CHRONIC PULMONARY ASPERGILLOSIS

1
Chronic Pulmonary Aspregillosis (CPA)

• George Dimopoulos MD, PhD, FCCP, FCCM
• Prof Critical Care Medicine
• Critical Care Department,
• University Hospital ATTIKON at Haidari,
  Athens-Greece
• Medical School, National and Kapodistrian
  University of Athens, Greece
• gdimop_at_med.uoa.gr

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Chronic Pulmonary Aspergillosis (CPA)History

• 1842 Edinburgh, UK
• 1st report of CPA as a fatal condition
• 1938 France
• radiological description of aspergilloma
  described as a
• mega-mycetome intra-bronchiectasique
• 1957 London, UK
• 1st CPA complicating tuberculosis (TB) treated
  with amphotericin
• 1960s London, UK
• Aspergillus antibody has been discovered
• Early 1980s
• term semi-invasive pulmonary aspergillosis/CPA
• 2003
• Criteria for the diagnosis and categorisation of
  patients

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Chronic Pulmonary Aspergillosis (CPA) Risk
factors for CPA development

• The predominant risk factors
• Tuberculosis
• Non Tuberculous Mycobacterium infection
• Allergic Bronchopulmonary Aspergillosis (ABPA)
• COPD
• Prior pneumothorax
• Treated lung cancer
• Less common risk factors
• Fibrocystic sarcoidosis
• Ankylosing spondylitis
• Pneumoconiosis
• Progressive massive fibrosis in silicosis

Smith NL et al Eur Respir J 2011 37 865872,
Kato T, et al. Chest 2002 121 118127, Parakh
UK et al Indian J Chest Dis Allied Sci 2005 47
199203, Lachkar S
et al. Rev Mal Respir 2007 24 943953, Bal A
et al Mycoses 2008 51 35735
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Chronic Pulmonary Aspergillosis (CPA) Clinical
phenotypes of CPA
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Chronic Pulmonary Aspergillosis (CPA) Definitions
Aspergilloma

1. Single pulmonary cavity containing a fungal ball
2. Serological/microbiological evidence implicating
   Aspergillus spp. in a non-immunocompromised
   patient with minor or no symptoms
3. No radiological progression over at least 3
   months of observation.

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Chronic Pulmonary Aspergillosis (CPA) Definitions
SAIA

• Invasive aspergillosis- mildly immuno-compromised
  patients, occurring over 13 months
• Variable radiological features including
  cavitation, nodules, progressive consolidation
  with abscess formation.
• Biopsy- hyphae in invading lung tissue,
  Aspergillus GM antigen in blood (or respiratory
  fluids).

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Chronic Pulmonary Aspergillosis (CPA) Definitions
CCPA

1. One or more pulmonary cavities possibly
   containing one or more aspergillomas or irregular
   intraluminal material
2. Serological / microbiological evidence
   implicating Aspergillus spp.
3. Significant pulmonary and/or systemic symptoms
4. Radiological progression (new cavities,
   increasing pericavitary infiltrates or increasing
   fibrosis) over at least 3 months of observation.

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Chronic Pulmonary Aspergillosis (CPA) Definitions
CFPA

1. Severe fibrotic destruction of at least two lobes
   of lung complicating CCPA leading
   to a major loss of lung function
2. Usually the fibrosis is manifest as
   consolidation, but large cavities with
   surrounding fibrosis may be seen.

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Chronic Pulmonary Aspergillosis (CPA) Definitions
Aspergillus nodules

1. One or more nodules which may or may
   not cavitate
2. They may mimic tuberculoma, carcinoma
   of the lung, coccidioidomycosis etc
3. Definitively diagnosed on histology.
4. Tissue invasion is not demonstrated,
   although necrosis is frequent.

