Adrenal suppression from glucocorticoids: preventing an iatrogenic cause of morbidity and mortality in children

AS in children treated with systemic GCs

Both clinical and biochemical evidence of AS have been well described in children after discontinuation of therapeutic doses of systemic GCs.10 12–14 Shorter term systemic GC exposure is associated with more transient AS.15 16 In practice, exposure for greater than 2 weeks is used as a threshold for risk of clinically important AS.6 Duration of AS after prolonged GC exposure has been reported to be up to 2 years.9 12 Symptomatic AS including adrenal crisis and death are well documented related to systemic GC therapy.3 8 13 17 Higher dose is a risk factor,18 while longer duration and timing of administration of GCs (evening vs morning and daily vs every other day) are theoretical risks.5 18 19

We did not find literature exploring risk of repeated intermittent GC exposure.

AS in children treated for asthma with ICS

Symptomatic AS associated with ICS use is rare but important and the risk can be reduced by using the lowest dose of ICS sufficient to maintain acceptable asthma control, as outlined in current asthma guidelines.20–22National asthma guidelines recommend consultation with asthma specialists if children or adolescents meet the criteria for treatment with high (or moderate) dose ICS therapy.20–22

There have been more than 90 case reports in the literature of adrenal crisis or death secondary to ICS use for the treatment of asthma.1 23–25 Pharmacokinetic and pharmacodynamic properties and dose, in addition to ICS mode of delivery, play a role in the risk of AS,2 and therefore, doses associated with increased risk of AS risk differ between medications (see table 1). Clinicians can consider the use of high-dose ICS therapy as defined by asthma guidelines as an important risk factor for AS, particularly because the current literature does not provide clear thresholds for AS risk.8 11 20–22 26–28An important exception to this rule is fluticasone, an ICS that has been associated with the majority of cases of symptomatic AS in doses of 500 µg daily or greater (500 µg is moderate dosing for children ≥12 years in some guidelines).1 2 4 8 24 29 30 In addition, ciclesonide, a comparatively newer ICS, appears to have reduced AS risk,2 4 20 25 31 32 although cases of AS have been reported at high doses.33

While the majority of cases of symptomatic AS have been reported in children exposed to high-dose ICS, there are rare reported cases of those receiving low to moderate dosing,2 33 highlighting the importance of consideration of AS in children presenting with possible signs or symptoms of AS regardless of ICS dose. Conversely, while high-dose ICS therapy increases the risk of AS, many children receiving high-dose therapy are not suppressed.11 A recent genome-wide association study suggests that a common genetic variant might lead to susceptibility to AS in patients exposed to ICS but further study is needed to support this finding.34 There are also many genetic variants of the GC receptor gene, which are thought to explain the wide interindividual variation in GC sensitivity5 and several single nucleotide polymorphisms that have been associated with HPA axis reactivity,3 both of which likely in part explain the variability in AS susceptibility. Other possible factors contributing to interpatient variability in the development of AS include inhaler technique, age and asthma severity which might impact both ICS deposition in the lungs and the amount of ICS absorbed into the systemic circulation.

In addition to high-dose ICS therapy, exposure to courses of systemic GCs for treatment of asthma puts children at risk of AS.1 2 4 31 Achieving good asthma control with skilled use of controller therapy, including appropriately dosed ICS, will prevent exacerbations and reduce the need for long-term and/or repeated courses of GCs.35 Other possible risk factors include concomitant intranasal corticosteroids, low body mass index and cumulative GC exposure.2 8 Duration of ICS exposure has not been found to be a risk factor; however, most studies have looked at exposures of 6 weeks or more.3 5 11 34

Clinicians need to be aware of the ICS doses contained in combination inhalers and should consider those as increasing the risk of AS based on the ICS component (see table 1).

AS in children treated with other forms of GCs

Studies of the risk of AS related to intranasal corticosteroids alone have had variable results, although use in conjunction with ICS is a risk factor.36–38

While the use of low to moderate potency topical corticosteroids is rarely associated with a risk of AS,39 there have been case reports of symptomatic AS and cushingoid features in infants receiving potent topical GCs for >1 month with misuse of the medication.40 Symptomatic AS associated with cushingoid features has also been reported with ocular GCs.41 AS has been associated with intra-articular GCs in adults.42

Studies suggest that children receiving swallowed ICS for eosinophilic esophagitis or inflammatory bowel disease are at risk of AS.8 43 44

Medications potentiating systemic effects of GCs

CYP3A4 inhibitors, including several antiretroviral medications, antifungal agents and select antidepressants, prolong the biologic half-life of GCs. These medications have been reported (1) in several cases of symptomatic AS associated with relatively low doses of ICS, and (2) with a prolonged duration of AS after systemic GC exposure.10 45 46

GC taper

There is no evidence to support a specific approach to GC taper for the prevention of AS.3 47 It has been demonstrated that a gradual GC taper does not prevent AS.12 GCs should be tapered or discontinued at a rate dictated by the underlying condition in order to maintain disease remission; if not indicated for prevention of disease relapse, a prolonged taper should be avoided to prevent unnecessary GC exposure. Physiological GC replacement should prevent symptoms of AS,6 so testing of the HPA axis prior to discontinuing or tapering GCs below a physiological dose (<8 mg/m²/day hydrocortisone equivalent) should be considered in children who have received prolonged courses of GCs (table 2, GC dose equivalencies). Symptoms of GC withdrawal can occur during a rapid taper and may mimic symptoms of AS despite biochemical evidence of HPA system integrity or adequate GC replacement.48 Clinicians need to be aware of this possibility, evaluate for possible AS and modify their taper accordingly.

