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1 From the Society for Applied Studies, Calcutta (DM); the Infectious Diseases Hospital, Calcutta (AC and SJ); the National Institute of Cholera and Enteric Diseases, Calcutta (MKB and MKC); the International Centre for Diarrhoeal Disease Research-Bangladesh, Dhaka (MAW); and the Department of Nutrition Sciences, University of Alabama at Birmingham, Alabama (MAK).
2 Supported by the Child Health Foundation, USA, and by the Nestlé Foundation. 3 Reprints not available. Address correspondence to D Mahalanabis, Society for Applied Studies, 108, Manicktala Main Road, Flat-3/21 Calcutta 700054, India. E-mail: dmahalanabis{at}vsnl.com.
ABSTRACT
Background: Zinc deficiency, common in developing countries, is associated with decreased immunocompetence. Zinc supplementation benefits children with acute and persistent diarrhea and prevents pneumonia. Most deaths from vaccine-preventable diseases are from measles and whooping cough; pneumonia is the most common complication of measles and often the proximate cause of related deaths.
Objective: We evaluated the effect of zinc supplementation on episodes of illness in children with measles accompanied by pneumonia.
Design: In a double-blind, randomized controlled trial, children aged 9 mo–15 y who were admitted to the Infectious Diseases Hospital in Calcutta with clinically severe measles accompanied by pneumonia and who had been ill for 7 d were randomly assigned to receive zinc (20 mg, in elemental form as acetate, twice daily for 6 d) or a placebo. All patients received standard treatment with antibiotics and an initial 100 000-IU dose of vitamin A (as palmitate) by mouth.
Results: Time-to-event analysis using the Cox proportional hazards model (42 in the zinc group and 43 in the placebo group) showed that the time needed for the resolution of fever and tachypnea, the return of appetite, and the achievement of a "much improved" or "cured" status was not different between the 2 groups. A high proportion of children had low serum retinol and zinc concentrations. Improvement in serum zinc and retinol concentrations after 6 d of treatment was not different between the 2 groups.
Conclusion: Children with severe measles accompanied by pneumonia treated with antibiotics and vitamin A did not show any additional benefit from also receiving a zinc supplement.
Key Words: Zinc supplementation • measles • pneumonia • children • clinical trial • India
INTRODUCTION
Most deaths from vaccine-preventable diseases are from measles and whooping cough. Pneumonia is the most common complication of measles and the principal proximate cause of measles-related deaths (1). Furthermore, pneumonia is a major cause of morbidity in children around the world and of mortality in children in developing countries (1). Zinc supplementation has been shown to be beneficial in substantially reducing the duration and severity of the episodes in children with acute and persistent diarrhea (2). Zinc was also shown to be beneficial in preventing pneumonia in children in developing countries (3). The diets of children in developing countries are deficient in animal protein and consequently are low in zinc (4). In addition, a high phytate-to-zinc ratio in the diet of these children reduces the bioavailability of zinc (4). Finally, major international health agencies, eg, the World Health Organization (WHO), the United Nations Children’s Fund, the World Bank, and the US Agency for International Development, have shown great interest in determining the public health value of the micronutrient zinc. In the present study, the role of zinc supplementation as adjunct therapy in children with measles and pneumonia was evaluated in a double-blind, randomized controlled trial.
SUBJECTS AND METHODS
Subjects
Children aged 9 mo–15 y with measles accompanied by pneumonia who were admitted to the Infectious Diseases Hospital in Calcutta were randomly allocated to 1 of 2 treatment groups: a group that received a zinc supplement and a group that received a placebo supplement. The effect of zinc therapy on the clinical course of illness was evaluated. The subjects were children admitted to the hospital with an illness that was compatible with measles (generalized maculopapular rash with fever and at least one of the following: cough, coryza, or conjunctivitis) and a clinical diagnosis of acute lower respiratory tract infection (tachypnea, lower chest indrawing and auscultatory signs, or both). The treatment effect was evaluated by comparing the 2 groups for the time needed for the resolution of fever, tachypnea (an indicator of acute lower respiratory tract infection), or "significant illness" [as judged by a clinician (AC) who was blinded to the treatment group assignment] during the 6 d of treatment with zinc under observation.
