Glycaemic and lipid profile in asthmatic children on inhaled Budesonide: A case control study

Glycaemic and lipid profile in asthmatic children on inhaled Budesonide: A case control study

Dissertation submitted to

THE TAMILNADU DR.M.G.R.MEDICAL UNIVERSITY

In partial fulfillment of the regulations for the award of degree of

M.D DEGREE (PEDIATRICS) BRANCH VII

INSTITUTE OF SOCIAL PEDIATRICS STANLEY MEDICAL COLLEGE

CHENNAI – 600 001

MAY 2018

DECLARATION BY THE CANDIDATE

I, Dr.M.Sree Divya hereby solemnly declare that this dissertation / thesis entitled

“

The dissertation is submitted to The Tamilnadu Dr.M.G.R Medical University towards the partial fulfillment of the rules and regulations for the M.D Degree Examination - BRANCH VII -Pediatrics.

Place: Chennai Signature of the candidate

Date:

Dr.M.SREE DIVYA

CERTIFICATE BY THE GUIDE

This is to certify that the dissertation entitled “Glycaemic and lipid profile in asthmatic children on inhaled Budesonide:A case control study” is a bonafide record of work carried out by Dr.M.Sree divya, in the Department of Pediatrics, Government Stanley medical college, under my guidance and supervision during the period of her post graduate study for M.D. Pediatrics from May 2015 to May 2018, submitted to The Tamilnadu Dr.M.G.R Medical University towards the partial fulfillment of the rules and regulations for the M.D Degree Examination - BRANCH VII (Pediatrics)

Place: Chennai Signature of the Guide

Dr. J.GANESH. MD,DCH

Date: Professor

Institute of Social Pediatrics Stanley Medical College Chennai-600001

CERTIFICATE BY THE INSTITUTION

This to certify that the dissertation titled “Glycaemic and lipid profile in asthmatic children on inhaled Budesonide: A case control study” is a bonafide record of work carried out by Dr.M.SREE DIVYA, in the Department of Pediatrics under our direct supervision and guidance, during the academic year 2015 -2018 submitted to The Tamilnadu Dr.M.G.R Medical University, Chennai in partial fulfillment of the requirement of the award for the degree of M.D BR ANCH VII (PEDIATRICS).

Dr.M.A.ARAVIND, MD Dr.PONNAMBALAM NAMASIVAYAM, MD

Professor and HOD Dean

Institute of Social Pediatrics Stanley Medical College, Chennai.

Stanley Medical College Chennai – 600 001.

Place : Chennai Date :

ACKNOWLEDGEMENT

It is with immense pleasure and gratitude that I, Dr. M. Sree Divya thank Dr.Ponnambalam Namasivayam M.D, DNB.,D.A., Dean, Stanley medical college for bestowing me the permission and privilege of presenting this study and enabling me to avail the facilities from the institution.

I am gratefully indebted to Professor Dr.M.A.Aravind, MD, Director, Institute of Social Pediatrics, Stanley medical college for his valuable guidance and motivation.

It is with great pleasure that I express a deep sense of gratitude to my teacher and guide, Prof.Dr.J.Ganesh M.D., D.Ch, Professor,Department of Pediatrics for his valuable guidance and support during the preparation of this dissertation and also inspiring me in every step of this study, for without him this study would not have been possible.

I express my gratitude to my co guides, Professor Dr. Vivekanandan V.E., M.D., and Dr.P.Venkatesh, M.D., Assistant professor, Department of Pediatrics for their valuable help and guidance throughout the study

I am very grateful to all my chiefs, Prof.Dr.Anuradha, M.D., D.Ch, Prof.Dr.J.Jayakumar, M.D., D.Ch, Prof. Dr.S.Shanthi, M.D., D.Ch, Prof.

Dr.Lakshmi M.D., D.Ch, Prof.Dr.DeviMeenakshi M.D., D.Ch, Prof.Dr.Subramanian M.D.,D.Ch and Prof.Dr. Megalai Suresh Kumar M.D.,D.Ch,for their valuable guidance and motivation and providing departmental resources for conducting the study.

I am extremely thankful to Dr.Ekambaranath.S M.D., Pediatric registrar for his valuable suggestions and guidance during this study.

I sincerely thank my professors Dr.Elango,M.D., D.Ch and Dr.Raja,M.D., for their timely help and support throughout the course of this study

I sincerely thank my Assistant professors Dr.Vinoth M.D., Dr.Parveen KumarM.D., Dr.Rajesh M.D.,Dr.SenthilKumar M.D., Dr.Sankarnarayanan M.D., Dr.Kumar D.Ch, Dr.Selvi M.D., Dr.AnandhiM.D. and Dr.Kabilan M.D.

for their valuable support throughout the course of this study.

I sincerely thank my parents and sister for helping me in all possible ways.

I sincerely thank all the patients and their parents for participating in this study.

I thank all the staff nurses and paramedical workers of the department of Pediatrics, Stanley medical college for their immense help in conducting this study.

Finally, I thank all the postgraduates in the Department of Pediatrics who have helped me. It was an immense pleasure working with you all

Dr.M. SREE DIVYA

PLAGIARISM CERTIFICATE

This is to certify that this dissertation work titled “Glycaemic and lipid profile in asthmatic children on inhaled Budesonide: A case control study” of the candidate Dr.M.Sree divya with registration number 201517053 for the award of M.D.PAEDIATRICS (Branch-VII).

I personally verified the urkund.com website for the purpose of plagiarism check. I found that the uploaded thesis file contains from the introduction to conclusion and result shows 2 percentage of plagiarism in the dissertation.

Guide and supervisor sign with seal

CONTENTS

S.NO TITLE PAGE NUMBER

1 INTRODUCTION

1

2 REVIEW OF LITERATURE

36

3 STUDY JUSTIFICATION

44

4 AIMS AND OBJECTIVES

45

5 METHODOLOGY

46

6 OBSERVATION AND RESULTS

53

7 DISCUSSION

74

8 CONCLUSION

80

9 BIBLIOGRAPHY 10 ABSTRACT 11 APPENDICES

INFORMATION SHEET CONSENT FORM

STUDY PROFORMA MASTER CHART

ABBREVIATIONS

ICS - Inhaled corticosteroids

LDL-C - Low density lipoprotein cholesterol HDL-C - High density lipoprotein cholesterol MDI - Metered dose inhaler

HbA1C - Glycosylated hemoglobin PEF - Peak expiratory flow

FEV1 - Forced expiratory volume in 1 second FVC - Forced vital capacity

GINA - Global Initiative for Asthma SABA - Short acting Beta agonist LABA - Long acting Beta agonist WHO - World Health Organization CDC - Centre for Disease Control HPA - Hypothalamo pituitary axis FBS - Fasting blood sugar

FLP - Fasting lipid profile

1

GLYCAEMIC AND LIPID PROFILE IN ASTHMATIC CHILDREN ON INHALED BUDESONIDE:A CASE CONTROL

STUDY

INTRODUCTION

Asthma is one of the chronic diseases worldwide with an estimated 300 million affected individuals.2,50,000people die every year due to asthma,which as an avoidable cause of death¹. The estimated prevalenceof asthma in childhood varies from 1.6%-36.8%³.

