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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.
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.
There are five 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.
- Severe asthma with fungal sensitisation (SAFS): severe asthma (despite standard treatment) with evidence of fungal sensitisation who do not meet the criteria for ABPA.
- Aspergilloma: the presence of a mycetoma (fungal ball) of aspergilli in a pre-existing pulmonary cavity (eg, 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 A. clavatus spores found in malt and mouldy hay. See separate Extrinsic Allergic Alveolitis article.
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)
- 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).
- An Australian study found that in a cohort of CF patients, colonisation rates with Aspergillus spp. were about 19%, with ABPA affecting about 5%.
- People with asthma and CF are mostly affected. Clinical manifestations are:
- Cough which may be severe with expectoration of large mucous plugs and haemoptysis.
- Generalised malaise.
- Severe headache.
- It 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.
- 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:
- 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.
- 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.
- 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.
- Destabilisation of asthma.
- Steroid dependence.
- Progressive pulmonary fibrosis in severe cases.
Severe asthma with fungal sensitisation (SAFS)
The term SAFS has been used to illustrate the high rate of fungal sensitivity in patients with persistent severe asthma and improvement with antifungal treatment.
- SAFS refers to patients with severe asthma (despite standard treatment) with evidence of fungal sensitisation who do not meet the criteria for ABPA.The total IgE is usually lower than for patients with ABPA (total IgE <1000 IU/mL).
- SAFS may affect 20-25% of patients with persistent asthma. The relationship between SAFS and ABPA is not fully understood and both diseases may represent a spectrum of fungal allergic disease.
- Most patients only react to one of two fungi, most often A. fumigatus or Candida albicans. Radioallergosorbent test (RAST) titres to A. fumigatus are much lower than titres in patients with ABPA.
- Patients with SAFS usually have chronic severe asthma symptoms despite maximal treatment, including steroids.
- Treatment of SAFS should initially be similar to that of severe asthma.
- SAFS responds to oral antifungal therapy as judged by large improvements in quality of life in about 60% of patients.
- Antifungal therapy with itraconazole is beneficial (fluconazole may be beneficial in those sensitised to Trichophyton spp.). The duration of antifungal therapy required is not yet fully established.
- Aspergilloma has a variable prevalence depending on the amount of cavitating lung disease affecting a population.
- The prevalence of clinically significant haemoptysis is associated with the absolute size of cavity and mass of aspergilloma.
- It can present with haemoptysis in up to 60% of patients. This can be massive and severe enough to threaten life.
- Cough or fever are features presenting less frequently.
- It may be asymptomatic and be detected after CXR in patients with pre-existing cavitating lung disease.
- It may affect HIV-positive patients with a history of Pneumocystis jirovecii pneumonia.
- 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.
- Treatment is usually initiated when patients become symptomatic.
- Surgical resection should be considered for all patients with pulmonary aspergilloma who have acceptable pulmonary reserve.
- Long-term oral itraconazole may be successful in up to 60% of patients.
- 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.
- Aspergilloma can be benign and non-progressive but there is a significant mortality associated with massive haemoptysis.
- In one study of postsurgical aspergilloma cases, operative mortality was 3.8%. Actuarial survival at three years was 90% and 100% for complex aspergilloma and simple aspergilloma respectively.
- Life-threatening haemoptysis.
- This is 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.
- It can also occur in advanced AIDS and in patients with chronic granulomatous disease.
- It affects significantly immunocompromised patients.
- Virtually any organ can be involved but sinopulmonary disease is most common.
- Symptoms include:
- 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.
- 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).
- 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.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.
- Polymerase chain reaction (PCR) techniques are also being studied to detect Aspergillus spp. in blood and BAL fluid.
- Results may be negative and empirical therapy is often started on clinical grounds in deteriorating patients.
- 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.
- Voriconazole is the treatment of choice. Posaconazole is an alternative. Amphotericin may be used if initial treatment fails.
- 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.
- Combination antifungal therapy needs further studies to confirm its efficacy.
- Treatment should be started without waiting for confirmation of diagnosis.
- Consideration should be given to reducing the dose of immunosuppressive medications and giving treatment for neutropenia, such as granulocyte colony-stimulating factor.
- Invasive aspergillosis has a poor outlook with mortality up to 90% in some circumstances.
- Central nervous system (CNS) involvement has 100% mortality, as does endocarditis, if it cannot be treated surgically.
- Immunosuppressed patients may respond to treatment but are prone to relapse during future periods of immunosuppression.
- Severe haemoptysis
- Respiratory failure
- Disseminated aspergillosis
- Multi-organ failure
Chronic necrotising pulmonary aspergillosis (CNPA)
- 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.
