Zinc supplementation as adjunct therapy in children with measles
accompanied by pneumonia: a double-blind, randomized
controlled trial1–3
Dilip Mahalanabis, A Chowdhury, S Jana, Mihir K Bhattacharya, MK Chakrabarti, Mohammed A Wahed,
and Mohammad A Khaled
ABSTRACT
Background: Zinc deficiency, common in developing countries,
is associated with decreased immunocompetence. Zinc supple-
mentation benefits children with acute and persistent diarrhea and
prevents pneumonia. Most deaths from vaccine-preventable dis-
eases are from measles and whooping cough; pneumonia is the
most common complication of measles and often the proximate
cause of related deaths.
Objective: We evaluated the effect of zinc supplementation on
episodes of illness in children with measles accompanied by
pneumonia.
Design: In a double-blind, randomized controlled trial, children
aged 9 mo–15 y who were admitted to the Infectious Diseases
Hospital in Calcutta with clinically severe measles accompanied
by pneumonia and who had been ill for ≤ 7 d were randomly
assigned to receive zinc (20 mg, in elemental form as acetate,
twice daily for 6 d) or a placebo. All patients received standard
treatment with antibiotics and an initial 100 000-IU dose of vita-
min A (as palmitate) by mouth.
Results: Time-to-event analysis using the Cox proportional haz-
ards model (42 in the zinc group and 43 in the placebo group)
showed that the time needed for the resolution of fever and
tachypnea, the return of appetite, and the achievement of a
“much improved” or “cured” status was not different between
the 2 groups. A high proportion of children had low serum retinol
and zinc concentrations. Improvement in serum zinc and retinol
concentrations after 6 d of treatment was not different between the
2 groups.
Conclusion: Children with severe measles accompanied by pneu-
monia treated with antibiotics and vitamin A did not show any
additional benefit from also receiving a zinc supplement. Am
J Clin Nutr 2002;76:604–7.
KEY WORDS Zinc supplementation, measles, pneumonia,
children, clinical trial, India
INTRODUCTION
Most deaths from vaccine-preventable diseases are from
measles and whooping cough. Pneumonia is the most common
complication of measles and the principal proximate cause of
measles-related deaths (1). Furthermore, pneumonia is a major
cause of morbidity in children around the world and of mortality
604 Am J Clin Nutr 2002;76:604–7. Printed in USA. © 2002 American Society for Clinical Nutrition
in children in developing countries (1). Zinc supplementation has
been shown to be beneficial in substantially reducing the duration
and severity of the episodes in children with acute and persistent
diarrhea (2). Zinc was also shown to be beneficial in preventing
pneumonia in children in developing countries (3). The diets of
children in developing countries are deficient in animal protein
and consequently are low in zinc (4). In addition, a high phytate-
to-zinc ratio in the diet of these children reduces the bioavailabil-
ity of zinc (4). Finally, major international health agencies, eg, the
World Health Organization (WHO), the United Nations Children’s
Fund, the World Bank, and the US Agency for International Devel-
opment, have shown great interest in determining the public health
value of the micronutrient zinc. In the present study, the role of
zinc supplementation as adjunct therapy in children with measles
and pneumonia was evaluated in a double-blind, randomized con-
trolled trial.
SUBJECTS AND METHODS
Subjects
Children aged 9 mo–15 y with measles accompanied by pneu-
monia who were admitted to the Infectious Diseases Hospital in
Calcutta were randomly allocated to 1 of 2 treatment groups: a
group that received a zinc supplement and a group that received
a placebo supplement. The effect of zinc therapy on the clinical
course of illness was evaluated. The subjects were children admit-
ted to the hospital with an illness that was compatible with
measles (generalized maculopapular rash with fever and at least
1
From the Society for Applied Studies, Calcutta (DM); the Infectious Dis-
eases Hospital, Calcutta (AC and SJ); the National Institute of Cholera and
Enteric Diseases, Calcutta (MKB and MKC); the International Centre for Diar-
rhoeal Disease Research-Bangladesh, Dhaka (MAW); and the Department of
Nutrition Sciences, University of Alabama at Birmingham, Alabama (MAK).
2
Supported by the Child Health Foundation, USA, and by the Nestlé Foun-
dation.
3
Reprints not available. Address correspondence to D Mahalanabis, Society
for Applied Studies, 108, Manicktala Main Road, Flat-3/21 Calcutta 700054,
India. E-mail: dmahalanabis@vsnl.com.
Received May 16, 2001.
Accepted for publication October 17, 2001.
