Trace Element Undernutrition: Biology to Interventions

Zinc Deciency, Infectious Disease and Mortality in the

Developing World1,2
Robert E. Black3
Department of International Health, Johns Hopkins Bloomberg School of Public Health,
Baltimore, MD 21205

KEY WORDS:  child nutrition  diarrhea  malaria  pneumonia  zinc

Zinc deficiency, which appears to be widespread in developing countries, has long been recognized to impair growth
and immune function (1,2). Although effects on the immune
system are known to occur with even mild zinc deficiency (3),
the importance of this with regard to the risk of childhood
infectious diseases has only recently become better understood
(4). Observational studies provide some evidence of a relationship between low plasma-zinc concentration in children and
higher risk of infectious diseases (5), but inferences from these
studies are limited owing to a lack of adequate zinc-deficiency
indicators at the individual level.

Randomized, controlled trials of zinc supplementation

provide the best evidence for the roles of zinc in infectious
diseases, which are presumably mediated through alterations in
host defenses including epithelial barriers and immune
responses. Results of these trials are reviewed and summarized
with regard to effects on diarrhea, pneumonia and malaria
incidence as well as on total child mortality. In addition to these
preventive trials in which zinc was given on a routine, usually
daily, basis for an extended period of time, there are other trials
in which zinc was provided as an adjunct to therapy for acute or
persistent diarrhea. This review is limited to published trials.
Prevention of infectious disease morbidity
The effects of zinc supplements on rates of diarrhea and
pneumonia incidence have been well studied, and there is also
some information on malaria incidence. In total, 11 trials are
available for inclusion in this review (617). Ten of these trials
assess the effect of zinc supplementation on the incidence of
diarrhea, five on the incidence of pneumonia and three on the
incidence of malaria (Table 1). These trials were performed
with preschool children who reside in typical developing
country settings. Although the settings of these trials might
be expected to include a substantial prevalence of zinc
deficiency as would be expected in most developing countries,
the populations of children were not preselected on the basis of
zinc deficiency. Six of the trials were performed with all
children in the targeted age group, whereas five of the trials had
some enrollment restrictions (Table 1). Two of these trials
employed children that were selected with at least a moderate
degree of undernutrition, whereas one trial stratified the
enrollment based on individuals who were or were not stunted.

1
Published in a supplement to The Journal of Nutrition. Presented as part of the
11th meeting of the international organization, Trace Elements in Man and Animals
(TEMA), in Berkeley, California, June 26, 2002. This meeting was supported by
grants from the National Institutes of Health and the U.S. Department of Agriculture
and by donations from Akzo Nobel Chemicals, Singapore; California Dried Plum
Board, California; Cattlemens Beef Board and National Cattlemens Beef
Association, Colorado; GlaxoSmithKline, New Jersey; International Atomic Energy
Agency, Austria; International Copper Association, New York; International Life
Sciences Institute Research Foundation, Washington, D.C.; International Zinc
Association, Belgium; Mead Johnson Nutritionals, Indiana; Minute Maid Company,
Texas; Perrier Vittel Water Institute, France; U.S. Borax, Inc., California; USDA/ARS
Western Human Nutrition Research Center, California and Wyeth-Ayerst Global
Pharmaceuticals, Pennsylvania. Guest editors for the supplement publication
were Janet C. King, USDA/ARS WHNRC and the University of California at Davis;
Lindsay H. Allen, University of California at Davis; James R. Coughlin, Coughlin &
Associates, Newport Coast, California; K. Michael Hambidge, University of
Colorado, Denver; Carl L. Keen, University of California at Davis; Bo L. Lonnerdal,
University of California at Davis and Robert B. Rucker, University of California at
Davis.
2
This work is funded in part by the Johns Hopkins Family Health and Child
Survival Cooperative Agreement with the U.S. Agency for International
Development.
3
To whom correspondence should be addressed. E-mail: [email protected].

0022-3166/03 $3.00 2003 American Society for Nutritional Sciences.

