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ARTICLE

A Randomized Controlled Trial of Zinc as Adjuvant


Therapy for Severe Pneumonia in Young Children
AUTHORS: Sudha Basnet, MD,a Prakash S. Shrestha, MD,a WHATS KNOWN ON THIS SUBJECT: Pneumonia is still
Arun Sharma, MD,a Maria Mathisen, PhD,b Renu Prasai, DCH,c a signicant problem in young children from developing countries
Nita Bhandari, PhD,d Ramesh K. Adhikari, MD,a Halvor where zinc deciency is prevalent. Although zinc supplementation
Sommerfelt, PhD,b,e Palle Valentiner-Branth, PhD,f Tor A. reduces the risk of childhood pneumonia, the effect of adjunct
Strand, PhD,b,e,g and members of the Zinc Severe zinc on severe pneumonia is unclear with conicting results.
Pneumonia Study Group
aChild Health Department, Institute of Medicine, Tribhuvan
WHAT THIS STUDY ADDS: The overall effect, if any, of zinc as
University, Kathmandu, Nepal; bCentre for International
adjuvant therapy for World Health Organizationdened severe
Health, University of Bergen, Bergen, Norway; cKanti Childrens
Hospital, Kathmandu, Nepal; dSociety for Applied Studies, New pneumonia in young children is small.
Delhi, India; eDivision of Infectious Disease Control, Norwegian
Institute of Public Health, Oslo, Norway; fDivision of Epidemiology,
Department of Epidemiology, Statens Serum Institut, Copenhagen,
Denmark; and gMedical Microbiology, Innlandet Hospital Trust
Lillehammer, Norway
KEY WORDS
abstract
zinc, pneumonia, young children, therapeutic, treatment failure BACKGROUND AND OBJECTIVE: Diarrhea and pneumonia are the lead-
ABBREVIATIONS ing causes of illness and death in children ,5 years of age. Zinc
CRchest radiograph supplementation is effective for treatment of acute diarrhea and can
LCIlower chest indrawing
SpO2oxygen saturation prevent pneumonia. In this trial, we measured the efcacy of zinc
WHOWorld Health Organization when given to children hospitalized and treated with antibiotics for
Drs Basnet, Shrestha, Sharma, Adhikari, Sommerfelt, and Strand severe pneumonia.
made primary contributions to the design, conduct, analysis,
METHODS: We enrolled 610 children aged 2 to 35 months who pre-
interpretation, and writing of this manuscript; Drs Prasai and
Mathisen contributed to the eld conduct, training and sented with severe pneumonia dened by the World Health Organiza-
standardization, collection of biological specimen, and quality tion as cough and/or difcult breathing combined with lower chest
control of the trial; Dr Mathisen was also responsible for the indrawing. All children received standard antibiotic treatment and
virus analyses; Drs Bhandari and Valentiner-Branth contributed
to the development and design of the trial and to the were randomized to receive zinc (10 mg in 2- to 11-month-olds and
interpretation of the study results; Dr Strand had full access to 20 mg in older children) or placebo daily for up to 14 days. The
all the data in the study and took the nal decision to submit primary outcome was time to cessation of severe pneumonia.
this report for publication.
RESULTS: Zinc recipients recovered marginally faster, but this differ-
This trial has been registered at www.clinicaltrials.gov
(identier NCT00252304). ence was not statistically signicant (hazard ratio = 1.10, 95% CI 0.94
www.pediatrics.org/cgi/doi/10.1542/peds.2010-3091 1.30). Similarly, the risk of treatment failure was slightly but not sig-
doi:10.1542/peds.2010-3091
nicantly lower in those who received zinc (risk ratio = 0.88 95% CI
0.711.10).
Accepted for publication Nov 28, 2011
CONCLUSIONS: Adjunct treatment with zinc reduced the time to ces-
(Continued on last page) sation of severe pneumonia and the risk of treatment failure only mar-
ginally, if at all, in hospitalized children. Pediatrics 2012;129:18

