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Endocrine Effects of Inhaled Corticosteroids in Children

ChiragR. Kapadia, MD;Todd D.Nebesio,MD; SusanE. Myers, MD;StevenWilli,MD; Bradley S.Miller, MD, PhD;

DavidB. Allen, MD; ElkaJacobson-Dickman,MD; for the Drugsand Therapeutics Committee

of the PediatricEndocrine Society

Inhaled corticosteroids are widely used as effective first-line

treatments for various chronic respiratory illnesses, including

asthma, cystic fibrosis, and allergic rhinitis.1 Although the

long-term use of ICSs has a more favorable safety profile than oral

corticosteroids, uncertainty about systemic complications persist.In children, the long-term use of oral corticosteroids can lead to

compromised linear growth and bone mineralization, diabetes

mellitus (types 1 and 2) (DM), Cushing syndrome, obesity, and sup-

pression of the hypothalamic-pituitary-adrenal (HPA) axis. Inhaled

corticosteroids have a similar adverse effect profile but with less

frequency and severity. We review the endocrine effects of ICSs

in children and the properties of the various formulations as

they relate to these adverse outcomes. We have provided grading

of the evidence associated with our conclusions and recommen-

dations based on guidelines from the Centre for Evidence Based

Medicine, in which a lower number indicates better evidence

(scale, 1-5), and A is the highest grade of recommendation (scale,

A-D).

2

Case Presentation

A 7-year-old girl presented with altered mental status and a new-

onset seizure. She was well until that day, when she developed

cough, fatigue, and fever and then had a generalized seizure.

When the ambulance arrived, her blood glucose level was 24

mg/dL (to convert to millimoles per liter, multiply by 0.0555). In

the emergency department, her blood pressure was 85/50 mm

Hg, and her pulse was 125/min. The results of head imaging and a

full sepsis workup were normal. Her medical history was signifi-

cant for asthma and seasonal allergies. At home she took a regi-

men of fluticasone propionate dry powder inhaler (two 110-µg

puffs twice daily), salmeterol xinafoate (21 µg /d), albuterol sulfateas needed, and cetirizine (10 mg/d) to which she was adherent.

She had a 5-day course of prednisone 4 months prior. Her growth

was normal.

She had a sodium level of 140mEq/L(to convert to millimoles

per liter, multiply by 1), and her potassium level was 4 mEq/L (to

convert to millimoles per liter, multiply by 1). A serum cortisol level

at the time of the hypoglycemia was low (2.1 µg/dL) (to convert to

nanomoles per liter,multiply by 27.588). Further testing revealed a

morning cortisol level of 0.8 µg/dL and an adrenocorticotropic

hormone (ACTH) level less than 5 pg/mL (to convert to picomoles

per liter, multiply by 0.22), suggesting central adrenal insufficiency

(AI). A low-dose 1-µg ACTH stimulation test confirmed AI with a

peak cortisol level of 1.4 µg/dL (reference range, >18 µg/dL). Thy-roid function test results, insulin-like growth factor 1 (IGF-1) levels,

and prolactin levels were normal. Maintenance hydrocortisone

treatment was initiated, and the family received stress dose corti-

costeroid education. Her pulmonologist reduced the inhaled corti-

costeroid (ICS) dose to 330 µg/d after adding montelukast, and

the asthma remained well controlled. The hydrocortisone dose

was gradually weaned and hydrocortisone use discontinued. Six

months later, an additional low-dose ACTH stimulation test result

was normal with a peak stimulatedcortisol level of 19.9 µg/dL.The

HPA axis suppression was attributed to her ICSs.

Inhaled corticosteroids (ICSs) are widely used as first-line treatmentfor various chronic

respiratory illnesses. Advances in devices and formulations have reduced their local adverse

effects. However, as delivery of ICSs to thelungsimproves, thesystemic absorption

increases, and an adverse effectprofile similar to, although milder than, oral corticosteroids

has emerged. The most serious potentialadverse effect is adrenal insufficiency, which canbe

life threatening.Adrenal insufficiencyoccurs most in patients takingthe highest doses of ICSs

butis reported with moderate or even lowdosesas well. Our recommendations include

greater vigilance in testing adrenal function thancurrent standard practice. In patients with

diabetes mellitus (types1 and2), an increase in glucose levelsis likely, anddiabetes

medication adjustment maybe needed when initiating or increasing ICSs. Therisk of linear

growthattenuationand adverse effects on bone mineral density is generallylow butshould

be considered in theface of additional risk factors.On behalfof thePediatric Endocrine

Society Drugs andTherapeutics Committee, we presenta reviewof theendocrine adverseeffects of ICSs in children andofferrecommendations relating to testing and referral.Limited

data in particular realms diminish the strength of certain recommendations, and clinical

judgment continues to be paramount.

JAMA Pediatr . doi:10.1001/jamapediatrics.2015.3526

Published onlineDecember 21, 2015.

Author Affiliations: Author

affiliationsare listed atthe endof this

article.

Group Information: Themembersof

the Drugsand Therapeutics

Committeeof thePediatricEndocrine

Society arelisted at theendof this

article.

Corresponding Author: Elka

Jacobson-Dickman, MD,Division of

Pediatric Endocrinology, Department

of Pediatrics,MaimonidesMedical

Center,4802 10thAve, Brooklyn, NY

11219 (ejacobson-dickman

@maimonidesmed.org).

Clinical Review & Education

Review

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Dose and Formulation Effects of ICSs

Primary Conclusions

Clinical effectiveness and systemic absorption have a strong posi-

tive correlation that can only be partially addressed by device and

formulation modifications (level of evidence 1).

Primary Recommendations

Device advancements have reduced local adverse effects. How-

ever, reducing thesystemic adverse effects of ICSs mayrequire in-

creasing protein binding and rapid clearance time and decreased

lipophilicity (grade of recommendation A).