- It affects patients with mild-to-moderate immunosuppression such as that caused by alcoholism or steroid dependency. There may be pre-existing lung disease - eg, chronic obstructive pulmonary disease (COPD).
- Symptoms include:
- Night sweats.
- 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.
- CXR and CT scanning show nonspecific features of nodules, cavitation and consolidation.
- Diagnosis requires the demonstration of fungal hyphae in sputum/biopsy/BAL fluid.
- Early administration of voriconazole or itraconazole.
- Surgical resection may be considered for cases unresponsive to medical therapy.
- Reduction or elimination of immunosupression should also be carried out where possible.
- 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.
- Pulmonary cavitation
- 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:
- Acute respiratory distress syndrome.
- Eosinophilic pneumonia.
- Granulomatosis with polyangiitis (Wegener's granulomatosis).
- Extrinsic allergic alveolitis.
- Other opportunistic infections in the immunocompromised.
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.
- 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.The limbs and head are the most common sites of infection. A. fumigatus is most commonly associated with invasive disease leading to skin infection.
- Primary cutaneous aspergillosis: this is less common. Infection tends to occur on the background of previous trauma, including wound infections at cannula and catheter sites and after venepuncture. A. 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.Primary skin infection can lead to invasive aspergillosis, particularly if the patient is immunocompromised.
- 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.
- For both primary skin infection and that associated with invasive aspergillosis, treatment has traditionally been with high-dose intravenous amphotericin. Voriconazole, itraconazole and caspofungin are other treatments that are used.Voriconazole is becoming the treatment of choice for invasive aspergillosis.Topical voriconazole combined with systemic antifungal agents has been used in cutaneous aspergillosis.
- Surgical excision has also been used successfully in primary cutaneous aspergillosis ± systemic antifungal treatment.
- Oral itraconazole is used in onychomycosis associated with Aspergillus spp.
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.Further information can be found in the separate Fungal Ear Infection (Otomycosis) and Otitis Externa and Painful, Discharging Ears articles.
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.
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.
- A. fumigatus is commonly involved but other fungi can also cause disease.
- 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.
Invasive sinus infection
- This can lead to tissue invasion and destruction of local structures - eg, the orbit.
- It may have rapid onset (acute fulminant type) but chronic and granulomatous types also exist.It tends to occur in the immunocompromised.
- Aspergillus spp. usually cause chronic/granulomatous infection.
- 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.
- Chronic/granulomatous infection may result in eye involvement and eye signs on examination.
- 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.
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.
- Laminar airflow or high-efficiency particulate air filtration of rooms of patients who receive bone marrow transplants and of other high-risk patients may prevent invasive aspergillosis.
- Inhaled amphotericin may be used for patients with solid organ transplants when Aspergillus spp. are cultured from sputum but there is no evidence of pneumonia.
- Sterile dressings should be used at susceptible sites to prevent primary cutaneous infection.
- Research into the development of vaccines against aspergillosis is ongoing.
Further reading and references
Guidelines on the management of invasive fungal infection during therapy for haematological malignancy; British Committee for Standards in Haematology (2008)
Agarwal R; Allergic bronchopulmonary aspergillosis. Chest. 2009 Mar135(3):805-26. doi: 10.1378/chest.08-2586.
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 Jul99(7):887-93. Epub 2005 Jan 26.
Tillie-Leblond I, Tonnel AB; Allergic bronchopulmonary aspergillosis. Allergy. 2005 Aug60(8):1004-13.
Knutsen AP, Bush RK, Demain JG, et al; Fungi and allergic lower respiratory tract diseases. J Allergy Clin Immunol. 2012 Feb129(2):280-91
Hogan C, Denning DW; Allergic bronchopulmonary aspergillosis and related allergic syndromes. Semin Respir Crit Care Med. 2011 Dec32(6):682-92. Epub 2011 Dec 13.
Agarwal R; Severe asthma with fungal sensitization. Curr Allergy Asthma Rep. 2011 Oct11(5):403-13.
Denning DW, O'Driscoll BR, Powell G, et al; Randomized controlled trial of oral antifungal treatment for severe asthma with fungal sensitization: The Fungal Asthma Sensitization Trial (FAST) study. Am J Respir Crit Care Med. 2009 Jan 1179(1):11-8. Epub 2008 Oct 23.
Lee JK, Lee YJ, Park SS, et al; Clinical course and prognostic factors of pulmonary aspergilloma. Respirology. 2014 Oct19(7):1066-72. doi: 10.1111/resp.12344. Epub 2014 Jul 3.
