aspergillosis

1. PULMONARY
MANIFESTATIONS OF
ASPERGILLOSIS
Dr.M.VIKAS

2. • Introduction
• Fungal virulence factors
• Manifestations
• Radiological findings
• Treatment aspects

3. INTRODUCTION
• Ubiquitous
• Saprophyte
• Recycle C & N
• 1-100 conidia/m3
• Conidia of 2-3um
• Most common
A.fumigatus
POSITIVE ASPECTS
• Composting
• Cell biology and
genetics
• Food production
• pharmaceuticals
NEGATIVE ASPECTS
• Plant and food
spoilage
• Allergic and invasive
diesease

4. • Of nearly 200 species of aspergillus 20 are pathogenic to humans
• Of which A.Fumigatus is the most frequently identified
• Others include A.niger, A.terreus, A.nidulans, A.flavus
• These are characterised by production of uniform 4-6 mm hyphae
with dichotomous branching at 45 degree.

6. VIRULENCE FACTORS
• Various factors determine aspergillus virulence including
proteolytic enzymes, phospholipases, ribotoxin, hemolysin,
gliotoxin and many others.
• Of which GLIOTOXIN plays a key role.

7. • It inhibis phagocytosis of macrophages
• Promote apoptosis of macrophages
• Inhibit ROS (reactive oxygen species) in neutrophils
• Block B and T cell activation
• Blocks angiogenesis

8. MANIFESTATIONS
• SIMPLE COLONISATION
• HYPERSENSITIVITY REACTIONS
- Allergic bronchial asthma
- ABPA (Allergic Broncho Pulmonary Aspergillosis)
- Bronchocentric Granulomatosis
- Extrinsic allergic Alveolitis

9. • SAPROPHYTIC GROWTH
- Aspergilloma
• INVASIVE INFECTION
- IBA (Invasive Bronchial Aspergillosis)
- CPA ( Chronic Pulmonary Aspergillosis)
- IPA ( Invasive Pulmonary Aspergillosis)
- Bronchial stump Aspergillosis

10. SIMPLE COLONISATION
• No uniform definition of colonization, can be considered in cases of
isolation of Aspergillus species from cultures of the respiratory tract
• Patients with structural lung diseases such as chronic obstructive
pulmonary disease (COPD), bronchiectasis are at increased risk for
persistent aspergillus colonization

11. • In fact, Aspergillus colonization has been shown to be a marker for
the development of IA ( invasive aspergillosis) in
immunocompromised individuals, particularly lung and bone
marrow transplant recipients, and may precede invasion for up to
3 months.

12. ALLERGIC BRONCHIAL ASTHMA
• It develops in patients who are atopic to aspergillus antigens and
causes acute bronchospasm
• In these patients
- Eosinophils and serum IgE antibodies are increased
- Immediate skin reaction to aspergillus antigens are positive but
specific precipitating antibodies IgG are negative
• Avoidance of exposure to aspergillus spores can diminish the frequency
and severity of bronchospasm

13. ABPA (Allergic Broncho Pulmonary Aspergillosis)
• Allergic bronchopulmonary aspergillosis (ABPA) is an
idiopathic inflammatory disease of the lung, characterized by
an allergic inflammatory response to colonization of the
airways by Aspergillus fumigatus or other fungi.
• It mostly develops in genetically susceptible patients with
asthma or cystic fibrosis because of increase activity of
A.fumigatus – specific Th2 CD4+ cells.

14. • Predisposing factors for ABPA include
- atopy
- HLA distinct phenotypes(HLA - DR2 and DR5 specific alleles),
- mutation in CFTR gene,
- polymorphisms of the collagen region of surfactant
protein A2.
• It is estimated that 7-14% of poorly controlled asthmatics and
7-9% of patients with cystic fibrosis meet the diagnostic criteria of
ABPA.
clin infect dis.2003:37:s225-s264

18. PATHOGENESIS
• The immune pathogenesis of ABPA is mainly due to
exaggerated immunological reaction to chronic airway
colonisation by aspergillus species.
• ABPA is characterized by an intense eosinophilic and
mononuclear cell inflammatory response, leading into areas
of parenchymal scarring, airway remodelling, and
bronchiectasis.