PEDIATRICS Volume 129, Number 4, April 2012 1


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The estimated number of deaths glob- to standard antibiotic treatment in re- were initially assessed for hypoxemia
ally in children aged ,5 years was ducing the time to cessation and the by using a pulse oximeter (Nellcor
8.8 million in 2008.1 Pneumonia and risk of treatment failure of a severe Puritan Bennett NPB-40, Pleasanton,
diarrhea combined are responsible for pneumonia episode. CA) with a pediatric sensor (Nellcor
45% of these deaths.2 It is estimated Pedichek D-YSPD) and presence of
that zinc deciency in association with METHODS wheezing. Oxygen saturation (SpO2)
diarrhea, pneumonia, and malaria con- was recorded twice after stabilization
This was a double-blind, randomized,
tributes to 4.4% of deaths and 3.8% of of the reading for 1 minute. The higher
placebo-controlled trial in young chil-
lost disability adjusted life years among of the 2 readings was used. For chil-
dren designed to measure the impact
children aged 6 to 59 months in Africa, dren with SpO2 of ,90%, oxygen was
of daily zinc administration for up to
Latin America, and Asia.3 In a meta- provided before further evaluation.
14 days on time to cessation of severe
analysis of clinical trials evaluating the Children with wheezing were given up
pneumonia. An important secondary
preventive role of zinc, daily supple- to 3 doses of nebulized Salbutamol 15
outcome was the risk of treatment fail-
mentation led to 14% and 8% reductions minutes apart, reassessed, and ex-
ure. Clearances were obtained from the
in the risk of diarrhea and pneumonia, cluded if LCI disappeared.16 A history of
ethical board of the Institute of Medi-
respectively.4 The World Health Orga- the childs illness was taken and phys-
cine, Tribhuvan University, and Nepal
nization (WHO) now recommends zinc ical examination carried out by using
Health Research Council, Kathmandu.
for the treatment of children with a standardized form. Children were
diarrhea5 because there is sufcient weighed by using an Electronic Scale
Sample Size Calculation
evidence demonstrating that supple- 890 (SECA, Hamburg, Germany) that
mentation reduces the severity and The study was based on the hypothesis measures to the nearest 100 g. Height
duration of the episode.6 The benet that zinc sulfate given as adjuvant was measured by using a standard
of zinc in the treatment of pneumonia therapy to standard antibiotic treat- wooden height measuring board, and
is, however, unclear. Although zinc as ment would result in a reduction of the recumbent length in children ,2 years
adjuvant therapy for hospitalized chil- median duration of hospital stay by was measured by using an infan-
dren with pneumonia was found to be 1 day. In a similar study in Bangladesh,7 tometer, both to the nearest 0.1 cm.
benecial in 1 clinical trial in Bangla- the median time to resolution from Stunting dened as length-for-age #2
desh,7 other trials in India8 and Aus- severe pneumonia was 3 days in the z score and wasting as weight-for-
tralia9 found no effect. In developing zinc and 4 days in the placebo group. length #2 z score were calculated by
countries, the estimated incidence of With a minimal detectable hazard ratio using the 2006 WHO Child Growth
clinical pneumonia in children aged of 1.30 for time to cessation of severe Standards.17 We measured hemoglo-
,5 years is 0.29 episodes per child pneumonia, we estimated a total sam- bin concentrations by using Hemocue
year.10 Despite a declining trend, the ple size of 500 children. Calculations (ngelholm, Sweden). A chest radio-
incidence of pneumonia in Nepal is were done with 80% power and an a graph (CR) taken in all children was
0.13 episodes per child per year with error of 5%. Assuming up to 20% loss to interpreted by a radiologist blinded to
severe pneumonia accounting for 1.2% follow-up, we enrolled 610 children. clinical data by using the WHO stan-
of the all cases of acute respiratory dardized tool for interpretation of CRs
infections.11 We have previously shown Enrollment, Baseline Clinical and ndings classied as endpoint con-
that zinc deciency is common in chil- Workup, and Initiation of solidation, other inltrates, or normal.18
dren12 and in women of reproductive Antibiotic Therapy Children with recurrent wheezing (de-
age13 in the Kathmandu valley. In a large Children aged 2 to 35 months pre- ned as .3 episodes over the past
community-based trial in Bhaktapur, senting to the Kanti Childrens hospital 6 months and on treatment with bron-
Nepal, zinc administration did not emergency or outpatient departments chodilators), disappearance of LCI after
reduce time till recovery or risk of with complaints of cough lasting ,14 nebulized salbutamol, severe wasting,19
treatment failure in children with pneu- days and/or difcult breathing of ,72 severe anemia (hemoglobin ,7 g/dL),
monia.14 Whether zinc administration hours duration with lower chest in- heart disease, documented tuberculo-
has a benecial effect when given to drawing (LCI) were screened for en- sis, or concomitant diarrhea with de-
children hospitalized with severe pneu- rollment by trained physicians. The hydration and those with severe illness
monia needs to be claried. We there- Integrated Management of Childhood requiring special care or surgical inter-
fore undertook a clinical trial to assess Illnesses algorithm was used to dene vention were excluded. Informed con-
the efcacy of zinc as adjuvant therapy severe pneumonia.15 Eligible children sent was obtained for eligible children.

