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Microbiology

• most cases due to Aspergillus fumigatus

• a few cases due to A. flavus or niger

Predisposing factors

• invasion by Aspergillus is rare except in the immunocompromised

• 90% of patients have at least 2 of the following:

  • neutropaenia (<0.5)

  • supranormal concentrations of adrenocorticoids

  • history of cytotoxic administration

Pathophysiology

Hyphae invade blood vessels and cause thrombosis, necrosis and haemorrhagic infarction

Syndromes

Acute invasive pulmonary aspergillosis

• highly lethal condition in the immunocompromised despite treatment. Investigation and treatment should be prompt and aggressive

• presents as an acute pneumonia in the immunocompromised

• 25-33% initially asymptomatic

• cough (usually dry)

• fever

• low grade chest pain. Often non-specific rather than pleuritic

• in neutropaenic patients occasionally presents with pneumothorax

• presentation may resemble pulmonary embolus

• infection progresses by haematogenous spread or spread to contiguous lung or other structures

Diagnosis

• Definitive diagnosis requires both histological evidence of acute-angle branching, septated nonpigmented hyphae measuring 2-4 mm in width and cultures yielding Aspergillus species from biopsy specimens of involved organs.

• In immunocompromised, but not immunocompetent, patients recovery of Aspergillus species from respiratory secretions may indicate invasive disease (positive predictive value as high as 80-90% in patients with leukaemia or bone marrow transplant recipients).

• Bronchoalveolar lavage with smear, culture and antigen detection has excellent specificity and reasonably good positive predictive value for invasive aspergillosis in immunocompromised patients.

• Radiology may give a clue to the diagnosis but not sufficiently specific to be diagnostic.

  • CXR:

    • Cavitation and pleural based wedge shaped lesions most distinctive appearance

    • Nodular shadowing ± cavitation, cavities and alveolar consolidation that coalesces over time to form small nodules are typical

    • Pleural effusions are rare

    • May be normal early in the course of rapidly progressive disease. CT is more sensitive.

  • CT: “halo sign” (area of low attenuation surrounding a nodular lung lesion) occurs early while the “crescent sign” (an air crescent near the periphery of a lung nodule) is a late feature.

• WCC and chemistry usually normal

Management

• Acutely ill immunocompromised patients: intravenous therapy should be initiated if there is suggestive evidence of invasive aspergillosis while further investigations to confirm or refute the diagnosis are carried out. 

• Standard therapy consists of voriconazole

  • loading dose of 6 mg/kg twice daily on day 1
  • maintenance dose of 4 mg/kg twice daily thereafter for at least 7 days

Prognosis

• Prognosis of focal (especially nodular) disease is better than diffuse

Aspergillus tracheobronchitis

• More common in patients with AIDS and lung transplant recipients than other immunocompromised patients

• Clinical features range from relatively mild tracheobronchitis to ulcerative tracheobronchitis with ulcers (often around suture line in lung transplant recipients) and extensive pseudomembranous tracheobronchitis

• Approximately 80% are symptomatic:

  • Cough

  • Fever

  • Dyspnoea

  • Chest pain

  • Haemoptysis

  • Patients with pseudomembranous tracheobronchitis may develop unilateral monophasic wheeze/stridor

• Many patients die of respiratory insufficiency secondary to occlusion of airway.

• CXR is usually normal initially

• Bronchoscopy with bronchial biopsy, microscopy and culture is the only way of making an antemortem diagnosis

• Therapy with itraconazole appears to be superior to systemic amphotericin for this condition but oral or NG itraconazole is only appropriate for patients with good GI function and who are not taking drugs that induce metabolism of cytochrome P450.

Aspergilloma

• severe haemoptysis due to aspergilloma is an indication for resection. Systemic antifungals have no role. Surgery also indicated for lesions impinging on great vessels or major airways.

Cerebral aspergillosis

• Occurs in 10-20% of all cases of invasive aspergillosis.Only rarely is brain the sole site of infection.

• Clinical features and pace of progression vary markedly with host group. Most immunocompromised present with nonspecific findings (ß mental state and fits) shortly before death. Slightly less immunocompromised patients are more likely to have focal features and headache.

• fever but this may be attributed to other co-existent infections

• meningism is rare

• CT appearances also vary with degree of immunosuppression

  • Highly immunocompromised: ³1 hypodense well-demarcated lesions. Haemorrhage and mass effect are unusual

  • Normal WCC: ring enhancement and surrounding oedema more frequent

  • Less immunocompromised: mass lesion, surrounded by oedema and midline shift, usually with contrast enhancement.

• Differential diagnosis of CT appearance depends on underlying illness:

  • Bone marrow transplant recipient: Candida

  • Liver transplant recipient: cerebral infarction and haemorrhage

  • Other solid organ transplant recipients: nocardiosis, toxoplasmosis, cryptococcosis, lymphoma

  • AIDS: toxoplasmosis, lymphoma

• CSF usually abnormal but changes are non-specific

• Definitive diagnosis requires biopsy/aspiration

• Treatment: IV amphotericin B 0.8-1 mg/kg/day (1-1.25 mg/kg/day for neutropaenic patients. If renal dysfunction is likely to be a major problem or patient is intolerant of amphotericin B or disease progresses despite an adequate dose give a lipid-associated preparation in doses of 4-5 mg/kg/day. Give a total of 2-2.5 g (empirical recommendation)

• >95% mortality

Prognosis

Factors associated with poor prognosis other than underlying illness and site of disease:

• Leukaemic relapse

• Persistent neutropaenia

• No reduction in immunosuppression

• Diffuse pulmonary disease

• Major haemoptysis

• Delayed therapy

• Low doses of amphotericin, especially during neutropaenia

• Undetectable or very low serum itraconazole concentrations

• Histological evidence of angioinvasion

Further reading

Stevens DA et al. Practice guidelines for diseases caused by Aspergillus. Clin.Infect.Dis 30:696-709, 2000.

Herbrecht R et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis.NEJM 347:408-415, 2002

©Charles Gomersall, May, 2008 unless otherwise stated. The author, editor and The Chinese University of Hong Kong take no responsibility for any adverse event resulting from the use of this webpage.
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