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See corresponding editorial on page 991.

See corresponding CME exam on page 1207.

Efficacy of zinc in the treatment of severe pneumonia in hospitalized


children 2 y old13
Anuradha Bose, Christian L Coles, Gunavathi, Hemanth John, Prabhakar Moses, P Raghupathy, Chellam Kirubakaran,
Robert E Black, W Abdullah Brooks, and Mathuram Santosham
the number in China (3). Pneumonia case management, which
relies on early diagnosis and prompt empiric antibiotic therapy,
has been effective, reducing pneumonia-related deaths by 47%
(4). However, the efficacy of this strategy may be diminished by
poor nutritional status (5, 6). Undernutrition is known to be
associated with greater severity of pneumonia, a higher frequency of complications, longer episodes of infection, and
greater case fatality rates (7, 8). In light of these issues, the
evaluation of interventions that may improve the effectiveness of
case management in children with poor nutritional status is
warranted.
In southern Asia, macronutrient malnutrition and micronutrient deficiencies, especially deficiencies of iron, zinc, and vitamin
A, are common in young children. This problem is attributed to
dietary insufficiency, limited nutrient bioavailability from local
diets, and excretion of nutrients during recurrent episodes of
infection. Of the micronutrients, zinc plays a critical role in
immunomodulation and in maintaining the integrity of the immune system (9, 10). Results of preventive trials in children
living in areas of endemic deficiency show that zinc supplementation significantly reduced the incidence of pneumonia and
persistent diarrhea (1113). Significant reductions in acute and
persistent diarrhea morbidity were also observed in zincsupplemented children in therapeutic trials (14).
Consensus as to whether zinc supplementation provides a similar therapeutic benefit to children with severe pneumonia has not
yet been established. Published results from a recent clinical trial
conducted in Bangladesh suggested that zinc supplementation

KEY WORDS
Pneumonia, severe pneumonia, zinc, supplementation, treatment, adjuvant therapy, India

1
From the Departments of Community Medicine (AB, G, and HJ) and
Child Health (AB, PM, PR, and CK), Christian Medical College, Vellore,
India; the Department of International Health, Bloomberg School of Public
Health, Johns Hopkins University, Baltimore, MD (CLC, REB, WAB, and
MS); and the Centre for Health and Population Research, International Centre for Diarrhoeal Disease, Research, Dhaka, Bangladesh (WAB).
2
Supported by the Global Research Activity Cooperative Agreement between the Johns Hopkins University Bloomberg School of Public Health and
the US Agency for International Development.
3
Reprints not available. Address correspondence to CL Coles, Department of International Health, Bloomberg School of Public Health, Johns
Hopkins University, 615 North Wolfe Street, Room E5545, Baltimore, MD
21205. E-mail: ccoles@jhsph.edu.
Received July 26, 2005.
Accepted for publication November 14, 2005.

INTRODUCTION

Worldwide, pneumonia is the leading cause of pediatric morbidity and mortality. It is estimated that pneumonia is responsible
for 2 million deaths each year in children 5 y old, which
represents 19% of the annual deaths in this age group (1). Approximately 95% of the pneumonia-related deaths occur in developing countries, and the youngest age groups have the highest
risk of death (2). India has the largest number of deaths of children 5 y old in the worldan estimated 2 402 000, or 3 times

Am J Clin Nutr 2006;83:1089 96. Printed in USA. 2006 American Society for Nutrition

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ABSTRACT
Background: Severe pneumonia remains a leading cause of morbidity and mortality in undernourished young children in developing
countries.
Objective: This study evaluated the effect of adjuvant zinc therapy
on recovery from severe pneumonia by hospitalized children in
southern India who were receiving standard antibiotic therapy.
Design: This randomized, double-blind, placebo-controlled clinical
trial was conducted at the Christian Medical College Hospital, an
1800-bed teaching hospital in Tamilnadu, India. Enrollment and
follow-up occurred between September 2003 and August 2004.
Children aged 223 mo (n 299) who were hospitalized with severe
pneumonia were randomly assigned to receive 10-mg tablets of zinc
sulfate or placebo twice a day during hospitalization, along with
standard therapy for severe pneumonia. All clinical signs and symptoms of pneumonia were assessed and recorded at 8-h intervals.
Results: There were no clinical or statistically significant differences in the duration of tachypnea, hypoxia, chest indrawing, inability to feed, lethargy, severe illness, or hospitalization. Zinc supplementation was associated with a significantly longer duration of
pneumonia in the hot season (P 0.015).
Conclusions: Zinc supplementation had no overall effect on the
duration of hospitalization or of clinical signs associated with severe
infection in young children hospitalized for severe pneumonia in
southern India. This finding differs from the results of 2 previously
reported trials wherein zinc supplementation was associated with a
shorter period of recovery from severe pneumonia. Given the conflicting results, further research in representative settings is required
to help clarify the role of zinc in the treatment of severe
pneumonia.
Am J Clin Nutr 2006;83:1089 96.