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ARTICLE

Literate parents signed the consent by trained study assistants who were dened as persistence of LCI or of any
form after they had read a written not otherwise involved in patient care. danger signs present at enrollment
statement in the local Nepali language. The zinc or placebo dispersions were despite 48 hours of treatment or ap-
For parents who were unable to read given as a single daily dose until dis- pearance of new danger signs or hyp-
or write, verbal informed consent was charge or for a maximum of 14 days. All oxia with deterioration of patients
obtained in the presence of a witness. children were observed for vomiting. clinical status anytime after initiation
After obtaining consent, blood was For children who vomited within the of treatment. A decision to change
collected for investigations, and the rst 15 minutes, a repeat dose was antibiotics was made only after con-
rst dose of intravenous antibiotics given. Children who vomited the second sultation with senior pediatricians in-
was administered. This was followed time were given the required amount in volved in the study. For children unable
by collection of nasopharyngeal aspi- 2 divided doses over a 24-hour period to eat/drink or breastfeed, intravenous
rate for identication of 7 respiratory from the next day onward. uids based on daily requirements
viruses. Details of the sampling tech- were initiated.19 Humidied oxygen
nique and the results of these analyses Outcome Denitions was given to children with documented
have been described in a separate The primary outcome, time to cessation hypoxia. During each physician visit,
publication20 of severe pneumonia, was dened as oxygen saturation was documented
the period starting from enrollment after a washout period of 5 minutes
Randomization, Intervention, and oxygen discontinued when they
and Blinding to the beginning of a 24-hour consec-
utive period of absence of LCI, hypoxia, were no longer hypoxic. The absence
The intervention was dispersible tab- and any danger signs. We used WHO of hypoxia was conrmed after a sec-
lets containing 10 mg of elemental zinc guidelines to dene hypoxia (SpO2 of ond reading taken 30 minutes later.
sulfate or placebo, manufactured and ,90%) and danger signs such as in- Study physicians were trained to as-
packed by Nutriset (Malaunay, France) ability to breastfeed or drink, vomit- sess and manage children with severe
in a blister pack with 15 tablets. Tablets ing everything consumed, convulsions, pneumonia, and their performance was
of both groups were identical in pack- lethargy, or unconsciousness.19 The monitored each day by experienced
aging, appearance, and inactive in- secondary outcome, treatment failure, pediatricians, who were also the inves-
gredients with no indication of group was dened as a requirement for tigators for this study. Standardization
identity and content. For each child in change in antibiotics, development of exercises were conducted before the
the study, there were 3 blister packs complications, such as empyema or start of the trial. Each physician was
with zinc or placebo tablets labeled pneumothorax requiring surgical in- assigned to record axillary tempera-
with a serial number to match the child tervention, or admission to the ICU ture, count respiratory rate, observe
study identication number. The ran- for ventilator or inotropic support. for LCI, and listen for wheezing and
domization list linking the treatment crepitations in at least 10 children.
groups to these identication numbers
Cointerventions Their ndings were matched against
was generated by and kept with a per- those of an experienced pediatrician un-
son not otherwise involved in the study. Enrolled children were admitted to
til the desired agreement was reached.
Children were allocated to either of the hospital and monitored by study
the 2 intervention groups by randomi- physicians at 8 hourly intervals un-
zation in blocks of 16 in a 1:1 ratio. til discharge. Benzyl penicillin (50 000 Data Management and Analysis
Randomization was stratied on age U/kg intravenously every 6 hours) and The completed forms with patient data
,12 months or $12 completed months gentamicin (7.5 mg/kg intravenously were collected by the study assistants
and on wheezing status before nebuli- once daily) were given until clinical on a daily basis. All forms were checked
zation. Study physicians selected blis- improvement, dened as absence of manually by 1 of the clinical supervi-
ter packs with the lowest number from danger signs, of hypoxia for 24 con- sors before data entry, which was done
a box specifying the stratum to which secutive hours and of LCI for a 48-hour within 48 hours. The data were double
each child belonged. Children ,12 period. Patients were then discharged entered into a database (Visual FoxPro
months were given 1 tablet and children with advice to continue oral amoxicillin 6.0, Microsoft Corp, Redmond, WA) with
$12 months were given 2 tablets dis- to complete treatment of a total dura- inbuilt logic, range, and consistency
solved in 5 mL of clean water or breast tion of 10 days. checks. Statistical analyses were under-
milk. The rst dose was dispensed by Antibiotics were changed to cefotax- taken by using Stata, version 10 (Stata
the study physician and subsequently ime in children with failure to improve, Corp, College Station, TX). Data cleaning,

