VITAMIN D SUPPLEMENTATION FOR SEVERE

PNEUMONIA IN UNDER-FIVE CHILDREN:

A RANDOMISED CONTROLLED STUDY

Protocol of Thesis to be submitted to the University of Delhi towards the

Partial Fulfilment of the Requirement for the Degree of

Doctor of Medicine (Pediatrics)

(Session: 2007-2010)

By

Name of candidate

Department of Pediatrics,

University College of Medical Sciences & GTB Hospital,

Delhi-110 095

2

VITAMIN D SUPPLEMENTATION FOR SEVERE

PNEUMONIA IN UNDER-FIVE CHILDREN:

A RANDOMISED CONTROLLED STUDY

Protocol of Thesis to be submitted to the University of Delhi towards the

Partial Fulfilment of the Requirement for the Degree of

Doctor of Medicine (Pediatrics)

(Session: 2007-2010)

Student: Dr. abcde …………………………………..

(Signature)

Supervisor: Dr. abc def …………………………………..

Professor, Pediatrics (Signature)

UCMS & GTB Hospital

Delhi-110 095

Co-Supervisor: Dr. K.K. Sharma …………………………………..

Professor & Head, Pharmacology (Signature)

UCMS & GTB Hospital

Delhi-110 095

Place of Work:

Department of Paediatrics,

University College of Medical Sciences &GTB Hospital, Delhi-110 095

3

ABSTRACT

Background: Pneumonia is one of the most common causes of morbidity and mortality

in children younger than 5 years of age, particularly in developing countries. Studies have

shown association of vitamin D deficiency with acute lower respiratory tract infection.

Study design: Double blind, randomized, placebo controlled clinical study

Objective: To assess the efficacy of vitamin D supplementation in children with severe

pneumonia

Subjects: 200 children (3months-5years of age) with severe pneumonia. Pneumonia will

be diagnosed in the presence of fever, cough, tachypnea and crepitations on auscultation.

Severe pneumonia will be indicated by pneumonia with lower chest in-drawing or at least

one other danger sign (inability to feed, lethargy, cyanosis).

Intervention: Vitamin D [1000 IU/d for infants (age <1 y), and 2000 IU/d for children

(age 1-5 years)], or placebo, administered orally at enrolment and then once daily 1 h

before breakfast for the next 4 days. The placebo/ drug will be dissolved in a teaspoon of

milk before being administered. Both groups will receive antibiotics as per IAP

guidelines.

Outcome measures: Primary outcome measures will include the time for resolution of

pneumonia and duration of hospitalization. Secondary outcome measures will include

time to resolution of tachypnea, lower chest indrawing, hypoxia, and inability to feed.

Statistical analysis: Kaplan-Meier survival function plots will be constructed to compare

the median duration for each outcome variable.

4

INTRODUCTION

Pneumonia remains a significant health problem in India with significant

morbidity and mortality. There is increasing recognition that nutritional deficiencies,

including micronutrients are important determinants of infections, including pneumonia,

and their outcomes.1 Identifying an effective nutritional agent that reduces the need for

antibiotics, duration of pneumonia and length of hospitalization would be highly cost-

beneficial.2

Vitamin D deficiency is a common and important nutritional deficiency in

children. Clinical and subclinical vitamin D deficiency in children has been reported to be

a significant risk factor for severe acute lower respiratory tract infection.3 Increased

susceptibility to respiratory infections in vitamin D deficiency may be explained on the

basis of physical factors, i.e., hypotonia and chest wall deformity, leading to reduced lung

volume, poor compliance of the chest wall, atelectasis and fibrosis. Apart from this, new

knowledge of the biological and clinical importance of the active form of vitamin D and

its receptor: has generated interest in its role in improving immune function.4

Although many observational studies have show association between vitamin D

deficiency and pneumonia, the evidence to demonstrate the effect of supplementation of

vitamin D in children with pneumonia/severe pneumonia is lacking.5-8

Considering this

lacuna, we plan to study whether Vitamin D, along with antibiotics, would improve the

outcome of severe pneumonia. The main objective of our study will be to evaluate the

effect of adding vitamin D in the routine treatment of severe pneumonia, in terms of

clinical recovery.

