Aspergillosis

Aspergillus spp. are widely distributed fungal moulds found in soil and other organic matter. They have also been isolated in air conditioning systems. There are more than a hundred different species but most human disease is caused by Aspergillus fumigatus or Aspergillus niger. Occasionally, Aspergillus clavatus and Aspergillus flavus cause human illness.

Inhalation of the fungal spores allows entry of the pathogen into the body. There are 4 main clinical syndromes caused by the organism which has a predilection for the respiratory tract:

• Allergic bronchopulmonary aspergillosis (ABPA): a hypersensitivity reaction to the colonisation of the airways/sinuses/lungs with Aspergillus spp. This predominantly affects patients with asthma, cystic fibrosis (CF) and bronchiectasis.
• Aspergilloma: the presence of a mycetoma (fungal ball) of aspergilli in a pre-existing pulmonary cavity (e.g. secondary to TB or sarcoid).
• Invasive aspergillosis: disseminated infection affecting the immunocompromised that often starts in the lungs but may involve other organs and tissues through haematogenous spread.
• Chronic necrotising pulmonary aspergillosis (CNPA): subacute pulmonary infection affecting those with moderate immunosuppression ± pre-existing lung disease, causing a cavitating pulmonary infiltration.

Another disease caused by Aspergillus spp. is an extrinsic allergic alveolitis known as Maltworker's lung. It is very rare and is due to the inhalation of Aspergillus clavatus spores found in malt and mouldy hay. There is a separate article on Extrinsic Allergic Alveolitis.¹

In a healthy, immunocompetent individual, macrophages and neutrophils normally defend against the inhaled fungus. A combination of toxic metabolites that attack neutrophils and macrophages, plus underlying immunosuppression affecting neutrophil numbers and function, means that this does not happen to the same extent in the immunocompromised. Steroid therapy can also affect neutrophil and macrophage function.

Epidemiology

• Allergy to Aspergillus spp. is relatively common amongst people with asthma and cystic fibrosis, demonstrated by skin allergen testing. However, the clinical syndrome of ABPA affects about 1% of those with asthma and 5 to 10% of those with cystic fibrosis (particularly if affected by bronchiectasis).²
• A recent Australian study found that in a cohort of CF patients, colonisation rates with Aspergillus spp. were about 19%, with ABPA affecting about 5%.³

Presentation

• Mostly affects people with asthma and CF.
• Clinical manifestations are:
  • Fever
  • Wheeze
  • Cough which may be severe with expectoration of large mucous plugs and haemoptysis
  • Generalised malaise
  • Severe headache
• Can be associated with allergic fungal sinusitis and cause symptoms of chronic sinusitis with purulent sinus discharge.
• Symptoms may relapse and remit or become progressive, leading to steroid dependency. In a small minority it can lead to untreatable pulmonary fibrosis.
• Pulmonary infiltrates do not respond to conventional antibiotics.

Investigations²

• The diagnosis is made on the basis of a deterioration in the patient's clinical condition (the underlying asthma or CF symptoms worsen), being a susceptible patient and the presence of the following:
  • Eosinophilia
  • Positive skin test to Aspergillus spp.
  • Elevated serum IgE
  • Positive serology for aspergilli
  • New infiltrates on CXR or CT
• Sputum microscopy and culture may also reveal the presence of aspergilli

Management

• Oral long-term high-dose steroids are the mainstay of management.
• Itraconazole has been shown to be of benefit when used in conjunction with steroids.⁴

Prognosis

• ABPA is usually responsive to steroid/itraconazole therapy if diagnosed early enough.
• Many patients become steroid-dependent.
• Late-diagnosed cases with established pulmonary fibrosis do worse.
• Control of asthma can become problematic in these patients.

Complications

• Destabilisation of asthma
• Atelectasis
• Bronchiectasis
• Steroid dependance
• Progressive pulmonary fibrosis in severe cases

Epidemiology

• Aspergilloma has a variable prevalence depending on the amount of cavitating lung disease affecting a population.
• In one series of patients with TB-related cavitary lung disease, 17% of patients were affected by aspergilloma.²

Presentation

• Presents with haemoptysis in up to 60% of patients. This can be massive and severe enough to threaten life.²
• Cough or fever are less frequent presenting features.
• May be asymptomatic and be detected after chest X-ray in patients with pre-existing cavitating lung disease.
• May affect HIV-positive patients with a history of pneumocystis carinii pneumonia.

Investigations

• Chest X-ray shows a mass within a pulmonary cavity, often in the upper lobe. A crescentic outline of air may be seen to surround a solid mass.
  
  
  
  
  
  
• CT scanning can reveal the structure of the mycetoma in more detail. Supine and prone CT scans should be performed to demonstrate the mobility of the mass, which is a highly suggestive sign.
• Most show elevated serum precipitin levels to aspergilli.²

Management

• Treatment is usually initiated when patients become symptomatic.
• Surgical treatment has been associated with high morbidity and mortality in the past. Recent improvements in technique and postoperative care may improve this outlook.⁵
• Long-term oral itraconazole may be successful in up to 60% of patients.²
• Placement of intracavitary catheters and instillation of antifungal agents such as amphotericin has been trialled.
• Life-threatening haemoptysis may need to be treated with embolisation of bronchial artery branches or emergency surgery.