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denition of outcome variables, exclu-
sion of cases as well as programming
of scripts in the statistical packages
were done before the analysis les
were merged with the randomization
lists. We used Cox proportional hazards
regression models to compare the
time to cessation of severe pneumonia
between the treatment groups, the
effect estimates expressed as hazard
ratios. Treatment failure, risk of pro-
longed illness and vomiting after the
rst dose of the intervention was com-
pared by using generalized linear re-
gression models with log link functions
and binomial distributions, yielding re-
lative risks. We coded the outcomes
and interventions so that hazard ratios
.1 and relative risks ,1 would repre-
sent a benecial effect of zinc. Differ-
ences were considered signicant when
a two-sided P value was ,.05.
FIGURE 1
RESULTS Trial prole of a randomized, placebo-controlled trial of zinc as adjunct therapy for severe pneumonia in
children aged 2 to 35 months of age in Kanti Childrens Hospital, Kathmandu, Nepal.
From January 8, 2006, to June 30, 2008,
we screened 2199 children meeting in-
clusion criteria. There were 1589 (72%) remaining 580 (288 in the zinc and 292 wheezing, crepitations, virus isolated
who were not eligible for randomiza- in placebo arms) stayed in the study in nasopharyngeal aspirate, endpoint
tion, of whom 1282 (58%) fullled the until recovery from severe pneumonia. consolidation on CR, wasting, and stunt-
predened exclusion criteria (Fig 1), Viruses were isolated from nasopha- ing. In the subgroup consisting of chil-
227 (10%) did not consent, and 80 (4%) ryngeal aspirates in 29% with details dren with endpoint consolidation, zinc
had been previously enrolled. After en- described elsewhere.20 Among 533 recipients recovered signicantly faster
rollment and randomization of the re- CRs available for interpretation, 520 than those in the placebo group (Fig 2).
maining 610 children, we discovered lms were of adequate quality. End- The effect of zinc, however, was not
that 11 with heart disease 1 with cough signicantly different between those
point consolidation was identied in
duration .14 days had been included. with and without radiographic pneu-
126 (24%), 196 (38%) had other inl-
These trial deviates were evenly dis- monia, that is, the interaction was not
trates, and 198 (38%) were normal.
tributed between the study arms (Fig 1) statistically signicant. We also com-
Most baseline characteristics were
and were excluded from the analysis. pared the proportion of children with
evenly distributed between groups
Of the remaining 598 children, 299 severe pneumonia at 72, 96, or 120
(Tables 1 and 2).
were randomized to receive zinc and hours after admission between the
299 to receive placebo. In the zinc Analyses were done by intention to study groups. These comparisons were
group, 199 of the 245 (81%) infants and treat. The time until cessation of se- also in favor of zinc, but none reached
45 of the 54 (83%) older children had vere pneumonia was slightly shorter statistical signicance (Table 3). The
wheezing. In the placebo group, 208 of among the zinc recipients, with a hazard risk of treatment failure was lower
the 248 (84%) infants compared with ratio of 1.10, 95% condence interval among the zinc recipients; however,
40 of the 51 (78%) older children pre- 0.94 to 1.30; P = .22 (Table 3). We ex- this was also not statistically signi-
sented with wheezing. Eleven children plored whether the effect of zinc was cant (risk ratio: 0.88; 95% condence
were lost to follow-up in the zinc arm different in subgroups on the basis of interval: 0.711.10). Adjusting for po-
and 7 in the placebo arm (Fig 1). The age, gender, presence of fever, hypoxia, tential confounders altered the results

