1. Chronic Pulmonary Aspergillosis
Dr. Iain Page

2. Intended Learning Outcomes
To recognise and diagnose cases of chronic pulmonary aspergillosis (CPA)
To be aware of the global burden of CPA
To be able to identify individuals at risk for CPA

3. Chronic pulmonary Aspergillosis
Chronic pulmonary aspergillosis (CPA) is a chronic progressive and destructive parenchymal lung infection in non-immunocompromised or subtly immunocompromised patients
Occurs almost exclusively (90%) in patients with current or previous underlying lung disease or immune deficit
Radiological presentation with formation of new cavities or expansion of the existing ones +/- fungal ball or nodule
Prominent respiratory and systemic symptoms occurring over months (>3 months)
Denning et al. Clin Infect Dis. 2003; 37(s3), pp.S265-S280.
Schweer et al Mycoses, :257–270

4. Clinical presentation
Respiratory
Constitutional
Productive cough
Breathlessness
Chest pain
Haemoptysis
Weight loss
Malaise
Poor appetite
Sweats
Swinging fevers (+/-)
None of these symptoms are pathognomonic for CPA
Jhun et al. Med. Mycol. 2013, 51, 811–817.
Patterson et al . Chest 2014, 146, 1358–1368

5. Radiological Phenotypes of CPA
CPA includes several disease manifestations, including (i) Aspergillus nodules , (ii) simple (surgical) aspergilloma, (iii) chronic cavitary pulmonary aspergillosis, and (iv) chronic fibrosing pulmonary aspergillosis
Aspergillus Nodule
Simple Aspergilloma
Chronic Cavitary Pulmonary Aspergillosis
Chronic Fibrosing Pulmonary Aspergillosis

6. Risk factors for CPA Condition Frequency Tuberculosis 17-80%
COPD±Emphysema
30-50%
Non-tuberculous mycobacterial infection
<20%
Pneumothorax or bullous lung disease
9-20%
Allergic bronchopulmonary aspergillosis
12-18%
Pulmonary fibrocystic sarcoidosis
9-17%
Lung irradiation
~5%
Rheumatoid arthritis
2-4%
Ankylosing spondylitis
<5%
None
2-10%
Smith et al Eur Resp J 2011;37: 865
Denning & Chakrabarti Lancet infect dis S (17)

7. ~3 million CPA cases globally; 1.2 million cases following TB
/100,000
1.38/100,000
31/100,000
15.9/100,000
22.4/100,000
78/100,000
24/100,000
6.2/100,000
Denning et al Bull WHO 2011; 89:864-72

8. CPA complicates 3-12% of sarcoidosis
37%
24%
~72,000 CPA cases complicating sarcoidosis globally
Denning et al . Eur Respir J Mar;41(3):621-6.

9. Innate and adaptive immune defects in CPA
Innate immune defects
CD56: 43%
Adaptive immune defects
CD19: 43%
CD8: 32%
CD4: 17%
Bongomin et al. J. Fungi 2017, 3, 26

10. CPA is a spectrum of disease entities that have considerable overlap and variation in severity
Single/simple
aspergilloma
Subacute Invasive aspergillosis (SAIA) or chronic necrotizing pulmonary aspergillosis (CNPA)
Aspergillus
nodule(s)
Chronic cavitary pulmonary
aspergillosis (CCPA)
A duration of disease longer than three months distinguishes CPA from acute and subacute invasive pulmonary aspergillosis
Chronic fibrosing
pulmonary aspergillosis (CFPA)
Denning et al. Eur Respir J 2016;47:45-68

11. A single (simple) aspergilloma
Single (simple) pulmonary aspergilloma is a single fungal ball in a single pulmonary cavity
Serological or microbiological evidence implicating Aspergillus spp
No radiological progression over months of observation
Very few, if any persistent pulmonary or systemic symptoms
Can be complicated by sudden, potentially fatal haemoptysis
Kosmidis and Denning. Thorax. 2015; 70:
Denning et al. Eur Respir J 2016;47:45-68

12. Chronic cavitary pulmonary aspergillosis
Formation or expansion of existing cavities (usually multiple) is characteristic
Cavities may or may not contain an aspergilloma (fungal ball)
Aspergilloma may or may not disappear
Associated with high mortality (50-85% at 5 years)
Causes of death include severe haemoptysis and respiratory failure
Most cases are likely to be associated with an underlying defect in innate immunity
Remove some details
Kosmidis and Denning. Thorax. 2015; 70:
Denning et al. Eur Respir J 2016;47:45-68

13. Chronic fibrosing pulmonary aspergillosis
Extensive fibrosis with fibrotic destruction of at least two lobes of lung complicating CCPA
Associated with major loss of lung function
CFPA can represent an end result of untreated CCPA
One or more aspergillomas may be present
Serological or microbiological evidence implicating Aspergillus spp. is required for diagnosis
Kosmidis et al. Infect Dis (Lond). 2017;49 (4):

