This document summarizes aspergillosis, including invasive pulmonary aspergillosis (IPA), chronic necrotizing aspergillosis (CNA), and aspergilloma. Aspergillus is a common mold that can cause a variety of pulmonary diseases. IPA predominantly affects immunocompromised patients and presents as pneumonia. Diagnosis involves tissue biopsy, galactomannan testing, and imaging. Voriconazole is recommended treatment. CNA occurs in patients with underlying lung disease and is characterized by slow lung tissue invasion. Itraconazole is effective treatment. Aspergilloma involves a fungus ball in a pre-existing lung cavity.

1. ASPERGILLOSIS

2. BACKGROUND
 Aspergillus species are ubiquitous molds found in organic
matter.
 Although more than 100 species have been identified, the
majority of human illness is caused byAspergillus fumigatus
and Aspergillus niger and, less frequently, by Aspergillus
flavus and Aspergillus clavatus
 The transmission of fungal spores to the human host is via
inhalation.
 Aspergillus may cause a broad spectrum of disease in the
human host, ranging from hypersensitivity reactions to
direct angioinvasion

4. INVASIVE PULMONARY ASPERGILLOSIS
 IPA was first described in 1953.
 The incidence of IPA has increased during the past two
decades due to widespread use of chemotherapy and
immunosuppressive agents.
 Groll et al. documented that the rate of invasive mycoses
increased from 0.4 to 3.1% of all autopsies performed
between 1978 and 1992
 IPA occurs predominantly in immunocompromised patients.

5. RISK FACTORS
 Prolonged neutropenia (<500 cells/mm3 for >10 days) or
neutrophil dysfunction
 Transplantation (highest risk is with lung and HSCT)
 Prolonged (>3 weeks) and high-dose corticosteroid therapy.
 Haematological malignancy (risk is higher with leukaemia)
 Cytotoxic therapy
 Advanced AIDS
 Critically ill patients
Am J Respir Crit Care Med 2006;173:707-17

6.  IPA is also becoming an important infectious disease in ICU
patients without the classical risk factors for this condition.
 Although many of the critically ill patients with IPA do not have
the classic risk factors for IPA (neutropenia, leukaemia, HSCT),
they usually have conditions that affect their immune system :
-COPD
-systemic corticosteroid therapy
-Non-haematological malignancy,
-liver failure, diabetes mellitus, or
-extensive burns
Crit Care 2005;9:R191-9.

7. CLINICAL MANIFESTATIONS
 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, sputum production, and dyspnea
- pleuritic chest pain
- haemoptysis,
 Aspergillus infection may also disseminate and spread
haematogenously to other organs, most commonly the brain:
- seizures,
- ring-enhancing lesions,
- cerebral infarctions,
- intracranial haemorrhage,
- meningitis, and epidural abscess
N Engl J Med 1976;295:655-8.

8. CLINICAL MANIFESTATIONS
 Other organs such as skin, kidneys, pleura, heart, oesophagus,
and liver may be involved.

9. DIAGNOSIS
 Histopathological diagnosis, by examining lung tissue
obtained by thoracoscopic or open-lung biopsy, remains the
'gold standard' in the diagnosis of IPA [1]
 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.[2]
[1] Ann Hematol2003;82 Suppl. 2:S141-8.
[2] Am J Med 1996;100:171-8

11. DIAGNOSIS
 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
- multiple nodules
- halo sign,
- air crescent sign,
- ground glass appearance and
- consolidation
Clin Microbiol Infect 2001;7 Suppl. 2:54-61.

16. DIAGNOSIS
 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. [1]
 Polymerase chain reaction (PCR) is another way to diagnose
IPA, by the detection of Aspergillus DNA in BAL fluid and
serum. [2]
A positiveAspergillus 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.
[1] Respir Med 1992;86:243-8.
[2] Br J Haematol 2006;132:478-86

17. DIAGNOSIS
 Galactomannan is a polysaccharide cell-wall component that is
released by Aspergillus during growth.
 Serum galactomannan can be detected 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.

