Theme 1: what are the indications for STS?

There is strong evidence for the use of STS in EoE. STS have very good remission rates, 71% symptomatically and 59% histologically in children not responding to proton pump inhibitor (PPI) medication.^{8 9} There is emerging evidence showing that combination therapy of STS with PPI may lead to even better outcomes.⁸ Currently, there are no data in pEoE showing that the use of STS will prevent oesophageal strictures or that strictures can be treated in isolation with STS. However, in practice, medical treatment is often trialled before therapeutic balloon dilatation. The main evidence supporting steroid use in moderate to severe oesophageal strictures is by using systemic steroids. A multicentre retrospective cohort study found that with systemic steroids 20/20 patients showed clinical improvement, 15/20 became asymptomatic and 19/20 had stricture resolution at endoscopy.¹⁰

Theme 2: which STS preparations are best and how should they be made up?

There are three main STS preparations: (a) oral viscous budesonide (‘budesonide slurry’) formed from budesonide respules combined with a viscous binding agent, (b) orodispersible budesonide (tablets) which melt on the tongue before being swallowed and (c) inhaled fluticasone sprayed into the buccal cavity and swallowed. There are currently no head-to-head trials on different preparations or on the ideal viscous binding agent to use to form the slurry. Expert opinion would advocate using an age appropriate preparation which is generally a budesonide slurry in younger children and orodispersible tablets in older children.

Theme 3: should dosing be based on age or height?

Research studies looking at histological remission rates and dosing in children with EoE have used either age ranges (<10 or ≥10 years) or heights (<1.5 or ≥1.5 m) to define cut-offs for medication dosing.¹¹ Expert opinion would advocate using age for simplicity. If a child deviates from their expected growth centiles then consideration should be given to using height instead of age to determine STS dosing.

Theme 4: what dose and duration should induction therapy be?

There is a lack of evidence surrounding the duration and dosing regimen of induction therapy. Expert consensus would favour a minimum of a 3-month induction period and twice daily dosing to promote increased contact time between the medication and oesophageal mucosa (most clinical studies have been conducted with twitch twice daily dosing).

In adults, data from randomised placebo-controlled trials show that in a dosage of 1 mg two times per day, orodispersible budesonide achieved remission after 12 weeks in 85% of patients.¹² Viscous budesonide formulations using sucralose or other substrates (evaluated in a prospective randomised placebo-controlled trial only) may be equally, less or more effective.

In children <10 years old, a standard total daily dose of 1 mg/day in divided doses can be safely used. In children ≥10 years old, a standard total daily dose of 2 mg/day in divided doses should be used. In select cases, doses of up to 2.8 mg/day (<10 years old) and 4 mg/day (≥10 years old) have been used.¹³ Clinician judgement should be used to balance up the optimal dosing frequency versus the chance of adherence in particular cases.

Theme 5: what dose and duration should maintenance therapy be?

Once histological remission has been accomplished, use of maintenance dosing of steroids appears to reduce the frequency and severity of relapse.^{9 14} There is currently limited evidence regarding how long maintenance therapy should be continued for. In adults, data from randomised placebo-controlled trials show that a dosage of orodispersible budesonide of 0.5 or 1 mg two times per day achieved persistent remission after 48 weeks in 73.5% and 75%, respectively.¹⁴ The viscous formulations using sucralose or other substrates (evaluated in a prospective randomised placebo-controlled trial only) may be equally, better or less effective.

Once histological remission has been achieved during the induction phase, maintenance therapy should be considered for a minimum of 1–2 years. Usually, maintenance dosing is started at half the daily induction dose. In the majority of published clinical studies, STS are given two times per day (18 studies), and only in three studies once daily (evening) and one study four times per day.⁹ Outside of clinical studies, in reality, as advised by our corresponding patient support organisations, patients and families sometimes struggle with the logistics of more frequent (more than once daily) dosing, with the morning dose often missed.¹⁵ Therefore, we recommend that consideration should be given and discussion take place to whether once or twice daily dosing is likely to result in improved adherence to longer term therapy and achievement of the desired effect. There are no data suggesting that twice daily dosing determines an increased risk, and no data indicating that once daily dosing has the same treatment effect. From a practical perspective, principles of dental hygiene and exposure of the oesophagus to the drug for over 30 min with no food or drink allowed determine which logistics are feasible for children and families on a daily basis.

Theme 6: how and when should STS be reduced or stopped?

Histological remission is defined as <15 eosinophils per high power field or 0.3 mm² in any oesophageal biopsy examined (proximal, mid and distal oesophagus). Systemic side effects of topical steroids are considered rare during the long-term treatment of patients with EoE in those naïve to STS and without pre-existing adrenal conditions.¹⁶ However, patients with EoE often have associated atopic conditions, and careful consideration should be given to the total daily steroid dose and steroid burden that these patients receive especially during seasonal exacerbations of their atopic disease. Consideration should be given to maintaining EoE on the lowest practical dose of STS to maintain histological remission.