 ZINC THERAPY IN CHILDREN WITH MEASLES AND PNEUMONIA 605

one of the following: cough, coryza, or conjunctivitis) and a clin- TABLE 1

ical diagnosis of acute lower respiratory tract infection (tachyp- Characteristics of subjects on admission and serum zinc and retinol
nea, lower chest indrawing and auscultatory signs, or both). The concentrations on admission and at discharge1
treatment effect was evaluated by comparing the 2 groups for the Zinc group Placebo group
time needed for the resolution of fever, tachypnea (an indicator (n = 42) (n = 43)
of acute lower respiratory tract infection), or “significant illness”
Age
[as judged by a clinician (AC) who was blinded to the treatment 9 mo–5 y 29 23
group assignment] during the 6 d of treatment with zinc under > 5 y–10 y 8 9
observation. > 10 y–15 y 5 11
Children aged 9 mo–15 y who had been ill for ≤ 7 d and who Male participants (%) 43 [18] 58 [25]
had no congenital anomalies, chronic diseases, or severe malnu- Duration of measles rash (d) 3.17 ± 1.062 3.07 ± 0.91
trition (ie, clinically obvious marasmus or edema) were enrolled Weight-for-age (z score) 1.85 ± 1.17 2.00 ± 1.08
in the study after written, informed consent was obtained from a Height-for-age (z score) 1.08 ± 1.64 1.28 ± 1.99
parent or guardian. A master randomization schedule was prepared Looking very ill (%) 93 [39] 95 [41]
Difficulty in eating or 88 [37] 88 [38]
by the use of permuted blocks of random numbers. Serially num-
feeding (%)
bered bottles were randomly allocated to contain either a zinc
Serum zinc (mol/L)
acetate mixture or a placebo mixture; the mixtures were identical On admission 10.740 ± 5.560 [40] 8.860 ± 3.260 [39]
in color, consistency, and taste. The serial numbers on the bottles At discharge 12.977 ± 5.582 [38] 11.672 ± 2.903 [36]
corresponded to the patients’ serial numbers. The medicine bot- Serum retinol (mol/L)
tles were prepared by a pharmaceutical manufacturer under the On admission 0.383 ± 0.279 [40] 0.387 ± 0.223 [38]
supervision of an independent pharmaceutical chemist acting on At discharge 1.178 ± 0.576 [38] 1.352 ± 0.520 [36]
our behalf. Random samples of the bottled mixture were tested by 1
n values in brackets. No significant differences between groups.
2–
atomic absorption spectrophotometry for zinc concentration. x ± SD.
A zinc acetate mixture containing 20 mg elemental Zn or a
placebo mixture was given twice daily for each day of stay. Placebo
consisted of the syrup base used for the zinc mixture to which per- (Centers for Disease Control and Prevention, Atlanta, and WHO,
mitted astringent material was added to give an astringent taste sim- Geneva). Baseline comparisons were made between the 2 treat-
ilar to that of the zinc mixture. A taste test was performed with adult ment groups. Categorical outcome variables were compared by
volunteers who were unaware of the nature of the mixture. All use of the chi-square test or Fisher’s exact test. Survival analysis
patients were treated for pneumonia and associated problems (Cox proportional hazards model) was used to compare the dura-
according to a standard treatment schedule based on the existing tion of events (eg, significant illness, fever, and tachypnea) to
practice at the study hospital. The antibiotics usually used were allow adjustment for censored information with STATA software,
either ampicillin and gentamicin or cefotaxime alone, all given by version 7.0 (Stata, College Station, TX). To compare the incre-
injection, as was the prevailing practice at this hospital. All patients ments in the serum zinc or serum retinol concentration in the zinc
received 100 000 U vitamin A (as palmitate) by mouth on the day of and placebo groups from admission to discharge, multiple linear
admission, because large-dose vitamin A supplementation in hospi- regression models were used to adjust for prognostic factors such
talized children with measles markedly reduces measles-associated as age, sex, and admission values.
mortality (5). Giving a large dose of vitamin A to patients admitted
with measles was not routine at this hospital. However, physicians
agreed to this dose of vitamin A after discussion with the investiga- RESULTS
tor. A complete blood count was performed and a chest X-ray was A total of 85 children aged 9 mo–15 y were admitted into the
taken on admission, as is routine at this hospital. Blood samples study, 42 in the zinc group and 43 in the placebo group (Table 1).
were also obtained on the day of admission and on day 6 for meas- In the group aged 10–15 y, there were slightly more than twice as
urement of serum zinc and serum retinol concentrations. The study many children recruited in the placebo group than in the zinc
protocol was approved by the Ethics Committee of the hospital. group. In addition, more girls were admitted in the placebo group.