Lee SH, Lee BJ, Jung DY, et al; Clinical manifestations and treatment outcomes of pulmonary aspergilloma. Korean J Intern Med. 2004 Mar19(1):38-42.
Lee JG, Lee CY, Park IK, et al; Pulmonary aspergilloma: analysis of prognosis in relation to symptoms and treatment. J Thorac Cardiovasc Surg. 2009 Oct138(4):820-5. doi: 10.1016/j.jtcvs.2009.01.019. Epub 2009 Apr 11.
Maturu VN, Agarwal R; Itraconazole in chronic pulmonary aspergillosis: In whom, for how long, and at what dose? Lung India. 2015 Jul-Aug32(4):309-12. doi: 10.4103/0970-2113.159523.
Citak N, Sayar A, Metin M, et al; [Results of surgical treatment for pulmonary aspergilloma with 26 cases in six years: a single center experience]. Tuberk Toraks. 201159(1):62-9.
Maschmeyer G, Haas A, Cornely OA; Invasive aspergillosis: epidemiology, diagnosis and management in immunocompromised patients. Drugs. 200767(11):1567-601.
Segal BH, Walsh TJ; Current approaches to diagnosis and treatment of invasive aspergillosis. Am J Respir Crit Care Med. 2006 Apr 1173(7):707-17. Epub 2005 Dec 30.
Zmeili OS, Soubani AO; Pulmonary aspergillosis: a clinical update. QJM. 2007 Jun100(6):317-34.
Karthaus M, Buchheidt D; Invasive aspergillosis: new insights into disease, diagnostic and treatment. Curr Pharm Des. 201319(20):3569-94.
Brakhage AA; Systemic fungal infections caused by Aspergillus species: epidemiology, infection process and virulence determinants. Curr Drug Targets. 2005 Dec6(8):875-86.
Thurnheer R, Moll C, Rothlin M, et al; Chronic necrotizing pulmonary aspergillosis complicated by pneumothorax. Infection. 2004 Aug32(4):239-41.
Tak V, Mathur P, Xess I, et al; A case of dual infection in a paediatric trauma victim of primary cutaneous aspergillosis caused by Aspergillus flavus and Aspergillus terreus. Indian J Med Microbiol. 2013 Apr-Jun31(2):193-6. doi: 10.4103/0255-0857.115232.
Bernardeschi C, Foulet F, Ingen-Housz-Oro S, et al; Cutaneous Invasive Aspergillosis: Retrospective Multicenter Study of the French Invasive-Aspergillosis Registry and Literature Review. Medicine (Baltimore). 2015 Jul94(26):e1018. doi: 10.1097/MD.0000000000001018.
Tahir C, Garbati M, Nggada HA, et al; Primary cutaneous aspergillosis in an immunocompetent patient. J Surg Tech Case Rep. 2011 Jul3(2):94-6. doi: 10.4103/2006-8808.92802.
Moreno G, Arenas R; Other fungi causing onychomycosis. Clin Dermatol. 2010 Mar 428(2):160-3. doi: 10.1016/j.clindermatol.2009.12.009.
Klein KC, Blackwood RA; Topical voriconazole solution for cutaneous aspergillosis in a pediatric patient after bone marrow transplant. Pediatrics. 2006 Aug118(2):e506-8. Epub 2006 Jun 30.
Vennewald I, Klemm E; Otomycosis: Diagnosis and treatment. Clin Dermatol. 2010 Mar 428(2):202-11. doi: 10.1016/j.clindermatol.2009.12.003.
Schubert MS; Allergic fungal sinusitis: pathophysiology, diagnosis and management. Med Mycol. 200947 Suppl 1:S324-30. doi: 10.1080/13693780802314809. Epub 2009 Mar 27.
Peral-Cagigal B, Redondo-Gonzalez LM, Verrier-Hernandez A; Invasive maxillary sinus aspergillosis: A case report successfully treated with voriconazole and surgical debridement. J Clin Exp Dent. 2014 Oct 16(4):e448-51. doi: 10.4317/jced.51571. eCollection 2014 Oct.
Perea S, Patterson TF; Invasive Aspergillus infections in hematologic malignancy patients. Semin Respir Infect. 2002 Jun17(2):99-105.
Kamalaporn H, Leung K, Nagel M, et al; Aerosolized liposomal Amphotericin B: a potential prophylaxis of invasive pulmonary aspergillosis in immunocompromised patients. Pediatr Pulmonol. 2014 Jun49(6):574-80. doi: 10.1002/ppul.22856. Epub 2013 Jul 10.
Hi everybody, I've been taking Terbinafine now for three weeks (eight week course) for a skin infection but i am yet to see any improvement. Is this normal only i expected to see some signs by now....steven50664
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