Background: Pulmonary aspergillosis is a spectrum of mycotic diseases caused by Aspergillus species, usually Aspergillus fumigatus. This intensely antigenic and ubiquitous soil fungus is commonly found in the sputum of healthy individuals. However, in susceptible hosts, its ability to invade the arteries and veins facilitates its hematogenous spread.

The development of disease and its histologic, clinical, and radiologic manifestations depend on the virulence and number of spores inhaled and, more importantly, on the patient’s immune status.

Pulmonary aspergillosis may take any of 4 forms:

1. Allergic bronchopulmonary aspergillosis (ABPA) is caused by a hypersensitivity reaction to the fungus and most commonly occurs in those with asthma.

    

2. Saprophytic aspergillosis, or aspergilloma, is the most common form. This form is noninvasive and involves colonization of preexisting cavities.

    

3. Chronic necrotizing aspergillosis, also called airway-invasive or semi-invasive aspergillosis, is a chronic cavitary pneumonic illness that often affect patients with preexisting chronic lung disease.

    

4. Angioinvasive aspergillosis affects immunocompromised patients and is often fatal.

Pathophysiology: A fumigatus exists in 2 forms: (1) conidiophores, the reproductive forms that produce and release thousands of spores, and (2) hyphae, which represent mature spores that are characterized by a 45° dichotomous branching pattern.

The fungus grows widely in soil, water, and decaying vegetable or animal material. The spores are readily inhaled, and the fungus is a common commensal organism in the upper respiratory tract. Most patients with pulmonary aspergillosis have either an underlying preexisting chronic lung disease or impaired immunity. Examples of preexisting chronic lung disease include bronchiectasis, chronic obstructive lung disease, and tuberculosis. Impaired immunity secondary to alcoholism, advanced age, poorly controlled diabetes mellitus, underlying malignancy, cirrhosis, malnutrition, sepsis, organ transplantation, or AIDS, for example.

ABPA represents a hypersensitivity reaction to A fumigatus in patients with long-standing asthma or cystic fibrosis. Excessive mucus production in association with impaired ciliary function leads to mucoid impaction of the airways. The plugs of inspissated mucus contain A fumigatus and eosinophils, but the organisms remain within the bronchial lumen; this feature differentiates ABPA from invasive aspergillosis.

Precipitating antibodies incite a type I acute hypersensitivity reaction with the subsequent release of immunoglobulin E (IgE) and immunoglobulin G (IgG). Immune complexes and inflammatory cells are then deposited within the bronchial mucosa. This deposition produce tissue necrosis and eosinophilic infiltrate, a type III reaction, and results in damage to the bronchial wall with the subsequent development of bronchiectasis. Patients may cough up mucus plugs from which hyphal elements can be cultured or observed at microscopy.

The primary diagnostic criteria for ABPA include the following:

• Asthma, 84-96%

   

• Blood eosinophilia, 8-40%

   

• Elevated serum IgE levels

   

• Positive skin test results for A fumigatus

   

• Elevated serum levels of IgE and IgG specific for A fumigatus

   

• Presence of precipitating antibodies to A fumigatus

The primary radiologic criteria include fixed or transitory pulmonary infiltrates and central bronchiectasis as a late manifestation. A set of secondary criteria can sometimes be applied; these include the presence of A fumigatus mycelia in the sputum, the expectoration of brown sputum plugs, and a delayed cutaneous reaction to A fumigatus antigen.

ABPA can be staged by using the following clinical and radiologic criteria:

• Stage I - Acute presentation with 6 of the 8 primary diagnostic criteria listed above

   

• Stage II - Resolving pulmonary infiltrates with decreasing IgE levels leading to remission

   

• Stage III - Recurrence of acute symptoms after a period of remission

   

• Stage IV - Steroid dependency

   

• Stage V - Irreversible lung damage leading to fibrosis

In the saprophytic form (ie, aspergilloma), noninvasive colonization of a preexisting cavity, cyst, bulla, or ectatic bronchus occurs. The most common underlying conditions are tuberculosis, sarcoidosis, and bronchiectasis. Others include cystic fibrosis, ankylosing spondylitis, bronchogenic cysts, pneumoconiosis, pulmonary sequestration, cavitating malignancy, and pneumatoceles secondary to Pneumocystis carinii pneumonia. Histologically, the aspergilloma represents a fungal ball, or mycetoma, which consists of a masslike conglomerate of intertwined hyphae intermingled with fibrin, cellular debris, mucus, and other blood products. This mycetoma may calcify in an amorphous or ringlike fashion. Elevated serum precipitin levels are present in approximately one half of the patients.