Of this approximately one tenth are from India². India has an estimated 15 to 20 million asthmatics with a prevalence of 10-15% in 5 to 11 year old children⁴.

The rising prevalence in developing countries is almost close to that of the developed countries, which seems to have plateaued⁵.

Health care expenditure on asthma is very high. Asthma is a major contributor to school and work absence and a major contributor to emergency department visits and hospitalizations³⁰. Though asthma cannot be completely cured, it can be well controlled with appropriate choice of preventer and controller therapy coupled with avoidance of allergen exposure and appropriate management of comorbidities¹¹.

In addition, the myths and stigma associated with the disease as well as use of inhalers are a major obstacle to the management. Inhaled

2

corticosteroids (ICS) is the main therapy in asthma. With long term usage there is propensity for various side effects. The side effects of oral corticosteroids on metabolism are well documented, which is not the case with ICS⁷. The major side effects are due to the local deposition of ICS in the pharynx, HPA axis suppression⁷.

The 2 major drugs used in asthma, Salbutamol and ICS can affect glucose and lipid metabolism. Pediatric studies on effects of inhaled steroids are scant⁷.

Yucel et al in a cross sectional study demonstrated no relationship between dose,duration of low dose Budesonide and glycosylated hemoglobin levels⁸.

Bindusha et al studied the lipid profile in addition to glycaemic profile and compared children on low dose ICS versus high dose ICS (Budesonide/Fluticasone). There was no significant difference in FBS, FLP between both the groups²².

Daniel et al conducted a study in Kerala on 170 asthmatic children on ICS for a minimum duration of 6 months and measured their FBS, PPBS, and HbA1c levels at baseline and at end of 6 months. There was a significant rise in glycosylated hemoglobin before and after ICS use. They concluded that the use of higher doses/medium doses for a longer period could worsen glycemic control.

3 ASTHMA IN CHILDREN

History of asthma dates back to the Hippocrates era(400BC). He was the first person to coin the term “asthma” which means panting for breath.

Asthma is a Greek word which means, “wind” or to “blow”. He identified the relationship between breathlessness and the environment and suggested that there exists a relationship between the disease and the environment.

Before invading India, Alexander the great used stramonium (substance related to the present day ipratropium and tiotropium used in MDI).

Asthma was described as gasping or breathlessness without the ability to make noise. If with running or any activity, breath becomes difficult, some Roman physicians described it as asthma.

The first asthma remedy that was used dates back to 50 AD by Pincy, the elder who used ephedra in red wine to treat asthma. In 1135-1204 A.D.

good personal hygiene and environment, intake of minimal quantity of wine and avoidance of opium, milk, cool vegetables, citrus fruits, legumes was recommended. In 1500 tobacco was used to induce cough and as an mucus expectorant. Allergy immunotherapy was introduced in 1900.Adrenaline and Aminophylline as anti asthma medications were introduced in 1950s.

4

The pressurized MDI for adrenaline and Isoprenaline was introduced in 1960’s followed by salbutamol and corticosteroids in 1970.

Beclomethasone was the first ICS introduced by Allen and Hanbury.

LABA has been in vogue since the last 10 years.

ETIOLOGY

No single etiological agent can be attributed to the causation.(30) Asthma is a result of the complex interlink between environmental factors, age of the host and genetic factors. These factors alter both innate and adaptive immunity thereby causing injury to the terminal airways making them hyperresponsive to infection, allergens and pollutants. With persistent inflammation, airway remodeling occurs.(30)

COMMON TRIGGERS

1. Viral infections-Respiratory syncytial virus, adenovirus, Influenza virus, metapneumo virus, parainfluenza virus.

2. Indoor allergens-dust mite, moulds, cockroaches

3. Air pollutants-tobacco smoke, coal and wood smoke, dust 4. Occupational exposure-cold air, emotions, pain, exercise 5. Drugs-Non steroidal anti inflammatory drugs, Beta blockers(30)

5

AIRWAY IN ASTHMA

Figure 1 Normal and asthmatic airway

The picture depicts the changes in the bronchioles following allergen exposure.

There is smooth muscle hyperplasia, basement membrane thickening, mucus hyper secretion and edema as a result of the activation of the inflammatory cascade following allergen exposure³¹.

6 PATHOPHYSIOLOGY OF ASTHMA

Figure 2 Cascade of events following allergen exposure

7

The pathophysiology responsible for asthma is obstruction of the airways that is reversible, caused by hypertrophy and hyper responsiveness of the smooth muscle of the bronchi causing bronchial smooth muscle hypertrophy and excessive mucus secretion³¹.

Inflammatory cells involved are eosinophil, macrophages, neutrophils, mast cells and lymphocytes. Type 2 helper cells are most critical among inflammatory mediators in asthma.

Hygiene hypothesis states that the immune mechanism in the causation of asthma can be altered by control of infections.

The recently proposed theory accounting for airway inflammation with bronchoconstriction is the integrity of the Epithelial mesenchymal trophic unit which is responsible for abnormal and heightened response to allergen exposure in asthma³³.

CLASSIFICATION OF ASTHMA

Broadly asthma is divided based on pathophysiology as 1.Atopic asthma

2. Non-atopic asthma

8 Atopic asthma

Atopic asthma is a result of type 1 hypersensitivity. On exposure to the triggering factor/antigen there is an excessive type 2 helper cell response against the antigen. Type 2 helper cells produce interleukin 4, interleukin 5,and interleukin13.

Interleukin 4 causes immunoglobulin E production. Eosinophils are activated by interleukin 5 and excessive mucus production by interleukin 13.IL-13 also increases immunoglobulin E production by mast cells³¹.

On allergen exposure there is an early and a late phase reaction.

Excessive mucus production, bronchospasm occur in the early phase.

Bronchospasm is due to stimulation of vagal receptors in sub epithelial layer.

Late phase is mediated by eosinophils and T2 helper cells. T2 helper cells are increasingly activated by chemokines produced by the epithelial cells. Repeated triggering and inflammation causes structural changes in the bronchi causing remodeling of the airways³¹.

Non-Atopic asthma

Inflammatory mediators triggering the bronchospasm are common to both atopic and non-atopic forms.

The main mechanism postulated is the decreased threshold of vagus receptors in sub epithelial layer by the virus induced airway inflammation.