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TABLE 1 Baseline Demographic Characteristics of Children aged 2 to 35 Months in a Clinical Trial in reducing time to cessation of severe
Evaluating Efcacy of Zinc as Adjuvant Therapy for Severe Pneumonia
pneumonia dened as a 24-hour con-
Characteristic Zinc Group Placebo Group secutive period of absence of LCI, hyp-
n Value n Value oxia, and any other danger sign.
Mean age in months (SD) 299 7.8 (6.0) 299 7.1 (5.6) In a study undertaken in Bangladesh,7
Age groups (months)
26, n (%) 299 167 (55.9) 299 185 (61.7)
children who received zinc recovered
711, n (%) 299 78 (26.1) 299 63 (21.1) faster, and fewer had treatment fail-
1223, n (%) 299 45 (15.1) 299 45 (15.0) ure and duration of severe pneumonia
2435, n (%) 299 9 (3.0) 299 6 (2.0)
lasting .72, 96, or 120 hours. The re-
Male subjects, n (%) 299 177 (59.2) 299 190 (63.6)
Mean age of mother, y (SD) 292 24.7 (4.2) 294 24.1 (4.1) sults from our trial were in the same
Illiteratea mother (%) 292 79 (27.1) 294 75 (25.5) direction but smaller. Another trial in
Illiteratea father (%) 293 20 (6.8) 295 18 (6.1) South India8 failed to show any bene-
Unemployedb mother (%) 290 205 (70.7) 294 213 (72.5)
Unemployedb father (%) 289 10 (3.5) 291 9 (3.1) cial effect of zinc on duration of illness
Child still breastfeeding 299 283 (94.6) 299 288 (96.3) in young children with severe pneu-
a No schooling with inability to read part or whole of a sentence. monia. In another study from Kolkatta,
b No work/housework.
India,21 although zinc was efcacious in
boys, the overall effect as well as the
TABLE 2 Baseline Clinical Characteristics of Children Aged 2 to 35 Months Enrolled in a Clinical interaction between gender and zinc
Trial on the Efcacy of Zinc as Adjuvant Therapy for Severe Pneumonia
administration was not statistically
Characteristic Zinc Placebo
signicant. All these studies, like our
n Value n Value study, were double-blind randomized
Mean duration of cough in days (SD) 299 4.0 (2.0) 299 4.2 (2.2) controlled trials assessing the efcacy
Mean duration of difculty breathing in hours (SD) 299 30.2 (20.2) 299 29.6 (18.3) of zinc in children with severe pneu-
Mean duration of fever in days (SD) 264 3.5 (2.0) 279 3.5 (2.1)
Wt for length/height #2 z scorea (%) 296 86 (29.1) 298 71 (23.8) monia. Inherent differences in the pop-
Length/height for age #2 z scorea (%) 299 28 (9.4) 299 22 (7.4) ulations studied and differences in the
Mean hemoglobin in g/dL (SD) 299 11.0 (1.4) 299 10.9 (1.4) illness characteristics including pre-
Mean axillary temperature in C (SD) 299 37.7 (0.8) 299 37.7 (0.9)
Febrileb (%) 299 46 (15.4) 299 46 (15.4)
enrollment duration and denition of
Mean respiratory rate in breaths per minute (SD) recovery would explain the discrepancy
211 mo 245 64 (12) 248 65 (12) between studies.
1235 mo 54 60 (13) 51 63 (10)
Mean oxygen saturation (SD) 299 86 (8) 299 87 (9) In the current trial, the proportion of
Oxygen saturation (%) children with wheezing was 82% com-
,90% 299 186 (62.2) 299 187 (62.5)
pared with 37% in the Bangladeshi7
,93% 299 255 (85.3) 299 249 (83.3)
Wheezing (%) 299 244 (81.6) 299 248 (82.9) and 62.5% in the South Indian trial.8
Crepitations (%) 299 273 (91.3) 299 276 (92.3) Because children with reactive airway
Endpoint consolidation on CR 258 60 (23.3) 262 66 (25.2) disease would meet criteria for inclu-
Symptoms of severe pneumonia
Child unable to drink/breastfeed (%) 299 30 (10.0) 299 24 (8.0) sion in our study, we excluded children
History of convulsions (%) 299 1 (0.3) 299 2 (0.7) with a history of recurrent wheezing
Vomiting everything child eats (%) 294 9 (3.1) 292 5 (1.7) and enrolled others only if LCI per-
Child unconscious/lethargic (%) 299 25 (8.4) 299 30 (10.0)
Signs of severe pneumonia sisted after salbutamol administration.
Nasal aring (%) 298 116 (38.9) 299 116 (38.8) Brooks et al reported that in children
Grunting (%) 299 60 (20.1) 299 71 (23.8) without wheezing, administration of zinc
Head nodding (%) 299 65 (21.7) 299 73 (24.4)
Central cyanosis (%) 299 1 (0.3) 299 2 (0.7) resulted in earlier resolution of clinical
a Derived by using the recent WHO Child Growth Standards.17 signs.7 The effect of zinc was not modi-
b Dened as axillary temperature of .38.5C. ed by wheezing status in our subgroup
analysis (Fig 2), a nding similar to that
only marginally. The proportion of chil- DISCUSSION reported from South India.8 However,
dren who vomited after the rst dose This study on zinc as adjunct therapy because there were only 106 children
of supplement was higher (14%) in inchildrenwithseverepneumonia shows without wheezing, we had insufcient
the zinc than in the placebo group (9%; a modest but not statistically signif- power to detect an effect of zinc in this
P = .052). icant effect of daily zinc administration subgroup.