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BOSE ET AL

given with empiric antimicrobial therapy can significantly


shorten the duration of severe pneumonia, tachypnea, hypoxia,
and chest indrawing and can also shorten the hospital stay for
young children with pneumonia (15). A therapeutic trial conducted in Kolkata, India, evaluated the effects of zinc and vitamin
A supplementation on recovery from acute lower respiratory
infection (16). These investigators reported significant reductions in the duration of severe illness and fever among male
children supplemented with zinc. However, for reasons that are
unknown, zinc supplementation had no effect on clinical outcomes in females, nor did it have any effect on any other acute
lower respiratory infectionrelated symptoms. More research is
needed to clarify the role of zinc in the treatment of children who
are hospitalized for severe pneumonia. We evaluated the efficacy
of zinc supplementation in the treatment of severe pneumonia in
hospitalized Indian children aged 223 mo who received standard antimicrobial therapy.
SUBJECTS AND METHODS

This study was a randomized, double-blind, placebocontrolled clinical trial conducted between September 2003 and
August 2004 at the Christian Medical College (CMC) Hospital in
Vellore, India. CMC Hospital is a large teaching hospital and
medical center that is accessed directly by the population of
Vellore and adjoining districts and by referrals from local medical practitioners.
Subject eligibility and randomization
Children between 2 and 23 mo of age admitted to the pediatric
wards of CMC Hospital were assessed by the study physicians
and considered eligible for enrollment in the trial if they fulfilled
the criteria for a diagnosis of severe pneumonia. Severe pneumonia was defined as a respiratory rate 50/min, which was
accompanied with crepitations on auscultation and the presence
of 1 of the following danger signs: lethargy, inability to feed,
chest indrawing, or central cyanosis. Children were excluded if
they had history of chronic cardiac or renal disease, illness severe
enough to require ventilation, malnutrition severe enough to
require immediate nutritional rehabilitation therapy [ie, weightfor-age 60% of the reference for Indian children (17)], illness
requiring hospitalization in the previous 21 d, or current zinc
supplementation.
Written consent was obtained after the parents or guardians
read a study information pamphlet and reviewed its contents with
a study physician. If the parents or guardians were illiterate, the
content of the pamphlet was read to them, and consent was
documented by a thumbprint impression of one of the parents or
guardians in the presence of an unrelated witness. The study was
approved by the institutional review boards of CMC Hospital and
The Johns Hopkins University Bloomberg School of Public
Health.
At the time of enrollment, study physicians collected information on demographics, current illness, and history of respiratory diseases for each subject. All physical findings, anthropometric data, chest X-ray findings, complete blood count results,
and baseline plasma zinc concentrations were recorded.
Randomization was conducted at the individual level and in
blocks of 8 and 10. The use of large blocks was part of an effort

Intervention
Children with severe pneumonia were randomly assigned to
receive supplementation with either elemental zinc or placebo
tablets. Each tablet contained 10 mg zinc sulfate or 10 mg placebo (ie, crystalline cellulose, cornstarch, and vanilla flavoring).
The zinc and placebo tablets were indistinguishable in appearance, consistency, and taste. The supplements were formulated
and manufactured as dispersible tablets by Nutriset (Malunay,
France) in collaboration with the WHO Department of Child and
Adolescent Health and Development and packaged in blister
packs of 14 tablets. The foil on the back of blister pack was
labeled with the patient identification number. It was assumed
that the study children would recover and be discharged within
14 d; therefore, each child was assigned 2 blister packs with the
same treatment code. Supplementation ceased once children
were discharged. The blister packs were stored on the pediatric
wards in cool, locked cabinets that could be accessed only by
study physicians who were responsible for dosing the participants at enrollment and at 0800 and 2000 every day during
hospitalization.
Children received 20 mg (2 tablets) of either zinc sulfate or
placebo by mouth at the time of enrollment. From day 2, they
received 10 mg of their assigned treatment by mouth twice a day
throughout the course of their hospitalization. For young infants,
the tablets were dissolved in a teaspoon of distilled water before
being administered.
All enrolled children were treated according to the standard
protocol for treatment of infants and children with pneumonia.
They were treated parenterally with a combination of benzyl
penicillin and gentamicin. If a consultant pediatrician was of the
opinion that the chest radiograph or clinical presentation was
consistent with staphylococcal pneumonia, the patient was
treated with a combination of cloxacillin and gentamicin. Patients who failed to improve after 48 h on this regimen of first-line
antimicrobial therapy were switched to a regimen of parenteral
cefotaxime.
During hospitalization, the childs condition was assessed at
the beginning of each 8-h shift by a study physician or a study
nurse, and the assessment was recorded in the patients chart.
Respiratory rate was measured for a full minute, after the childs
upper-torso clothing was removed. If the respiratory rate was
50 breaths/min, it was measured again, and if the count was
different by 5 breaths/min, a third reading was taken, and the 2
closer readings were averaged. The count was done at a time
when the child was not crying. Pulse oximetry was measured
with the use of a probe (Nellcor Inc, Hayward, CA) placed on a
finger or toe. For intercurrent readings in patients who required
oxygen supplementation, the oxygen supply was discontinued
for 5 min before pulse oximetry. Axillary temperature was measured by using a standard mercury thermometer. The presence of
cough, crepitations, wheezing, chest indrawing, cyanosis, inability to feed, and lethargy was also noted in the patients chart.