9

These group of children are less likely to have a positive family history ³¹.

GENETICS AND ASTHMA

Certain gene expressions in children have been found out to be responsible for triggering the inflammatory cascade coupled with environmental factors.

Many genes in a locus on chromosome 5q regulate production of the inflammatory mediators.

Genetic loci on chromosome 20q regulate bronchial smooth muscle hypertrophy and fibroblast proliferation by coding for ADAM 33.

YKL-40, a chitinase family enzyme levels are proved to correlate with asthma severity³¹.

According to recent meta analyses of genome wide association studies, 4 genetic loci responsible for asthma susceptibility are located on long arm of chromosome 17. They include ILIRL1, ILI8R1, TSLP, and LL33 genes³².

10 DIAGNOSIS OF ASTHMA

There are many guidelines available for management of asthma like GINA, National Heart, Lung, and Blood Institute (NHLBI), National asthma education and prevention programme expert panel report and British Thoracic society(BTS)guidelines⁶.

With variations in classification of severity and symptom control all guidelines stress on the daily use of inhaled corticosteroid alone or in combination as the preferred choice of treatment for asthma.

In this study we have used GINA 2016 guidelines for diagnostic criteria, assessing symptom control and management protocols.

Exacerbations are managed as per the hospital protocols (Pediatric Emergency Medicine Course protocol)^37.

GINA

Global initiative for asthma (GINA) was formed in 1992 by collaboration of the World Health Organization with US based National Heart, Lung and Blood institute to cut down deaths by forming and implementing guidelines for prevention and management of asthma. The guidelines are evidence based and updated every year¹¹.

GINA categorizes patients into 2 categories based on age. Children younger or older than five years in defining asthma, diagnostic criteria and treatment strategies¹¹ .

11 DEFINITION OF ASTHMA

GINA 2016(Children above 5 years)

“Asthma is a heterogeneous disease usually characterized by chronic airway inflammation. It is defined by history of respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough that vary over time and intensity together with variable expiratory airflow limitation¹¹.”

Evidence of variable expiratory airflow limitation can be made by

1. Limitation of airflow documented by spirometry, FEV1/FVC <90%.

2. Reversibility following bronchodilator, FEV1>12% from predicted.

3. Peak expiratory flow variability>13%,measured in day and night to document diurnal variation difference.

4. Fall in FEV1 following exercise challenge and bronchial provocation¹¹.

In resource limited setting, PEF values are used when spirometry cannot be easily performed to make a diagnosis¹¹. The main difference in making a diagnosis in children younger than 5 years is that the diagnosis is made on clinical grounds as establishing evidence for variable expiratory airflow limitation is difficult¹¹.

12 DEFINITION OF ASTHMA

GINA 2016(Children younger than 5 years)

In children younger than 5 years, definitive diagnosis of asthma cannot be made.

Diagnosis is made on symptom pattern as described below.

A child is likely to be asthmatic if he/she has

 Wheeze or cough which is aggravated by exercise, laugh, crying in the absence of respiratory infection.

 History of allergies like allergic rhinitis, eczema or family history of asthma.

 Clinical improvement with a therapeutic trial of 2-3 months controller medication.

 Deterioration of clinical symptoms on withdrawal of the controller therapy¹¹.

13

ALGORITHM FOR DIAGNOSING ASTHMA IN CLINICAL PRACTICE AT PRESENTATION¹¹

Patient with symptoms typical of asthma?

History and examination support diagnosis of asthma

Perform spirometry/peak expiratory flow rate with reversibility testing

Support diagnosis of asthma?

Treatment for asthma NO YES

YES

NO

YES

NO

IN CASES OF CLINICAL URGENCY Empirical treatment with ICS, SABA

Check response

Diagnostic test in 1-3 months

Further tests for alternate diagnosis

Repeat tests and

arrange further testing.

if no alternate diagnosis-TRIAL OF TREATMENT AND REFERRAL

14 Diagnosis in low resource settings

GINA states that “In low resource settings, variable airflow limitation can be confirmed by peak expiratory flow rate before and after a therapeutic trial with as and when needed SABA and regular inhaled corticosteroids along with a week trial of oral steroids will help confirm the diagnosis of asthma before long term treatment is commenced.

The diagnosis is based on a symptom/syndrome-based approach¹¹. FOLLOW UP OF ASTHMATIC CHILDREN

Assessment of symptom control

 Asthma control questionnaire

 Childhood asthma control

 GINA classification of symptom control

 Test for Respiratory and asthma control in kids ¹¹.

15 Table 1: GINA classification of symptom control

RISK FACTORS RESPONSIBLE FOR EXACERBATIONS 1. Modifiable risk factors

2. Independent risk factors

3. Risk factors for fixed airflow limitation 4. Risk factors for medication side effects¹¹.

Asthma symptom control Yes/no

Level of symptom control

Well controlled

Partly controlled

uncontrolled

Day time symptoms more than twice a week?

None 1-2 of these

3-4 of these

Any night awakening due to asthma?

Reliever use>2/week?

Activity limitation due to asthma

16 Modifiable risk factors.

 Uncontrolled asthma symptoms

 High controller usage

 Inadequate preventer therapy (ICS)

 FEV1<60%Predicted

 Psychological issues

 Major socioeconomic problems

 Exposure to smoke,allergens if sensitized

 Comorbidities-obesity,confirmed food allergy,rhino sinusitis

 Sputum and blood eosinophilia

 Pregnancy¹¹.

Independent risk factors

 Intubation/PICU admission for asthma

 More than 1 severe exacerbation in past 1 year¹¹ For fixed airflow limitation

 Lack of inhaled corticosteroid use

 Exposure to tobacco smoke, occupational allergen exposure

 Local side effects are more with high dosages and high potent steroids

 Systemic side effects occur with frequent oral steroids, high dosages of ICS¹¹.

17

There is no definite time frame for evaluation and testing of the various side effects of the inhaled corticosteroids.

Categorization of asthma patients as having mild, moderate and severe asthma can be made after a period of regular controller treatment.

Mild asthma-well controlled with as and when needed salbutamol or low dose inhaled corticosteroids/leukotriene receptor antagonists.

Moderate asthma is when adequate control is achieved with low dose ICS/long acting beta agonist.

Severe asthma requires higher doses of ICS for control,without which it might become uncontrollable to treatment¹¹.