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TABLE 3 Primary and Secondary Outcomes in a Randomized, Placebo-Controlled Trial on Oral Zinc as Adjunct Therapy for Severe Pneumonia in
Children 2 to 35 Months of Age
Zinc Group Placebo Group Hazard Ratioa (95% CI) P

n Value (IQR) n Value (IQR)


Median time to cessation of severe pneumonia in hours 288 49 (33, 77) 292 49 (29, 91) 1.10 (0.94 1.30) .22
Proportion with duration of severe pneumonia in hours Risk Ratiob (95% CI)
.72 295 83 (28) 297 104 (35) 0.80 (0.631.02) .07
.96 294 56 (19) 296 64 (22) 0.88 (0.641.21) .44
.120 293 31 (11) 294 46 (16) 0.67 (0.441.03) .07
Proportion with treatment failure 296 98 (33) 298 111 (37) 0.88 (0.711.10) .29
Proportion with vomiting after supplementc 299 41 (14) 299 26 (9) 1.57 (0.992.50) .05
IQR, interquartile range.
a Hazard ratio for time until cessation of severe pneumonia was estimated by using Cox proportional hazards models. A value of .1 indicates benecial effect of zinc.
b From generalized linear models with a log link function and binomial distribution.
c After the rst dose.

study site is the only government hos-


pital and referral center for children
living in as well as outside Kathmandu.
We had study physicians who were
well trained and dedicated only to this
trial. Daily doses of supplement were
provided by study assistants and not
the physicians recruited for the study.
Limiting duration of difculty breath-
ing to #72 hours ensured that we en-
rolled children with an acute episode
of pneumonia. We used objective out-
comes for dening resolution, disap-
pearance of LCI and SpO2 $90%, which
are replicable ndings. In a review as-
sessing the precision of clinical signs
in the diagnosis of pneumonia, Margolis
et al concluded that there is better
agreement among observers for a
clinical sign that can be observed, such
as respiratory effort retractions (k =
0.48), than for an auscultatory sign,
such as presence of adventitious sounds
(k = 0.3).22
The high proportion of children with
wheezing is a limitation of this study, a
nding likely due to use of WHO criteria
FIGURE 2
The efcacy of oral zinc given during an episode of severe pneumonia in Nepalese children aged 2 to in dening severe pneumonia. This def-
35 months in selected subgroups. Hazard ratios for time until cessation of severe pneumonia were inition has high specicity for severe
estimated by using Cox proportional hazards models. A value .1 indicates benecial effect of zinc. lower respiratory tract infection but
Weight for length/height #2 z score by using WHO child growth standards. Length/height for age #2
z score by using WHO child growth standards. does not dene the etiology.23 Severe
pneumonia includes a wide spectrum
of causes and predisposing factors that
This study enrolled 610 children and conducted in an area where zinc de- may respond differently to zinc adminis-
to our knowledge is the largest trial ciency is common12,13 and in a country tration. Furthermore, this heterogeneity
conducted to date on zinc given dur- where pneumonia in young children can also result in poor specicity of
ing severe pneumonia. The study was is a signicant health problem.11 The the outcomes, which again may dilute