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Downloaded from jn.nutrition.org by guest on January 19, 2015

ABSTRACT Zinc deciency places children in many low-income countries at increased risk of illness and death
from infectious diseases. Randomized controlled trials of zinc supplementation provide the best estimate of this risk
through demonstrated preventive benets. In six of nine trials that evaluated prevention of diarrhea, signicantly
lower incidence of diarrhea occurred in the zinc group than in the controls; a pooled analysis demonstrated 18%
(95% condence interval, 728%) less diarrhea. In ve trials, a lower rate of pneumonia infection was found in the
zinc-supplemented groups, and there was some indication of a preventive effect in three trials with a clinical malaria
outcome. Zinc was also found to have a therapeutic benet in seven trials of acute diarrhea and ve of persistent
diarrhea. Studies to evaluate the effect of zinc supplementation on mortality are under way, but a recently published
study from India identied a 68% reduction in mortality in small-for-gestational-age term infants that were
supplemented with zinc from 1 to 9 mo of age. The important effects of zinc deciency are now clear, and nutrition
programs should address this prevalent problem. J. Nutr. 133: 1485S1489S, 2003.

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TABLE 1
Trials evaluating effects of zinc supplementation on preventing morbidity in children
Country

Ref.

Zinc supplement
(mg) and type

Duration (wk)

No. of children in
zinc/control group

Age
(mo)

Enrollment restriction1

The Gambia
Vietnam
India
Mexico
Guatemala
Papua New Guinea
Jamaica
Peru
Ethiopia
Burkina Faso
India

(6)
(7)
(8,9)
(10)
(11)
(12)
(13)
(14)
(15)
(16)
(17)

70, acetate
10, sulfate
10, gluconate
20, methionate
10, sulfate
10, gluconate
5, sulfate
10, gluconate
10, sulfate
12.5, sulfate
10/20, gluconate

60
22
26
54
28
46
12
26
26
26
16

55/54
73/73
286/293
97/97
45/44
136/138
31/30
80/79
92/92
356/353
1,241/1,241

628
436
635
1836
69
660
624
635
612
631
635

W/A and H/A , 2z

Recovered from acute diarrhea

W/H , 2z
Recovered from persistent diarrhea
Stratied on H/A , 2z

W/A, weight for age; H/A, height for age; W/H, weight for height.

diagnosed by clinical examination by two physicians using

specific predefined clinical criteria (17).
The information regarding the effects of zinc supplementation on malaria is more limited. Studies in the Gambia and
Papua New Guinea reveal reductions of about one-third in
the rate of visits to health facilities for a clinical syndrome
consistent with malaria and confirmed by parasitologic examination of the blood. Given the extremely high rate of
malaria parasitemia in some endemic populations, visits to
health facilities with confirmed malaria are generally considered
to be the most valid measure of malaria incidence and have
been used by the World Health Organization (WHO) to
estimate the malaria burden of disease (19). The third trial of
zinc supplementation that examined an effect on malaria was
done in Burkina Faso. This trial had only community-based
surveillance of malaria and did not ascertain health-facility
visits. The study found no effect of zinc supplementation on
rates of fever as ascertained from household visits 6 d/wk. This
may not be surprising in that the study in Papua New Guinea
did not find an effect of zinc supplementation on malaria as
ascertained from community-based surveillance but did find
a significant benefit with regard to malaria visits to the health
facilities (12).
Therapeutic effects for diarrhea

TABLE 2
Effects of zinc in prevention of diarrhea, pneumonia, malaria
and mortality in children

Country
The Gambia
Vietnam
India
Mexico
Guatemala
Papua New Guinea
Jamaica
Peru
Ethiopia
Burkina Faso
India
1
2

Diarrhea Pneumonia Malaria Mortality

incidence incidence incidence (% lower)
Ref. (% lower) (% lower) (% lower)
(6)
(7)
(8,9)
(10)
(11)
(12)
(13)
(14)
(15)
(16)
(17)

441
8
371
181
12
8
121
551
161
N/A2

441
431

88
15

261

Statistically signicant, i.e., P , 0.05.

N/A, not available.

