Ir Med J. 2009 Jan;102(1):26-8.

L Glackin, G Leen, B Elnazir, P Greally
Department of Respiratory Medicine, National Children’s Hospital, Tallaght, Dublin 24

Abstract
Allergic bronchopulmonary aspergillosis (ABPA) can cause a significant clinical deterioration in patients with cystic fibrosis. There is very little research in the current literature with regard to alternatives for treatment, apart from long courses of steroids. We conducted a retrospective review of all our patients with ABPA treated with the antifungal voriconazole and found there was a significant drop in IgE levels post treatment as well as a decrease in steroid dosing. The improvement in FEV¹ was not statistically significant; however there was a very wide variation in pre-treatment levels.

Introduction
Allergic bronchopulmonary aspergillosis (ABPA) is a common complication of cystic fibrosis (CF), affecting up to 10% of children aged over six years¹ and is associated with deterioration in lung function and clinical status. It is a hypersensitivity disease of the lung due to an immune response to aspergillus fumigatus allergens. Antifungal therapies are postulated to reduce the fungal load and may allow a decrease in corticosteroid dosing, which are the mainstay of treatment and are associated with significant sideeffects. A Cochrane review revealed a paucity of data on antifungals in the treatment of ABPA for patients with CF². However one recent series of 21 children with a spectrum of aspergillus diseases treated with voriconazole showed promising results³. This is a more recent antifungal drug and has better absorption and bioavailability compared to the traditional itraconazole⁴.

Methods
The aim of our study was to review the efficacy of voriconazole in the treatment of ABPA, by carrying out a chart review of our cohort of 110 children with cystic fibrosis.

The diagnostic criteria from the 2003 Consensus Conference on ABPA in cystic fibrosis 1 are: (1) Acute or sub acute deterioration in lung function (FEV1) not attributable to another aetiology (2) Total serum IgE >500 IU/ml (3) Specific IgE to Aspergillus fumigatus and (4) One of (a) precipitans or IgG antibody to A. fumigatus, or (b) new or recent abnormalities on chest x-ray that have not cleared with antibiotics and standard physiotherapy.

The end points measured, to assess efficacy of voriconazole, were a change in steroid dose, total IgE levels and patients’ FEV¹. Dosing was prescribed as per the British National Formulary for children⁵ which is a six week or three month course of 100mg or 200mg twice a day depending on body weight. Liver function tests were measured prior to starting therapy and fortnightly thereafter.

Results
There were twelve episodes of ABPA treated with voriconazole, in ten patients, that met the definition criteria. One patient who started treatment for ABPA died before finishing her course of voriconazole from complications of her end-stage lung disease. Therefore results from eleven episodes of ABPA, in nine patients, are reported. Of these nine patients, there were four girls and five boys whose mean age was 14.4 years (+/- 0.2yrs). Eight had a previous history of ABPA, but not treated with voriconazole. Ten out of the eleven were on a prolonged course of oral steroids prior to starting voriconazole, their dose ranging from 7.5mg/day to 40 mg/day prednisolone (mean = 16mg/day). After treatment, there was a mean decrease of 7.5mg/day (95% C.I.-0.36 – 15.4mg) P<0.06. The total serum IgE levels pre-treatment ranged from 520 – 3790 IU/ml. There was a mean drop post-treatment of 826 IU/ml (95% C.I. 321-1331) P<0.005.

FEV1 levels pre-treatment ranged from 22% - 93% of predicted(mean 56.8%). There was a mean increase post-treatment of 4.2% (95% C.I. -1.3 - 9.7) P=0.12, which although not statistically significant, is probably biologically important. One patient developed minor side effects of visual disturbance and photosensitivity while on voriconazole. She later completed a second course with no ill effects. There were no other reported adverse events or derangement of liver function tests.

Discussion
Our results are encouraging and suggest a role for voriconazole in conjunction with oral steroids in the treatment of ABPA, as it may have a steroid sparing effect. However further prospective randomised control trials are required in this area.

Correspondence:
L Glackin
Department of Respiratory Medicine, National Children’s Hospital, Tallaght, Dublin 24
Email:[email protected]

References

1. Stevens DA, Moss RB, Kurup VP, et al. Allergic Bronchopulmonary Aspergillosis in Cystic Fibrosis – state of the art: Cystic Fibrosis Foundation Consensus Conference. Clin Infect Dis 2003;37:S225-64.
2. Elphick H, Southern K. Antifungal therapies for allergic bronchopulmonary aspergillosis in people with cystic fibrosis. Cochrane Database Systematic Review 2000;4:CD002204.
3. Hilliard T, Edwards S, Buchdahl R, et al. Voriconazole therapy in children with cystic fibrosis. Journal of Cystic Fibrosis 2005;4:215- 220.
4. Johnson LB, Kauffman CA. Voriconazole: a new triazole antifungal agent. Clinical Infectious Diseases 2003;36:630 -7.
5. BNF for children from BMJ Publishing Group Ltd, RPS Publishing, RCPCH Publications LTD 2006. P. 355.