effect of cows milk protein intolerance on recurrent respiratory
TRANSCRIPT
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
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
Cow milk protein allergen
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
Cow milk protein allergen
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
Cow milk protein allergen
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
Cow milk protein allergen
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
Cough before and after advised diet
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
Cow milk protein allergen
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
Cough before and after advised diet
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