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ALGORITHM FOR CHILDREN WITH SEVERE ASTHMA BEFORE CONSIDERING STEP UP/REFERRAL¹¹

CHECK INHALER TECHNIQUE DISCUSS ADHERANCE

DIAGNOSIS OF ASTHMA TO BE CONFIRMED

REMOVE POTENTIAL RISK FACTORS

ASESSEMENT AND MANAGEMENT OF COMORBITIES

CONSIDER TREATMENT STEP UP

REFERRAL TO A SPECIALIST ASTHMA CLINIC

19

TREATMENT OF ASTHMA IN CHILDREN OLDER THAN 5 YEARS

Aims of treatment

1. Reduction of symptoms.

2. To prevent discomfort or hindrance to normal daily activities.

3. To decrease flare ups.

4. To prevent airway remodelling as a result of frequent flare ups.

5. Decrease medication side effects¹¹. Drugs used in treatment

1. Controller therapy 2. Reliever therapy

Despite slight variations in treatment protocols of various guidelines, all of them recommend initiation of controller (low dose inhaled

corticosteroid) at the earliest.

The major groups of anti inflammatory drugs used are inhaled corticosteroids and leukotriene receptor antagonist ³³.

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Table 2:Step wise asthma management in children older than 5 years

DRUGS STEP 1 STEP 2 STEP 3 STEP 4 STEP 5

Controller Low dose

ICS

Medium- high dose ICS

Medium-high dose

ICS/LABA

Refer (trial of biological agents)

Other controllers

Low dose ICS

Leukotriene receptor antagonist (LTRA)

Medium dose ICS Low dose ICS+

LTRA

Tiotropium High dose ICS+LTRA (Theophylline)

Reliever SABA sos SABA sos/low dose ICS/Formetrol

Almost all steps of management of asthma in children more than 5 year, require ICS use and long duration of treatment needed for symptom control and prevent flare up⁽¹¹⁾.

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Table 3:ICS-Dosage categorization for child>5 years of age¹¹.

The below table classifies the dosage of various ICS as low, medium and high dosage as per GINA guidelines.

Drug name

Daily dosing in microgram

Low Medium High

Beclomethasone dipropionate-

BDP (CFC) 100-200 >200-400 >400

BDP (HFA) 50-100 >100-200 >200

Budesonide 100-200 >200-400 >400 Budesonide (nebules) 250-500 >500-1000 >1000

Ciclesonide 80 80-160 >160

Fluticasone propionate (DPI) 100-200 200-400 >400 Fluticasone propionate (HFA) 100-200 200-500 >500

Mometasone furoate 110 >220-440 >440

Triamcinolone acetonide 400-800 >800-1200 >1200

22

Table 4:Step wise asthma management in children younger than 5 years¹¹

Before step up, physician must consider confirmation of diagnosis, ensure good adherence, proper technique and avoidance of allergen exposure.

Co morbities should also be addressed.

Upto 3 years of age, pressurized metered dose inhaler with spacer and facemask would be appropriate for drug delivery.

For children, 4-5 years of age, p MDI with spacer and mouthpiece should be used.

Drugs Step

1 Step2 Step3 Step 4

Preferred controller

Daily low dose ICS

Double low dose ICS

Continue controller and refer to

specialist Other

controller

LTRA Intermittent ICS

Low dose ICS+LTRA

Add LTRA Increase ICS frequency

Add intermittent ICS

Reliever As needed short acting beta agonist (all children)

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STEP UP AND STEP DOWN OF TREATMENT

Stepping up treatment

 Sustained step up

 Short term step up

 Day to day adjustment Sustained step up

After confirming diagnosis and checking inhaler technique, step up for a period of 2-3 months is done as a therapeutic trial with frequent reviews and continued in case of improvement. If not, further step up is planned after work up for alternate diagnosis.

Short term step up

This is done for a period of 1-2 weeks in occasions of viral illness, unavoidable allergen exposure.

Day to day adjustment

A combination of inhaled corticosteroids and long acting beta agonists (LABA) is adjusted as per symptoms while continuing maintenance dosage¹¹.

24 Stepping down of treatment

If asthma symptoms are well controlled for 3 months and lung functions plateau, step down is planned.

By stepping down treatment, the aim is to reach the minimum possible treatment dose, which will be effective and give good symptom control, minimize exacerbations and be cost effective with lowest side effects

During step down, symptom control and frequency of exacerbations are to be closely monitored. Any step down is a therapeutic trial and dosages are to be adjusted appropriately¹¹.

25

MANAGEMENT OF ACUTE EXACERABATIONS³⁷.

Figure 3 Management of asthma in Emergency room

The above picture depicts the management of moderate asthma and acute severe asthma in the emergency room. It also depicts the diagnosis of moderate and acute severe asthma based on pediatric assessment triangle.

26

Figure 4 Management of life threatening and near fatal asthma The above picture depicts management of life threatening and near fatal asthma in the emergency room. It also depicts the diagnosis of these entities based on pediatric assessment triangle.

27 CO MORBIDITIES IN ASTHMA

 Obesity

 Gastro esophageal reflux disease

 Anxiety

 Depression

 Food allergy

 Anaphylaxis

 Rhinitis, sinusitis, nasalpolyps ¹¹.

Comorbidities have to be promptly evaluated and treated to achieve good control of asthma and before planning stepping up of therapy.

INHALED CORTICOSTEROIDS IN ASTHMA

There are minor variations among the numerous guidelines for classification, assessment of severity and treatment of asthma in children, but all the guidelines stress on daily Inhaled corticosteroid treatment alone or in combination as the preferred modality of treatment of asthma.

Mechanism of action

1. Major anti inflammatory agent (genomic and non genomic mechanisms)

2. Prevent remodeling of the airways.

3. Reduces the hyper perfusion of the asthmatic airways.

28

4. Decreases permeability of bronchial vasculature, thereby decreasing plasma leakage into lumen causing obstruction.

5. Prevents delayed allergic response than the early response ³⁴.

Inhaled corticosteroids have a better safety profile compared to the oral steroids in view of reduced systemic absorption.

29

INHALED CORTICOSTEROIDS-PHARMACOKINETICS

Figure 5 Pharmacokinetics of inhaled corticosteroids

On inhaling the corticosteroid, most of it is deposited in the pharynx, leading to side effects like oropharyngeal candidiasis which can be decreased by advising the swish and spit technique.

If mouth is not well rinsed, drug is swallowed and absorbed. A portion of the drug, which is not removed by first pass metabolism in the liver, enters the systemic circulation from the gastrointestinal tract, which is responsible for systemic side effects.

30

A small amount of the ICS reaching the lungs is absorbed from the pulmonary vessels to reach the systemic circulation leading to systemic side effects³⁵.

Bioavailability of the inhaled corticosteroid depends on 1. Type of molecule

2. Dosage used

3. Route of administration

4. Pharmacological properties of the drug

With newer drug delivery systems in vogue, targeted delivery of ICS is possible. Still some amount of ICS can be absorbed into the systemic circulation causing side effects, doses at which this occurs is not clearly defined or proved¹³.

