Diagnosis and Treatment of Allergic Bronchopulmonary Aspergillosis (ABPA) and Aspergillus bronchitis in Children and Adults with Cystic Fibrosis

Publication: 08/01/2018  --
Last review: 01/01/1900  
Next review: 08/01/2021  
Clinical Guideline
CURRENT 
ID: 5304 
Approved By: Trust Clinical Guidelines Group 
Copyright© Leeds Teaching Hospitals NHS Trust 2018  

 

This Clinical Guideline is intended for use by healthcare professionals within Leeds unless otherwise stated.
For healthcare professionals in other trusts, please ensure that you consult relevant local and national guidance.

Diagnosis and Treatment of Allergic Bronchopulmonary Aspergillosis (ABPA) and Aspergillus bronchitis in Children and Adults with Cystic Fibrosis

Summary
Diagnosis and Treatment of Allergic Bronchopulmonary Aspergillosis (ABPA) and Aspergillus bronchitis in Children and Adults with Cystic Fibrosis

ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS (another section below on Aspergillus bronchitis)

Key diagnostic criteria:

Diagnosis requires clinical features of Allergic Bronchopulmonary Aspergillosis (ABPA) plus at least two positive investigations supporting a diagnosis of ABPA.

Clinical Features of ABPA:

  • Wheeze, reduced exercise tolerance, chest tightness, cough, airway obstruction (reduced FEV1).
  • Malaise.
  • Sputum containing black/brown flecks/casts.

Investigations supporting a diagnosis of ABPA (at least 2 required):

  • Increased total serum IgE >500 ku/L, especially if significant rise on previous level.
  • Positive Aspergillus specific IgE >0.35 kua/L, especially if risen to more than 3.5 kua/L, or significant rise on previous level.
  • Eosinophil count elevated >0.5 x 109/L.
  • Positive Aspergillus IgG (Immunocap) >90 mgA/L (note that if Immunocap is elevated in the absence of raised IgE and raised eosinophils then Aspergillus Bronchitis should be considered and steroid treatment may not be indicated – see Aspergillus Bronchitis section).
  • Bronchoconstriction reversible with salbutamol.
  • Chest x-ray demonstrating pulmonary shadowing >1cm diameter, “finger in glove” mucus impaction +/- segmental collapse (11).

Investigations required

  • Full Blood Count (for eosinophil count).
  • Total serum IgE and Aspergillus specific IgE.
  • Aspergillus specific IgG (Immunocap).
  • Baseline liver function tests.
  • Baseline ECG - triazole antifungal drugs (e.g. Itraconazole electronic Medicines Compendium information on Itraconazole , Voriconazole electronic Medicines Compendium information on Voriconazole , Posaconazole electronic Medicines Compendium information on Posaconazole), should be used only with extreme caution in patients with prolonged QT or on other drugs whilst may cause QT prolongation.
  • Chest x-ray – if lobar collapse is present bronchoscopy should be considered to attempt re-inflation (12).

Treatment

The mainstay of treatment is suppression of the allergic response with systemic corticosteroids, in combination with antifungal treatment. First line antifungal (Itraconazole electronic Medicines Compendium information on Itraconazole) is tolerated and effective in the majority of subjects but drug levels should be checked as these can often be sub-therapeutic. Second and third line antifungals are considerably more expensive and generally have more potential side effects. Use of Posaconazole electronic Medicines Compendium information on Posaconazole should be instigated under the instruction of a CF consultant and requires authorisation by microbiology.

For dosages please see; Doses of IV drugs in cystic fibrosis or Nebulised drugs in cystic fibrosis

First Line

Oral prednisolone at a dose of 1-2 mg/kg/day up to a maximum dose of 40 mg daily for 2 weeks.
This is then followed by a reducing regimen, with the daily dose reducing by 5mg every week, until it is weaned off.
All patients should be counselled about the risk of glucose intolerance and infection risk prior to commencing steroids.

Itraconazole electronic Medicines Compendium information on Itraconazole , course duration usually 3 months, response should be reviewed at 4 weeks.
Liver function tests should be checked monthly.
There is an increased risk of adrenal insufficiency when using triazole antifungals in patients taking inhaled corticosteroids. (13,14). It is recommended that the inhaled corticosteroid (ICS) dose should be reduced to 50% on commencement of Itraconazole electronic Medicines Compendium information on Itraconazole and increased again if necessary when the Itraconazole electronic Medicines Compendium information on Itraconazole course is completed.

Trough Itraconazole electronic Medicines Compendium information on Itraconazole levels should be checked together with LFTs, after 5-7 days of treatment (for details regarding levels see pathology page)
For dosages please see Appendix 1 or Drug doses in cystic fibrosis
There are LTHT guidelines on the use of Itraconazole in adults

Second Line Options

Pulsed monthly intravenous methylprednisolone if oral prednisolone causes problematic glucose intolerance, is not tolerated, or concordance is poor. Hospital admission and close monitoring required.
Posaconazole electronic Medicines Compendium information on Posaconazole should be considered if Itraconazole electronic Medicines Compendium information on Itraconazole is ineffective despite good serum levels or not tolerated. This is a protected antimicrobial and should only be used with microbiology approval. Liver function tests should be checked monthly.

Voriconazole electronic Medicines Compendium information on Voriconazole should be considered if itraconazole and Posaconazole electronic Medicines Compendium information on Posaconazole are ineffective despite good serum levels or not tolerated. Caution re side effects and interactions.
Liver function tests should be checked weekly for the first month and then monthly thereafter. Pre-dose blood levels should be taken 5-7 days after starting treatment or dose alterations. A patient information card about Voriconazole electronic Medicines Compendium information on Voriconazole and the risk of skin cancer will be supplied by pharmacy, and should be discussed with the patient by the prescriber.

