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Aspergillus lung disease in Cystic Fibrosis

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Overview

Aspergillus is a fungus with spores that can be inhaled and deposited into airways. The fungus can produce toxic and allergenic exoproducts and cause a number of problems in Cystic Fibrosis (CF).

Generally the advice is to avoid environments where high levels of fungus can occur; damp straw such as in horse stables, building sites, and exposure to compost.

Allergic Bronchopulmonary Aspergillosis (ABPA)

ABPA is a serious potential cause of lung damage and has a prevalence of about 10% in Cystic Fibrosis (CF) clinics. The presence of Aspergillus (usually Aspergillus fumigatus but more rarely other Aspergillus fungi) in the airways of some individuals with CF prompts vigorous antibody (IgE and IgG) and cell-mediated immune responses to Aspergillus antigens. Over time, the immune reactions, combined with direct toxic effects of the fungus, lead to airway damage with dilatation and progression to bronchiectasis and fibrosis.

Early detection depends on screening and high clinical suspicion. Baseline screening should be done at annual review and on hospital admission if any clinical concern with blood tests and all sputum/cough swabs/BAL samples should be checked for presence of Aspergillus.

Diagnostic criteria

This can be a very difficult diagnosis to make in CF, because most of the diagnostic criteria overlap with common manifestations of CF.

Clinical
Increased wheezing/chestiness particularly if failing to respond to antibiotics and inhaled anti-inflammatory or bronchodilator medications
Fever and malaise (fever less common in CF)
Thick sputum with brown or black bronchial casts
Indolent deterioration and weight loss

Investigations

Major criteria
CXR pulmonary infiltrates > 1cm diameter and segmental collapse
High serum IgE - especially an abrupt recent rise (usually described as fourfold increase) and/or above 500 IU/ml (normal < 100 IU/ml) that falls with prednisone therapy
High specific aspergillus IgE RAST. Normal value <0.35IU/ml may rise 10-100x in ABPA
Positive IgG aspergillus precipitins (which can remain high in CF for prolonged periods and obscure a relapse or further episode)
Eosinophilia (>0.4 x 109/l)
Reversible bronchoconstriction
Central bronchiectasis
Minor criteria
Aspergillus fumigatus culture from sputum (NB found in 30% of all CF patients)
Brown/black plugs in sputum
Skin prick testing (Not commonly used in NZ)

Treatment

Oral corticosteroids

Prednisone, given in the morning after food (not enteric coated as it is not well absorbed in CF) is usually started at a dose of 2mg/kg/day (max 40mg) for 2-4 weeks, 1mg/kg/day for 2-4 weeks, then 1mg/kg/alt day for 2-4 weeks. Reduction of steroids should be guided by clinical response, improvement of symptoms, improvement of chest x-ray, and a reduction of the IgE which should be measured at 2-4 weekly intervals.

Attention must be paid to potential adverse effects:

With prolonged or repeated treatments:

Pulsed IV methylprednisolone

This can be considered for those difficult to treat, non-adherent or with frequent relapses and may have fewer side effects, although these still occur. IV methylprednisolone 10 mg/kg, ONCE per day for 3 days, every month (maximum 1 gram). The 3-day pulses are usually given on 3 occasions, a month apart, but may need to be longer depending on the response.

Oral anti-fungal: Itraconazole

Itraconazole is used routinely in the treatment of ABPA, in conjunction with corticosteroids. For patients < 12 years give 5mg/kg, twice daily (max 200mg, twice daily) or > 12 years 200mg, twice daily, orally, and continue for 1-2 months after stopping steroids (the longer time especially if relapsed).

Itraconazole capsules are poorly absorbed in children with cystic fibrosis so they are recommended to be taken with an acidic liquid (i.e. Coca-Cola® or orange juice) and food. A liquid formulation is available with better absorption but is not palatable and not currently funded. Stop ranitidine/omeprazole if possible to improve absorption.

Itraconazole levels - trough sample should be taken after itraconazole has been taken for 14 days. If the level is appropriate - further testing may not be needed (testing is expensive). However levels may be required if there are concerns regarding poor response, a high or low initial level, concerns regarding toxicity, or if interacting drugs are introduced.

Liver function tests should be performed if blood is being taken for repeat ABPA markers, otherwise do 1-2 monthly for prolonged courses or if known liver dysfunction.

Oral anti-fungal: Voriconazole

Voriconazole is an oral antifungal which has better absorption than Itraconazole and is not affected by gastric pH. It may be useful as a 2nd line agent for patients who have not responded to, or cannot tolerate, Itraconazole. It is expensive and is not currently funded. Some international CF centres that have access to other, newer, antifungals do not recommend it as adverse events such as photosensitivity and liver toxicity are of concern.

Nebulised amphotericin

Amphotericin (non-liposomal) may be used in difficult cases at a dose of 5-10 mg twice daily after physiotherapy (check for bronchoconstriction and use bronchodilator pre-dose). This is not currently funded.

Relapse or recurrent episodes

Relapse or recurrent episodes is common within 2-3 years of initial episode. IgG percipitins and IgE RASTs can remain at high levels after an initial episode making repeat diagnoses more difficult. With relapse, steroids are often needed for a long time and the antifungal treatment can be extended for a longer period after steroid completion. With repeated and difficult to treat relapses other alternatives such as iv methylprednisolone, or other antifungals (voraconazole, posaconazole, nebulised amphotericin) may be considered. None of these are currently funded (2018). Discussion with a CF and/or Infectious Diseases consultant recommended.

Other manifestations of Aspergillus lung disease

Positive culture only

Aspergillus can be found in routine sputum or BAL samples and is prevalent in about 30% of children with CF.

Aspergillus bronchitis

This is recognised in children who persistently grow Aspergillus in sputum and have chronic respiratory symptoms but don't fulfil the criteria of ABPA. They will often have a positive aspergillus IgG but not the immunological response with raised total or specific IgE, This diagnosis would only be considered once treatment of the usual bacteria pathogens was undertaken. Treatment is with a 3 month course of an oral antifungal agent (Itraconazole).

Invasive Disease

Rare, but may occur with severe disease, immunosuppression, or neutropenia. It is associated with worsening respiratory symptoms, progression of radiological changes sometimes with cavitation, haemoptysis, and pleuritic pains. Chest CT scan can be useful to confirm the diagnosis. Intravenous antifungal treatment is needed (amphotericin, caspofungin) but discussion with a CF and/or ID consultant recommended.

References

Document last reviewed: March 2019

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