SK Roy1, Rubhana Rakib1, Wajiha Khatun1,T' Azim1

1
Zinc supplementation in the management of
shigellosis in malnourished children in Bangladesh

• SK Roy1, Rubhana Rakib1, Wajiha Khatun1,T. Azim1
• George J Fuchs2
• 1ICDDR,B Centre for Health and Population
  Research, Dhaka, Bangladesh 
• 2 Department of Pediatrics, Arakansas University
  for Medical Science, AR USA
• Scaling up of Zinc- The Way Forward
• May 6-7, 2007
•  

2
Background

• The worldwide incidence of shigellosis is
  estimated to be 164.7 million, of which 163.2
  million are in developing countries (with 1.1
  million deaths)
• A total of 69 of all episodes and 61 of all
  deaths attributable to shigellosis involved
  children under 5 years of age
• Zinc supplementation had shown reduced clinical
  duration, severity of acute persistent
  diarrhoea, growth faltering and morbidity of the
  malnourished children

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Background

• In a study in shigella patients, Zinc acetate (15
  mg per day) was given to see the effect on
  intestinal permeability changes and protein loss.
  The study had shown that --
• -- There was no significant differences in
  duration of shigellosis and stool volume in the
  zinc supplemented group compared to the placebo
  group.
• (Alam AN , 1994)

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Background

• Zinc supplementation improved immunity
  (Lymphocyte proliferation, specific
  immunoglobulin G response) in shigella patients
• (Raqib R, Roy SK, 2004)
• Zinc treatment also enhanced seroconversion to
  shigellocidal antibody titre and increased the
  proportions of B lymphocytes and plasma cells
  during the acute phase of shigellosis
• (Rahman MJ, Roy SK, 2005)

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Physiological Functions of Zinc
Brain development
Synthesis and metabolism of protein and
nucleic acid
Immunity
Zinc
Wound and burn healing
Functioning of insulin
Epithelial cell lining
Membrane stabilization
Calcification and mineralization of bone
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Zinc metabolism in diarrhoea

• Zinc is excreted proportionately high with
  severity of diarrhoea
• Zinc absorption is substantially reduced during
  diarrhoea

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Loss of total zinc (mg) over 4 days in stool
during diarrhoea and recovery phase Di
arrhoea Recovery p value Rice sujiZn
(15) 35.511.12 5.03.34 lt0.001 Rice suji
Placebo (19) 9.86.2 4.44.5
0.24 Chicken diet zn (15) 28.110.5 8.27.0 0.00
4
Roy et al 2001
t-test
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Animal model study on net transport of water and
electrolytes during in-vivo Perfusion
(Mean SEM)
Absorption ZD ZAL ZDR
Per/cm/hr (n5) (n5) (n5)
Water (?l) 27.62.0
48.55.8 57.75.2
Sodium (mmol) 3.51.1
7.22.0 7.73.0
Potassium (mmol) 0.070.2
0.070.02 0.030.1
 
Roy et al 1985
plt0.001 plt0.005
4
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Zinc in Cholera
Net secretion of water, sodium and potassium in
zinc deficient,
acutely
repleted
and ad
Libitum
zinc fed rats in response to cholera toxin (mean
SEM)
Water
2
Sodium
Potassium
10
0
0
-
10
of water
-
2
-
20
Micro liter/cm/hr
Electrolytes m.mol/cm/hr
-
4
Transport
-
30
-
40
-
6
-
50
ZD
-
8
-
60
ZDR
-
70
-
10
ZAL
Roy et al. 1985,2006
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Diarrhoea resulted from Zn deficient animal
study Deficient Zn in diet
Growth
Clinical abnormalities
Intestinal mucosa
Ultra-structural abnormality
Enterocyte size
Enterocyte population
Membrane defect
Lateral space
Desmosome defect
Mitochondrial disruption
Lysosomal activity
Endoplasmic reticulum defect
Ribosomal defect
Reduced absorption
Increased secretion
Increased net secretion of Water and electrolytes
Diarrhoea
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Total stool weight/kg body weight median
(range) Placebo Zinc p
value All children 329 (32 - 1464) 238
(35 - 2416) 0.06 n
37 n 37 Height/age
326 (31 - 1460) 232 (33 - 2496)
0.02lt 95 n 33 n
34 Serum zinc 330 (99 - 1464) 279
(43 - 2416) 0.05(lt14 ?mol/L
) n 25 n 30
Mann-Whitney U test

