Medicine. Publications: â¢Lipid profile of children's in high risk family â Best ... Scientific Study of Intellectual Disabilities (IASSID)). Books: "With love from Babli - A .... assistance/hospitalization for respiratory complications after CMP free diet.
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 & Publications: Medicine •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 Diarrhe a
Asthm a
Vomit
Colic
Skin Rash Eczema
Wheezing and Coughing
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
Geographical Location
Chennai
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 1. Infectious diseases 2. Allergy
Down Syndrome 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 Year DS 1 1.17 in 1000 or 1985 1 in 853 2 0.81 in 1000 1998
Location
Project
Hyderabad
Source Isaac et al. 1985
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
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.
Study Plan 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 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
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 78.8 80 66.7 61.3
70
Frequency in {ercentage
60
50
38.7
Negative
33.3 40
Positive
30
21.2
20
10
0 0.5 - 3
3.1 - 6
6.1 - 10
Incidence of Cow Milk Protein Intolerance (Allergen) Cow milk protein allergen
Total
Allergen 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) 69
70
Frequency in Percentage
60
50 31 40
30
20
10
0 CMPI Positive
CMPI Negative
Hemoglobin With Cow milk protein allergen Cow milk protein allergen
Total
Total Hb 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 Cow milk protein allergen
Total
PCV 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)
White blood cells with Cow milk protein allergen Cow milk protein allergen
WBC
Total Positive
Negative
Normal
26 (28.6%)
65 (71.4 %)
91
Abnormal
5 (55.6%)
4 (44.4%)
9
Total
31
69
100
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 Cow milk protein allergen
Total
Total IgE 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 Pre and Post condition of cough among Cow milk protein allergen (Positive / Negative) cases Cough after advised diet
Cow milk protein allergen
Positive
Negative
Cough before Dry advised diet With Expectoration Total Pre study condition
Dry With Expectoration
Total
No cough 1 (100)
Dry 0
16 (53.3) 17
13 (43.3) 13
1 (3.4) 1
30
12 (19.4) 0
50 (80.6) 1 (14.3) 51
0
62
6 (85.7) 6
7
12
With expectoration Total 0 1
31
69
There is highly statistical significant difference (p