Nebulised liposomal amphotericin (Ambisome electronic Medicines Compendium information on Ambisome ®) should be considered if oral anti-fungals are ineffective, contraindicated or not tolerated. This use is off licence but widely used and accepted for many years and included in the LTHT nebuliser guidelines for both adults and paediatrics.

Intravenous Ambisome electronic Medicines Compendium information on Ambisome ® should be considered if oral anti-fungals are ineffective, contraindicated or not tolerated. Requires hospital admission, test dose, monitoring of renal function, and potassium, magnesium and phosphate levels at least twice weekly. Allergic reactions are relatively common, which can be severe.

Intravenous Caspofungin electronic Medicines Compendium information on Caspofungin should be considered if oral anti-fungals ineffective, contraindicated or not tolerated. Should be started in hospital for loading dose and to check tolerability but is available for home intravenous use.

Third Line

Omalizumab is unlicensed, based on case report only, and would require individual funding request.

ASPERGILLUS BRONCHITIS

Key diagnostic criteria:

Diagnosis requires clinical features of Aspergillus bronchitis plus at least one positive investigation supporting a diagnosis of Aspergillus bronchitis.

Clinical Features of Aspergillus bronchitis:

  • Productive cough not responding to antibiotic therapy.
  • Airway obstruction (reduced FEV1).
  • Sputum containing black/brown flecks/casts.

Investigations supporting a diagnosis of Aspergillus bronchitis (at least 1 required):

  • Positive Aspergillus IgG (Immunocap) >90 mgA/L (note that if Aspergillus specific IgE and eosinophils are also elevated then ABPA should be considered and steroid treatment may be indicated, see ABPA section above)
  • Positive culture of Aspergillus from airway secretions (note that Aspergillus may be frequently found in sputum samples from individuals with cystic fibrosis and does not necessarily require treatment in the absence of clinical features of aspergillus bronchitis).
  • Bronchial wall thickening or focal consolidation on chest x-ray.

Investigations required

  • Sputum culture for fungi
  • Full Blood Count (for eosinophil count).
  • Total serum IgE and Aspergillus specific IgE.
  • Aspergillus specific IgG (Immunocap).
  • Baseline liver function tests.
  • Baseline ECG - triazole antifungal drugs (e.g. Itraconazole electronic Medicines Compendium information on Itraconazole , Voriconazole electronic Medicines Compendium information on Voriconazole , Posaconazole electronic Medicines Compendium information on Posaconazole ), should be used only with extreme caution in patients with prolonged QT or on other drugs whilst may cause QT prolongation.
  • Chest x-ray.

Treatment

Treatment of Aspergillus bronchitis consists of anti-fungal therapy. First line antifungal (itraconazole) is tolerated and effective in the majority of subjects but drug levels should be checked as these can often be sub-therapeutic. Second and third line antifungals are considerably more expensive and generally have more potential side effects. Use of Posaconazole electronic Medicines Compendium information on Posaconazole should be instigated under the instruction of a CF consultant and requires authorisation by microbiology. Steroid therapy is not indicated for the treatment of Aspergillus bronchitis.

For dosages please see; Doses of IV drugs in cystic fibrosis or Nebulised drugs in cystic fibrosis

First Line

Itraconazole electronic Medicines Compendium information on Itraconazole , course duration usually 3 months, response should be reviewed at 4 weeks.
Liver function tests should be checked monthly.
There is an increased risk of adrenal insufficiency when using triazole antifungals in patients taking inhaled corticosteroids (13,14). It is recommended that the inhaled corticosteroid dose should be reduced to 50% on commencement of itraconazole and increased again if necessary when the Itraconazole electronic Medicines Compendium information on Itraconazole course is completed.
Trough itraconazole levels should be checked together with LFTs, after 5-7 days of treatment or any dose alterations (for details regarding levels see pathology page)
For dosages please see Appendix 1 or Drug doses in cystic fibrosis
There are LTHT guidelines on the use of Itraconazole in adults

Second Line Options

Posaconazole electronic Medicines Compendium information on Posaconazole should be considered if itraconazole is ineffective despite good serum levels, contraindicated or not tolerated. This is a protected antimicrobial and should be used with microbiology approval. Liver function tests should be checked monthly. There is an increased risk of adrenal insufficiency when using triazole antifungals in patients taking inhaled corticosteroids (13,14). It is recommended that the inhaled corticosteroid dose should be reduced to 50% on commencement of Posaconazole electronic Medicines Compendium information on Posaconazole and increased again if necessary when the Posaconazole electronic Medicines Compendium information on Posaconazole course is completed.

Voriconazole electronic Medicines Compendium information on Voriconazole should be considered if Itraconazole electronic Medicines Compendium information on Itraconazole and Posaconazole electronic Medicines Compendium information on Posaconazole are ineffective despite good serum levels, contraindicated or not tolerated. Caution regarding side effects and interactions.
Liver function tests should be checked weekly for the first month and then monthly thereafter. Pre-dose blood levels should be taken 5-7 days after starting treatment or dose alterations. A patient information card about Voriconazole electronic Medicines Compendium information on Voriconazole and the risk of skin cancer will be supplied by pharmacy, and should be discussed with the patient by the prescriber. There is an increased risk of adrenal insufficiency when using triazole antifungals in patients taking inhaled corticosteroids (13,14). It is recommended that the inhaled corticosteroid dose should be reduced to 50% on commencement of Voriconazole electronic Medicines Compendium information on Voriconazole and increased again if necessary when the Voriconazole electronic Medicines Compendium information on Voriconazole course is completed.

Nebulised liposomal amphotericin (Ambisome electronic Medicines Compendium information on Ambisome ®) should be considered if oral anti-fungals are ineffective, contraindicated or not tolerated. This use is off licence but widely used and accepted for many years and included in the LTHT nebuliser guidelines for both adults and paediatrics.

