Typically presenting in immunocompromised individuals, invasive aspergillosis is hallmarked by respiratory symptoms, positive sputum and pulmonary nodules with or without the presence of halo sign.
Description
Invasive aspergillosis is a severe and potentially life-threatening infection caused by the ubiquitous environmental mould Aspergillus. The most common species responsible is Aspergillus fumigatus. The fungus primarily affects the respiratory system, leading to a range of conditions from allergic reactions to severe invasive infections. These invasive infections are most common in patients with a compromised immune system and can disseminate to virtually any organ, particularly the brain, heart, and kidneys.
Pathogenesis
Inhalation of Aspergillus conidia (fungal spores) leads to their deposition in the alveoli. In a competent immune system, these spores are destroyed by neutrophils and macrophages. In immunocompromised individuals, these conidia germinate, producing hyphae that invade blood vessels leading to haemorrhage, infarction and necrosis. This vascular invasion allows hematogenous dissemination to other organs.
Subtypes
Invasive aspergillosis has two primary clinical forms depending on the type of tissue invasion:
- Airway Invasive Aspergillosis: This subtype is characterised by invasion of the Aspergillus organisms into the bronchial mucosa and the lung parenchyma. It can lead to necrotising bronchopneumonia and may form lung cavities, particularly in patients with chronic lung disease. It tends to be a more indolent form of the disease.
- Angioinvasive Aspergillosis: This more aggressive subtype involves invasion of the fungi into the vasculature, leading to widespread vascular thrombosis, tissue infarction and haemorrhage. This can lead to rapidly progressive and often fatal disseminated disease, particularly in severely immunocompromised patients. Imaging findings can include multiple nodules, often with a halo sign on CT imaging due to the surrounding ground-glass opacities that represent haemorrhage. It can also cause an “air crescent sign” on imaging when the necrotic lung parenchyma contracts away from the cavity wall.
Despite their differences, both types predominantly affect immunocompromised individuals, with a particular predilection for patients with neutropenia.
Epidemiology, Risk Factors & Associations
- Immunosuppression, particularly in patients with haematological malignancies, organ transplant recipients and those undergoing chemotherapy (major risk factor).
- Neutropenia.
- Long term corticosteroid use.
- Advanced HIV infection.
- Chronic lung disease.
Clinical Features
- Fever unresponsive to antibiotics.
- Cough, often with haemoptysis.
- Dyspnoea.
- Chest pain.
- Symptoms related to dissemination to other organs e.g. focal neurological deficits if spread to brain.
Complications
- Disseminated disease can involve the CNS, skin, liver, kidney and heart.
- Pulmonary infarcts and abscesses.
- Cerebral abscesses in case of CNS involvement.
- Poor prognosis with high mortality if not treated promptly.
Pathological Features
Histopathology
- Macroscopic: Lung tissue reveals necrotic, haemorrhagic lesions.
- Microscopic: Septate hyphae with 45-degree branching is characteristic of Aspergillus.
Serology
- Positive galactomannan antigen and beta-D-glucan assay are indicative of invasive aspergillosis.
Biochemistry
- Non-specific changes. Patients may present with elevated inflammatory markers (CRP, ESR).
Radiological Features
General Features
- Pulmonary nodules, often with surrounding ground-glass opacity (halo sign) is a classic finding.
- Cavitation may develop within the nodules leading to ‘air-crescent’ sign.
Pulmonary Imaging
XR
- May reveal nonspecific findings such as focal consolidation or nodules.
CT
- Non-contrast: Pulmonary nodules with or without halo sign. Cavitary lesions may be seen in advanced stages.
- C+ Arterial: Helps delineate vascular invasion by the fungus.
CNS Imaging
MRI
- T1: Hypointense or isointense lesions in case of cerebral abscesses.
- T2/FLAIR: Hyperintense lesions. May show surrounding vasogenic edema.
- T1 Gad+: Rim enhancement can be seen in abscesses.
Grading and Staging
There is no established grading or staging system for invasive aspergillosis.
Diagnosis
The diagnosis is often difficult and requires a combination of clinical suspicion (especially in the appropriate patient population), imaging findings, and microbiological evidence (culture, microscopic identification, or antigen testing).
Differential Diagnosis
- Bronchogenic Carcinoma: Typically presents as a mass lesion, often with post-obstructive pneumonia. It can sometimes mimic airway invasive aspergillosis, especially if it presents with cavitation.
- Bacterial Pneumonia: This can cause a similar pattern of consolidation and cavitary lesions, though it typically affects different patient populations and is usually associated with an acute febrile illness.
- Tuberculosis: This can cause cavities and nodules similar to those seen in invasive aspergillosis, however, it has a distinct epidemiology and is usually associated with other systemic symptoms.
- Mucormycosis: This is another opportunistic fungal infection that can occur in immunocompromised patients, and has a similar angioinvasive pattern. It typically manifests as more aggressive disease, and the infection may extend into adjacent tissues such as the orbits or brain.
- Metastatic Neoplasms: These can present with multiple nodules as seen in angioinvasive aspergillosis. However, the clinical context and a history of known malignancy usually help in differentiating.
- Cryptococcosis: This fungal infection also can present with pulmonary nodules, but it’s associated with a distinct demographic (e.g., HIV patients) and often involves the CNS, causing meningoencephalitis.
- Granulomatosis with polyangiitis: This autoimmune condition can present with nodules, cavities, and hemorrhage similar to angioinvasive aspergillosis, but it is typically associated with renal disease, sinusitis, and positive c-ANCA.
- Pulmonary Emboli: Especially in septic patients, pulmonary emboli can cause infarcts that may mimic the nodules of angioinvasive aspergillosis. Contrast-enhanced CT would show the filling defects in pulmonary arteries, which aids in differentiation.
Management
Management is primarily with antifungal medication, typically voriconazole. Surgical intervention may be necessary in case of complications such as abscesses. Immunocompromised patients may require modification of their immunosuppressive regimen.