Adverse effect of inhaled corticosteroids

Sasikarn Suesirisawad, MD

Local side effect

Dysphonia The most common complaint is of hoarse voice May occur > 50 % of pts using MDI.

Thrush  Mouth should be rinse discarded

Cough and throat irritation accompanied by reflex bronchoconstriction,

given via MDIs. rectified by switching to DPI. Unusual local complications: perioral

dermatitis, tongue hypertrophy, increased thirst.

Roland NJ et al. Chest. 2004;126(1)213

Skeletal effect

Growth deceleration

Stuart W. Stoloff et al. Current Opinion in Allergy and Clinical Immunology 2011, 11:000–000

Theresa W. J Allergy Clin Immunol 2011;128: 956-63.

Background

Children with persistent asthma of at least moderate severity eventually attain adult height( predicted range).

Lone Agertoft. N Engl J Med 2000;343:1064-9

These children might delay linear growth associated with ICS therapy.

CAMP. N Engl J Med 2000;343:1054-63

Theresa W. J Allergy Clin Immunol 2011;128: 956-63

P children with asthma

I 142 BUD treated children with asthma

C 18 Control asthma who never receive ICS51 Healthy sibling of pt in BUD gr

O BUD gr attained adult ht after 9.2 y of BUD treatmentMean daily BUD dose 412 μgMean cumulative dose BUD 1.35 gBDU gr: Mean difference target adult ht +0.3 cm (95%CI -0.6 to + 1.2)Control: Mean difference target adult ht -0.2 cm (95%CI -2.4 to + 2.1)Sibling: Mean difference target adult ht +0.9 cm (95%CI -0.4 to + 2.2)

Prospective, long term study Excluded

Chronic disease GA<32 wk Prednisolone > 2 wk/yr

All children visited clinic at 6 mo interval for 1-2 yr ( run-in period)

332 children controlled without continuous use of ICS asked to change to treatment with BUD.Lone Agertoft. N Engl J Med 2000;343:1064-9

Each mo visited, recorded number of hospital admission, age, ht,wt. LFT, dose and frequency of prescribed drug.

Through study, pt seen by same 2 physician, all measurement of wt, ht and LFT performed by same 3 nurse.

Data analyzed collected from Jan 1986-Aug1999

Lone Agertoft. N Engl J Med 2000;343:1064-9

Adult Ht in relation to target adult Ht in 142 children treated with BUD for 3-13 yr.

Measure target adult Ht

Lone Agertoft. N Engl J Med 2000;343:1064-9

Difference between adult Ht and target adult Ht

Lone Agertoft. N Engl J Med 2000;343:1064-9

N Engl J Med2000;343: 1054-63

P 1041 children age 5-12 y with mild to moderate asthma Treated participant 4-6 y

I 311 children receive 400 μg of BUD 312 children receive 16 mg of necocromil

C Placebo: 418 children

O Mean increase in ht in BUD gr 1.1 cm less than placebo gr (22.7 vs. 23.8 cm, P=0.005)This difference was evident mostly within the first year.Ht increase was similar in nedocromil and placebo gr

Standing Ht and standing Ht velocity

during 4 yr of follow-up

CAMP. N Engl J Med 2000;343:1054-63

BUD less ht 1.1 cmP=0.005

J Pediatr 2009;154:682-7

P 1041 children with mild to moderate asthma in CAMP study, 941 (90%)

I 4.3 yr of 400 μg of BUD 16 mg nedocromil

C placebo

O Gr treated continuously during trial BUD or nedocromil did not differ from gr given placebo in LFT,control of asthma, psychologic status at the end of posttrial follow-up.

Decrease ht in BUD gr relative to placebo at the end of trial(1.1cm;P=0.005).Remained significant ( 0.9cm; P=0.01) after additional 4.8 yr and more pronounced in girl (1.7 cm; P=0.001) than boy(0.3cm;P=0.49)

P 285 participants age 2 0r 3 yr with positive API

I FP 88 μg twice daily

C Placebo

O ICS gr greater proportion of episode-free day(P=0.006) and lower rate of exacerbation(P<0.001) and supplementary use of controller medication(P<0.001)

ICS gr increase ht 1.1 cm less at 24 mo (P<0.001)The end of trial, ht increase 0.7 cm less (p=0.008)

N Engl J Med 2006;354:1985-97

The Prevention of Early Asthma in Kids (PEAK study)

Toddler-aged children with recurrent wheeze at high risk for development of asthma based on positive modified API treated for 2 yr with FP(176 μg/d).

1.1 cm reduction in ht gained at the end of treatment compared with placebo.

1.1 cm, P<0.001

0.7 cm

7.3 cm/y

6.6 cm/y

mAPI versus original API

Theresa W. J Allergy Clin Immunol 2004; 114: 1282-7

1. Child must have history of ≥ 4 wheezing episodes with at least one physician diagnosis.2. In addition, child must have history of ≥ 4 wheezing episodes with at least 1 confirmed by physician.

Study design and treatment

PEAK is multicenter, DBRCT parallel group comparison trial of FP with placebo in children 2 yr and 3 yr.