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Chronic Pulmonary Aspergillosis (CPA) CPA-
Diagnosis

• Diagnosis of CPA combination of characteristics
• a consistent appearance in thoracic imaging (CT)
• direct evidence of Aspergillus infection or
  an
  immunological response to Aspergillus spp
• exclusion of alternative diagnoses
• The findings must be present for at least 3
  months
• Patients are usually not immunocompromised

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Chronic Pulmonary Aspergillosis
(CPA) CPA-Differential Diagnosis

• Tuberculosis
  
• the diagnosis does not excude CPA
• Depending on geographical loacation
• pulmonary histoplasmosis,
  paracoccidioidomycosis
  
• and coccidioidomycosis
• Conventional bacteria
  
  Str. pneumoniae, Haemophilus influenzae,
  Staphylococcus aureus,
  Pseudomonas aeruginosa, anaerobic
  bacteria

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Chronic Pulmonary Aspergillosis (CPA) CPA- Key
tests

• Respiratory samples for patients with cavitary or
  nodular pulmonary infiltrate in
  non-immunocompromised patients
• Direct microscopy for hyphae
• Fungal culture (sputum or BAL)
• Histology
• Fungal cultures (transthoracic aspiration)
• Aspergillus PCR (respiratory secretion)
• Bacterial cultures (sputum or BAL)

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Chronic Pulmonary Aspergillosis (CPA) CPA-
Microscopy, culture and PCR

• Aspergillus spp
• in sputum not diagnostic
• in BAL consistent with infection, including CPA
  
• Microscopy
• sputum or bronchoscopy specimens often reveals
  fungi, but
  has not been systematically studied
• Culture-positive rates 5681
• Respiratory samples cultured on media specific
  for fungi have a higher yield than bacterial
  culture plates
• Positive cultures during antifungal therapy are
  consistent with azole resistance
• Molecular detection methods, such as PCR, are
  more sensitive than
  culture

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Chronic Pulmonary Aspergillosis (CPA) CPA-
Antigens / Galactomannan (GM)
Study Parameters Sensitivity Specificity
Izumikawa K et al Med Mycol 2012 50 811817. BAL (cut-off level of 0.4) Serum (cut-off level of 0.7 ) 77.2 66.7 77.0 63.5
Kono Y, et al Respir Med 2013 1071094-1100 BAL (cut-off level gt0.5) 85.7 76.3
Shin B et al J Infect 2014 68 494499. . Serum 23
BAL and not serum GM should be used in diagnosis
of CPA
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Chronic Pulmonary Aspergillosis (CPA) CPA-
Galactomannan / better in BAL than in blood
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Chronic Pulmonary Aspergillosis (CPA) CPA-
Antibodies

• All patients suspected of having CPA should be
  tested for A. fumigatus IgG
  antibody or precipitins
• False negative results do occur
• If the clinical suspicion is high
• Aspergillus fumigatus IgE test especially in
  asthmatic and cystic fibrosis patients and an
  alternative IgG test should be performed, with
  consideration given to other means of achieving
  the diagnosis (sputum culture and PCR,
  Aspergillus antigen, percutaneous
  biopsy/aspiration etc.)
• Antibody titres slowly fall with successful
  therapy but rarely become undetectable
• A sharply rising antibody titre sign of
  therapeutic failure or relapse
• Cross-reactivity with other fungi, such as
  Histoplasma or Coccidioides spp. may affect some
  tests

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Chronic Pulmonary Aspergillosis (CPA) CPA-
Histology

• Findings after biopsy or resection of lesions
• Definitive distinction between (SAIA) subacute
  invasive aspergillosis and CCPA and better
  definition of the tissue
  response to Aspergillus infection
• Chronic inflammatory reaction
• Septate hyphae may be found in a resected
  cavity, sometimes
  filling and obliterating it with
• Granuloma
• Fibrosis surrounding or mixed with
  inflammatory infiltrate
• SAIA
• Hyphae in lung parenchyma with acute
  inflammatory or necrotic tissue response

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Chronic Pulmonary Aspergillosis (CPA) CPA-
Radiological diagnosis

