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Zinc as adjunct treatment in infants aged between 7 and 120 days with probable serious bacterial infection: a randomised, double-blind, placebo-controlled trial

Articles
Zinc as adjunct treatment in infants aged between 7 and
120 days with probable serious bacterial infection:
a randomised, double-blind, placebo-controlled trial

Shinjini Bhatnagar, Nitya Wadhwa, Satinder Aneja, Rakesh Lodha, Sushil Kumar Kabra, Uma Chandra Mouli Natchu, Halvor Sommerfelt, Ashok Kumar Dutta, Jagdish Chandra, Bimbadhar Rath, Mamta Sharma, Vinod Kumar Sharma, Mohini Kumari, Tor A Strand Lancet 2012; 379: 2072–78
Background Serious bacterial infections are a major cause of death in early infancy in developing countries.
Published Online
Inexpensive and accessible interventions that can add to the eff ect of standard antibiotic treatment could reduce
infant mortality. We measured the eff ect of zinc as an adjunct to antibiotics in infants with probable serious
bacterial infection.
See Comment page 2031
Methods In this randomised, double-blind, placebo-controlled trial, we enrolled infants aged 7–120 days with probable
Centre for Diarrhoeal Diseases
serious bacterial infection at three hospitals in New Delhi, India, between July 6, 2005, and Dec 3, 2008. With
and Nutrition Research
computer-generated sequences, we randomly assigned infants in permuted blocks of six, stratifi ed by whether
N Wadhwa MD), Department of
patients were underweight or had diarrhoea at enrolment, to receive either 10 mg of zinc or placebo orally every day
Paediatrics (R Lodha MD,
in addition to standard antibiotic treatment. The primary outcome was treatment failure, which was defi ned as a need
Prof S K Kabra MD), All India
to change antibiotics within 7 days of randomisation, or a need for intensive care, or death at any time within 21 days.
Institute of Medical Sciences,
New Delhi, India; Paediatric
Participants and investigators were masked to treatment allocation. All analyses were done by intention-to-treat. This
Biology Centre, Translational
trial is registered with ClinicalTrials.gov, number NCT00347386.
Health Science and Technology
Institute, Gurgaon, Haryana,
Findings 352 infants were randomly assigned to receive zinc and 348 to placebo. 332 given zinc and 323 given placebo
India (Prof S Bhatnagar,
N Wadhwa, U C M Natchu MD);
could be assessed for treatment failure. Signifi cantly fewer treatment failures occurred in the zinc group (34 [10%])
Department of Paediatrics,
than in the placebo group (55 [17%]; relative risk reduction 40%, 95% CI 10–60, p=0·0113; absolute risk reduction
Lady Hardinge Medical College
6·8%, 1·5–12·0, p=0·0111). Treatment of 15 (95% CI eight to 67) infants with zinc would prevent one treatment
and Kalawati Saran Children’s
failure. Ten infants receiving zinc died compared with 17 given placebo (relative risk 0·57, 0·27–1·23, p=0·15).
Hospital, New Delhi, India
Interpretation Zinc could be given as adjunct treatment to reduce the risk of treatment failure in infants aged
7–120 days with probable serious bacterial infection.
Prof B Rath MD); Department of
Nutrition, Harvard School of
Public Health, Boston, MA, USA
Funding Department of Biotechnology, Government of India; the European Commission; the Meltzer Foundation; and
(U C M Natchu); Centre for
the Research Council of Norway.
International Health,
University of Bergen, Bergen,
Introduction
morbidity, raised the number of circulating T cells Norway (Prof H Sommerfelt PhD,
T A Strand PhD); Division of
Of the 7·8 million deaths a year in children younger than (especially CD4 cells), and improved the cutaneous Infectious Disease Control,
5 years in Africa, southeast Asia, and the eastern delayed hypersensitivity reaction.
Norwegian Institute of Public
Mediterranean, more than 3 million are in neonates.1 A reduced risk of treatment failure will shorten time in Health, Oslo, Norway
(Prof H Sommerfelt, T A Strand);
Sepsis and pneumonia—responsible for 25% of these hospital, lower use of high-generation antimicrobials and Department of Paediatrics,
cult to distinguish in treatment cost, and possibly reduce mortality. We aimed Deen Dayal Upadhyay Hospital,
young infants. Of the 1 million neonatal deaths that to estimate the effi Hari Nagar, New Delhi, India
occur annually in India, more than a quarter are combined with standard antibiotic treatment in infants M Kumari MD); and Medical
attributed to serious bacterial infections, such as pneu- aged between 7 and 120 days with probable serious Microbiology, Department of
monia, sepsis, and meningitis.2 Many young in fants in bacterial infection.
