Audit on the Management of ABPA in CF patients at Alder Hey Children ’ s Hospital

Background: Allergic bronchopulmonary aspergillosis (ABPA) is a persistent problem for many cystic fibrosis (CF) patients. It is a challenging condition to diagnose and manage. Aim: The CF team at Alder Hey Children’s Hospital aimed to assess how consistently and effectively they were managing the condition. A diagnosis and management monitoring tool was used to systematically draw data for auditing. Methods: Out of 87 patients under the care of the CF team, 20 had previously been diagnosed with ABPA. 60% had 4 out of the 4 minimal diagnostic criteria. 75% grew cultures positive for A. fumigatus at some point since their diagnosis of ABPA. All patients had received prednisolone therapy at some point since diagnosis, with 7 patients receiving the maximum starting dose of 40 mg and 1.29 mg/kg for those below maximum dose. 14 patients were prescribed antifungal therapy. 5 patients had levels ordered when they started the therapy, 5 had levels ordered between 45 and 1149 days after prescription, and 3 have had no levels ordered to date. A second audit was performed one year later to complete the audit cycle. Results: This cohort of patients had a much higher prevalence of ABPA than the general CF population. Discussion: Research into the relationship between ABPA exacerbation and concurrent infections or antibiotic therapy could help identify risk factors for developing an exacerbation. There should be discussions about how to improve the consistency in initial dosing of prednisolone, considering guidelines. Conclusion: There should be more itraconazole levels taken to ensure safety and effectiveness of antifungal therapy. Copyright Royal Medical Society. All rights reserved. The copyright is retained by the author and the Royal Medical Society, except where explicitly otherwise stated. Scans have been produced by the Digital Imaging Unit at Edinburgh University Library. Res Medica is supported by the University of Edinburgh’s Journal Hosting Service: http://journals.ed.ac.uk ISSN: 2051-7580 (Online) ISBN: 0482-3206 (Print) Res Medica is published by the Royal Medical Society, 5/5 Bristo Square, Edinburgh, EH8 9AL Res Medica, 2014, 22(1): 111-119. doi:10.2218/resmedica.v22i1.808 Res Medica 2014, Volume 22, Issue 1 Beresford, HE. & Hunter, E. Audit on the Management of ABPA in CF patients at Alder Hay Children’s Hospital. Res Medica 2014, 22(1): pp. 111-119. doi:10.2218/resmedica.v22i1.808 111 Audit on the Management of ABPA in CF patients at Alder Hey Children’s Hospital


Introduction
Allergic bronchopulmonary aspergillosis (ABPA) in cystic fibrosis (CF) patients is the colonization by the fungus Aspergillus fumigatus in the lungs with an allergic response.ABPA occurs in approximately 10% of CF patients and accounts for about 10% of pulmonary exacerbations in these patients. 1 fumigatus spores are largely found in soil but may become airborne.When inhaled by a susceptible host, the fungus can colonize and produce toxic and allergenic products.
The clinical features are included in Box 1.

Box 1. Clinical features of ABPA 2
Early symptom recognition and initiation of effective treatment are important in reducing long-term complications.There is discrepancy between various organizations' use of diagnostic criteria as patient presentation can be atypical and still show a response to ABPA treatment.The minimum diagnostic criteria used for reference in this paper are displayed in Box 2.
Box 2. Diagnostic criteria for ABPA in CF as according to Cystic Fibrosis Consensus 3 Diagnosing ABPA can be a significant challenge because there are a wide range of infections that CF patients are vulnerable to that can present with similar respiratory symptoms.The management of ABPA, according to the Cystic Fibrosis Trust guidelines, starts with an oral corticosteroid (prednisolone) usually given at around 0.5-2 mg/kg up to a maximum dose of 40 mg.This is then weaned down on the basis of IgE levels, chest radiography, spirometry, and pulmonary symptoms, ideally within in  5 There is also evidence that oral itraconazole is poorly absorbed by children with CF 6 ; therefore, it is recommended that drug serum levels are measured during therapy. 7This is also important in recognizing when levels are too high, because adverse events will occur more often. 8It is therefore extremely important to find and maintain the balance between optimizing treatment while minimizing the risk of side effects.
The purpose of this audit is to assess the management of ABPA in CF patients treated at Alder Hey Children's Hospital.There were no exclusion criteria used.   2 show data on the number of exacerbations experienced by each patient.

Diagnosis
Table 1 shows a summary of the demographic data.Ages are rounded to the last month.Fifteen (75%) had grown A. Fumigatus in respiratory cultures at some point throughout their treatment.

Prednisolone prescribing
All patients were started on prednisolone once diagnosed.Figure 3     In patients who had an unsatisfactory antifungal medication level, the dose was changed and levels repeated until a satisfactory level was recorded.

Key findings
This audit studied a population of patients who have a greater prevalence of ABPA than is reported in previous studies.There Most of the records reported the symptoms and signs that lead to suspicion of ABPA but many lacked investigation results.

Diagnosis
It is interesting to observe that prevalence of ABPA in this cohort was significantly higher than has been previously reported, at 2-10%.

Limitations
The small sample size (n = 20) of the audit means any conclusions may not be reliable; however, there is a paucity of data published on the subject of ABPA.The lack of specialist knowledge of the auditors may have meant that certain important factors may have been missed, but regular discussions with the CF team were held to ensure all key features were included.

Conclusion
There are several recommendations that can be drawn from the first evaluation.Firstly, it is important that documentation fully states any diagnoses, any change of dose and the date.Furthermore, it would be useful to complete the proforma of ABPA treatment fully, to allow easy monitoring of progress.
It would be beneficial for the team to discuss a consistent method of prescribing prednisolone, whilst considering the guidelines provided on prescribing as well as clinicians' own experience of the efficacy and safety of various doses.
The team should discuss how to improve monitoring of itraconazole levels to prevent children from either being below therapeutic levels, or having high levels and risking liver damage.