Pharmacodynamics and pharmacokinetics vary among ICS

formulations. This is a result of differences in oral bioavailability,

glucocorticoid receptor affinity, variable deposition in the lung,

volumes of distribution, lipophilic qualities,rates of clearance, and

modes of delivery.1,3

There are a variety of ICS delivery devices, including metered-

doseinhalers,dry powderinhalers,and nebulizers;metered-dosein-

halers are often used with spacer devices that reduce oral deposi-

tion andincrease lung delivery. Oral depositionand lung delivery are

alsoaffectedbyparticlesize,withsmallerparticleshavinglessoraland

greater lung deposition.4 Local adverse effects, such as candidiasis,

dysphonia,pharyngitis,and cough,are minimizedwith proper inha-

lation technique and postinhalation oropharyngeal rinsing. Com-

pounds with a high rate of first-pass metabolism have lesssystemic

drugeffectfrom oral depositionthan those with lower rates.5

TheclinicallyefficaciousICSdepositedinthelungisalsothemain

source for systemic absorption5,6; therefore, improved lung deliv-

ery of ICS actually increases the risk of endocrine adverse effects.

Although the shiftfrom chlorofluorocarbonsto hydrofluoroalkane

allows smaller particle sizesand better lungdeliveryfor manycom-

pounds, it canalso resultin greater systemic absorption.7

There are variable degrees of cortisol suppression or systemicbioavailability among delivery devices8-10; however, for most ICSs,

respiratoryeffectiveness correlateswith systemicbioavailability. De-

vices that result in greater lung deposition should thus be used at

lower doses. Postulation regarding the effect of discrepant in-

tralungabsorptionhas arisen,for example,whether there is greater

systemicabsorption fromalveolithan bronchi, but datain thisarea

are lacking.4 What appears clear, however, is that in healthy lungs

or healthierasthmatic lungs,absorption is greater than in statesof

active disease and airflow obstruction, hence supporting clinical

guidelines advocating step-down therapy for those who achieve

asthma control.11,12

Compounds or metabolites that are more tightly bound to al-

bumin and other proteins and less systemically active have feweradverse effects, as do thosecleared from the circulationmore rap-

idly. Although not well investigated, some experts13 assert that in-

creased lipophilicity leads to greater systemic adverse effects be-

cause of widerdistributionand slower clearance, particularly in the

case of fluticasone. Thus, although efforts to reduce oral deposi-

tion have resulted in fewer local adverse effects, the effort to re-

duce systemic adverse effects mayultimately need to focus on in-

creasing protein binding, more rapid clearance, and decreasing

lipophilicity. Bindingand clearance dataforcommonlyused ICSsare

summarized in Table 1.14

The compound ciclesonide hydrofluoralkane14 is convertedto

ametabolitethathasahighfirst-passmetabolismrate,ishighlypro-

tein bound, is rapidly cleared, and thus would be expected to de-

liver clinicaleffectat thelungswhile resulting in lower systemic con-sequence. However, experience with ciclesonide is not as long

standing or aswidespread aswith fluticasone proprionate dry pow-

der inhaler, andit took many years of clinical usefor endocrine ad-

verseeffectsof fluticasone to surface.13-15 Thus, althoughthe phar-

macodynamic profile of ciclesonide appears to be promising,

cautious optimism is recommended.

Effects on the HPA Axis

Primary Conclusions

TheHPA axissuppression,although rare,is themost serious poten-

tial ICS adverse effect and can occur even in children taking stan-dard dosages (levelof evidence 1).

Ata Glance

• Inhaled corticosteroids (ICSs) are widely used as effective

first-linetreatment forvarious chronic respiratory illnesses.

Althoughthe long-term useof ICSs hasa more favorable safety

profile thanthat of oralcorticosteroids, uncertainty about

systemic complications persists.

• With the advancement of devices and in drug pharmacokinetics,

lung delivery andbioavailability ofICSs have improved,and anadverse effect profile similar to oralcorticosteroids is emerging,

albeitmilder and withless frequency.

• Hypothalamic-pituitary-adrenal axissuppression is a potentially

life-threatening adverse effect of ICSs. Adrenal function should

be tested in symptomatic patients, those withgrowth

attenuation, and high-riskasymptomaticpatients.

• Data onlinear growthand bone mineral density (BMD) are

generallyreassuring, but height attainment should be carefully

monitored, andtestingfor BMD shouldbe considered in

high-riskpatients.Deterioratingblood glucose level control in

patients with preexistingdiabetesmellitus(types 1 and2) (DM)

is common with ICSs, andDM medication dose adjustments are

likelyrequired at theinitiation ofICS treatment andwithICS

dose increases.

Table 1. Pharmacodynamics and Pharmacokinetics of CommonlyUsed Inhaled GlucocorticoidFormulationsa

Inhaled GlucocorticoidOralBioavailability, %

ParticleSize, μm

ProteinBinding, %

SystemicClearance, L/h

Beclomethasone dipropionate hydrofluoroalkane 20/40b <2.0 87 150/120b

Budesonide DPI 11 >2.5 88 84

Ciclesonide hydrofluoroalkane <1/<1b <2.0 99/99b 152/228b

Fluticasone propionate DPI ≤1 2.8 90 66

Abbreviation:DPI, dry powder

inhaler.

a Adapted fromAhmet etal.14

b Activemetabolite.

Clinical Review & Education Review Endocrine Effects of Inhaled Corticosteroids in Children

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Children taking ICSs with hypoglycemia or altered mental status

should be urgently evaluated for adrenal insufficiency andtreated,

if necessary (gradeof recommendationA). Children withgrowth fail-

ure, anorexia, or weight loss should be tested for AI (grade of rec-ommendation B). Children taking high-dose ICSs or those requir-

ing periodic oral corticosteroids treatment or additional long-term

intranasal corticosteroid treatment, especially in conjunction with

a low body mass index (BMI) (calculated as weightin kilogramsdi-

videdbyheightinmeterssquared),shouldbetestedroutinely(grade

of recommendation C).

A testing algorithm is outlined in Table 2 and described in the

textbelow. Stimulationtestinginterpretationis level ofevidence 1b,

asis makinga diagnosisof AIfroma morning cortisollevellessthan

3 µg/dL in a symptomatic patient.

Assurance of adrenalsufficiency in asymptomaticpatients with

a morning cortisollevel greater than10 µg/dLis levelof evidence5,

expertopinion.Thus, if suspicionis high, one shouldnot rely solelyon adequate morning cortisol values.

It is well known that oral and injectable corticosteroidscan re-

sult insuppressionof theHPAaxisandwithprolonged usecanlead

to adrenocorticalatrophy. Afterthe introductionof corticosteroids

in the late 1940s to treat rheumatoid arthritis, reports of sudden

deaths after surgery began to emerge.16 When ICSs were intro-

duced for asthmacontrol, HPA axis suppressionwas thought tobe

rare but still a consideration when used at high doses for a pro-

longed period.17,18 Reassuringstudies19,20 didnot haveevidence of

AI at standarddoses of ICSs.