Laboratory Medicine, Innlandet
hospital have been admitted because of these severe Hospital Trust, Lillehammer,
infections.3 Despite advances in antimicrobial treatment, Norway (T A Strand)
outcomes remain poor.4 Development of inexpensive and Study design and participants
accessible interventions that could improve treatment We undertook a randomised, double-blind, placebo- outcomes and reduce case fatality is important.
controlled trial from July 6, 2005, to Dec 3, 2008, at three Several animal and human studies5–7 have shown that tertiary hospitals in New Delhi, India (Kalawati Saran zinc is crucial for immune function. Zinc given orally Children’s Hospital, Deen Dayal Upadhyay Hospital, and shinjini.bhatnagar@thsti.res.in
during an episode of childhood diarrhoea reduces All India Institute of Medical Sciences). We screened duration and severity of illness.8–11 In a community- infants aged 7–120 days in emergency depart ments for any based trial of infants and children with diarrhoea in of the following clinical symptoms or signs of possible North India,12 zinc supplements reduced diarrhoeal serious bacterial infection: convulsions, fast breathing, www.thelancet.com Vol 379 June 2, 2012
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severe chest indrawing, grunting, bulging fontanelle, elemental zinc) or placebo dissolved in 2·5 mL expressed axillary temperature 37·5°C or higher or lower than breastmilk or distilled water orally every 12 h until 35·5°C, refusal to feed or drink, uncon sciousness or recovery—ie, end of a 2 day period with no symptoms or lethargy, no attachment to or suckling at breast (in signs of probable serious bacterial infection and a daily breastfed infants), excessive crying or irritability, diarrhoea, weight gain of at least 10 g with exclusive oral feeding— or cyanosis (appendix). These criteria were adapted from or until the completion of 21 days’ treatment, whichever See Online for appendix
the defi nitions used by the Integrated Management of was earlier. Treatment was repeated in infants who
Neonatal and Childhood Illnesses strategy.13
vomited within 15 min of receiving the tablet.
We included preterm infants (≤32 weeks of gestation) Study physicians examined patients for all relevant only when they were older than 2 months at screening. clinical features every 6 h or more often when clinically We excluded infants who weighed 1500 g or less; needed indicated until recovery or end of day 21. They repeated mechanical ventilation, inotropic drugs, or exchange the respiratory rate count when it was 60 or more breaths transfusion; had major congenital anomalies, inborn per min in infants younger than 2 months or 50 or more errors of metabolism, severe birth asphyxia, renal failure, breaths per min in those older than 2 months, and surgical or other disorders interfering with oral feeding, recorded the second count.13 Study staff recorded weights pre-existing seizure disorders, or any other serious of naked infants at randomisation and every 24 h underlying medical problems; were born to HIV-infected until recovery or end of day 21. The site supervisor (a mothers; or had received zinc during the present episode paediatrician) oversaw at least one daily assessment done We measured serum C-reactive protein concentra- Infants were treated according to a standardised tion with a semi-quantitative latex agglutination assay protocol with recommended doses (appendix) of intra-(Plasmatec Laboratory Products, Bridport, Dorset, UK) venous ampicillin and an aminoglycoside (intra venous immediately after eligibility was established. Infants with gentamicin or amikacin) when infants were not a concentration of 12 mg/L or higher were judged to have receiving antibiotic treatment at admission, or of a probable serious bacterial infection and were eligible for third-generation cephalosporin and one of the amino-the trial. Study physicians were present 24 h a day and glycosides when patients had already been treated with obtained written informed consent from the guardians antibiotics. Intravenous cloxacillin was given when of these patients (or with a thumbprint from those who staphylo coccal infection was suspected. Patients who were illiterate) in the presence of a witness. Patients were had not recovered by the end of 21 days were no longer then randomly assigned to receive zinc or placebo. monitored by the study staff but were managed by Infants who could not be fed orally were observed for up hospital physicians.
to 24 h of stabilisation and randomly assigned only when Researchers in the laboratory at the All India Institute they were able to tolerate oral feeding. The ethics com- of Medical Sciences cultured blood specimens at mittees of all hospitals and WHO’s Ethics Review admission with BACTEC (Becton Dickinson, Sparks, Committee approved the study protocol.
