Aspergillosis

Aspergillus species 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.

Typically, inhalation of the fungal spores allows entry of the pathogen into the body and the organism has a predilection for the respiratory tract. However, primary cutaneous infection with Aspergillus species can also occur, as well as onychomycosis (fungal nail infection). Otomycosis, or fungal infection of the external auditory canal, can also occur with Aspergillus species as the causative organism. Aspergillus species may also be implicated in sinus infection.

There are 4 main clinical syndromes caused by Aspergillus species gaining entry via the respiratory tract:

• Allergic bronchopulmonary aspergillosis (ABPA): a hypersensitivity reaction to the colonisation of the airways/sinuses/lungs with Aspergillus species. 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 species 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.

Pathophysiology

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.

Allergic bronchopulmonary aspergillosis (ABPA)

• Epidemiology:
  • Allergy to Aspergillus species 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).¹
  • A recent Australian study found that in a cohort of CF patients, colonisation rates with Aspergillus species were about 19%, with ABPA affecting about 5%.²
• 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.
• Investigations:¹
  • 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 species
    • Elevated serum IgE
    • Positive serology for Aspergillus species
    • New infiltrates on CXR or CT
  • Sputum microscopy and culture may also reveal the presence of Aspergillus species.
• 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.³
• 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

Aspergilloma

• 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.¹
• Presentation:
  • Can present with haemoptysis in up to 60% of patients. This can be massive and severe enough to threaten life.¹
  • 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 jiroveci (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 Aspergillus species.¹
• 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.⁴
  • Long-term oral itraconazole may be successful in up to 60% of patients.¹
  • 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.⁵
• Complications:
  • Life-threatening haemoptysis

Invasive aspergillosis

• 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.¹
  • 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.⁶
  • 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 haematogenously and affect the kidneys, brain, heart, spleen, liver, thyroid, gastrointestinal tract, eyes and skin. Angioinvasion of hyphae can lead to vascular thrombosis, tissue infarction and coagulative necrosis.⁶
• 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).⁶
  • The sputum, lung tissue from biopsy, or bronchoalveolar lavage (BAL) fluid may show the characteristic hyphae using appropriate special stains. Aspergillus species may also be cultured from these sources.
  • There is an assay to detect a component of the Aspergillus species 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.⁶
  • PCR techniques are also being studied to detect Aspergillus species in blood and BAL fluid.⁶
  • 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.¹
  • Voriconazole is the treatment of choice.^6,1
  • Amphotericin B and caspofungin are alternatives.
  • Combination antifungal therapy needs further studies to confirm its efficacy.⁶
  • Treatment should be started without waiting for confirmation of diagnosis.¹
  • 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.⁷
  • CNS involvement has 100% mortality as does endocarditis, if it cannot be treated surgically.¹
  • 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

Chronic necrotising pulmonary aspergillosis (CNPA)

• 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.⁸
  • 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

This occurs most commonly as a result of disseminated (or invasive) infection with Aspergillus species. However, primary skin infection can sometimes occur, particularly if there have been burns or skin trauma.⁹

• Invasive aspergillosis: skin lesions can occur in 5-10% of patients with disseminated infection. Appear as single or multiple erythematous or violaceous plaques or papules which may be tender, often with a central necrotic ulcer.⁹ The limbs and head are the most common sites of infection. Aspergillus fumigatus is most commonly associated with invasive disease leading to skin infection.⁹
• Primary cutaneous aspergillosis: this is less common. Infection tends to occur on the background of previous trauma, including wound infections at canula and catheter sites and after venepuncture. Aspergillus flavus or Aspergillus terreus are the most frequent causes of primary infection. Localised cellulitis is usually followed by development of a necrotic ulcer. Onychomycosis due to infection with Aspergillus species can also occur.⁹ Primary skin infection can lead to invasive aspergillosis, particularly if the patient is immunocompromised.⁹

Investigation

• Skin biopsy can suggest Aspergillus infection when special staining is used, however, it is difficult to differentiate between other fungi.
• Aspergillus species may also be cultured.
• Galactomannan detection may be used in invasive disease, as described above.
• Other investigations should be carried out, as described above, if invasive aspergillosis is suspected.

Treatment

• For both primary skin infection and that associated with invasive aspergillosis, treatment has traditionally been with high-dose intravenous amphotericin B. Voriconazole, itraconazole and caspofungin are other treatments that are used.⁹ Voriconazole is becoming the treatment of choice for invasive aspergillosis.^6,1 Topical voriconazole combined with systemic antifungal agents has been used in cutaneous aspergillosis.¹⁰
• Surgical excision has also been used successfully in primary cutaneous aspergillosis ± systemic antifungal treatment.⁹
• Oral itraconazole is used in onychomycosis associated with Aspergillus species.⁹

Approximately 1 in 8 otitis externa infections are fungal in origin. Approximately 90% of these are caused by Aspergillus species.¹¹ Further information can be found in the separate articles Otomycosis and Otitis Externa and Painful, Discharging Ears.

Fungal sinus infections are uncommon. They usually occur in the immunocompromised, however, they are becoming more common in the immunocompetent individual and Aspergillus species may be implicated.¹²

Non-invasive sinus infection

• The underlying pathology can be either an allergic sinusitis or a sinus mycetoma.
• They can cause symptoms of sinusitis that are usually chronic.
• Aspergillus fumigatus is commonly involved but other fungi can also cause disease.¹²
• Both pathologies can occur in immunocompetent individuals, with allergic sinusitis commonly occurring in those with underlying lung disease such as asthma.
• Nasal polyps can be a common finding and people with mycetoma often report unilateral symptoms and blowing 'gravel-like material' from the nose.¹²

Invasive sinus infection

• This can lead to tissue invasion and destruction of local structures e.g. the orbit.
• May have rapid onset (acute fulminant type) but chronic and granulomatous types also exist.¹² Tends to occur in immunocompromised.
• Aspergillus species usually cause chronic/granulomatous infection.¹²
• Patients with rapid onset infection are usually severely unwell and need to be admitted to hospital; dark ulcers may be seen on the nasal septum, turbinates or palate.¹²
• Chronic/granulomatous infection may result in eye involvement and eye signs on examination.

Management

• CT and MRI scanning can help in diagnosis.
• Removal of secretions from the sinus can allow isolation of Aspergillus species.
• Treatment generally involves surgical debridement. Surgical removal of the fungal ball is required in mycetoma.
• Systemic and topical nasal steroids may be used post-operatively in allergic fungal sinusitis.
• If there is no invasion, systemic antifungals are not usually required.¹²

• 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.
• Sterile dressings should be used at susceptible sites to prevent primary cutaneous infection.
• Research into the development of vaccines against aspergillosis is ongoing.⁶