In a meta-analysis21 examining the adverse effects of ICSs, no

evidence of AI with ICS doses at 400 µg/d or less was found, re-

gardlessofthedrug.Athigherdoses,theriskofAIwasincreased 17,18,21

andcommon when growth suppression was also present.13,22

Since then, however, there have also been reports of AI occur-ringevenatlowerdoses.Pateletal22described8 childrenwho pre-

sentedwith AI despite 7 of these children being prescribed a stan-

dardrecommended dose ofICS. Twopresented withhypoglycemia,

both without a history of abrupt cessationof ICS or illness; several

children also had poor weight gain.13,22 In another case, a 7-year-

old boy whopresented in an acute adrenal crisis had been treated

with fluticasone at a typicallyprescribed dose of 220 µg/d for sev-

eral years.13

As cases of AI associated with ICSs became increasingly re-

ported, a survey was sent to pediatricians and endocrinologists in

the United Kingdom to investigate the frequency of acute adrenal

criseswithICS use.13 Thirty-three patients(28 children)were iden-

tified: 23 patients presented with hypoglycemia, including 13 withdecreasedlevel ofconsciousnessor coma and 9 with coma andsei-

zures(1 withcomaand seizurelaterdied).Mostcases involved high-

dose ICSs that were still within recommended guidelines for se-

verepersistentasthma.13 Ina similar surveyfrom France,46 patients

with AI were identified, of whom 18% were not receiving high-

dose ICSs.23

It is importantto acknowledgethe lack of testing standardiza-

tionacrossstudies.24 Incasesof secondary orcentralAI from exog-

enous corticosteroid use, the adrenal cortex lags behind the pitu-

itary gland in the recovery process.25 Therefore, although a basal

Table 2. AdverseEffectsof ICSs

Adverse EffectPatients atHighest Risk Signs and Symptoms Testing and Action

Test ResultInterpretation

Growth suppression All patients takingICSs and additionalgrowth-impairingmedications

Decrease of >2 SDs inheight or retardedgrowth velocitybelow age andpubertal norms(persisting after

1 year of therapy)

Refer to a specialist Not applicable

Adrenal insufficiency Symptomaticpatients Andasymptomaticpatients with riskfactors: high dailydose, taking anICS and anothercorticosteroid, orlow BMI

Cushingoid features,anorexia, weightloss, fatigue, growthfailure, orhypoglycemia;typical symptoms ofchronic adrenalinsufficiency may notoccur; hence, alsotest all high-riskasymptomaticpatients

Symptomatic: ifmorning cortisol levela

<3 µg/dL, adrenalinsufficiency is likely;if morning cortisol level≥3 µg/dL, 1-µg ACTHstimulation testAsymptomatic but athigh risk: if morningcortisol level <3 µg/dL,1-µg ACTH stimulationtest; if morning cortisollevel 3-10 µg/dL, referto a specialist

A stimulated cortisolvalue <18 µg/dL isabnormal

Hyperglycemia ordiabetes mellitus(types 1 and 2)

Patients with riskfactors or signs ofinsulin resistancetaking high dailydose

Polyuria, polydipsia Annual hemoglobin A1c

levels and fastingglucose

Refer to a specialistif hemoglobin A

1c

≥6.0% or fastingglucose >100 mg/dL

Worsening bloodglucose level controlin diabetes mellitus(types 1 and 2)

Patients withdiabetes mellitusafter ICS treatmentis initiated or if doseis increase

Worsening bloodglucose control

Adjust diabetesmedications

Not applicable

Decrease in bonemineral density

Chronic disease,malnutrition, ortaking long-termmedications thatreduce bone mineraldensity

Generallyasymptomatic

No routine testingunless at high risk;if not at high risk,400- to 800-IU vitaminD supplementation andensure adequatecalcium intake

Higher-dose vitamin Dsupplementation forlevels <30 ng/mL

Abbreviations: ACTH,

adrenocorticotropin hormone;

BMI, body mass index;ICS,inhaled

corticosteroid.SI conversionfactors: To convert

cortisolto nanomoles per liter,

multiply by 27.588;glucose to

millimoles per liter, multiply by

0.0555;vitamin D

(25-hydroxyvitamin D) to nanomoles

per liter, multiply by 2.496.

a Morning cortisol level is defined as a

serumcortisol levelmeasured

between 7 and9 AM.

Endocrine Effects of Inhaled Corticosteroids in Children Review ClinicalReview & Education






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cortisol level may be normal in a child treated with an ICS, it does

not ensure a sufficient cortisol increase in the setting of stress or

illness.26 Thelackof uniform testing forAI hasresultedin inconsis-

tent and conflicting conclusions.26

In accordance with these concerns, Zöllner27 searched the lit-

eratureforstudiesofchildrentreatedwithICSswhoweretestedfor

AI with dynamic adrenal function test results. Only 4 studies were

identified.

19,28-30

Using dynamic adrenal testing, those studiessought to determine the prevalence of HPA axis suppression

in 26 children with asthma treated with ICSs and intranasal

corticosteroids.31 With hypocortisolemia defined as a basal morn-

ing cortisol level less than 3 µg/dL, none of the children had a low

basalcortisol level.However, metyrapone testing revealedthat 35%

had HPA axis suppression; this test is now difficult to perform be-

cause ofthe unavailability ofthis agent.A larger study32bythesame

groupfound that6% hadhypocortisolemia,the degreeof biochemi-

calsuppressioncanoccurinuptotwo-thirdsofchildrentreatedwith

corticosteroids, andsuppression may even occur at lowdoses. An

older study29 identified a morning ACTH level less than 11.7 pg/mL

tocorrelatewithAIonstimulationtesting,butlargerstudies28,30,33,34

did not corroborate this finding.

Concomitantnasal corticosteroid use, low BMI, and cumulative

dose of ICS are contributing factors to the development of HPA axis

suppression.31,32Growthfailure isa late finding andis nothighlysen-

sitivefor detectingHPAaxissuppression.30Thus,practitioners should

testmost at-riskpatientsbefore growthfailureoccurs.However, when

growthfailure is detected, HPA axis function shouldbe tested.22,35

Poor adherenceto ICS treatmenthas a protective effect, likely

due to partial recovery andincomplete suppression of theadrenal

glands.32 However, poor adherence also likely conversely leads to

poorer asthma control and additional oral corticosteroid doses.

