Original Article
A Randomized, Controlled Trial of Vitamin A in Children with Severe Measles
N Engl J Med 1990; 323:160-164July 19, 1990
- Abstract
- Abstract
Background.
Measles kills about 2 million children annually, and there is no specific therapy for the disease. It has been suggested that vitamin A may be of benefit in the treatment of measles.
Methods.
We conducted a randomized, double-blind trial involving 189 children who were hospitalized at a regional center in South Africa because of measles complicated by pneumonia, diarrhea, or croup. The children (median age, 10 months) were assigned to receive either vitamin A (total dose, 400,000 IU of retinyl palmitate, given orally; n = 92) or placebo (n = 97), beginning within five days of the onset of the rash. At base line, the characteristics of the two groups were similar.
Results.
Although clinically apparent vitamin A deficiency is rare in this population, the children's serum retinol levels were markedly depressed (mean [±SEM], 0.405±0.021 μmol per liter [11.6±0.6 /μg per deciliter]), and 92 percent of them had hyporetinemia (serum retinol level <0.7 μmol per liter [20 μg per deciliter]). Serum concentrations of retinol-binding protein (mean, 30.1 ±2.0 mg per liter) and albumin (mean, 33.4±0.5 g per liter) were also low. As compared with the placebo group, the children who received vitamin A recovered more rapidly from pneumonia (mean, 6.3 vs. 12.4 days, respectively; P<0.001) and diarrhea (mean, 5.6 vs. 8.5 days; P<0.001), had less croup (13 vs. 27 cases; P = 0.03), and spent fewer days in the hospital (mean, 10.6 vs. 14.8 days; P = 0.01). Of the 12 children who died, 10 were among those given placebo (P = 0.05). For the group treated with vitamin A, the risk of death or a major complication during the hospital stay was half that of the control group (relative risk, 0.51; 95 percent confidence interval, 0.35 to 0.74).
Conclusions.
Treatment with vitamin A reduces morbidity and mortality in measles, and all children with severe measles should be given vitamin A supplements, whether or not they are thought to have a nutritional deficiency. (N Engl J Med 1990; 323:160–4.)
Media in This Article
Table 1
Base-Line Clinical Findings in 189 Children with Measles, According to Treatment Group.*Table 2
Base-Line Blood and Serum Values, According to Treatment Group.Article Activity
- Article
MEASLES remains a devastating disease, for which specific therapy is lacking. Hopes for its control and eventual eradication rest on immunization, but measles kills about 2 million children each year1 and cripples an untold number through blindness2 and lung disease.3 , 4 The idea that vitamin A may have a protective effect in measles was first suggested more than 50 years ago5 but was ignored until Barclay et al.,6 in a randomized clinical trial, found twice as many deaths in the control group (12 of 92) as among children given high doses of vitamin A (6 of 88).6 Although the overall results did not reach statistical significance, vitamin A was significantly protective in the group under two years of age.6
That vitamin A should be of benefit in measles is biologically plausible.7 Measles depresses serum levels of vitamin A,8 9 10 11 and hyporetinemia (a serum retinol level below 0.7 μmol per liter [20 μg per deciliter]) is associated with increased mortality from the disease, particularly in children under two years of age.11 In almost every known infectious disease, vitamin A deficiency is known to result in greater frequency, severity, or mortality.12 Increased susceptibility to infection was one of the first features of nutritional vitamin A deficiency to be recognized,13 and even mild deficiency appears to be associated with an increased risk of pneumonia, diarrhea, and death in childhood.14 15 16 17 According to Scrimshaw et al., "no nutritional deficiency in the animal kingdom is more consistently synergistic with infection than that of vitamin A."12 They list nearly 50 studies (including 8 in humans) of diseases of bacterial, viral, or protozoan origin in which vitamin A deficiency resulted in increased frequency, severity, or mortality.12 In fact, vitamin A is sometimes referred to as the "anti-infective" vitamin.18
We embarked on this study because measles is a pressing problem in our part of the world19 and because the results of Barclay et al.6 and the circumstantial evidence appeared promising. Subsequently, acting on the same evidence, the World Health Organization recommended routine vitamin A supplementation for all children with measles in regions where vitamin A deficiency was a recognized problem and suggested that elsewhere "in countries where the fatality rate of measles is 1% or higher it would be sensible to provide vitamin A supplements to all children diagnosed with measles."20 One difficulty with this advice is that in the communities in which measles poses the greatest problem, the mortality rate is often unknown. Another is that the recommendation is based on the less than conclusive evidence from the only two studies to have addressed the question of vitamin A therapy in measles.5 , 6 These are some of the reasons why vitamin A supplementation is still not given routinely to children who are seriously ill with measles in South Africa, and presumably elsewhere.