(Roy et al, 1990)
Impact of zinc supplementation on stool output
in children during acute diarrhoea
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Analysis Effect Measure Effect
Size (95 CI) Pooled Analysis Lower
Probability of 15 (8, 22)(n3)
Continuing Diarrhea Pooled-Analysis
Reduction in 16 (7, 26) (n4)
Mean DurationZinc
investigators collaborative group.Pooled analysis
of zinc supplementation trials effects on
diarrhoea and pneumonia,2001
Effect of Zinc Supplementation on Duration of
Acute Diarrhea Episode
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WHO/UNICEF Recommendations (2004)

• Provide children with 20 mg per day of zinc
  supplementation for 1014 days (10 mg per day for
  infants under six months old)

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Hypothesis
Zinc supplementation in malnourished children
with S. flexneri infection decreases the severity
of the acute illness and promotes subsequent
growth
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General objectives
To evaluate the impact of zinc supplementation in
children with Shigellosis.  
Specific objectives

• To evaluate the impact of zinc supplementation
  on
•     Duration of recovery
•   Disappearance of blood and mucous in stool.
•   Weight gain during recovery and beyond
•   Length gain in subsequent period
• Episodes of illness during follow-up

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Materials and Methods
Study design
Randomized double blind,placebo controlled
clinical trial Dhaka Hospital of ICDDR,B
Centre for Health and Population
Research  
Setting
Study Population 56 Children with Shigellosis
aged 12-59 months. 28 children in zinc group
and 28 children in Placebo group.
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Inclusion criteria

• Age 12-59 months
• Sex Both
• Diarrhoea Within 24 hours of onset
• Moderate malnutrition(61-75 Weight/Age NCHS
  Median)
• Duration of diarrhoea less then 3 days
• Culture confirmed S. flexneri in stool on
  enrolment

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Randomization Zinc or Placebo  
Study group     Zinc Group Placebo
Group (Zinc Multivitamin
( Multivitamin
Pivmecillinum )
Pivmecillinum )
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Dose of zinc 20mg elemental zinc daily for two
weeks. Dose of pivmecillinum Syp/tab 60mg . kg
body wt-1d-1 in 4 divided doses for 5 days
Clinical management Diet     Standardized
hospital diet 100- 125 Kcal and 3-4 g protein in
mixed food.     The zinc content of the
hospital diet was ?7-8 mg/d. Follow-Up Two
weekly Follow up was done at home for 6 months.
Data Analysis Data were analyzed using SPSS/PC
version 10.0 and EPI STAT version 6.    
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Trial profile
98 children were screened for shigellosis
56 children were recruited in the study

Zinc
Placebo
28
28
56
4 Withdrawal during 1-7 days of treatment
2 Withdrawal during 1-7 days of treatment
50
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Clinical response of patients with Shigellosis
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Proportion of children with probability of having
diarrhea by recovery days
P 0.02
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Comparison of duration of clinical recovery
(median days) between children receiving zinc and
placebo


Mann Whitney
U test
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Impact of Zinc supplementation on weight gain
during shigellosis (Mean S.D)
Body Weight (Kg)
On Admission
At Discharge Weight gain p Value

(g. kg-1 bdwt)
Placebo 9.31.4
9.61.8 27.8 0.12
(n24) Zinc
8.81.2 9.20.4 47.7
0.00 (n26) Paired t-test




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Effect of zinc supplementation on morbidity
during 6 months of followup after Shigellosis
(Geometric Mean, 95 CI)
Data were log transformed before using Students
t-test    
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Effect of zinc on cumulative weight gain in
shigella patients during 6 months of follow-up (
Repeated measure ANOVA)
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Impact of zinc on linear growth in shigella
patients during 6 months of follow-up (Repeated
measure ANOVA)
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Conclusion

• Zinc supplementation along with antibiotic
  therapy during shigellosis had distinct benefits-
• Reduced duration of recovery to half.
• Increased weight gain during hospitalization.
• Reduced diarrhoeal episodes during subsequent
  follow-up months.

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Recommendations

• The result of the present study proposes that
  zinc supplementation should be routinely provided
  to children with shigellosis.
• Further studies with larger sample size is
  recommended for confirming our results and
  exploring more benefits.

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Thank You