11 Monograph Pages

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A Research Project of

CENTRAL COUNCIL FOR RESEARCH IN YOGA & NATUROPATHY

(Deptt. of AYUSH, Ministry of Health & F. W., Government of India)

61-65, Institutional Area, Janakpuri, New Delhi - 110058 (India)

A Randomized ControlledTrial on the Efficacy of Yoga in

the Management of Bronchial Asthma


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Editor-in-Chief :Prof. Dr. B.T.Chidananda MurthyDirector

Published by :

CENTRAL COUNCIL FOR RESEARCH IN YOGA & NATUROPATHY

(Deptt. of AYUSH, Ministry of Health & F. W., Government of India)

61-65, Institutional Area, Janakpuri, New Delhi - 110058 (India)

Website : www.ccryn.org Email : [email protected]

Phone : 011-2852 0430, 31, 32 Fax : 011-2852 0435

Central Council for Research in Yoga & Naturopathy

Compiled by :

Dr. Rajiv RastogiAsstt. Director (Naturopathy)

Dr. H.S. Vadiraj B.N.Y.S, Ph.D.

Consultant (N & Y)

First Edition : 1000 copies, 2010

Produced by :

MAX PRINT SHOP

A-110, VIKAS TOWER,

VIKASPURI, NEW DELHI-18

PHONE-9971171799


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FOREWORD

Lo kLF; l sok egkfuns kky ;fu e kZ. k ou ] u bZfn Yy h & 110108

Hkkj r l j d kj

GOVERNMENT OF INDIA

DIRECTORATE GENERAL OF HEALTH SERVICES

Nirman Bhawan, New Delhi - 110108

Tel. No.: 91-11-23061438, 23061063

Fax No.: 91-11-23061924

E-mail: [email protected]

The 11th Research Monograph developed by the Central Council for Research in Yoga &Naturopathy (CCRYN) based on the research findings of research project A RandomizedControlled Trial on the Efficacy of Yoga in the Management of Bronchial Asthma underlinesthe effectiveness of Yoga before the scientific brethren.

Bronchial asthma is a global concern in asthma epidemiology and clinical spectrum. Anapparent increase has shown in several geographic areas of the world. The condition of Indiais also not very upbeat where more than 15 million people suffered from this disease.However, Yoga can play a vital role in this direction.

The beneficial effects of yoga in bronchial asthma are not difficult to understand. Yogicpractices bring about improvement in pulmonary functions. Yoga improves quality of life andreduces need for medication in bronchial asthma more effectively than conventionaltreatment alone.

The finding of this research project will be useful for common people and landmark for the

medical fraternity of various disciplines.

I accolade the Director, CCRYN for publishing this important monograph.

I wish the Council all the very best.

Dr. R.K. SRIVASTAVA

M.S. (Ortho) D.N.B. (PMR)

Director-General

(Dr. R.K. SRIVASTAVA)


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PREFACE

(Prof. Dr. B.T.Chidananda Murthy)

Director(vi)

Bronchial Asthma is a common chronic inflammatory disease of the airways characterized by variable

and recurring symptoms, airflow obstruction, and bronchospasm. Signs of an asthmatic episode

include wheezing, prolonged expiration, a rapid heart rate (tachycardia), and rhonchous lung sounds.

Symptoms are often worse at night or in the early morning, or in response to exercise or cold air.During severe attacks, an asthma sufferer can turn blue from lack of oxygen and can experience chest

pain or even loss of consciousness. It causes 2.5 lakhs deaths per year worldwide. Public attention in

the developed world has increased but the developing hemisphere is still lagging behind.

Yoga can make a substantial contribution to the treatment of Bronchial Asthma. It is observed that in

chronic airway obstruction, yogic breathing exercises brought about increase in pulmonary functions

and exercise capacity. An integrated Yogic intervention decrease in heart rate, sympathetic reactivity

and an increase in peak inspiratory flow, breath holding time (BHT) and chest expansion. Among the

well known triggers which precipate attacks of bronchial asthma are infections and mental stress? By

enhancing immunity, yoga can reduce the frequency of infections and mental stress, which generallyconsider the main triggers for it

Yogic exercises like the poses, Yoga breathing and relaxation techniques control the mind and

emotions, making the body more relaxed and thus breathe easier. A comprehensive package of these

modalities integrated in a form of yoga based lifestyle management program produce better results for

diseases related to psychosomatic in origin including asthma. Yoga improves quality of life and

reduces need for medication in bronchial asthma more effectively than conventional treatment alone.

To reduce the frequency of bronchial asthma through Yoga , the Central Council for Research in Yoga

& Naturopathy (CCRYN) conducted a study on A Randomized Controlled Trial on the Efficacy of

Yoga in the Management of Bronchial Asthma at Deptt. of Physiology, All India Institute of Medical

Sciences, New Delhi. The important findings of the study have been incorporated in the monograph.

thIt is the 11 Research Monograph in series of research publications of research findings. The earlier

Ten research publications were accepted and appreciated by the Medical fraternity, Yoga and

Naturopathy practitioners, which promoted the Council to reprint them.

Few studies are available on the efficacy of yoga in bronchial asthma and well-controlled randomized

trials are still fewer. None of the previous studies has investigated the possible immunological

mechanisms through which yoga may influence bronchial asthma. Finally, very few of the previous

studies have looked at yoga as comprehensive change in lifestyle: most of them have confined the

practice of yoga to a few asanas or breathing exercises. The present study seeks to overcome these

limitations.


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Prof. Dr. K.K. Deepak is Professor of Physiology at All India Institute of Medical Sciences,

New Delhi, India. He has contributed significantly to research and development (R&D) in

autonomic nervous system, its quantification and modification through non-

pharmacological means. Dr. Deepak established a Clinical Autonomic Function Lab in

1989 in his Department, which provides facility for autonomic functions testing varioushealth and disease conditions. He also established a Lifestyle Health Clinic in the

Department of Physiology at B.P. Koirala Institute of Health Sciences, Dharan, Nepal in

the year 1998, which offers therapeutic interventions to the patients based on the

principles of Indian Traditional Yoga.

His scientific approach is based on non-invasive assessment of physiological signal and

attempts to extract information on brain mechanisms from peripheral signals. His

emphasis is on applying a reductionistic approach towards the in-depth analysis of

physiological signals.

Prof. K. K. Deepak has published 35 full-length refereed articles published in indexed

journal, also written 9 chapters in the books, 70 abstracts published in indexed journals,

and more than 40 scientific communications published. One of his papers has been cited

in BRAIN AND MIND BULLETIN OF BREAKTHROUGHS, LA, California, USA and which was

published in BIOFEEDBACK AND SELF REGULATION on Meditation and epilepsy. His

commendable contribution at international level during recent years is writing a

complete chapter on Meditation in a popular and widely circulated book on

Complementary and Alternative Therapies for Epilepsy- New York (2004).

Dr. Deepak believes and practices the philosophy of 'working together' thus, his group has

wide collaborations with several clinical departments for exploring basic mechanisms of

autonomic dysregulation. He has been working on various aspects of physiological

interventions such as Yoga, Meditation and Biofeedback for the past two decades. His

work on Meditation as an interventional strategy in drug resistant epilepsy has been

widely acclaimed.

(viii)


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CONTENTS

vForeword............................................................................................................i

Preface................................................................................................................vi

Project Profile...................................................................................................x ii

Abbreviations...................................................................................................xiv

Introduction.........................................................................................................1

Material & Methods............................................................................................3

Data Analysis & Statistics.................................................................................20

Results...............................................................................................................23

Discussion.........................................................................................................44

Conclusion.........................................................................................................63

Bibiliography.....................................................................................................64

4Abstract..............................................................................................................7

1.

2.

S.No. Page No.

3.

4.

5.

6.

7.

8.

9.

10.

(x)

11.

12.


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PROJECT PROFILE

1. Title of Project:

2. Research Centre:

3. Principal Investigator:

4. Co-Investigator:

5. Period:

6. Reviewed by:

A Randomized Controlled Trial on the Efficacyof Yoga in the Management of BronchialAsthma

Deptt. of Physiology,All India Institute of Medical Sciences,New Delhi

Dr. K.K. Deepak,Professor,Deptt. of Physiology,

All India Institute of Medical Sciences,New Delhi

Dr. Randeep Guleria,Professor,Department of Medicine,All India Institute of Medical Sciences,New Delhi

4 year (2002 to 2006)

I) Dr. Shibdas Chakrabarti,Sr. Chest Specialist,D/o Respiratory Medicine,Safdarjung Hospital, New Delhi

ii) Prof. M. Lal,Director, Mahaprabhu Yog Divya Mandir,Institutional Area, R. K. Puram, Sector-6,New Delhi

iii) Prof. Asha Gandhi,Head,D/o Physiology,Lady Harding Medical College,

New Delhi

(xii)


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PEFR - Peak Expiratory Flow Rate

FEV - Forced Expiratory Volume in 1 second

BHT - Breath Holding Time

FVC - Forced Vital Capacity

VC - Vital Capacity

PEF - Peak Expiratory Flow

ECP - Eosinophilic Cationic Protein

EIB - Exercise Induced Bronchoconstriction

AQLQ - Asthma Quality of Life Questionnaire

OD - Optical Density

IQR - Inter Quartile Range

ES - Exercise Sensitive

ER - Exercise Resistant

MID - Minimal Important Difference

-BMI Body Mass Index

GLM - Generalized Linear Model

BLI - Bronchial Liability Index

VIP - Vasoactive Intestinal Polypeptide

CRH - Cortricotropin Releasing Hormone

ABBREVIATIONS

(xiv)


