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Asthma treatment in children: A guide to screening for and management of hypothalamic-pituitary-adrenal axis suppression.

Inhaled corticosteroids (ICS) and to a lesser extent nasal steroids (NS) have undoubtedly revolutionised asthma therapy and improved quality of life in a cost-effective way. However, current evidence suggests that every asthmatic child on corticosteroids is at risk of hypothalamic-pituitary-adrenal axis suppression (HPAS). As most patients with this complication are asymptomatic, those most at risk should be screened. If screening is inconclusive, adrenal function testing should be performed. On the basis of its outcome the most appropriate management should be determined.

In a recently published approach to paediatric asthma management, [1] 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. [5] At supraphysiological ICS doses, 50% of children can be expected to develop HPAS, [21] while at physiological doses (i.e. a cortisol production rate of 3.0 - 10.6 mg/[m.sup.2]) [6] dose and effect have an inverse relationship. [2] 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is usually seen in all children after 6-42 months of ICS therapy, [3] but has been observed as early as 2 months (EWZ, unpublished data, 2011).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) [9] are coadministered, metabolism of corticosteroids is reduced, resulting in HPAS or Cushing's syndrome. [10]

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. [11] Management suggestions that could not be substantiated by evidence are labelled 'ungraded best practice'. [12]

Diagnosis of HPAS

HPAS presents as a spectrum (Table 1). Adrenal crisis is the most devastating presentation, but occurs rarely. [13] Chronic adrenal insufficiency (CAI) is frequently overlooked owing to its nonspecific clinical features. [7] 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. [14] 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. [15] Clinicians utilising the ACTH stimulation test need to be aware of several pitfalls. [16] 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. [17] 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. [18] Measurement of early morning salivary cortisone has been suggested, [19] 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. [21] A 06h00-08h00 serum cortisol level of <83 nmol/L to suggest HPAS would be ideal, [21] but may be impractical. There is no scientific basis for labelling a level >276 nmol/L as safe. [22] 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. [2] 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. [24] 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. [10] Rescue oral corticosteroids should never be given for more than 3 days [25] and should not be provided to parents to be used when necessary. Treatment modification for HPAS has been found to be effective. [26] Even when ICS doses are not reduced, HPAS seems to resolve in some patients. [27] 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.

Conclusions

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.

Declaration. None.

Acknowledgements. None.

Author contributions. Sole author.

Funding. None.

Conflicts of interest. None.

[1.] Masekela R, Jeevanathrum A, Kling S, et al. Asthma treatment in children: A pragmatic approach. S Afr Med J 2018;108(8):612-618. https://doi.org/10.7196/SAMJ.2018.v108i8.13164

[2.] Zollner EW, Lombard CJ, Galal U, Hough FS, Irusen IM, Weinberg E. Hypothalamic-pituitaryadrenal axis suppression in asthmatic school children. Pediatrics 2012;130(6):e1512-e1519. https:// doi.org/10.1542/peds.2012-1147

[3.] Zollner EW. Hypothalamic-pituitary-adrenal axis suppression in asthmatic children on inhaled corticosteroids (Part 2) - the risk as determined by gold standard adrenal function tests: A systematic review. Pediatr Allergy Immunol 2007;18(6):469-474. https://doi.org/10.1111/j.13993038.2007.00539.x

[4.] Zollner EWA. Effects of corticosteroids on adrenal function in children with asthma. Curr Allergy Clin Immunol 2014;27(4):194-197. https://hdl.handle.net/10520/EJC162825 (accessed 6 April 2019).

[5.] Hawcutt DP, Jorgensen AL, Wallin N, et al. Adrenal responses to a low-dose short synacthen test in children with asthma. Clin Endocrinol 2015;82(5):648-656. https://doi.org/10.1111/cen.12655

[6.] Linder BL, Esteban NV, Yergey AL, et al. Cortisol production rate in childhood and adolescence. J Pediatr 1990;117(6):892-896.

[7.] Shenoy SD, Swift PGF, Cody D. Growth impairment and adrenal suppression on low-dose inhaled beclomethasone. J Paediatr Child Health 2006;42(3):143-144. https://doi.org/10.1111/j.14401754.2006.00814.x

[8.] Patel L, Wales JK, Kibirige MS, Massarano AA, Couriel JM, Clayton PE. Symptomatic adrenal insufficiency during inhaled corticosteroid treatment. Arch Dis Child 2001;85(4):330-334. htttps://doi. org/10.1136/adc.85.4.330

[9.] Horn JR, Hansten PD. Inhaled corticosteroids: Watch for drug interactions. Pharmacy Times 2004(September):66.