Our recommendations, as summarizedin Table2, include test-

ing cortisol levels between 7 and 9 AM in all symptomatic patients

notin crisis. Ifthe morning cortisollevelis less than 3 µg/dL,a diag-

nosisof AIis made.However, ifthe morning cortisollevel is3 µg/dLor greater, an ACTH stimulationtestis required.Symptomsof AI in

patients taking ICSs are similar to those seen with other forms of

ACTHinsufficiency, includinganorexia, weight loss, growth failure,

and hypoglycemia; unique to these cases are possible signs of ap-

parent corticosteroid excess, such as cushingoid features.

Symptomsof adrenal crisis, suchas hypotension,lethargy, and

hypoglycemia, should provoke immediate testing, including a cor-

tisol level in all cases and stimulation testing when possible. If the

patient is unstable or ill appearing, treatment with stress doses of

corticosteroids should be prompt while awaiting results.

Wealso recommend testingin certaincategoriesof asymptom-

aticpatients taking ICSs,including those taking highdaily ICS doses

or an ICS withothersystemicallyabsorbed corticosteroids, particu-larly patients with low BMI. The 10-µg/dL threshold is acknowl-

edgedbyourgroupassomewhatarbitrary;however,itiswidelyused

in clinicalpractice by endocrinologists.Referralfor stimulationtests

on allat-riskpatientsis impractical.With this in mind, high-riskpa-

tientsshould be monitored for symptoms of AI even with reassur-

ing morning cortisol levels.

We acknowledge that althoughthe 1-µg ACTH test is notdefi-

nitely superior to the standard 250-µg ACTH stimulation test, it is

generallyregardedasmoresensitiveforsecondary(central)HPAaxis

suppression.36 At a minimum, baseline and 30-minutecortisolval-

ues should be measured, although sampling at more frequent in-

tervals increases testing reliability (ie, 10-, 15-, 20-, and 25-minute

samples).37 A peak cortisol level below 18 µg/dL indicatesAI.38

When HPA axis suppression from ICS use is detected in symp-

tomaticpatients, daily treatment withcorticosteroids are required.

In milderor asymptomaticcases, treatment may be neededonly in

thesetting ofillnessor physical stress.All cases ofHPA axis suppres-

sion should be referred to an endocrinologist, and these patientsshouldfollow up closelywiththeirpulmonologistor allergist forcon-

siderationof ICSdose reduction if safe, possiblyby addinga cortico-

steroid-sparing agent (ie, leukotriene receptor antagonists).

Effects on Linear Growth

Primary Conclusions

In most patients, ICSs have minor and short-term effects on

growth and very mild but potentially persistent long-term effects

(level of evidence 2) (few studies followed through to final height

attainment).


The minor growth risksare outweighed by the respiratorybenefits

of ICSs (grade of recommendation B). Patients at higher risk in-

clude those usingadditional growth-impairing medications (grade

of recommendationD) (primarily based on expert opinion).

Oral corticosteroids impair linear growth through suppression

of growth hormone secretion, down-regulating the growth hor-

mone receptor, reduction of IGF-1 concentration, and suppression

of collagen synthesisat thegrowth plate.39

The effect of ICSs on linear growth has been evaluated via

knemometry, a technique that measures the distance from the sur-

faceoftherightflexedkneetothebottomofthesoleandisaprecise

method of monitoring short-term growth.40-42 A placebo-

controlled, crossover trial found a reduction in growth by 32% after2 weeks of budesonide dry powder inhaler therapy.41 Similar meth-

ods have been used to reveal growth reduction with short-term

therapy with other ICSs, including fluticasone and beclomethasone

dipropionate hydrofluoroalkane.42-44 Ciclesonide, thus far, has not

beenfoundtocausemajorgrowthimpairmentusingknemometry.43

Intermediate-terminvestigationsof theeffect of ICSson growth

have found mildimpairment. Using inhaledchlorofluorocarbonand

beclomethasone dipropionate dry powder inhaler at 200 µg twice

daily, the Dutch Pediatric Asthma Study Group45 found a signifi-

cant but small reduction in height (−0.28 SD) in 1 year. A subse-

quent study46 found thatdoublingthe doseof chlorofluorocarbon-

beclomethasone dipropionate dry powder inhaler (400 µg twice

daily)hadamoresignificanteffectonheight(−0.27SD)thanastan-dard chlorofluorocarbon-beclomethasone dipropionate dry pow-

derinhalerdose(200 µgtwicedaily;−0.16 SD)for 1 year, andthere

was no added benefit. Of note, there was a disparity in the results

atthe same dose from thesamegroup,perhapshighlighting thevari-

able short-term effects of ICSs on growth.

In a large,prospective, open-label studyof bothbudesonideand

fluticasone,Anthracopouloset al47 found growth reductionin both

groupsin thefirst 6 to12 months(−0.08 SD), whichwasconsistent

with previous studies.48,49 However, patients’ heights returned to

thebaselineby 24 and36 months.


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number of small studies of adults73,74 have similarly linked hyper-

glycemia among diabetic individuals, but not individuals without

DM, toICS use.

Ofnote,anumberofinvestigations75,76havesuggestedthatICSs

caninduceinsulinresistanceamongindividualswithoutDM.Alarge

epidemiologicstudy77 fromCanadaidentifieda34%to64%higher

incidenceofnew-onsetDMamongthosetakingICSs,aswellasa34%

to54%higherrateofprogressiontoinsulinuseamongpatientswith

established DM taking ICSs, although the researchers did not ad-

just for BMI. Both these studies established a dose-response asso-

ciationbetweenICSandbloodglucoselevels,withdailydosesinex-

cessof 1000µg offluticasonepropionate drypowderinhaler having

the mostpronounced effect.

The only pediatric study78 to date examining glycemic effects

of ICSs reported a small but statistically significant increase in he-

moglobin A1c levels in children with asthma who were taking ICSs.