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Bronchial asthma is a common disease, to the treatment of which yoga can make a

substantial contribution. A few scientific studies are now available which support the role

of yoga in the management of bronchial asthma. Most of the studies have reported

subjective improvement along with improvement in some objective parameters like PEFR

and FEV An important study using both patients and controls was carried out on 53 subjects1.

for a period of 30 months and it was found that there was an improvement in weekly

number of attacks, scores of drug treatment, subjective well being and PEFR (Nagarathna

and Nagendra 1985). In a still larger trial by the same investigators involving 570 patients

given an integrated course on yoga and followed up for 3-54 months, it was found that PEFR

moved towards normal and 72%, 69% and 66% of patients could stop or reduce parenteral,

oral and steroid medication respectively (Nagendra and Nagarathna 1986). Further, in an

effort to see the effects of pranayamic breathing only, Singh (1987) conducted a study on 12

asthmatics by using pink city lung exerciser and found an increase in PEFR. But a

subsequent study by Singh et al (1991) using a placebo controlled double-blind cross over

design revealed that pranayamic type of breathing using pink city lung exerciser brings

about a significant reduction in airway reactivity but no change in PEFR, FEV symptom1,

score and inhaler use. Similarly, Tandon (1978) observed that in chronic airway obstruction,

yogic breathing exercises brought about increased exercise tolerance without any

improvement in pulmonary function.

Studies have also been conducted in adolescents with childhood asthma. In 46 young

asthmatics with childhood asthma given integrated yoga therapy, it was found that there

was an increase in pulmonary functions and exercise capacity. When the subjects were

followed up for up to 2 years, there was a reduction in symptom score and drug

requirement (Jain et al 1991). In another study, improvement in exercise tolerance was

found in 466 indoor adult asthmatic patients given an integrated yoga therapy program

with better lung functions and symptom scores (Jain and Talukdar 1993).

Findings of the Research Project

INTRODUCTION


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In a recent study, Khanam et al (1996) gave an integrated Yogic intervention to 9 asthmatics

for 7 days and found that there was significant decrease in heart rate, sympathetic

reactivity and an increase in peak inspiratory flow, breath holding time (BHT) and chest

expansion. At the same time, there was no change in other pulmonary functions like FEV1,

FVC and PEFR and parasympathetic activity. Another study involving both controls and

patients given integrated yoga therapy did not find any improvement in pulmonary

functions and drug requirements though there was improvement in subjective parameters

(Vedanthan et al 1998).

The beneficial effects of yoga in bronchial asthma are not difficult to understand. Yogic

practices bring about improvement in pulmonary functions. Nayar and his associates (1975)

observed that Yogic practices bring about an increase in VC, BHT and FVC. A 10-week course

in Pranayama and Yogasanas resulted in a reduction in resting respiratory rate and an

increase in VC, FEV BHT and maximum voluntary ventilation (MVV) (Makwana et al 1988).1,

Later on Joshi et al (1992) observed similar effects with a 6-week course in Pranayama. A

12-week course involving asanas for 30 minutes/day led to an increase in BHT and

maximum inspiratory and expiratory pressures (Madanmohan et al 1992). Among the well

known triggers which precipate attacks of bronchial asthma are infections and mental

stress. By enhancing immunity, yoga can reduce the frequency of infections. This may be at

least partly due to mental relaxation, which has an immunoenhancing effect through

psychoneuroimmunological mechanisms (Walker et al, 1993). Further, asthma being

basically a disorder characterized by deranged immunity, improved immunocompetence

may get at the root of the disease. Thus there is a strong logic behind the beneficial effects

of yoga in bronchial asthma.

Very few studies are available on the efficacy of yoga in bronchial asthma. Further, well-controlled randomized trials are still fewer. Moreover, none of the previous studies has

investigated the possible immunological mechanisms through which yoga may influence

bronchial asthma. Further, the previous studies have not investigated the effects of yoga

on integrated cardiorespiratory parameters of exercise. Finally, very few of the previous

studies have looked at yoga as comprehensive change in lifestyle: most of them have

confined the practice of yoga to a few asanas or breathing exercises. This study seeks to

overcome these limitations.


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Objectives

To investigate the efficacy of yoga in bronchial asthma through a randomized controlled

trial as assessed by -

1. Pulmonary function tests.

2. Selected biochemical and immunological indicators known to be indicators of mast

cell activation and the course of the disease.

3. Health related quality of life.

Material & Methods

Subjects

Sixty patients (n=60), who were both eligible and willing to participate in the study, were

recruited through local newspaper advertisements, posters in the institute and the

community at large, and by referral from the consultants in Medical OPD of the institute.

There was an initial screening procedure for all the potential participants to assess thedegree of reversibility of airway obstruction in response to bronchodilator. The reversal was

considered significant if there was10% increase or200-mL absolute increase in FEV 15

minutes after the administration of 2 puffs of a short-acting B -agonist, salbutamol2

(Quanjer et al., 1993a). Only those patients who had significant reversal were considered

potential patients.

1


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Objective :

PEF or FEV1 80% of predicted values

A > 10% increase in FEV1 in response to short-acting inhaled beta2-agonist

Mild Persistent Asthma

Clinical :

Symptoms > 2 times a week but < 1 time a day

Nocturnal Symptoms > 2 times a month

Exacerbations may affect activity

Objective :

PEF or FEV180% of predicted values

A12% FEV1 response to short-acting inhaled B -agonist2

Moderate Persistent Asthma

Clinical :

Daily symptoms

Nocturnal Symptoms > 1 time a week

Exacerbations 2 times a week; may last days and affect activity

Daily use of inhaled short-acting B -agonist2

Objective :

PEF or FEV1 60-80% of predicted values

FEV1/FVC 50-65% absolute values

A > 15% FEV1 response to short acting inhaled B -agonist2


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Patients having at least two clinical criteria and one objective criterion were included in

the study. Although there is a strict criterion for classification of asthma severity, it is

applicable only before starting any treatment, but in this study all the patients had already

continuing with conventional treatment, therefore the classification was mainly based on

their clinical features with only one objective criteria from the above listed.

Exclusion Criteria

Participants were excluded if they had any respiratory tract infection during the past 4

week, were on systemic or oral corticosteroid therapy, were smokers (anyone who had

smoked during the last one year was considered a smoker), had any other associated major

illness such as coronary heart disease, renal disease or diabetes, or had an unstable

medical condition, or had done yoga practice during 6 months preceding the study and who

can not attend yoga course for any reason.

Selection of subjects

All patients by either referral or direct approach were screened initially to assess thedegree of reversibility of airway obstruction in response to short acting inhaled B -agonistbronchodilator along with the relevant clinical history. Once the diagnosis is confirmed inaccord with American Thorasic Society guidelines (American Thorasic Society, 1987).Patients who had significant reversal ( 10% increase or 200-mL absolute increase inFEV ) were further classified into mild, moderate and severe asthma based on the criteriamentioned elsewhere (NHLBI, 1995; Antonicelli et al., 2004). Patients having at least twoclinical criteria and one objective criterion of mild to moderate cases were finallyincluded in the study.


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Ethical Clearance

The ethics committee of All India Institute of Medical Sciences (AIIMS) for human studies

approved the protocol of the study. The patients were informed about the aims and

methods of the study, expected duration of their participation, the benefits that might

reasonably be expected from the outcome of research to the subject or to others, and

potential risks to the subject associated with the study. Participants were also assured

about the maintenance of confidentiality of records, provision of free treatment for

research at anytime without penalty or loss of benefits to which the subject would

otherwise be entitled. The participants gave their written informed consent before being

enlisted for the study.

Research Design

The present study has attempted to understand the efficacy of an integrated

comprehensive lifestyle modification program based on principles of yoga at an outpatient

clinic by a randomized controlled trial on patients having bronchial asthma. This study also

confirms the add on study design, in which both groups have been receiving conventional

treatment, but yoga group received yogic intervention in addition to the regularconventional treatment. After making sure that the patients met the selection criteria,

eligible participants were randomly divided into either Group I (yoga) or Group II (wait-

listed control).

After recording the baseline parameters, Group I was given an integrated course on

lifestyle based on the principles of yoga for 2 weeks while continuing with the conventional

treatment. At the end of the 2-wk training, participants were asked to continue the

practice at home for an additional 6 weeks during which parameters were recorded at

regular intervals. During the follow-up period, the patients were expected to continue the

yoga practice daily. Their compliance was monitored by a diary, which they brought at

each visit.


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Group II was a wait-listed control group. For the first 8 weeks, the patients in Group II did

not receive any yogic intervention but they continued to receive conventional treatment.

The parameters were recorded at regular intervals as in Group I. At the end of 8 weeks, the

patients in Group II were also offered yoga intervention as for Group I, i.e. a two-week

course. Parameters from both the groups were recorded at regular intervals at 2 wk, 4 wkand 8 wk, although the last time point for recording parameters was not equally separated,

taking our patients convenience and continued compliance into consideration, we have

kept 4 wk separation for last study visit as indicated in Fig.1 given below. During each study

visit two activities were performed, i.e. recording of parameters and individual yoga

practice session. Individual yoga practice session was to reinforce patients practice during

their follow-up period. In yoga group, the first 2 wk all the patients were given a supervised

yoga practice including other associated components such as theory sessions on yoga,

meditation, stress management, fundaments on nutrition, and health education. Details

of the course are given in Table 1.