MD, USA; model PEDS PLUS/F). Study physicians obtained blood specimens at baseline, 72 h, and the end Randomisation and masking
of the study. Serum was stored at –20°C. We measured We stratifi ed patients by whether they were underweight serum concentrations of zinc with a fl ame furnace atomic (ie, weight-for-age Z scores14 <–2) or had diarrhoea at absorption spectrophotometer (GBC Avanta, Dandenong, enrolment. A scientist not involved in the study generated VIC, Australia) as per standard procedures,15 C-reactive allocation sequences with STATA (version 9.0). Within protein concentrations with a commercial ELISA each hospital and stratum, patients were randomly (Biocheck, Foster City, CA, USA), and procalcitonin assigned equally in permuted blocks of six to receive zinc concentrations with a chemi-immuno luminescence assay or placebo. WHO provided identical blister packs that (BRAHMS, Hennigsdorf, Germany).
contained dispersible tablets with or without zinc The primary outcome was treatment failure, which was sulphate (10 mg of elemental zinc; Nutriset, Malaunay, defi ned as a need to change antimicrobial treat- France). Each pack had been labelled with a unique ment within 7 days of randomisation, or a need for serial number according to the randomisation list, intensive care (mechanical ventilation or vasoactive which was not available to investigators until data had drug infusion, or both), or death at any time within been obtained, entered, and locked. Participants and 21 days of randomisation. According to this defi nition, investigators were masked to treatment allocation. We the worst outcome was reported. The decision to change maintained masking during data analysis by coding antimicrobial drugs was made by two senior paedia-treatment allocation with two letters.
tricians (site investigators) on the basis of a priori guidelines—ie, persistence beyond 72 h of random isation Procedures
of any clinical symptom or sign suggestive of probable After randomisation, the study physician gave every serious bacterial infection identifi ed at enrolment, infant half a dispersible tablet of zinc (ie, 5 mg of worsening of an initial symptom or sign of the disorder, www.thelancet.com Vol 379 June 2, 2012
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401 required assisted ventilation258 required inotropic support 39 had inborn errors of metabolism40 had chromosomal abnormality 6936 infants with signs of PSBI and no exclusion criteria 104 had surgical disorders precluding oral feeding206 had pre-existing seizure disorders176 had serious chronic illness 326 already received zinc during present illness Figure 1: Trial profi le
PSBI=possible serious bacterial infection.
or identifi cation of one or more new symptoms or signs Statistical analysis
any time after the initial 24 h (appendix).
On the basis of an audit of the participating hospitals, Secondary outcomes were time to clinical recovery (ie, to we estimated that the risk of treatment failure in the the end of a 2 day period with no symptoms or signs of placebo group would be 25%. With the assumption of a probable serious bacterial infection), time to achieve 5% loss to follow-up, we needed to recruit 700 infants exclusive oral feeding (ie, to the end of a 2 day period on (350 in each group) to identify an effi exclusive oral feeding), time to weight gain (ie, to the end more against treatment failure with 90% power and of a 2 day period with daily weight gain of at least 10 g on 95% confi dence.16exclusive oral feeding), and time to overall recovery (ie, to Site supervisors checked all case report forms twice the end of a 2 day period with no symptoms or signs of before they were sent for double data entry in Microsoft probable serious bacterial infection and daily weight gain Access (2007 version) with in-built logic, range, and of at least 10 g on exclusive oral feeding).
consistency checks. For intention-to-treat analyses, we To ensure uniformity between hospitals, the site super- used STATA (version 11.0) to calculate the proportion of visors underwent training in patient assessment and treatment failures in the two trial groups and the outcomes, according to our standard operating procedures. corresponding relative risk (RR) and risk diff erence We standardised the study procedures and did regular (RD). Irrespective of whether treatment had failed and exercises of clinical outcomes and laboratory procedures with censoring of children at the time of withdrawal of to minimise intra-observer and inter-observer variability consent, we used Cox proportional hazards regression within and across the three hospitals. An independent data to compare the time to recovery between the trial and safety monitoring board com posed of a paediatrician, groups. A hazard ratio greater than 1 indicated a a paediatric surgeon, a medical intensive care specialist, benefi cial eff ect of zinc. We censored patients who did and a biostatistician reviewed every serious adverse event not recover by 504 h (day 21) at that time. We censored (death or need for intensive care) and met every 6 months infants who died at 505 h (ie, 1 h longer than 21 days). to ensure that the study was done according to protocol.