Children aged 9 mo–15 y who had been ill for 7 d and who had no congenital anomalies, chronic diseases, or severe malnutrition (ie, clinically obvious marasmus or edema) were enrolled in the study after written, informed consent was obtained from a parent or guardian. A master randomization schedule was prepared by the use of permuted blocks of random numbers. Serially numbered bottles were randomly allocated to contain either a zinc acetate mixture or a placebo mixture; the mixtures were identical in color, consistency, and taste. The serial numbers on the bottles corresponded to the patients’ serial numbers. The medicine bottles were prepared by a pharmaceutical manufacturer under the supervision of an independent pharmaceutical chemist acting on our behalf. Random samples of the bottled mixture were tested by atomic absorption spectrophotometry for zinc concentration.
A zinc acetate mixture containing 20 mg elemental Zn or a placebo mixture was given twice daily for each day of stay. Placebo consisted of the syrup base used for the zinc mixture to which permitted astringent material was added to give an astringent taste similar to that of the zinc mixture. A taste test was performed with adult volunteers who were unaware of the nature of the mixture. All patients were treated for pneumonia and associated problems according to a standard treatment schedule based on the existing practice at the study hospital. The antibiotics usually used were either ampicillin and gentamicin or cefotaxime alone, all given by injection, as was the prevailing practice at this hospital. All patients received 100 000 U vitamin A (as palmitate) by mouth on the day of admission, because large-dose vitamin A supplementation in hospitalized children with measles markedly reduces measles-associated mortality (5). Giving a large dose of vitamin A to patients admitted with measles was not routine at this hospital. However, physicians agreed to this dose of vitamin A after discussion with the investigator. A complete blood count was performed and a chest X-ray was taken on admission, as is routine at this hospital. Blood samples were also obtained on the day of admission and on day 6 for measurement of serum zinc and serum retinol concentrations. The study protocol was approved by the Ethics Committee of the hospital.
Methods
Sample size
The consensus among clinicians treating such patients at the Infectious Diseases Hospital was that 50% of the patients would have no significant illness after 5 d of treatment. With zinc as adjunct therapy, we expected that 80% would be free of significant illness. The number calculated for each group (with 80% power and a 5% significance level) would be 41, including a dropout rate of 10%. With the use of similar assumptions for the proportion of patients having fever or tachypnea after 5 d of treatment, the calculated sample size would be the same.
Analysis
Data were recorded on standard forms, entered into a microcomputer, and edited by the use of EPI INFO software, version 6.03 (Centers for Disease Control and Prevention, Atlanta, and WHO, Geneva). Baseline comparisons were made between the 2 treatment groups. Categorical outcome variables were compared by use of the chi-square test or Fisher’s exact test. Survival analysis (Cox proportional hazards model) was used to compare the duration of events (eg, significant illness, fever, and tachypnea) to allow adjustment for censored information with STATA software, version 7.0 (Stata, College Station, TX). To compare the increments in the serum zinc or serum retinol concentration in the zinc and placebo groups from admission to discharge, multiple linear regression models were used to adjust for prognostic factors such as age, sex, and admission values.
RESULTS
A total of 85 children aged 9 mo–15 y were admitted into the study, 42 in the zinc group and 43 in the placebo group (Table 1). In the group aged 10–15 y, there were slightly more than twice as many children recruited in the placebo group than in the zinc group. In addition, more girls were admitted in the placebo group. Most children were admitted after 2–4 d of rash. These patients generally were very ill. About 88% had difficulty in eating or feeding, and 57 children were in a state of altered consciousness on admission. Forty-eight children received some antibiotics before admission. A history of measles immunization was available for only 12% of the children. Most of the children came from poor homes. Most (80 of 85) were clinically diagnosed as having pneumonia; the rest had tachypnea and fever with a history of cough and fulfilled the WHO criteria for a diagnosis of pneumonia. In the placebo group, 2 patients had associated bloody diarrhea (ie, dysentery) and 3 had measles and encephalopathy accompanied by pneumonia, as judged by the clinician.
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TABLE 1 . Characteristics of subjects on admission and serum zinc and retinol concentrations on admission and at discharge1
The parents of 5 children in the placebo group and of 3 children in the zinc group withdrew their children at various points before the study had lasted 6 d. One child in the zinc group was dropped from the study because the assigned medicine bottle was broken on the first day. One child in the placebo group died 36 h after admission. This 1-y-old boy had been admitted in a coma, and a clinical diagnosis of septicemia was made by the attending physician.