For the purposes of data collection for the study, the trial was over at 8 wk. The yoga

course was offered to the control group at 8 wk because it would be unethical to deny a

useful intervention to the control group. However, we could not collect the data after 8 wk

of study period from either group.

Yogic intervention

+

Conventional Treatment

Conventional Treatment

Randomization

Group I

Group II

Measurements at

0, 2, 4, and 8 wk

0 2 4 6 8

Time (wk)

Experimental Design: In-group I (n=30), initial 2 wk yogic intervention course followed by

6 wk of follow-up period whereas in-group II (n=30), the first 8 wk was study period with

regular conventional treatment followed by 2 wk yoga course offered to all the patients in

that group. Arrows indicate parameters recording points at 0, 2, 4 and 8 wk.

Fig.1


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Sample size calculation

Sample size was calculated as the minimum number of patients in each group by taking into

consideration the most important variable (FEV1) based on the results obtained in previousstudies (Jain et al., 1991) and by using an online software (Uitenbroek, 1997) for 80% power

at a 2-tailed =.05 to detect a significant difference in FEV values at the end of the study1

period in yoga group.

Randomization

In an intervention trial, randomization refers to the use of a probability device to assign

patients to a particular treatment. Randomization improves the chances of the studygroups being comparable. This allows us to use statistical methods to make valid

statements about the difference between treatments for this set of subjects. Standard

software was used (Epistat DOS version, Epistat Services, TX, USA) to generate the random

assignment numbers. Based on a randomization table potential eligible participants were

allocated/assigned to either the yoga group (Group I) or a wait-listed control group (Group

II).

Yogic intervention

Patients assigned to the yoga group underwent a comprehensive yogic intervention. The

yogic intervention was mainly included yoga practices and related components such as

stress management program for about 3-4 hours a day for 2 weeks. The program consisted

of lectures and practical sessions on asanas (physical postures), pranayama (breathing

techniques),kriyas (cleansing techniques), meditation and shavasan (relaxation

techniques). The lectures were on yoga, its place in daily life, its application to stress

management, fundamentals of nutrition, and health education relevant to their illness.Each participant also had at least one session of individualized counseling. The protocol of

the course is given in Table 5, and the set of yoga practices included in the course in Table 2.


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The physical practices consisted of preliminary breathing exercises and loosening

exercises followed by asanas under four categories (standing, sitting, prone and supine),

paranayama techniques, kriyas and meditation based on raja yoga. Participants were

instructed to follow a specific breathing pattern during each asana and asked to hold each

pose in the final position for up to 30 sec without holding their breath. Soothing

instrumental music was played while the participants were practicing the yoga techniques

to induce relaxation. Participants practiced yoga with awareness focused on their physical

movements and breath. Each strenuous posture was followed by an appropriate relaxation

posture for a short period. The class concluded with deep relaxation for about 15 minutes

as a pre-requisite for guided imagery. Participants were provided printed material and

audio cassettes to supplement live instructions.

The diet recommended was predominantly vegetarian, consisting of a combination of

cereals and pulses, preferably unrefined, as the staple food; moderate amounts of

judiciously chosen fat; about 500g of vegetables and fruits daily, vegetables predominantly

of the leafy green variety and at least some eaten raw; moderate amounts of milk and milk

products; and spices in moderation (Bijlani, 2003). The patients are also explained why it is

not advisable to take tea, coffee, alcohol, and other similar products. Further, theknowledge of nutrition is integrated with Yoga. It is made clear that specific inclusion or

exclusion of certain items of the diet does not make a diet yogic. A diet becomes yogic

when food is looked upon as sustenance rather than as a source of sensory pleasure. A

detached attitude towards sensory pleasures is both a part of the pursuit of yoga and its

consequence. The patients are explained how simple food which is good for the body can

also be relished, and they are helped in overcoming their previous conditioning about

regarding only certain foods such as sweets, fried foods, or meat as worthy of enjoying.

Individualized advice session with a doctor for individualized advice, especially about diet,

physical activity and behavior modification. During these sessions, the patients also find

the doctor to be a patient listener with whom he can in confidence share personal

problems. Some counseling is also provided for these problems based on yogic psychology.


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Control group intervention

Participants assigned to the wait-listed control group received only conventional

intervention. They were also encouraged to do any kind of exercise like walking or jogging

other than yoga during the study period of 8 weeks. After that, they were offered the same

yoga course as the experimental group.

The conventional intervention is an established treatment used to prevent and control

asthma symptoms, reduce the frequency and severity of asthma exacerbations, and

reverse airflow obstruction. Asthma medications are thus categorized into two general

classes: long-term-control medications taken daily on a long-term basis to achieve and

maintain control of persistent asthma (these medications are also known as long-term

preventive, controller, or maintenance medications) and quick-relief of accompanying

bronchoconstriction (these medications are also known as reliever or acute rescue

medications).

Long-term-control medications are those that attenuate inflammation, which included

anti-inflammatory agents like inhaled corticosteroids, long-acting bronchodilators like

salmeterol. Because many factors contribute to the inflammatory response in asthma,

many drugs may be considered anti-inflammatory. It is not yet established, however, which

anti-inflammatory actions are responsible for therapeutic effects, such as reduction in

symptoms, improvement in expiratory flow, reduction in airway hyperresponsiveness,

prevention of exacerbations, or prevention of airway wall remodeling. All the patients

were instructed at the beginning of the study either not to change their dosage or type of

long-term control medication during the study period, but if any, it should be as perphysician's advice.

Quick-relief medication or rescue medication which included short-acting beta2-agonists

such as salbutamol (asthalin), albuterol and terbutaline, either inhaled puffs or oral

tablets and oral syrups (in the absence of inhaled puffs). This was mainly used for relief of

acute symptoms by the patients as SOS medication. Details of all medications are listed

under Table 5.


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Follow-up schedule

In yoga group, at the end of the 2-wk yogic intervention course training, participants were

asked to continue with the yoga practice at home for an additional 6 weeks. The

participant's compliance during the follow up period was monitored by a diary, which they

filled in everyday and brought during each visit. An individual yoga practice session was

offered to the participants during study follow-up visits. During the follow-up period,

telephonic support was also provided for motivation of participants to maintain highest

compliance. During follow-up period in addition to the recording of the parameters,

patients from yoga group had individual yoga practice sessions. The purpose of follow-up

yoga practice sessions was to reinforce the on going yoga practice at home and to increase

the motivation levels among patients. In control group, initial 8-wk all the subjects to

continue on conventional treatment, but asked them to record everything about

medication in a diary provided on every follow-up visit. At the assessments, completed

diary (filled out at home during previous weeks) was collected, and blank diaries were

furnished.


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1 Mon/Tue History taking2

Wed

Theory

Practice

Introduction to one another

Introduction to yoga

Shavasana

3

Thu

Practice

Theory

Practice

Counseling

Asanas / Pranayama / Kriyas / Special techniqes

Break

Meditation

Meditation

Individualized advice

4

Fri

Practice

Theory

Practice

Counseling


Break

Fundamentals of nutrition

Meditation


5

Sat

Practice

Practice


Shavasana

6

Sun

Off

7

Mon

Practice

Film show

Practice


Break

Samattvam (Equanimity)

Meditation / Shavasana

8

Tue

Practice

Film show

Practice


Break

Stress management


9

Wed

Practice

Film show

Practice

Counseling


Break

About your illness



10

Thu

Practice

Theory

Practice

Counseling


Break

Yogic attitude in daily life



11

Fri

Practice

Theory

Practice


Break

Stress management

Meditation / Shavasana 12 Sat Practice

Interaction

Asanas / Pranayama / Kriyas / Special techniqes Interactive session on stress management Course feedback Closing session

Day WeekDay

Type ofactivity

Name of activity

Table 1: PROTOCOL OF THE YOGIC INTERVENTION*

* Description of the yogic practices are given in Table 2.


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Category Category details Name of the practice

Sitting Tiger, Rabbit, Shashankasana

Standing Hands-in-out, Hands stretch, Ankle stretch

1. Breathing

exercises Supine Straight leg raising (single & both)

Sukshma Vyayama

(Joint movements) Warm ups starting from the head, working

towards the toes:

Neck rolls, Shoulder rotation, Arm rotation,

Elbow movements, Wrist movements,

Finger movements, Waist movements, Knee

rotation, Ankle rotation, Toe movements.

ShithilikaranaVyayama

(Warm-ups)

Forward and backward bending, Sidebending, Twisting, Pawana-muktasana

Kriya.

2. Loosening

exercises

Suryanamaskar

(Sun-salutation) 12 postures with slow and rhythmic

breathing

Standing

(6 asanas) Ardhakatichakrasan, Paarsva Konasan,

Padahastasan, Ardhachakrasan,Trikonasan,

Parivritta Trikonasan

Sitting

(6 asanas)

Vajrasan, Vakrasan, Janu-shirasan,

Ushtrasan, Shashankasan, Gomukhasan

Prone

(4 asanas)

Bhujangasan, Adhomukha-svanasan,

Shalabhasan, Dhanurasan

3.

