EFFICACY OF ORAL CORTICOSTEROIDS IN THE TREATMENT OF ACUTE WHEEZING EPISODES IN ASTHMATIC PRESCHOOLERS: SYSTEMATIC REVIEW WITH META-ANALYSIS

Jose A. Castro-Rodriguez,Andrea A. Beckhaus and Erick FornoPediatric Pulmonology · April 2016

Presented by : Surg Lt Cdr Manas R MishraModerator : Lt Col Deepak Joshi

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THE WHEEZING CHILD

Common paediatric presenting problem

End point of variety of pathological processes

Large burden of disease Frequent diagnostic uncertainty Wide variations in management

protocols and guidelines

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THE WHEEZING CHILD

Bronchiolitis

AsthmaVirus-

induced wheeze

Pneumonia Chronic cough

AGE OF PRESENTATION

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VIRUS-INDUCED WHEEZE

Between one quarter and one half of all pre-school children have symptoms of wheeze with a respiratory infection

Most do not go on to develop asthma

Under-5s with episodic wheeze but without interval symptoms do not have asthma-type airway inflammation, and are not helped by steroids

Episodes of wheeze and a history of atopy are strongly predictive of those who will develop asthma

May 1, 2023 Dr Manas R Mishra, Department of Pediatrics, AFMC

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EPISODIC VIRAL WHEEZING

Wheezing during discrete time periods in an otherwise healthy child who is without symptoms between these episodes.

Wheezing episodes are generally associated with a clinical diagnosis of viral upper respiratory tract infection (URTI).

Rhinovirus, respiratory syncytial virus (RSV), coronavirus, human metapneumovirus, parainfluenza virus, and adenovirus

Dr Manas R Mishra, Department of Pediatrics, AFMC

May 1, 2023

ASTHMA

Asthma is a chronic inflammatory condition of lung airway resulting in episodic airway obstruction.

Annual rate of emergency department (ED) visits is 23–42 per 1,000 for preschoolers versus less than 15 per 1,000 for those aged 6–70 years.

48% of preschoolers with asthma have an exacerbation in the preceding year

May 1, 2023 Dr Manas R Mishra, Department of Pediatrics, AFMC

May 1, 2023 Dr Manas R Mishra, Department of Pediatrics, AFMC

May 1, 2023 Dr Manas R Mishra, Department of Pediatrics, AFMC

May 1, 2023 Dr Manas R Mishra, Department of Pediatrics, AFMC

May 1, 2023

OBJECTIVES OF THE STUDY

Evaluate the efficacy of oral corticosteroids use in children up to 6 years of age (including infants, toddlers, and preschoolers) presenting with recurrent wheezing exacerbations or acute asthma.

Reason : In recent trials efficacy of oral corticosteroids in preschoolers does not support their efficacy

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METHODS

This study was Registered with International Prospective

Register of Systematic Reviews (PROSPERO) PRISMA (Preferred Reporting Items for

Systematic Reviews and Meta-Analyses) guidelines followed

Search and Selection Criteria: Studies published in MEDLINE, EMBASE, CINAHL,

SCOPUS,and the Cochrane Controlled Trials Register (CENTRAL) databases and ClinicalTrials.gov until May 2015 included.

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INCLUSION CRITERIA

Studies which met the following : Children < 6 years of age with recurrent

wheezing/asthma exacerbations of any severity presenting to the ED, receiving t/t at home (“outpatient studies”) or hospitalized (“inpatient studies”)

Randomized clinical trials (RCTs; parallel group or cross-over design) of any duration

Comparison of oral Corticosteroids (any type) versus placebo.

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TECHNICAL ASSESSMENT

According to recommendations outlined in the Cochrane Handbook

Adequacy of sequence generation; Allocation concealment; Blinding of participants and investigators; Blinding of outcome assessment; Incomplete outcome data; Selective outcome reporting, and other bias.

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EXCLUSION CRITERIA

Studies involving: Abstracts, letters, reviews, pooled analysis, Unregistered RCT.

Studies Failing Technical assessment Studies not meeting inclusion criteria Sample duplication: Studies including the same

population as another study

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OUTCOMESPRIMARY :

Hospital Admission, Need for additional courses of SCSUnscheduled visits to the ED in the 4weeks

period following the trialLength of hospital stay,

SECONDARY

Improvement of lung function measured (FEV1) or (PEF), symptom scores, withdrawals (total and due to adverse effects [AEs]), and safety (AEs and serious AEs)

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DATA EXTRACTION AND ASSESSMENT OF RISK OF BIAS:

Independently analyzed by the two authors

Risk of bias assessment according to the Recommendations outlined in the Cochrane Handbook

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DATA ANALYSIS Analysis was performed by intention to treat and

included all participants to minimize bias.

Outcomes were pooled using mean differences (MD) (inverse variance method) or Mantel–Haenszel risk ratios (RR).

