The document provides information on pulmonary aspergillosis, caused by inhalation of the Aspergillus fungus. It discusses the main disease entities: allergic bronchopulmonary aspergillosis (ABPA), aspergilloma, invasive aspergillosis, and chronic necrotizing pulmonary aspergillosis. ABPA involves hypersensitivity reactions in asthma/CF patients. Aspergilloma forms fungal balls in pre-existing lung cavities. Invasive aspergillosis mainly affects immunocompromised individuals and can disseminate. Chronic forms progress over months-years in patients with underlying lung disease. Clinical features, diagnosis, treatment and prognosis are outlined

1. Pulmonary Aspergillosis:
Aspergilloma In Focus
Respiratory Unit
Dept of Medicine
OAUTHC Ile-Ife

2. Outline
• Introduction
• The organism/Ecology
• Epidemiology
• Disease Entities
• Pathophysiology
• Clinical features
• Differential Diagnosis
• Investigation
• Treatment
• Prognosis
• References

3. Introduction
• Aspergillosis refers to illness due to allergy, airway or
lung invasion, cutaneous infection, or
extrapulmonary dissemination caused by pathogenic
species of Aspergillus
• Aspergillus species are ubiquitous molds found in
organic matter/decaying vegetation
• Tissue invasion is uncommon and occurs most
frequently in the setting of immunosuppression

4. The causative organism
• More than 100 species have been identified,
majority of human illness is caused by
- A. fumigatus
- A. niger and, less frequently, by
- A. flavus
-A. clavatus and
-A. nidulans.
- A. terreus
• Transmission is via inhalation of fugal spores

6. The Organisms and Ecology
• Hyaline (non-pigmented),narrow, septate,
branching mold
• Produces vast numbers of conidia (spores) on
stalks above the surface of mycelial growth.
• Aspergillus hyphae are histologically distinct
from other fungi in that the hyphae have
frequent septae, which branch at 45° angles.
• The hyphae are best visualized in tissue with
silver stains.

7. The organism

8. Epidemiology
• Aspergillus antigen is present in about 25% of
people with asthma and 50% of patients with
CF
• ABPA is much less common
• Surveys & ABPA registry,
- 0.25-0.8% of people with asthma
- 7% of patients with Cystic fibrosis
• Higher incidence in steroid-dependent
asthma 7-10% and bronchiectasis

9. • Study of 77 patients in UMTH
• 20-30yrs F>M; 30-40yrs M>F
• Based on cavity frequency and Aspergillus IgG serology 19,000 new cases of
chronic pulmonary aspergillosis (CPA) with a 5 year period prevalence of 60,377
cases is expected (Denning, 2011)
• CNPA is rare, found at autopsy,
Journal of Medicine and MedicalSciences Vol. 4(6) pp. 237-240, June, 2013

10. • CNPA is rare, found at autopsy, frequency may be
underestimated.
• Frequency of invasive aspergillosis parallells disease states
and treatments: neutropenia and immunosuppression.
• Occur in 5-13% of recipients of bone marrow transplants, 5-
25% of patients with heart or lung transplants, and 10-20% of
patients receiving intensive chemotherapy for leukemia.
• Aspergilloma is not rare in patients with chronic cavitary lung
disease and CF.
• In one survey of patients with cavitary lung disease due to
tuberculosis, 17% developed aspergilloma.

11. Risk factors
• Immunocompromised states
- Coticosteroid use
- Advanced HIV infection
- Neutropenia
- Bone marrow /solid organ transplant
• Chronic granulomatous disease: TB, Sarcoidosis
• Cystic Fibrosis
• Asthma

12. Pulmonary aspergillosis
Primarily affects the lungs, causing the
following 4 main syndromes:
• Allergic bronchopulmonary aspergillosis
(ABPA)
• Aspergilloma
• Invasive aspergillosis
• Chronic necrotizing Aspergillus pneumonia (or
chronic necrotizing pulmonary aspergillosis
[CNPA])

13. In patients who are severely immunocompromised,
Aspergillus may hematogenously disseminate beyond
the lung, potentially causing ;
•Endophthalmitis,
•Endocarditis, and
•Abscesses in the myocardium, kidney, liver, spleen,
soft tissue, and bone

14. Transmission
• The transmission of fungal spores to the human host
is via inhalation
• Daily exposures vary from a few to many millions of
conidia;
• High numbers of conidia are encountered in hay
barns and other very dusty environment
• Required size of the infecting inoculum is uncertain
• Intense exposures (e.g., during construction work)
are required to cause disease in healthy individuals.
• Allergic syndromes may be exacerbated by
continuous antigenic exposure from sinus/airway
colonization or from nail infection