Methods
Children with acute measles who required hospital admission for the treatment of associated complications were entered in a randomized, double-blind, placebo-controlled trial to assess the effect of oral vitamin A on morbidity and mortality. The study was limited by a priori considerations to a fixed termination date, with a maximal enrollment of 200 cases. It was conducted from March to July 1987 at the City Hospital for Infectious Diseases, a regional center serving a population of about 2 million in Cape Town and surrounding areas. The Medical Faculty's ethics and research committee approved the study protocol.
Patient Selection and Randomization
All children under 13 years of age who were referred to the hospital for admission with measles were eligible for entry into the trial. The criteria for exclusion were vitamin A therapy before admission, xerophthalmia on admission or thereafter, rash for more than four days, or lack of parental consent.
Patients in the trial were randomly assigned to receive either 400,000 IU (120 mg) of water-miscible vitamin A (retinyl palmitate; Arovit drops, Roche, Basel, Switzerland) or an identical-appearing placebo from syringes coded according to a random-number table. The senior ward nurse gave half the dose on admission and the remainder a day later, either by mouth or by nasogastric tube. The children were cared for by the regular ward staff. Concurrent therapy included oxygen, intravenous fluids, and antibiotics as appropriate, but no additional vitamin supplements. One of the study investigators assessed the patients each day. The treatment-assignment codes were broken only at the completion of the trial.
Initial Investigations
The children's weight and height were recorded, and a venous-blood sample was drawn on entry into the trial. The weights and heights were evaluated against the standards of the National Center for Health Statistics.21 Hemoglobin levels, white-cell counts (by Coulter model S5, Coulter Electronics, Hialeah, Fla.), and differential counts were estimated, and serum was stored at -70°C. Serum levels of total protein and albumin were measured by automated analysis (Astra-8, Beckman Instruments, Brea, Calif.). Serum concentrations of vitamin A (as retinol) were measured by high-performance liquid chromatography (Dupont Instruments, Wilmington, Del.), with concentrations of vitamin E (as alpha-tocopherol) obtained incidentally.22 A programmable integrator was used to quantify the Chromatographic results (Spectra-Physics, San Jose, Calif.). Retinol-binding protein was measured by radial immunodiffusion with a commercial kit (LC-Partigen, Behringwerke, Marburg, Federal Republic of Germany). Chest radiography and other investigations were performed when indicated.
Assessment of Outcomes
Outcomes were assessed solely on the basis of clinical criteria. The outcome variables used were death and the severity of illness, as indicated by the duration of the hospital stay; the duration of pneumonia or diarrhea; the incidence of "postmeasles" croup or herpes stomatitis; and the need for a transfer to the Red Cross War Memorial Children's Hospital for intensive care. Pneumonia was defined as the presence of tachypnea (frequency of respiration >40 per minute) with retractions, crackles, or wheezes. Diarrhea was defined as the passage of four or more liquid stools a day. Measles croup was defined as croup presenting on or within a day of admission. Croup that developed subsequently was categorized as postmeasles.
Statistical Analysis
The data were analyzed by computer with the Epi-Info program (version 3, USD, Stone Mountain, Ga.). Categorical data23 (e.g., the number of patients per group) were evaluated by the chi-square test, with Yates' correction for continuity applied routinely,24 or by Fisher's exact test when the expected number in a cell was five or less.24 Confidence intervals for the relative risks were calculated according to the method of Greenland and Robins.25 Continuous data23 (e.g., vitamin level) were compared by the nonparametric Kruskal-Wallis test.23 , 24 All P values reported are two-tailed, with values of less than 0.05 considered statistically significant.