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a measureable effect of zinc. Using CRs an aspect that needs to be taken into and the study physicians for their contri-
to improve the diagnosis enabled us to account when the results from this trial bution to the study aswell as other staff of
identify only 24% with radiographic as well as those of other completed, the Child Health Research Project. We
pneumonia. It is also noteworthy that ongoing, and planned studies are in- thank the director of the Kanti Children
there was signicant benecial effect of terpreted and summarized to deter- Hospital and staff of the Emergency, Ob-
zinc in this subgroup. Future studies are mine the role of zinc in the treatment servation, Acute Respiratory Illness/Oral
needed exploring the role of zinc in se- of severe pneumonia. Rehydration Therapy, Medical, Paying
vere pneumonia in which children with and Special Cabin wards for their invalu-
wheezing are excluded and CR, micro- able support. We also thank the head
biologic, and inammatory markers are ACKNOWLEDGMENTS of the Department of Child Health, Pro-
used in an attempt to arrive at a more The Zinc Severe Pneumonia Study Group fessor Pushpa Raj Sharma, and other
specic diagnosis.24 is: RameswarMan Shrestha, MD; Uday Raj faculty members for their support, the
Upadhaya, DCH; Chandeshwar Mahaseth, Department of Microbiology, Tribhuvan
MRCP; Rojen Sundar Shrestha, DCH; University Teaching Hospital, Kathmandu,
CONCLUSIONS Puja Shrestha, MBBS; Geetika KC, MBBS; for providing the laboratory facilities and
This trial yielded a small but not sta- Yagya Ratna Shakya, MBBS; Ujma Shrestha, Dr Dhiraj Man Shrestha for interpreta-
tistically signicant efcacy estimate MBBS. tion of chest radiographs. We thank Sol-
for zinc in the resolution of severe pneu- We thank all the children and their fam- frid Vikren for excellent administrative
monia in hospitalized 2- to 35-month-old ilies who took part in the study. We are support and Hans Steinsland for gen-
children. All study participants received indebted to eld assistants Mahesh erating the randomization list and main-
optimized antibiotic and other therapies, Kumar Thapa and Ram Krishna Khatri taining it until the end of the study.

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Address correspondence to Tor A. Strand, PhD, Medical Microbiology, Innlandet Hospital Trust, Anders Sandvigsgate 17, 2629 Lillehammer, Norway. E-mail: tors@me.
com
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright 2012 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have no nancial relationships relevant to this article to disclose.
FUNDING: Supported by a grant from the European Commission (EU-INCO-DC contract INCO-FP6-003740); by funding from the Meltzer Foundation in Bergen, Norway;
by the Danish Council of Developmental Research (project 91128); and by the Research Council of Norway (projects 151054 and 172226). The sponsors of the study
had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

8 BASNET et al
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A Randomized Controlled Trial of Zinc as Adjuvant Therapy for Severe
Pneumonia in Young Children
Sudha Basnet, Prakash S. Shrestha, Arun Sharma, Maria Mathisen, Renu Prasai, Nita
Bhandari, Ramesh K. Adhikari, Halvor Sommerfelt, Palle Valentiner-Branth, Tor A.
Strand and members of the Zinc Severe Pneumonia Study Group
Pediatrics; originally published online March 5, 2012;
DOI: 10.1542/peds.2010-3091
Updated Information & including high resolution figures, can be found at:
Services /content/early/2012/02/29/peds.2010-3091
Citations This article has been cited by 6 HighWire-hosted articles:
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly


publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
Grove Village, Illinois, 60007. Copyright 2012 by the American Academy of Pediatrics. All
rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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A Randomized Controlled Trial of Zinc as Adjuvant Therapy for Severe
Pneumonia in Young Children
Sudha Basnet, Prakash S. Shrestha, Arun Sharma, Maria Mathisen, Renu Prasai, Nita
Bhandari, Ramesh K. Adhikari, Halvor Sommerfelt, Palle Valentiner-Branth, Tor A.
Strand and members of the Zinc Severe Pneumonia Study Group
Pediatrics; originally published online March 5, 2012;
DOI: 10.1542/peds.2010-3091

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
/content/early/2012/02/29/peds.2010-3091

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly


publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2012 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

Downloaded from by guest on January 4, 2017

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