Yogasanas

(Postures)

Supine

(4 asanas)

Viparitakarani, Matsyasan,

Pavanamuktasan, Setubandhasan

Supine-Shavasan

Quick relaxation, Deep relaxation

4.

Relaxation

techniques

Prone

Makarasan, Balasan

Breathing Agnisara

5.

Kriyas

(Cleansingtechniques)

Water

Jalaneti, Vamandhouti (Kunjal)

6.

Breathing

Practices

Pranayama

Sectional breathing, Ujjai, Surya-anuloma

viloma (SAV), Nadi-shuddhi (NS) without

kumbhak

7.

Meditation

Raja yoga

Based on raja yoga (5 step method)

8.

Assisted yoga

techniques

Customized

practice

Yoga-Chair breathing (Nagarathna et al.,

1991 b), practiced once in a week.

Table 2: LIST OF YOGIC PRACTICES

S.No.


28/8815

From the above practices, a few are scheduled to repeat on daily basis and some on weekly

basis. All the patients from yoga group are encouraged to follow a standard sequence of

practices to maintain homogeneity with similar benefits.

Assisted yoga techniques are helpful whenever patients have an acute attack as SOS

practice, but advised to practice on weekly basis.

Raja yoga meditation based on asana, pranayama, pratyahara, dharana and dhyana.

Parameters measured

The following parameters were measured:

a) Indices of ventilatory pulmonary function (FEV1, FVC, PEFR, FEV1/FVC%, FEF 25-

75).

b) Quality of life under four domains i.e. symptoms, activity limitation, emotional

function, and reactivity to environmental stimuli; and total quality of life.

c) Immunological parameter: Serum Eosinophilic Cationic Protein (ECP) to know the

course of the disease activity.

d) Exercise induced bronchoconstriction (EIB), i.e. percentage fall in FEV1 with

exercise challenge.

e) Biochemical parameter: marker of mast cell activation (urinary prostaglandin D2

metabolite, 11 -PGF2 ), i.e. difference in pre-post exercise urinary excretion of

11 -PGF2 .

f) Serum soluble interleukin 2 receptor.

g) Frequency of rescue medication use for the 2 weeks preceding the study visit.

The parameters were measured at 0 wk (baseline), 2 wk, 4 wk and 8 wk from both groups.


29/8816

Respiratory flows, volumes and capacities

2The respiratory flows, volumes and capacities were recorded using K4b Spirometry

2(COSMED, Italy), which was calibrated weekly. K4b measures flow and volume using a

bidirectional digital turbine that ensures a great accuracy within a wide flow range (up to

20 lit/sec). The volume resolution (4 mL) together with a very low resistance (


30/8817

Serum Eosinophilic Cationic Protein

During every visit, 4 ml of venous blood was collected before exercise challenge from a

cubital vein directly into a plain glass tube for serum ECP analysis. The blood was allowedo

to clot at room temperature (20 C) for 1- hour + 5 minutes and then centrifuged at 1350 go

for 10 minutes. The serum was withdrawn and aliquots were frozen at - 20 C until they were

used in the ECP assay. Serum ECP levels assessed by sandwich ELISA kit (MBL ECP ELISA kit,

Japan; Code No. 7618E). MBL ECP ELISA Kit measures human ECP by sandwich ELISA. This

ELISA detects human ECP with a minimum detection limit of 0.125 ng/ml and does not

cross-react with EDN. In the wells coated with anti-human ECP monoclonal antibody,

samples to be measured or standards are incubated. After washing, a peroxidase

conjugated anti-human ECP polyclonal antibody is added into the microwells and

incubated. After another washing, the peroxidase substrate is mixed with the chromogen

and allowed to incubate for an additional period. An acid solution is then added to each

well to terminate the enzyme reaction and to stabilize the developed color. The optical

density (O.D.) of each well is then measured at 450 nm using a microplate reader. The

concentration of ECP is calibrated from a standard curve based on reference standards.

This ELISA detects human ECP with a minimum detection limit of 0.125 ng/ml and does not

cross-react with EDN. Standard curve obtained from OD values using 4-parameter logistic

model (Volund, 1978) by MESACUP SYSTEM Version 3.0.9 for Windows software (Medical &

Biological laboratories Co., Ltd., Japan).

Serum soluble Interleukin 2 receptor

The receptor of the cytokine interleukin 2 (IL2) plays a crucial role in the regulation of the

immune response. Binding of IL-2 to its receptor (IL2R) on the surface of T- lymphocytes

triggers a series of intracellular signaling events that result in the activation and

proliferation of resting T cells and, ultimately, in the generation of helper, suppressor andcytotoxic T cells, which mediate immune reactions. It has been found that soluble IL2

receptor is present at low levels in serum of healthy individuals and at significantly

elevated levels in a broad range of disorders such as neoplastic diseases, autoimmune

diseases, organ allograft rejection and different infections. Thus, it appears that sIL2R can

serve as a marker for diagnosis, therapeutic evaluation and management of cancer, as well

as an indicator of a wide spectrum of disorders involving immune activation. For the

quantitative measurement of soluble interleukin 2 receptor (IL2R) IMMULITE 1000 Analyzer

was used by solid-phase, two-site chemiluminescent immunometric assay.


31/8818

oThe serum samples stored at - 20 C were thawed and diluted 1:5 with IL2R sample diluent.

The sIL-2R levels of the serum samples were determined by Immulite (Diagnostic

Products), a chemiluminescent immunoassay system. The analytical sensitivity of sIL-2R

assay was 5 U/ml. the sIL2R results were based on only 43 patients (21 yoga group, 22

control group) at 0 and 2 wk from both the groups.

Exercise Induced Bronchoconstriction (EIB)

All the participants were given standard exercise load for every visit on a stationary bicycleR

ergometer (Bodyguard 990, BodyGuard, Sandnes, Norway) for 3 to 7 min at 80-85% of

maximum workload. Patients were instructed to pedal at a rate of 60 revolutions per

minute (rpm) and they were encouraged to push themselves to the limits of their

dyspnoea, without exceeding a heart rate equal to 85% of the predicted maximal heartrate. To indicate the level of physiological strain and intensity during an exercise session,

heart rate was monitored continuously through a sensor attached to the patient's chest

(Polar Electro Inc., Finland) and the data was displayed on computer via a remote heart

frequency receiver and temperature probe plugged to K4b2 machine. The exercise testo

was performed in an air-conditioned room with an ambient temperature between 20 C ando

27 C and relative humidity of 40 to 50%. Immediately before exercise, lung function

measured for the baseline value and the measurement was repeated at 3, 8, 15 and 30 min

after exercise for post-exercise values. In each case, the best of three FEV measurements1

was considered for purposes of calculation. The bronchoconstriction in response to

exercise was determined by the maximum fall in FEV among repeated measurements at1

different time points after cessation of exercise compared to baseline value {FEV1

(baseline) - FEV (after EC)/ FEV (baseline)}X 100 = percent fall in FEV1 1 1.

Urinary Prostaglandin D2 metabolite (11 -Prostaglandin F2 )

Participants emptied their bladder 5 min before exercise and again at 30 + 5 min after the

exercise challenge for collection of urine samples. Urine samples were stored, without theo

addition of any preservatives, at - 20 C untill analysis. The amount of 11 -prostaglandin

F2 excretion in non-purified urine was analyzed by using Enzyme Immuno Assay(EIA,

Cayman Chemical , Ann Arbor, MI, USA; Catalog No. 516521). This assay is based on the

competition between 11 -PGF2 and an 11 -PGF2 acetylcholinesterase (AChE)

conjugate (11 -PGF2 tracer) for a limited number of 11 -PGF2 specific rabbit

antiserum binding sites. Because the concentration of the 11 -PGF2 tracer is held


32/8819

constant while the concentration of 11 -PGF2 varies, the fraction of 11 -PGF2 tracer

that is able to bind to the rabbit antiserum will be inversely proportional to the

concentration of 11 -PGF2 in the well. This rabbit antiserum- 11 -PGF2 (either free or

tracer) complex binds to the rabbit IgG mouse monoclonal antibody that has been

previously attached to the well. The plate is washed to remove any unbound reagents andthen Ellman's Reagent (which contains the substrate to AChE) is added to the well. The

product of this enzymatic reaction has a distinct yellow color and absorbs strongly at 412

nm. The intensity of this color, determined spectrophotometrically, is proportional to the

amount of 11 -PGF2 tracer bound to the well, which is inversely proportional to the

amount of free 11 -PGF2 present in the well during the incubation; or Absorbance [Bound

11 -PGF2 Tracer] x 1/[11 -PGF2 ]. The Cayman Chemical 11 -PGF2 Assay is a

competitive assay that provides accurate measurements of 11 -PGF2 within the range of

7.8 1000pg/mL, typically with a detection limit (80% B/BO) of 5-10 pg/ml. Inter andintra-assay CV's of less than 15% were achieved at most concentrations of the standard

curve. This assay allows sensitive detection of 11 -PGF2 in the most common sample

matrix, which is urine. Plasma concentrations of 11 -PGF2 are generally below the

detection limit of the assay. For calculating the assay results by a computer excel workbook

spreadsheet program (Cayman Chemical, Ann Arbor, MI) was used by plotting the standard

curve (4-parameter logistic or log-logit curve fit) from %B/B for standards versus 11 -o

PGF2 concentration (in pg/ml). Cross reactivity of the 11 -prostaglandin F2 antibody

against an array of related compounds are: 2, 3-dinor-11 -prostaglandin F2 , 10%; PGD ,2


33/8820

puffs use of B-agonist was recorded on a daily basis in the diaries; an average for the 2 wk

preceding the study visit was used in the analyses. It was measured as frequency of average

use of inhaled bronchodilator or oral bronchodilators (in the absence of inhaled

bronchodilators per day.)