Intravenous Ambisome electronic Medicines Compendium information on Ambisome ® should be considered if oral anti-fungals are ineffective, contraindicated or not tolerated. Requires hospital admission, test dose, monitoring of renal function, and potassium, magnesium and phosphate levels at least twice weekly. Allergic reactions are relatively common, which can be severe.

Intravenous Caspofungin electronic Medicines Compendium information on Caspofungin should be considered if oral anti-fungals ineffective or not tolerated. Should be started in hospital for loading dose and to check tolerability but is available for home intravenous use.

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Background

Aspergillus fumigatus is a filamentous fungus common in the environment. In people with CF, Aspergillus can cause Aspergillus Bronchitis characterised by Aspergillus growing in the sputum, and often an elevated Aspergillus IgG immunocap, or, more commonly, allergic bronchopulmonary aspergillosis (ABPA) in 3%-10% of CF patients (1). Aspergillus does not have to be isolated for a diagnosis of ABPA and many patients with positive Aspergillus sputum isolates and elevated markers remain asymptomatic and do not appear to require treatment. ABPA is thought to be caused by an over-reaction of the T-helper cell (Th2) response to Aspergillus antigen present in the airway (2). As well as causing acute respiratory symptoms, if undertreated lung damage such as bronchiectasis can occur (2). The mainstay of treatment for ABPA is suppression of the allergic response using corticosteroids, and reducing or eliminating fungal load using antifungal therapy (1-3). Aspergillus bronchitis is treated with antifungal therapy.

In order to reduce the risk of developing either Aspergillus Bronchitis or ABPA, people with CF should be advised to avoid the following situations, where Aspergillus spores may be present in increased concentrations: Mucking out horses or animal sheds, adding material to garden compost heaps or turning compost heaps, environments with building/renovation work involving old plaster (3,4) (C).

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Clinical Diagnosis

Diagnosis of ABPA or Aspergillus bronchitis remains a challenge. There are no specific diagnostic tests, test results have to be interpreted in conjunction with clinical symptoms, and in the case of ABPA trends in serum levels of total and specific IgE are more important than absolute values. Aspergillus can be detected in sputum culture in approx. 30% of CF subjects and often does not require treatment unless the clinical situation and other investigations suggest treatment is necessary (3,4) The North American Cystic Fibrosis Foundation has produced consensus diagnostic criteria, and this guideline is based on these and other existing guidelines. (1,3,4). (C).

ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS (ABPA)

Diagnosis requires clinical features of ABPA plus at least two positive investigations supporting a diagnosis of ABPA.

Clinical Features of ABPA:

  • Wheeze, reduced exercise tolerance, chest tightness, cough, airway obstruction (reduced FEV1).
  • Malaise.
  • Sputum containing black/brown flecks/casts.

Investigations supporting a diagnosis of ABPA (at least 2 required):

  • Increased total serum IgE >500 ku/L, especially if significant rise on previous level.
  • Positive Aspergillus specific IgE >0.35 kua/L, especially if risen to more than 3.5 kua/L, or significant rise on previous level.
  • Eosinophil count elevated >0.5 x 109/L.
  • Positive Aspergillus IgG (immunocap) >90 mgA/L (note that if Immunocap is elevated in the absence of raised IgE and raised eosinophils then Aspergillus Bronchitis should be considered and steroid treatment may not be indicated – see Aspergillus Bronchitis section)(9)(C).
  • Bronchoconstriction reversible with salbutamol.
    Chest x-ray demonstrating pulmonary shadowing >1cm diameter, “finger in glove” mucus impaction +/- segmental collapse.(11)

ASPERGILLUS BRONCHITIS

Diagnosis requires clinical features of Aspergillus bronchitis plus at least one positive investigation supporting a diagnosis of Aspergillus bronchitis.

Clinical Features of Aspergillus bronchitis (11):

  • Productive cough not responding to antibiotic therapy.
  • Airway obstruction (reduced FEV1).
  • Sputum containing black/brown flecks/casts.

Investigations supporting a diagnosis of Aspergillus bronchitis (at least 1 required):

  • Positive Aspergillus IgG (Immunocap) >90 mgA/L (note that if Aspergillus specific IgE and eosinophils are also elevated then ABPA should be considered and steroid treatment may be indicated, see ABPA section above)
  • Positive culture of Aspergillus from airway secretions (note that Aspergillus may be frequently found in sputum samples from individuals with cystic fibrosis and does not necessarily require treatment in the absence of clinical features of aspergillus bronchitis).
  • Bronchial wall thickening or focal consolidation on chest x-ray.

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Investigation

Prior to commencing treatment the following investigations are required (if not already performed)(1,3,4)(C):

  • Sputum culture for fungi
  • FBC (for eosinophil count).
  • Total serum IgE and aspergillus specific IgE.
  • Aspergillus specific IgG (Immunocap).
  • Baseline liver function tests.
  • Baseline ECG - triazole antifungal drugs (e.g. Itraconazole electronic Medicines Compendium information on Itraconazole , Voriconazole electronic Medicines Compendium information on Voriconazole , Posaconazole electronic Medicines Compendium information on Posaconazole ) should be used only with extreme caution in patients with prolonged QT or in patients on other drugs likely to prolong QT interval.
  • Chest x-ray.

Once treatment is commenced the following investigations should be arranged:

  • Liver function tests are required for all antifungal treatment courses >1 month. Voriconazole electronic Medicines Compendium information on Voriconazole requires liver function tests weekly during the first month and then monthly thereafter.
  • Antifungal levels (trough) should be performed for azole antifungals shortly after starting treatment or after dose alterations. - see individual antifungals for details.
  • Blood pressure every clinic visit for patients taking systemic steroids.
  • Urinalysis for glucose every clinic visit for patients taking systemic steroids.
  • Blood glucose should be checked urgently for any patient developing polydipsia, polyuria, glycosuria on urine dipstick, or malaise whilst taking systemic steroids.