COMPARISON AMONG COMMONLY USED ICS IN ASTHMATIC CHILDREN

Budesonide and Beclomethasone propionate are equipotent in children as preventer therapy

When compared to Budesonide and Beclomethasone, Fluticasone propionate is twice as potent.

Fluticasone and the drug used in our study, Budesonide have a better safety profile than Beclomethasone, Triamcinolone and Flunisolide.

New generation ICS like Mometasone and Ciclesonide have excellent safety profile¹⁴.

31

SIDE EFFECTS OF INHALED CORTICOSTEROIDS¹²

The side effects of inhaled corticosteroids can be broadly classified as systemic side effects and local side effects

Systemic side effects

 HPA suppression

 Adrenal insufficiency

 Decreased bone mineral density

 Cataract

 Glaucoma Local side effects

 Dysphonia

 Pharyngitis

 Bronchospasm

 Reflex cough

 Oropharyngeal candidiasis

32

GLUCOCORTICOIDS AND GLYCAEMIC CONTROL Mechanism of dysglycemia

 Decreased insulin secretion(pancreatic beta cell dysfunction)

 Increased insulin resistance

 Decreased insulin sensitivity

 Increased neoglucogenesis and glycogenolysis¹³, depicted in the figure below.

Steroids also cause body fat redistribution. Leptin, Adiponectin from adipose tissue alters insulin signalling and causes insulin resistance, worsening dysglycemia¹³.

Figure 6 Corticosteroids and glucose metabolism

33

Glycosylated hemoglobin and fasting blood sugars are parameters used to assess glycemic status in this study.

HbA1c is a better parameter than FBS and PPBS because it is a correlate of glucose levels over the life span of an RBC approximately, 80-120 days¹⁶.

With various methods to detect glycosylated hemoglobin, values are accepted only if labs are NGSP –National glycosylated hemoglobin program certified and standardized to Diabetes control and complication trial assay¹⁶.

Before interpreting glycosylated hemoglobin reports causes of false high and low values must be excluded.

Causes of Falsely low HbA1c

 Hemolysis

 Hemoglobinopathies

 Hemorrhage

 Drugs

 Chronic liver disease False high HbA1c

 Iron deficiency

 Vitamin B12 Deficiency

 Alcoholism

 Uremia

 Hyperbilirubinemia

34

Drugs can cause falsely low or elevated glycosylated hemoglobin by affecting either glycation/hemoglobin/increased erythrocyte destruction

Falsely low values of HbA1C

 Dapsone

 Ribavirin

 Antiretroviral

 Trimethoprim-sulfamethoxazole

 Hydroxyurea

 Vitamin C

 Vitamin E

 Small doses of aspirin

Falsely high glycosylated hemoglobin

 Large doses of aspirin

 Long term opioid usage

35

GLUCOCORTICOIDS AND LIPID METABOLISM

Steroids induce lipolysis and cause increased triglycerides and free fatty acids in circulation, causing altered lipid profile

Steroids also cause body fat redistribution¹³.

Figure 7 Glucocorticoids and lipid metabolism

The above figure depicts the mechanism of alteration of lipid metabolism by glucocorticoids.

Glucocorticoids act on adipose tissue and liver. They up regulate Phosphoenylpyruvatecarboxykinase (PEPCK) in liver and down regulate in adipose tissue. This results in increases free fatty acids, resulting in insulin resistance and gluconeogenesis.

36

REVIEW OF LITERATURE

OyaYucel et al conducted a study for 1 year in Turkey to study the HbA1c levels in 141 children with asthma using low dose inhaled corticosteroids, either Budesonide or Fluticasone for at least 6 months.

According to this study, glycosylated hemoglobin levels in children with persistent asthma were significantly higher than in the control group (p=0.006). No significant correlation was found between the cumulative dose of ICS and glycosylated hemoglobin levels. The values did not vary with increasing duration of usage (p=0.96). They concluded that asthmatic children on low dose ICS have higher glycosylated hemoglobin values than healthy children⁸ This study used healthy children as controls, and not asthmatic children not on steroids, which is of concern because of reports of implication of the asthma disease process altering the glucose homeostasis ^17.

Bindusha et al in their 1 year study compared the alteration in glycaemic and lipid profile between children on high versus low dose ICS (Budesonide/Fluticasone) for a minimum duration of 6 months. This well structured study included 1 to 12 year old children with less than400 microgram/day for at least 6 months (n=83) and more than 400 microgram/day (n=112).In lieu with the other studies there was no significant difference in mean glycosylated hemoglobin among both the groups(p=0.305),mean fasting blood sugar(p=0.447) and mean fasting lipid profile. They concluded that, increasing the dose of inhaled steroids will not

37

alter the carbohydrate and lipid parameters in asthmatic children. As Budesonide/Fluticasone are the commonly prescribed steroids in various asthma clinics, the results of the study is widely applicable and is promising ²².

Ernst et al published a review of articles on the safety of the use of ICS in asthma, published in 2012. It states that ICS is a very effective and has good safety at lower dosages, that is usually prescribed for a majority of asthmatic children. Side effects like acquisition of tuberculosis, onset of diabetes mellitus and its progression may occur only with higher dosages.

There is no risk of asthmatic children unlike COPD patients in acquiring pneumonia with ICS use. The cumulative dose, duration and corresponding side effects are not well documented in this article, except stating that risk is high with higher doses of inhaled corticosteroids²³.

Harrison et al studied the effects of the two commonly used inhaled steroids, Fluticasone and Budesonide, in asthmatic and healthy subjects. On systemic absorption of these drugs based on systemic markers, namely urinary total cortisol metabolites after giving Budesonide (1600 microgram/day) and Fluticasone (1500microgram/day). They came to conclusion that fluticasone had greater effect on the hypothalamopituitary axis of healthy subjects, than with Budesonide¹⁷. So healthy children cannot be taken as controls and studies using a particular ICS cannot be extended to other inhaled corticosteroids as systemic absorption varies with each drug ¹⁷.

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The study by Donnelly et al. was conducted in Nottingham, due to paucity of studies on pharmacokinetics and systemic side effects of Budesonide following inhalation.15% of Budesonide reach lungs following use of a pMDI, higher (32%) with breath actuated dry powdered inhaler.

They concluded that area under the concentration time curve and peak plasma concentration are dose dependent and there is wide inter individual variation which an important limitation in conducting studies on dose effect on various systemic parameters in children on inhaled corticosteroids¹⁸.

Canis et al in their study suggested that there is a different pathogenesis between asthma and chronic obstructive pulmonary disease, which is the most important reason for difference in carbohydrate metabolism between asthma and COPD patients on ICS. Severity of baseline mucosal inflammation in asthma and COPD alters the effects of ICS apart from other parameters such as duration of treatment, dosage of ICS, age and BMI²⁸.