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REVIEW OF LITERATURE

Clinical pneumonia (defined as respiratory infections associated with clinical

signs of pneumonia, principally pneumonia and bronchiolitis) in children under five years

of age is still the leading cause of childhood mortality in the world1. According to the

United Nations Children's Fund (UNICEF) and the World Health Organization (WHO),

pneumonia kills more children than any other illness – more than AIDS, malaria and

measles combined2. The WHO estimates that acute respiratory infection (ARI), mostly in

the form of pneumonia, is the leading cause of death in under-five children, killing over 2

million children annually2. More than 95% of clinical pneumonia in young children

worldwide occurs in developing countries. Recent estimates from India suggest that

pneumonia in children under five years of age constitutes 24 % of National burden of

disease and 13% of deaths.9 Mortality estimates suggest that 2.3 million children less

than five years die every year in India and 20% of these deaths are due to pneumonia.

Factors that put the children at increased risk of pneumonia include environmental

pollution (both indoor and outdoor), improper childcare practices, increased transmission

of pathogens, and nutrition-related practices and disorders. Consequently considerable

research has aimed at finding effective interventions against ALRI such as immunization3

and case-management involving antibiotics.4 Micronutrient supplementation is another

potential intervention. The role of micronutrient deficiency in pneumonia related

mortality and morbidity is now gaining importance. Various studies have documented the

role of Zinc in treatment of pneumonia.5. Conflicting results are reported about the role of

Vitamin A in lower respiratory tract infections. Many trials have investigated the benefits

6

of vitamin A supplements, and found that vitamin A supplementation significantly

decreases morbidity and mortality from ALRI due to measles, and also decreases the

overall under-5 mortality.6

Vitamin D and Acute Respiratory Tract Infections

Vitamin D deficiency is known to cause rickets and retard skeletal growth.

Studies in developing countries have suggested an association between nutritional rickets

and pneumonia. In Iran 43% of 200 children with rickets had radiologically proven

pneumonia, and 44% of 250 children with Vitamin –D deficiency rickets in Kuwait had

pneumonia.7,8

A hospital based case control study from Egypt showed that acute

respiratory tract infections were present in 81% of children with rickets as compared to

58% of controls.9 In a study of 300 consecutive outpatients in Ethiopia, 41% had clinical

signs of rickets, while in an inpatient setting, rickets was associated with 13-fold

increased risk of pneumonia in children less than 5 y of age.10,11

In another study of 131

patients with rickets between 1979 and 1988, compared with age matched and sex

matched controls without rickets, pneumonia was more common in rachitic patients than

in controls.12

Subclinical vitamin D deficiency is a significant risk factor for severe acute

lower respiratory tract infection in Indian children less than five years of age.13

Hitherto, the cause of increased susceptibility to respiratory infections in rickets

was being explained on the basis of physical factors, i.e., hypotonia and chest wall

deformity, leading to reduced lung volume, poor compliance of the chest wall, atelectasis

and fibrosis13

. The interesting new development is the role of vitamin D as an

immunomodulator and a specific factor responsible for augmenting the innate immunity,

7

specifically to protect against respiratory tract infections. This has been already

demonstrated experimentally in tuberculosis, a major pulmonary disease.14-17

The present research assumes importance given the increasing evidence that sub-

clinical vitamin D deficiency is common even in countries at low latitude and with

plentiful sunshine, including India.18-20

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AIM AND OBJECTIVE

Aim

To study the efficacy of vitamin D supplementation in the treatment of severe pneumonia

in children under 5 years of age.

Objective

To compare the time to resolution of the illness (tachypnea, lower chest indrawing,

hypoxia, and inability to feed), and duration of hospitalization in children with severe

pneumonia receiving vitamin D supplementation or placebo, in addition to routine

antibiotics and supportive therapy .

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SUBJECTS AND METHODS

Study Setting

This prospective study will be hospital based, to be conducted in the Department of

Pediatrics at UCMS and GTB hospital, Delhi. A clearance from ethical committee of the

institute will be obtained. Written informed consent will be obtained from the family

members or any surrogate for participation in the study (Annexure 1). The study will be

conducted from May 2008 to April 2009, including enrollment (9 months) and analysis

and writing (3 months),.

