effect of cmpi (cow’s milk protein intolerance) and ... · dr. priya chandrasekhar ... • dr. b....

Effect of CMPI (Cow’s milk protein

Intolerance) and recurrent respiratory

infections in children with Down’s

syndrome

Dr. Priya Chandrasekhar MBBS, DNB,

MNAMS

INDIRA CHILD CARE CENTER

CHENNAI, INDIA

Dr. Priya Chandrasekhar Principal Investigator

Consultant in Pediatrics Medicine and Adolescent health

Indira Child Care Center & Apollo Hospitals Group

National Instructor for PALS (Pediatric Advanced Life Support) by American Heart Association in India

Fellow of Royal society of Medicine – UK

Member National Academy of Medical Sciences

Accolades:

• Dr. James Flett Endowment Award - Social and Preventive Pediatrics

(2000)

• Maitlander Memorial Prize for surgery

• Dr. B. Ramamurthy Gold Medal for Neurology, Neurosurgery &

Medicine Publications:

•Lipid profile of children's in high risk family – Best Paper award Indian

journal of Pediatrics (2000)

Dr. Surekha Ramachandran Co-Investigator

Accolades

Co-Founder and Chairperson of the Down's Syndrome

Federation of India (Tamilnadu Chapter)

PhD in Cognitive Deficit and Depression in Down

Syndrome

Promoter of Mathru Mandir, Chennai

Board Member of Down Syndrome International (DSi)

"Woman of the Year" Award in 1998 "For the sake of

honor" award (International Association for the

Scientific Study of Intellectual Disabilities (IASSID))

Books:

"With love from Babli - A child with Down's Syndrome" –

(A Referral Guide)

"Life starts at Sixteen - Down's Syndrome“

"Positive approach to Down Syndrome - Guide for

Down Syndrome children”

What is CMPI ?

Non-immunological reactions against

cow’s milk protein are defined as

cow's milk protein intolerance (CMPI)

Cow's milk protein intolerance (CMPI),

are reproducible adverse reactions to

cow's milk protein(s) and may be due

to the interaction between one or more

milk proteins.

World Incidence of CMPI

3 - 7.5% of babies are allergic to cow's

milk in the world (Host A et.al)

Very few studies confirm the

prevalence of CMPI in India (Poddar U

et.al)

To our knowledge there is no

exclusive study conducted for DS

children with CMPI and respiratory

complications

Signs and Symptoms

Eczema Wheezing and Coughing

Skin Rash

Colic

Vomit

Diarrhe

a

Asthm

a

Allergy – Short Primer

Top ‘5’ Food Allergens

Cow’s Milk

Tree nuts

Peanuts

Wheat

Eggs

Historical records of food allergy

Ca. 400 BC

Hippocrates Comment on Cheese:

….but there are some who do not bear it well,

their constitutions are different…..

1908

Dr. Alfred Schofield

successfully treated a boy who suffered from

angioedema and asthma because of an allergy

to eggs

Conclusion: Food allergies can cause

illness,

disease and poor health

Chennai

Geographical Location

Rationale of the Study

Down’s syndrome is a disorder

unattended by the various health

authorities more specifically in

developing countries.

The healthcare program for children

with Down’s syndrome (DS) is of

least priority.

Recurrent respiratory infections are

common in children with DS

Rationale of the Study

To study the frequency of antibiotics

used for recurrent infections

To demarcate between allergy induced

respiratory complications and infection

related

To study the effect of quality of life in

DS children

Causes of Respiratory

disorders Normal Children Down Syndrome

1. Infectious

diseases

2.Allergy

1. Infectious diseases

2.Allergy

3.Genetic Conditions

4.Abnormal immune

responses

5.Accelerated ageing

6.Oxidative Stress

7.Micro aspiration (due

to deranged anatomy)

Prevalence

The prevalence of Down’s syndrome in

Indian sub continent slightly varies from

global data (1 in 750 live births)(BDRI,

Chennai-India).

Exact prevalence was impossible to

collect from Indian sub continent as there

is a lack of central registry for DS and

other Intellectual and genetic disorders.

South East Asia Regional Neonatal

Prenatal Database (SEAR-NPD) 2010

reported 0.05% (n=1948) of Down

syndrome cases in India

Published sources of DS in

India S.No Prevalence of

DS

Year Location Project Source

1 1.17 in 1000 or

1 in 853

1985 Hyderabad Isaac et al. 1985

2 0.81 in 1000 1998 Delhi SOMDI* Verma et al. 1998

3 1.04 in 1000 1998 Baroda SOMDI* Modi et al. 1998

4 1 in 1510 1998 Bombay SOMDI* Barucha 1998

* Study of malformations and Down’s syndrome in India

Why DS study

Children with DS are predisposed to following health

conditions transcending various systems.