Davison et al. conducted a study on 12 children in a hospital in Australia and documented a significant difference in peak blood sugar levels following frequent high dose salbutamol nebulizations¹⁹.

Abdulla Janger et al studied the effect of inhaled Beclomethasone in low and moderate doses in asthmatic adult subjects. This study clearly demonstrates statistical difference in glycosylated hemoglobin and fasting blood sugar levels following a 3 month usage of

39

Beclomethasone.Beclomethasone has lesser water solubility and slower hepatic metabolism than Budesonide. Beclomethasone has more side effects than Budesonide. The major strength of the study was that they had baseline values of the patients which were compared with those after a 3 month ICS course²⁰.

Faul et al. conducted a randomized control trial on effect of ICS on glucose control in type 2 diabetes mellitus adults with asthma/COPD using Fluticasone and oral placebo/Inhaled placebo and monteleukast for a duration of 6 weeks. Neither of the two led to an increase in mean glycosylated hemoglobin compared to the initial values.

They did not recommend adjustment of ICS dosage for asthmatic diabetes patients when used at lower dosages. Though monitoring of blood sugar levels in DM patients initiated on ICS and appropriately managed diabetes mellitus when steroids are warranted at high dosages for asthma control. Major limitation of this study was a small sample size of only 12 children of whom only 10 completed the study. So extrapolation of the results to clinical practice will be less reliable²⁴.

In a similar study, Lakshmi Dey et al. conducted a study on 80 patients as 2 groups. The first group of 40 patients were asthmatic diabetes and second asthmatic non-diabetes. They studied effects of use of high dose inhaled corticosteroids (1600 microgram/day Budesonide or 1000 microgram/day Fluticasone) for duration of 1 month. Outcomes measured

40

were improvement or worsening of clinical features, blood sugar values, and lipid profile. There was no significant change in glucose and lipid profile following use of high dose ICS for a period of 1 month with a statistical significant improvement in lung function (p<0.001)²¹.

Yavuz et al. after a study of 11 asthmatic patients on high dose ICS clearly demonstrated no statistically significant change in serum fasting triglyceride levels (p>0.05) and a decrease in fasting cholesterol (p=0.03) and increase in HDL (p=0.01). They concluded that the use of high dose Budesonide for a long time in asthmatic patients may have minor effects on lipid metabolism. The duration of treatment was 1 month, of 1600 microgram/day of Budesonide, which is not applicable to the current scenario, where we do not usually use such high doses even in poorly controlled asthmatics. Multiple add on therapies are available to use before escalating steroid dosages to such high levels²⁶.

In contrary to above mentioned studies, Turpeinen et al demonstrated a significant rise in HDL-C by about 22% in children on high dose ICS (>400 microgram/m2) and when dose was lowered, HDL-C declined (p=0.0319)²⁵.

Kirvanta et al compared 15 asthmatic adults with healthy controls, treated with high dose Budesonide/Beclomethasone for 5 months, followed by low dose for 3 months. They compared the blood sugar, serum insulin, and plasma cortisol. The effect of high dose ICS in poorly controlled

41

asthmatic adult initially reduced the insulin resistance followed by increase in insulin sensitivity, which is beneficial. The results were contrary to what were published earlier²⁷.

Daniel et al. conducted a study on 170 asthmatic children, 3-12 years of age, on inhaled corticosteroids for a period of at least 6 months.

Parameters measured at baseline and after ICS use were, fasting blood sugar, post prandial blood sugar and glycosylated hemoglobin. There was a significant rise in mean glycosylated hemoglobin before (4.98%) and after (5.13%)ICS treatment for a minimum of 6 months (p<0.001). They concluded that use of higher dosages for longer periods could worsen mean HbA1c¹⁰.

Albano et al analyzed safety of ICS based on available literature.

ICS used in most of the studies were Budesonide, Beclomethasone and Fluticasone. According to this study there is no evidence on role of ICS in causing adrenal failure, though there may be HPA axis suppression.

Parameters to assess hypothalamopituitary axis suppression were by biochemical parameters that are highly sensitive. Though biochemical alterations have been reported in many studies, there is still a big lacuna in understanding their clinical relevance. Usage of high dose of ICS for a long duration necessitates monitoring for osteoporosis by measurement of calcium, phosphate, alkaline phosphatase, osteocalcin, urinary calcium, DEXA scan. Though there are no good quality trials to support or documented alteration in these parameters with the use of high dose ICS.

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Another important side effect analyzed is the detrimental effects of ICS on growth of the children. They concluded that usage of high dose of inhaled corticosteroids does not affect the growth velocity or the final stature of the child, though it has effects on short term growth.

Moreover growth seemed to be affected more by poor control of asthma than use of ICS.

With no well controlled trials available, they support use of lowest possible dosage to minimize side effects for the benefit of asthmatic children.

Local side effects depend on the technique of inhalation, spacer usage, duration and dosage of steroids used and drug characteristics. Common local adverse effects include, candidiasis, dysphonia, cough and contact allergy.

Very rare side effects include, psychosis, cataract and glaucoma. These side effects occurred with older age groups and not observed in children. No significant alteration in carbohydrate and lipid metabolism was observed with inhaled steroid use²⁹.

E.Hosny et al in their review, analyzed side effects of inhaled corticosteroids. They indicated the need for monitoring of blood sugar levels in diabetic children on inhaled corticosteroids. The analyses are extrapolated from adult studies, as pediatric studies on effect of ICS on carbohydrate metabolism are scant. Rare side effects include bruising and increased fragility of skin; hypertrichosis beginning as early as even 1 month after start of ICS use and decreases melanogenesis.

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There is decreased incidence of depression/psychoses in children on Budesonide contrary to analyses of Albano et al. Goodadherence, appropriate dosing and drug delivery devices and careful watch for side effects is the key to management of asthma³⁴.

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STUDY JUSTIFICATION

The incidence of asthma is increasing in all age groups, especially children. Inhaled corticosteroids are being extensively used as the mainstay of treatment of asthma as recommended by national and international guidelines.

There are a number of studies to evaluate the side effects of ICS.Majority of the studies are conducted on adult patients.

Studies evaluating effects of ICS on metabolism and in children are scant.

In view of paucity of studies and conflicting reports, this study was planned to evaluate the alterations in the glycaemic and lipid profile of asthmatic children on inhaled Budesonide in addition to salbutamol for a minimum of 6 months as compared to asthmatic children on inhaled salbutamol as and when needed alone.

Mixed reports on role of ICS in causing dysglycemia and altered lipid profile warrants large scale prospective studies.