18. DIAGNOSIS
 A meta-analysis study was undertaken by Pfeiffer et al. to assess
the accuracy of a galactomannan assay for diagnosing IPA.
 Overall, the assay had a sensitivity of 71% and specificity of 89%
for proven cases of invasive aspergillosis. The negative predictive
value was 92–98% and the positive predictive value was 25–62%
Pfeiffer CD et al Diagnosis of invasive aspergillosis using a galactomannan
assay: a meta-analysis. Clin Infect Dis 2006;42:1417-27

19. TREATMENT
 Early initiation of antifungal therapy in patients with strongly
suspected invasive aspergillosis is warranted while a diagnostic
evaluation is conducted [1]
 For primary treatment of invasive pulmonary aspergillosis, IV or
oral voriconazole is recommended for most patients [2]
[1] IDSA Guidelines Clin Infect Dis. (2008) 46 (3):327-360.
[2] Voriconazole versus amphotericin B for primary therapy of
invasive aspergillosis. N Engl J Med 2002;347:408-15.
Patients receiving voriconazole had a higher 12-week survival
(71% vs. 58% for amphotericin).

20. TREATMENT
 L-AMB may be considered as alternative primary therapy in some
patients . [1]
 For salvage therapy, agents include
LFABs ,
Posaconazole [2],
Itraconazole ,
Echinocandins [caspofungin , or micafungin] [3] .
[1] Amphotericin B lipid complex for invasive fungal infections: analysis of
safety and efficacy in 556 cases. Clin Infect Dis1998;26:1383-96
[2] Treatment of invasive aspergillosis with posaconazole in patients who are
refractory to or intolerant of conventional therapy: an externally controlled
trial. Clin Infect Dis 2007;44:2-12
[3] Efficacy and safety of caspofungin for treatment of invasive aspergillosis in
patients refractory to or intolerant of conventional antifungal therapy.
Clin Infect Dis 2004;39:1563-71

21. TREATMENT
 Combination antifungal drugs from different classes other than
those in the initial regimen may be used as salvage therapy
Marr, Kieren A., et al. "A randomised, double-blind study of combination
antifungal therapy with voriconazole and anidulafungin versus
voriconazole monotherapy for primary treatment of invasive
aspergillosis." Mortality 27: 0-0868.

22. TREATMENT
 Immunomodulatory therapy, such as using
- colony-stimulating factors (i.e. G-CSF, GM-CSF )[1] or
- interferon-γ [2]
- Granulocyte transfusions [3]
could be used to decrease the degree of immunosuppression,
and as an adjunct to antifungal therapy for the treatment of IPA.
[1] Blood 1995;86:457-62
[2] Curr Clin Top Infect Dis 2000;20:325-34
[3] Med Mycol 2006;44(Suppl):383-6

23. 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
Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with
neutropenia. N Engl J Med2007;356:348-59.

24. TREATMENT
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.
Full thoracoscopic approach for surgical management of invasive
pulmonary aspergillosis. Ann Thorac Surg 2002

25. CHRONIC NECROTIZING ASPERGILLOSIS
 It is an indolent, cavitary, and infectious process of the lung
parenchyma secondary to local invasion by Aspergillus species .
 In contrast to IPA, CNA runs a slowly progressive course over
weeks to months,and vascular invasion or dissemination to
other organs is unusual.

26. CHRONIC NECROTIZING ASPERGILLOSIS
 CNA usually affects middle-aged and elderly patients with altered
local defences, associated with underlying chronic lung diseases
such as
-COPD,
- previous pulmonary tuberculosis,
- thoracic surgery,
- radiation therapy,
- pneumoconiosis,
- cystic fibrosis,
- lung infarction, or
- sarcoidosis.
Respir Med1994;88:465-8

27. CHRONIC NECROTIZING ASPERGILLOSIS
 It may also occur in patients who are mildly immunocompromised
due to
-diabetes mellitus,
- alcoholism,
- chronic liver disease,
- low-dose corticosteroid therapy,
- malnutrition, and
- connective tissue diseases such as rheumatoid
arthritis and ankylosing spondylitis.
Medicine (Baltimore)1982;61:109-24.

28. CHRONIC NECROTIZING ASPERGILLOSIS
 It may be difficult to distinguish CNA from aspergilloma, especially
if a previous chest radiograph is not available.
 However, in CNA there is local invasion of the lung tissue and
a pre-existing cavity is not needed, although a cavity with a fungal
ball may develop in the lung as a secondary phenomenon, due to
destruction by the fungus.