[10.] Daveluy A, Raignoux C, Miromont-Salame G, et al Drug interactions between inhaled corticosteroids and enzymatic inhibitors. Eur J Clin Pharmacol 2009;65(April) :743-745. https://doi.org/10.1007/ s00228-009-0653-4

[11.] Swiglo BA, Murad MH, Schunemann HJ, et al. A case for clarity, consistency, and helpfulness: Stateof-the-art clinical practice guidelines in endocrinology using the grading of recommendations, assessment, development, and evaluation system. J Clin Endocrinol Metab 2008;93(3):666-673. https:// doi.org/10.1210/jc.2007-1907

[12.] Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of primary adrenal insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metabol 2016;101(2):364-389. https://doi.org/10.1210/jc.2015-1710

[13.] Todd GRG, Acerini CL, Ross-Russel R, Zahra S, Warner JT, McCance D. Survey of adrenal crisis associated with inhaled corticosteroids in the United Kingdom. Arch Dis Child 2002;87(6):457-461. https://doi.org/10.1136/adc.87.6.457

[14.] Zollner EW. Hypothalamic-pituitary-adrenal axis suppression in asthmatic children on inhaled corticosteroids: Part 1. Which test should be used? Pediatr Allergy Immunol 2007;18(5):401-409. htttps://doi.org/10.1111/j.1399-3038.2007.00540.x

[15.] Crowley S, Hindmarsh PC, Holownia P, et al. The use of low doses of ACTH in the investigation of adrenal function in man. J Endocrinol 1991;130(3):475-479. https://doi.org/10.1677/joe.0.1300475

[16.] Zollner EW. Letter to the Editor. Author's reply to 'Testing for hyp othalamic-pituitary-adrenal axis suppression in asthmatic children'. Pediatr Allergy Immunol 2008;19(5):468-470. https://doi. org/10.1111/j.1399-3038.2008.00725.x

[17.] Kline GA, Buse J, Krause RD. Clinical implications for biochemical diagnostic thresholds of adrenal sufficiency using a highly specific cortisol immunoassay. Clin Biochem 2017;50(9):475-480. https:// doi.org/10.1016/j.clinbiochem.2017.02.008

[18.] Zollner EW, Lombard CJ, Galal U, Hough FS, Irusen IM, Weinberg E. Screening for hypothalamicpituitary-adrenal axis suppression in asthmatic children remains problematic: A cross-sectional study. BMJ Open 2013;3(8):e002935. https://doi.org/10.1136/bmjopen-2013-002935

[19.] Blair J, Lancaster G, Titman A, et al. Early morning salivary cortisol and cortisone, and adrenal responses to a simplified low-dose short Synacthen test in children with asthma. Clin Endocrinol 2014;80(3):376-383. https://doi.org/10.1111/cen.12302

[20.] Kazlauskaite R, Evans AT, Villabona CV; Consortium for Evaluation of Corticotropin Test in Hypothalamic-Pituitary-Adrenal Insufficiency. Corticotropin tests for hypothalamic-pituitaryadrenal insufficiency: A metaanalysis. J Clin Endocrinol Metab 2008;93(11):4245-4253. https://doi. org/10.1210/jc.2008-0710

[21.] Agwu JC, Spoudeas H, Hindmarsh PC, Pringle PJ, Brook CGD. Tests of adrenal insufficiency. Arch Dis Child 1999;80(4):330-333. https://doi.org/10.1136/adc.80.4.330

[22.] Kapadia CR, Nebesio TD, Myers SE, et al. Endocrine effects of inhaled corticosteroids in children. JAMA Pediatr 2016;170(2):163-170. https://doi.org/10.1001/jamapediatrics.2015.3526

[23.] Masekela R, Levin M, Jeena PM, et al. Looking beyond the magic bullet: Novel asthma drugs or education, which works better? S Afr Med J 2018;108(8):619-623; https://doi.org/10.7196/SAMJ.2018. v108i8.13163

[24.] Derendorf H, Meltzer EO. Molecular and clinical pharmacology of intranasal corticosteroids: Clinical and therapeutic implications. Allergy 2008;63(10):1292-1300. https://doi.org/10.1111/j.13989995.2008.01750.x

[25.] Zora JA, Zimmerman D, Carey DL, O'Connell EJ, Yunginger JW. Hyp othalamipituitary-adrenal suppression after short-term, high-dose glucocorticoid therapy in children with asthma. J Allergy Clin Immunol 1986;77(1):9-13. https://doi.org/10.1016/0091-6749(86)90315-5

[26.] Zollner EW. Is adrenal suppression in asthmatic children reversible? A case series. S Afr Med J 2018;108(6):502-505. https://doi.org/10.7196/SAMJ.2018.v108i6.13031

[27.] Gangadharan A, McCoy P, Phyo A, et al. Recovery of hypothalamic-pituitary-adrenal axis suppression during treatment with inhaled corticosteroids for childhood asthma. J Asthma Allergy 2017;10:317326. https://doi.org/10.2147/JAA.S142874

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 (zollner@sun.ac.za)
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
Author:Zollner, E.W.
Publication:SAMJ South African Medical Journal
Article Type:Report
Date:May 1, 2019
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