We compared the change in serum zinc concentration www.thelancet.com Vol 379 June 2, 2012
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from baseline to recovery between the two groups with Zinc (n=352)
Placebo (n=348)
the Student’s t test. The eff ect of zinc on laboratory markers of infl ammation (C-reactive protein and pro- calcitonin) at 72 h and at recovery was compared with We did predefi ned subgroup analyses to assess whether diarrhoea or infants being underweight at enrolment modifi ed the eff ect of zinc. Interactions were assessed with interaction terms in generalised linear models of the binomial family with log links to estimate RRs and identity links for RDs. We also did Signs of possible serious bacterial infection a post-hoc analysis restricted to infants aged 7 to This trial is registered with ClinicalTrials.gov, number Role of the funding source
The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. SB, NW, TAS, RL, UCMN, and HS had full access to all the data in the study and had fi nal responsibility for the decision to submit for publication. Previous antimicrobial treatment in present illness Figure 1 shows the trial profi le. Table 1 shows baseline charac teristics. 148 (42%) of 352 in the zinc group versus Absolute neutrophil count (×10⁹ cells/L) 137 (39%) of 348 given placebo received ampicillin and an amino glycoside; 163 (46%) versus 163 (47%) received a third-generation cephalosporin and an aminoglycoside; and 41 (12%) versus 48 (14%) were given intravenous Concentrations of C-reactive protein and procalcitonin at baseline were high in both groups (table 1). Median concentration of C-reactive protein was lower in infants with diarrhoea (28·7 mg/L, IQR 15·2–53·8) than in those without diarrhoea (37·3 mg/L, 20·2–64·2). 44% of all patients (302 of 681) had serum zinc concentrations of less than 9·2 μmol/L at baseline. Median serum zinc Data are mean (SD), n (%), or median (IQR).*≥60 breaths per min for infants <2 months; ≥50 breaths per min for concentrations were 10·2 μmol/L (IQR 8·1–12·9) in infants ≥2 months. †Axillary temperature ≥37·5°C. ‡Zinc n=351; placebo n=346. §Zinc n=341; placebo n=340. children with diarrhoea compared with 9·3 μmol/L Table 1: Baseline characteristics
(7·4–11·7) in those without diarrhoea. No protocol devia-tions were recorded in either group.
Treatment failure could be assessed in 655 infants within 7 days (table 2). Although we classed death as a (fi gure 1). Four patients (one given zinc; three placebo) treatment failure at any time up to day 21, seven of eight who had treatment failure left the study before recovery who died after 7 days of treatment had a change of could be recorded. Treatment effi cacy—ie, reduction in antibiotics in the fi rst week and therefore fulfi lled relative risk of treatment failure—was 40% (95% CI criteria for treat 10–60; p=0·0113; table 2). The absolute risk reduction Nearly two-thirds of decisions to change antibiotics was 6·8% (1·5–12·0; p=0·0111); therefore, 15 (eight to 67) (17 of 29 in zinc group; 33 of 47 in placebo group) infants with probable serious bacterial infection would occurred within 96 h of randomisation. 15 (5%) of the need to be treated with zinc in addition to antibiotics to 332 infants given zinc and 17 (5%) of the 323 given prevent one treatment failure. A similar effi cacy (54%, placebo needed a second change in antibiotics within 20–74; p=0·0045) was noted when analysis was restricted to infants aged between 7 and 60 days.
