Interaction of Aspergillus with the host
Acute IA
Subacute IA
ABPA
Severe asthma with
fungal sensitisation
Allergic sinusitis
Aspergilloma
Chronic pulmonary
Immune dysfunction
Frequency of aspergillosis
Frequency of aspergillosis
A unique microbial-host interaction
Immune hyperactivity
.
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
Airways/nasal
exposure to
airborne
Aspergillus
Persistence
without disease
- colonisation of
the airways or
nose/sinuses
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 treatment
Minor
• CD4penia
• Inherited immunodeficiency (ie CGD)
• Lung or sinus damage/disease
• Severe liver disease
• Exposure to high inocula
Risk of acquisition (and pace of progression)
Examples of at-risk patients and pace of progression
25%
20%
15%
10%
5%
Degree of immunocompromise
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
CDC Group IV
Neutropenia <1000 x 106/L
Corticosteroid therapy
Prior pulmonary infection
4 (1%)
289 (72%)
92/202 (46%)
79/202 (39%)
124/169 (73%)
Khoo & Denning, Clin Infect Dis 1994; 19 (S1) 541
Lymphoma and corticosteroids
4 days later
www.aspergillus.org.uk
CT scan showing nodules with halo – lung cancer and
neutropenia
Aspergillus, IPA and COPD
~ 22% of
Aspergillus in
COPD = invasive
aspergillosis
Guinea et al, Clin Microbiol Infect 2010;16:870
Aspergillus, IPA and COPD
Guinea et al, Clin Microbiol Infect 2010;16:870
Aspergillus, IPA and COPD
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
Guinea et al, Clin Microbiol Infect 2010;16:870
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
Aspergillus detected,
no infection
N = 89
Invasive aspergillosis
+ treatment
N = 73
Invasive aspergillosis
no treatment
N = 12
Vandewoude et al, Critical Care 2006;10:R31.
Invasive Aspergillosis in
Children in the USA in 2000
Incidence of 437 cases per 100,000 immunocompromised children
MORTALITY RATES
Disease
Acute Leukemia
(ALL)
Patients with
Patients without
Invasive Aspergillosis Invasive Aspergillosis Relative Risk
(151,537 children)
(666 children)
of Death
1%
21%
14.9
Acute Leukemia
(AML)
3%
20%
5.0
Brain Tumor
2%
69%
21.6
Bone Marrow
Transplant
8%
44%
3.8
Zaoutis TE, et al. Pediatrics 2006;117:e711
Pseudomembranous Aspergillus
tracheobronchitis
Wheezing 4 days before death,
immunocompromised
Tait, Thorax 1993;48: 1285
Pseudomembranous Aspergillus
tracheobronchitis
Pseudomembranous Aspergillus
tracheobronchitis with IPA in COPD
Bulpa Eur Resp J 2007;30:782
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
www.aspergillus.org.uk
Cultures for Aspergillus from sputum
and BAL
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
Horvath & Dummer, Am J Med 1996;100:171
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
•
GM > 1.5 in at least two sequential samples
Adult
Pediatric
– Sensitivity
88.6%
100%
– Specificity
97.5%
89.9%
– 450 adult allogeneic HSCT patients (3883 samples)
– 347 children with hematologic malignancies (2376 samples)
• 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
Halo
Small vessel
angioinvasion
Herbrecht, Denning et al, NEJM 2002;347:408-15.
IPA
www.aspergillus.org.uk
Pulmonary nodules a useful feature if
invasive pulmonary aspergillosis
CT features in 48 CTs of which 17 IPA
Halo
Nodules
Masses
IPA
13/17
14/17
6/17
Other
0/31
11/31
2/31
Kami, Mycoses 2002;45:287-94.
Microscopy
Fluorescent brighteners
such as Calcufluor white,
Blankophor increase
sensitivity and speed
Ruchel R, www.aspergillus.org.uk/images
Cultures for Aspergillus from sputum
and BAL
Yield in IA from BAL and sputum ~30%
Bacteriological
media inferior to
fungal media – 32%
higher yield on
fungal media
Horvath & Dummer, Am J Med 1996;100:171-8.