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Study design and setting

to maintain blinding of the treatment assignments and to increase


the likelihood that the treatment groups would be well balanced.
The randomization codes were generated by a scientist at the
headquarters of the World Health Organization (WHO), which
was not associated with the study. Treatment codes were kept in
an envelope in a locked cabinet at WHO headquarters in Geneva,
Switzerland.

ZINC THERAPY FOR SEVERE PEDIATRIC PNEUMONIA

Enteral feeds were started once the childs respiratory rate fell
to 60 breaths/min, oxygen saturation was 93%, and the baby
was able to tolerate small sips of feeds. Feeds were started as
early as possible to optimally balance caloric intake with the need
for caution in initiating feeds in a tachypneic child. Oral antibiotics were started when the child was feeding well and when
oxygen saturation and respiratory rate were stabilized. Once the
patient was on oral antibiotics, he or she remained under observation on the ward for a further 24 h before discharge. Study
subjects were discharged when they were being fed entirely with
oral feeds, the respiratory rate was 50 breaths/min, oxygen
saturation was 93%, and the attending pediatrician decided that
the patients clinical condition had resolved and did not require
further hospital care. A blood sample for zinc measurement was
taken at the time of discharge.
Measurement of plasma zinc concentration

indrawing, respiratory rate 50 breaths/min, and oxygen


saturation 93%.
The duration of hospitalization was defined as the time (in h)
between study enrollment and discharge. In addition, we also
examined the time to resolution of the clinical symptoms of chest
indrawing, tachypnea (ie, respiratory rate 50/min), inability to
feed orally, hypoxemia (ie, arterial O2 saturation 93%), fever
(ie, axillary temperature 37.5 C), and cough. Time to resolution from wheezing was evaluated as a secondary outcome.
The research team was composed of 3 study physicians and 2
research nurses. The medical officers and nurses received 2 wk
of training in the assessment of clinical findings and study outcomes to ensure the reproducibility of results.
Sample size
We aimed to enroll 136 children with severe pneumonia in
each treatment group, for a total of 272 children. The sample size
was calculated to detect a minimum reduction of 30% in the
duration of hospitalization between treatment groups. The figure
assumes 80% power, a 2-sided type 1 error of 5%, loss to
follow-up of 10%, and a mean duration of hospitalization for
pneumonia of 5.7 d in children in this age group. The estimate
was also valid for detecting similar reductions in duration of
clinical signs and symptoms associated with severity in the 2
treatment groups. To account for exclusions due to possible readmissions and on the recommendation of the Data and Safety
Monitoring Board, 6 mo after the start of enrollment, the original sample size was increased from 272 to 300 (150 each in the
zinc and placebo groups).
Statistical analysis
The effects of zinc supplementation on outcomes of interest
were analyzed on an intention-to-treat basis. The data were analyzed by using STATA software (version 8.0; Stata Corp, College Station, TX). The t test for continuous variables and the
2-tailed chi-square analysis or Fishers exact test for contingency
data were used, as appropriate, to assess treatment group differences at baseline. Kaplan-Meier survival functions were used to
measure the median duration of outcomes and to assess the effect
of treatment on the study outcomes. Cox proportional hazard
regression models were constructed to adjust the treatment effects for potential confounding factors and to evaluate effect
modification. The risk ratios (RRs) compare the recovery rates
from the indicators in the zinc-supplemented group with those in
the placebo group. RRs 1 are associated with the probability
that the duration of the outcome will be shorter in the zinc group.
Analyses were based on clinical outcomes, and time to recovery
was defined as the end of the last consecutive 16-h period in
which the case did not meet the definition of severe pneumonia.
All analyses were by intention-to- treat.

Definition and measurement of outcomes

RESULTS

The primary clinical outcomes of the study were time to resolution (no longer meeting the definitions as outlined below) of
severe pneumonia and the duration of hospitalization. Because
there is no accepted standard definition of cessation of severe
pneumonia, we used 3 definitions of severe pneumonia to evaluate recovery: 1) respiratory rate 50 breaths/min and oxygen
saturation 93%; 2) inability to drink, respiratory rate 50
breaths/min, and oxygen saturation 93%; and 3) chest

Between 15 September 2003 and 31 August 2004, we approached the parents of 307 children who were eligible for participation in the trial (Figure 1); the parents of 7 children refused.
The remaining 300 children were enrolled, and half were randomly assigned to each of the treatment groups. One child in the
zinc group withdrew from the study before discharge (331 h
after enrollment). Two children in the placebo group left against
medical advice: one child left after 2 h, and that child was