14. Sub-acute invasive pulmonary aspergillosis (chronic necrotising pulmonary aspergillosis)
Tissue biopsy demonstrates hyphal invasion of lung parenchyma
Detectable Aspergillus antigen in blood and respiratory samples
Detectable Aspergillus antibody in blood
More rapid development of symptoms (i.e., weeks as opposed to months)
Radiological pattern of nodules, consolidation with or without a solitary cavity with thin walls
Clinical and radiological features are similar to CCPA but is more rapid in progression
The computed tomography scan shows a dual cavity with moderately thick walls, an external irregular edge and some material within the cavity on an almost normal lung background. L: left side; R: right side.
Denning et al. Eur Respir J 2016;47:45-68

15. Sub-acute invasive pulmonary aspergillosis (chronic necrotising pulmonary aspergillosis)
SAIA occurs in mildly immunocompromised or very debilitated patients
Risk factors includes:
Diabetes mellitus
Malnutrition
Alcoholism
Advanced age
Prolonged corticosteroid administration or other modest immunocompromising agents,
Chronic obstructive lung disease,
Connective tissue disorders
Radiation therapy
Non-tuberculous mycobacterial (NTM) infection or
HIV infection
The computed tomography scan shows a dual cavity with moderately thick walls, an external irregular edge and some material within the cavity on an almost normal lung background. L: left side; R: right side.
Denning et al. Eur Respir J 2016;47:45-68

16. Aspergillus nodules Aspergillus nodules occur in immunocompetent hosts
May be single or multiple, with or without cavitation
Patients are usually asymptomatic or have minor pulmonary symptoms
Aspergillus IgG titre may be raised
Natural history is poorly described, but progression to
CCPA can occur
Muldoon et al. BMC Pulm Med. 2016; 18;16(1):123.

17. The clinical spectrum of pulmonary aspergillosis
Pathological features and characteristics of various forms of pulmonary aspergillosis. CGD, chronic granulomatous disease; CPA, chronic pulmonary aspergillosis; GVHD, graft versus host disease; HSCT, haematopoietic stem cell transplant; IPA: invasive pulmonary aspergillosis.
Kosmidis and Denning. Thorax. 2015; 70:

18. Diagnostic criteria Criteria ESCMID/ERS/ECMM IDSA 1
One or more cavities with or without a fungal ball
present or nodules
on thoracic imaging
All present
for ≥3
month
Three month of chronic pulmonary symptoms or chronic illness or progressive radiographic abnormalities, with cavitation, pleural
thickening, pericavitary infiltrates, and sometimes a fungus ball 2
Direct evidence of Aspergillus infection or an immunological
response to Aspergillus spp.
Aspergillus IgG antibody
elevated or other microbiological data 3
Exclusion of
alternative diagnosis
No or minimal immunocompromise,
usually with
one or more underlying
pulmonary disorders
Denning et al. Eur Respir J. 2016;47:45–68.
Patterson et al. Clin Infect Dis. 2016;63:e1–e60..

19. Functional antibody testing
Laboratory diagnosis
Immunology
/Serology
Mycological
(Sputum)
Aspergillus PCR
Culture + Sensitivity
Microscopy
Immune biomarkers
Functional antibody testing
Aspergillus IgG
Precipitins

20. Laboratory diagnosis Aspergillus specific IgG Aspergillus precipitin
“Gold standard” for CPA diagnosis
Positive in ~95% of the cases
Positive predictive value ~100%
Used in combination with other tests to confirm diagnosis of CPA
Used for monitoring treatment response
Aspergillus precipitin
Low sensitivity
Qualitative
Culture of Aspergillus
~50% positivity
Cannot distinguish contamination, colonisation or infection
High volume fungal culture more sensitive
Useful in monitoring for resistance
Galactomannan
Unclear utility in the diagnosis of CPA
Aspergillus PCR
Higher sensitivity than conventional culture
No much data in CPA patients
Useful in identification of antifungal resistance
Signal strength correlates with treatment success or failure
Page et al. Med. Mycol. 2015, 53, 417–439.
Fayemiwo et al. J Microbiol Methods. 2017;140:32-39
Hope et al. Med. Mycol. 2005, 43, S207–S238.

21. Summary
CPA occurs in patients with underlying lung diseases such as previous tuberculosis, atypical mycobacteria, COPD, sarcoidosis or lung cancer
The clinical presentation and radiological features OF CPA overlap substantially with the underlying diseases themselves
Aspergilloma are only present in a minority of CPA cases
Aspergillus-specific IgG measurement is therefore key to diagnosis
The predicted global prevalence is around 3 million cases, mostly secondary to tuberculosis
At present most of these cases go undiagnosed

22. END