19. • Immunologic studies demonstrate the presence of a
- type I hypersensitivity reaction, with elevated serum levels
of total IgE and A. fumigatus - specific IgE
- an exaggerated Type III hypersensitivity reaction, indicated
by the presence of A. fumigatus-specific IgG antibodies
- circulating immune complexes during disease
exacerbations

20. CLINICAL FEATURES
• The typical presenting complaints are non specific and
include
- dyspnea, wheeze
- cough with sputum containing thick brown mucus plugs,
- malaise ,
- low grade fever and occasionally hemoptysis
• ABPA is usually suspected on clinical grounds, and the
diagnosis is confirmed by radiological and serological testing.

21. DIAGNOSTIC CRITERIA FOR ABPA
Seropositive ABPA (ABPA-S)
• History of asthma (almost always difficult to control)
• Elevated total serum IgE (usually >1000 IU/mL)
• Immediate skin test reactivity to Aspergillus fumigatus OR elevated
specific serum IgE to A.fumigatus
• Presence of serum precipitins (by gel diffusion) or elevated specific
serum IgG to A. fumigatus
ABPA central bronchiectasis (ABPA-CB)
• Above criteria are positive
• Central bronchiectasis by high-resolution CT scan or CXR
Patterson criteria

22. Other supportive clinical findings
• Peripheral blood eosinophilia (often absent, especially if patient is on
oral or inhaled corticosteroids)
• Patchy, fleeting infiltrates (often absent, especially if patient is on oral
corticosteroids)
• Expectoration of brown mucus plugs
• Mucoid-impacted bronchi evident on radiographic studies
• Sputum culture positive for A. fumigatus
Patterson criteria

23. Radiographic findings :
- During acute exacerbations, fleeting pulmonary infiltrates are
characteristic feature of the disease that tends to be in the upper lobe
and central in location.
- There may be transient areas of opacification due to mucoid impaction
of the airways which may present as band-like opacities emanating
from the hilum with rounded distal margin (finger in glove appearance)
- The ’ring sign’ and ’tram lines’ are radiological signs that represent the
thickened and inflamed bronchi may be seen on chest radiographs.
- Central bronchiectasis and pulmonary fibrosis may develop at later
stages.

25. • RADIOGRAPHIC FINDINGS

32. CLINICAL STAGING
Clinical Stage I : Acute Stage of ABPA
- Acute asthma symptoms
- Elevated serum IgE (>1000 IU/mL)
- Peripheral blood eosinophilia (may be absent in patients treated
with oral corticosteroids)
- Fleeting infiltrates on chest X-ray (may be absent in patients
treated with oral corticosteroids)
- Positive specific IgE, IgG, skin test reactivity, or precipitins to
Aspergillus fumigatus
- Responds to steroids/antifungal therapy

33. Stage II: Remission
- Resolution of symptoms
- Resolution of pulmonary infiltrates
- Improvement in eosinophilia and A. fumigatus specific blood
abnormalities
Stage III: Exacerbation/Recurrence
- Recurrence/worsening of clinical symptoms
- Recurrent pulmonary infiltrates
- Rising IgE levels

34. Stage IV: Steroid-Dependent Asthma
- Refractory steroid-dependent asthma
- Persistently elevated serum IgE levels
- Persistently elevated A. fumigatus–specific blood abnormalities
Stage V: Fibrotic Lung Disease
- Refractory steroid-dependent asthma
- Fibrotic lung disease (irreversible obstructive and restrictive defects
with impaired diffusing capacity)
- Chronic bronchiectasis symptoms (sputum production, frequent
infections)

35. TREATMENT
• Treatment of allergic bronchopulmonary aspergillosis (APBA) should
consist of a combination of corticosteroids and anti fungals
• Corticosteroid therapy is the mainstay of therapy for ABPA , with
improved pulmonary function and fewer episodes of recurrent
consolidation.

36. • Dose – 0.5-1 mg/kg of prednisolone for 1-2 weeks followed by
0.5 mg/kg for 6-12 weeks in acute exacerabation
• Antifungals has been effective in improving symptoms, facilitating
weaning from corticosteroids, decreasing Aspergillus titres, and
improving radiographic abnormalities and pulmonary function.

37. BRONCHOCENTRIC GRANULOMATOSIS
• Bronchocentric granulomatosis is a rare hypersensitivity syndrome that
is characterized histologically by replacement of bronchial mucosa with
necrotizing granulomatous tissue.
• Eosinophilic infiltration of bronchioles and fibrosis is prominent,
whereas there is no evidence of Aspergillus invasion.
• Diagnosis is made by bronchial biopsy or often retrospectively after
removal of the lesion.