Data analysis and StatisticsCategorical variables were analyzed using chi-square analysis. Continuous variables wereanalyzed using the Mann-Whitney U test or the independent sample t test, depending onthe distribution of the data. Data was subjected to computation of differences betweenmean values of all time intervals with GLM repeated measures, followed by post Hocanalysis (Bonferroni) for each group separately to evaluate the trends.

Raw data of pulmonary function indices and AQLQ score, percentage of predicted values ofpulmonary function indices and logarithmically transformed ECP values were used forappropriate analysis. Urinary 11 -prostaglandin F2 concentrations were not normallydistributed; therefore, median (interquartile range, IQR) values are reported, but tonormalize the data the percentage change in 11 -PGF2 following exercise challenge wasused for analysis. Maximum percentage of exercise induced fall in FEV values were usedfor non-parametric test analysis. Sub-group analysis was also done for participants whoexperienced a decrease of 15% in their FEV values following EC at 0 wk (considered as1exercise-sensitive, ES) and for those in whom change was < 15% (exercise-resistant, ER).Separate group and sub-group analysis was done for maximum fall in FEV and % change inurinary 11 -PGF2 values by Mann-Whitney U test to test the differences at individual timepoints between groups, Friedman test to measure the change with respect to time in eachgroup, if the data distribution was not normal. The results of sIL2R are presented as medianvalues, and the interquartile range (IQR) is provided. Wilcoxon signed rank test to find outdistribution of variables compared with baseline values using the exact p values and yogaand control groups were compared with the use of the Mann-Whitney U test. Friedman andMann-Whitney U test analyzed rescue medication scores as average frequency per day forthe 2 wk preceding the study visit.


34/8821

The notion of taking a continuous variable, specifying a threshold that defines an

important difference, and examining the proportion of patients who reach that threshold

is not a new approach. But what we have done for disease specific asthma quality of life

(AQOL) data is to anchor the threshold difference using the smallest difference that

patients consider important- the minimal important difference because superficial

examination of mean differences can produce very misleading conclusions. When mean

differences fall below the minimal important difference, clinicians may intuitively

conclude that the treatment has a small, and possibly unimportant effect. Similary,

doctors who observe a mean difference that is appreciably greater than the minimal

important difference may be ready to assume that each patient benefits. This is not

necessarily the case (Gyuatt et al., 1998). This approach does not restrict to health related

quality of life or functional status measures, but applies to any clinical variable.

Therefore, we have taken a value (0.5) that can be considered clinically meaningful based

on previous literature (Juniper et al., 1994), which is usually referred to as the Minimal

Important Difference (MID). Based on MID, we calculated the number of patients who

experienced clinically meaningful improvement in both the groups. We have categorized

all the participants, based on MID, into three categories: improved (>0.5), stayed the sameor unchanged (0.5) and deteriorated (


35/8822

Yoga

Control Improved (x) >0.5

Unchanged (y) 0.5

Deteriorated (z)


36/8823

Results

Patients for the Study

The study was carried out on patients having mild to moderate bronchial asthma. The

patients were referred from Respiratory Clinic, Department of Medicine or reported

directly to the Integral Health Clinic, Department of Physiology, All India Institute of

Medical Sciences (AIIMS), New Delhi. Of the 138 patients, 66 did not meet the study

eligibility criteria. Out of 72 eligible participants, the 60 patients who agreed to

participate in the study were randomized into yoga and control groups. In the yoga group (n

= 30) one patient missed his follow-up visits from 4 wk onwards because of being too busy.Hence, in the yoga group only the data on 29 patients were analyzed. One subject, whose

data was incomplete, was excluded from the analysis. In control group (n = 30), only 28

patients completed all the visits. Two patients from the control group were lost to follow-

up because one relocated to another city because of his job, and in case of the other,

contact was lost completely inspite of all efforts. Hence, in the control group, only the

data on 28 patients were analyzed. The two patients, whose data were incomplete, were

excluded from analysis. Thus the data from 57 patients was analyzed (yoga group, n = 29;

control group, n = 28) since they completed the final follow-up measures up to 8 wk.

Baseline Data

Demographics and disease characteristics of the study groups

In yoga group, there were 13 males and 16 females, with mean age of 33.511.4 years.

There were 13 mild and 16 moderate asthmatic patients in the group. In yoga group, the

average time since they were having asthma was 11.69.6 yr and 13 patients had family

history of asthma. In the control group, there were 20 males and 8 females, with mean age

33.411.5 years. There were 11 mild and 17 moderate asthmatic patients in the group. In

control group, the chronicity of asthma was 10.511.9 yr and 11 patients had a family

history. Other demographic data collected was age, sex, height and weight of the study


37/8824

2groups. The Body Mass Index (BMI) was computed using the formula Wt / (Ht) where Wt is

weight in kilograms, Ht is height in meters. Both the groups in clinical characteristics and

other demographics are comparable as analyzed by chisquare analysis. Table 4. gives the

demographics of the study.

Yoga group

(n = 29)

Control group

(n = 28) p-value

Male 13 (45) 20 (71) 0.29

Female 16 (55) 8 (29) 0.19

Family history 13 (44.8) 11 (39.3) 0.67

Mild asthma 13 (44.8) 11 (39.3) 0.78 Moderate asthma 16 (55) 17 (60.7) 0.82

Asthma duration, yr (mean SD) 11.6 9.5 10.5 11.9 0.22

Body Mass Index (BMI) 23.4 4.3 22.6 4.0 0.44

33.5 11.4 33.4 11.5 0.96

30.0 12.4 31.9 11.6 0.67

Age, yr (all patients)

- Male

- Female 36.4 10.0 37.2 10.9 0.85

Table 4: Demographics and Disease characteristics at baseline

p-value obtained from Chi-square analysis, Mann-Whitney U test, or t test.Values in parenthesis are %

Medication (regular medication) use by study groups

The anti-asthmatic medications being taken by the patients at the beginning of the study

have been tabulated in Table 5. As per the study protocol, all the patients in both the

groups continued to take medications for asthma as prescribed by their physicians.Patients were given a diary in which the medication use was noted as frequency of

medication use on each day. There was no significant difference between yoga and control

groups in baseline medication use. Inhaled steroid dose was estimated as mean inhaled

steroid use in micrograms per day in the form of inhalers, which have direct impact on

airways. The inhaled steroid was calculated as inhaled dose of beclomethasone or its

equivalent content of budesonide or fluticasone. These were calculated on the assumption

that beclomethasone 2000g = budesonide 1600g = fluticasone 1000g.


38/8825

Yoga group

(n = 29)

Control group

(n = 28)Type of Medication

No of patients (%)

p-value

Inhaled bronchodilators:

-

Salbutamol

-

Salmeterol

-

Ipratropium

-

Tiotropium

-

Theophylline

22 (75.9)

1 (3.4)

1 (3.4)

-

1 (3.4)

24 (85.4)

2 (7.1)

5 (17.8)

1 (3.6)

-

0.34

0.30

0.07

-

-

Oral bronchodilator tablets:

-

Deriphyllin

-

Salbutamol

-

Theophylline

10 (34.5)

4 (13.8)

2 (6.8)

14 (50)

2 (7.1)

7 (25)

0.23

0.240.05

Bronchodilator syrups:

-Salbutamol

- Terbutaline 3 (10.3)

2 (6.8)2 (7.1)

4 (14.3)0.32

0.22

Inhaled corticosteroids:- Beclomethasone-

Budesonide

-Fluticasone

3 (10.3)-

14 (48.3)

2 (7.1)2 (7.1)

11 (39.3)

0.32

-

0.67

Corticosteroid nasal sprays:

-

Beclomethasone

-

Fluticasone

1 (3.4)

1 (3.4)

-

-

-

-

Anti-allergics:

-

Cetrizine

-

Levocetrizine

-

Pheniramine maleate

-

Fexofenadine

4 (13.8)

2 (6.8)

1 (3.4)

-

4 (14.3)

-

-

1 (3.6)

0.29

-

-

-

Other medications:

- Ayurveda

- Homeopathy

4 (13.8)

2 (6.8)

1 (3.6)

2 (6.8)

0.15

0.38

Table 5: Details of medication at baseline

p-value obtained from Chi-square analysis or fisher Exact test.

Some patients are using more than one type of bronchodilators.


39/8826

There was no significant difference in baseline medication of oral bronchodilators, inhaled

bronchodilators and bronchodilator syrups. There was no significant difference of inhaled

corticosteroids per day, ug/day (320.4158.8 vs 360151.4; p=0.48) between groups at the

baseline visit (Table 6). Patients taking anti-allergic medication were also not differed

significantly between yoga (n = 7) and control groups (n=5) and a few patients were on non-conventional medication such as ayurveda and homeopathy (yoga, 6; control, 3), which is

not significantly different between groups.