◦ Endocrine (Yousra Hawli et al., 2009)

◦ Cardiovascular (Vis et.al 2009, Bhatia 1991)

◦ Respiratory (Pandit et.al 2011)

◦ Immune (Nespoli et. al 1993, Pueschel et. al 1990)

◦ Gastro intestinal (Pueschel et. al 1990)

◦ Obesity (Melville et al 2005)

◦ Musculo skeletal (Caide MS et al 2006, Mik G et al

2008)

◦ Hematological systems (Lang B 2000)

Hospitalization and DS

A population cohort study - children with intellectual disability had ◦ hospital admission on more occasions

◦ longer hospitalization

◦ larger range of clinical diagnosis

This study also revealed that children with DS comprise 40% of the total population in the study ◦ (Williams et al 2005)

Increased hospitalization of DS children is consistent across the globe and more references are point towards respiratory disorders ◦ (So SA et.al. 2007, Bloemers BL et.al 2010).

Respiratory tract infections in

DS children

RTI in DS is caused by diverse pathologic origin e.g. viruses, bacteria, fungi or combination.

Frequency of URTI is (12% have more than 3 URTI in 12 months) increased compared to healthy controls. Recurrent Respiratory infection (includes any one of..)

≥ 6 respiratory infections per annum,

≥ 1 respiratory infections per month involving the upper airways from September to April,

≥ 3 respiratory infections per annum involving the lower airways.

(Gruppo di Studio di Immunologia della Societá Italiana di Pediatria, 1988)

RTI in DS children

Upper Respiratory Tract infections (URTI)

URTI may be due to abnormal anatomy of

respiratory tract in DS individuals

◦ Hypoplasia of nose and sinuses

◦ Midface hypoplasia with small nasal area and

sinuses.

Lower Respiratory Tract infections (LRTI)

LRTI is the major cause of hospitalization leading

to pulmonary complication and intensive medical

care

Acute lung injury may be attributed to elevated rate

of apoptosis of leucocytes, epithelial cells or

granulocytes.

Title

Effect of CMPI (Cow’s milk protein Intolerance)

and respiratory infections on children with Down’s

syndrome

Study Duration 12 months

Study Center(s) Single-center

Objectives

Primary Objective

To observe the effect of CMPI in relation with

recurrent respiratory infection in DS children

Secondary Objective

Effect of removing cow’s milk protein and

follow-up of incidence of respiratory infection

Diagnosis and

Main Inclusion

Criteria

Children with DS, positive for CMP antibody

usually IgE mediated

Study Design Quasi experimental

Study Plan

Study End Points

Primary Endpoint

To study the change from baseline in

dependence of medical

assistance/hospitalization for

respiratory complications after CMP

free diet

Secondary Study Endpoints

Effect of removing cow’s milk protein

and follow-up of incidence of

respiratory infection

Study End Points

Exploratory Endpoints

To observe the QOL* parameters from Parents perspective during the study and thereafter

* QOL - Quality of Life

Study Population Population No Comments

Total Screened 108

Screen failed 2 Had major illness

Lost to follow 3 Moved to other state

Refused blood test

3

Non compliant

Study Population

100

Subject Selection

Children (1 – 10 years)with DS,

confirmed by Karyotyping or genetic

analysis

Children dependent on cow’s milk

The patient is in satisfactory health

Informed consent obtained from legal

parents

The patient and parents are willing

and able to comply with scheduled

visits and tests

Diet intervention

Screened children were advised to

stop cow’s milk and use alternative

products.

Few alternatives to cow’s milk

Soy milk formula

(Isomil, Nusobee and Prosobee)

Partially Hydrolyzed Formulas

(Gentlease and Good Start Supreme)

Extensively Hydrolyzed Formulas

(Nutramigen Lipil, Pregestimil and Alimentum)

Free Amino Acid Formulas

(Neocate and Elecare)

Exclusion Criteria

DS Children with Cardiac

complications

Children not cooperative for blood

collection and routine tests

Children with acute malignancy

Early Withdrawal of Subjects

Children requiring hospitalization for

respiratory condition.

Safety reasons at the discretion of the

Principal Investigator.

Failure of subject to adhere to protocol

requirements.

Withdrawal of consent for study.