38. EXTRINSIC ALLERGIC ALVEOLITIS
• It is mainly due to heavy or repeated exposure to Aspergillus
conidia and mycelia resulting in a hypersensitivity reaction
affecting the alveoli in non atopic individuals.
• Repeated exposure to moldy straw or grain in malt workers,
distillers, brewers may lead to malt worker’s lung or farmer’s
lung or to the development of granulomatous disease or
interstitial fibrosis.

39. • The immunopathogenesis of extrinsic allergic alveolitis involves
cell-mediated immunity (type IV response) and immune complex
deposition (type III response).
• In acute conditions radiographic findings include diffuse reticulo nodular
infiltrates which will progress to pulmonary fibrosis with honey combing
in chronic exposure.
• Removal or avoidance of the source of antigen exposure remains
crucial in management and corticosteroids may be helpful in acute
conditions

40. ASPERGILLOMA
• Saprophytic colonisation of a parenchymal lung cavity by Aspergillus is
referred to as Aspergilloma / Mycetoma / Fungal ball.
• It usually develops in a pre-existing cavity in the lung and is composed
of both dead and living mycelial elements, fibrin, mucus, amorphous
debris, inflammatory cells, degenerating blood and epithelial elements.
• Spontaneous shrinkage is seen in 7-10 % of cases and rarely increases
in size
• The most common species of Aspergillus recovered from such lesions is
A. fumigatus and also A.Niger in patients with diabetes milletus

41. PATHOPHYSIOLOGY
• Pathogenesis mainly involves colonisation and proliferation of the
fungus in pre existing pulmonary cavity (secondary aspergilloma)
• Many cavitary lung diseases are complicated by aspergilloma,
including
- Tuberculosis ( the most common)
- Sarcoidosis,
- Histoplasmosis and blastomycosis
- Pulmonary or bronchial cysts
- Rheumatoid nodules
- Pneumonia and/or lung abscess
- Pulmonary fibrosis and pulmonary infarction

42. • Primary aspergilloma, arise from bronchial tree with proliferation of
Aspergillus leading to pulmonary cavity is less common.
• The clinical conditions leading to initiation of cavitary process and
formation of fungal ball include IPA, CNPA and ABPA.
• Aspergilloma formation is linked with the ability of the fungus to form
an extracellular hydrophobic matrix with typical biofilm characteristics
under different static conditions including interaction with bronchial
epithelial cell

43. CLINICAL FEATURES
• Most patients will experience mild hemoptysis, but severe and life
threatening hemoptysis may occur, particularly in patients with underlying
tuberculosis.
• Bleeding usually occurs from bronchial blood vessels, and may be due to
- local invasion of blood vessels lining the cavity,
- endotoxins released from the fungus, or
- mechanical irritation of the exposed vasculature inside the
cavity by the rolling fungus ball
- proteolytic activity

44. • Less commonly, patients may develop cough, dyspnoea that is
probably more related to the underlying lung disease, and fever, which
may be secondary to the underlying disease or bacterial superinfection
of the cavity.

45. DIAGNOSIS
• The diagnosis of pulmonary aspergilloma is usually based on the clinical
and radiographic features, combined with serological or microbiologic
evidence of Aspergillus spp.
• Chest radiographs reveal a solid round mass within a cavity (3–5 cm
diameter) partially surrounded by a radiolucent crescent (Monod’s sign)
• A solitary lesion in the upper lung fields is the most common radiographic
feature of aspergilloma, as pre-existing tuberculosis cavities is the most
common predisposing condition

46. • Chest CT may be helpful in further delineating the radiographic features
of an aspergilloma that are not apparent on chest radiographs.
• CT angiography may also provide useful information for patients with
hemoptysis by identifying hypertrophic bronchial arteries that often
supply the cystic wall of aspergillomas.
• Sputum cultures are positive for aspergillus in more than half of the
patients

47. RADIOLOGY

51. DD of air crescent sign :
• Non neoplastic - aspergilloma in pre formed cavity
- haematoma (blood clot in a pre-existing cavity)
- inspisated pus in abscess cavity
- disintegrating hydatid cyst
- cavitating Wegener’s granulomatosis
- cavernolith
• Neoplastic - cavitating bronchogenic carcinoma
- bronchogenic carcinoma within bulla or cyst
- sclerosing hemangioma
Lillington text book

