Asthma treatment in children: A guide to screening for and management of hypothalamic-pituitary-adrenal axis suppression.
In a recently published approach to paediatric asthma management,  treatment modifications included a 3-day course of rescue oral corticosteroids, intermittent use of ICS, a single ICS dose in the morning if possible, and a more prominent role for non-steroid controller medication. All these measures will protect the hypothalamic-pituitary-adrenal axis from suppression. However, the article neither recommended screening for nor suggested any management of HPAS.
Whenever exogenous corticosteroids are prescribed, endogenous cortisol production is reduced. This 'systemic effect' is determined by the dose, delivery device, technique, adherence, body surface area, body mass index (BMI) and duration of therapy, the number of corticosteroids being used and their pharmacokinetic characteristics, and genetic and epigenetic factors. [2-4] Age and gender are not predictors, unless the dose has not been adjusted to body surface area.  At supraphysiological ICS doses, 50% of children can be expected to develop HPAS,  while at physiological doses (i.e. a cortisol production rate of 3.0 - 10.6 mg/[m.sup.2])  dose and effect have an inverse relationship.  Hypocortisolaemia has even been described at physiological doses. [2,7,8] HPAS is usually seen in all children after 6-42 months of ICS therapy,  but has been observed as early as 2 months (EWZ, unpublished data, 2011). Under basal conditions no untoward effects will be apparent, because the decreased product ion of cortisol is balanced by the supply of exogenous corticosteroids. In the long term, the adrenal glands may atrophy. During a stressful event such as an infection, injury, burn or surgical operation, or even an asthma exacerbation, demand for cortisol may outstrip its exogenous supply. The stress can precipitate an adrenal crisis, which may lead to death. When CYP3A4 enzyme inhibitors (antiretrovirals, antifungals, calcium-channel blockers, certain antibiotics and antidepressants)  are coadministered, metabolism of corticosteroids is reduced, resulting in HPAS or Cushing's syndrome. 
In order to make recommendations for diagnosis, screening and management of HPAS in asthmatic children, I have reviewed the existing literature and presented the quality of the evidence assessed in three tables. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used. It classifies the quality of the evidence as high, moderate, low or very low, with the recommendations being either strong or weak.  Management suggestions that could not be substantiated by evidence are labelled 'ungraded best practice'. 
Diagnosis of HPAS
HPAS presents as a spectrum (Table 1). Adrenal crisis is the most devastating presentation, but occurs rarely.  Chronic adrenal insufficiency (CAI) is frequently overlooked owing to its nonspecific clinical features.  For these reasons it is essential to diagnose HPAS in its subclinical state. The overnight metyrapone test should be used to make the definitive diagnosis of HPAS.  If metyrapone is not available, the 0.5 [microg/1.73 [m.sup.2] adrenocorticotrophic hormone (ACTH) stimulation test is a good second choice, provided serum cortisol levels are measured at 10, 15, 20, 25, 30 and 35 minutes.  Clinicians utilising the ACTH stimulation test need to be aware of several pitfalls.  Interpretation of results is assay specific. In 2015, Roche launched its Elecsys Cortisol II assay. It is more specific than the older cortisol assay and shows lower cross-reactivity, generating cortisol levels that are ~30% lower.  The pass criterion for the test therefore has to be down-adjusted to 350 nmol/L (from 500 nmol/L). No adjustments need to be made for levels <250 nmol/L, because the old and new assays correlate well at lower levels.
Screening for HPAS
Screening for HPAS (Table 2) is problematic, because no useful screening test has been identified so far.  Measurement of early morning salivary cortisone has been suggested,  but its routine use is premature because it has not been evaluated against a gold-standard adrenal function test. Its low positive predictive value would also argue against its use. Endocrinologists diagnose adrenal insufficiency when the 08h00 - 10h00 serum cortisol level is <138 mmol/L, [12,20,21] while a serum cortisol level of >350 nmol/L (as measured with the Elecsys Cortisol II assay) virtually excludes HPAS.  A 06h00-08h00 serum cortisol level of <83 nmol/L to suggest HPAS would be ideal,  but may be impractical. There is no scientific basis for labelling a level >276 nmol/L as safe.  Given the poor performance of the serum cortisol screen, only patients at high risk should be screened. If the results are inconclusive, the patient should be referred to an endocrinologist for definitive testing.