• CxR
• the first imaging modality for the suspicion and
  diagnosis of CPA
• CT of the thorax
• provides better definition and location of
  imaging abnormalities
  as well as their distribution and extent
• CT- angiography
• is required at least for the baseline CT scan
  prior to therapy
• is useful to evaluate new haemoptysis, and in
  failure treatment
• use of average intensity projection
  post-processing of a CT could create slabs of
  variable thickness akin to a chest radiograph
  appearance
• Positron emission tomography (PET)
• doesnt appear to be useful

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Chronic Pulmonary Aspergillosis (CPA) CPA-
Imaging findings

• Combination of the findings
• related to underlying lung disorders
• and changes secondary to Aspergillus infection
  itself reflecting
  the chronic inflammatory and immune response
  to Aspergillus spp
• CPA most commonly develops in..
• a pre-existent bronchopulmonary or less usually
  pleural cavity
• but also
• directly causes the formation and expansion of
  new cavities or
  nodule and rarely alveolar consolidation
• Changes secondary to the Aspergillus infection
  itself range from
• the appearance of a fungus ball within a lung
  cavity
  (single or simple aspergilloma)
• to complex pleuroparenchymal features related to
  a progressive destructive cavitary disease

Godet C et al. Chronic pulmonary aspergillosis
an update on diagnosis and treatment. Respiration
2014 88 162174
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Chronic Pulmonary Aspergillosis (CPA) CPA-
Imaging findings / distinctive hallmarks

• New and/or expanding cavities
• variable wall thickness in the setting of chronic
  lung disease
• with or without intracavitary fungal ball
  formation
• with pleural thickening and
• marked parenchymal destruction and/ or fibrosis
• Aspergillus empyema may be seen
• Enlargement of bronchial or non-bronchial
  systemic arteries
• Pseudo-aneurysms leading to sometimes fatal
  haemoptysis

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Chronic Pulmonary Aspergillosis (CPA) CPA-
Imaging findings / Aspergilloma

• Prior to Aspergilloma formation
• fungal growth on the interior surface of the
  cavity
• a distinctive appearance of a bumpy or irregular
  interior cavity
• An aspergilloma typically starts as
• a surface infection following colonisation in a
  lung cavity
  or a bronchiectasis
• an upper-lobe, solid, round or oval intracavitary
  mass, partially
  surrounded by a crescent of air, the
  air-crescent sign, mobile
  on prone position
• a fixed and immobile, irregular sponge-work
  filling the cavity
  and containing air spaces
• Calcification may be seen
• Fungus balls do not enhance after IV injection of
  contrast media
• Adjacent pleural thickening is often observed
• Aspergilloma may coexist with any underlying
  condition
• There are some mimics of aspergilloma including
  necrotic lung carcinoma

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Chronic Pulmonary Aspergillosis (CPA) CPA-
Imaging findings/ Aspergilloma
Cavity with irregular edge and aspergilloma
Apical pleural thickening bordering
the cavity Axial view with lung window at
the level of the left upper
lobe

• Aspergilloma in CCPA
• air-crescent sign
• a thick-walled and slightly
  irregular cavity.

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Chronic Pulmonary Aspergillosis (CPA) CPA-
Imaging findings / Multiple aspergillomas

• Female 34 years old, medical history of TB
• Anti-TB treatment for 12 months (1996)
• Recurrent heamoptysis (since 2000)
• Respiratory fuctioning tests mild obstruction
• Rx PO itraconazole for 3 months

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Chronic Pulmonary Aspergillosis (CPA) CPA-
Imaging findings / CCPA