Results
Exclusion of Patients
Of 224 patients under 13 years of age who were admitted to the hospital with measles during the study, 35 were excluded from the trial. In 12 of these cases the rash was present for five or more days, in 2 vitamin A had previously been given, in 18 consent could not be obtained because the child was unaccompanied by a parent on admission, and in 3 the parents refused consent. Hence, 189 patients were entered in the trial. There were no exclusions for xerophthalmia or withdrawals after entry.
Base-Line Characteristics
The placebo and treatment groups were generally comparable (Tables 1Table 1
Base-Line Clinical Findings in 189 Children with Measles, According to Treatment Group.* and 2Table 2Base-Line Blood and Serum Values, According to Treatment Group.), except that the patients in the vitamin A group were admitted about 12 hours earlier in terms of the duration of the rash and had lower serum levels of total protein and albumin than those in the placebo group. Two thirds of the children were 12 months old or younger (median, 10 months; range, 2 months to 5 years), and most were boys (58 percent). Blacks predominated (72 percent), and the remainder were of mixed race. The five white patients admitted with measles were excluded: consent was refused in the cases of two, and three were more than 13 years old. The hospital is open to all. Immunization and socioeconomic factors are thought to account for differences in racial makeup between the study population and the general population 14 years of age or under in Cape Town (57 percent mixed race, 25 percent black, 18 percent white).27 Heights were not measured for 11 patients. Height for age was below the fifth percentile in 52 children (29 percent) — a prevalence similar to that in the local reference population.28 Weight for age (below the fifth percentile in 50 percent), and weight for height (below the fifth percentile in 39 percent) were considered to reflect short-term weight losses from measles29 , 30 rather than preexisting acute protein-energy malnutrition, since that occurs in 1 percent or less of the local reference population.28 A combination of pneumonia and diarrhea was the usual indication for hospital admission (64 percent). Diarrhea (16 percent), pneumonia (13 percent), or measles croup (7 percent) appearing as isolated symptoms precipitated the other admissions.No blood samples were obtained from 15 patients, and only partial results were available for another 19 (Table 2). Serum levels were low for total protein (mean [±SE], 56.2±0.7 g per liter), albumin (mean, 33.4±0.46 g per liter), retinol-binding protein (mean, 30.1 ±2.02 mg per liter), and vitamin A as retinol (mean, 0.405±0.021 μmol per liter [11.6±0.6 μg per deciliter]). Low levels of total protein principally reflect depressed serum albumin concentrations (r2 = 72.6 percent, P<0.001). Serum retinol levels were below the lower limit of the normal range (0.7 μmol per liter [20 μg per deciliter]) in 92 percent of the children (143 of 156), and 46 percent (72) had levels below 0.35 μmol per liter (10 μg per deciliter), placing them at risk for xerophthalmia,31 although no cases of this were observed. Vitamin E levels were in the normal range.
Outcome
The children who received vitamin A had markedly diminished mortality and morbidity (Table 3Table 3
Mortality and Morbidity in 189 Children with Measles, According to Treatment Group.*), with no clinically apparent adverse effects. Of the 12 children who died (6.3 percent), 10 were in the placebo group (P = 0.046). The children who died were 5 to 29 months of age, and seven were boys. Death occurred 3 to 32 days after admission (median, 10.5). Pneumonia3 , 32 caused 10 deaths, and the two remaining children died after 15 and 32 days, respectively, of fulminant sepsis following chronic diarrhea and measles-induced kwashiorkor. Croup was present as an incidental finding in 5 of the 10 children who died of pneumonia.Cases of pneumonia lasted almost twice as long in the placebo group as in the vitamin A group (P<0.001), and 66 percent of the children with chronic pneumonia (>10 days) were in the placebo group (P = 0.008). Similarly, diarrhea continued for a third longer in the placebo group (P<0.001), and 72 percent of the children with chronic diarrhea were in that group (P = 0.023). Postmeasles croup was more common in the placebo group (P = 0.033), as was herpes stomatitis (P = 0.08). Finally, the hospital stay of the survivors was shorter by a third in the vitamin A-treated group (P = 0.004).