In order to identify patients at high risk, meticulous attention should be paid to an individual asthma patient's treatment, the corresponding doses and calculation of the total steroid dose, relating this to body surface area. In addition, cognisance needs to be taken of the child's BMI, adherence to therapy and the ICS route of administration, as lung deposition, and hence dose, varies between devices. [1,3]
Management of HPAS
Management of adrenal crisis is life-saving (Table 3). Treatment modification (besides hydrocortisone) for CAI or subclinical HPAS is essentially the same. The aim of the intervention is to keep the total steroid dose well within the lower-normal physiological range.  Steroid-sparing controllers available include leukotriene receptor antagonists, long-acting beta-agonists, long-acting theophylline, tiotropium bromide, and the biological agents omalizumab, mepolizumab and dupilumab. [1,23] Early-morning dosing of inhaled and nasal budesonide, ciclesonide, mometasone, and fluticasone propionate and furoate should be prescribed whenever symptom control allows it, thereby ensuring that the early-morning surge of ACTH is not suppressed. These four drugs have minimal systemic absorption.  Should HPAS develop while on nasal beclomethasone or budesonide, nasal therapy should therefore be switched to one of the newer agents. However, beclomethasone is the preferred ICS/ NS for any child treated with an enzyme inhibitor in addition to a steroid, because it is not metabolised by cytochrome P450.  Rescue oral corticosteroids should never be given for more than 3 days  and should not be provided to parents to be used when necessary. Treatment modification for HPAS has been found to be effective.  Even when ICS doses are not reduced, HPAS seems to resolve in some patients.  This may be due to poor adherence to therapy or an increase in airway diameter with age, resulting in better control with reduced ICS doses.
Any asthmatic child on corticosteroids may develop HPAS. In the absence of clinical features, serum cortisol should be used to screen those most at risk. Screening should start 6 months into therapy and include children on supraphysiological steroid doses, those on multiple steroids or enzyme inhibitors, and those adherent to therapy or who are thin. If screening is inconclusive, adrenal function testing should be performed by a paediatric endocrinologist. Appropriate management, including asthma therapy modification, should be instituted if necessary.
Author contributions. Sole author.
Conflicts of interest. None.
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Accepted 18 March 2019.
E W Zollner, PhD, MMed, MB ChB, DCH, DTM&H, DPH
Endocrine Unit, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
Corresponding author: E WZollner (firstname.lastname@example.org)
Table 1. Diagnostic features of HPAS Presentation Clinical features Serum cortisol Clinical Adrenal crisis Hypoglycaemia*// Usually <138 nmol/L depressed level of consciousness/coma, convulsions; nausea (hypotension, syncope, severe weakness, abdominal pain, vomiting, backache, hyponatraemia, hyperkalaemia, hypercalcemia)' CAI Lassitude, weakness, <138 nmol/L at dizziness, nausea, 08h00-10h00 headache, poor growth, weight loss, (orthostatic hypotension) ' Subclinical Hypocortisolaemia Inability to respond <138 nmol/L at appropriately to stress 08h00-10h00 Failed adrenal Inability to respond 138-350 nmol/ function test appropriately to stress L[section] at ([double dagger]) 08h00-10h00 Strength of recomm- Presentation endation/level of evidence Clinical Adrenal crisis Strong/moderate CAI Weak/very low Subclinical Hypocortisolaemia Weak/low Failed adrenal Strong/moderate function test ([double dagger]) HPAS = hypothalamic-pituitary-adrenal axis suppression; CAI = chronic adrenal insufficiency; ACTH = adrenocorticotropic hormone. * Hypoglycaemia is the most common presentation of adrenal crisis in the paediatric age group. ([dagger]) These clinical/laboratory findings are classic features, but have not been described in case series. ([double dagger]) Metyrapone or 0.5 [micro].g/1.73 [m.sup.2] ACTH stimulation test. ([section]) As measured by the Elecsys Cortisol II