If liver function tests (AST or ALT) become elevated >3x upper limit of normal at any stage, the expertise of a specialist CF Pharmacist should be sought and antifungal drugs should normally be paused or stopped.
Once liver function tests return to normal, an alternative antifungal drug should be tried, with careful liver function monitoring.

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Treatment

Treatment of ABPA requires systemic steroids as it is an allergic response and antifungal therapy is used as adjunct steroid sparing agent (3,4,5,6,7,11)(C). .

Treatment of Aspergillus Bronchitis requires anti-fungal treatment only and steroid therapy is not indicated.

First Line for ABPA

Oral prednisolone at a dose of 1-2 mg/kg/day up to a maximum dose of 40 mg daily for 2 weeks

This is then followed by a reducing regimen, with the daily dose reducing by 5mg every week, until it is weaned off.

All patients should be counselled about the risk of glucose intolerance and infection risk prior to commencing steroids. They should contact the CF team immediately in the event of polydipsia and polyuria, or in the event of contact with viral infections such as chicken pox. Patients should be given a steroid card and be advised not to stop the course of steroids suddenly.

Blood glucose monitoring: CF patients 12 years or above commencing oral prednisolone should monitor pre and post meal blood sugars (e.g. by fingerprick) for the first 48 hours of the prednisolone course to check that glucose tolerance remains acceptable

Second Line for ABPA

Pulsed intravenous methylprednisolone

Indications/consideration:

  • Difficulty with blood sugars on oral prednisolone or pre-existing CF related diabetes (blood sugars can be closely monitored and controlled with insulin sliding scale whilst in hospital).
  • Compliance/behavioural difficulties
  • Requires hospital treatment

Dose:
I.V. methylprednisolone 10-15mg/kg (maximum dose 1gram) once daily, for 3 consecutive days.
May be repeated monthly.
See The Leeds Children’s Hospital Administration Guide Intravenous methylprednisolone for Allergic Bronchopulmonary Aspergillosis (ABPA) in patients with Cystic Fibrosis.

Antifungal Therapy for ABPA or Aspergillus Bronchitis

First Line

Itraconazole

To be prescribed as liquid wherever possible as absorption considerably better than with capsules.

Starting dose in children is twice that indicated in the BNFc i.e. 5mg/kg twice a day - Max initial dose: 200mg twice a day (3)(C)

Starting dose in adults is 2.5mg/kg twice a day, max: 200mg twice a day (3)(C)

Liquid preparations should be taken on an empty stomach to improve absorption.

Absorption of the capsules is significantly improved by acidic conditions, and should be taken immediately after a meal. Orange juice or cola may improve absorption, whereas proton pump inhibitors and H2 antagonists reduce absorption and should be discontinued if possible.

Liver function tests should be checked monthly.
Trough Itraconazole electronic Medicines Compendium information on Itraconazole levels should be checked and a trough sample should be taken after patient has been taking for at least 5-7 days (e.g. taken with discharge bloods, or at next clinic)
Range: trough level should be maintained above 0.5mg/L.
Toxicity may be associated with levels above 4mg/L.

Dose can be increased above 200mg twice daily, in response to low levels, if necessary.

Response should be reviewed at 4 weeks. The typical course duration is 3 months, although this can be extended.

Beware of interactions, particularly clarithromycin, erythromycin, rifampicin, ciclosporin, tacrolimus, omeprazole, ivacaftor, lumacaftor, and caution with concomitant use of inhaled steroids which can lead to adrenal suppression. There is an increased risk of adrenal insufficiency when using Itraconazole electronic Medicines Compendium information on Itraconazole in patients taking inhaled/nasal corticosteroids. This is due to Itraconazole electronic Medicines Compendium information on Itraconazole inhibiting the metabolism of systemically absorbed steroid, which can accumulate (13,14).

It is recommended that the inhaled corticosteroid dose should be reduced to 50% on commencement of Itraconazole electronic Medicines Compendium information on Itraconazole and increased again if necessary when the Itraconazole electronic Medicines Compendium information on Itraconazole course is completed.

Itraconazole electronic Medicines Compendium information on Itraconazole also increases exposure to methyl-prednisolone, prednisolone to a lesser extent (16).

Common side-effects include: nausea, vomiting, diarrhoea, skin rashes and deranged liver function. These are more likely with higher doses.

Serum cortisol should be considered one month post treatment in adults that have had recurrent courses of Itraconazole electronic Medicines Compendium information on Itraconazole who are on high dose inhaled steroids.

Please see LTHT guidance on itraconazole in adults for more details.

Second line

These should be considered if no response to itraconazole at adequate levels (as above) or if regimen not tolerated. Posaconazole electronic Medicines Compendium information on Posaconazole is recommended as the most appropriate second line choice. Voriconazole electronic Medicines Compendium information on Voriconazole is less favoured due to photosensitivity and increased risk of skin cancer. Nebulised or intravenous antifungals are considered when oral antifungals are contra-indicated, have not proved effective, or have not been tolerated.

Posaconazole electronic Medicines Compendium information on Posaconazole

Can be considered when there is no clinical response and/or intolerance to Itraconazole electronic Medicines Compendium information on Itraconazole . Due its high cost its use is restricted and requires microbiological approval.

It is not licensed in children but has LTHT approval in over 8 year olds and adults.

Tablets are preferred formulation as absorption much better.

N.B doses for tablets and liquid are different and therefore not interchangeable.

Dose over 8years of age:
Posaconazole electronic Medicines Compendium information on Posaconazole tablets 300mg twice a day first day and then 300mg once daily thereafter.

Posaconazole electronic Medicines Compendium information on Posaconazole liquid 400mg twice a day (note; tablets are the preferred formulation, see above).

Liver function tests should be checked monthly.
Trough Posaconazole electronic Medicines Compendium information on Posaconazole levels should be checked at/after 7 days of treatment and levels should be maintained above 1.25mg/L. There are currently no toxic levels of Posaconazole electronic Medicines Compendium information on Posaconazole .