Prognosis

• Aspergilloma can be benign and non-progressive but there is a significant mortality associated with massive haemoptysis.
• In a series of surgically treated patients, 10-year survival was 78% in cases of complex aspergilloma and 92% for uncomplicated cases.⁶

Complications

• Life-threatening haemoptysis

Epidemiology

• Extremely rare amongst immunocompetent patients.
• Prevalence is rising due to the increasing number of patients undergoing intensive chemotherapy to treat neoplasms and receiving organ transplants.
• Estimated to affect 5 to 13% of patients following bone marrow transplants, 5 to 25% of patients following organ transplantation and 10 to 20% of people with leukaemia who undergo intensive chemotherapy.²
• Can also occur in advanced AIDS and patients with chronic granulomatous disease.

Presentation

• Affects significantly immunocompromised patients.
• Can involve virtually any organ but sinopulmonary disease is most common.⁷
• Symptoms include:
  • Cough
  • Fever
  • Shortness of breath
  • Pleuritic chest pain
  • Haemoptysis (can be a presenting feature)
    Nasal congestion and pain (if Aspergillus Sinusitis develops)
• Signs of pneumonic consolidation may develop with a rapidly worsening clinical condition and severe hypoxia.
• The fungus may spread in the blood and affect the kidneys, brain, heart, spleen, liver, thyroid, gastrointestinal tract and eyes. Angioinvasion of hyphae can lead to vascular thrombosis, tissue infarction and coagulative necrosis.⁷

Investigations

• Invasive aspergillosis is a difficult condition to diagnose and must be specifically sought in symptomatic patients who are severely immunocompromised.
• Chest X-ray may show nodules, cavitary lesions or pulmonary infiltrates.
• CT may show characteristic changes in the lungs including the 'halo sign' (a haziness surrounding a nodule or infiltrate).⁷
• The sputum, lung tissue from biopsy, or bronchoalveolar lavage (BAL) fluid may show the characteristic hyphae using appropriate special stains. Aspergilli may also be cultured from these sources.
• There is an assay to detect a component of the Aspergillus spp. cell wall called galactomannan. This has the potential to be used as screening in those at high risk of invasive aspergillosis. Serum levels can be monitored on a regular basis. Galactomannan can also be detected in BAL fluid.
• Another fungal cell wall constituent, B-glucan, can also be detected in the serum and has a potential role in diagnosis.⁷
• PCR techniques are also being studied to detect aspergilli in blood and BAL fluid.⁷
• Results may be negative and empirical therapy is often started on clinical grounds in deteriorating patients.

Management

• Due to its high morbidity and mortality, prevention in susceptible patients is always better (see below).
• In post-organ transplant patients, inhaled amphotericin may be used to treat colonisation as evidenced by sputum culture.²
• Voriconazole is the treatment of choice.^7,2
• Amphotericin B and caspofungin are alternatives.
• Combination antifungal therapy needs further studies to confirm its efficacy.⁷
• Treatment should be started without waiting for confirmation of diagnosis.²
• Consideration should be given to reducing the dose of immunosuppressive medications and giving treatment for neutropenia such as granulocyte colony-stimulating factor.

Prognosis

• Invasive aspergillosis has a poor outlook with mortality up to 90% in some circumstances.⁸
• CNS involvement has 100% mortality as does endocarditis, if it cannot be treated surgically.²
• Immunosuppressed patients may respond to treatment but are prone to relapse during future periods of immunosuppression.

Complications

• Severe haemoptysis
• Respiratory failure
• Disseminated aspergillosis
• Multi-organ failure
• Death

Epidemiology

• CNPA appears to be rare, but has an unknown incidence as it is thought to be significantly underdiagnosed.
• It is often a diagnosis made at post mortem.
• Its prevalence is thought to be increasing as the cohort of immunocompromised patients increases.

Presentation

• Affects patients with mild to moderate immunosuppression such as that caused by alcoholism or steroid dependency. There may be pre-existing lung disease, e.g. COPD.
• Symptoms include:
  • Fever
  • Night sweats
  • Cough
  • Anorexia and weight loss
• It has the characteristics of an indolent pneumonia that doesn't respond to usual antibiotic therapy. The pneumonic consolidation may spread gradually and undergo cavitation.
• It should be suspected in appropriate patients who have pneumonia that does not respond to antibiotics or empirical anti-TB therapy.

Investigations

• CXR and CT show non-specific features of nodules, cavitation and consolidation.
• Diagnosis requires the demonstration of fungal hyphae in sputum/biopsy/BAL fluid.

Management

• Early administration of voriconazole or itraconazole.
• Surgical resection may be considered for cases unresponsive to medical therapy.⁹
• Reduction or elimination of immunosupression should also be carried out where possible.

Prognosis

• CNPA has a significant mortality of up to 40%, even if promptly recognised and treated.
• It is easy to miss and in such cases carries a worse prognosis.

Complications

• Pulmonary cavitation
• Pneumothorax
• Segmental or lobar collapse
• Progressive respiratory failure

The differentials of the various clinical syndromes are wide, depending on the presenting symptoms, radiological findings and clinical course. Conditions to consider include:

• Asthma
• Acute respiratory distress syndrome
• Bronchiectasis
• Eosinophilic pneumonia
• Wegener's granulomatosis
• Extrinsic allergic alveolitis
• Other opportunistic infections in the immunocompromised
• Tuberculosis
• Sarcoidosis

• Immunocompromised patients can be protected from contracting invasive aspergillosis by use of strict aseptic techniques and isolation in air-filtered/positive-pressure rooms.
• Oral fluconazole or inhaled amphotericin may be used as prophylactic agents in susceptible individuals.
• Research into the development of vaccines against aspergillosis is ongoing.⁷