52. TREATMENT
• Definitive treatment include surgical resection
• Intracavitary instillation of anti fungal agents like AMB-D
• Bronchial artery embolization
• Oral itraconazole

53. CHRONIC PULMONARY
ASPERGILLOSIS
• Based on clinical and radiological findings various types are
CCPA ( chronic cavitary pulmonary aspergillosis )
CNPA ( chronic necrotising pulmonary aspergillosis )
CFPA ( chronic fibrosing pulmonary aspergillosis)

54. • CNPA – It comprises a syndrome of slowly progressive cavitary lung
disease, chronic respiratory symptoms, and the presence of
precipitating antibodies against aspergillus, and in most of the cases,
there is no tissue invasion despite the presence of
extensive and progressive tissue damage.

55. • CCPA - refers to cases in which there is formation and expansion of
multiple cavities over time,
• CFPA - refers to cases in which cavity formation is followed by a
pronounced fibrotic reaction.
it has been recommended that any case with proven hyphal invasion of
tissue should be classified as CNPA.

56. • Defects in mucociliary clearance associated with structural lung disease
appear to be a critical factor in the pathogenesis of CPA.
Predisposing factors for CPA include -
• Prior mycobacterial lung infection,
• emphysema and/or COPD1 (most common)
• asthma,
• sarcoidosis,
• pneumoconiosis,
• lung cancer,
• thoracic surgery,
• Legionella infection
1- chest nov 2014

57. • CPA tends to affect middle-aged mostly males who are relatively
immunocompetent
• CPA has an indolent and progressive course that lasts for years.
• Chronic productive cough and weight loss with mild hemoptysis,
dyspnea, and fatigue are the usual presenting symptoms.
• Pleural fibrosis and Aspergillus empyema appear to complicate some
cases of CPA.

58. • Typical radiographic findings include the presence of one or more
cavities, which may or may not contain fungus balls, often located in the
upper lobe with sequential chest radiographs are typically required to
confirm the progressive nature of CPA lesions.
• New cavity formation and expansion of pre-existing cavities are also
characteristic of CPA.

59. • CPA requires prolonged treatment with systemic antifungals
• Surgery has a limited role in the treatment because of poor
lung function

62. INVASIVE BRONCHIAL
ASPERGILLOSIS
• It refers to the infection involving large airways
• On bronchoscopic appearance classified into
- Tracheobronchitis
- Pseudomembranous tracheobronchitis
- Ulcerative tracheobrochitis

63. • Tracheobronchitis is the least invasive form characterised by the
presence of superficial inflammation, intact mucosa with no abnormality
• Pseudomembranous tracheobronchitis is characterised by significant
necrosis of bronchial epithelium and formation of pseudomembranous
plaques of white/gray/black colour.
• It is mostly seen in lung transplant recepients within 3 months
• Persistant stridor in neutropenic or severely immunocompromised pts or
lung transplant pts should raise suspicion of IBA

64. • Ulcerative tracheobronchitis is the most aggressive form with
endobronchial plaques, nodules with areas of ulceration and necrosis
with adjacent invasion of pulmonary vasculature and parenchyma
• It occurs mostly at the site of bronchial anastomosis in lung transplant
recepients

67. • Treatment includes systemic antifungals.
• Surgical resection and stent placement may be necessary in conjunction
with systemic antifungals if dehiscence of anastomosis occurs

68. INVASIVE PULMONARY
ASPERGILLOSIS
• It has become one of the most common cause of infectious death in
severely immunocompromised patients
• It has emerged as the most common invasive fungal infection in HSCT
( Hematogenous stem cell transplant ) and solid organ transplant
recepients with very high mortality rate

69. RISK FACTORS
• prolonged, profound neutropenia because of a hematological
malignancy (5%–25% risk) or aplastic anemia;
• recipients of allogeneic HSCTs (5%–30% risk), or
• lung transplants (17%–26% risk);
• those with AIDS, severe combined immunodeficiency, or CGD (25%–
40% lifetime risk)
• burn patients; and
• patients receiving corticosteroids, critical illness, chronic liver disease,
COPD,DM.
chest nov 2014, 146#5

70. • IPA typically occurs following inhalation of aspergillus conidia although
hematogenous dissemination from cutaneous or gastro intestinal route
may be seen.
• Damage to respiratory epithelium due to radiotherapy, chemotherapy,
GvHD, prior infection (RSV, influenza) may facilitate the conidia to
breach the epithelium

71. • Patients present with symptoms that are usually non-specific
(more than 80% cases involve the lung) and consistent with
bronchopneumonia:
- fever unresponsive to antibiotics,
- cough and dyspnea
- pleuritic chest pain
- massive haemoptysis,

72. DIAGNOSIS
• Histopathological diagnosis, by examining lung tissue obtained by
thoracoscopic or open-lung biopsy, remains the 'gold standard' in the
diagnosis of IPA .
• The significance of isolating Aspergillus sp in sputum samples depends
on the immune status of the host.
• Isolation of an Aspergillus species from sputum is highly predictive of
invasive disease in immunocompromised patients.