Contraindicated with rifampicin (as are all azoles).
There is an increased risk of adrenal insufficiency when using triazole antinfungals in patients taking inhaled corticosteroids (13,14). It is recommended that the inhaled corticosteroid dose should be reduced to 50% on commencement of Posaconazole electronic Medicines Compendium information on Posaconazole and increased again if necessary when the Posaconazole electronic Medicines Compendium information on Posaconazole course is completed.

Voriconazole electronic Medicines Compendium information on Voriconazole

Age Weight Dose of oral Voriconazole electronic Medicines Compendium information on Voriconazole
2-<12 years All 9mg/kg twice a day. Max: 350mg twice a day
12-14 years <50kg 9mg/kg twice a day. Max: 350mg twice a day
≥50kg 400mg every 12 hours for two doses, then 200mg twice a day
15-17 years <40kg 200mg every 12 hours for two doses, then 100mg twice a day
≥40kg 400mg every 12 hours for two doses, then 200mg twice a day
Adults <40kg 200mg every 12 hours for two doses, then 100mg twice a day
≥40kg 400mg every 12 hours for two doses, then 200mg twice a day

Liver function tests should be checked weekly for the first month and then monthly thereafter (fulminant liver failure is a rare but recognised complication).

Voriconazole electronic Medicines Compendium information on Voriconazole levels
Trough Voriconazole electronic Medicines Compendium information on Voriconazole levels should be checked after patient has been taking for 5 - 7 days
Range: > 2.0mg/L to < 5.5mg/L
See pathology page for details.

Response should be reviewed at 4 weeks. The typical course duration is 3 months although this can be extended.

Beware of interactions, particularly rifampicin, tacrolimus, sirolimus, NSAIDs, ivacaftor, lumacaftor and omeprazole.
There is an increased risk of adrenal insufficiency when using triazole antinfungals in patients taking inhaled corticosteroids (13,14). It is recommended that the ICS dose should be reduced to 50% on commencement of Voriconazole electronic Medicines Compendium information on Voriconazole and increased again if necessary when the Voriconazole electronic Medicines Compendium information on Voriconazole course is completed.

Photosensitivity is common and may be severe or permanent. Patients should be warned about this, the importance of sun protection at all times, and the increased risks of skin cancer in later life. A patient information card about the risks of Voriconazole electronic Medicines Compendium information on Voriconazole will be provided by pharmacy when dispensed.

Other common side effects include liver function disturbance, hair loss, visual disturbances and adrenal suppression in patients on Voriconazole electronic Medicines Compendium information on Voriconazole also taking inhaled corticosteroids. Please read the MHRA advice for further information.

Nebulised liposomal amphotericin AmBisome®

This can be considered for patients who cannot tolerate, do not improve with oral antifungals or in whom triazole antifungals are contraindicated. Ambisome electronic Medicines Compendium information on Ambisome can be very effective, especially when there is a heavy airway growth of aspergillus, frequent episodes, or failure of other therapeutic options. Generally unpleasant for patients in terms of taste and volume (6ml), and commonly causes cough and wheeze. Therefore generally just used for short courses. Can be used as outpatient after first dose, supervised in hospital. (8)(C).

Dose
Liposomal amphoteracin (Ambisome electronic Medicines Compendium information on Ambisome ®) 25mg nebulised twice a day for 10 days. This can cause bronchoconstriction.
This use is off licence but widely used and accepted for many years and included in the LTHT nebuliser guidelines for both adults and paediatrics.

First dose must be supervised in hospital as a test dose. Pre-medication with inhaled salbutamol is recommended.

Requires prescribing and dispensing by hospital.

Intravenous Ambisome electronic Medicines Compendium information on Ambisome ®

Considered for patients who cannot tolerate, do not improve with oral antifungals or in whom triazole antifungals are contraindicated. Severe allergic and anaphylactic reactions are relatively common. Requires hospital admission and not possible to give as home intravenous therapy. Generally given for 14 days, guided by clinical response. Test dose required as per BNF, see below.

Dose

Adults: Initial test dose* followed by;
Day 1: 1mg/kg once daily
Day 2: 2mg/kg once daily
Day 3: 3mg/kg once daily

Adult patients have experienced reactions when starting at 3mg/kg, and therefore a decision has been made to increase the dose incrementally over three days as above. This is not necessary in children.

Paediatrics: Initial test dose* followed by 3mg/kg once daily as per BNFc (there is no need for day 1, day 2 doses, as per adults - see above for details).

*Test dose of 100micrograms/kg (max 1mg) iv over 10-15 minutes, observe for 30 minutes, then continue treatment. Test dose should only be administered during daytime hours.

Monitor renal function, potassium, magnesium, and phosphate levels at least twice weekly. Caution with other nephrotoxic drugs. Consider rounding dose to nearest 50mg where appropriate.

Intravenous Caspofungin electronic Medicines Compendium information on Caspofungin

Can be considered for patients who cannot tolerate, do not improve with oral antifungals or in whom trizazole antifungals are contraindicated. Should be started in hospital for loading dose and to check tolerability but is available for home intravenous use.

Limited evidence for children under 18 years.

Dose (reduce dose in hepatic impairment)
Adults:
Day 1: 70mg once daily
Day 2 onwards: 50mg once daily (if weight greater than 80kg increase daily dose to 70mg once daily)

Child: 1–18 years:
As per BNFc: 70mg/m2 (max. 70mg) on first day, then 50mg/m2 (max. 70mg) once daily;
increased to 70mg/m2 (max. 70mg) daily if lower dose tolerated but inadequate response. Caution with calculating the dose; the maximum dose is 70mg daily.