Changes implemented
After presenting the conclusion and recommendations, it was agreed that the team would use the "diagnosis and followup" form for all patients with a diagnosis of ABPA, updating information at each outpatient clinic.The team took names of those who still needed itraconazole levels so they could be ordered at their next clinic.It was also agreed to discuss the variations in prednisolone prescribing between clinicians and agree a consistent method of deciding initial doses.

Second audit
Upon the second audit, there had been no new CF patients diagnosed with ABPA.18 patient notes were available for data extraction.Of these, 3 had moved to adult services and as such were not included and 2 patients' notes were not available.From the remaining 15 patients, 3 episodes of ABPA had been treated within the last year, all 3 with prednisolone starting doses of 40 mg.
The dosing of prednisolone was still unrelated to the patients' weight and so further discussion may be needed to elicit the reasoning of the healthcare team.Of these 3 patients, only 1 had the ABPA form completed fully, which meant that tracking prednisolone dosing and episodes was difficult.Furthermore, only 3 of the 9 patients remaining on itraconazole had their levels measured within the last year.This is still an area which needs improvement and it is recommended that all patients on itraconazole should be recalled for levels at the next clinic.

Learning points
What is already known?
 ABPA is a challenging condition for patients and for clinicians who manage it.
 Diagnostic criteria are difficult to define, with many patients not fitting the full criteria, despite responding positively to ABPA therapy.
 There are guidelines on how to manage ABPA effectively, as published by the Cystic Fibrosis Trust.

What this study adds
 Insight into the demographics of patients who have been diagnosed with ABPA in CF in the Mersey area.
 Further information on diagnostic criteria to be used in the discussion of how to define ABPA.
 Recommendations on the consistency of prednisolone dosing, based on existing guidelines.
 Recommendations on the importance of improving the consistency of itraconazole monitoring, based on guidelines and studies into the toxicology of the drug.

The
CF team aimed to assess the rates of consistency of managing the condition and assess the importance of any trends highlighted during the audit process.The aim is to provide recommendations based on any trends or discordance with guidelines.Methods An ABPA "diagnosis and follow-up" form for each patient was used as the audit tool for this retrospective audit.It was formulated by the CF team at Alder Hey, and will be used throughout each ABPA patient's treatment.It includes an entry for each ABPA therapy adjustment with inclusion of measurements of IgE, lung function testing (specifically, FEV1), liver function tests (LFTs), respiratory cultures, clinical features, and dose changes.This document helps track these test results and allows an overview of clinical response to treatment.Data were systematically extracted from patient notes, using clinic letters, inpatient notes, and investigation results from the hospital database to retrieve IgE, LFTs, FEV1, culture testing, and dose changes.Raw data were processed using a spreadsheet program to produce tables and graphs for data presentation.The Cystic Fibrosis Consensus Conference 2003 guidelines for ABPA diagnosis were used for diagnostic criteria. 4The Cystic Fibrosis Trust guidelines for treatment was used as the audit standard. 5level monitoring, improved consistency of prednisolone dosing, and improved record keeping.Inclusion criteria included patients with a diagnosis of CF and patients with a previous diagnosis of ABPA.
Of the 87 patients with CF, 20 (23%) had previously been diagnosed with ABPA.60% of the cohort were boys.The mean current age of the patients was 13.53 years (range 5.58-18.33)with a mean age at diagnosis of ABPA of 8.98 years (range 2.91-16.75).

Figure 1 .
Figure 1.Number of episodes experienced by each patient

Figure 2
Figure 2 shows the proportions of patients who met the 4 minimal diagnostic criteria for ABPA diagnosis, as included above.

Figure 2 .Figure 3 . 7
Figure 2. Proportions of diagnostic criteria met displays the initial doses prescribed.15 (75%) were given alternate day doses at some point during their prednisolone therapy.The total days on prednisolone during each patient's first episode ranged from 36 to 945 days, with an average of 285.95 days.14 (70%) had their doses reduced within 2 weeks and 4 (20%) patients had not had any dose reduction by 4 weeks after first dose.4 (20%) patients were never completely weaned off their first prednisolone course due to a new exacerbation or because weaning was ongoing at the time of the study.During subsequent episodes 11 (55%) patients had their dose reduced within 2 weeks but 5 (25%) patients had not had a dose reduction by 4 weeks after their first dose.

Figure 4 . A table to show the initial doses of prednisolone Itraconazole prescribing 14 patients were on antifungal therapy, 8 (
Figure 4.A table to show the initial doses of prednisolone

Figure 5 .
Figure 5. Antifungal drug level results are significant challenges in diagnosing ABPA due to the number of differential diagnoses that could be causing an exacerbation of respiratory symptoms in a CF patient.There are challenges in achieving optimal management of the condition; it is important to achieve a balance between symptom control and the side effects that prolonged steroid use and antifungal therapy pose.The data showed inconsistencies in steroid prescribing and a lack of therapy level monitoring for patients on this antifungal agent.Record keeping Only 1 patient had a "diagnosis and followup" form completed.The form could be an important tool in monitoring the progression of ABPA and managing it effectively, and should be filled in regularly following any change of ABPA treatment.The form displays an overview of ABPA features, treatment and investigation results.

No. given at maximum 40 mg 7 Number given at > 2 mg/kg 1 Number given at 1.50-1.99 5 Number given at 1.0-1.49 4 Number given at < 1 mg/kg
1 patient was prescribed voriconazole due to itraconazole intolerance.Figure5displays the results of antifungal drug level monitoring.