cacy of zinc was higher in infants with diarrhoea Cause of treatment failure was assigned by worst at enrolment than in those without diarrhoea (p=0·0260; outcome and fi rst cause (table 2). Of 89 infants who fi gure 2). Three children (one in the zinc group; two had treatment failure, 76 had their antibiotics changed in the placebo group) needed a change of antibiotics www.thelancet.com Vol 379 June 2, 2012
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Zinc (n=332)*
Placebo (n=323)*
Relative risk (95% CI)
Risk diff erence (95% CI)
For worsening of initial clinical features For persistence of initial clinical features Treatment failure (by fi rst cause of failure) For worsening of initial clinical features For persistence of initial clinical features All data are n (%), unless otherwise specifi ed. *Number of infants in whom primary outcome (treatment failure) could be assessed. †No infants were classifi ed as having treatment failure because they developed new symptoms alone. Table 2: Eff ect of zinc given orally on treatment failure
zinc (3·3 μmol/L, SD 6·9) than in those receiv Zinc group
Placebo group
RR (95% CI)
placebo (1·2 μmol/L, 5·2), with a diff erence of 2·0 μmol/L (95% CI 1·1–3·0; p<0·0001). The eff ect of zinc on laboratory markers of infl ammation (C-reactive protein and procalcitonin) did not diff er between the two groups (appendix). The risk of adverse events that were not components of the clinical outcomes was also alike in the two groups (appendix). Table 4 shows the symp- toms and signs of probable serious bacterial infection Figure 2: Eff ect of zinc given orally on treatment failure in infants with probable serious bacterial infection by
recorded at the time of treatment failures.
stratifi cation factor
Denominators are the numbers of infants in whom treatment failure could be assessed in each stratum.
Discussion
RRs derived from generalised linear models with a log link function. Infants were classed as underweight if their weight-for-age Z score was less than –2. RR=relative risk.
We have reported that zinc reduced treatment failure in infants younger than 120 days with probable serious bacterial infection by 40%. Use of zinc also reduced the Zinc (n=352)
Placebo (n=348) Hazard ratio (95% CI)
number of deaths, although the diff erence between the groups was not signifi cant. When analysis was restricted Time to achieve exclusive oral feeding (h) to infants 60 days or younger, we still recorded a bene- fi cial eff ect. Time to recovery, weight gain, or exclusive oral feeding was not aff ected by zinc supple ments, and Weight at recovery (kg)*
weight at recovery did not diff er signifi cantly. As far as Data are median (IQR) unless otherwise stated. Time to clinical recovery was to the end of a 2 day period with no we are aware, zinc as adjunct treatment in infants with symptoms or signs of probable serious bacterial infection. Time to achieve exclusive oral feeding was to the end of a probable serious bacterial infection has not been reported 2 day period on exclusive oral feeding. Time to weight gain was to the end of a 2 day period with daily weight gain of at least 10 g on exclusive oral feeding. Time to overall recovery was to the end of a 2 day period with no symptoms or Treatment failure in children with probable serious signs of probable serious bacterial infection and daily weight gain of at least 10 g on exclusive oral feeding. *Includes only infants in whom recovery was documented (zinc n=317; placebo n=302); p=0·38 .
bacterial infection diagnosed with clinical criteria and measurements of C-reactive protein concentrations is Table 3: The eff ect of zinc given orally on secondary clinical outcomes
likely to be even more common than in a study set-ting. In high-burden, resource-limited settings, routine for persistence of diarrhoea of the 27 children whose clinical care is often less intensive than during studies treatment failed because symptoms present at enrolment with additional personnel and resources. Therefore, the cacy did not diff er between absolute risk reduction from zinc treatment could be underweight infants and those not underweight (p=0·39; larger than the value we have reported, and fewer than fi gure 2). Case fatality did not vary signifi cantly (table 2). the estimated 15 children would need to be treated to Time to overall recovery and other forms of recovery also Zinc is important for mucosal barrier function and The mean change in serum zinc concentration from components of innate and adaptive immunity, such as enrolment to recovery was higher in the children given lytic activity of phagocytes and natural killer cells, and www.thelancet.com Vol 379 June 2, 2012
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Panel: Research in context
Systematic review
We searched PubMed for reports of the use of zinc as an adjunct to antibiotic treatment in infants with serious No attachment to or suckling at breast (in breastfed infants) or acute refusal to feed or drink bacterial infection initially in August, 2004, and later extended the search to Sept 10, 2011. We included studies published at any time up to this date. We used the search terms “serious bacterial infection”, “sepsis”, “infant”, and “zinc”. Our main hypothesis that zinc reduces the risk of treatment failure in infants with probable serious bacterial infections was based on studies showing that zinc is crucial for immune function,5–7 and the proven benefi t of oral zinc in infectious diseases such as acute childhood diarrhoea.8–11 The studies assessing the benefi t of zinc as an adjunct in Data are n (%). A child could have more than one component sign or symptom at treatment of childhood pneumonia have had confl icting results.17,18 We identifi ed no previous randomised trials of zinc Table 4: Component symptoms and signs of probable serious bacterial
as an adjunct treatment in infants with probable serious infection at the time of treatment failure
Interpretation
sion of cytokines.5–7,19 Oral zinc supplementation In our investigation, adjunct treatment with 10 mg of increases serum thymulin and CD4 counts and decreases elemental zinc daily in addition to standard treatment with the occurrence of opportunistic infections in clinical antibiotics led to a signifi cant reduction in the risk of immuno suppressive disorders.20 Reduced incidence of treatment failure in infants aged 7–120 days with probable infections has also been reported in patients with sickle serious bacterial infection. Zinc could become an accessible cell disease, in whom zinc supplementation increased and inexpensive intervention to improve treatment outcomes interleukin 2 production.21 Heightened activity of com- of such infections and thereby reduce infant mortality.