Aspergillus Antigen in BAL
• 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
• 17/17 (100%) in neutropenic patients before antifungal Rx,
0% after 3d antifungal therapy
Becker, Br J Haem 2003;121:448; Sanguinetti, JCM 2003;41:3922; Musher, JCM 2004;42:5517.
Diagnosis of IPA in leukaemia using blood
PCR
130 haematology patients
Itraconazole prophylaxis for AML and HSCT
Fluconazole prophylaxis for others (ALL, lymphoma
etc)
EORTC/MSG criteria applied
2x weekly sampling
Barnes et al, J Clin Pathol 2009;62:64
Diagnosis of IPA in leukaemia using blood
PCR and Aspergillus antigen (EIA)
Barnes et al, J Clin Pathol 2009;62:64
Chronic pulmonary aspergillosis
Infection of the lung by Aspergillus
Single fungal
ball or
aspergilloma
in a preexisting cavity
Simple (single) aspergilloma
Patient RK
Haempotysis,
nil else
Positive
Aspergillus
antibodies in
blood
Lobectomy
Wythenshawe Hospital
Simple (single) aspergilloma
Patient NM
August 2006
May 2009
Community acquired
pneumonia requiring
ICU care
New cough
Positive Aspergillus
antibodies in blood
Lobectomy
Wythenshawe Hospital
Chronic pulmonary aspergillosis
Infection of the lung by Aspergillus
Single fungal
ball or
aspergilloma
in a preexisting cavity
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
Wythenshawe Hospital
Chronic cavitary pulmonary aspergillosis (CCPA) –
sputum production
Aspergillus cultures positive in
CCPA in 10-40% of cases only
Wythenshawe Hospital
Chronic cavitary pulmonary aspergillosis (CCPA) –
coughing up blood (haemoptysis)
Wythenshawe Hospital
Underlying diseases in patients with CPA (%)
Classical tuberculosis
Atypical tuberculosis
ABPA
COPD/emphysema
Pneumothorax
Lung cancer survivor
Pneumonia
Sarcoidosis (stage II/III)
Thoracic surgery
Rheumatoid arthritis
Asthma / SAFS
Ankylosing spondylitis
None
Smith, Eur Resp J 2010 In press
Frequency of chronic pulmonary aspergillosis after TB
25-33% of patients with TB are left with a cavity
~10% of all cases of pulmonary TB get CPA
Anonymous. Tubercle 1970;51:227; Sonnenberg et al, Lancet 2001;358:1687
Global CPA cases per region related to TB
5 year prevalence estimates
Denning, Pleuvry & Cole, Bull WHO 2011 in press
Chronic pulmonary aspergillosis
Chronic cavitary
pulmonary
aspergillosis
complicating ABPA
Chronic cavitary pulmonary
aspergillosis with bilateral
aspergillomas complicating
sarcoidosis
www.aspergillus.org.uk
ABPA and development of CPA
1985
1981
2002
1995
1993
www.aspergillus.org.uk
Bronchoscopy in
an ABPA patient
on no treatment
UHSM, unpublished
Bronchoscopy in
an ABPA patient
on no treatment
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.
UHSM, unpublished
Routine versus high volume culture versus real
time PCR for Aspergillus
Aspergillus positive samples (%)
Aspergillus culture
MycAssay
Aspergillus real time
Routine High volume
PCR
Sample
n
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)
Fraczek, ECCMID Abstract submitted
Molecular detection of Aspergillus spp.
in sputum
Laboratory result
Culture positive for A. fumigatus
qPCR positive for Aspergillus spp
ABPA
CPA
Normals
0/19
7/42
(16.7%)
0/11
15/19
(78.9%)
30/42
(71.4%)
4/11
(36.4%)
Denning et al. Clin Infect Dis 2011;
Colonisation in ‘normal’ lungs
22 of 30 (73%) grew a fungus
in both lung samples taken
10/30 (33%) grew >1 species
Lass-Florl et al, Br J Haematol 1999;104:745
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.
www.aspergillus.org.uk