32

381

681

58

There are currently 12 published trials of zinc supplementation in the therapy of acute or persistent diarrhea that are
available for review (2030). Seven of these trials are for acute
diarrhea (Table 3). The five trials on persistent diarrhea are
likely the only ones that will be available, because WHO has
recommended that zinc be used in the treatment of persistent
diarrhea, which makes controlled trials no longer appropriate.
Five additional trials of zinc supplementation for acute diarrhea
have been conducted. Although these are as-yet unpublished,
they were reviewed in a recently published meeting report (31).
Most find beneficial effects of zinc supplementation as do the
published trials.
The trials on persistent diarrhea, i.e., episodes lasting $14 d,
demonstrate overall benefits of zinc supplementation (Table 4).
Generally, the zinc-supplemented children have shorterduration episodes, lower stool frequency or stool volume and
importantly, in three of the four studies, a reduction in
treatment failure or death. A meta-analysis of these five trials
yields a statistically significant summary effect (32). Overall, in
this analysis there is a 42% (95% CI, 1063%) reduced rate of
treatment failure or death. In a pooled analysis of these trials,

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Two of the trials enrolled children after they had recovered

from either acute or persistent diarrhea. Taken collectively, the
studies were done in settings that represent a wide range of
conditions with regard to nutritional status and risk of
infectious diseases.
These trials are consistent in showing that zinc-supplemented children have lower rates of diarrhea than control
children (Table 2). Six of the nine studies had statistically
significant differences between the zinc and control groups. A
pooled analysis that includes most of these studies reveals the
overall incidence of diarrhea in zinc-supplemented children to
be 18% [95% confidence interval (CI), 728%] less than in
children who did not receive zinc (18). This analysis shows
trends (not statistically significant) that children with lower
plasma zinc concentrations or wasting, or were female or in
their second or later year of life (versus infants) have greater
effects of zinc supplementation.
The five studies with available information are also
consistent in showing that zinc-supplemented children have
a lower incidence of pneumonia than control children (Table
2). In the pooled analysis, there was a 41% (95% CI, 1759%)
lower rate of pneumonia in zinc-supplemented children (18). A
study that was more recently completed shows a statistically
significant 26% reduction in the incidence of pneumonia as

ZINC DEFICIENCY, INFECTIOUS DISEASE AND MORTALITY

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TABLE 3
Trials evaluating therapeutic effects of zinc in diarrhea
Country

Ref.

Zinc supplement
and type

No. of children in
zinc/control group

Age
(mo)

India
India
India
Bangladesh
Bangladesh
Indonesia
Peru
Pakistan
Bangladesh
India
Bangladesh
Nepal

(20)
(21)
(22)
(23)
(24)
(25)
(14)
(26)
(27)
(28)
(29)
(30)

20 mg, sulfate
20 mg, sulfate
20 mg, gluconate
20 mg, acetate
20 mg, acetate
45 mg/kg, acetate
20 mg, gluconate
3 mg/kg, sulfate
14/40 mg, acetate
40 mg, sulfate
20 mg, acetate
15/30 mg, gluconate

25/25
20/20
456/481
57/54
95/95
739/659
139/136
43/44
343/341
44/36
44/44
445/449

618
618
635
324
324
325
635
636
623
324
624
635

Enrollment restriction1
Exclude moderate-severe malnutrition
Exclude moderate-severe malnutrition
Exclude severe malnutrition
Include W/A , 76th percentile

Include W/A , 2z
Exclude severe malnutrition
Include W/A , 80%
Include W/A , 2z

Type of
diarrhea
Acute
Persistent
Acute
Acute
Persistent
Acute
Persistent
Persistent
Acute
Acute
Persistent
Acute

W/A, weight for age.