However, the study failed to identify a dose-response association

between ICSs and glucose levels. Furthermore, the only study79 to

examinethe effects of asthma treatmenton childrenwith preexist-

ingDM containedan insufficientnumber treated with ICSs todraw

meaningful conclusions.Our recommendationswith regard tothe effectsof ICSson glu-

cose metabolism are summarized in Table 2. They include adjust-

ing DM medications as needed when ICS use is initiated or ad-

justed. For chi ldren without DM, our recommendati ons in clude

testing those at risk because of obesity compounded by an addi-

tional factor, suchas high-riskethnicgroup or family history of type

2 DM.Evidence about levelsof fastingglucoseand hemoglobin A1c

thresholds placing children into a higher DM risk category contin-

uesto be a pointof debate;however, ourteamhaschosena fasting

glucoselevelof100mg/dLandahemoglobinA1c levelof 6.0%based

on available data.80,81

Conclusions

Inhaledcorticosteroidsaregenerallysafe, effectivedrugs, butadverse

endocrine effectsmayoccur. Althoughadverseeffectsandthe thresh-

olds definedas high dose by asthmaguidelinesdo notprecisely cor-

relate,forthesakeofclinicalpractice,highdoseforanyparticularcom-

poundissimilartothatdefinedbytheNationalAsthmaEducationand

PreventionProgram.82Wesummarizedosingguidelinesin Table3. We

agree with the step-up and step-down approach put forth in these

guidelines,82meaningthatpatientswithpoorasthmacontrol needan

increase in dosing, followed by reductions in dosingwhen adequateasthmacontrolisachieved.WedonotrecommenddecreasingtheICS

doseifitisdeemednecessarytopreventpulmonaryexacerbationsand

recurrent treatment with oral corticosteroids.

ARTICLE INFORMATION

Accepted for Publication: September20, 2015.

Published Online: December 21, 2015.

doi:10.1001/jamapediatrics.2015.3526.

Author Affiliations: Phoenix Children'sHospital,

Phoenix, Arizona (Kapadia);Riley Hospital for

Children, Indiana UniversitySchool of Medicine,

Indianapolis(Nebesio);Department of Pediatrics,

St LouisUniversity,Cardinal Glennon Children's

Hospital, St Louis,Missouri (Myers); Children's

Hospital of Philadelphia, Philadelphia, Pennsylvania

(Willi); Universityof Minnesota Masonic Children's

Hospital, Minneapolis(Miller);Departmentof

Pediatrics,Universityof Wisconsin School of

Medicine and PublicHealth,Madison (Allen);

Division of Pediatric Endocrinology, Departmentof

Table 3. Categorization of Daily Doses of Inhaled Corticosteroids

Corticosteroid

Daily Dose by Age, y

Low Medium High

0-4 5-11>12 toAdults 0-4 5-11

>12 toAdults 0-4 5-11

>12 toAdults

Beclomethasone dipropionatehydrofluoroalkane(40 or 80 µg per puff), µg

NA 80-160 80-240 NA >160-320 >240-480 NA >320 >480

Budesonide

DPI (90, 180, or200 µg), µg

NA 180-400 180-600 NA >400-800 <600-1200 NA >800 >1200

Inhaled (inhaledsuspension), mg

0.25-0.5 0.5 NA >0.5-1.0 1.0 NA >1.0 2.0 NA

Funisolide

Standard (250 µgper puff), µg

NA 500-750 500-1000 NA 1000-1250 >1000-2000 NA >1250 ≥2000

Hydrofluoroalkane(80 µg per puff), µg

NA 160 320 NA 320 >320-640 NA ≥640 ≥640

Fluticasone dipropionate

Hydrofluoroalkane/MDI (44,110, or 220 µg per puff), µg

176 88-176 88-264 >176-352 >176-352 >264-440 >352mcg >176-352 >440

DPI (50, 100, or 250 µgper puff), µg

NA 100-200 100-300 NA >200-400 >300-500 NA >200-400 >500

Mometasone DPI (220 µg), µg NA NA 200 NA NA 400 NA NA <400

Triamcinolone acetonide(75 µg per puff), µg

NA 300-600 300-750 NA >600-900 >750-1500 NA >600-900 >1500

Abbreviations: DPI,dry powder inhaler; MDI,metered-dose inhaler; NA, not

applicablebecause notapproved, notavailable, nodata available, or safetyand

efficacy notestablishedin this agegroup.

a Adapted from the National Asthma Educationand PreventionProgram.82








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8/18/2019 Kapadia 2015



Pediatrics,MaimonidesMedical Center,Brooklyn,

New York (Jacobson-Dickman).

Author Contributions: Dr Jacobson-Dickmanhad

fullaccess to allthe data in thestudy andtakes

responsibility forthe integrityof thedataand the

accuracy of thedataanalysis.

Study concept and design: Kapadia, Nebesio, Myers,

Willi, Jacobson-Dickman.

Acquisition, analysis, or interpretation of data:

Kapadia, Myers, Willi,Miller,Allen.Draftingof the manuscript: Kapadia, Nebesio,

Myers, Willi,Miller,Jacobson-Dickman.

Critical revision of the manuscript for important

intellectualcontent: Kapadia, Nebesio, Myers, Willi,

Miller, Allen.

Administrative, technical, or material support:

Kapadia, Myers, Willi.

Study supervision: Kapadia, Nebesio, Willi,Allen,

Jacobson-Dickman.

Conflict of Interest Disclosures: Nonereported.

Group Information: Themembersof thePediatric

Endocrine Society Drugand Therapeutics

Committeeare Preneet Brar, MD,Mark D. DeBoer,

MD,Patricia Fechner, MD,Rubina Heptulla, MD,

RyanMiller,MD, Deborah Mitchell, MD,Kathleen

Moltz,MD, Sripriya Raman, MD,Takara Stanley, MD,

NaveenUli,MD, andMariaVogiatzi, MD.

Additional Contributions: WethanktheBoardof

Directors of the Pediatric Endocrine Society for

theiroversight,review, and approval of the

manuscript andin particularJohn S.Fuqua, MD,

and Mitchel Geffner,MD, for theirguidance.

REFERENCES

1. HübnerM, Hochhaus G, DerendorfH.

Comparative pharmacology, bioavailability,

pharmacokinetics,and pharmacodynamics of

inhaled glucocorticosteroids. Immunol Allergy Clin

North Am. 2005;25(3):469-488.

2. Zöllner EW. Hypothalamic-pituitary-adrenal axis

suppression in asthmaticchildren on inhaled

corticosteroids (part 2)—the risk as determinedby

gold standard adrenal function tests: a systematic

review. Pediatr Allergy Immunol . 2007;18(6):469-474.

3. Johnson M. Pharmacodynamics and

pharmacokinetics of inhaled glucocorticoids.

J Allergy Clin Immunol . 1996;97(1,pt 2):169-176.