29. CLINICAL FEATURES
 Patients frequently complain of constitutional symptoms such as
- fever,
- weight loss of 1–6 months’ duration,
- malaise, and fatigue,
- chronic productive cough and haemoptysis,
Occasionally, patients may be asymptomatic

30. DIAGNOSTIC CRITERIA
 Clinical : * Chronic ( > 1 month) pulmonary or systemic
symptom: including at least one of:
- weight loss; productive cough; haemoptysis
* No overt immunocompromising conditions
( e.g. Haematological malignancy, neutropenia
, organ transplantation)
 Radiological :
* Cavitary pulmonary lesion with evidence of
paracavitary infiltrates
* New cavity formation, or expansion of cavity
size over time

31. DIAGNOSTIC CRITERIA
 Laboratory : * Elevated levels of inflammatory markers
(C-reactive protein, plasma viscosity, or ESR )
* Isolation of Aspergillus spp from pulmonary or
pleural cavity,
* Immediate skin reactivity for Aspergillus
antigen
* Positive serum Aspergillus precipitin test
Clin Infect Dis 2003;37 Suppl. 3:S265-80

32. TREATMENT
Treatment of this infection may prevent progressive destruction
of lung tissue in patients who are already experiencing impaired
pulmonary function and who may have little pulmonary reserve
The greatest body of evidence regarding effective therapy supports the use
of orally administered itraconazole .[1]
Although voriconazole [2](and presumably posaconazole) is also likely to
be effective, there is less published information available for its use in
CNPA
[1] Mayo Clin Proc 1996;71:25-30.
[2] Chest2007;131:1435-41

33. TREATMENT
Treatment is best evaluated by following clinical, radiological,
serological, and microbiological parameters. Useful parameters
of response include
 weight gain and energy levels,
 improved pulmonary symptoms,
 falling inflammatory markers and total serum IgE level,
 improvement in paracavitary infiltrates, and eventually a
reduction in cavity size.

34. TREATMENT
Surgical resection plays a minor role in the treatment of CNA,
being reserved for
 Healthy young patients with focal disease and good pulmonary
reserves,
 patients not tolerating antifungal therapy, and
 patients with residual localized but active disease despite adequate
antifungal therapy.
Medicine (Baltimore)1982;61:109-24.

35. ASPERGILLOMA
 Aspergilloma is the most common and best recognized form of
pulmonary involvement due to Aspergillus.
 Pulmonary aspergilloma usually develops in a pre-existing cavity in
the lung.
 The aspergilloma (fungus ball) is composed of fungal hyphae,
inflammatory cells, fibrin, mucus, and tissue debris.
 The most common species of Aspergillus recovered from such
lesions is A. fumigatus; however, other fungi may cause the
formation of a fungal ball, such as Zygomycetes and Fusarium.

36. ASPERGILLOMA
 Many cavitary lung diseases are complicated by aspergilloma,
including -tuberculosis,
-sarcoidosis,
-bronchiectasis,
- bronchial cysts and bulla,
- ankylosing spondylitis,
-neoplasm, and
-pulmonary infection,
 Tuberculosis is the most common associated condition. In a study
on 544 patients with pulmonary cavities secondary to tuberculosis,
11% had radiological evidence of aspergilloma.
Clinical evaluation of 61 patients with pulmonary aspergilloma.
Intern Med 2000;39:209-12

37. ASPERGILLOMA
 Inadequate drainage is thought to facilitate the growth of
Aspergillus on the walls of these cavities.
 The fungus ball may move within the cavity, but does not usually
invade the surrounding lung parenchyma or blood vessels

38. CLINICAL FEATURES
 Most patients with aspergilloma are asymptomatic.
 When symptoms are present, most patients will experience mild
haemoptysis, but severe and lifethreatening haemoptysis 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.
 The mortality rate from haemoptysis related to aspergilloma ranges between
2% and 14%.
 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.

39. 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 radiography is useful in demonstrating the presence of a mass in
a pre-existing cavity.
 Aspergilloma appears as an upper-lobe, mobile, intra-cavitary mass
with an air crescent in the periphery. Localized pleural thickening is
characteristic
 A change in the position of the fungus ball after moving the patient on
his side or from supine to prone position ( Tilt test ) can be seen
Semin Respir Crit Care Med 2004;25:203-19.

40. DIAGNOSIS
 Chest CT scan may be necessary to visualize aspergilloma that is
not apparent on chest radiograph.These radiological appearances
may be seen in other different conditions
- haematoma,
- neoplasm,
- abscess,
- hydatid cyst, and
- Wegener’s granulomatosis.
.

41. TREATMENT
 Treatment is considered only when patients become symptomatic,
usually with haemoptysis
 Surgical resection of the cavity and removal of the fungus ball is
usually indicated in patients with recurrent haemoptysis, if their
pulmonary function is sufficient to allow surgery.
 It is the definitive treatment
Aspergilloma: a series of 89 surgical cases. Ann Thorac Surg 2000;69:898-903.

42. TREATMENT
 Bronchial artery embolization should be considered as a
temporary measure in patients with life threatening haemoptysis,
since haemoptysis usually recurs due to the presence of massive
collateral blood vessels
Cardiovasc Intervent Radiol 2000;23:351-7.