Study Design

Double blind, randomized, placebo controlled clinical study.

Sample Size

The sample size will be based on a hospital based randomized control study on the role of

zinc for severe pneumonia in very young children.21

According to the sample size

formula for testing difference of mean in two samples,22

a total of 98 children in each

group would be required to detect a meaningful difference of 1 day (SD=2.5days) in

duration of severe pneumonia with an alpha error of 0.05 and power of 80%. Although

attrition is not expected, the final sample size will be kept at 200 to allow for possible

cases of withdrawal.

Inclusion Criteria

Children aged between 3 months to 5 years with a clinical diagnosis of severe pneumonia

(clinical presentation with cough, fever, tachypnea and crepitations on auscultation, along

10

with presence of either lower chest indrawing or at least one other danger sign [inability

to feed, lethargy, cyanosis].

Exclusion criteria

Receipt of vitamin D or calcium supplementation within last 4 weeks before admission;

severe malnutrition (weight for height less than 70%; and/or height for age < 85 %, or

presence of edema as per WHO classification of undernutrition).23

WHO Growth Charts24

for under five children will be used for the reference weight and height; known

asthmatics; concurrent empyema thoracis or illness severe enough to require ventilation;

clinical evidence of any heart disease, renal or hepatic insufficiency; and known

hypercalcemia or allergy to vitamin D

Randomization and Allocation Concealment

The eligible candidates will be allotted a study number. These numbers shall correspond

to the order of patients entering the study. Simple randomization will be done according

to a computer generated random number table on a master list to one of two treatment

strategies. Allocation concealment will be done by sealed envelope technique, the

envelope to be opened at the time of intervention. Both the caregiver and the subject will

be blind regarding the content of the drug being given.

Intervention

Children with severe pneumonia will be randomly assigned to receive supplementation

with either vitamin D or placebo. The drug will be available in granule form and given

dissolved in milk. Both drug and the placebo will be identical with respect to appearance,

color, odor, amount and taste. The placebo shall be prepared in collaboration with the

11

Department of Pharmacology, University College of Medical Sciences. The dose of

vitamin D supplementation will be as 1000 IU per day for 5 days for infants (age < 1 yr),

and 2000 IU per day for 5 days for children (age 1-5 yrs).

We chose this dose because it is the tolerable upper limit as specified by the Food

and Nutrition Board of the Institution of Medicine, USA.25

Moreover, the doses being

given will be well below the „lowest observed adverse effect level‟ (LOAEL), and „no

observed adverse effect level‟ (NOAEL) for vitamin D, set at 95 mcg (3800 IU) and 60

mcg (2,400 IU) per day, respectively.26

The drug/placebo shall be administered at the time of enrolment (oral, nasogastric),

within 4 hrs of the first dose of parenteral antibiotics on the day of admission, and then

once daily 1 hr before breakfast for the next 4 days.

Obtaining Baseline Characteristics

Eligible cases will be evaluated with a detailed clinical history (nature and

duration of symptoms) and background characteristics including feeding practices

(breastfeeding history and age of introduction of complementary foods), immunization

status, and socio-demographic variables such as the parental education, occupation,

family income, number of siblings, housing, details of cooking fuel used in the

household, smoking, and history of lower RTI in a family member. Information will be

collected regarding the practice of exposure of the child to sunlight. Physical examination

will include vital signs (temperature, heart rate, respiratory rate, and blood pressure);

assessment of breathing effort, cyanosis, mental status, chest auscultation for crepitations

or wheezing, or both; and anthropometrical measurements. Respiratory rate will be

counted for full 60 seconds, after removing all clothes from the torso; chest indrawing

12

will be observed at the same time. The average of two readings will be recorded. If the

readings differ by more than 5 breaths per minute, a third reading will be taken and the

two closest readings will be averaged. The child has to be awake and not crying during

these measurements. Axillary temperature will be taken with a standardized mercury

thermometer. Fever will be defined as temperature >38C. Baseline oxygen saturation

will be measured using a pulse oximeter with a probe on a finger or toe, in room air.