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Blood samples for the measurement of plasma zinc concentrations were collected at enrollment and at discharge by using a
disposable syringe and needle; the samples were transferred to a
zinc-free polypropylene tube containing 100 IU lithium heparin
of negligible zinc content. The blood was centrifuged at 3500
rpm for 10 min (Heraeus Multifuge 3-S; Kendro Laboratory
Products, Langensebold, Germany), and the plasma was separated immediately by using a disposable Pasteur pipette and
stored in a zinc-free polypropylene tube at 20 C until analysis.
All errors due to glassware, sample collection, processing, and
analysis were eliminated according to previously established
methods (18, 19). Measurement of the zinc concentrations in
plasma was carried out by using an Atomic Absorption Spectrophotometer (model Analyst 100; Perkin Elmer, Boston, MA)
with air-acetylene as the oxidant. Certified zinc standard (Cat no.
Z-2750; Sigma Chemical Co, St Louis, MO) was used in the
assay. Plasma was diluted 1:5 (0.2 mL plasma 0.8 mL distilled
deionized water) in disposable zinc-free polypropylene tubes.
The assay was done in duplicate. The diluted samples were directly aspirated into the Atomic Absorption Spectrophotometer,
and the reading obtained was compared with a standard containing 25 g zinc/100 mL. Glyceryol [5% (by vol)] was used as the
blank solution because the working standard was prepared in 5%
glycerol. The result was calculated by using a formula: plasma
zinc (in g/100 mL) reading of test in g/100 mL 5. Internal
quality control of bovine origin stabilized with 15% (by vol)
Ethanediol was used during every assay to monitor the precision,
and a level 2 control (BioRad, Hercules, CA) was used every 2
wk to assess the accuracy. The results obtained for the above
controls were well within the WHO criteria of 8% for internal
quality control and within a mean (2 SD) for quality control of
accuracy. The normal value obtained for plasma zinc by using
this method was 70 125 g/100 mL (10.719.1 mol/L).

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excluded from the analysis; another left after 69 h. There was


one death in the placebo group, which occurred 8 h after
enrollment.
Baseline characteristics of the children were well balanced
between treatment groups (Table 1). Approximately 70% of the
children were male, and 70% were 211 mo old. In addition,
202 (67%) of the 299 children followed were admitted during the
rainy season (SeptemberFebruary). Enrollment by season significantly differed by age group. Of those children enrolled during the rainy season, only 44 (21.8%) were 12 mo old. In
contrast, the distribution during the hot season (MarchAugust)
was more equitable: 46 (47.6%) of the 97 children admitted
during that season were 12 mo old. Approximately 78% of our
patients were anemic; ie, their hemoglobin concentrations were
11 g/dL. Mean plasma zinc concentrations on admission did
not differ significantly between groups (Table 2). At discharge,
mean (SD) plasma zinc concentrations were significantly
higher in the zinc group than in the placebo group (13.0 2.5 and
12.0 4.1 mol/L, respectively; P 0.013).
There was no significant difference between the zinc and
placebo groups in the time to recovery from severe pneumonia, as defined by inability to feed, arterial O2 saturation
93%, and respiratory rate 50 breaths/min (Table 3). The
lack of association between the recovery experience and treatment group was also apparent when survival curves were used
(Figure 2). RRs for recovery from severe pneumonia did not
differ significantly, irrespective of the definition of severe
pneumonia that was used. Moreover, the median length of
hospitalizations did not differ significantly between the zinc

and placebo groups (Table 3). No significant differences were


observed when recovery from other clinical features was
assessed.
TABLE 1
Baseline characteristics (as categorical variables) of the zinc and placebo
treatment groups1
Characteristic

Zinc group
Placebo group
(total n 150) (total n 149)
n (%)

Male
Age group
211 mo
1223 mo
Season of enrollment
Hot season (MarchAugust)
Rainy season (SeptemberFebruary)
Antibiotic use in week before admission
Fever (temperature 38C)2
Chest indrawing
Cyanosis
Inability to feed
Wheeze
Hypoxia (arterial O2 saturation 93%)
Hemoglobin 11.0 g/dL
Weight-for-age z score 2.0
1

107 (71.3)

101 (67.3)

100 (66.7)
50 (33.3)

110 (73.8)
39 (26.2)

49 (32.7)
101 (67.3)
49 (32.7)
50 (33.6)
124 (82.7)
0 (0)
109 (72.7)
94 (62.7)
69 (46.0)
116 (77.3)
62 (41.3)

48 (32.2)
101 (67.8)
45 (30.2)
47 (31.5)
114 (76.5)
0 (0)
102 (69.7)
93 (62.4)
62 (42.0)
111 (74.5)
56 (37.6)

None of the differences between groups were significant by chi-square


analysis.
2
Total n 149.

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FIGURE 1. Trial profile.