4. Barnes NC.Theproperties of inhaled

corticosteroids: similaritiesand differences. Prim

Care Respir J . 2007;16(3):149-154.

5. Randell TL,DonaghueKC,AmblerGR, CowellCT,

Fitzgerald DA,van Asperen PP. Safetyof thenewer

inhaled corticosteroids in childhood asthma.

Paediatr Drugs. 2003;5(7):481-504.

6. KannistoS, KorppiM, Remes K, VoutilainenR.

Adrenalsuppression,evaluated bya lowdose

adrenocorticotropintest, and growthin asthmatic

children treated withinhaled steroids. J ClinEndocrinol Metab. 2000;85(2):652-657.

7. AllenDB. Inhaled corticosteroids and growth:

still an issue after alltheseyears. J Pediatr . 2015;166

(2):463-469.

8. Dempsey OJ, WilsonAM, CoutieWJ,Lipworth

BJ. Evaluation of theeffect of a large volumespacer

on the systemicbioactivityof fluticasone

propionate metered-dose inhaler. Chest . 1999;116

(4):935-940.

9. Nair A, Menzies D,Hopkinson P, McFarlaneL,

Lipworth BJ. Invivo comparisonof therelative

systemicbioavailability of fluticasonepropionate

fromthree anti-static spacers anda metered dose

inhaler. Br J Clin Pharmacol . 2009;67(2):191-198.

10. Martin RJSS,Szefler SJ, ChinchilliVM, etal.

Systemiceffect comparisonsof six inhaled

corticosteroid preparations. Am J Respir Crit Care

Med . 2002;165(10):1377-1383.

11. MintoC, Li B, Tattam B, BrownK, SealeJP,

Donnelly R. Pharmacokineticsof epimeric

budesonideand fluticasonepropionateafter repeatdose inhalation:intersubject variabilityin systemic

absorption from thelung. Br J Clin Pharmacol .

2000;50(2):116-124.

12. BrutscheMH, BrutscheIC, Munawar M,et al.

Comparison of pharmacokineticsand systemic

effects of inhaled fluticasone propionate in patients

withasthma and healthy volunteers:a randomised

crossover study. Lancet . 2000;356(9229):556-561.

13. ToddGR, Acerini CL,Ross-Russell R, Zahra S,

Warner JT, McCance D.Survey of adrenal crisis

associated withinhaled corticosteroids in the

UnitedKingdom. Arch Dis Child . 2002;87(6):457-461.

14. Ahmet A, KimH, Spier S.Adrenal suppression:

a practicalguideto thescreeningand management

of this under-recognized complicationof inhaled

corticosteroid therapy. Allergy Asthma Clin Immunol .2011;7(7):13.

15. MortimerKJ, TataLJ,SmithCJ,et al.Oraland

inhaled corticosteroids and adrenal insufficiency:

a case-control study. Thorax . 2006;61(5):405-408.

16. FraserCG, PreussFS, BigfordWD.Adrenal

atrophy and irreversibleshock associated with

cortisone therapy. J Am Med Assoc . 1952;149(17):

1542-1543.

17. Russell G. Inhaled corticosteroid therapy in

children:an assessment of thepotential forside

effects. Thorax . 1994;49(12):1185-1188.

18. DluhyRG. Clinical relevanceof inhaled

corticosteroids and HPAaxis suppression. J Allergy

Clin Immunol . 1998;101(4 Pt 2):S447-S450.

19. Goldstein DE,KönigP. Effectof inhaledbeclomethasone dipropionateon

hypothalamic-pituitary-adrenal axis function in

children withasthma. Pediatrics. 1983;72(1):60-64.

20. KatsunumaT,AkasawaA, IikuraY.Adrenal

function of children withbronchial asthma treated

with beclomethasone dipropionate. Ann Allergy .

1992;69(6):529-532.

21. Lipworth BJ.Systemicadverse effects of

inhaled corticosteroid therapy:a systematic review

and meta-analysis. Arch Intern Med . 1999;159(9):

941-955.

22. Patel L, WalesJK, Kibirige MS, MassaranoAA,

CourielJM, Clayton PE. Symptomatic adrenal

insufficiencyduring inhaled corticosteroid

treatment. Arch Dis Child . 2001;85(4):330-334.

23. DrakeAJ, Howells RJ, ShieldJPH,PrendivilleA,WardPS, Crowne EC. Symptomatic adrenal

insufficiencypresenting with hypoglycaemia in

children withasthma receiving highdose inhaled

fluticasone propionate. BMJ . 2002;324(7345):

1081-1082.

24. Zöllner EW. Hypothalamic-pituitary-adrenal

axis suppressionin asthmatic children on inhaled

corticosteroids, part1: whichtest shouldbe used?

Pediatr Allergy Immunol . 2007;18(5):401-409.

25. MeakinJW,Grabbé J,Bayles TB,Nelson DH.

Pituitary-adrenalfunction following long-term

steroid therapy. Am J Med . 1960;29(3):459-464.

26. Molimard M,Girodet PO, PolletC, etal.

Inhaled corticosteroids and adrenal insufficiency:

prevalenceand clinical presentation. Drug Saf .

2008;31(9):769-774.

27. Zöllner EW. Hypothalamic-pituitary-adrenal

axis suppression in asthmatic children on inhaled

corticosteroids (Part2)--therisk as determinedbygold standard adrenal function tests: a systematic

review. Pediatr Allergy Immunol . 2007;18(6):469-474.

28. KleinR, Waldman D,Kershnar H,et al.

Treatment of chronic childhood asthma with

beclomethasone dipropionateaerosol, I:

a double-blindcrossover trial in nonsteroid-

dependent patients. Pediatrics. 1977;60(1):7-13.

29. Vaz R, SeniorB, Morris M, Binkiewicz A.

Adrenal effects of beclomethasone inhalation

therapy in asthmatic children. J Pediatr . 1982;100

(4):660-662.

30. Zöllner EWLC, Lombard CJ, Galal U,HoughS,

IrusenEM, WeinbergE. Screeningfor

hypothalamic-pituitary-adrenal axis suppression

in asthmatic children remains problematic:

a cross-sectional study. BMJOpen. 2013;3(8):e002935.

31. Zöllner EWLC, Lombard C, Galal U,HoughS,

IrusenE, Weinberg E. Hypothalamic-pituitary-

adrenal axis suppression in asthmaticchildren on

inhaled and nasalcorticosteroids:more common

thanexpected? J Pediatr Endocrinol Metab. 2011;24

(7-8):529-534.

