Zinc:

From Research to Programs

RCS Presents Seminar Series

September 2, 2004

The USAID Micronutrient Program

Diarrhea and Child Mortality

 11 million child deaths each year, two thirds of

these are preventable
 2 million child deaths from diarrhea
 88% of diarrhea deaths are preventable with
widespread use of ORS and zinc
supplementation for diarrhea treatment

Black, Morris, Bryce. Lancet 2003.

Jones, Steketee, Black et al. Lancet 2003.

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Global Diarrhea Treatment Policy

 WHO and UNICEF signed a joint policy for the

treatment of diarrhea in children in May 2004
 Treatment should include
– Liberal use of low-osmolarity Oral Rehydration
Solution to correct and prevent dehydration
– Zinc supplementation for 10-14 days to shorten
duration and severity of diarrhea
– Continued feeding
WHO/UNICEF. Joint statement on the clinical management of acute diarrhea. 2004.

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WHO and UNICEF Joint Statement

“Many more lives can be saved if these

advances are used in conjunction with
effective home treatment and use of
appropriate health services. To be the most
effective these revised recommendations
must become routine practice both in the
home and the health facility.”

WHO/UNICEF. Joint statement on the clinical management of acute diarrhea. 2004.

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Low Osmolarity ORS

 Lower levels of glucose and salt to

achieve lower osmolarity (245 mOsm/L)
 Results
– Improved efficacy of ORS
– Decreased the need for intravenous therapy
– Decreased stool output by 20%
– As safe and effective in children with cholera

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Global Zinc Deficiency

< 14.9% < 15-24.9% > 25%

Hotz & Brown. Food Nutr Bull 2004.

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Human Zinc Deficiency

 Nutritional dwarfism first recognized among

adolescent boys in Iran and Egypt in 1960’s
 Zinc deficiency now recognized as causing
hypogonadism, growth retardation, dermatitis,
decreased immune functions, and increased
infections

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Zinc for the Treatment of
Diarrhea: History

 Research started in the 1980s

 12 trials in acute diarrhea
 5 trials in persistent diarrhea
 Age groups: 3-60 mo
 Dose of zinc:  20 mg/d (range 5-45 mg/d)

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Zinc for the Treatment of
Diarrhea: Research Findings

• 25% reduction in duration of acute diarrhea

• 29% reduction in duration of persistent
diarrhea
• 40% reduction in treatment failure or death
in persistent diarrhea

Zinc Investigators’ Collaborative

Group.
Am J Clin Nutr 2000.
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 Effect of Zinc Supplementation on Duration of Acute
Diarrhoea/Time to Recovery
*India, 1988
*Bangladesh, 1999
*India, 2000
*Brazil, 2000
*India, 2001
Indonesia, 1998
India, 1995
Bangladesh, 1997
India, 2001
India, 2001
Nepal, 2001
Bangladesh, 2001

Pooled
0.5 0.75 1 1.25
*Difference in mean and 95% CI
Relative Hazards and 95% CI
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Therapeutic Effects of Zinc on
Diarrhea Severity
Diarrhea Percent
Country Outcome Reduction
India Frequency 18

India Frequency 39

Bangladesh Output 28

India Output 38

Brazil Frequency 59

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 Additional Preventive Aspects of
Zinc Treatment

• Zinc supplementation for 10-14 days has

preventive effect on childhood illnesses in the
2-3 months after treatment
• 25% reduction in diarrhea (9 studies)
• 34% reduction in pneumonia (5 studies)
• 36% reduction in malaria (2 studies)

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Preventive Effect of 10-14 days of Zinc
Supplementation on Diarrhea Incidence

Bangladesh (I)

Bangladesh (II)

Pakistan

Bangladesh (III)

Pooled
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2 2.25 2.5
Odds Ratio and 95% CI
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 Community-based Trial Demonstrates
Effectiveness of Zinc in Treating Diarrhea

 30 clusters in rural Bangladesh randomized for

health workers to deliver ORS alone or ORS +
zinc (20mg/d for 14 days) for diarrhea treatment
 2-year study with almost 12,000 child-years of
observation
 23% decrease in duration of all diarrhea
episodes in zinc treatment clusters compared to
control clusters (RH 0.77, 95% CI 0.69-0.86)
Baqui, Black, Arifeen. BMJ 2003.

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 Community-based Trial Demonstrates
Preventive Benefits of Zinc

• Zinc supplementation decreased . . .