Table 6: Summary of inhaled corticosteroids and rescue medication dose atbaseline in both groups

Daily dose of inhaled steroids in beclomethasone ug equivalents over the past 1-2 wk.

These were calculated on the assumption that beclomethasone 2000g = budesonide 1600g

= fluticasone 1000g.

Rescue medication = Inhaled rescue bronchodilator intake (or) oral rescue bronchodilators in the

absence of inhaled bronchodilators per day an average for 2 weeks preceding the study visit.

p-value obtained from Chi-square analysis or Mann-Whitney U test.

Rescue medication was estimated from filled diaries received from the patients and from

personal interviews on every visit. The average rescue medication use per day is frequency

of rescue medication use an average for 2 weeks preceding the study visit, measured as

average number of inhaled bronchodilator use per day or oral short acting B2-

bronchodilators (oral tablets or syrups in the absence of inhaled bronchodilators) use per

day. The baseline average rescue medication use per day was statistically similar between

yoga vs control groups (2.27 1.5 vs 1.98 2.09; p=0.19).

Type of Medication Yoga(n = 29)

Control(n = 28)

p-value

Mean inhaled steroid dose, g/day (mean SD) 320.4 158.8 360 151.4 0.48

Rescue medication use;

times per day, average of l ast 2 wk 2.27 1.5

1.98 2.09 0.19(mean SD),

Baseline rescue medication use

Baseline values of outcome parameters

The yoga and control groups did not differ significantly regarding baseline values of most

variables except PEFR of percentage predicted values (p=.031). Although most baseline

values were not significantly different, the control group consistently exhibited more

disability on all spirometric measurements than the intervention group. As randomization


40/8827

does not necessarily produce comparable groups, there can be minor and some times

major differences in the baseline comparisons between groups (Altman & Dore, 1990). The

statistical analysis for respiratory function indices were done from both absolute values

and predicted values calculated according to the age, height and weight of the patient

with ethnic group correction and compared to the corresponding measured data tomeasure FEV , PEFR, FEV /FVC and FEF 25-75%. The post-bronchodilator response in FEV1 1 1

before the recruitment of the patients into the study is given in Table 7.

Table 7: Post-bronchodilator response in FEV for screening the patients1

FEV , forced expiratory volume in 1 second; 2 puffs of salbutamol inhaler was used to see post-1bronchodilator response p-value obtained by unpaired 't' test.

For Asthma Quality of Life Questionnaire (AQLQ), on a 7-point scale (i.e.7=no impairment

and 1=maximum impairment) and the symptoms quality of life domain, which is designated

here as 'QOL symptoms' is the mean of scores of item numbers 6, 8, 10, 12, 14, 16, 18, 20,

22, 24, 29 and 30; activity limitation quality of life domain, which is designated as 'QOL

activity limitation' is the mean scores of item numbers 1, 2, 3, 4, 5, 11, 19, 25, 28, 31 and

32; emotional function quality of life domain, which is designated as 'QOL emotional

function' is the mean of item numbers 7, 13, 15, 21 and 27; response to environmental

stimuli quality of life domain, which is designated as 'QOL environmental stimuli' is the

mean of item numbers 9, 17, 23 and 26; and the overall score is the mean of all the items.

There are no baseline differences between yoga and control groups either in any of thedomains of asthma quality of llife or overall quality of life. Baseline values of serum

Eosinophilic Cationic Protein (ECP) are not statistically different to each other between

yoga and control groups (mean SD, 42.9 59.9 vs 28.7 31.6; p=0.89). At baseline, there

are no differences between groups in change in urinary 11 -prostaglandin F2 with

exercise challenge (i.e. Urinary 11 -prostaglandin F2 ), which means that the exercise

induced mast-cell activation levels are not statistically different between groups. These

values are expressed in picograms per milligrams of creatinine units of measurement with

median and an interquartile range (26.9, 7.4-218 vs 38.4, 3.1-108; p=0.55). however, for

Parameter Yoga

(n = 29)

Control(n = 28)

p-value

Pre FEV1(L) (mean SD) 1.98 0.70 1.70 0.63 0.11

Post-bronchodilator response in FEV1(L) 2.36 0.79 2.10 0.77 0.19 Post -bronchodilator response in FEV (% change) 21.0 11.2 24.3 12.1 0.29

1


41/8828

analysis purpose the data was converted into percentage of change in excretion of urinary

11- -prostaglandin F2 after exercise challenge, which is also not significantly different

between yoga vs control groups at baseline (mean SD, 17.6 18.6 vs 16.6 21.0; p=0.97)

(Table 8).

Category Parameter Yoga(n = 29)

Control(n = 28)

p-value

FEV 1(L), absolute values 1.94 0.70

1.76 0.68 0.12

PEFR (L/sec)

4.36 1.44

3.94 1.73 0.065

FVC (L)

2.99 0.96

2.89 0.86 0.59

FEV 1/FVC%

66.2 10.1

60.1 12.2 0.006

FEF 25-75(L/sec)

1.38 0.65

1.21 0.69 0.043FEV 1, % predicted

70.2 17.4

62.5 19.2 0.11

PEFR

68.6 18.4

57.4 19.7 0.03

FVC

78.7 13.3

75.2 15.0 0.35

FEV 1/FVC%

80.4 11.5

73.7 14.8 0.06

Respiratoryfunctionindices

FEF 25-75

38.4 14.5

33.9 18.3 0.31

EIB

% fall in FEV 1after exercise

challenge

15.0 14.0

9.1 10.8 0.16

QOL overall score

3.72 1.17

3.64 1.14 0.80

QOL symptom score

3.77 1.34

3.62 1.42 0.70QOL activity limitation

3.66 1.13

3.67 1.17 0.95

QOL emotional function

3.94 1.47

3.59 1.39 0.35

Qualityof

Life

QOL environmental stimuli

3.72 1.17

4.04 1.42 0.14

Serum ECP levels in ng/mL 42.9 59.9 28.7 31.6 0.89

IMMU Serum sIL2R, median (IQR)

(yoga, n=21; control, n=22)

699 (578-813.5) 785 (571-

1025.8)

0.34

BIO -CHEM

Urinary 11 -prostaglandin F2(pg/mg of creatinine), median (IQR)

26.9 (7.4-218) 38.4 (3.1-108) 0.55

Table 8: Baseline values of respiratory function indices, quality of life, serumECP, 11 -prostaglandin F2

Abbreviations: AQOL, Asthma Quality of Life Questionnaire; FEV , force expiratory volume in 11

second; FEF %, forced mid-expiratory flow between 25% and 75%; FVC, forced vital capacity;25-75

PEFR, peak expiratory flow rate; ECP, eosinophilic cationic protein; IQR, inter quartile range; EIB,

exercise-induced bronchoconstriction; IMMU, immunological; BIOCHEM, biochemical parameters.

p-value obtained by 't' test or Mann-Whitney U test. All values are expressed in mean SD, except

11 -PGF2 which is expressed as median with interquartile range.


42/8829

Effects of Intervention

Pulmonary function based on absolute values

The absolute values of various indices of pulmonary function at different points in time

during the study have been given in Table 9. GLM repeated measures with post-hoc analysis

was applied individually within each group from data of absolute values. None of the

indices measured showed any significant change during the study in the control group.

However, in the yoga group, as compared to the baseline (0 wk value), a significant

improvement was seen in FVC at 8 wk (p = 0.041) marginally; PEFR at 2 wk (p=0.02), 4 wk

(p=0.002) and 8 wk (p=0.000) and FEF25-75 only within group overall significance by

considering all time points (p=0.019) but not at any individual time point. We have also

done a separate analysis on percentage of predicted values of pulmonary function indices

with full factorial model GLM repeated measures followed by post-hoc analysis with

Bonferroni correction.


43/8830

Parameter Group 0 wk 2 wk 4 wk 8 wk

Yoga 1.94 0.70 2.01 0.71 2.07 0.73 2.12 0.66

FEV 1 (L) Control 1.76 0.68 1.77 0.71 1.68 0.68 1.67 0.64

Yoga 4.36 1.44 4.87 1.72* 5.18 1.71 5.41 1.69

PEFR (I/sec) Control 3.94 1.73 3.97 1.82 3.85 1.98 3.77 1.64

Yoga 2.99 0.96 2.95 0.91* 2.99 0.89 3.10 0.87

FVC (L) Control 2.89 0.86 2.87 0.90 2.81 0.85 2.76 0.79

Yoga 66.2 10.1 68.1 11.6 69.0 11.8 68.4 10.8

FEV 1/FVC% (%) Control 60.1 12.2 61.0 11.6 59.1 12.7 59.7 11.4

Yoga

1.38

0.65

1.50

0.77

1.61

0.83

1.60

0.81FEF 25-75(I/sec) Control 1.21 0.69 1.20 0.69 1.15 0.67 1.11 0.66

Table 9: Pulmonary function indices at different points during the study(based on absolute values) in both groups

*p


44/8831

In FVC, yoga group showed only a significant overall change (p=.03). However, in post-hoc

pair wise comparisons, none of the follow-up visits was significantly different from

baseline values in either group. There is no significant group mean difference also

observed between yoga and control groups.

In FEV1/FVC%, yoga group showed a significant overall change (p=.027). However, in post-

hoc pair wise comparisons none of the visits was significantly different from baseline in

either group, but significant group mean difference was seen between yoga and control

groups (p=.011).