Chronic necrotizing aspergillosis, or semi-invasive aspergillosis, is an indolent disease that affects patients with mild immunosuppression due to chronic debilitating illness, particularly those with chronic obstructive pulmonary disease (COPD). Other recognized predisposing illnesses include alcoholism, advanced age, and prolonged steroid administration. Bronchiolitis and bronchopneumonia develop, with slowly progressive cavitating consolidation predominating in the upper lobes. This consolidation may be indistinguishable from tuberculosis. Histologically, a proliferation of organisms within the alveolar spaces, intra-alveolar hemorrhage, and bronchial wall invasion that leads to tissue necrosis with microabscess formation are present, but no angioinvasion is observed.

Invasive aspergillosis is the most common fungal pulmonary infection in severely immunocompromised patients, particularly those with reticuloses. Transplant recipients are also at particular risk. The spores proliferate in the airways; this proliferation leads to transbronchial angioinvasion that causes hemorrhagic infarction. These areas may become cavitated and contain a devitalized sequestrum of infected lung; these areas can mimic a mycetoma. Also, the fungus can disseminate systemically and affect the heart, brain, kidneys, liver, spleen, thyroid, and gastrointestinal tract.

A fumigatus may also infect the pleura, causing an empyema in patients with pulmonary tuberculosis or bronchopleural fistulae. Occasionally, A fumigatus may secondarily infect an existing bacterial empyema.

Frequency:

• In the US: Approximately 1-2% of asthmatic patients and 10% of patients with cystic fibrosis have ABPA. Aspergillomas are reported to account for 0.02% of hospital admissions. The precise incidence of chronic necrotizing aspergillosis is unknown, but it is thought to be increasing.

  Recently, the number of patients with invasive aspergillosis has substantially increased. One of the reasons for this increasing incidence is the development of new intensive chemotherapy for leukemia, lymphoma, and myeloma, as well as the increasing numbers of solid organ transplantations. Invasive pulmonary aspergillosis is reported in 5% of bone marrow transplant recipients, 3-9% of renal transplant recipients, and 1-5% of heart and/or lung or liver transplant recipients.

• Internationally: Aspergillomas are complications in 15-20% of patients with lung cavities 2 cm or larger. The incidence of invasive aspergillosis in AIDS patients is 1-12% worldwide. In the United Kingdom, the incidence is around 4-5%.

Mortality/Morbidity: The mortality and morbidity rates with pulmonary aspergillosis depend on the type of disease.

• In most patients, ABPA responds to steroids, but a small proportion of cases are refractory to treatment and progress to stage V disease.

• Approximately 10% of mycetomas resolve spontaneously. Massive hemoptysis is a well-recognized complication. Most patients are not candidates for surgery and treated conservatively. However, the mortality rate in these patients can be as high as 50%, compared with a 1-23% surgical mortality rate.

• Chronic necrotizing aspergillosis has a significant morbidity rate, and, if left untreated, it has a significant mortality rate. However, the precise incidences are unknown. The slow progression of clinical and radiologic findings may contribute to a delay in diagnosis.
  
  
• The prognosis in invasive aspergillosis is uniformly poor, and the mortality rate is high. Early diagnosis and prompt treatment are essential in determining survival.

Sex: The male-to-female ratio is 3:1.

Age: Pulmonary aspergillosis mostly affects adults aged 20-90 years.

Anatomy: Most mycetomas derive their blood supply from the bronchial arteries. The bronchial arteries not only perfuse the bronchi but also contribute blood supply to the mid esophagus, diaphragm, mediastinal visceral pleura, and vasa vasora of the aorta and pulmonary arteries. In addition, an occasional contribution to the thoracic spinal cord and the myocardium may be present. Knowledge of the bronchial arterial supply is important to prevent potentially catastrophic complications from arterial embolization of mycetomas.

Clinical Details: Acute clinical symptoms in ABPA include a low-grade fever, wheezing, productive cough, weight loss, malaise, headaches, and chest pain. Patients with ABPA also have a history of recurrent pneumonia.

Patients with aspergillomas are frequently asymptomatic. The most common clinical manifestation is hemoptysis, which may be life threatening.

Symptoms of chronic necrotizing aspergillosis are often insidious at onset and nonspecific. These symptoms include a productive cough, fever, and constitutional upset and represent acute tracheobronchitis, bronchiolitis, or bronchopneumonia. Hemoptysis occurs in only 15% of patients.