Most children were admitted after 2–4 d of rash. These patients
Methods generally were very ill. About 88% had difficulty in eating or feed-
ing, and 57 children were in a state of altered consciousness on
Sample size
admission. Forty-eight children received some antibiotics before
The consensus among clinicians treating such patients at the Infec- admission. A history of measles immunization was available for
tious Diseases Hospital was that 50% of the patients would have no only 12% of the children. Most of the children came from poor
significant illness after 5 d of treatment. With zinc as adjunct therapy, homes. Most (80 of 85) were clinically diagnosed as having pneu-
we expected that 80% would be free of significant illness. The number monia; the rest had tachypnea and fever with a history of cough
calculated for each group (with 80% power and a 5% significance level) and fulfilled the WHO criteria for a diagnosis of pneumonia. In
would be 41, including a dropout rate of 10%. With the use of similar the placebo group, 2 patients had associated bloody diarrhea
assumptions for the proportion of patients having fever or tachypnea (ie, dysentery) and 3 had measles and encephalopathy accompa-
after 5 d of treatment, the calculated sample size would be the same. nied by pneumonia, as judged by the clinician.
The parents of 5 children in the placebo group and of 3 chil-
Analysis dren in the zinc group withdrew their children at various points
Data were recorded on standard forms, entered into a micro- before the study had lasted 6 d. One child in the zinc group was
computer, and edited by the use of EPI INFO software, version 6.03 dropped from the study because the assigned medicine bottle was
606 MAHALANABIS ET AL

TABLE 2
Duration of clinical indicators of disease: results of time-to-event (survival) analysis adjusted for age and sex1
Zinc group2 (n = 40) Placebo group2 (n = 38) Hazards ratio (95% CI)
h h
Time to return of appetite3 110 (92, 135) 104 (73, 104) 0.82 (0.47, 1.44)
Time to absence of fever4 96 (72, 116) 96 (74, 116) 1.08 (0.67, 1.74)
Time to absence of tachypnea5 72 (47, 92) 68.5 (47, 82.5) 1.26 (0.78, 2.05)
Time to much improved or cured status6 132 (117, 139) 122 (106.5, 140.5) 1.07 (0.64, 1.78)
1
Cox proportional hazards model. Each model was adjusted for age and sex. There were no significant differences between the groups for any variable.
2
Medians; quartiles in parentheses.
3
As judged by the caretaker.
4
Skin temperature ≤ 36.7 °C.
5
Respiratory rate of < 40 breaths/min.
6
As judged by a clinician who was unaware of the assigned treatment group.

broken on the first day. One child in the placebo group died 36 h
after admission. This 1-y-old boy had been admitted in a coma,
and a clinical diagnosis of septicemia was made by the attending
physician.
The clinical status of each patient was evaluated and recorded
each day by the same physician (AC), who had no knowledge of
the treatment group to which any of the patients belonged. Eval-
uation on day 6 of the study showed that 34 children in the zinc
group and 33 in the placebo group were judged to be cured or
much improved. Median (quartiles) time (h) required for resolu-
tion of fever and tachypnea, return of appetite, and achievement of
a much-improved or cured status, as evaluated by a physician, in
the zinc and placebo groups is reported in Table 2. There was no
significant difference in any of these clinical features between the
2 groups (Cox proportional hazards model adjusted for age and
sex and including censored data).
In 36 patients in each group, serum zinc concentrations were
estimated by atomic absorption spectrophotometry (6) both on
admission and at discharge (6). A high proportion of patients had
very low serum zinc concentrations (< 9.95 mol/L): 50% in the
zinc group and 68% in the placebo group; these proportions
dropped to 21% and 31%, respectively, at discharge. Improvement
in the serum zinc concentration (analysis of variance adjusted for
age, sex, and serum zinc and retinol concentrations on admission)
was not significantly different between the 2 groups (Table 3).
Similarly, serum retinol concentrations were estimated on
admission and discharge by the use of HPLC in 36 patients from
each group (7). The serum retinol concentrations were very low
(< 0.349 mol/L) on admission in 63% and 53% of patients in the
TABLE 3
Increases in the serum concentrations of zinc and retinol from admission
to discharge1
Zinc group Placebo group
Serum value (n = 36) (n = 36)
Zinc increment (mol/L) 2.384 (4.81) 2.47 (3.06)
Retinol increment (mol/L) 0.805 (0.553) 0.969 (0.516)
1 Zinc is essential for human metabolism, growth, and immune
Adjusted P values from multiple linear regression analysis. In 2 regres-
sion models, the increments in serum zinc and serum retinol concentrations
were adjusted for age, sex, and admission values of serum zinc and serum
retinol. In the regression model, zinc concentration on admission was an
independent predictor (inversely related) of zinc increment (P = 0.001). No
significant differences between groups.
zinc and placebo groups, respectively. All patients received a sin-
gle oral dose (100 000 IU) of vitamin A on admission. A marked
improvement was noted in the serum retinol concentrations in both
groups by day 6 (Tables 1 and 3).
DISCUSSION
The study did not show a clinically worthwhile benefit from the
administration of zinc as an adjunct therapy in children with
measles and pneumonia. These children routinely received a large
dose of vitamin A, which is known to reduce the morbidity and
mortality associated with measles (5).
