August 2006 May 2009

Community acquired New cough pneumonia requiring ICU care


Single fungal ball or

aspergillomain a pre-

existing cavity

Infection of the lung by Aspergillus

Invasive aspergillosis /community

acquired infection

Chronic cavitary

pulmonary aspergillosis+/- fungal

ball

Chronic fibrosing

pulmonary aspergillosis+/- fungal

ball

‘Multicavity’ disease is the hallmark of chronic cavitary pulmonary aspergillosis

(CCPA)


+ Aspergillus IgG antibodies (precipitins)

+ symptoms

Chronic cavitary pulmonary aspergillosis (CCPA) – sputum production


Aspergillus cultures positive in CCPA in 10-40% of cases only

Chronic cavitary pulmonary aspergillosis (CCPA) – coughing up blood (haemoptysis)


Underlying diseases in patients with CPA (%)

Smith, Eur Resp J 2010 In press

Classical tuberculosis

Atypical tuberculosis ABPACOPD/emphysema

PneumothoraxLung cancer survivor PneumoniaSarcoidosis (stage II/III)Thoracic surgeryRheumatoid arthritis

Asthma / SAFSAnkylosing spondylitis

None

Frequency of chronic pulmonary aspergillosis after TB

Anonymous. Tubercle 1970;51:227; Sonnenberg et al, Lancet 2001;358:1687

25-33% of patients with TB are left with a cavity

~10% of all cases of pulmonary TB get CPA

Global CPA cases per region related to TB5 year prevalence estimates

Denning, Pleuvry & Cole, Bull WHO 2011 in press



Chronic cavitary pulmonary

aspergillosis complicating ABPA

Chronic cavitary pulmonary aspergillosis

with bilateral aspergillomas

complicating sarcoidosis

ABPA and development of CPA


19811985

199319952002

Bronchoscopy in an ABPA patient

on no treatment

UHSM, unpublished

Bronchoscopy in an ABPA patient

on no treatment

UHSM, unpublished

BAL

Abundant mixed inflammatory cells with ciliated columnar cells

and a few fungal hyphae, in keeping with

Aspergillus. A few Charcot leyden crystals. No

maligant cells.

Routine versus high volume culture versus real time PCR for Aspergillus

Fraczek, ECCMID Abstract submitted

Sample n

Aspergillus positive samples (%)

Aspergillus culture MycAssay Aspergillus real

time PCRRoutineHigh volume

Pre-bronch sputum 4 0 4 (100) 4 (100)

Post-bronch sputum 4 0 1 (25) 4 (100)

First trap aspiration 3 0 2 (67) 3 (100)

First BAL (10-20mL) 5 0 0 4 (80)

Second BAL (10-50mL

5 0 0 4 (80)

Molecular detection of Aspergillus spp.

in sputum

Denning et al. Clin Infect Dis 2011;

Laboratory result ABPA CPA Normals

Culture positive for A. fumigatus

0/197/42

(16.7%)0/11

qPCR positive for Aspergillus spp

15/19 (78.9%)

30/42 (71.4%)

4/11 (36.4%)

Colonisation in ‘normal’ lungs

Lass-Florl et al, Br J Haematol 1999;104:745

22 of 30 (73%) grew a fungus in both lung

samples taken

10/30 (33%) grew >1 species

Antifungal therapy

IDSA guidelines. Walsh et al. Clin Infect Dis 2008;46:327

Time to initial response with posaconazole therapy

6 months 12 months

Mean

95% confidence interval

Felton et al. Clin Infect Dis 2010. In press.

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