The angioinvasive form often causes nonspecific constitutional symptoms, which make clinical diagnosis difficult. Patients often have an unremitting fever and pleuritic chest pain, which may mimic the findings of pulmonary embolism.

Preferred Examination: Chest radiography is an initial examination of choice in patients with respiratory symptoms or suspected pulmonary disease. However, many different causes of bronchiectasis, including ABPA, cannot be accurately diagnosed on chest radiographs. Also, radiographic features of pulmonary aspergillosis are generally nonspecific.

Although the CT features of ABPA are not specific, the demonstration of bronchial dilatation, wall thickening, and centrilobular nodules in an asthmatic patient should suggest the diagnosis. The demonstration of a mobile mass within a cavity on supine and prone scans is virtually diagnostic of a mycetoma. The CT appearances of chronic necrotizing aspergillosis also are nonspecific, but CT does provide useful information regarding the extent of pulmonary disease and any associated pleural thickening. CT findings in angioinvasive aspergillosis are more specific, and the presence of nodules with a halo of ground-glass attenuation in the appropriate clinical setting allows confident diagnosis.

Limitations of Techniques: The appearances of the different types of thoracic aspergillosis are nonspecific, and a wide variety of lesions can mimic an aspergilloma. Examples of these include chronic necrotizing aspergillosis, angioinvasive aspergillosis, a tuberculous cavity with a Rasmussen aneurysm, cavitating bronchogenic carcinoma, lung abscess, hematoma, and P carinii pneumonia. Similarly, bronchial dilatation has a variety of causes.

DIFFERENTIALS

Asthma
Bronchiectasis
Bronchogenic Cyst
Pneumonia, Pneumocystis Carinii
Wegener Granulomatosis, Thoracic

Other Problems to be Considered:

Differential diagnosis of cavitating upper lobe consolidation

Chronic necrotizing aspergillosis
Mucormycosis
Tuberculosis
Amyloidosis
Sarcoidosis
Mycobacterium avium-intracellulare complex infection
Viral and mycoplasma pneumonia

Differential diagnosis of multiple pulmonary nodules

Angioinvasive aspergillosis
Hemorrhagic metastases
Infection with Mucorales fungi, Candida species, herpes simplex virus, or cytomegalovirus, Wegener granulomatosis
Kaposi sarcoma

X-RAY

Findings: In ABPA, chest radiographic appearances include the following: (1) fleeting alveolar subsegmental or lobar infiltrates, which are usually bilateral (65%) and predominant in the upper lobes (50%); (2) central 1-2-cm ring shadows that represent varicose or cystic bronchiectasis; and (3) tram-link bronchial walls due to edema. The second-order bronchi may become plugged with mucus, and they may be visible as 2.5-6-com long V- or Y-shaped branching tubular opacities that may grow over time and persist for months; this is the so-called finger-in-glove sign.

Other features include lobar consolidation, atelectasis, postobstructive pneumonia, cavitation, air trapping, and parenchymal scarring or fibrosis, all of which are more pronounced in the upper lobes. Focal pleural thickening is also reported. Occasionally, mycetomas develop in ectatic bronchi.

The characteristic chest X-ray appearance of an aspergilloma is that of a round or oval mass with the opacity of that of a soft-tissue mass. Often, an adjacent crescent-shaped air space (ie, the air-crescent sign) separates the fungal ball from the cavity wall. The mycetoma may rarely contain amorphous or rimlike calcification. The fungal ball is usually mobile and moves when the patient changes position. Often, extensive adjacent apical pleural thickening may be present; this finding may herald the development of the mycetoma.

The radiologic manifestations of chronic necrotizing aspergillosis include unilateral or bilateral segmental areas of consolidation that are predominant in the upper lobes; frequently, these progress to cavitation. Pleural thickening also is a recognized feature.

The most common chest radiographic appearance of invasive aspergillosis is that of patchy areas of consolidation, which progress despite the use of broad-spectrum antibiotics. Multiple nodules and peripheral wedged-shaped lesions due to hemorrhagic infarcts are also observed as the disease progresses. These frequently become cavitated, and an air-crescent sign that mimics mycetoma may also be observed.

Degree of Confidence: The many different causes of bronchiectasis, including ABPA, cannot be accurately diagnosed with radiographs. Also, the radiographic features of pulmonary aspergillosis are generally nonspecific.

False Positives/Negatives: An air-crescent sign may occur in the following: aspergilloma, chronic necrotizing aspergillosis, angioinvasive aspergillosis, tuberculous cavity with a Rasmussen aneurysm, cavitating bronchogenic carcinoma, lung abscess, hematoma, and P carinii pneumonia.