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ZINC THERAPY FOR SEVERE PEDIATRIC PNEUMONIA


TABLE 2
Baseline characteristics (as continuous variables) of the zinc and placebo
treatment groups1

Characteristic
Age (mo)
Respiratory rate (breaths/min)
Arterial O2 saturation of room air (%)
Temperature (C)
Pulse (beats/min)
Zinc concentration (mol/L)
Hemoglobin concentration (g/dL)
Days of illness before admission (n)

Placebo
group
(n 149)

Zinc group
(n 150)
9.9 6.1
64.1 10.5
92.8 4.5
37.7 0.8
149.7 24.3
11.0 2.2
9.9 1.6
5.8 11.0

9.1 5.7
63.5 9.9
93.2 4.1
37.6 0.9
152.3 23.5
10.9 2.4
10.0 1.5
4.7 6.2

All values are x SD. None of the differences between groups were
significant by Students t test.
1

DISCUSSION

The current study did not show a clinically or statistically


significant reduction in duration or severity of pneumonia or a
reduction in overall hospital stay for children 2 y old given
daily zinc supplementation along with standard antimicrobial
therapy. We could identify no subgroups that benefited from zinc
supplementation. We noted that the season modified the association between treatment and outcome. Specifically, zinc-treated
children had a slower recovery than did those receiving placebo
in the hot season but not during the rainy season. We are unable
to explain this association. It may be possible that the effect is
related to differences in the etiology of pneumonia by season or
differences in the pattern in micronutrient deficiencies that are
due to seasonal variations in diet. In the Vellore area, viral,
bacterial, and mixed respiratory infections predominate in the
rainy season, whereas there is a low incidence of viral respiratory
infections in the hot season (20, 21). Consistent with this observation is the high prevalence of wheeze in children in the rainy
season and a marked decrease in wheeze in the hot season. Thus,
our data may imply that zinc can prolong the duration of severe

TABLE 3
Effect of treatment on recovery time by clinical indicator1
Outcome
Severe pneumonia
Definition 1: inability to feed, O2 saturation 93%, RR 50
Definition 2: chest indrawing, O2 saturation 93%, RR 50
Definition 3: O2 saturation 93%, RR 50
Hospitalization
Tachypnea (RR 50)
Chest indrawing
Hypoxia (O2 saturation 93%)
Inability to feed
Lethargy
Fever (temperature 38C)
Cough
Wheeze

Zinc group2
(n 150)

Placebo group2
(n 149)

RR3

87.2 (70.7, 95.2)


111.3 (88.5, 138.0)
82.2 (70.3, 92.2)
71.1 (68.1, 87.3)
72.0 (68.5, 88.0)
88.1 (71.5, 99.9)
70.7 (65.5, 87.2)
71.5 (68.1, 88.0)
70.8 (68.1, 87.3)
70.8 (68.1, 87.3)
107.3 (82.5, 176.9)
71.1 (67.1, 88.1)

76.2 (72.3, 88.1)


96.7 (78.2, 112.9)
75.9 (71.2, 88.0)
72.3 (67.7, 79.6)
73.0 (64.5, 82.8)
84.3 (73.2, 97.2)
72.3 (67.7, 76.2)
72.3 (69.0, 79.8)
72.3 (68.5, 79.8)
72.3 (68.5, 79.8)
98 (51.3, 168.0)
73.2 (67.7, 82.8)

0.93 (0.72, 1.21)


0.86 (0.62, 1.18)
0.95 (0.74, 1.23)
0.93 (0.74, 1.17)
0.97 (0.77, 1.22)
0.92 (0.70, 1.22)
0.94 (0.74, 1.18)
0.93 (0.74, 1.17)
0.94 (0.75, 1.18)
0.94 (0.74, 1.18)
0.81 (0.57, 1.12)
0.91 (0.72, 1.15)

0.589
0.353
0.722
0.550
0.819
0.563
0.575
0.511
0.598
0.501
0.199
0.439

1
Recovery criteria were met for 16 consecutive hours after the last report of a clinical indicator. RR, risk ratio. Data were analyzed by using Cox
proportional hazards regression models.
2
Median; 95% CI in parentheses.
3
95% CI in parentheses.

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In our subgroup analysis, we discovered that there was a significant negative treatment effect during the hot season but not
during the rainy season (Table 4). During the hot season, the
median duration of severe illness was significantly longer in the
zinc-supplemented group than in the placebo group (97 and
72.3 h, respectively; RR 0.60, P 0.015), as was the length of
hospitalization (95.2 and 73.0 h, respectively; RR 0.57, P
0.008). Significant treatment effects favoring the placebo group
were observed with all clinical indicators except cough. There
was, however, no difference in treatment effect by sex, age, age
group, nutritional status, number of days before illness, wheeze,
and antibiotic use before admission. None of the 3-way interaction models was statistically significant.
There was one death in the placebo group, which occurred 8
h after enrollment. There were no other adverse events. Thirty
percent of the children in the zinc group and 23% of those in the
placebo group had to be switched from a first-line antibiotic to a
second-line antibiotic. The difference in the proportion of treatment failures between treatment groups was not statistically significant.

FIGURE 2. Kaplan-Meier survival curves of recovery from severe pneumonia in the placebo group (solid line) and the zinc-supplemented group
(broken line).