32. Zöllner EWLC, Lombard CJ, Galal U,HoughFS,

IrusenEM, Weinberg E. Hypothalamic-pituitary-

adrenal axis suppression in asthmaticschool

children. Pediatrics. 2012;130(6):e1512-e1519.

33. KampsAW, Molenmaker M, KempermanR,

vander VeenBS, Bocca G, Veeger NJ. Children with

asthma havesignificantly lowerlong-term cortisol

levelsin their scalp hair than healthy children. Acta

Paediatr . 2014;103(9):957-961.

34. Zöllner EW, LombardC, Galal U,HoughS,

IrusenE, Weinberg E. Hypothalamic-pituitary-

adrenal axis suppression in asthmaticchildren on

inhaled and nasalcorticosteroids:is the

early-morning serumadrenocorticotropichormone

(ACTH) a usefulscreeningtest? Pediatr Allergy

Immunol . 2011;22(6):614-620.

35. ToddG, DunlopK, McNaboeJ, Ryan MF, Carson

D,Shields MD. Growthand adrenal suppression in

asthmatic children treated with high-dose

fluticasone propionate. Lancet . 1996;348(9019):

27-29.

36. KazlauskaiteR, EvansAT, Villabona CV, et al;

Consortium for Evaluationof CorticotropinTestin

Hypothalamic-Pituitary Adrenal Insufficiency.

Corticotropin tests for hypothalamic-pituitary-adrenal insufficiency: a metaanalysis. J Clin

Endocrinol Metab. 2008;93(11):4245-4253.

37. Crowley S,HindmarshPC, Holownia P,

HonourJW,BrookCGD.The useof lowdosesof

ACTH inthe investigationof adrenalfunctionin

man. J Endocrinol . 1991;130(3):475-479.

38. KazlauskaiteR, Maghnie M.Pitfallsin the

diagnosis of central adrenal insufficiency in

children. EndocrDev . 2010;17:96-107.

Endocrine Effects of Inhaled Corticosteroids in Children Review ClinicalReview & Education




http://www.ncbi.nlm.nih.gov/pubmed/16054538
































































































































































































8/18/2019 Kapadia 2015



39. Allen DB.Effectsof inhaled steroids on growth,

bonemetabolism,and adrenal function. Adv Pediatr .

2006;53:101-110.

40. Wolthers OD.Methodology and implications

of knemometryin growthassessment of inhaled

glucocorticoids. Pediatr Allergy Immunol . 2010;

21(1,pt 2):e190-e198.

41. Wolthers OD,WaltersEG. Short-termlower

leggrowth in 5- to11-year-oldasthmatic children

usingbeclomethasonedipropionateinhalerswithchlorofluorocarbon or hydrofluoroalkane

propellants:a 9-week, open-label,randomized,

crossover, noninferiority study. ClinTher . 2011;33

(8):1069-1076.

42. Wolthers OD,PedersenS. Short-termgrowth

duringtreatment with inhaled fluticasone

propionate and beclomethasone dipropionate. Arch

Dis Child . 1993;68(5):673-676.

43. Agertoft L, PedersenS. Lower-leggrowth rates

in children withasthma duringtreatment with

ciclesonideand fluticasone propionate. Pediatr

Allergy Immunol . 2010;21(1 Pt 2):e199-e205.

44. Doull IJ, Freezer NJ, Holgate ST. Growthof

prepubertal children withmild asthma treated with

inhaled beclomethasone dipropionate. Am J Respir

Crit Care Med . 1995;151(6):1715-1719.

45. VerberneAA, FrostC, RoordaRJ, vander Laag

H, Kerrebijn KF;The DutchPaediatric Asthma Study

Group.One yeartreatmentwith salmeterol

compared withbeclomethasonein children with

asthma. Am J Respir Crit Care Med . 1997;156(3,pt 1):

688-695.

46. VerberneAA, FrostC, DuivermanEJ,Grol MH,

Kerrebijn KF;The DutchAsthmaStudy Group.

Addition of salmeterolversus doubling thedoseof

beclomethasone in children withasthma. Am J

RespirCrit Care Med . 1998;158(1):213-219.

47. Anthracopoulos MB, Papadimitriou A,

Panagiotakos DB, et al. Growthdeceleration of

children on inhaled corticosteroids is compensated

for after the first 12 months of treatment. Pediatr

Pulmonol . 2007;42(5):465-470.

48. Saha MT, Laippala P, LenkoHL. Growthof

asthmaticchildren is slower duringthan before

treatmentwith inhaled glucocorticoids. Acta Paediatr .

1997;86(2):138-142.

49. TheChildhood Asthma Management Program

Research Group.Long-term effects of budesonide

or nedocromilin children withasthma. N EnglJ Med .

2000;343(15):1054-1063.

50. HooverRMEJ, ErramouspeJ, Bell EA,

Cleveland KW. Effect of inhaled corticosteroids on

long-termgrowth in pediatric patients withasthma

and allergic rhinitis. Ann Pharmacother . 2013;47(9):

1175-1181.

51. Arend EEFG,Fischer GB,Debiasi M,Schmid H.

Inhaled corticosteroid treatmentand growthof

asthmaticchildren seenat outpatientclinics.

J Pediatr (Rio J). 2006;82(3):197-203.

52. KellyHW,Sternberg AL,Lescher R, etal; CAMP

Research Group.Effect of inhaled glucocorticoids in

childhood on adultheight. NEngl JMed . 2012;367

(10):904-912.

53. Raissy HH,Blake K. Does useof inhaled

corticosteroid for managementof asthma in

children makethem shorter adults? Pediatr Allergy

Immunol Pulmonol . 2013;26(2):99-101.

54. SkverskyAL, Kumar J,AbramowitzMK,

Kaskel FJ, Melamed ML. Associationof

glucocorticoiduse and low 25-hydroxyvitamin D

levels: resultsfrom theNational Health and

Nutrition ExaminationSurvey (NHANES):

2001-2006. J Clin Endocrinol Metab. 2011;96(12):

3838-3845.

55. Tse SMKH,KellyHW,LitonjuaAA, Van Natta

ML, WeissST,Tantisira KG;Childhood Asthma

Management Program Research Group.Corticosteroid use and bonemineral accretion

in children withasthma: effect modificationby

vitamin D. J Allergy Clin Immunol . 2012;130(1):

53-60.e4.