The clinical status of each patient was evaluated and recorded each day by the same physician (AC), who had no knowledge of the treatment group to which any of the patients belonged. Evaluation on day 6 of the study showed that 34 children in the zinc group and 33 in the placebo group were judged to be cured or much improved. Median (quartiles) time (h) required for resolution of fever and tachypnea, return of appetite, and achievement of a much-improved or cured status, as evaluated by a physician, in the zinc and placebo groups is reported in Table 2. There was no significant difference in any of these clinical features between the 2 groups (Cox proportional hazards model adjusted for age and sex and including censored data).
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TABLE 2 . Duration of clinical indicators of disease: results of time-to-event (survival) analysis adjusted for age and sex1
In 36 patients in each group, serum zinc concentrations were estimated by atomic absorption spectrophotometry (6) both on admission and at discharge (6). A high proportion of patients had very low serum zinc concentrations (< 9.95 µmol/L): 50% in the zinc group and 68% in the placebo group; these proportions dropped to 21% and 31%, respectively, at discharge. Improvement in the serum zinc concentration (analysis of variance adjusted for age, sex, and serum zinc and retinol concentrations on admission) was not significantly different between the 2 groups (Table 3).
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TABLE 3 . Increases in the serum concentrations of zinc and retinol from admission to discharge1
Similarly, serum retinol concentrations were estimated on admission and discharge by the use of HPLC in 36 patients from each group (7). The serum retinol concentrations were very low (< 0.349 µmol/L) on admission in 63% and 53% of patients in the zinc and placebo groups, respectively. All patients received a single oral dose (100 000 IU) of vitamin A on admission. A marked improvement was noted in the serum retinol concentrations in both groups by day 6 (Tables 1 and 3).
DISCUSSION
The study did not show a clinically worthwhile benefit from the administration of zinc as an adjunct therapy in children with measles and pneumonia. These children routinely received a large dose of vitamin A, which is known to reduce the morbidity and mortality associated with measles (5).
Serum retinol concentrations were very low in these children on admission, which may have represented both a state of deficiency and a consequence of severe infection. It has also been shown that, apart from an acute phase response after infection, retinol may be lost in the urine, particularly in the context of a febrile illness (8). The retinol concentrations improved markedly in these very ill children: 3.3% on admission and 83.3% at discharge had serum retinol concentrations > 0.698 µmol/L. This improvement may have been due to a combination of factors such as recovery from a severe acute illness and the administration of vitamin A on admission.
Serum zinc concentrations were low on admission in most of these children, which could have been a consequence of a state of deficiency, an infection, or both. The serum zinc concentration does not consistently reflect zinc status. Very low serum zinc concentrations may be attained in conditions such as an acute phase response, in which the element is redistributed to other tissues. However, after 5 d of zinc administration (40 mg/d as oral acetate) to the study group and of a placebo to the control group, serum zinc status improved in both groups. The hospital diet did not contain items known to have a high zinc content. This suggests that the low zinc concentrations on admission were more likely to be due to redistribution after infection, as discussed above. Serum zinc concentrations are homeostatically controlled and, in states of marginal zinc deficiency, may be maintained within the normal range.
Zinc is essential for human metabolism, growth, and immune function (9). Many aspects of the immune system can malfunction, and epithelial barriers are compromised during infection (10). The oral administration of zinc as adjunct therapy for acute diarrhea in children in developing counties has shown consistent benefits in reducing the duration and the severity of that illness (2). Several studies have also shown that routine zinc supplementation in children in developing countries prevents acute lower respiratory tract infection and pneumonia (3). However, therapeutic trials of zinc as adjunct therapy for pneumonia alone or in association with measles have not been reported. We can only speculate as to why zinc supplementation in children with measles accompanied by pneumonia did not lead to any measurable clinical improvement. The therapeutic effect of zinc in acute diarrhea can be explained by its direct effect on the mucosa and a gut-associated immune response, which may be different from an immune response in the respiratory system. Whereas a favorable immune response to zinc supplementation may explain why pneumonia is prevented in children, in an acute illness such as measles-associated pneumonia, there probably is insufficient time for mounting an immune response to favorably modify an acute illness. Thus, the administration of zinc to severely ill children with measles and pneumonia treated with vitamin A and supportive therapy showed no additional benefit.
ACKNOWLEDGMENTS
We thank S Karmakar for preparing and editing the manuscript and Zakir Hussain for assisting with the data analysis.
REFERENCES