• Overall diarrhea prevalence by 15%
(RR 0.85, 95% CI: 0.76, 0.96)
• Hospitalization from diarrhea by 19%
(RR 0.81, 95% CI: 0.65, 1.00)
• ALRI prevalence by 7%
(RR 0.93, 95% CI: 0.78, 1.10)
• Hospitalization from ALRI by 19%
(RR 0.81, 95% CI: 0.53, 1.23)

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 Community-based Trial Demonstrates
Preventive Benefits of Zinc

• Decreased overall mortality (non-injury) by 59%

(RR 0.49 95% CI: 0.25, 0.94)

• Decreased inappropriate antibiotic use rate from

34% in control clusters to 13% in zinc clusters
(p<0.01)

• Increased ORS use from 50% in control clusters

to 75% in zinc clusters (p<0.01)

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Safety of Zinc Supplementation
 8,500 children <5 y supplemented in 17 trials
 11,880 child years of observation in one trial
 Vomiting is the only reported adverse effect
– 5/7 trials report no differences between zinc and
placebo
– 2 trials report slightly higher vomiting rates in zinc
supplemented children
 4/4 trials show no difference in copper status
after 2 weeks of zinc supplementation

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Cost Effectiveness of ORS and
Zinc Supplementation
 Benefit in diarrhea therapy and benefit on
mortality indicates cost-effectiveness
 Decreases the need for expensive
hospitalization
 Decreases the use of unnecessary antibiotics
and other drugs
 Further cost-benefit analyses are needed

Robberstad, Strand, Sommerfelt, and Black. Bull WHO 2004.

Baqui, Black, Arifeen. J Health Pop Nutr (In Press).

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Diarrhea Treatment -- Research to
Policy: Accomplishments to Date
• Recognition of the importance of decreasing
osmolarity in ORS
• Recognition of the positive effect of zinc on
duration and severity of diarrhea
• Recognition of the positive effect of zinc on
subsequent episodes on diarrhea and
pneumonia
• Recognition of the positive joint effect of ORS
and zinc on diarrhea mortality

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Diarrhea Treatment -- Research to
Policy: Accomplishments to Date
• Joint policy statement by WHO and UNICEF
recommending
– Low osmolarity ORS
– Zinc supplementation for 10-14 days
• Dispersible tablets developed and used in large-
scale research trials
• Applied for inclusion of zinc on the WHO
Essential Drug List
• Organization of a Global Task Force for
management of diarrhea
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Diarrhea Treatment -- Policy to
Programs
 Developing guidelines/training materials for use
in country programs & emergency situations
 Need to establish capacity to produce and
procure the zinc supplements & ORS supplies
 Develop delivery mechanisms, designed locally
 Social marketing proposed will require
public/private partnerships
 Need to test and perhaps create standards for
zinc supplies already on the market (quality
control)
 Need continuing donor financial support
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ORS and Zinc
Treatment of diarrhea is now
more effective
This is the chance to make a
difference

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Key references
 Reduced osmolarity oral rehydration salts (ORS) formulation. Consensus
statement of WHO and UNICEF. Geneva: World Health Organization; 2001.
Document WHO/FCH/CAH/01.22
 Jones G, Steketee RW, Black RE. How many child deaths can we prevent this
year. Lancet 2003;5(362):65-71.
 Black RE, Morris SS, Bryce J. Where and why are 10 million children dying every
year? Lancet 2003;28(361):2226-34.
 Baqui AH, Black RE, El Arifeen S. Effect of zinc supplementation started during
diarrhoea on morbidity and mortality in Bangladeshi children: community
randomised trial. BMJ 2002; 325(7372):1059-65.
 Hotz C and Brown KH. Estimated risk of zinc deficiency by country. Food Nutr
Bull 2004;25(4):S189-S195.
 Zinc Investigators’ Collaborative Group. Therapeutic effects of oral zinc in acute
and persistent diarrhea in children in developing countries: pooled analysis of
randomized controlled trials. AJCN 2000;72:1516-22.
 Robberstad B, Strand T, Black RE, and Sommerfelt H. Cost-effectiveness of zinc
as adjunct therapy for acute childhood diarrhoea in developing countries. Bull
WHO 2004; 82(7):523-31.

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 WHO/UNICEF. Joint statement on the clinical management of acute diarrhoea. 2004.
 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(6):689-97.
 Black RE. Zinc deficiency, infectious disease, and mortality in the developing world. J
Nutr 2003;133:1485S-1489S.
 Zinc Investigators’ Collaborative Group. Effect of zinc supplementation on clinical
course of acute diarrhoea. J Health Popul Nutr 2001;19(4):338-46.
 International Zinc Nutrition Consultative Group (IZiNCG) Technical Document #1.
Food Nutr Bull March 2004;25 Supplement 2.
____________________________________________________________________

THANK YOU
For more information contact: Phil Harvey, pharvey@istiinc.com or
Roy Miller, rmiller@istiinc.com

The USAID Micronutrient Program