15. Transmission2
• Aspergillus spores are inhaled regularly by all
individuals.
• Colonization of the respiratory tree may occur,
especially after heavy exposure.
• The incubation period of invasive aspergillosis
after exposure is highly variable 2 to 90 days.
• Outbreaks usually are directly related to a
contaminated air source in the hospital

17. Pathophysiology
• A. fumigatus is the most common cause of
infection in humans.
• Possess ability to grow at normal human body
temperature
• Most other sp cannot

18. Pathophysiology
• Human host defense against the inhaled spores
begins with the mucous layer and the ciliary
action in the respiratory tract.
• Macrophages and neutrophils encompass, engulf,
and eradicate the fungus.
• However, many species of Aspergillus produce
toxic metabolites that inhibit macrophage and
neutrophil phagocytosis.
• Corticosteroids also impair macrophage and
neutrophil function.

19. Pathophysiology
• Underlying immunosuppression contributes
directly to neutrophil dysfunction or
decreased numbers of neutrophils.
• Vascular invasion is common in
immunosuppressed states
• May result in infarction, hemorrhage, and
necrosis of lung tissue.
• Granuloma formation and alveolar
consolidation may occur in CNPA

20. Pathophysiology
• Colonization of previously formed cavities in the
lung
• Inhaled Aspergillus spores may also colonize the
mucus within the bronchi,
• As obtained in moderately severe asthma with
thick and tenacious mucus
• Aspergillus spores may invade adjacent lung
tissues and produce a gradually progressive and
destructive process in lung containing
centrilobular emphysema

22. Disseminated Infections
• The most lethal form of aspergillosis is disseminated or
pyemic aspergillosis.
• the fungi will grow within the alveoli and invade adjacent
vascular structures, leading to occlusion of these vessels.
• Necrosis follows occlusion of the vessels, leading to wedge-
shaped areas of infarction.
• Metastatic abscesses in brain, lung, liver, heart, and other
organs are common.
• Skin involvement gives rise to a characteristic lesion: an
area of central necrosis and a black eschar (ecthyma
gangrenosum)
• Occasionally, Aspergillus endocarditis may follow pyemic
spread or surgery

23. ABPA
• characterised by an exaggerated response of the
immune system (a hypersensitivity response) to the
fungus Aspergillus (most commonly A. fumigatus).
• Occurs most often in patients with asthma or cystic
fibrosis 1 about 1% and 15% resp
• Associated with certain HLA class II types DR2 and
DQ2; increased and reduced risks respectively
polymorphisms of IL 4Ra, IL-10, and SPA2 genes;
• Heterozygosity of the cystic fibrosis transmembrane
conductance regulator (CFTR) gene.
• Occasional cases are reported in patients without
either of these diseases

25. • Patients develop a hypersensitivity response, both a type I
response (atopic, with formation of IgE) and a type III
hypersensitivity response (with formation of IgG).
• The reaction of IgE with Aspergillus antigens results in mast
cell degranulation with bronchoconstriction and increased
capillary permeability.
• Immune complexes (a type III reaction) and inflammatory
cells deposited within the mucous membranes leading to
necrosis and an eosinophilic infiltrate.
• Type 2 T helper cells secreting interleukin 4 and interleukin
5, and attraction of neutrophils by interleukin 8 are also
involved

26. • In spite of this pronounced immune reaction, the
fungus is not cleared from the airways.
• Proteolytic enzymes are released by the immune
cells, and toxins are released by the fungi.
• Together these result in bronchiectasis, most
pronounced in the central parts of the airways.
• Repeated acute episodes left untreated can result
in progressive pulmonary fibrosis that is often
seen in the upper zones and can give rise to a
similar radiological appearance to that produced
by tuberculosis.

27. • The otherwise-severe course of underlying
asthma is punctuated by episodes of worsening,
when thick mucus plugs become inspissated in
bronchi, causing an inflammatory process distal
to the obstruction.
• This propensity to cause bronchial obstruction
gives rise to the characteristic radiographic
pattern of the disease, the so-called finger-in-
glove appearance, in which multiple adjacent
bronchi are distended with the mucus plug

29. • Diagnostic Features of Allergic Bronchopulmonary Aspergillosis
(ABPA)
Main Diagnostic Criteria
• Bronchial asthma
• Pulmonary infiltrates
• Peripheral eosinophilia (>1000/L)
• Immediate wheal-and-flare response to Aspergillus fumigatus
(positive skin-prick test)
• Serum precipitins to A. fumigatus ; primarily IgG, but also Ig A and
IgM, antibodies
• Elevated serum IgE(usually >1000 IU/mL)
• Central bronchiectasis