Ethics

To conform with International and

National regulations for Research on

humans

Adherence with ICMR (Indian Council of

Medical Research) Guidelines for

research on human

“Ethical Down syndrome research”

Ethics

Name of the EC: National Ethics Committee

Chennai, India

Reg No: US-OHRP – IORG0006162

List of Documents approved ◦ Protocol v. 1.1

◦ Parental permission/ Research Informed Consent (Bilingual – English and Tamil) v 1.1

◦ Case Report Form

Study Procedures Activity Screening End of Study

Medical history

√

√

Vitals

√

√

Blood Collection

√

√

Questionnaire Administration

√

√

Monthly questionnaire administration and vitals for 9 months

Medical history

Medical history

Complete physical examination

Screening for inclusion criteria of the

protocol

Consent

Ethics committee approved version of

the Informed Consent Form (ICF) was

given to parent for perusal

Detailed Study procedure explained

including schedule for blood tests

Consent was obtained after

clarification session

Bi-lingual versions (English and Tamil)

were used

Past medical history

◦ Major illness

◦ Respiratory illness

◦ Antibiotic regimen

◦ Use of paracetamol and anti-histamines

◦ Hospitalization, treated for infections,

respiratory problems

Vitals

Baseline vitals recorded

Considerations for dietary habits of DS

children

Overall health status

Vaccination history chart

Growth chart was reviewed

Hematology

Milk: Allergen Specific IgE ◦ Chemiluminescence/ ImmunoCAP

Total IgE, Serum

Hemoglobin, Hemocrit

Total Leukocyte count

Differential count

Central Lab:

SRL – Super Religare Laboratories Ltd.,

(CAP- College of American Pathologist and NABL approved Laboratory)

Research Tools

Informed Consent Forms (version 1.1) (Bi-Lingual – English and Tamil)

Questionnaire (version 1.1) (Bi-Lingual – English and Tamil)

Data Collection Sheet for monthly

assessments (version 1.0)

Patient record for other medical illness

during the study

ICF - English

ICF - Tamil

Questionnaire

Data Analysis

Primary Endpoint

To study the change from baseline in dependence of medical assistance/hospitalization for respiratory complications after CMP free diet

Secondary Study Endpoints

To observe the change in the clinical presentation before and after CMP free diet

Statistical Analysis

Statistical analyses were done using SPSS v. 17 (Chicago, IL, USA)

Chi-Square was used to analyze the significant difference between proportions

Variables were analyzed as categorical or continuous

Mc-Namer test was used for categorical data

Proportional analysis were also used for analysis

Statistical results were presented graphically

Results

Demographic

CMPI incidence

Hemoglobin level

Haematocrit level

WBC / Lymphocytes level

Total IgE level

Cough before and after advised diet

Interventions before and after advised diet

Following slides graphically summarizes the clinical findings in the DS children

Age distribution in CMPI positive

and negative group

Age group

(years)

CMPI

positive

CMPI

negative

Total

(%)

0.5 – 3

3.1 – 6

6.1 – 10

7 (21.2%)

12 (33.3%)

12 (38.7%)

26 (78.8%)

24 (66.7%)

19 (61.3%)

33

36

31

Total 31 69 100

Age distribution in CMPI positive

and negative group

0

10

20

30

40

50

60

70

80

0.5 - 3 3.1 - 6 6.1 - 10

78.8

66.7

61.3

21.2

33.3

38.7

Fre

qu

en

cy

in

{erc

en

tage

Negative

Positive

Incidence of Cow Milk Protein

Intolerance (Allergen)

Allergen

Cow milk protein allergen

Total

Positive Negative

Positive 31

(100.0%)

0

(0.0%)

31

Negative 0

(0.0%)

69

(100.0%)

69

Total 31 69 100

Chi square = 100; p value = 0.000 From the above table we have

arrived the comparison between cow milk protein allergen

among groups. We’ve also arrived significant difference (since

p< 0.05) by applying chi square test and we conclude that the

above said variables are associated (i.e dependant each other)

Incidence of Cow Milk Protein

Intolerance (Allergen)

0

10

20

30

40

50

60

70

CMPI Positive CMPI Negative

31

69

Fre

qu

en

cy

in

Perc

en

tage

Hemoglobin With Cow milk protein allergen

Total Hb


Total

Positive Negative

Normal 15

(30.6%)

34

(69.4%)

49

Abnormal positive 14

(28.6%)

35

(71.4%)

49

Abnormal negative 2

(100.0%)

0

(0.0%)