Testing for AS

Testing for AI, including AS, is a challenge for clinicians due to lack of standardisation of cortisol assays and lack of clinical association with established cortisol thresholds used for diagnosis.49 50 Of particular note are newer generation assays including the Roche Cortisol II immunoassay, which is reported to measure cortisol levels approximately 30% lower than the older Roche immunoassay.51 Clinicians must be aware of the thresholds associated with the assay used in their local laboratory.

Cortisol thresholds cited within this section are reported from studies that have employed older generation immunoassays, and as such, need to be interpreted with caution. First morning cortisol (07:00–09:00) is often used in screening for AI. A first morning cortisol is specific for diagnosis of AI if ≤100 nmol/L (≤3.6 µg/dL) in individuals with a normal sleep–wake cycle in whom GCs are withheld for at least 24 hours.52 53 GCs with longer duration of action must be held for longer than 24 hours. Clinicians must assess the safety of discontinuing GC therapy for testing and modify their approach accordingly (see table 3). Since cortisol production is under circadian regulation, a low morning cortisol is poorly predictive of AS in infants and children who do not have a regular sleep–wake cycle, and dynamic testing is indicated.54 A first morning cortisol value of ≥350–500 nmol/L (≥13–18 µg/dL) can predict normal HPA axis function.53 55 56 The Paediatric Endocrine Society Pharmacy and Therapeutics guideline about endocrine side effects of ICS suggests that a first morning cortisol value of 275 nmol/L (10 µg/dL) may be considered as a screening threshold in asymptomatic patients.2 However, there is no single absolute cut-off for morning cortisol that can be used to confidently rule in or out AS.

Provocative testing is typically required for diagnosis of central AI including AS. Both standard dose (250 µg) and low dose (1 µg) ACTH stimulation tests are used in clinical practice for evaluation of central AI with significant debate about which is superior, some studies suggesting that the low dose stimulation test is significantly more sensitive but less specific with other studies not supporting this finding.50 55 57 Peak cortisol thresholds of 440–600 nmol/L (16–22 µg/dL) are commonly used to rule out AI but varies between studies and institutions since many factors must be considered when interpreting results (eg, cortisol assay, timing of cortisol draws relative to corticotropin administration, medications affecting cortisol binding, time of day).54 58 59 Clinicians must therefore refer to their local protocols for guidance. Appropriate preparation and procedures for testing of the HPA axis are required (see table 3).

How can we reduce the risk of AS and adrenal crisis?

Despite being largely preventable, morbidity and mortality associated with AS continue to be reported. We suggest that the following measures be considered to reduce this risk:

1. Clinician education and awareness about the risk of AS including an understanding of the relatively high frequency of AS in patients being treated with ≥500 mcg of fluticasone or high-dose ICS therapy as defined by national or international asthma guidelines.

2. Clinicians should prescribe the lowest effective dose of GCs with regular re-evaluation. If once-daily GC dosing is appropriate, GCs should be given in the morning to minimise suppression of the HPA axis.

3. Families should be educated about the risk of AS with an understanding that the benefits of GC therapy outweigh the risks, and that medication adherence and clinical follow-up are the best preventative measures for symptomatic AS.

4. All children with possible signs or symptoms of AS, including poor growth, and with current or recent history of GC/ICS use should be tested for AS. Symptomatic children with biochemical evidence of AS should be treated with both physiological GC replacement and stress dosing GCs (table 4).

5. Stress dosing should be provided for critical illness or major surgery, in all children being actively treated with GCs and should be considered in all children who have recently discontinued GC therapy (up to a year for those with prolonged exposure) unless they have been proven to have a normal HPA axis. Cortisol should be drawn prior to initiating stress dosing during a critical illness if the diagnosis of AS is not confirmed.

6. Screening of children at high risk of AS should be considered. An alternative approach may be to provide empiric stress dosing once GC doses are tapered to <30 mg/m²/day of hydrocortisone equivalent and for up to 6–12 months following GC discontinuation. There is no evidence to support a specific approach to asymptomatic children with AS.

7. Children with biochemical evidence of AS should receive stress dosing. Treatment with physiological GC dosing should be considered.

8. Families of children with proven or suspected AS should be educated about stress dosing (table 4) and provided with a stress dosing card or handout outlining doses, indications for stress dosing and indications to seek emergency help. Wearing a medical alert identification should be considered.

9. Family/caregiver education for administration of intramuscular hydrocortisone for use during severe illness or when unable to tolerate oral therapy should be considered for all children with possible or proven AS, especially in those who live or travel remotely.