Third line for ABPA only

Omalizumab

Used to treat immune system mediated airway inflammation this has a potential to be used in severe non-responsive cases. This is off-licence, based on case report only, and subject to individual funding requests. Dose is generally 300mg-600mg subcutaneously every 2 weeks for a 16 week trial, with efficacy measured by reduction in exacerbations, ability to reduce prednisolone dose, and improvement in patient reported outcome (eg AQLQ or CFQ-R). Improvement is often not seen until 8-12 weeks into treatment (7)(C).

Counselling of parents/patients

Patients/parents should be given the ABPA or Aspergillus bronchitis patient information leaflet, as appropriate.

All patients with ABPA should be counselled about the risk of glucose intolerance and infection risk prior to commencing steroids. They should contact the CF team immediately in the event of polydipsia and polyuria, or in the event of contact with viral infections such as chicken pox. Patients should be given a steroid card. They should be advised not to stop the course of steroids suddenly.

Patients with ABPA or Aspergillus bronchitis should be advised that antifungal drugs have potential side effects, thus there will be careful monitoring, particularly of liver function. Patients or parents should be made aware that a number of drugs interact with antifungal drugs and they should check with CF team before starting new medications. They should also be advised to report any suspected side effects of treatment promptly. In addition, advice should be given that ABPA can often recur once treatment completed, and to avoid environments with higher risk of Aspergillus.

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Provenance

Record: 5304
Objective:

Aims

  • To improve the diagnosis and management of Allergic Bronchopulmonary Aspergillosis (ABPA) and Aspergillus bronchitis in people with cystic fibrosis

Objectives

  • To provide evidence-based recommendations for appropriate diagnosis and investigation of Allergic Bronchopulmonary Aspergillosis (ABPA) and Aspergillus bronchitis in people with cystic fibrosis.
  • To provide evidence-based recommendations for treatment of Allergic Bronchopulmonary Aspergillosis (ABPA) and Aspergillus bronchitis in people with cystic fibrosis
  • To recommend appropriate dose, route of administration and duration of antifungal agents and corticosteroids
  • To advise on second and third line options in the event of treatment failure, antimicrobial allergy, toxicity or other contra-indications.
Clinical condition:

Allergic Bronchopulmonary Aspergillosis and Aspergillus bronchitis

Target patient group: Adults and children with cystic fibrosis (CF)
Target professional group(s): Secondary Care Doctors
Secondary Care Nurses
Adapted from:

Evidence base

References

  1. Maturu VN, Agarwal R. Prevalence of Aspergillus sensitization and allergic bronchopulmonary aspergillosis in cystic fibrosis: Systematic review and meta-analysis. Clin Exp Allergy July 2015;14
  2. Katelari A., et al. The role of basophil activation test in allergic bronchopulmonary aspergillosis and Aspergillus fumigatus sensitisation in cystic fibrosis patients. J of Cystic Fibrosis 2016; Feb 25 [Epub ahead of print]
  3. Royal Brompton and Harefield NHS Foundation Trust Aspergillus Lung Disease Guidelines www.rbht.nhs.uk/healthprofessionals/clinical-departments/paediatrics/childrencf/respiratory-care/aspergillus-lung-disease/ (accessed 01/07/2016)
  4. Stevens DA et al. Allergic bronchopulmonary aspergillosis in cystic fibrosis - State of the Art: Cystic Fibrosis Foundation Consensus Conference. Clin Infect Dis 2003; 37 (Suppl 3): S225-64
  5. Greenberger PA, et al. Allergic Bronchopulmonary Aspergillosis. J Allergy Clin Immunol Pract 2014; 2(6): 703-708
  6. Emiralioglu N, et al. Omalizumab treatment for Allergic Bronchopulmonary Aspergillosis in Cystic Fibrosis. Ann Pharmacother 2016; 50: 188-93
  7. Sanchez-Sousa A, et al. Control of aspergillus bronchial colonization in cystic fibrosis patients: Preliminary data using Ambisome® aerosolized therapy. Israel J Med Sci 1996; 32: S256
  8. Shoseyov D, et al. Aspergillus bronchitis in cystic fibrosis. Chest 2006; 130: 222-226
  9. Agarwal R, et al., for the ABPA complicating asthma ISHAM working group. Clinical & Experimental Allergy 2013 (43) 850–873.
  10. Kosmidis C, et al. The clinical spectrum of pulmonary aspergillosis. Thorax 2015; 70: 270–277
  11. Whitaker P, et al., Sequential bronchoscopy in the management of lobar atelectasis in patients with cystic fibrosis. Journal of Bronchology and Interventional Pulmonology 2011; 18: 57-60
  12. Gilchrist FJ, et al., Itraconazole and inhaled fluticasone causing hypothalamic-pituitary-adrenal axis suppression in adults with cystic fibrosis. J Cystic Fib 2013; 12: 399-402
  13. Albert BB et al., An unusual cause of growth failure in cystic fibrosis: A salutary reminder of the interaction between glucocorticoids and cytochrome P450 inhibiting medication. J Cyst Fibros. 2015;14:e9-11.
  14. Lebrun-Vignes B, et al., Effect of itraconazole on the pharmacokinetics of prednisolone and methylprednisolone and cortisol secretion in healthy subjects. British Journal of Clinical Pharmacology. 2001;51(5):443-450.
  15. Stockley’s Drug Interactions. Accessed 20/01/2017 https://www.medicinescomplete.com

Evidence levels:
A. Meta-analyses, randomised controlled trials/systematic reviews of RCTs
B. Robust experimental or observational studies
C. Expert consensus.
D. Leeds consensus. (where no national guidance exists or there is wide disagreement with a level C recommendation or where national guidance documents contradict each other)

Approved By

Trust Clinical Guidelines Group

Document history

LHP version 1.0

Related information

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Appendix 1: Itraconazole Prescribing information

Indication
Patients with allergic bronchopulmonary aspergillosis (ABPA).