45

AIMS AND OBJECTIVES

Primary aim

To compare the alterations in glycaemic (glycosylated hemoglobin and fasting blood sugar levels) and lipid profile (serum triglyceride, cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol levels) of asthmatic children using inhaled Budesonide in addition to inhaled Salbutamol as and when needed for a minimum of 6 months to that of the asthmatic children on inhaled Salbutamol as and when needed alone.

Secondary aim

To correlate the changes in fasting blood glucose, glycosylated hemoglobin and lipid profile parameters with the dose, duration of the inhaled Budesonide therapy and symptom control of asthma.

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METHODOLOGY

Study design: Case control study

Study place: OPD, Pediatric asthma clinic, Institute of Social Pediatrics, Government Stanley Medical College, Chennai-600001.

Study period : December 2016-September 2017.

Ethical clearance: Approved by Institutional Ethical Committee.

Sample size calculation

Based on a previous study⁸,by comparison of means

OpenEpi version 2 (comparison of two means) was used to calculate the sample size.

Sample size 119

Control case ratio used was 0.5 Case group-79 children

Control group -40 children Total -119 children

Power-80%

Confidence interval 95%

47 Inclusion Criteria

Case group

Children between five to twelve years of age diagnosed as per GINA guidelines and on inhaled Budesonide in addition to salbutamol as metered dose inhaler+/- spacer for at least past 6 months.

Control group

Children between five to twelve years of age diagnosed as asthma as per GINA guidelines whose symptoms are controlled by inhaled salbutamol as and when needed alone as metered dose inhaler +/- spacer.

Exclusion criteria

Children using systemic glucocorticoids Children with diabetes mellitus

Co existent pulmonary, cardiac, renal disease Children on aspirin therapy

Children with hemoglobinopathies

Child younger than 5 years and older than 12 years

Children who are not compliant to inhaled corticosteroids Children of parents who do not consent to the study

48 Compliance

Compliance was checked using a compliance chart issued to the parents of the children in asthma clinic and regularly reviewed by the physicians.

Children with good compliance were included in the study.

Inhaler technique

Inhaler technique was monitored during visit to the asthma clinic, Institute of Social Pediatrics before being included into the study

After informed consent was obtained, preformed questionnaire was filled.

Blood sampling

4ml of blood was drawn in the fasting state to measure the serum lipid profile, fasting blood glucose, glycosylated hemoglobin, serum triglycerides, total cholesterol, HDL-C and LDL-C levels.

Blood samples for glycosylated hemoglobin levels was collected in 2ml K3 EDTAvacutainer tubes (Yucca tubes, Yuccadiagnostics, India) Serum samples for fasting blood sugar and lipid profile was collected in 2ml vacutainer tubes with clot activator (Hem tube TM, MB Lab consumables, India)

49

Table 5:Method of estimation of glycaemic and lipid parameters³⁹.

Parameter Method

Glycosylated hemoglobin

High performance liquid chromatography

Fasting lipid profile Enzymatic/CHOD/POD Fasting blood sugar Hexokinase method

Table 6 : Reference values Table 6a: Fasting blood sugar³⁶.

Values Interpretation

<100 mg/dl Normal

100-125mg/dl Impaired fasting glucose

>126 mg/dl Diabetes mellitus (further testing needed to confirm)

50 Table 6b: Glycosylated hemoglobin^{36, 38}

Value Interpretation

>6.5% Diabetes

6.0-6.5% Pre diabetes

<6% Normal

Table 6c: Fasting lipid profile¹⁵

Parameter Acceptable Borderline high

High Total cholesterol <170mg/dl 170-199

mg/dl

>200 mg/dl

LDL-C <110 mg/dl 110-129

mg/dl

>130 mg/dl Triglyceride 0-9

years

<75mg/dl 75-99 mg/dl >100 mg/dl 10-

19 years

<90 mg/dl 90-129 mg/dl >130 mg/dl

Parameter Acceptable Borderline

low

Low

HDL-C >45 mg/dl 40-45 mg/dl <40 mg/dl

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Inhaled corticosteroid used in the study was pressurized metered dosed inhaler Budesonide, 200 microgram/puff and Asthalin (Salbutamol) CFC free, Cipla Pvt Ltd. Both the drugs were procured by hospital pharmacy by Tamil Nadu Government Supplies.

Table 7:Classification of cases based on ICS (Budesonide) dosage¹¹.

CLASSIFICATION OF CASES BASED ON SYMPTOM CONTROL GINA assessment of symptom control was used to assess asthma 4 questions will be asked

 Daytime symptoms more than twice a week?

 Any night awakening due to asthma?

 Reliever use>2/week?

 Activity limitation due to asthma?

If none of the above is present, it is well controlled asthma If 1-2 of the above is present, it is partly controlled asthma If 3-4 of the above symptoms are present, uncontrolled asthma¹¹.

Daily Dosage of Budesonide

Classification

<200 microgram Low dose

200- 400 microgram Medium dose

>400 microgram High dose

52 ALGORITHM OF METHODOLOGY

Ethical clearance

Consent and enrollment

History and examination, questionnaire filling

Sampling for glycaemic and lipid profile and analysis

Data collection, entry, tabulation Hypothesis, Evidence collection, protocols

Statistical analysis

Conclusion

53

OBSERVATION AND RESULTS

STATISTICAL ANALYSIS

The collected data were analysed with IBM.SPSS statistics software 23.0 Version. To describe about the data descriptive statistics frequency analysis, percentage analysis were used for categorical variables and the mean & S.D were used for continuous variables. To find the significant difference between the bivariate samples in Independent groups the Unpaired sample t-test was used. For the multivariate analysis the one way ANOVA with Tukey's Post-Hoc test was used. To find the influence factors of the cases the Logistics regression model was used with backward stepwise (Wald) method. To find the significance in categorical data Chi- Square test and Fisher's Exact was used. In all the above statistical tools the probability value .05 is considered as significant level.

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Table 8: Baseline characteristics of the case and control group

The age,sex and family history of allergy and asthma is comparable in both the case and control groups as depicted in table above.

Characteristic

Case (n=79)

Control (n=40)

P

Age (years)

5-6 28(35.4%) 14(35%)

0.853 7-9 35(44.3%) 18(45%)

10-12 16(20.3%) 8(20%)

Sex

Male 38(48.2%) 20(50%)

0.845 Female 41(51.8%) 20(50%)

Family history of

asthma/allergy

Yes 54(68.4%) 21(52.5%)

0.091 No 25(31.6%) 19(47.5%)

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Table 9: Comparison of mean age and BMI among cases and controls

The mean age of the asthmatic children on inhaled Budesonide with inhaled salbutamol as and when needed is 7.47 years (1.92) which is comparable to asthmatic children on on as and when needed salbutamol alone which is 7.40 years (1.851),p=0.853.