Heterogeneity was measured by the I2 test ≤25% absence of bias; 26–39% unimportant; 40–60% moderate; and 60–100% substantial bias).

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Subgroup analyses : Type of oral Corticosteroids Age (<2 vs. >2 years old) Severity of exacerbation (mild vs. moderate to

severe) Trials sponsored by pharmaceutical industry

versus independent trials.

The meta-analysis was performed with the Review Manager 5.3.5 software

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Snap shot pg 3

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Total 11 RCTs- UK- 6, USA- 3, Israel- 1, Finland- 1 OPD-4, IPD-5, ED-2

Steroids Used: Prednisolone-07 , Prednisone-02 , Methylprednisolone -01 Hydrocortisone followed by prednisolone- 01

(Most studies maintained the treatment for 3–5 days) Single dose of OCS- 02

RESULTS : PRIMARY OUTCOME Hospital Admissions:

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OVERALL HOSPITAL ADMISSIONS Fig 2 a

OUTPATIENT STUDIES AND HOSPITAL ADMISSIONS

ED STUDIES AND HOSPITAL ADMISSIONS.

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HOSPITAL ADMISSIONS

Dr Manas R Mishra, Department of Pediatrics, AFMC

OCS placebo

Overall No difference(RR-1.0, CI: 0.49-2.05)

ED/Inpatient Low riskRR-0.58CI-0.37-0.92

Out patient Higher riskRR-2.15

Subgroup <2 yrs older

No differencce

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ADDITIONAL COURSE OF SYSTEMIC CORTICOSTEROIDS

Inpatient studies : significant difference favoring OCS group (RR: 0.57;95%CI: 0.40–0.81; I2=0%, P=0.34)

Outpatient studies reported the need for additional courses of SCS showing no significant difference between OCS and placebo(RR: 0.74; 95%CI: 0.40–1.34)

Over 4 years of age there was no significant difference in OCS and placebo group.

Subgroup analysis was not performed due to insufficient data.

Fig 3a

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UNSCHEDULED VISITS Three inpatient studies reported there was no

significant statistical difference between OCS and placebo (RR: 0.73; 95%CI: 0.35–1.52)

One out patient study reported more ED consults in OCS group than placebo during treatment period

Subgroup analysis was not performed due to insufficient data.

Fig 4

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HOSPITAL LENGTH OF STAY

No difference in hospital length of stay in both groups.

Only one study reported the OCS group had a shorter stay.

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SECONDARY OUTCOMES

Outpatient and ED studies did not give any data on pulmonary function.

Two inpatient studies found an improvement in PEF measurements in the OCS

Outpatient and in patient studies found no differences between OCS and placebo on symptom scores but ED studies found better symptom improvement in the OCS group

No relevant AEs reported.

Insufficient data to perform meta analysis of AE

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PATHOPHYSIOLOGY AND DRUG RESPONSE

Asthma in pre school children is mostly triggered by episodic viral infection with different virus producing different immune response.

Other factors affecting OCS response Dosage of OCS Timing of administration Vitamin D deficiency Genetic predisposition

May 1, 2023 Dr Manas R Mishra, Department of Pediatrics, AFMC

Prednisolone reduces wheezing relapse in children with acute rhinovirus infection, this effect was not observed in children with acute respiratory syncytial virus infection.

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DISCUSSION In studies conducted in ED, OCS treatment was

associated with a lower hospitalization rates

In the inpatient settings, OCS treatment was associated with a lower need for additional courses of SCS

In the outpatient studies, however, OCS administration was associated with more hospital admissions

It was stated that, the dosage (single or multiple) of OCS used in these eleven RCTs was adequate.

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Considering the overall group there is no evidence that OCS administration is effective compared to placebo in any primary or secondary outcomes.

Largest study in this group had a high rate of treatment noncompliance

Behavioral changes have been reported in children during OCS therapy, and this factor might affect the clinical decision to admit to the hospital

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The use of OCS in the treatment of recurrent wheezing in infants, toddlers, and preschoolers remains controversial.

Dr Manas R Mishra, Department of Pediatrics, AFMC

May 1, 2023

PITFALLS OF THE STUDY

Allocation concealment in most were unclear

Different protocols were used in each study

One study was post hoc analysis

Mean age was preschool age group but some studies included older children.

Not enough data to measure lung function or symptom score or adverse effect. (secondary outcomes)

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SUMMARY Current evidence is inadequate to formulate any

broad clinical recommendations regarding the use of OCS in infants, toddlers, and preschoolers with recurrent episodes of acute wheezing.

OCS might potentially be beneficial (lower hospital admission rates and less need for additional courses of systemic steroids) in children with more severe asthma/wheezing exacerbations that present to the ED or require hospitalization

Future studies should have standardized case definition, larger sample size, and more homogeneous methodological quality

THANK YOU…..