Aspergillosis

What is Aspergillosis?

Aspergillosis is a name for a group of conditions caused by exposure to Aspergillus spp. Some are due to the direct effects of infection and others are due to the body's immune reaction to the fungus.

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.

Pulmonary aspergillosis

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 the separate Hypersensitivity pneumonitis article.

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 13% of those with asthma which is severe enough to be managed in secondary care, and 5-10% of those with CF (particularly if affected by bronchiectasis). It is probably underdiagnosed in both groups. ^{1 2}

Presentation

• People with asthma and CF are mostly affected. Clinical manifestations are:

  • Fever.

  • Wheeze.

  • 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.
  

Investigations³

• Diagnosis is made on the following basis:

  • Presence of all of the following:

    • Predisposing conditions (asthma or CF).

    • Positive specific IgE to Aspergillus at a level of > 0.35 kU_A/l.

    • Serum Total IgE > 500iu/ml.

  • Two or more of the following:

    • Bronchiectasis on CT chest.

    • Blood eosinophilia > 0.5 x 10⁹/L.

    • Aspergillus specific IgG > 27 mgA/l.

Management⁴

• Management of ABPA is always decided in secondary care, using oral corticosteroids (OCS) and anti-fungals (itraconazole and voriconazole). Monoclonal antibodies such as omalizumab may also be used.

• Primary care involvement may include prescribing of oral anti-fungal agents under a shared care agreement, which means that the patient must be stable on the drug before prescribing moves to primary care. This should specify the necessary monitoring (which may include drug levels, LFTs and ECGs), who does the monitoring and how specialist advice can be obtained if needed by the GP. Patients should generally not be discharged from secondary care follow-up while a shared care agreement is active, and shared care should only take place if the GP freely gives consent and feels that it is safe.

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.

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.⁵

Epidemiology

• SAFS refers to patients with severe asthma (despite standard treatment) with evidence of fungal sensitisation who do not meet the criteria for ABPA. ⁶ 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.⁷

Presentation

• 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.

Management

• The management is generally similar to that of ABPA.

• All patients should be managed in secondary care - some will progress to ABPA.

Aspergilloma

Aspergilloma is diagnosed when there is a fungal ball of hyphae, cellular debris and mucus, which occurs in a pre-existing lung cavity. The cavity may be present because the person has had TB in the past.

Epidemiology

• 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.⁸

Presentation

• It can present with haemoptysis in up to 60% of patients. This can be massive and severe enough to threaten life.⁹

• 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 patients who have HIV and have a history of Pneumocystis jirovecii pneumonia.

Investigations¹⁰

• 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.

Management

• Treatment is usually initiated when patients become symptomatic; it may include long-term oral itraconazole and/or surgical resection.

• 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 non-progressive but there is a significant mortality associated with massive haemoptysis.

• One study of postsurgical aspergilloma cases showed an operative mortality of 3.3% and a morbidity rate of 33.3%.¹¹

Complications
Life-threatening haemoptysis.

Invasive aspergillosis¹²

This is a condition with significant mortality and should be suspected in immunosuppressed patients with acute respiratory illness.

Epidemiology

• This is extremely rare amongst immunocompetent patients - it is usually seen in the following groups:

  • Patients who have had a bone marrow or solid organ transplant, or immunotherapy for an autoimmune condition.

  • Those with chemotherapy–induced neutropenia.

  • Patients with advanced HIV.

  • Patients with a haematological malignancy.

  • In severe COVID-19 or influenza infection (ie those admitted to ITU).

• Prevalence is rising due to the increasing number of patients undergoing intensive chemotherapy to treat neoplasms and receiving organ transplants.

Presentation

• It affects significantly immunocompromised patients.

• Virtually any organ can be involved but sinopulmonary disease is most common.

• 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.

Investigations¹⁰

• 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).¹³

• 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.¹⁴

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.¹⁵

• Voriconazole is the treatment of choice. Posaconazole is an alternative. Amphotericin may be used if initial treatment fails. ¹⁵¹⁶

• 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.¹⁷

• Combination antifungal therapy needs further studies to confirm its efficacy.¹⁸

• Treatment should be started without waiting for confirmation of diagnosis.¹⁵

• Consideration should be given to reducing the dose of immunosuppressive medications where possible, and giving treatment for neutropenia, such as granulocyte colony-stimulating factor.

Prognosis

• Invasive aspergillosis has a poor outlook with mortality nearing 100% once central nervous system involvement occurs.¹⁹

• The development of endocarditis has a similar poor outlook, if it cannot be treated surgically.

• 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)

This is now also known as subacute invasive pulmonary aspergillosis (SIPA).

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

• 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:
  

  • 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.²⁰

• Reduction or elimination of immunosuppression 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

Most types of aspergillosis are probably underdiagnosed. A useful message for primary care is to consider this in patients whose asthma is severe, or uncontrolled despite optimal therapy, and to request IgG to Aspergillus. If positive, a patient who has been referred to the respiratory team may be seen more quickly.

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.

• Granulomatosis with polyangiitis.

• Hypersensitivity pneumonitis.

• 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.²¹

• 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.²² The limbs and head are the most common sites of infection. A. fumigatus is most commonly associated with invasive disease leading to skin infection.²³

• 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.²⁴ Primary skin infection can lead to invasive aspergillosis, particularly if the patient is immunocompromised.²²

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. Voriconazole, itraconazole and caspofungin are other treatments that are used.¹⁵ Voriconazole is becoming the treatment of choice for invasive aspergillosis.¹⁵ Topical voriconazole combined with systemic antifungal agents has been used in cutaneous aspergillosis.²⁵

• Surgical excision has also been used successfully in primary cutaneous aspergillosis ± systemic antifungal treatment.¹⁵

• Oral itraconazole is used in onychomycosis associated with Aspergillus spp..¹⁵

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..²⁶ Further information can be found in the separate 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.²⁷

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.²⁷

• 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.²⁸ It tends to occur in the immunocompromised.

• Aspergillus spp. usually cause chronic/granulomatous infection.²⁸

• 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.²⁸

• 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.

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 although this is not supported by extensive evidence.²⁹

• 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.³⁰

• Sterile dressings should be used at susceptible sites to prevent primary cutaneous infection.

• Research into the development of vaccines against aspergillosis is ongoing.¹³