assay. Table 2. Screening recommendations for subclinical HPAS Strength of recommendation/ level of evidence Patients at A. On a Strong/moderate highest risk supraphysiological total steroid dose (ICS + NS), i.e. >10.6 mg HC equivalent/[m.sup.2]/d (>BUD 848 |g/[m.sup.2]/d or >FP 424 [micro]g/ [m.sup.2]/d given by MDI + spacer) B. On a physiological total steroid dose ([less than or equal to] 10.6 mg HC equivalent/[m.sup.2]d) On multiple steroids ICS + prednisone: daily, Strong/low alternate-day or recurrent 5-day courses <10 days apart ICS + NS Strong/moderate ICS + topical potent steroids* Strong/low Adherent to ICS + NS therapy Strong/high BMI z-score <0+ Strong/moderate On an enzyme inhibitor Strong/varies with inhibitor Screening test Serum cortisol at 08h00--10h00 interpretation <138 nmol/L: hypocortisolaemia Weak/low >350 nmol/L ([double dagger]): Weak/low normal axis 138/350 nmol/L: refer for Strong/moderate metyrapone or 0.5 [micro]g/1.73 m2 ACTH stimulation test Screening If serum cortisol > 350 nmol/L, Ungraded best frequency screen 6-monthly if steroid practice dose not reduced HPAS = hypothalamic-pituitary-adrenal axis suppression; ICS = inhaled corticosteroids; NS = nasal steroids; HC = hydrocortisone; BUD = budesonide; FP = fluticasone propionate; MDI = metered-dose inhaler; BMI = body mass index; ACTH = adrenocorticotropic hormone. * Clobetasol propionate, betamethasone valerate, hydrocortisone butyrate. ([dagger]) BMI z-score 0--2 does not exclude HPAS, but <0 is more likely. ([dagger]) As measured by the Elecsys Cortisol II assay. Table 3. Management recommendations for HPAS Management Strength of Clinical HPAS recommendation/ level of evidence Adrenal crisis HC 2 mg/kg (50//100 Strong/moderate mg/[m.sup.2]) IV bolus, followed by Ungraded best HC 2 mg/kg/d (50// practice 100 mg/[m.sup.2]/d) Ungraded best IV divided 6/hourly practice For hypoglycaemia: 5 mL/kg of 10% DW IV at 3 mL/kg/h If in shock, treat with normal saline (0.9%) 20 mL/kg (maximum 60 mL/kg within 1 hour) CAI HC orally at 8 mg/ Weak/low [m.sup.2]/d, 2/3 given in the morning, 1/3 2 hours after lunch; continued for about 1 year until axis has recovered Modify asthma Weak/low therapy by reducing steroid load on the axis Substitute lower ICS and NS dose by using steroid-sparing medication If possible, prescribe single morning dose of ICS and NS If possible, use newer-generation NS* Aim for a steroid load of HC [less than or equal to] 6 mg/[m.sup.2]/d (BUD 480 [micro]g/ [m.sup.2]/d or FP 240 [micro]g/ [m.sup.2]/d given by MDI + spacer) Subclinical HPAS Hypocortisolaemia As for CAI Ungraded best practice Failed adrenal As for CAI, but Ungraded best function test omit HC practice Sick-day management Home management of Ungraded best illness with fever practice >38[degrees]C Double HC replacement until recovery (usually 3 days) >39[degrees]C Treble HC replacement until recovery (usually 3 days) Unable to tolerate HC IM/SC given at a Ungraded best oral therapy due to bolus dose of 50 mg practice gastroenteritis or for primary school trauma age children and 100 mg for adolescents; continue IV/IM as for adrenal crisis or switch to oral regimen depending on clinical Asthma exacerbation If prednisone is Ungraded best given, there is no practice need to give HC as well Minor surgery Double or treble HC Ungraded best dose practice Major surgery, IV HC regimen as for Ungraded best trauma or disease adrenal crisis, but practice requiring intensive tapering rapidly and care switching to oral regimen depending on clinical state Additional Medic Alert bracelet Ungraded best management Educate family practice Ungraded best practice HPAS = hypothalamic-pituitary-adrenal axis suppression; HC = hydrocortisone; IV = intravenous; DW = dextrose water; CAI = chronic adrenal insufficiency; ICS = inhaled corticosteroids; NS = nasal steroids; BUD = budesonide; FP = fluticasone propionate; MDI = metered-dose inhaler; IM = intramuscular; SC = subcutaneous. * Fluticasone, ciclesonide, mometasone.
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|Title Annotation:||CLINICAL PRACTICE|
|Publication:||SAMJ South African Medical Journal|
|Date:||May 1, 2019|
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