Hypoxia will be defined as oxygen saturation <95% in room air. Weight and height will

be measured using standard techniques.19

The findings will be recorded in a Performa

(Annexure 2). A blood sample will be obtained for hematocrit, serum electrolytes,

creatinine, C-reactive protein (CRP), arterial blood gas, calcium, phosphorus, alkaline

phosphatase and blood culture. Chest X-ray will be done at the time of admission and at

discharge.

Treatment of Severe Pneumonia

Measures will be taken to establish and maintain a patent airway, breathing and

circulation, and oxygenation, if required. As soon as the cardio respiratory status has been

stabilized, an IV access will be established and blood samples obtained. Patients will be

treated for severe pneumonia as per IAP protocol 2006.27

Hospital Stay

Data for respiratory rate, chest indrawing, oxygen saturation, auscultatory

findings, fever, feeding, cyanosis and mental status will be obtained every 8 hours, at the

beginning of the nursing shift (Annexure 3). Worsening of any one sign will qualify as

worsening condition and no change in any sign will constitute failure to improve. The

child will be reclassified from severe pneumonia to non-severe pneumonia when lower

13

chest indrawing and hypoxia are absent for 24 consecutive hrs, at which time oral

antibiotic, and oral feeding will be started. If any severe signs recur, the child will be

reclassified as severe. All children will receive atleast days of IV/oral antibiotics.

In case there is deterioration i.e. failure to maintain SaO2 > 92% in fiO2 > 0.6; the

patient is in peripheral circulatory failure; there is rising respiratory and pulse rate with

clinical evidence of severe respiratory distress and exhaustion with or without raised

paCO2 or there is recurrent apnea or slow irregular breathing, the child will be

transferred to the intensive care unit

Outcome Measures

Primary outcome variables: The primary outcome of interest will be the time to

resolution of severe pneumonia, and the duration of hospitalization. Resolution of severe

pneumonia will be considered when lower chest retraction and the danger signs (inability

to feed, lethargy, cyanosis or hypoxia) are no longer present. This will be measured in

hours. The duration of hospitalization will be defined as the time (in hours) between

study enrolment and discharge. The patient will be considered fit for discharge when

he/she is afebrile (axillary temperature < 37.5C), tachypnea has subsided, there is no

lower chest indrawing, and oral feeding has resumed, for a minimum continuous period

of 24 hr.

Secondary outcome variables: The secondary outcome variables shall include the

durations of tachypnea (respiratory rate cut off for severe pneumonia as per age), lower

chest retractions, and inability to feed.

Statistical Analysis

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The effect of vitamin D supplementation on outcome variable will be analyzed on

an intention to treat basis. The data will be analyzed by using SPSS software (version 11:

SPSS; Chicago). Chi square test or Fisher‟s Exact test will be used to compare

categorical variables. All quantitative variables shall be compared by unpaired t test or

analysis of variance (ANOVA).

Kaplan–Meier survival function plots will be constructed to compare the median

duration for each outcome variable. The admission will be set as time zero. Cox

proportional hazard regression model will be constructed to adjust the treatment effects

for potential confounding factors and to evaluate the effect modification. Risk ratio (RR)

will be estimated to compare the recovery rate in the two groups. P < 0.05 will be

considered as significant.

15

REFERENCES

1. United State Agency for International Development. Acute Respiratory Infection (ARI)

Programs. Global Health - Child Survival. Washington, DC: USAID;2002.

2. UNICEF/WHO. Pneumonia: The forgotten killer of children. Geneva: WHO;2006.

3. Monto AS, Lehmann D. Acute respiratory infections (ARI) in children: prospects for

prevention. Vaccine 1998;16:1582-8.

4. World Health Organization. The Management of Acute Respiratory Infection in

Children: Practical Guidelines for Outpatient Care. Geneva: WHO;1995.

5. Zinc Investigators' Collaborative Group. Prevention of diarrhea and pneumonia by zinc

supplementation in children in developing countries: pooled analysis of randomized

controlled trials. J Pediatr 1999;135:687-97.