The mean BMI of the asthmatic children on inhaled Budesonide with inhaled salbutamol as and when needed is 15.51 Kg/m2 (0.909) which is comparable to asthmatic children on as and when needed salbutamol alone which is 15.55 Kg/m2 (0.753),p=0.789.

The Body mass index (BMI) of all children are within normal limits for age as per the revised IAP charts

Parameter Groups N Mean SD p

Age(years)

Cases 79 7.47 1.920

0.85

Controls 40 7.40 1.851

BMI(kg/m2)

Cases 79 15.51 0.909

0.78 controls 40 15.55 0.753

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Table 10: Comparison of glycaemic and lipid profile parameters among cases and controls

The mean of serum triglyceride levels in children on inhaled budesonide in addition to as needed inhaled Salbutamol, 91.94 mg/dl (9.13) is higher as compared to children on only as and when needed salbutamol, 88.53 mg/dl (8.237), which is statistically significant, p=0.049

Parameter Groups N Mean SD P

Fasting blood sugar(mg/dl)

Cases 79 86.94 11.68

0.215 Controls 40 84.18 10.82

Glycosylated hemoglobin(%)

Cases 79 5.44 0.44

0.751

Controls 40 5.47 0.41

Serum

Triglyceride(mg/dl)

Cases 79 91.94 9.13

0.049 Controls 40 88.53 8.23

Total

Cholesterol(mg/dl)

Cases 79 137.51 17.91

0.340 Controls 40 134.08 19.51

HDL-C(mg/dl)

Cases 79 49.31 6.27

0.318 Controls 40 50.49 5.63

LDL-C(mg/dl)

Cases 79 69.90 18.12

0.260 Controls 40 65.84 19.16

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There is no difference in the mean glycosylated hemoglobin of the case group 5.44%(0.44) compared to the control group 5.47(0.41),p=0.751,mean fasting blood sugar, of the case group 86.94 mg/dl(11.68) compared to the control group 84.18(10.82), p=0.215, mean HDL-C, of the case group 49.31mg/dl (6.27) compared to the control group 50.49mg/dl (5.63), p=0.318, mean LDL-C of the case group 69.90 mg/dl (18.12) compared to the control group 65.84 mg/dl(19.16) ,p=0.260 and mean total cholesterol levels of the case group 137.51mg/dl (17.91) compared to the control group 134.08mg/dl(19.51),p=0.340.

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Derangement in glycosylated hemoglobin levels among cases and controls

Figure 8 Derangements in HbA1c

Of the 79 cases and 40 controls, no child has a HbA1C of >6.5%, which is considered as diabetic range.

Of the cases (n=79), 19% children have glycosylated hemoglobin of pre diabetes range compared to 15% among the controls (n=40).

Derangement in fasting blood sugar levels among cases and controls All cases and controls have fasting blood sugar within the normal range (60-100 mg/dl).

No cases or controls have impaired fasting glucose/diabetic range/hypoglycemia.

0%

20%

40%

60%

80%

100%

Controls Cases

HBA1C

<6% 6-6.5%

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Table 11: Pre diabetes Vs. Acceptable glycosylated hemoglobin levels among cases and controls

Of the 40 asthmatic children on as and when needed inhaled salbutamol, 6 have glycosylated hemoglobin in the high risk range (6-6.5%) as compared to 15 of the 79 asthmatic children on inhaled Budesonide in addition to as and when needed salbutamol.

The difference between the two groups of children not being significant, p=0.590.

Parameter Levels

Controls (N=40)

n(%)

Cases (N=79)

n(%)

p

Glycosylated hemoglobin

Acceptable (n=98)

34(85) 64(81) 0.590

Pre diabetes (n=21)

6(15) 15(19)

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Table 12: Borderline vs. acceptable lipid profile parameters among cases and controls

Of the 40 asthmatic children on as and when needed inhaled salbutamol, 7.5% have borderline low HDL-C as compared to 22.8% of asthmatic children on inhaled Budesonide in addition to as and when needed salbutamol. The difference between the two groups of children is significant, p=0.044.

Parameter Level

Controls (n=40)

n(%)

Cases (n=79)

n(%)

p

HDL-C

Acceptable 37(92.5) 61(77.2)

0.044 Borderline

low 3(7.5) 18(22.8)

Serum triglyceride

Acceptable 8(20) 14(17.7)

0.805 Borderline

high 32(80) 65(82.3)

Total cholesterol

Acceptable 37(92.5) 74(93.7)

1.000 Borderline

high 3(7.5) 5(6.3)

LDL-C

Acceptable 39(97.5) 75(94.9)

0.662 Borderline

high 1(2.5) 4(5.1)

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Among the asthmatic children on inhaled Budesonide in addition to as and when needed salbutamol 82.3% have borderline high serum triglyceride, 6.3% have borderline high total cholesterol and 5.1% borderline high LDL-C, as compared to 80%, 7.5% and 2.5% asthmatic children with borderline high serum triglyceride, total cholesterol and LDL-C respectively.

There is no statistically significant alteration between cases and controls with acceptable and borderline high values of LDL-C (p=0.622), serum cholesterol (p=1.00) and serum triglyceride (p=0.805).

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Table 13:Multivariate logistic regression analyses of children with borderline risk and acceptable glycaemic and lipid parameters.

The risk of having borderline high LDL-C is 6.4 times more in asthmatic children on inhaled Budesonide as compared to children on inhaled Salbutamol as and when needed alone.

The risk of having borderline low HDL-C is 3.6 times more in asthmatic children on inhaled Budesonide as compared to children on inhaled Salbutamol as and when needed alone.

As shown in table above there is no statistically significant risk of asthmatic children on inhaled Budesonide in addition to salbutamol as and when needed to have elevated (borderline high) values of FBS, HbA1C, Serum triglyceride, cholesterol,as Compared to asthmatic children on as and when needed salbutamol alone.

Parameter p OR Confidence interval

(95%) Glycosylated

hemoglobin 0.737 1.205 0.405-3.590

Total

cholesterol 0.334 0.291 0.024-3.556

Serum

triglyceride 0.894 1.076 0.364-3.185

HDL-C 0.059 3.635 0.951-13.891

LDL-C 0.268 6.410 0.239-171.727

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Figure 9 Distribution of cases based on dosage of inhaled Budesonide

The above pie chart depicts the distribution of asthmatic children on inhaled Budesonide in addition to as and when needed inhaled Salbutamol based on dosage of Inhaled budesonide used.

Of the 79 children, 37children (47%) are on low dose inhaled budesonide, 37children(47%) on medium dosage and 5 children ( 6%) in the high dosage category.

47%

47%

6%

Dose of Budesonide

Low Medium High