30. Other Diagnostic Features
• History of brownish plugs in sputum
• Culture of A. fumigatus from sputum
• Aspergillus radioallergosorbent assay test
Elevated IgE (and IgG) class antibodies specific
for A. fumigatus

31. Clinical Features
• Episodes of bronchial obstruction with
mucous plugs leading to coughing fits,
"pneumonia," consolidation, and
breathlessness are typical.
• Coughing up thick sputum casts, usually
brown or clear
• fever and pulmonary infiltrates that are
unresponsive to antibacterial therapy

32. • Hemoptysis.
• Wheezing
• People with asthma who have ABPA may have
poorly controlled disease and difficulty tapering
off oral corticosteroids.
• ABPA may occur in conjunction with allergic
fungal sinusitis
• Development of chronic fibrous changes, the
restrictive lung function pattern is overlaid on top
of the reactive airways disease

33. ABPA may be progressive, and the following 5
stages have been described
• Acute disease
• Remission
• Exacerbation or recurrence
• Corticosteroid-dependent asthma
• End-stage fibrosis

34. • increased IgE levels (especially specific IgE levels),
• peripheral blood eosinophilia, and
• expectoration of bronchial plugs
• sputum staining and sputum cultures can be
useful.
• FBC; eosinophilia more than 10%
• skin-prick test is almost always positive to
Aspergillus fumigatus (a negative skin test result
excludes the diagnosis of ABPA)

35. Radiology
CXR
fleeting pulmonary infiltrates
mucoid impaction
central bronchiectasis
Mucoid impaction of bronchiectatic
areas may cause a lobulated infiltrate,
which has been likened to a cluster of
grapes or a hand in a mitten/finger in
glove
CT Scan

36. Aspergilloma
• Aspergilloma (fungal ball) occurs in up to 20%
of residual chest cavities 2cm in diameter.
• Some fungal balls remain stable in a single
cavity for many years, and 10% resolve
spontaneously.
• They are often a feature of chronic pulmonary
aspergillosis with its associated features

38. Classification
• Pulmonary aspergilloma is classified as
- simple
- complex pulmonary aspergilloma (CPA),
• based on the radiological aspect, which reveals the
nature and extent of the pulmonary impairment
caused by the pre-existing disease.
• SPA : Well-localized lesion, thin-walled cavities, and
little or no change in the adjacent lung tissue.
• CPA : disseminated lesions, thick walls, parenchymal
sequelae resulting from the previous lung disease-in
most cases TB

39. Radiology
CXR; a mass in a preexisting cavity, usually in
an upper lobe, manifested by a crescent of air
partially outlining a solid mass.
CT Scan; may demonstrate multiple
aspergillomas in areas of extensive cavitary
disease. As the patient is moved onto his or
her side or from supine to prone, the mass is
observed to move within the cavity
confirmed by sputum culture

40. Aspergilloma2
• Vast majority of fungal balls are caused by A.
fumigatus
• A. niger implicated in diabetic patients;
aspergillomas due to
• A. niger can lead to oxalosis with renal
dysfunction

41. Clinical Features
• May manifest as an asymptomatic
• Radiographic abnormality in a patient with
pre-existing cavitary lung disease due to
sarcoidosis, TB, necrotizing pulmonary
processes, CF, emphsematous bullae
• May occur in cystic areas resulting from prior
Pneumocystis jiroveci pneumonia in patients
with HIV disease

42. Clinical Features
• Aspergillomata can form in other body
cavities.
• abscesses in the brain, usually in people who
are immunocompromised.
• They can also form within the different sinuses
in the face, within the kidneys and urinary
system, the ear canal, and on the heart valves

43. Clinical Features
• Typically, individuals who are affected by
aspergillomata do not have symptoms related
to the infection
• Hemoptysis is the major feature 40-60%
(rarely, occasional exsanguinating
hemorrhage)
• Less commonly, cough and fever.
• wheezing, and mild fatigue

44. Invasive Aspergillosis
• Both the frequency of invasive disease and the
pace of its progression increase with greater
degrees of immunocompromise
• Invasive aspergillosis is arbitrarily divided into
acute and subacute forms that have courses of 1
month and 1–3 months, respectively.
• More than 80% of cases of invasive aspergillosis
involve the lungs.
• The keys to early diagnosis in at-risk patients are
a high index of suspicion, screening for circulating
antigen, and urgent CT of the thorax.

46. Features
• occurs almost exclusively in patients who are
immunocompromised.
• Neutropenia and corticosteroid therapy are
major risk factors
• increasingly observed in patients with COPD
on long-term corticosteroid therapy
• Dissemination to other organs, particularly the
central nervous system, may occur.