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BOSE ET AL

TABLE 4
Effect of treatment on median number of hours to recovery by clinical indicator and by season of enrollment1
Outcome

Placebo group3

RR4

97.0 (74.5, 103.7)


70.8 (64.8, 92.2)

73.0 (64.7, 88.1)


79.7 (72.8, 98.9)

0.60 (0.41, 0.91)


1.11 (0.78, 1.57)

0.015
0.539

95.2 (74.5, 101.6)


68.1 (63.8, 70.8)

72.3 (64.8, 84.3)


73.2 (67.5, 84.3)

0.57 (0.38, 0.86)


1.20 (0.91, 1.58)

0.008
0.201

95.2 (74.5, 101.6)


68.2 (64.0, 71.5)

72.3 (62.8, 84.3)


73.2 (67.5, 86.1)

0.57 (0.38, 0.87)


1.19 (0.89, 1.60)

0.009
0.231

121.2 (95.2, 189.5)


70.2 (64.5, 87.3)

75.9 (69.0, 90.8)


96.7 (71.8, 112.9)

0.43 (0.26, 0.72)


1.34 (0.96, 1.87)

0.001
0.084

95.2 (74.5, 101.6)


64.8 (57.5, 69.5)

72.3 (64.8, 84.3)


72.8 (67.2, 76.9)

0.58 (0.38, 0.87)


1.21 (0.90, 1.61)

0.009
0.206

97.0 (74.5, 103.1)


68.1 (63.7, 70.8)

72.3 (64.8, 84.3)


73.2 (67.5, 84.3)

0.58 (0.38, 0.87)


1.14 (0.87, 1.52)

0.009
0.333

90.2 (73.3, 101.6)


68.1 (63.8, 70.8)

72.3 (64.8, 84.3)


71.8 (67.5, 82.3)

0.58 (0.39, 0.88)


1.15 (0.87, 1.52)

0.011
0.316

95.2 (74.5, 101.6)


68.1 (63.7, 70.8)

72.3 (64.8, 84.3)


71.8 (67.5, 82.3)

0.58 (0.38, 0.88)


1.15 (0.87, 1.52)

0.010
0.316

95.2 (72.7, 103.1)


66.3 (63.0, 71.1)

79.8 (66.3, 90.0)


71.8 (67.0, 82.3)

0.62 (0.41, 0.95)


1.04 (0.78, 1.40)

0.028
0.748

Recovery criteria were met for 16 consecutive hours after the last report of a clinical indicator. RR, risk ratio. Data were analyzed by using Cox
proportional hazards regression models. Interaction between zinc treatment and season: severe pneumonia (P 0.024), hospitalization (P 0.007), tachypnea
(P 0.007), chest indrawing (P 0.001), hypoxia (P 0.013), inability to feed (P 0.007), lethargy (P 0.010), fever (P 0.010), and wheeze (P 0.054).
Cough was not statistically significant (P 0.560).
2
n 49 and 101 in the hot and rainy seasons, respectively. Median; 95% CI in parentheses.
3
n 48 and 101 in the hot and rainy seasons, respectively. Median; 95% CI in parentheses.
4
Adjusted for age group (12 mo or 12 mo). 95% CI in parentheses.
5
Severe pneumonia: inability to feed, O2 saturation 93%, RR 50. Results for the other 2 definitions for severe pneumonia were similar.

pneumonia caused by bacterial infection. Given that the results


were obtained from subgroup analyses, implications are speculative, but they may have some importance for the generation of
new hypotheses. We did not find evidence of any other treatment
effects.
In contrast to the main findings of the current study, results
from 2 clinical trials showed significant benefit associated with
zinc supplementation in children with severe pneumonia. In a
clinical trial conducted in Bangladesh (15), zinc supplementation
resulted in a reduction by 12 h in the duration of severe pneumonia and a reduction by 16 h in the hospital stay, in addition to
reductions in tachypnea, chest indrawing, and hypoxia. Likewise, investigators who conducted a similar trial in Kolkata,
India reported a reduction by half in the duration of severe illness
and a reduction by two-thirds in the duration of fever (16). The
endpoints in the Kolkata study were different from those in the
Bangladesh study, although both studies evaluated cessation of
signs of severe pneumonia. In Kolkata, there were no effects on
tachypnea and feeding status, and the effects of treatment on
chest indrawing, hypoxia, and wheeze were not reported. This
study reported that zinc supplementation benefited only male

children; it did not have any effect on females. The finding


remains unexplained.
There were several differences in the population characteristics between our study and the Kolkata and Bangladesh trials.
Mean plasma zinc concentrations in Vellore study subjects at
enrollment (11.0 mol/L) were significantly higher than those in
subjects in Bangladesh (10.1 mol/L) and Kolkata (9.6 mol/L).
Although the differences are statistically significant (P 0.001),
it is unclear whether this difference is of clinical importance.
Unlike the other studies, the current study evaluated the effect of
plasma zinc status (9.18 mol compared with 9.18 mol
Zn/L) on treatment and found no evidence of effect modification.
In addition, the time of blood collection is known to cause variation in plasma zinc concentrations (22). In all 3 randomized
trials, blood samples for plasma zinc assessment were collected
at enrollment and at discharge, which occurred at any hour of the
day or night throughout the study. Therefore, the time of blood
collection is unlikely to be a confounder. The average number of
days during which the children reported being ill before admission in the current study was double that in the Bangladesh study