73. • Chest radiographs are not sensitive in detecting early forms of IPA.
• The routine use of HRCT of the chest early in the course of IPA leads to
earlier diagnosis and improved outcomes in these patients.
• The typical chest CT scan findings in patients suspected to have IPA
include
- halo sign ( small wedge shaped subpleural lesions or
nodules typically surrounded by intermediate attenuation)
- air crescent sign,
- ground glass appearance and
- consolidation

76. DD of halosign :
• Hemorrhagic nodules of infectious origin (mucormycosis, candidiasis,
tuberculosis, viral pneumonia, and invasive aspergillosis--the last being
the most common cause of the CT halo sign);
• Hemorrhagic nodules of noninfectious origin (Wegener granulomatosis,
Kaposi sarcoma, and hemorrhagic metastases);
• Tumor cell infiltration (bronchioloalveolar carcinoma, lymphoma, and
metastasis with intra-alveolar tumor growth); and
• Nonhemorrhagic lesions (sarcoidosis and organizing pneumonia)

77. • Bronchoscopy with bronchoalveolar lavage (BAL) is generally helpful in
the diagnosis of IPA
• The sensitivity and specificity of a positive result of BAL fluid are about
50% and 97% respectively.
• Polymerase chain reaction (PCR) is another way to diagnose IPA, by
the detection of Aspergillus DNA in BAL fluid and serum.
• A positive aspergillus PCR in BAL fluid has an estimated sensitivity of
67–100% and specificity of 55–95% for IPA.
• PCR sensitivity and specificity have also been reported as 100% and
65–92% respectively, in serum samples.
Br J Haematol 2006;132:478-86

78. • Galactomannan is a polysaccharide cell-wall component that is released
by Aspergillus that is released into circulation during fungal growth in
tissues
• Serum galactomannan can be detected by ELISA as low as 0.5 ng/ml
several days before the presence of clinical signs, an abnormal chest
radiograph, or positive culture.
• This may allow earlier confirmation of the diagnosis, and serial
determination of serum galactomannan values may be useful in
assessing the evolution of infection during treatment.
J Infect Dis2004;190:641-9.

79. TREATMENT
• Early initiation of antifungal therapy in patients with strongly suspected
invasive aspergillosis is warranted while a diagnostic evaluation is conducted
• For primary treatment of invasive pulmonary aspergillosis, IV or oral
voriconazole is recommended for most patients
N Engl J Med 2002;347:408-15.

80. • L-AMB may be considered as alternative primary therapy in some
patients
• Other agents include
Posaconazole
Itraconazole ,
Echinocandins [caspofungin , or micafungin]
Clin Infect Dis 2007;44:2-12

81. • Immunomodulatory therapy, such as using
- colony-stimulating factors (i.e. G-CSF, GM-CSF )
- interferon-γ
- Granulocyte transfusion
could be used to decrease the degree of immunosuppression, and
as an adjunct to antifungal therapy for the treatment of IPA

82. PROPHYLAXIS
• Antifungal prophylaxis with posaconazole can be recommended
- HSCT recipients with GVHD who are at high risk for
invasive aspergillosis and in
- patients with acute myelogenous leukemia or myelodysplastic
syndrome who are at high risk for invasive aspergillosis
N Engl J Med2007;356:348-59.

83. • Surgical therapy may be useful in patients with lesions that are
contiguous with the great vessels or the pericardium, hemoptysis from
a single cavitary lesion, or invasion of the chest wall .
• Another relative indication for surgery is the resection of a single
pulmonary lesion prior to intensive chemotherapy or HSCT.
Ann Thorac Surg 2002

84. ANTIFUNGALS

85. • IDSA guidelines for aspergillosis 2008
• CHEST 2014.146#5

86. THANK
YOU