47. Clinical Features
• Asymptomatic commonly
• fever
• cough (sometimes productive),
• nondescript chest discomfort,
• trivial hemoptysis,
• shortness of breath.
• Although the fever often responds to
glucocorticoids, the disease invariably progresses

48. Diagnosis
Imaging study results in invasive aspergillosis are as follows:
• CXR; features are variable, with solitary or multiple
nodules, cavitary lesions, or alveolar infiltrates that are
localized or bilateral and more diffuse as disease progresses
• CT Scan; In early disease, xtic halo sign (ie, an area of
ground-glass infiltrate representing hrragic infarction
surrounding nodular densities)
• In later disease, CT scans may show a crescent of air
surrounding nodules, indicative of cavitation
• Because Aspergillus is angioinvasive, infiltrates may be
wedge-shaped, pleural-based, and cavitary, which is
consistent with pulmonary infarction

49. Radiology

50. Chronic pulmonary aspergillosis
• chronic cavitary pulmonary aspergillosis
• semi-invasive aspergillosis,
• chronic necrotizing aspergillosis,
• complex aspergilloma

51. Features
• subacute pneumonia unresponsive to
antibiotic therapy
• developing over <3 months is better classified
as subacute invasive aspergillosis
• progresses and cavitates over weeks, months
or years with expanding cavities
• have underlying disease, such as steroid-
dependent COPD or alcoholism

52. CPA
• almost all cases occur in patients with prior
pulmonary disease: TB, atypical mycobacterial
infection, sarcoidosis and other granulomatous
lung disease, ankylosing spondylitis, rheumatoid
lung disease, pneumothorax, bullae, ILD or prior
lung surgery
• Cavities may have a fluid level or a well-formed
fungal ball, but pericavitary infiltrates and
multiple cavities—with or without pleural
thickening—are typical

53. • Some patients have concurrent infections—
even without a fungal ball—with atypical
mycobacteria and/or other bacterial
pathogens, such as Staphylococcus aureus or
Pseudomonas aeruginosa
• Antibodies to Aspergillus are almost always
detectable in blood, usually as precipitating
antibody and sometimes at high titers

54. • Chest radiograph usually shows an infiltrative
process in the upper lobes or the superior
segments of the lower lobes. A fungal ball may
be seen in nearly half of the case (2). Adjacent
pleural thickening is a characteristic finding
and may be an early indication of a locally
invasive process (3).

55. Clinical features
• May last 1-6months include
• Fever, cough, night sweats, and weight loss
• Hemoptysis
• If untreated, typically progresses (sometimes
relatively rapidly) to unilateral or upper-lobe
fibrosis.
• This end-stage entity is termed chronic
fibrosing pulmonary aspergillosis.

56. • Clinical diagnosis of CNA can be made using the
following criteria (1):
• 1.Clinical and radiologic features consistent with
the diagnosis
• 2.Isolation of Aspergillus species by culture from
sputum, bronchoscopic or percutaneous samples
• 3.Exclusion of other conditions with similar
presentations, such as active TB, atypical
mycobacterial infection, chronic cavitary
histoplasmosis or coccidioidomycosis

57. References
• Harrison’s Principles Of Int Med 18th ed
• 1.Joshi JM. Hydatidothorax. Lung India 2011;28:315-6. Back to cited text no.
1 [PUBMED]
• 2.Biswas D, Dey A, Biswas S, Chakraborty M. It's easy to miss complicated hydatid
cyst of lung. Lung India 2010;27:164-6. Back to cited text no. 2 [PUBMED]
• 3.Sarkar SK, Kumar V, Sharma SD, Bhatnagar M, Khandelwal PP. Crescent sign in
pulmonary hydatid cyst. Lung India 1988;6:155-6. Back to cited text no. 3
• 4.Flisser A. Larval cestodes. In: Collier L, Balows A, Sussman M, editors. Topley and
Wilson's microbiology and microbial infections. Parasitology. 9 th ed. Vol. 5. New
York, NY: Oxford University Press; 1998. p. 539-60. Back to cited text no. 4
• 5.Ulkü R, Yilmaz HG, Onat S, Ozçelik C. Surgical treatment of pulmonary hydatid
cysts: Report of 139 cases. Int Surg 2006;91:77-81. Back to cited text no. 5
• 6.Sharif A, Ansarin K, Rashidi F, Taghizadieh A. Bronchoscopic diagnosis and
removal of a ruptured hydatid cyst. J Bronchology Interv Pulmonol 2011;18:362-4.