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Severe pneumonia5
Hot season
Rainy season
Hospitalization
Hot season
Rainy season
Tachypnea (RR 50)
Hot season
Rainy season
Chest indrawing
Hot season
Rainy season
Hypoxia (O2 saturation 93%)
Hot season
Rainy season
Inability to feed
Hot season
Rainy season
Lethargy
Hot season
Rainy season
Fever (temperature 38C)
Hot season
Rainy season
Wheeze
Hot season
Rainy season

Zinc group2

ZINC THERAPY FOR SEVERE PEDIATRIC PNEUMONIA

The zinc supplements were well tolerated and safe, and no


vomiting was noted. The plasma zinc concentrations at the time
of admission were lower than those at discharge in both the zinc
and placebo groups. The change in plasma zinc status is consistent with zincs negative acute phase response to infection.
The current study found that zinc supplementation had no
effect on the duration of hospitalization or of clinical signs associated with severe infection in young children hospitalized for
severe pneumonia in southern India. Differences in the study
populations and methods between the current study and the 2
studies that found zinc to be beneficial may help to explain
differences in the outcomes. The possibilities also exist that zinc
supplementation for the treatment of severe pneumonia may
benefit only an as-yet-undefined subpopulation of pediatric
pneumonia patients and that the etiology of the pneumonia is a
deciding factor. Alternatively, it may be that zinc is not efficacious in the treatment of acute pneumonia. In light of the conflicting study results, additional large trials in representative
settings are required to help clarify the role of zinc in the treatment of severe pneumonia.
We thank Jayaprakash Muliyil (Department of Community Medicine,
Christian Medical College, Vellore, India) for his sage advice on data analysis and S Swaminathan (Department of Biochemistry, Christian Medical
College, Vellore, India) for his excellent technical assistance.
WAB, CLC, MS, RB, AB, PM, PR, and CK conceived and designed the
study; AB, HJ, G, CLC, PM, PR, and CK implemented the study; AB, HJ, and
G were responsible for data collection, patient enrollment, and monitoring;
AB, HJ, G, and CLC supervised the data management; CLC, AB, HJ, and G
analyzed the data; AB and CLC wrote the manuscript; and PR, REB, MS, and
WAB contributed to the writing and editing of the manuscript. None of the
authors had any personal or financial conflicts of interest.

REFERENCES
1. Bryce J, Boschi-Pinto C, Shibuya K, Black RE. WHO estimates of the
causes of death in children. Lancet 2005;365:114752.
2. Mulholland K. Global burden of acute respiratory infections in children:
implications for interventions. Pediatr Pulmonol 2003;36:469 74.
3. Black RE, Morris SS, Bryce J. Where and why are 10 million children
dying every year? Lancet 2003;361:2226 34.
4. Sazawal S, Black RE. Meta-analysis of intervention trials on casemanagement of pneumonia in community settings. Lancet 1992;340:
528 33.
5. Scrimshaw NS, SanGiovanni JP. Synergism of nutrition, infection, and
immunity: an overview. Am J Clin Nutr 1997;66(suppl):464S77S.
6. Brundtland GH. Nutrition and infection: malnutrition and mortality in
public health. Nutr Rev 2000;58:S1 4.
7. Caulfield LE, de Onis M, Blossner M, Black RE. Undernutrition as an
underlying cause of child deaths associated with diarrhea, pneumonia,
malaria, and measles. Am J Clin Nutr 2004;80:193 8.
8. Fishman SM, Caulfield LE, de Onis M, et al. Childhood and maternal
underweight. In: Ezzati M, Lopez AD, Rodgers A, Murray CJL, eds.
Comparative quantification of health risks: global and regional burden of
disease attributable to selected major risk factors. Geneva, Switzerland:
World Health Organization, 2004:39 162.
9. Shankar AH, Prasad AS. Zinc and immune function: the biological basis
of altered resistance to infection. Am J Clin Nutr 1998;68(suppl):447S
63S.
10. Prasad AS. Zinc: an overview. Nutrition 1995;11:939.
11. Bhutta ZA, Black RE, Brown KH, et al. Prevention of diarrhea and
pneumonia by zinc supplementation in children in developing countries:
pooled analysis of randomized controlled trials. Zinc Investigators Collaborative Group. J Pediatr 1999;135:689 97.
12. Walker CF, Black RE. Zinc and the risk for infectious disease. Annu Rev
Nutr 2004;24:25575.
13. Black RE, Sazawal S. Zinc and childhood infectious disease morbidity
and mortality. Br J Nutr 2001;85(suppl 2):S1259.
14. Bhutta ZA, Bird SM, Black RE, et al. Therapeutic effects of oral zinc in