• Typical appearances of CCPA
• unilateral or bilateral areas of consolidation
• multiple expanding usually thick-walled cavities
  that may contain
  one or more aspergillomas
• concomitant pleural thickening of variable extent
• Thickened pleura
• frequently associated with abnormally dense extra
  pleural fat
• may not be differentiated in some cases from the
  neighbouring alveolar consolidation or the wall
  of the cavities.
• Asymmetric findings
• predominantly located in the areas with
  pre-existing anomalies
  related to the underlying pulmonary
  disease
• Radiological evolution
• slower and may take several years
• Differential diagnosis
• TB, NTM, histoplasmosis, actinomycosis,
  coccidioidomycosis and
  lung carcinoma

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Chronic Pulmonary Aspergillosis (CPA) CPA-
Imaging findings / CCPA
CCPA a) 2007 and b) 2012. Left in both
images A large cavity with pleural thickening
with additional small cavities and contraction of
the left upper lobe. Right side Interval
development of a large cavity, with some pleural
thickening. Neither cavity contains a fungal ball

• CCPA (axial view) at the level of RUL
• Multiple cavities
• Fungus ball lying within the largest one.
• The wall of the cavities cannot be distinguished
  from the thickened
  pleura or the neighbouring
  alveolar consolidation
• The extra pleural fat is hyperattenuated (white
  arrows).

Lung window
Mediastinal window
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A COPD patient with history of TBC and steroids
treatment. Antibiotic treatment for infectious
exacerbation. Bronchial secretions and Ag GM
Aspergillus ()
Treatment with Voriconazole Duration of therapy
6 months Final diagnosis CCPA
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Chronic Pulmonary Aspergillosis (CPA) CPA-
Imaging findings / CFPA

• CFPA terminal evolution of CCPA
• When CCPA remains untreated
• Resulting in extensive pulmonary fibrosis
• The fibrosis may be limited to one or both upper
  lobes but also commonly involves the whole
  hemithorax
• There is no distinctive feature of fibrosis
  related to CPA, other than the cavitation and
  fungal balls seen in close proximity

CFPA with atelectasis and fibrosis of the whole
left lung, secondary to untreated CCPA. The
cavity contains strands of Aspergillus.
Denning DW et al Clin Infect Dis 2003 37 Suppl.
3, S265S280.
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Chronic Pulmonary Aspergillosis (CPA) CPA-
Imaging findings / Aspergillus nodules
Very similar in appearance to malignancy,
coccidioidal nodules, NTM and actinomycosis as
well as rheumatoid nodules Rounded in
appearance with low attenuation or cavitation
within. Single or multiple and have an area of
central cavitation.
Nodule of the right, upper lobe, with irregular
and slightly spiculated borders
Aspergillus nodules, of variable size and
borders, and a fungus ball filling a cavity with
a wall of variable thickness in a patient with
pre-existing bronchiectasis and cicatricial
atelectasis of the middle lobe.
Yoon SH et al Acta Radiol 2011 52 756761, Lim
J et al. Int J Tuberc Lung Dis 2010 14
16351640, Baik JJ et al. Respirology 1999 4
3135
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Chronic Pulmonary Aspergillosis (CPA) CPA-
Imaging findings / SAIA
Absence of any prior cavitary lesion is usual
Usually a single area of consolidation is found
in an upper lobe which progresses over days or
weeks with cavitation Sometimes the
predominant feature is a thin walled cavity that
expands over 13 months Pleural thickening
and fungus balls may occur as well as
pneumothorax and pleural effusion An
air-crescent sign may be seen, a probable sign
of the development of necrosis, thereby an
indication of the worsening of the disease

1. Dual cavity with moderately thick walls
2. External irregular edge
3. Some material within the cavity on
   an almost
   normal lung background.