Serum retinol concentrations were very low in these children
on admission, which may have represented both a state of defi-
ciency and a consequence of severe infection. It has also been
shown that, apart from an acute phase response after infection,
retinol may be lost in the urine, particularly in the context of a
febrile illness (8). The retinol concentrations improved markedly
in these very ill children: 3.3% on admission and 83.3% at dis-
charge had serum retinol concentrations > 0.698 mol/L. This
improvement may have been due to a combination of factors such
as recovery from a severe acute illness and the administration of
vitamin A on admission.
Serum zinc concentrations were low on admission in most of
these children, which could have been a consequence of a state of
deficiency, an infection, or both. The serum zinc concentration
does not consistently reflect zinc status. Very low serum zinc con-
centrations may be attained in conditions such as an acute phase
response, in which the element is redistributed to other tissues.
However, after 5 d of zinc administration (40 mg/d as oral acetate)
to the study group and of a placebo to the control group, serum
zinc status improved in both groups. The hospital diet did not con-
tain items known to have a high zinc content. This suggests that
the low zinc concentrations on admission were more likely to be
due to redistribution after infection, as discussed above. Serum
zinc concentrations are homeostatically controlled and, in states
of marginal zinc deficiency, may be maintained within the nor-
mal range.
function (9). Many aspects of the immune system can malfunc-
tion, and epithelial barriers are compromised during infection
(10). The oral administration of zinc as adjunct therapy for acute
diarrhea in children in developing counties has shown consistent
benefits in reducing the duration and the severity of that illness (2).
 ZINC THERAPY IN CHILDREN WITH MEASLES AND PNEUMONIA
Several studies have also shown that routine zinc supplementation
in children in developing countries prevents acute lower respira-
tory tract infection and pneumonia (3). However, therapeutic tri-
als of zinc as adjunct therapy for pneumonia alone or in associa-
tion with measles have not been reported. We can only speculate
as to why zinc supplementation in children with measles accom-
panied by pneumonia did not lead to any measurable clinical
improvement. The therapeutic effect of zinc in acute diarrhea can
be explained by its direct effect on the mucosa and a gut-associ-
ated immune response, which may be different from an immune
response in the respiratory system. Whereas a favorable immune
response to zinc supplementation may explain why pneumonia is
prevented in children, in an acute illness such as measles-associ-
ated pneumonia, there probably is insufficient time for mounting
an immune response to favorably modify an acute illness. Thus,
the administration of zinc to severely ill children with measles and
pneumonia treated with vitamin A and supportive therapy showed
no additional benefit.
We thank S Karmakar for preparing and editing the manuscript and
Zakir Hussain for assisting with the data analysis.
REFERENCES
1. Stansfield SK, Suepond DS. Acute respiratory infection. In: Jamison DT,
Mosley WH, Measham AR, Bourdilla JL, eds. Disease control prior-
ities in developing countries. Oxford, United Kingdom: Oxford Uni-
versity Press (for the World Bank), 1993:67–90.
607
2. Zinc Investigators Collaborative Group. Therapeutic effects of oral
zinc in acute and persistent diarrhea in children in developing coun-
tries: pooled analysis of randomized controlled trials. Am J Clin Nutr
2000;72:1516–22.
3. Zinc Investigators Collaborative Group. Prevention of diarrhea and
pneumonia by zinc supplementation in children in developing coun-
tries: pooled analysis of randomized controlled trials. J Pediatr 1999;
155:689–97.
4. Gibson RS, Ferguson EL, Lehrfeld J. Complementary foods for infant
feeding in developing countries: their nutrient adequacy and improve-
ment. Eur J Clin Nutr 1998;52:764–70.
5. Mahalanabis D, Bhan MK. Micronutrients as adjunct therapy of acute
illness in children: impact on the episode outcome and policy impli-
cations of current findings. Br J Nutr 2001;85(suppl 2):S1–9.
6. AOAC. Official methods of analysis of AOAC International
(OMA). 15th ed. Gaithersburg, MD: AOAC, 1991:81. (2nd supple-
ment, 1991.)
7. Driskell WJ, Neese JW, Bryant CC, Bashor MM. Measurement of
vitamin A and vitamin E in human serum by high performance chro-
matography. J Chromatogr 1982;231:439–44.
8. Mitra AK, Alvarez JO, Guay-Woodford L, Fuchs GJ, Wahed MA,
Stephensen CB. Urinary retinol excretion and kidney function in chil-
dren with shigellosis. Am J Clin Nutr 1998;68:1095–103.
9. Aggett PJ, Comerford JG. Zinc and human health. Nutr Rev 1995;53:
S16–22.
10. Shankar AH, Prasad AS. Zinc and immune function: the biological
basis of altered resistance to infection. Am J Clin Nutr 1998;
68(suppl):437S–63S.