Downloaded from ajcn.nutrition.org by guest on May 22, 2015

(5.0 and 2.5 days, respectively; P 0.001). Although this difference may suggest that the children in our study were more
likely to have a milder illness or to be in recovery at admission
than were the Bangladeshi children, our data do not support this
idea. In our subgroup analysis, days of illness before admission
(3 compared with 3 d) did not alter the lack of treatment
effect.
Moreover, the proportion of children with wheeze at admission was significantly higher in our study population than in the
Bangladeshi study (62.5% and 37%, respectively; P 0.001).
This may suggest a difference in the etiology of pneumonia
between populations, because wheeze is frequently associated
with viral infection. Brooks et al (15) noted that the association
between zinc and recovery from severe pneumonia and the other
clinical indicators of illness was strongest in children who presented without wheeze at admission. Because wheeze is commonly associated with viral infection, the authors hypothesize
that zinc supplementation may have a greater effect on bacterial
infections. However, this possibility remains controversial. Evidence from laboratory investigations suggests that the zinc deficiency impairs cell-mediated immunity in addition to reducing
antibody production (9, 23). If this is correct, then supplementation is likely to aid in the restoration of immunity to both viral
and bacterial infections. Moreover, as was mentioned previously, zinc supplementation was significantly associated with a
prolonged recovery in the hot season, a time when the incidence
of viral infections is thought to be low (20, 21). Finally, the results
of our stratified analysis show no modification of treatment effect
by wheeze status.
All 3 trials mentioned above used comparable study designs,
enrollment criteria, and supplement dosages and standardized
antibiotic protocols. However, there were also several differences in method between the current trial and the other 2 trials,
which may have affected the association between zinc and recovery from pneumonia. The Bangladesh trial was conducted in
a research ward of a small hospital in a rural district, where all
clinical decisions and assessments of recovery status were made
by study physicians using objective criteria. In contrast, our study
was conducted on 3 pediatric wards in a large general hospital.
Although study physicians at the CMC Hospital were responsible for recording observations according to well-defined criteria,
all clinical decisions and determinations of recovery status were
based on the clinical judgment of the attending pediatricians, as
they were in the Kolkata trial. The implication of this is that some
potential exists for nondifferential misclassification of recovery
status, which would shift the association between zinc and recovery from pneumonia toward the null hypothesis. The consistency between the objective observations recorded by the study
physicians and the subjective assessments of recovery status by
the attending pediatricians suggests that this is unlikely to have
masked the effect of treatment.
In the current study, emphasis was given to infant feeding,
reduction of hypoxia, and a reduction in respiratory rate to 60
breaths/min for initiating oral feeds and to 50 breaths/min for
decision to discharge. This protocol was in keeping with that for
the treatment of infants with severe pneumonia and is dictated by
both the high prevalence of malnutrition, which necessitates
earlier enteral feeding, and a high demand for beds, which necessitates discharge even when the respiratory rate is 40
breaths/min.

1095

1096

15.
16.

17.
18.

BOSE ET AL

acute and persistent diarrhea in children in developing countries: pooled


analysis of randomized controlled trials. Am J Clin Nutr 2000;72:1516 22.
Brooks WA, Yunus M, Santosham M, et al. Zinc for severe pneumonia
in very young children: double-blind placebo-controlled trial. Lancet
2004;363:1683 8.
Mahalanabis D, Lahiri M, Paul D, et al. Randomized, double-blind,
placebo-controlled clinical trial of the efficacy of treatment with zinc or
vitamin A in infants and young children with severe acute lower respiratory infection. Am J Clin Nutr 2004;79:430 6.
Nutrition Sub-committee of the Indian Academy of Pediatrics. Report of
the Convener (19711972). Indian Pediatr 1972;9:360.
Swaminathan S, Seshadri MS, Srikrishna G, Mathew P, Kanagasabapathy AS. Detection and elimination of preanalytical errors in the determination of zinc in biological samples. Indian J Med Res 1993;98:199 201.

19. George SS, Swaminathan S, Kanagasabapathy AS, Seshadri L. Maternal


zinc indices and small babies. Natl Med J India 1998;11:120 1.
20. John TJ, Cherian T, Steinhoff MC, Simoes EA, John M. Etiology of
acute respiratory infections in children in tropical southern India. Rev
Infect Dis 1991;13(suppl):S4639.
21. Cherian T, Simoes EA, Steinhoff MC, et al. Bronchiolitis in tropical
south India. Am J Dis Child 1990;144:1026 30.
22. Hotz C, Peerson JM, Brown KH. Suggested lower cutoffs of serum zinc
concentrations for assessing zinc status: reanalysis of the second National Health and Nutrition Examination Survey data (1976 1980).
Am J Clin Nutr 2003;78:756 64.
23. Prasad AS. Effects of zinc deficiency on Th1 and Th2 cytokine shifts.
J Infect Dis 2000;182(suppl):S62 8.

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