Cautions

  • Liver disease. LFT’s are required if treatment exceeds 1 month or if anorexia, nausea, vomiting, fatique, abdominal pain or dark urine develop.
  • Renal impairment
  • Congestive heart failure
  • Pregnancy and breast-feeding
  • Drug Interactions-See below. Itraconazole electronic Medicines Compendium information on Itraconazole interacts with many drugs and the summary of product characteristics (SPC) should be consulted for full details.

Dose
To be prescribed as liquid formulation wherever possible as absorption considerably better than with capsules.

Children: Starting dose is twice that indicated in the BNFc i.e. 5mg/kg twice a day - Max initial dose: 200mg twice a day.
Adults: starting dose 2.5mg/kg twice a day, Max initial dose: 200mg twice a day

If a decision is made to change the patient onto capsules it is worth noting that absorption of the capsules is improved by acidic conditions, so should be taken immediately after a meal, and orange juice or cola may improve absorption, whereas proton pump inhibitors and H2 antagonists reduce absorption and concomitant prescribing should be avoided.
Conversely, Itraconazole electronic Medicines Compendium information on Itraconazole liquid should be taken on an empty stomach and no food should be consumed for 2 hours after dosing to improve absorption.

Administration
The oral bioavailability of Itraconazole electronic Medicines Compendium information on Itraconazole is maximal when itraconazole liquid is taken without food. When the oral solution is taken with food, steady-state plasma concentrations of Itraconazole electronic Medicines Compendium information on Itraconazole are about 25% lower. It is therefore recommended to take it an hour before food or on an empty stomach.
During chronic administration, steady-state is reached after 1-2 weeks.

Drug Interactions-check SPC
Oral midazolam is contra-indicated with Itraconazole electronic Medicines Compendium information on Itraconazole as metabolism is reduced significantly.
Itraconazole electronic Medicines Compendium information on Itraconazole is mainly metabolised through the cytochrome CYP3A4 and Itraconazole electronic Medicines Compendium information on Itraconazole itself can inhibit the metabolism of drugs metabolised by the cytochrome 3A family. Consequently there are many drug interactions. Check SPC.
Rifampicin is an inducer of many cytochrome P450 isoenzymes, including CYP3A4, and therefore increases the metabolism of Itraconazole electronic Medicines Compendium information on Itraconazole markedly or very markedly reduces the exposure to Itraconazole electronic Medicines Compendium information on Itraconazole ; they should not be prescribed together.
Itraconazole electronic Medicines Compendium information on Itraconazole is predicted to increase the exposure to ivacaftor significantly.
Lumacaftor decreases the exposure to Itraconazole electronic Medicines Compendium information on Itraconazole .

Side-effects (in order of frequency)
The most frequently reported were of gastro-intestinal origin, such as diarrhoea, nausea, abdominal pain and vomiting.
Less frequently reported adverse experiences include headache, dizziness, raised liver enzymes, menstrual disorders.
Allergic reactions, hepatitis and cholestatic jaundice (especially if treatment is longer than 1 month), heart failure, peripheral neuropathy, and Stevens-Johnson syndrome reported.
On prolonged use; hypokalaemia, oedema and hair loss reported.

Monitoring levels
Itraconazole electronic Medicines Compendium information on Itraconazole levels are measured to ensure that the patient is achieving adequate levels, since the absorption and pharmacokinetic properties are altered in CF patients.

  • Obtain trough levels at 5-7 days after starting therapy. LTHT pathology states seven days.
  • Patient must miss the dose on the sample day
  • The trough level is taken.
  • Ideal levels: The trough level should be greater than 0.5mg/Litre

Further information available at:
Itraconazole- LTHT prescribing guidelines for adults
http://www.pathology.leedsth.nhs.uk/testandtubes/ShowTest

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Appendix 2: Methylprednisolone for ABPA in Cystic Fibrosis Monograph

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Appendix 3: Posaconazole Prescribing Information

Posaconazole electronic Medicines Compendium information on Posaconazole

Posaconazole electronic Medicines Compendium information on Posaconazole is an alternative when itraconazole is not tolerated, or on the advice of microbiology. It is not licensed for children less than 18 years of age, so it is a consultant decision to use in children. Posaconazole electronic Medicines Compendium information on Posaconazole is expensive and as a ‘Red’ drug cannot be prescribed by GPs.

Dose

Tablets, 100mg

(preferred formulation where possible for all patients)

Adult over 18 years; 300 mg (three 100mg tablets) twice daily on first day, then 300 mg (three 100mg tablets) once daily.

Children: no data, but based on the fact that, for the suspension, adult doses are used, it may be assumed that children age 8 or over can use adult doses of the adult formulation.

May be taken without regard to food.

Posaconazole electronic Medicines Compendium information on Posaconazole tablets are the preferred formulation to optimize plasma concentrations and generally provide higher plasma drug exposures than Posaconazole electronic Medicines Compendium information on Posaconazole oral suspension.

Suspension, 200 mg/5 mL

(only for patients unable to take tablets, due to poorer bioavailability)

Adult over 18 years; 400 mg (10mLs) twice daily with food or if food not tolerated, 200 mg (5mLs) four times daily.

Children: data exists for children age 8 or over using adult doses

To be taken with food or meals.

Posaconazole electronic Medicines Compendium information on Posaconazole tablets are the preferred formulation to optimise plasma concentrations and generally provide higher plasma drug exposures than Posaconazole electronic Medicines Compendium information on Posaconazole oral suspension. The tablet and oral suspension are not to be used interchangeably due to the differences in the dosing of each formulation.

Posaconazole electronic Medicines Compendium information on Posaconazole suspension should be administered during or immediately (i.e. within 20 minutes) following a full meal or liquid nutritional supplement to significantly enhance absorption of the drug.
Of note, the suspension is affected by H2 antagonists and PPIs causing a reduction in Itraconazole electronic Medicines Compendium information on Itraconazole levels, but the tablets are NOT affected.