Greene R. Med Mycol 2005 43 Suppl. 1,
S147S154, Baxter CG et al Thorax 2011 66
638640, Franquet T et al. Radiographics 2001
21 825837, Rajalingham S, J Med Case Rep 2012
6 62, Schweer KE et al Dtsch Med Wochenschr
2014 139 22422247.
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Chronic Pulmonary Aspergillosis (CPA) CPA- A case
of SAIA

• 19/7/2013 Admission to the hospital
• Haemoptysis
• Cavity lession
• Checked for TB
• () Mantoux
• Positive galactomannan antigen bronchial
  (BAL)/serum
• CT angiography. Absence of visible bleeding site
• Voriconazole
• 18/10/2013 New bleeding
• 18/03/2014 Discontinuous treatment for
• Aspergilossis

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Chronic Pulmonary Aspergillosis (CPA) CPA- A case
of SAIA

• Male 69 yrs
• 28/01/2015 3 episodes of massive haemoptysis
  06.02.2015 Admission to ICU due to
• massive haemoptysis
• aspiration
• desaturation
• loss of consciousness
• Intubation- mechanical ventilation

• 2006 prostate cancer, prostatectomy
• 2013 radiotherapy 03-23/05/2013
• 2013 nephrotic syndrome / AKF
• kidney biopsy ? diffuse proliferative
  
  glomerulonephritis
• IGC immunocomplex associated
  
  immunodifficiency /chronic thrombotic
  
  microangiopathy possibly due to radiotherapy
• Methylprednisolone and cyclophosphamide.
• Oral methylprednisolone

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Chronic Pulmonary Aspergillosis (CPA) CPA- A case
of SAIA
During the next two years

• Therapeutic interventions in summary
• Voriconazole 07/13-03/14 (9 months)
• Patient stops therapy for 4 months
• Restarted voriconazole 07/14 stops in 10/14 (3
  months)
• Patient stops therapy again for 2 months
• Haemoptysis 04/01/15 voriconazole was restarted
• New episode of haemoptysis
• Admission to the Internal Medicine Clinic

• Symptoms
• Weakness
• Weight loss
• Haemoptysis
• Tests
• 8 CT and CTA
• Never embolized

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Chronic Pulmonary Aspergillosis (CPA) CPA- A case
of SAIA

• Admission to ICU 06/02/2015
• Sedation
• Analgesia
• Intubation - Ensuring airway

• Diagnostic tests performed
• TB / Nocardia (-)
• Biopsy nasal mucosa (-)
• GM serum and bronchial aspirates ()
• Precipitins IgG 6.5 / IgM 0.4 / IgA 1.1
• Biopsy bronchial mucosa (-)
• Lung Biopsy (Confers aspergillosis)
• Voriconazole

• Patient problems
• Frequently hemoptysis
• Imminent airway
• Inadequate ventilation and
  oxygenation

• Actions performed
• Double lumen intubation tube
• Bronchoscopy
• Early tracheostomy day 5

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Chronic Pulmonary Aspergillosis (CPA) CPA- A case
of SAIA
06/03 Surgical removal of the cavity Patient
returned to the ICU
16/03 surgical stump opens bronchopulmonary
fistula
27/04 surgical closure of broncho- pulmonary
fistula with pericardial patch
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Chronic Pulmonary Aspergillosis (CPA) CPA- A case
of SAIA

• The patient after 4 months of hospitalization
  in the ICU died due to septic shock
  and multiorgan failure (MOF)

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Chronic Pulmonary Aspergillosis (CPA) CPA-
Imaging findings / SAIA
Female patient with leukemia ARDS / Resp
failure Intubation Mechanical Ventilation BAL
Aspergillus / GM () Voriconazole Death Autopsy
SAIA
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Chronic Pulmonary Aspergillosis (CPA) CPA-
Treatment

• Treatment with Antifungals
• Surgical treatment
• Treatment of hemoptysis
• Local cavity therapy
• Corticosteroids
• INF-?

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Chronic Pulmonary Aspergillosis (CPA) CPA
Treatment with antifungals

• PO triazole therapy
• Patients type of disease or clinical phenotype
  and eligibility for
  surgical treatment
• Main target QUALITY OF LIFE
• CCPA Voriconazole or itraconazole PO
• Duration at least 4-6 months, slow
  response
• CFPA Long-term itraconazole PO ?
  stabilizing patients
• SAIA Treatment as in IPA
• IV administration
• WHERE ?
  