plement C3 and phagocytes and the ratio of naive to memory T cells in children with diarrhoea caused by enterotoxigenic Escherichia coli given zinc indicates WHO defi nition to infants 60 days or older, because that this supplement enhances innate immunity.22 In a similar infections continue to occur in these children. murine polymicrobial sepsis model,23,24 short-term zinc Additionally, we enhanced the specifi city of the diagnosis supplementation decreased the bacterial load and reduced with the additional criterion of a C-reactive protein the NF-κB activity in vital organs. The researchers postu- concentration of 12 mg/L or higher.25 Concentrations of lated that zinc modulates innate immune responses to procalcitonin were greater than 0·5 μg/L in more than polymicrobial sepsis through the regulation of NF-κB.23,24 70% of participants and greater than 0·3 μg/L in more cacy of zinc in infants who had than 90%, further suggesting that they did indeed have diarrhoea at enrolment than in those who did not serious bacterial infection.26,27 The loss to follow-up was merits further investigation. Serum concentrations of small and is unlikely to have biased our effi C-reactive protein were lower in infants with diarrhoea at admission than in those without diarrhoea, sug- treatment for probable serious bacterial infection in gesting that they could have had milder disease. Another other settings—specifi cally, other studies should meas- explanation is that zinc supplementation replenishes ure the eff ect of zinc supplementation on important stores depleted by stool losses, with zinc thereby outcomes in children who are diagnosed with serious becoming available for protective mechanisms to bacterial infections without measurements of concen-respond to bacterial infection. In our study, the reduced trations of C-reactive protein. If such trials show improve- risk of treatment failure in infants with diarrhoea at ment in treatment outcomes, the use of zinc as an enrolment was not because of a quick resolution of adjunct to antibiotic treatment might lead to sub stantial diarrhoea, indicating that zinc treatment contributed to reductions in infant mortality, particularly in resource-the resolution of probable serious bacterial infection constrained settings where second-line anti biotics and rather than to resolution of any one symptom or sign.
appropriate intensive care might be unavailable. Care Our study was not powered to assess the eff ect of zinc providers at small health-care facilities can be trained to on case fatality and did not include neonates in the fi rst initiate treatment of probable serious bacterial infection week of life. We used a symptom-based defi nition of with antibiotics and zinc before transferring infants to probable serious bacterial infection, but such criteria are appropriately equipped facilities. Zinc syrup or dis-often applied in settings like ours.13 We extended the persible tablets are already available in the public and www.thelancet.com Vol 379 June 2, 2012
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private health-care systems for treatment of acute 9 Bhatnagar S, Bahl R, Sharma PK, Kumar GT, Saxena SK, Bhan MK. diarrhoea in many countries of low and middle income Zinc with oral rehydration therapy reduces stool output and duration of diarrhea in hospitalized children: a randomized and the incremental costs to make this intervention controlled trial. J Pediatr Gastroenterol Nutr 2004; 38: 34–40.
available for young infants with probable serious bacterial 10 Lazzerini M, Ronfani L. Oral zinc for treating diarrhoea in children. Cochrane Database Syst Rev 2008; 3: CD005436.
