Pulmonary Aspergillosis: Aspergilloma In Focus

Respiratory Unit Dept of MedicineOAUTHC Ile-Ife

Outline

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

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

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

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.

The organism

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

• 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 Medical Sciences Vol. 4(6) pp. 237-240, June, 2013

• 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.

Risk factors

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

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])

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

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

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

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

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.

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

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

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

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

• 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

• 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.

• 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

• 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

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

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

• 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

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

• 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)

RadiologyCXRfleeting pulmonary infiltrates mucoid impaction central bronchiectasisMucoid 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 gloveCT Scan

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

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

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 cavityconfirmed by sputum culture

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

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

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

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

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.

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.

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

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

Radiology

Chronic pulmonary aspergillosis

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

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

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

• 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

• 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).

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.

• 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

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