6. Vitamin A and Pneumonia Working Group. Potential interventions for the prevention of

childhood pneumonia in developing countries: a meta-analysis of data from field trials to

assess the impact of vitamin A supplementation on pneumonia morbidity and mortality.

Bull WHO 1995;73:609-619.

7. Salimpour R. Rickets in Tehran. Arch Dis Child 1975;50:63-5.

8. Lubani MM, Al-Sheb TS, Sharda DC, Quattawi SA, Ahmed SAH, Moussa MA, et al.

Vitamin-D deficiency rickets in Kuwait: the prevalence of preventable disease. Ann Trop

Paediatr 1989;3:134-9.

9. Lawson DEM, Cole TJ, Salem SI. Aetiology of rickets in Ethiopian children. Hum Nutr

Clin Nutr 1987;41:199-208.

16

10. Auss-Kettis A, Bjornesjo KB, Manneimer E, Cvibach T, Clark P, Mammo D. the

occurrence and clinical picture of disease in a clinic in Addis Ababa. Ethiopia Med J

1965;3:109-21.

11. Muhe L, Lulseged S, Mason KE, Simoes EAF. Case control study of the role of

nutritional rickets in the risk of developing pneumonia in Ethiopian children. Lancet

1997;349:1801-4.

12. Lulseged S. Severe rickets in a children hospital in Addis Ababa. Ethiopia Med J

1990;28:175-81.

13. Wayse V, Yousafzai A, Mogale K, Filteau S. Association of subclinical vitamin D

deficiency with severe acute lower respiratory infection in Indian children under 5 years.

Eur J Clin Nutr 2004;58:563-7.

14. Davis PD. Tuberculosis and migration. The Mitchell Lecture 1994. J R Coll Phys London

1995;29:113-8.

15. Wilkinson RJ, Pasvol G. Tuberculosis, HIV, hormones and Children. J R Coll Phys

London 1995;29:86-8.

16. Grange JM, Davis PD, Brown RC, Woodhead JS, Kardijito T. A study of vitamin D

levels in Indonesian patients with untreated pulmonary tuberculosis. Tubercle

1985;66:187-91.

17. Wilkinson RJ, Llewelyn M, Toossi Z, Patel P, Pasvol G, Lalvani A, et al. Influence of

vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among

Gujarati Asians in west London: a case control study. Lancet 2000;355:618-21.

18. Atiq M, Suria A, Nizami SQ, Ahmed I. Vitamin D status of breastfed Pakistani infants.

Acta Paediatr 1998;87:737-40.

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19. Goswami R, Gupta N, Goswami D, Marwaha RK, Tandon N, Kochupillai N. Prevalence

and significance of low 25-hydroxyvitamin D concentrations in healthy subjects in Delhi.

Am J Clin Nutr 2000;72:472-5.

20. Andran N, Yordam N, Ozon A. Risk factors for vitamin D deficiency in breast-fed

newborns and their mothers. Nutrition 2002;18:47-50.

21. Brooks WA, Yunus M, Santoshan M, Wahed MA, Nahar K, Yeasmin S, et al. Zinc for

severe pneumonia in very young children; double- blinded placebo- controlled trial.

Lancet 2004;363:1683-8.

22. Indrayan A, Gupta P. Sampling techniques, confidence intervals, and sample size. Nat

Med J India 2000;13:29-36.

23. Gupta P, Shah D. Protein Energy Malnutrition. In: Ghai OP, Gupta P, Paul VK. Essential

Pediatrics. 6th

edition. New Delhi: CBS Publishers and Distributors; 2004. p. 101-3.

24. de Onis M, Garza C, Onyango AW, Martorell R. WHO Child Growth Standards. Acta

Paediatr 2006;95 (Suppl 450):1-104.

25. Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes for Calcium,

Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, DC: National Academy

Press; 1999.

26. Office of Dietary Supplements: NIH Clinical Center. Dietary Supplement Fact Sheet:

Vitamin D. Bethesda: National Institutes of Health; 2007.

27. Agarwal R, Singh V, Yewale V. RTI Facts. IAP Consensus Guidelines on Rational

Management of Respiratory Tract Infections in Children. Mumbai: Indian Academy of

Pediatrics; 2006.