11 Lukacik M, Thomas RL, Aranda JV. A meta-analysis of the eff ects of Contributors
oral zinc in the treatment of acute and persistent diarrhea. Pediatrics SB formulated the research question and designed the study. SB, HS, 2008; 121: 326–36.
and TAS wrote research grants. SB, NW, SA, RL, SKK, UCMN, AKD, JC, 12 Sazawal S, Jalla S, Mazumder S, Sinha A, Black RE, Bhan MK. Eff ect BR, MS, VKS, MK, and TAS developed the standard operating of zinc supplementation on cell-mediated immunity and lymphocyte procedures. SB, NW, RL, SKK, AKD, JC, BR, MS, VKS, and MK subsets in preschool children. Indian Pediatr 1997; 34: 589–97.
implemented the trial. SB, NW, SA, and TAS supervised clinical and data 13 WHO, UNICEF, and the Ministry of Health and Family Welfare management. SB, NW, SA, RL, UCMN, HS, and TAS analysed data. Government of India. Integrated management of neonatal and SB, NW, RL, UCMN, HS, and TAS interpreted the fi ndings. SB, NW, SA, childhood illness: physician chart booklet. 2003. http://mohfw.nic.
RL, SKK, UCMN, HS, and TAS wrote the report.
in/NRHM/IMNCI/IMNCI_index.htm (accessed March 1, 2012).
14 National Center for Health Statistics. Individual growth charts. Confl icts of interest
May 30, 2000. http://www.cdc.gov/growthcharts/charts.htm We declare that we have no confl icts of interest.
Acknowledgments
15 Hambidge KM, King JC, Kern DL, English-Westcott JL, Stall C. The study was funded by the Department of Biotechnology, Ministry of Pre-breakfast plasma zinc concentrations: the eff ect of previous Science and Technology, Government of India (BT/PR5238/MED/14/ meals. J Trace Elem Electrolytes Health Dis 1990; 4: 229–31.
610/2004). We also received funding from the European Commission 16 Smith PG, Morrow RH. Field trials of health intervention in (EU-INCO-DC contract number INCO-FP6-003740), the Meltzer developing countries: a toolbox, 2nd edn. London: Macmillan Education, 1996: 42–71.
Foundation (Bergen, Norway), and the Research Council of Norway (project number 172226). We thank the medical and nursing staff of the three 17 Natchu UC, Fataki MR, Fawzi WW. Zinc as an adjunct for childhood pneumonia—interpreting early results. Nutr Rev 2008; hospitals for their contribution; the patients and their parents; 66: 398–405.
Ritu Chawla, Uday Pal Singh Kainth, Anil Gulati, Arvind Bagga, and 18 Valentiner-Branth P, Shrestha PS, Chandyo RK, et al. A randomized controlled trial of the eff ect of zinc as adjuvant therapy in children Madhulika Kabra for providing clinical support to patients enrolled in 2–35 mo of age with severe or non severe pneumonia in Bhaktapur, the study at the Deen Dayal Upadhyay Hospital and All India Institute of Nepal. Am J Clin Nutr 2010; 91: 1667–74.
Medical Sciences; Arti Kapil for supervising the blood cultures; 19 Beck FW, Prasad AS, Kaplan J, Fitzgerald JT, Brewer GJ. Changes Anil Kumar Sharma for assisting in quality assurance and supervision of in cytokine production and T cell subpopulations in experimentally the research staff ; Savita Saini for undertaking the micronutrient assays induced zinc-defi cient humans. Am J Physiol 1997; 272: E1002–07.
and providing technical support for all other laboratory work; 20 Mocchegiani E, Veccia S, Ancarani F, Scalise G, Fabris N. Benefi t of Mukesh Juyal for secretarial support; Dharmendra Sharma for data oral zinc supplementation as an adjunct to zidovudine (AZT) management support and analysis of data; and Olivier Fontaine (WHO) therapy against opportunistic infections in AIDS. for providing the intervention (zinc and placebo tablets from Nutriset) Int J Immunopharmacol 1995; 17: 719–27.
and periodic reviews of study procedures.
21 Prasad AS, Beck FW, Kaplan J, et al. Eff ect of zinc supplementation References
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