Effects on child mortality

Diarrhea, pneumonia and malaria are the most common
causes of death among children in developing countries. The
consistent and sizeable effects of zinc supplementation on the
incidence and severity of these infectious diseases logically

leads to the hypothesis that there will be a reduction in child

mortality with zinc supplementation. One recent study in India
provides preliminary evidence that this is correct (33). A
randomized, double-blind, controlled trial enrolled 1,154 fullterm small-for-gestational-age infants to receive one of the
following supplements: riboflavin; riboflavin and zinc (5 mg as
sulfate); riboflavin, calcium, phosphorus, folate and iron; or
riboflavin, zinc, calcium, phosphorus, folate and iron. Children
were supplemented between 30 and 284 d of age and visited 6
d/wk to provide the supplement and conduct surveillance for
illness and death. When the main effects of the zinc or the
other micronutrients are examined by survival analysis, it is
found that zinc supplementation is associated with a significantly lower mortality with a ratio of 0.32 (95 CI, 0.120.89).
Calcium, phosphorus, folate and iron supplementation are not
associated with a reduction in mortality.
The widespread demonstration that zinc supplements
reduce the incidence of diarrhea and the two-thirds reduction
in mortality that was found in the Indian study have led to the
initiation of three large trials of zinc supplementation in India,
Nepal and Zanzibar. All trials will evaluate the effect of zinc on
child mortality, and the studies in India and Zanzibar will also
assess the effects on hospitalizations from infectious diseases
(diarrhea and pneumonia in both and malaria also in Zanzibar).
Results are expected by 2004.

TABLE 4
Effects of zinc in therapy of acute and persistent diarrhea
Country

Ref.

Episode duration

India
India
India
Bangladesh
Bangladesh
Indonesia
Peru
Pakistan
Bangladesh
India
Bangladesh
Nepal

(20)
(21)
(22)
(23)
(24)
(25)
(14)
(26)
(27)
(28)
(29)
(30)

9% Shorter duration
19% Shorter duration
21% Reduced probability of continuing diarrhea1
14% Reduced probability of continuing diarrhea
15% Reduced probability of continuing diarrhea
11% Reduced probability of continuing diarrhea1
18% Reduced probability of continuing diarrhea1
2% Reduced probability of continuing diarrhea1
20% Reduced probability of continuing diarrhea
32% Shorter duration1
55% Reduced probability of continuing diarrhea1
26% Reduced probability of continuing diarrhea1

Statistically signicant, i.e., P , 0.05.

Severity
18%
21%
39%
28%

Less stool frequency

Less stool frequency
Less stool frequency1
Lower stool output

No effect

38% Lower stool output1

8% Less stool frequency1

Treatment
failure/death

63% Less1

19% Less
58% More

75% Less1

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the subgroups of children who are , 12 mo of age, wasted or

male have statistically significant effects of zinc supplementation. The corresponding alternative groups have smaller
beneficial effects that are not statistically significant (Table 4).
Of the seven trials on acute diarrhea, all find that the episode
duration is shorter in zinc-supplemented children, and four of
these trials are individually statistically significant. Likewise, all
of the five trials that measure an effect on diarrhea severity find
that zinc-supplemented children have less diarrheal stool
output than controls; three of these trials find statistically
significant benefits. In a pooled analysis with original data from
three of these trials, within subgroups by age (, 12 mo versus $
12 mo), wasting (, 22z versus $ 22z weight per height) and
sex, each subgroup has significant benefits of zinc supplementation. In subgroups of children with lower or higher initial
plasma zinc concentrations, there are significant pooled effects
in both groups, although the effects tend to be greater in the
subgroup with lower plasma zinc concentration.

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DISCUSSION

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The substantial prevalence of zinc deficiency in children in

developing countries and its important consequences for higher
rates of illness and death from infectious diseases in children in
developing countries leads to the conclusion that the global
burden of disease due to this nutritional problem is very large.
This unnecessary burden can be reduced by existing means of
improving the available zinc in the diet (34). Although this may
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consistent with those reported here and are briefly summarized
in the meeting report. The report concludes that there is now
enough evidence demonstrating the efficacy of zinc supplementation on the clinical course of acute diarrhea. Although
there is encouraging information from several large-scale,
community-based studies that use zinc supplements to treat
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settings. In particular, there is a need to understand how to
promote zinc supplements to treat diarrhea without interfering
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of treatment. The meeting concludes that future studies should
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maximize adherence to therapy.
The important role of zinc deficiency in childhood infectious
diseases is now clear. The challenge is to develop the public
health response to address this deficiency and thereby improve
child health.

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