In a systematic review on adrenal insufficiency in children with EoE, adrenal testing was abnormal in 15.8%; however, adrenal insufficiency between topical steroids and placebo was not statistically different over 2–12 weeks of treatment.¹⁷ In observational studies, the risk of adrenal insufficiency increased from 0–10% up to 30–66% in patients with multiple steroid treatments (eg, for asthma or rhinitis).¹⁷ In a multicentre study from the USA, 5% of children on STS were considered to show signs of adrenal gland insufficiency while on STS for longer than 6 months.¹⁶

Children with symptoms suggestive of adrenal insufficiency or risk factors for developing the condition (eg, patients receiving multiple steroids or on twice daily induction regimens for more than 6 months) should be evaluated as per local protocols. The short synacthen test (low-dose injected adrenocorticotropic hormone) is the preferred investigation in most centres.¹⁷

Continued monitoring of growth, bone mineral density and adrenal suppression is recommended in children and adolescents.⁷ Subtle decrease in linear growth was observed in a retrospective multicentre study in children with EoE receiving topical steroid treatment, and sex differences were observed affecting girls treated with combined elemental diet and topical steroids.¹⁸ Children with nutritional deficits (eg, secondary to behavioural or dietetic restrictions) should be carefully monitored for adequate growth (eg, centile, nutritional assessment, biochemically) and bone health (eg, DEXA (dual energy x-ray absorptiometry) scan).¹⁹

Theme 7: when should endoscopy be repeated?

There is no clear paediatric guidance on when an endoscopy should be repeated following diagnosis. In children, histological findings often correlate very poorly with symptoms.^{9 20} Endoscopy and biopsy should be used to ensure that STS treatment strategies are effective, enable management changes and investigate worrying symptoms.

Efficacy, palatability and adherence

Twice daily dosing theoretically allows for a minimum of a daily anti-inflammatory dose especially if one dose is missed. The WG were advised that for adherence to maintenance therapy once daily dosing is more acceptable.¹⁵ Individual circumstances should be discussed and tailored according to lifestyle and activities. As there are currently no licensed preparations of STS in children, a variety of carrier substances for budesonide STS preparations to coat the oesophagus have been used for administration and palatability (online supplemental appendix 1).^21–26 This is heavily reliant on local expertise and there are no head-to-head trials to advocate use of one over another. Orodispersible budesonide (tablets) are licensed in adults and are increasingly being used off-label. Prospective paediatric studies for STS have been conducted and first results have been submitted for peer-reviewed presentation,²⁷ indicating good prospects for suspensions and tablets, subject to pharmaceutical licensing, for future application in children.

Side effects

Children with EoE have a 70% association with atopic comorbidity, steroids are often prescribed by other physicians (dermatology, respiratory, general paediatrics) which potentially increases the cumulative steroid burden. The largest multicentre study reported that 5% of children showed signs of adrenal gland insufficiency while on STS for EoE for longer than 6 months.¹⁶ In study protocols, baseline cortisol levels, short synacthen testing and follow-up while on maintenance treatment have been applied; however, there is controversy of the standardisation and interpretation of test results, we recommend performing these as clinically indicated and according to local endocrinology advice. Other monitoring should include growth parameters and bone mineral densities. Candida infection is rare and can be treated simultaneously with topical antifungal or oral medication.⁷

Endoscopy, prognosis, withdrawal and escalation

In the absence of validated clinical activity scores or non-invasive biomarkers, the group agree that endoscopic reassessment with histology should be used after any significant treatment start or modification. As STS are effective in more than 80% of children when taken according to protocols and usually well tolerated, prognosis is very good. Withdrawal is indicated in non-responders, disease progression under therapeutic dosage of STS or clinically relevant adrenal gland insufficiency. We found limited evidence for escalation of treatment with regard to dosage of STS.^{18 20}

Limitations

There is no evidence for the ideal carrier substance used to generate the optimal formulation of STS. There is a lack of studies to compare potential effects of once or twice daily administration of a defined daily dose of STS on efficacy and long-term outcomes. STS have been considered mainly in isolation and combination therapy has not been investigated as they have been discussed elsewhere.^{8 18 20 28}

Implications for clinicians and policymakers

This project is a starting point for pEoE in the UK and beyond; further work should be considered with other professionals in paediatric practice to develop a collaborative multisystem approach to pEoE care including allergy and transition to adult settings. This would ensure continued evolution of the clinical reference flow chart when better access to medication occurs; merging paediatric and adult practice should be the gold standard to aim for.