  Progressive disease, PO failure, intolerant
  of triazoles, resistance
• WITH WHAT ?
• IV Micafungin 150mg/day vs Voriconazole (response
  to treatment vs 60 vs 53),
  Liposomal AmB 3 mg/kg/ day, Caspofungin 5070
  mg/day

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Chronic Pulmonary Aspergillosis (CPA) CPA
Surgical treatment

• Aspergilloma in patients with adequate
  pulmonary function
• Full resection without spillage of fungal
  elements into the pleural space.
• Recurrence of disease and haemoptysis are rare in
  simple aspergilloma
• CCPA carries a lower success rate
• Surgery in all patients with severe haemoptysis
• Careful patient selection to avoid peri- and
  post-operative complications
• Bullectomy, segmentectomy, sublobar resection,
  wedge resection, lobectomy,
  pleurectomy, pneumonectomy
• Post-operative complications
• persistent air-leak, empyema, pneumonia, wound
  infection, bronchopleural fistula, respiratory
  failure, massive haemorrhage, and death
• Catheter embolisation of bronchial arteries
• prior to surgery and a bridge towards selective
  surgery

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Chronic Pulmonary Aspergillosis (CPA) CPA Local
cavity therapy

• Aim to control recurrent haemoptysis if
  surgical treatment is not an option in those
  without a haemorrhagic diathesis when systemic
  use of antifungals is ineffective or prevented by
  Aes
• Instillation of antifungals through
• an endobronchial catheter under bronchoscopic
  guidance
• via a percutaneous transthoracic needle or
• catheter placed into the aspergilloma cavity
• Antifungals
• Amphotericin B (as paste or solution), the drug
  of choice (50 mg in 20 mL 5 Dextrose solution)
• azoles (miconazole, itraconazole)
• sodium iodide and nystatin (as paste with
  amphotericin B).
• Complications
• cough, chest pain, pneumothorax or endobronchial
  reflux
• Short-term response rates 70 to 100.

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Chronic Pulmonary Aspergillosis (CPA) CPA
Therapies for haemoptysis

• Mild, moderate or life-threatening haemoptysis
• CCPA and simple aspergilloma usually
• Tranexamic acid (typically 500 mg three times
  daily)
• Moderate or severe haemoptysis
• Embolisation either as a temporising measure
  before surgery or as a
  definitive treatment
• Complications of embolisation
• chest wall pain, stroke with cortical blindness
  or impaired vision
• chest wall or spinal cord infarction, as well as
  renal impairment and allergic reactions to the
  contrast dye.

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Chronic Pulmonary Aspergillosis (CPA) CPA
Corticosteroids / IFN-?

• Patients with underlying diseases
• sarcoidosis, rheumatoid arthritis, COPD, ABPA or
  asthma may be dependent on corticosteroids
• Prednisolone 530 mg/day may carefully be
  considered for symptom control
  only if are adequately treated with antifungals
• ?nterferon (IFN)-? deficiency
• Impaired production of IFN-? and IL-12 necessary
  to produce IFN-?
• IFN-? substitution (Adjunctive therapy) with
  5060 µg subcutaneously, three times weekly
• Clinical improvement

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Chronic Pulmonary Aspergillosis (CPA) CPA
Follow up

• After resection surgery of Aspergillus nodule
• Single and completely excised aspergilloma
• The patient does not require antifungal therapy
  unless immunocompromised
• A single nodule not completely resected
• Quantitative Aspergillus IgG serology,
  inflammatory markers and radiology
  
• at 3-monthly intervals to determine if
  antifungal therapy required
• Multiple nodules
• Antifungals ? reduction in size of most or all
  nodules over time
• An increase in size may represent another
  disease process, such as a malignancy
• Close radiological follow-up (initially 3
  monthly)
• To ensure there has been no progression
• In all cases, corticosteroid exposure should be
  minimised