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 spp. can also occur, as well as onychomycosis (fungal nail infection). Otomycosis, or fungal infection of the external auditory canal, can also occur with Aspergillus spp. as the causative organism. Aspergillus spp. may also be implicated in sinus infection.

Pulmonary aspergillosis

There are 4 main clinical syndromes caused by Aspergillus spp. gaining entry via 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 tuberculosis (TB) or sarcoid).
• Invasive aspergillosis: disseminated infection affecting the immunocompromised, which 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 malt worker's lung. It is very rare and is due to the inhalation of Aspergillus clavatus spores found in malt and mouldy hay. See separate article 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 spp. is relatively common amongst people with asthma and CF, demonstrated by skin allergen testing.
  • However, the clinical syndrome of ABPA affects about 1% of those with asthma and 5-10% of those with CF (particularly if affected by bronchiectasis).¹
  • 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%.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 spp.
    • Elevated serum immunoglobulin E (IgE).
    • Positive serology for Aspergillus spp.
    • New infiltrates on CXR or CT scan.
  • Sputum microscopy and culture may also reveal the presence of Aspergillus spp.
• 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 dependence.
  • 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 features presenting less frequently.
  • May be asymptomatic and be detected after CXR in patients with pre-existing cavitating lung disease.
  • May affect HIV-positive patients with a history of Pneumocystis jirovecii pneumonia.
• Investigations:
  • CXR 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 spp.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 with emergency surgery.
• Prognosis:
  • Aspergilloma can be benign and nonprogressive 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.
  • It is estimated to affect 5-13% of patients following bone marrow transplants, 5-25% of patients following organ transplantation and 10-20% of people with leukaemia who undergo intensive chemotherapy.¹
  • It can also occur in advanced AIDS and in patients with chronic granulomatous disease.
• Presentation:
  • It 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 spp. 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.
  • CXR may show nodules, cavitary lesions or pulmonary infiltrates.
  • CT scanning 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 spp. may also be cultured from these sources.
  • There is an assay to detect a component of the cell wall of Aspergillus spp., called galactomannan.⁷ 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. Serum galactomannan can be detected several days before the presence of clinical signs, an abnormal chest radiograph, or positive culture.
  • Another fungal cell wall constituent, B-glucan, can also be detected in the serum and has a potential role in diagnosis.⁶
  • Polymerase chain reaction (PCR) techniques are also being studied to detect Aspergillus spp. 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 Posaconazole is an alternative.
  • Echinocandin derivatives such as caspofungin, micafungin, and anidulafungin are effective agents in the treatment of invasive pulmonary aspergillosis (IPA) refractory to standard treatment, or if the patient cannot tolerate first-line agents.⁷
  • 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.⁸
  • Central nervous system (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 postmortem.
  • Its prevalence is thought to be increasing as the cohort of immunocompromised patients increases.
• Presentation:
  • It 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. chronic obstructive pulmonary disease (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 scanning show nonspecific 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

Differential diagnosis of pulmonary aspergillosis

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.
• TB.
• Sarcoidosis.

Cutaneous aspergillosis

This occurs most commonly as a result of disseminated (or invasive) infection with Aspergillus spp. However, primary skin infection can sometimes occur, particularly if there have been burns or skin trauma.¹⁰

• Invasive aspergillosis: skin lesions can occur in 5-10% of patients with disseminated infection. It appears as single or multiple erythematous or violaceous plaques or papules which may be tender, often with a central necrotic ulcer.¹⁰ The limbs and head are the most common sites of infection. Aspergillus fumigatus is most commonly associated with invasive disease leading to skin infection.¹⁰
• 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 spp. can also occur.¹⁰ Primary skin infection can lead to invasive aspergillosis, particularly if the patient is immunocompromised.¹⁰

Investigation

• Skin biopsy can suggest Aspergillus spp. infection when special staining is used; however, it is difficult to differentiate between other fungi.
• Aspergillus spp. 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.¹⁰ 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.¹¹
• Surgical excision has also been used successfully in primary cutaneous aspergillosis ± systemic antifungal treatment.¹⁰
• Oral itraconazole is used in onychomycosis associated with Aspergillus spp.¹⁰

Otomycosis caused by Aspergillus spp.