Treated for 2 yr by Aerochamber with mask with FP(176 μg/d) MDI-CFC.

Primary safety analysis: linear growth

Loss F/U 12%

Loss F/U 28%

Outcome measures

Height measured every 4 months during 36 mo of study and at 48 mo.

Medical history symptom evaluation, family and environmental history and eo count.

Study population

Original cohort 285 children, remained 102 children in both gr.

2 treatment groups were similar except higher eo in ICS gr.

No significant different in number of complete clinic visit, dropouts, treatment failures, serious adverse event between gr.

Overall growth analysis

0.9cm

0.2

Change in height(cm) from baseline to 24 and 48 mo

Stratifying variable

Strata No. Δ Height 24 mo(cm)

Δ Height 48 mo(cm)

Over all cohort 204 -0.9 -.0.2

Age 2 y 105 -1.1 -0.8

3 y 99 -0.8 0.4

Baseline wt < 15 kg 104 -1.0 -0.5

≥ 15 kg 100 -0.9 0.0

Sex Female 124 -0.9 -0.1

Male 80 -0.9 -0.3

Race White 118 -1.0 -0.3

Nonwhite 86 -0.8 -0.2

Age 2 y < 15 kg 70 -1.3 -1.6

≥ 15 kg 35 -0.8 -0.1

Age 3 y < 15 kg 34 -0.6 0.6

≥ 15 kg 65 -0.9 0.1

ΔHt 1 cm; P=0.007

ΔHt 0.5 cm; P=0.38

cm

Z-score

Subgroup analysis by wt

Subgroup analysis by age

ΔHt, 1.1 cm; P= 0.006 Z-score

24 mo

48 mo

Subgroup analyses by age and wt at enrollment

Particular risk for less linear growth during treatment were age of 2 yr and wt < 15-17 kg at enrollment.

Overall cohort

Age 2 yr

Age 3 yr

Subgroup analyses by age and wt

ΔHt 1.3 cm; P=0.002

ΔHt 1.6 cm; P=0.008

ΔHt 0.1 cm; P=0.94

24 mo

48 mo

Age 2 yr

ΔHt 0.6 cm; P=0.53

ΔHt 0.1 cm; P=0.85

Age 3 yr

Medication use and asthma symptoms during 2-year follow-up after

treatment discontinuation

Subgroup analysis by baseline characteristics

No significant differences in linear growth during treatment or 2 yr after treatment discontinuation for baseline characteristics.

Discussion

2 yr of FP treatment is associated with less linear growth that dissipates over time after treatment discontinuation.

ICS gr catch-up growth during 2 yr after treatment discontinuation.

Subgroup of younger with lesser wt ( age 1 yr and 17 kg at enrollment) : not catch-up growth.

Discussion

Murray: ICS compared with placebo had greater effect on linear growth in younger (2y) versus older (3y) children.

PEAK study, school aged children with persistent asthma treated with BUD(400μg/d) for 4.3 y in CAMP study had gained 1.1 cm less in ht at the end of period compared with placebo gr and remained significant(0.9cm, P=0.01) additional 4.8 y after study medication stopped.

Discussion

Gr of younger with lesser wt whom growth suppressive effect pronounced, this effect did not diminish with time after ICS discontinued.

Discussion

Younger children of lesser wt likely received higher relative exposure(μg/kg) of FP than older children.

Not appear to solely wt effect because older children of lesser wt ( 3y and <17 kg at enrollment) not show same growth effect and significant catch-up growth once ICS discontinued.

Discussion

This study younger children of lesser wt not catch-up growth over time.

Unlike CAMP study in older children with persistent asthma, not find that girl in PEAK study more likely less linear growth.

Discussion

FP CFC estimated 10 μg/kg/d is upper limit dose to avoid potential effect of long term daily ICS use on growth in children 2-3 y of age.

Average ht percentage of younger children of lesser wt at enrollment was 43.2%.

Not perfectly mirror growth of reference population(children with recurrent wheezing might not same growth of reference population).

Discussion

33% of children were > 75 th percentile for wt compared with reference population, reflect increase obesity rate in older children with asthma.

Potential for reduced linear growth among children receiving ICS who are 2 yr of age and weigh < 17 kg should be balanced with level of asthma control to maximize benefit/risk ratio of treatment.

Ocular side effect

Intraocular pressure  Increase risk of glucoma

Cataracts Risk factor for posterior subcapsular

cataract

Gonzalez AV et al.Pulm Pharmacol Ther. 2010Pelkonen A et al. JACI.2008;122(4):832.

Systemic side effect

Skin change and bruising

dose dependent at high daily doses

Adverse airway effects

No evidence for atrophy of airway epithelium

Infection

High dose ICS increase risk activation of TB

No increase risk pneumonia

Psychiatric effect

Psychiatric disturbancePierre Ernst et al. Curr Opin Pulm Med 2012, 18:85–89

Stuart W. Stoloff et al. Current Opinion in Allergy and Clinical Immunology 2011, 11:000–000