BEWARE! The dose of Posaconazole electronic Medicines Compendium information on Posaconazole is dependent upon the formulation.
When writing prescriptions be aware of the differences in the doses, refer to the BNF and specify ‘tablets’ or ‘liquid’ on the prescription.

Relevant drug interactions
Posaconazole electronic Medicines Compendium information on Posaconazole is metabolised via UDP glucuronidation (phase 2 enzymes) and is a substrate for p-glycoprotein (P-gp) efflux in vitro. Therefore, inhibitors (e.g. verapamil, ciclosporin, quinidine, clarithromycin, erythromycin etc.) or inducers (e.g. rifampicin, rifabutin, certain anticonvulsants, lumacaftor etc.) of these clearance pathways may increase or decrease Posaconazole electronic Medicines Compendium information on Posaconazole plasma concentrations, respectively. Posaconazole electronic Medicines Compendium information on Posaconazole is predicted to increase the exposure to ivacaftor. Some of these interactions are highly significant and should be considered before prescribing Posaconazole electronic Medicines Compendium information on Posaconazole .

Drugs whose levels are significantly increased by the concomitant prescribing of Posaconazole electronic Medicines Compendium information on Posaconazole include tacrolimus, ciclosporin and midazolam.

There is an increased risk of adrenal insufficiency when using triazole antinfungals in patients taking inhaled corticosteroids (13,14). It is recommended that the inhaled corticosteroid dose should be reduced to 50% on commencement of Posaconazole electronic Medicines Compendium information on Posaconazole and increased again if necessary when the Posaconazole electronic Medicines Compendium information on Posaconazole course is completed.

Posaconazole electronic Medicines Compendium information on Posaconazole levels
If blood levels are required a trough level is taken after 5-7days. The absorption and metabolism of Posaconazole electronic Medicines Compendium information on Posaconazole will vary from patient to patient.Trough levels should be maintained above 1.25mg/L for treatment. If levels are below this - ensure drug is taken with fatty food if suspension and consider increasing the dose or examining concomitant medications. As yet, the level at which Posaconazole electronic Medicines Compendium information on Posaconazole becomes toxic has not been defined.

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Appendix 4: Voriconazole Prescribing Information

Voriconazole electronic Medicines Compendium information on Voriconazole in the treatment of allergic bronchopulmonary aspergillosis (ABPA) in patients with cystic fibrosis. Revised September 2016

Indications for use:

  • Patients with ABPA who have failed to respond to Itraconazole electronic Medicines Compendium information on Itraconazole , or have failed to achieve adequate plasma levels of Itraconazole electronic Medicines Compendium information on Itraconazole .
  • Treatment of clinically stable patients on IV antifungal therapy who require oral treatment to be discharged.
  • If patient is systemically unwell with aspergillus infection and an inpatient, consider intravenous therapy initially to obtain adequate systemic levels of Voriconazole electronic Medicines Compendium information on Voriconazole . See Summary of Product Characteristics (SPC) for full dosing information.
  • Voriconazole electronic Medicines Compendium information on Voriconazole is licensed for children aged 2 years and above.

In all of these situations the decision should be made in conjunction with a Consultant and Microbiology. As the dose has increased significantly for children in the recent changes of the SPC, be extra vigilant for adverse effects and report to the MHRA using the ‘yellow card’ scheme.

Age

Weight

Dose of oral Voriconazole electronic Medicines Compendium information on Voriconazole

2-<12 years

All

9mg/kg twice a day. Max: 350mg twice a day

12-14 years

<50kg

9mg/kg twice a day. Max: 350mg twice a day

≥50kg

400mg every 12 hours for two doses, then 200mg twice a day

15-17 years

<40kg

200mg every 12 hours for two doses, then 100mg twice a day

≥40kg

400mg every 12 hours for two doses, then 200mg twice a day

Adults

<40kg

200mg every 12 hours for two doses, then 100mg twice a day

≥40kg

400mg every 12 hours for two doses, then 200mg twice a day

In children with cystic fibrosis and ABPA being treated as an outpatient, it is NOT necessary to ‘load’ them with intravenous Voriconazole electronic Medicines Compendium information on Voriconazole . Giving an intravenous loading dose ensures that adequate levels are obtained more quickly and should be considered for systemically unwell patients. Without an intravenous loading dose, adequate levels are expected after approximately 5 days.

Oral: The tablets should be taken at least one hour before, or one hour following a meal, as high fat meals can reduce the absorption of Voriconazole electronic Medicines Compendium information on Voriconazole significantly.

Dose Adjustments

  • Due to large inter-individual variability in Voriconazole electronic Medicines Compendium information on Voriconazole exposure, some children and young adolescents may have much higher Voriconazole electronic Medicines Compendium information on Voriconazole exposure at the proposed dosing regimens. Therefore, these regimens should be considered as the initial dosing recommendation and close monitoring of patients’ tolerability profile is highly recommended.
  • If the patient’s response in inadequate, the oral dose may be increased by 1mg/kg steps (or 50mg steps if the maximum oral dose of 350mg was used initially).
  • For patients unable to tolerate treatment, the oral dose may be reduced by 1mg/kg steps (or by 50mg steps if the maximum oral dose of 350mg was used initially).
  • Use in paediatric patients aged 2 to <12 years with hepatic or renal insufficiency has not been studied.

Other
Post marketing data suggest there might be a higher occurrence of skin reactions (esp.erythema) in the paediatric population compared to adults.
Voriconazole: reminder of risk of liver toxicity, phototoxicity, and squamous cell carcinoma Drug Safety Update - GOV.UK

Voriconazole electronic Medicines Compendium information on Voriconazole is considered a ‘RED' drug with LTHT and therefore cannot be prescribed by general practitioners.

See algorithm below for prescribing Voriconazole electronic Medicines Compendium information on Voriconazole in patients with cystic fibrosis and ABPA.

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