ASPERGILLOSIS

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

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.

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

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.

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.

CLINICAL MANIFESTATIONS

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

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

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.

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

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.

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

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).

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

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.

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

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.

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

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.

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

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.

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.

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

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

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

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

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.

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.

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.

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

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

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.

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.

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.

.

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.

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.

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

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.

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.

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.

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

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.

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.

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

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.

THANKS