43. TREATMENT
 Administration of amphotericin B percutaneously guided by CT
scan can be effective for aspergilloma, especially in patients with
massive haemoptysis, with resolution of haemoptysis within few
days. [1]
 The role of medical therapy is uncertain Oral itraconazole
or voriconazole may be used [2]
[1] Intern Med 1995;34:85-8
[2] IDSA Guidelines Clin Infect Dis. (2008) 46 (3):327-360

44. ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS
 ABPA is a pulmonary disease that results from hypersensitivity to
Aspergillus antigens, mostly due to A. fumigatus.
 The majority of cases of ABPA occur in people with asthma or cystic
fibrosis. It is estimated that 7–14% of corticosteroid-dependent
asthmatics and 6% of patients with cystic fibrosis develop ABPA.
 The pathogenesis of ABPA is not completely understood:
Aspergillus-specific IgE-mediated type I hypersensitivity reactions,
specific IgG-mediated type III hypersensitivity reactions, and
abnormal T-lymphocyte cellular immune responses all appear to
play important roles in its pathogenesis.

45. ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS
 Most significant findings were involvement of the bronchi and
bronchioles, with
-bronchocentric granulomas
- mucoid impaction
-granulomatous inflammation consisting of palisading
histiocytes surrounded by lymphocytes, plasma cells, and
eosinophils.
- Fungal hyphae were seen,but without evidence of tissue
invasion.

46. CLINICAL FEATURES
 ABPA is usually suspected on clinical grounds, and the diagnosis is
confirmed by radiological and serological testing.
 Almost all patients have
-clinical asthma, and patients usually present
with episodic wheezing,
- expectoration of sputum containing brown plugs,
- pleuritic chest pain, and
- fever.

47. DIAGNOSIS
Diagnostic criteria for ABPA
 Asthma
 Immediate skin reactivity to Aspergillus
 Serum precipitins to A. fumigatus
 Increased serum IgE and IgG to A. fumigatus
 Total serum IgE >1000 ng/ml
 Current or previous pulmonary infiltrates
 Central bronchiectasis
 Peripheral eosinophilia (1000 cells/ml)
Greenberger PA. Allergic bronchopulmonary aspergillosis.
J Allergy Clin Immunol2002;110:685-92

48. DIAGNOSIS
 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
(gloved finger 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.

50. DIAGNOSIS
 Patterson et al. have also subdivided the clinical course of ABPA into
five stages that help to guide the management of the disease. These
stages need not occur in order.
 The first four are potentially reversible, with no long-term sequelae.
 Stage I (acute stage) is the initial acute presentation with asthma,
elevated IgE level, peripheral eosinophilia, pulmonary infiltrates,
and IgE and IgG antibodies to A. fumigatus.
 In Stage II (remission stage), the IgE falls but usually remains
elevated, eosinophilia is absent, and the chest radiograph is clear.
Serum IgG antibodies to Aspergillus antigen may be slightly
elevated.
 Stage III (exacerbation stage) is the recurrence of the same findings as
in Stage I in patients known to have ABPA. IgE rises to at least double
the baseline level.

51. DIAGNOSIS
 Stage IV (the corticosteroid-dependent stage) occurs in patients
who have asthma in which control of symptoms is dependent on
chronic use of high-dose corticosteroid therapy and exacerbations
are marked by worsening asthma, radiographic changes, and an
increase in IgE level may occur. Frequently, the chest CT scan will
show central bronchiectasis. Unfortunately, most patients are
diagnosed at this stage.
 In stage V (fibrotic stage), bronchiectasis and fibrosis develop, and
usually lead to irreversible lung disease. Patients in this stage, may
present with dyspnoea, cyanosis, rales, and cor pulmonale.
Clubbing may be present. The serum IgE level and eosinophil count
might be low or high.
Ann Intern Med 1982;96:286-91

52. TREATMENT
 Treatment of allergic bronchopulmonary aspergillosis (APBA) should
consist of a combination of corticosteroids and itraconazole.
 Corticosteroid therapy is the mainstay of therapy for ABPA , with
improved pulmonary function and fewer episodes of recurrent
consolidation. [1]
 Itraconazole has been effective in improving symptoms, facilitating
weaning from corticosteroids, decreasing Aspergillus titres, and
improving radiographic abnormalities and pulmonary function. [2]
[1] Chest 1993;103:1614-7.
[2] A randomized trial of itraconazole in allergic bronchopulmonary
aspergillosis. N Engl J Med 2000;342:756-62.

53. THANKS