In forced mid-expiratory flow (FEF 25-75%), yoga group showed overall significant change

(p=.005), but no significant change was observed in post-hoc pair wise comparisons with

baseline in either group. However, significant group mean difference was seen between

yoga and control groups (p=.035).

Parameter Group Week 0 Week 2 Week 4 Week 8 p-value

Yoga 68.6 18.4 76.5 20.5* 81.5 20.9 85.3 20.7 PEFR

% predicted

Control

57.4 19.7

58.2 22.0

56.9 26.2

56.2 22.0

0.000

Yoga

70.2 17.4

73.9 19.6

76.1 20.1

77.9 17.2*FEV1

% predicted

Control

62.5 19.2

63.1 20.5

60.5 21.6

59.9 19.1

0.009

Yoga

78.7 13.4

78.0 12.6

79.3 13.0

82.2 10.7FVC

% predicted

Control

75.0 15.0

74.7 18.3

73.4 18.1

72.5 17.5

NS

Yoga

80.4 11.5

82.6 13.3

83.7 13.4

83.1 12. 2FEV1/ FVC

% predicted

Control

73.7 14.9

74.8 13.9

72.4 15.1

73.3 13.8

0.011

Yoga

38.4 14.6

42.0 19.4

45.0 20.5

45.0 19.7FEF25-75

% predicted

Control

34.0 18.3

33.8 17.8

32.4 18.1

31.1 17.1

0.035

Table 10: Effect of 8-wk intervention (yogic/control) on respiratory functionindices based on percentage of predicted values

All values are expressed as mean SD. P-value was based on group mean differences between yoga

and control groups, NS not significant

* p


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Results of serum Eosinophilic Cationic Protein

The serum eosinophilic cationic protein (ECP) values are highly variable and since they are

not following normal distribution, for analysis purpose the values were converted into log-

transformed values with base 10 (Table 11). However, the actual values are represented in

box plots with median (horizontal line) and an interquartile range (IQR 25 to 75 percentile

in a box) excluding outliers, vertical lines indicate the range. Neither the within subjects

nor the between groups was statistically significant. In post-hoc analysis separately, none

of the follow-up visits was significantly different from baseline visit in either groups.

Group

(mean SD)

Week 0 Week 2 Week 4 Week 8 p-value

Yoga (n=29) 1.32 0.51 1.23 0.58 1.29 0.60 1.19 0.49 0.44

Control (n=28) 1.25 0.43 1.20 0.49 1.28 0.49 1.20 0.44 0.73

Table 11: Log-transformed serum ECP values in both groups (ng/mL)

All values are logarithmically transformed values, mean SD

p-value based on GLM repeated measure in each group separately

Results of serum soluble IL2R

The serum soluble interleukin-2 receptor levels were measured only in 43 patients (21 yoga

group, 22 control group) from 0 wk samples. There were no significant differences between

yoga and control group at baseline values of serum sIL-2R levels. However, yoga group

showed significant difference in serum levels of sIL-2R at 2 wk compared with baseline

values, U/ml (median, IQR; 699, 578-813.5 vs 607, 551.5-790.5; p


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Group Number 0 wk, median (IQR) 2 wk, median (IQR) p-value

Yoga n = 21 699 (578 - 813.5) 607 (551.5 -790.5) 0.029

Control n = 22 785 (571 - 1025.8) 734 .5 (564.5-980.5) 0.314

Table 12: Serum soluble Intereukin 2 receptor values at 0 and 2 wk

p-value was based on Wilcoxon Signed Ranks test between 0 wk and 2 wk

Asthma Quality of Life Questionnaire (AQLQ)

The Asthma Quality of Life was measured under four sub-domains separately and overall

quality of life was computed from total scores of the four sub-domains. There were no

significant baseline value differences between yoga and control groups in QOL symptoms,

but there was a significant linear improvement seen within yoga group (p =.000) and

control group (p =.000). In post-hoc pair-wise comparisons, yoga group shown significant

improvements when compared with 0 wk at all follow-up visits i.e. 2, 4 and 8 wk (p =.000)

and in control group at 4 wk (p =.004) and 8 wk (p =.001) only. Significant group mean

difference also observed between groups (p =.033). Results of AQLQ domains and overall

scores are shown in Table 13.

In QOL activity limitation, there was a significant linear trend within yoga group (p=.000)

and a marginal improvement in control group (p=.048). In post-hoc analysis, yoga group

alone showed significant differences at 2, 4 and 8 wk from baseline visit (p=.000).

Significant group mean difference was observed between yoga and control groups

(p=.003).

In QOL emotional function, there is significant linear trend seen within yoga group (p=.000)

and in control group (p=.029). However, in post-hoc analysis, yoga group showed significantdifferences at 2 wk (p=.001), 4 and 8 wk (p=.000) which was not observed in control group

at any follow-up visit. Significant group mean difference was observed between yoga and

control groups (p=.006).

There was a significant linear improvement seen within QOL environmental stimuli (QOL of

response to environmental stimuli) within only yoga group (p=.000). In post-hoc pair wise

comparisons, yoga group showed significant improvements at all follow-up visits (p=.000)


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i.e. 2, 4 and 8 wk, but not the control group. In addition, there is no significant group mean

difference between groups. Below profile plot shows an interaction, this is clearly

displayed as a cross-over interaction between follow-up visits and groups. This means that

there is an increase in QOL environmental stimuli scores with time, but with a deviation

form this pattern for control group between 0 and 2 wk.

In total quality of life (TQOL), considering scores of all sub-domains the overall quality of

life shown a significant linear improvement within yoga group (p=.000) and control group

(p=.000). In post-hoc analysis, yoga group showed significant differences at 2, 4 and 8 wk

(p=.000) and control group at 4 wk (p=.044) and 8 wk (p=.005) from baseline values. There

is also significant group mean difference observed between groups (p=.013). Overall AQLQ

scores started from the same point on baseline but there is no cross over interaction

between follow-up visits and groups. However, the yoga group showed maximum

improvement in initial 2 weeks during yoga training period since then the scope of

improvement was not much, whereas control group showed almost a linear improvement

over a period of 8 wk.


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AQLQ

domains

Group Week 0 Week 2 Week 4 Week 8 p-value

(BG)

Yoga 3.77 1.34

5.07 1.37

5.38 1.11

5.42 1.23

Symptoms

Control 3.63

1.42

3.96

1.67

4.42

1.50

4.70

1.67

0.033

Yoga 3.66

1.14

4.82

1.29

5.21

1.05

5.47

1.08

Activity

limitation

Control 3.67

1.17

3.74

1.52

3.90

1.36

4.20

1.46

0.003

Yoga 3.94

1.47

5.10

1.65

5.45

1.32

5.71

1.29

Emotional

function

Control 3.60

1.40

4.01

1.64

4.15

1.81

4.32

1.75

0.006

Yoga 3.46

1.54

4.64

1.55

5.00

1.43

5.30

1.61

Response to

environmental

stimuli Control 4.04

1.43

3.83

1.55

4.08

1.65

4.40

1.76

NS

Yoga 3.72

1.17

4.93

1.31

5.28

1.03

5.46

1.12

Total Quality

of Life

Control 3.64

1.15

3.90

1.46

4.17

1.40

4.50

1.51

0.013

Table 13: Effect of 8-wk intervention (yogic/control) on overallquality of life and its sub-domains

All values are expressed as mean SD.

P-value was based on group mean differences between yoga and control groups, BG between

groups; NS not significant

P


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Interpreting Asthma Quality of Life data

The Minimal Important Difference (MID) of 0.5 was considered and based on this figure, all

the patients were sub divided into improved (>0.5), unchanged (0.5) and deteriorated

(0.5

(MID) change i.e. improved, the proportion of improvement would be 12/29 = 0.41. The

following Table 14 gives the proportion of change in under each sub-category and in both

groups.

Yoga Group (n=29)

AQLQ Domain Improved Unchanged Deteriorated

QOL Symptoms 0.41 0.14 0.38

QOL Activity limitation 0.48 0.21 0.31

QOL Emotional function 0.45 0.21 0.31

QOL Environmental stimuli 0.41 0.28 0.31

Total Quality of life 0.45 0.24 0.31

Control Group (n=28)

QOL Symptoms 0.25 0.25 0.50

QOL Activity limitation 0.14 0.14 0.71

QOL Emotional function 0.21 0.14 0.64 QOL Environmental stimuli 0.18 0.07 0.75

Total Quality of Life 0.18 0.29 0.54

Table 14: Effect of 8-wk intervention (yogic/control) on the proportion ofchange in quality of life under sub-categories based on MID in both groups

The above proportions were based on average change occurred in QOL sub-domains between 0-2

wk, 2-4 wk and 4-8 wk study periods.

MID, 0.5 considered as 'unchanged'; above is 'improved' and below is 'deteriorated.


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Based on the above proportions who improved, remained the same, and deteriorated

relative to their baseline status in both yoga and control groups, we calculated the net

proportion benefiting from yoga (proportion benefiting from conventional treatment and

yoga minus proportion benefiting from conventional treatment alone) (Table 20). The

reciprocal of this value gave us the number-needed-to-treat (NNT). NNT worked out to be

as 2.41 in QOL symptoms, 1.66 in QOL activity limitation, 1.91 in QOL emotional function,

1.70 in QOL environmental stimuli and 1.82 in total quality of life which means that

between 2 and 3 patients need to be treated with yoga plus conventional treatment for one

patient to have a clinically meaningful improvement in sub-domains and total quality of

life over and above that which he or she would have experienced on conventional

treatment alone. The details of sub-categories based on MID that are clinically significant

are shown in Table 15.