2

Total 31 69 100

Chi square = 4.59; p value = 0.10 From the above table we have arrived the comparison between cow milk allergen and hemoglobin. We’ve also arrived insignificant difference (since p> 0.05) by applying chi square test and we conclude that the above said variables are not associated (i.e. independent each on other)

Haematocrit (PCV) levels in

study population

PCV


Total

Positive

Negative

Normal

24 (26.9%)

57 (70.4 %)

81

Abnormal

7 (36.8%)

12 (44.4%)

19

Total

31

69

100

Chi square = 0.374; p value = 0.541 From the above table we have

arrived the comparison between cow milk allergen and total IgE

We’ve also arrived insignificant difference (since p> 0.05) by

applying chi square test and we conclude that the above said

variables are not associated (i.e. independent on each other)

WBC


Total

Positive

Negative

Normal

26 (28.6%)

65 (71.4 %)

91

Abnormal

5 (55.6%)

4 (44.4%)

9

Total

31

69

100

White blood cells with Cow milk protein

allergen

Chi square = 2.788; p value = 0.095 Chi square = 4.59; p value = 0.10 From the

above table we have arrived the comparison between cow milk allergen

and WBC. We’ve also arrived insignificant difference (since p> 0.05) by

applying chi square test and we conclude that the above said variables are

not associated (i.e. independent each on other)

WBC count

Lymphocytes

Total IGE with Cow milk

protein allergen

Total IgE


Total

Positive Negative

Normal 12

(20.8%)

64

(84.2%)

76

Abnormal 19

(79.2%)

5

(15.8%)

24

Total

31

69

100

Chi square = 34.252; p value = 0.000 From the above table we have arrived the comparison between cow milk protein allergen and total IgE. We’ve also arrived significant difference (since p< 0.05) by applying chi square test and we conclude that the above said variables are associated (i.e. dependant on each other)

Total IgE levels in study population


There is highly statistical significant difference (p<0.05) among positive cases than

negative cases, using proportional analysis.

Pre and Post condition of cough among Cow milk protein allergen (Positive / Negative) cases


Cough after advised diet

Total No

cough Dry With

expectoration

Positive

Cough before advised diet

Dry 1 (100) 0 0 1

With Expectoration

16 (53.3)

13 (43.3)

1 (3.4)

30

Total 17 13 1 31

Negative Pre study condition

Dry 12 (19.4)

50 (80.6)

0

62

With Expectoration

0 1 (14.3)

6 (85.7)

7

Total 12 51 6 69


0

10

20

30

40

50

60

70

80

90

100

No cough afteradvised diet

Dry cough afteradvised diet

Cough withexpectoration after

advised diet

100

0 0

53.3

43.3

3.4

Fre

qu

en

cy

in

Perc

en

tage

Dry cough before advised diet

With expectoration before adviseddiet

Respiratory complications before and after

advised diet

CMPI

No. of episodes – after study

Total 1 2 3

Positive

No. of

episodes

before

advised

diet

4 0 8 (61.5) 5 (38.5) 13

5 0 8 (57.1) 6 (42.9) 14

6 0 1 (25.0) 3 (75.0) 4

Total 0 17 14 31

No. of episodes after advised

diet

Total

Negative

No. of

episodes

before

study

1 2 3

3 1 (100) 0 0 1

4 0 18 (66.7) 9 (33.3) 27

5 0 13 (41.9) 18 (58.1) 31

6 0 3 (30.0) 7 (70.0) 10

Total 1 34 34 69

Discussion

Total screened children – 108 Enrolled in trial – 100 CMPI positive children were advised to

stop cow milk use in any form All procedures were followed after EC

approval Demographical and Hematological

parameters were collected and analyzed statistically

Laboratory confirmed CMPI children

Positive - 31 Negative - 69

Discussion

Study reveals that in children who were CMPI positive (antibodies towards cow’s milk) following dietary modification resulted in ◦ Decrease in incidence of respiratory

infections

◦ Decrease in use of antibiotics

◦ Decrease in hospitalization

◦ Improvement in respiratory symptoms

◦ Overall improvement in health and well being

Take home ..

Breast feed as much as possible

Check CMPI antibody early

If positive institute suitable diet

modifications

Recurrent Respiratory infections can

be reduced significantly

Associate Research Team

A. Zechariah Jebakumar Associate Professor

Bio statistics and Research Methodology

Dept. of Scientific & Research studies

Prince Sultan Military Medical College of Health

Sciences, Dhahran, Kingdom of Saudi Arabia

Manoj Gnanaprakasam

Research Coordinator

Indira Child Care Center, Chennai