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ANNEXURE-I

INFORMED CONSENT

I ------------------------ parent/guardian of ---------------------------- exercise my free will,

hereby, give my consent to include my son/daughter as subject in the clinical study titled

“Vitamin D for severe pneumonia in under five children”, a double blind randomized

placebo controlled STUDY. I have been informed to my satisfaction, in a language

understood by me by the investigators, of the purpose and nature of study including

laboratory investigations. I have been explained about the possible consequences of the

study, which I find acceptable.

Signature of parent/ surrogate Signature of investigator

Signature of witness

Name:

Address:

Date:

19

Insert copy of consent form in the vernacular

20

ANNEXURE-II: CASE RECORD FORM

Name: Age: C.R number

Age Date of admission

Sex Date of discharge

Date of birth Serial number

Father‟s name Allocation number

Address: Allocation group

Phone:

Education of parents: Literate/ illiterate

Environment temperature: Max Minimum

Type of weather: cloudy / clear

Temperature during last four days: Range --------- to ---------

Type of weather during last 4 days: cloudy / clear

Term / preterm / LBW:

Immunization status:

Family history of tuberculosis:

History of previous pneumonia in child:

Breast-feeding given: Yes / no

Duration of breast feeding (in months):

Exclusive breast-feeding given: Yes / no, if yes then duration.

If not then type of top feed (cereal / milk based):

Duration when complementary feeding were started:

History of smoking in family:

Fuel used for cooking / lightening: Kerosene / coal / wood / electricity.

No. of person among the same room with the child:

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Dwelling status:

Socioeconomic status:

Father‟s education

Father‟s occupation

Father‟s income ( Rs)

Daily activity (Out door/ Domestic):

Percentage of body covered with clothes when outdoor:

Diet taken: Veg / non veg.

SYMPTOMS

Sr. No. Symptoms 1 = yes / 2 = no Duration in hrs

1. Cough

2. Running nose

3. Fever

4. Average temp.

5. Cyanosis

6. Respiratory distress / tachypnea

7. Poor oral intake

8. Altered sensorium / irritability

9. Apnoea

10. Others

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EXAMINATION

A) ANTHROPOMETRY

S.no Parameter Present Expected

1 Weight (kg)

2. Length (cm)

3. Chest circumference (cm)

4. Head circumference (cm)

5. Midarm circumference (cm)

B) PHYSICAL EVALUATION ON ADMISSION

General physical examination

HR: RR: BP: Temperature:

Pallor/cyanosis/icterus/clubbing/pedal edema/significant lymphadenoapthy

Spo2/ hydration status.

Systemic examination

A) Respiratory system

Chest retractions: supraclavicular/ infraclavicular/ subcostal.

Accessory muscles of respirations

Crepitations

Bronchial breathing

Wheezing

B) CVS

C) Abdominal system

Liver

Spleen

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D) CNS

GCS

Investigations

1. Haemogram

2. C reactive protein

3. Blood glucose

4. Blood urea

5. Serum electrolytes

6. Serum Ca/Ph/AlkPO4

7. ABG

8. Blood culture

9. Chest Xray findings: Shadowing (patchy/diffuse) / Pleural effusion / Hyperinflation /

Atelectasis / Pneumothorax / Hilar adenopathy / bronchovacular markings / Others

24

Drug Dispensing

Day Date Time Dose given Watch for vomiting

for next 15 min,if yes

then repeat the dose

Watch for

adverse effects

1.

2.

3.

4.

5.

-When was oral feed started

-Details of antibiotic recieved

Final Outcome –Improved and discharged / LAMA / death / absconded

25

ANNEXURE-III: MONITORING SCHEDULE

Date\

Time

Pulse

Rate

Respiratory

Rate

Lower Chest

retractions

Spo2 Temperature Cyanosis Cough Oral

intake

Altered

sensorium

Day 1

0 hrs

8 hrs

16 hrs

24 hrs

Day 2

8 hrs

16 hrs

24 hrs

Day 3

8 hrs

26

16 hrs

24 hrs

Day 4

8 hrs

16 hrs

24 hrs

Day 5

8 hrs

16 hrs

24 hrs