AQLO domain Group Deteriorated

< MID (0.5)

p-value Improved

> MID (0.5)

p-value

Yoga 0.068 0.22 0.944 0.23 Symptoms

Control 0.083 0.23

0.98

0.839 0.26

0.24

Yoga 0.132 0.20 0.925 0.20 Activity limitation

Control 0.035 0.27

0.45

0.830 0.26

0.44

Yoga 0.095 0.23 1.052 0.33 Emotional function

Control -0.042 0.29

0.18

0.924 0.17

0.52

Yoga 0.109 0.20 1.010 0.39 Response to

environmental stimuli Control -0.087 0.29

0.039

0.714 0.17

0.047

Yoga 0.175 0.16 0.918 0.21 Total Quality of Life

Control 0.085 0.28

0.27

0.820 0.25

0.21

Table 15: Comparisons between yoga and control groups undersub-categories based on MID

All values expressed as mean SD.

P


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Yoga

Control Improved

(0.45) (x)

Unchanged

(0.24) (y)

Deteriorated

(0.31) (z)Improved (0.18) (a) 0.08 (ax) 0.04 (ay) 0.06 (az)

Unchanged (0.29) (b) 0.13 (bx) 0.07 (by) 0.09 (bz)

Deteriorated (0.54) (c) 0.24 (cx) 0.13 (cy) 0.17 (cz)

Table 16: Calculating the proportion of patients who benefitedfrom receiving yoga in a parallel group trial*

Data from the over all AQLQ scores. The number-needed-to-treat for one patient to benefit from

yoga is calculated by adding up cells of those who improved (bx+cx+cy), subtracting the cells of

those who ceteriorated (ay+az+bz), and dividing by the result.

Results of Exercise Induced Bronchoconstriction (EIB)

The values of percentage fall in FEV in response to exercise challenge did not follownormal distribution, hence non-parametric tests were used such as Friedman groupanalysis to know the linear trend in each group separately and Mann-Whitney U tests usedfor testing significant differences between groups at follow-up visits. There was asignificant linear decrease in percentage fall in FEV1 observed in yoga group (p=.005), butnot in control group. In addition, no significant differences observed between groups atany follow-up visit. In sub-group analysis patients attained 15 percent fall in FEV1 withexercise challenge at 0 wk were considered sensitive to the exercise challenge. There wasa significant linear change observed in both yoga (p=.003) and control (p=.015) groups withrespect to time. There was also significant difference seen between groups at 4 wk(p=.025).


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Table 17: Effect of 8-wk intervention (yogic/control) on exercise-induced

broncho-constriction (EIB) indicated as percentage fall in FEV1

after exercise challenge in yoga, control groups and ES & ER sub-groups

p-valueCategory Group Week 0 Week 2 Week 4 Week 8

WG BG

Yoga

(n = 29)

15.05

14.0

8.81

12.9

5.65

12.9

5.18

11.8

0.005% fall in

FEV1 with

exercise

challengeControl

(n = 28)

9.13

10.8

9.50

11.1

10.28

10.9

5.81

10.1

NS

NS

(all

visits)

Yoga

(n = 13)

26.71

12.7

13.33

16.1

9.90

14.5

7.95

15.1

0.003ES patients

(> 15% fall

in FEV1) Control

(n = 9)

21.47

6.4

8.83

9.8

18.69

8.2

12.71

9.1

0.015

0.025

(4wk)

Yoga

(n = 16)

5.58

5.1

5.13

8.4

2.20

10.6

2.93

8.0

NS ES p atients

(< 15% fall

in FEV1) Control

(n = 19)

3.29

6.6

9.82

11.9

6.31

9.8

2.53

9.0

NS

NS

(all

visits)

All values are expressed as mean SD. WGwithin group comparison; BGbetween groups

comparison; NS not significant; ES exercise sensitive; ER exercise resistant *p - value

was based on Friedman test applied on % fall in FEV1 after exercise challenge within each

group separately. Between groups comparisons were made by Mann-Whitney U test at


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Results of urinary Prostaglandin D metabolite2

The urinary 11 -prostaglandin F2 concentrations were not normally distributed and there

was a high variability in the data of different visits within same individual. Therefore, the

data was reported here in median with interquartile range (IQR). In addition, to normalize

the data for analysis, the percentage change with exercise challenge, i.e. percentage

change in 11 -PGF2 after exercise challenge was considered.

Sub-group analysis was also done for participants experienced a decrease of15% in their

FEV1 values following EC considered as exercise-sensitive (ES) and


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Exercise-Condition Week 0 Week 2 Week 4 Week 8

Pre-Ex

455.4

(107.2-1098.1)

293.5

(112.1-844.1)

456.4

(141.6-947.4)

476.1

(135.5-997.6)

Yoga (n=29)

11 - prostaglandin-

F2 in pg/mg creatinine (median, IQR)

Post-Ex 474.0

(127.4-1318.7) 324.0

(130.4-976.9) 461.4

(147.7-1132) 506.5

(137.5-1117.7)

Pre-Ex 223.7

(98.8-562.7) 247.4

(142.8-853.9) 365.3

(100.9-662.6) 305.1

(100.4-725.9)Control (n=28)

11 -

prostaglandin-

F2 in pg/mg

creatinine (median, IQR)

Post-Ex

264.6

(119.5-698.6)

261.4

(136.2-975.5)

452.2

(116.9-858.4)

371.7

(106.8-848.1)

Table 18: Effect of standard exercise challenge on ? urinary11 -prostaglandin-F2 in both groups

All values are expressed as median with interquartile range (IQR).

The above values are pre and post exercise condition values of 11 -prostaglandin-F2 in pg/mg

creatinine. The exercise load was kept constant on every timepoint as 80-85% of maximum work

load. The urine samples were collected at before exercise and 30 min after exercise.

Group Week 0 Week 2 Week 4 Week 8

Yoga

(n = 29) 26.9

(7.4-217.4) 24.9

(6.0-173.7) 19.2

(1.7-229.1) 24.0

(3.2-140.5) 11 -

prostaglandin-

F2 in pg/mg

creatinine

(median, IQR)

Control

(n = 28) 34.5

(3.0-73.5) 19.1

(5.9-158.5) 39.6

(2.2-142.7) 26.8

(4.0-148.0)

Yoga (n = 13)

37.2 (7.7-251.9)

27.5 (5.4-177.3)

19.2 (4.6-274.8)

30.3 (5.4-140.4)

ES patients

(median, IQR) Control (n = 9)

39.7 (11.5-110.5)

10.3 (-4.8-234.2)

143.4 (21.9-323.9)

59.1 (11.0-210.9)

Yoga (n = 16)

24.3 (3.9-205.9)

20.9 (6.5-203.7)

22.5 (-4.0-153.8)

17.0 (1.64 -179.4)

ES patients

(median, IQR) Control

(n = 19)

11.6

(1.9-73.6)

20.6

(5.5-94.4)

20.1

( -2.8-109.8)

9.9

(-3.0-2.0)

All values are expressed as median with interquartile range (IQR).

ES exercise sensitive; ER exercise resistant patients.

Table 19: Effect of 8-wk intervention (yogic/control) on urinary

11 -prostaglandin-F2 with exercise challenge(absolute values) in both groups


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Group Week 0 Week 2 Week 4 Week 8 p-

value

Yoga(n = 29)

17.6 18.6 19.7 24.7 14.7 16.5 16.8 19.7 0.49(NS)

11 -prostaglandin -

F2 (mean

SD)

Control

(n = 28)

16.621.0 18.622.0 16.322.3 20.723.5 0.84

(NS)

Yoga

(n = 13)

18.3 22.2 20.4 29.5 13.8 16.8 12.3 16.9 0.63

(NS)

ES patients

(mean SD)

Control

(n = 9)

15.5 21.2 13.3 18.1 28.5 16.3* 18.9 8.2 0.11

(NS)

Yoga

(n = 16)

17.115.9 19.021.0 15.416.8 20.421.5 0.79

(NS)

ES patients

(mean SD)Control

(n = 19)

17.0 21.5 21.1 23.6 10.6 22.8 21.6 28.2 0.08

(NS)

All values are expressed as percentage change of 11 -prostaglandin-F2 with exercise challenge. *P

value was based on Friedman test in each group separately from % change in 11 -PG-F2 . p


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Parameter Group 0 wk 2 wk 4 wk 6 wk 8 wk p-value*

Yoga 2.27

1.49

1.12

1.33

0.62

0.84

0.83

0.99

0.80

0.99

0.000Average

rescue

medication

use per day

Control 1.98

2.09

2.19

2.04

a

1.89

1.94

1.56

2.12

1.57

2.09

0.013

All value are mean SD.

*p-value was based on Friedman test for overall group significance.ap


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activity marker (urinary prostaglandin D2 metabolite 11 -PGF2 ) was also measured

before and after exercise. The urinary concentrations of 11 -PGF2 showed a trend similar

to % fall in FEV1 but again the changes were statistically not significant in either group

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