Approximately 1 in 8 otitis externa infections are fungal in origin. Approximately 90% of these are caused by Aspergillus spp.¹² Further information can be found in the separate articles Fungal Ear Infection (Otomycosis) and Otitis Externa and Painful, Discharging Ears.

Sinus infection caused by Aspergillus spp.

Fungal sinus infections are uncommon. They usually occur in the immunocompromised; however, they are becoming more common in the immunocompetent individual and Aspergillus spp. may be implicated.¹³

Noninvasive 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.¹³
• 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.¹³

Invasive sinus infection

• This can lead to tissue invasion and destruction of local structures, e.g. the orbit.
• It may have rapid onset (acute fulminant type) but chronic and granulomatous types also exist.¹³ It tends to occur in the immunocompromised.
• Aspergillus spp. usually cause chronic/granulomatous infection.¹³
• 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.¹³
• 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 spp.
• Treatment generally involves surgical debridement. Surgical removal of the fungal ball is required in mycetoma.
• Systemic and topical nasal steroids may be used postoperatively in allergic fungal sinusitis.
• If there is no invasion, systemic antifungals are not usually required.¹³

Prevention of Aspergillus spp. infection

• 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

Document references

1. Harman EM; Aspergillosis (Pulmonology perspective), eMedicine, Dec 2009
2. Skov M, McKay K, Koch C, et al; Prevalence of allergic bronchopulmonary aspergillosis in cystic fibrosis in an area with a high frequency of atopy. Respir Med. 2005 Jul;99(7):887-93. Epub 2005 Jan 26. [abstract]
3. Tillie-Leblond I, Tonnel AB; Allergic bronchopulmonary aspergillosis. Allergy. 2005 Aug;60(8):1004-13. [abstract]
4. Shiraishi Y, Katsuragi N, Nakajima Y, et al; Pneumonectomy for complex aspergilloma: is it still dangerous? Eur J Cardiothorac Surg. 2006 Jan;29(1):9-13. Epub 2005 Dec 6. [abstract]
5. Akbari JG, Varma PK, Neema PK, et al; Clinical profile and surgical outcome for pulmonary aspergilloma: a single center experience. Ann Thorac Surg. 2005 Sep;80(3):1067-72. [abstract]
6. Segal BH, Walsh TJ; Current approaches to diagnosis and treatment of invasive aspergillosis. Am J Respir Crit Care Med. 2006 Apr 1;173(7):707-17. Epub 2005 Dec 30. [abstract]
7. Zmeili OS, Soubani AO; Pulmonary aspergillosis: a clinical update. QJM. 2007 Jun;100(6):317-34. [abstract]
8. Brakhage AA; Systemic fungal infections caused by Aspergillus species: epidemiology, infection process and virulence determinants. Curr Drug Targets. 2005 Dec;6(8):875-86. [abstract]
9. Thurnheer R, Moll C, Rothlin M, et al; Chronic necrotizing pulmonary aspergillosis complicated by pneumothorax. Infection. 2004 Aug;32(4):239-41. [abstract]
10. Chiu A et al; Aspergillosis (Dermatology perspective), eMedicine, Mar 2010
11. Klein KC, Blackwood RA; Topical voriconazole solution for cutaneous aspergillosis in a pediatric patient after bone marrow transplant. Pediatrics. 2006 Aug;118(2):e506-8. Epub 2006 Jun 30. [abstract]
12. Garry JP et al; Otitis Externa, eMedicine, Feb 2010
13. Ramadan HH; Sinusitis, Fungal, eMedicine, Apr 2009

Internet and further reading

• Russell K, Broadbridge C, Murray S, et al; Gardening can seriously damage your health. Lancet. 2008 Jun 14;371(9629):2056.
• Guidelines on the management of invasive fungal infection during therapy for haematological malignancy, British Committee for Standards in Haematology (2008)

Acknowledgements