56. Turpeinen M, PelkonenAS,NikanderK, et al.

Bonemineral density in children treated withdaily

or periodical inhaled budesonide:the Helsinki Early

Intervention Childhood Asthma study. Pediatr Res.

2010;68(2):169-173.

57. Harris M,Hauser S,Nguyen TV, etal. Bone

mineral density in prepubertalasthmaticsreceiving

corticosteroid treatment. J Paediatr Child Health.

2001;37(1):67-71.

58. KellyHW,VanNattaML, Covar RA,Tonascia J,

GreenRP,Strunk RC; CAMPResearch Group. Effect

of long-termcorticosteroid use on bone mineraldensity in children:a prospectivelongitudinal

assessmentin thechildhood Asthma Management

Program (CAMP) study. Pediatrics. 2008;122(1):

e53-e61.

59. SharmaPK, Malhotra S,Pandhi P, Kumar N.

Effect of inhaled steroids on bonemineral density:

a meta-analysis. J Clin Pharmacol . 2003;43(2):

193-197.

60. Gregson RK,Rao R, Murrills AJ, Taylor PA,

Warner JO.Effect of inhaled corticosteroids on

bonemineral density in childhood asthma:

comparison of fluticasone propionate with

beclomethasone dipropionate. Osteoporos Int .

1998;8(5):418-422.

61. RaoR, GregsonRK, Jones AC,MilesEA,

Campbell MJ,Warner JO.Systemic effects of inhaled corticosteroids on growthand bone

turnover inchildhoodasthma:a comparisonof

fluticasonewith beclomethasone. EurRespir J .

1999;13(1):87-94.

62. AltintasDU,Karakoc GB,Can S,Yilmaz M,

KendirliSG. The effects of long term useof inhaled

corticosteroids on lineargrowth, adrenal function

and bonemineral density in children. Allergol

Immunopathol (Madr). 2005;33(4):204-209.

63. Allen HD, ThongIG, Clifton-BlighP,Holmes S,

Nery L, WilsonKB. Effects of high-doseinhaled

corticosteroids on bonemetabolismin prepubertal

children withasthma. Pediatr Pulmonol . 2000;29

(3):188-193.

64. Griffiths AL,Sim D,Strauss B, Rodda C,

Armstrong D,Freezer N. Effect of high-dosefluticasonepropionateon bonedensity and

metabolismin children withasthma. Pediatr

Pulmonol . 2004;37(2):116-121.

65. WeldonD. The effects of corticosteroids on

bonegrowth and bonedensity. Ann Allergy Asthma

Immunol . 2009;103(1):3-11.

66. AbramsSA. Dietary guidelines forcalcium and

vitaminD: a newera. Pediatrics. 2011;127(3):566-568.

67. Turpeinen M, SorvaR, Juntunen-Backman K.

Changes in carbohydrate and lipidmetabolismin

children withasthma inhaling budesonide. J Allergy

Clin Immunol . 1991;88(3 Pt 1):384-389.

68. Willi SM,KennedyA, Wallace P, Ganaway E,

Rogers NL, Garvey WT. Troglitazone antagonizes

metabolic effects of glucocorticoids in humans:

effects on glucose tolerance,insulin sensitivity,

suppression of free fattyacids,and leptin. Diabetes.

2002;51(10):2895-2902.

69. Slatore CG,BrysonCL, Au DH.Theassociation

of inhaled corticosteroid use withserum glucoseconcentration in a largecohort. Am J Med . 2009;

122(5):472-478.

70. PaganoG, Cavallo-PerinP,CassaderM, etal.

Anin vivo and invitro study ofthemechanismof

prednisone-induced insulinresistance in healthy

subjects. J Clin Invest . 1983;72(5):1814-1820.

71. Ranta F, AvramD, BerchtoldS, etal.

Dexamethasoneinduces cell deathin

insulin-secretingcells, an effect reversed by

exendin-4. Diabetes. 2006;55(5):1380-1390.

72. Lambillotte C, Gilon P, Henquin JC.Direct

glucocorticoidinhibitionof insulinsecretion. An in

vitro studyof dexamethasone effects in mouse

islets. J Clin Invest . 1997;99(3):414-423.

73. Faul JL,Wilson SR,Chu JW, Canfield J,

Kuschner WG.Theeffect of aninhaled

corticosteroidon glucose controlin type 2 diabetes.

Clin MedRes. 2009;7(1-2):14-20.

74. O’ByrnePM, Rennard S,GersteinH, etal. Risk

of newonset diabetes mellitus inpatientswith

asthma or COPDtaking inhaled corticosteroids.

Respir Med . 2012;106(11):1487-1493.

75. Kiviranta K, Turpeinen M.Effect of eight

months of inhaled beclomethasone dipropionate

and budesonideon carbohydrate metabolism in

adultswith asthma. Thorax . 1993;48(10):974-978.

76. Kruszynska YT, GreenstoneM, HomePD,

Cooke NJ. Effectof high doseinhaled

beclomethasone dipropionateon carbohydrate and

lipid metabolism in normalsubjects. Thorax . 1987;

42(11):881-884.

77. SuissaS, Kezouh A, ErnstP.Inhaled

corticosteroids andthe risks of diabetesonsetand

progression. Am J Med . 2010;123(11):1001-1006.

78. Yucel O,EkerY,Nuhoglu C, CeranO.

Hemoglobina1c levelsin children with asthmausing

low dose inhaled corticosteroids. Indian Pediatr .

2009;46(4):300-303.

79. WrightNP, WalesJK. The incidenceof

hypoglycaemiain childrenwith type 1 diabetesand

treated asthma. Arch Dis Child . 2003;88(2):155-156.

80. Shah S,Kublaoui BM,OdenJD,WhitePC.

Screeningfor type 2 diabetes inobeseyouth.

Pediatrics. 2009;124(2):573-579.

81. KapadiaCR. Arethe ADA hemoglobinA(1c)

criteriarelevant forthe diagnosisof type 2 diabetes

in youth? Curr DiabRep. 2013;13(1):51-55.

82. National Asthma Education and Prevention

Program. Expert Panel Report3 (EPR-3):Guidelines

forthe Diagnosisand Management of

Asthma-Summary Report 2007. J Allergy Clin

Immunol . 2007;120(5 suppl):S94-S138.






















































































































































































































































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