Aspergillosis

Aspergillosis is a spectrum of disease caused by Aspergillus species, most commonly Aspergillus fumigatus. It ranges from allergic hypersensitivity in patients with asthma or cystic fibrosis, through chronic colonisation of pre-existing pulmonary cavities, to invasive, angioinvasive disease in profoundly immunocompromised patients. Each clinical syndrome requires an entirely distinct management approach.

Classification

Allergic bronchopulmonary aspergillosis is a hypersensitivity reaction to Aspergillus colonising the airways, occurring predominantly in patients with asthma or cystic fibrosis.

Aspergilloma (fungal ball) develops from Aspergillus colonisation of a pre-existing lung cavity, typically from prior tuberculosis, sarcoidosis or other cavitary lung disease, without tissue invasion.

Chronic pulmonary aspergillosis is a more indolent, progressive cavitary and destructive lung disease. It occurs in patients with underlying structural lung disease but relatively preserved immune function.

Invasive pulmonary aspergillosis is angioinvasive infection in profoundly immunocompromised patients (prolonged neutropenia, haematopoietic stem cell transplantation, high dose corticosteroid therapy). It carries substantial mortality if not promptly recognised and treated.

Allergic bronchopulmonary aspergillosis presents with poorly controlled asthma, wheeze, productive cough with characteristic brown mucus plugs, and recurrent pulmonary infiltrates, often with peripheral blood eosinophilia.

Aspergilloma is frequently asymptomatic, discovered incidentally on imaging. Haemoptysis, sometimes massive and life threatening, is the principal clinical concern.

Chronic pulmonary aspergillosis presents with a subacute to chronic course of cough, haemoptysis, weight loss, fatigue and progressive breathlessness over months to years.

Invasive pulmonary aspergillosis presents with fever unresponsive to broad spectrum antibiotics in a neutropenic or otherwise significantly immunocompromised patient. Pleuritic chest pain and cough accompany it and, in advanced disease, haemoptysis. The initial presentation is non specific and early treatment is critical, so a high index of suspicion is required.

Allergic bronchopulmonary aspergillosis diagnosis combines elevated total and Aspergillus specific IgE, peripheral eosinophilia, positive Aspergillus skin prick testing or specific IgE, and characteristic imaging findings (central bronchiectasis, mucus plugging).

Aspergilloma is diagnosed radiographically, with a characteristic mobile intracavitary mass (the air crescent or Monod sign) on chest radiograph or computed tomography. Serum Aspergillus IgG (precipitins) is typically positive.

Chronic pulmonary aspergillosis diagnosis combines a compatible clinical and radiographic picture (progressive cavitary change, often with surrounding fibrosis) persisting beyond three months with positive Aspergillus IgG serology. Microbiological or histological confirmation is added where obtained.

Invasive pulmonary aspergillosis diagnosis in the appropriate high risk host combines characteristic computed tomography findings with serum or bronchoalveolar lavage galactomannan antigen testing and beta D glucan. Culture or histopathological demonstration of septate hyphae with acute angle branching also supports it.

The computed tomography findings are nodules with a surrounding ground glass halo sign early in the disease, or an air crescent sign in late disease as the lesion cavitates. Biopsy or bronchoalveolar lavage is used for culture or histopathology where feasible.

Treatment should not be delayed while awaiting definitive microbiological confirmation, given the high mortality associated with any delay in treatment initiation.

Allergic bronchopulmonary aspergillosis is treated with oral corticosteroids (prednisolone 0.5 mg per kg daily, typically 30 to 40 mg, tapered over three to six months) to control the underlying hypersensitivity inflammatory process.

Itraconazole 200 mg twice daily is added as a steroid sparing agent for relapsing or corticosteroid dependent disease, given for a minimum of sixteen weeks. Monitor itraconazole levels given variable absorption and significant drug interactions.

Asymptomatic aspergilloma without haemoptysis may be managed with observation alone. Significant or recurrent haemoptysis warrants bronchial artery embolisation as first line intervention for acute bleeding.

Consider surgical resection for definitive management in patients with adequate pulmonary reserve, particularly where embolisation has failed or bleeding recurs.

Chronic pulmonary aspergillosis is treated with prolonged oral azole therapy: itraconazole 200 mg twice daily or voriconazole 200 mg twice daily (following an initial loading dose regimen). Continue for a minimum of six months and frequently longer.

Therapeutic drug monitoring is essential given significant interpatient pharmacokinetic variability. Consider surgical resection in selected patients with localised disease and adequate pulmonary reserve.

Invasive pulmonary aspergillosis requires immediate treatment with voriconazole as first line therapy. Give an intravenous loading dose of 6 mg per kg twice daily on day one, followed by a maintenance dose of 4 mg per kg twice daily intravenously.

Transition to oral voriconazole 200 mg twice daily once clinically stable and able to absorb oral medication. Therapeutic drug monitoring targets a trough level of 1 to 5.5 mg per litre, given substantial interpatient variability in metabolism and the narrow therapeutic index of this agent.

Isavuconazole (intravenous or oral, 200 mg three times daily for the first two days then 200 mg once daily) is an effective alternative to voriconazole with a more favourable drug interaction and hepatotoxicity profile.

Liposomal amphotericin B (3 to 5 mg per kg once daily intravenously) is used as an alternative or salvage agent, particularly where azole intolerance, significant drug interactions or resistance is a concern.

Duration of treatment for invasive disease is a minimum of six to twelve weeks, guided by clinical and radiographic response and, critically, by resolution or improvement of the underlying immunosuppression. Reduction in immunosuppression wherever clinically feasible is an essential adjunct to antifungal therapy.