Overall, 77 children had adverse outcomes (Table 3), of whom 52 were in the placebo group (P = 0.004). As compared with the children in the placebo group, the children treated with vitamin A were at lower relative risk for death (relative risk, 0.21; 95 percent confidence interval, 0.05 to 0.94), prolonged pneumonia ≥10 days (relative risk, 0.44; 95 percent confidence interval, 0.24 to 0.80), prolonged diarrhea ≥10 days (relative risk, 0.40; 95 percent confidence interval, 0.19 to 0.86), postmeasles croup (relative risk, 0.51; 95 percent confidence interval, 0.28 to 0.92), airway intervention (relative risk, 0.35; 95 percent confidence interval, 0.10 to 1.26), herpes stomatitis (relative risk, 0.23; 95 percent confidence interval, 0.05 to 1.06), and the need for intensive care (relative risk, 0.38; 95 percent confidence interval, 0.13 to 1.16). The overall risk for an adverse outcome in children treated with vitamin A was half that in the control group (relative risk, 0.51; 95 percent confidence interval, 0.35 to 0.74). Of the 77 children who had adverse outcomes, only 2 were ≥2 years of age (P = 0.002), and the risk in a child ≥2 years old was substantially lower than in younger children (relative risk, 0.15; 95 percent confidence interval, 0.02 to 0.91). No child with a serum retinol concentration ≥0.7 μmol per liter (20 μg per deciliter) died, but the smallness of this group (n = 14) leaves the significance of the finding in doubt.
Discussion
The results of our randomized, controlled trial indicate a remarkable protective effect of vitamin A in severe measles, notwithstanding the provision of good general medical care and the presence of complicated advanced disease. Vitamin A reduced the death rate by more than half and the duration of pneumonia, diarrhea, and hospitalization by about one third. Vitamin A also appeared to reduce the incidence of herpes stomatitis and the need for intensive care. The consistency of benefit with respect to all measures of outcome is noteworthy, since mortality is not a sensitive criterion. Because of their reliance on mortality rates, previous studies of measles5 , 6 lacked the statistical power to establish the benefit of vitamin A therapy.
The favorable response to vitamin A therapy may be understood in terms of the very high incidence (92 percent) of hyporetinemia in our patients (Table 2). Hyporetinemia implies a state of vitamin A deficiency at the tissue level, since there are virtually no peripheral-tissue stores of vitamin A except in the retina.33 34 35 36 Serum retinol levels below 0.7 μmol per liter (20 μg per deciliter) appear to be inadequate for the body's biologic needs.33 Oral vitamin A is absorbed well even in patients with diarrhea,37 so the observed effects of treatment may reasonably be ascribed to correction of the tissue deficit of vitamin A. We do not know, however, whether the deficit was rectified by increases in the serum retinol concentration or by some other mechanism, since serum retinol levels were not measured after therapy.
Hyporetinemia appears almost invariable in children with severe measles,8 9 10 11 as in this study, and the reduction in the serum retinol level is associated with increasingly severe disease.11 Since many of these data come from populations in which nutritional vitamin A deficiency is a known problem,8 9 10 it has been inferred that hyporetinemia in measles represents the exhaustion of hepatic stores.6 , 7 , 20 There is a possible alternative mechanism, however. Hyporetinemia may occur in the presence of adequate hepatic stores of vitamin A when the stores are not mobilized fast enough to meet demand.36 This has been found in fever, pneumonia, rheumatoid arthritis, hepatitis, acute tonsillitis, and rheumatic fever36; in protein-energy malnutrition38; and now also in measles.8 Inadequate mobilization of hepatic stores may therefore underlie the hyporetinemia in children with severe measles from Kinshasa, Zaire,11 and Cape Town, where nutritional vitamin A deficiency is uncommon. A study 25 years ago showed vitamin A deficiency to be rare in Cape Town, even in children with severe protein-energy malnutrition,38 and it still appears to be rare. A search of the computer data-base listing of inpatients at our children's hospital, which predominantly serves the local underprivileged community, found only three instances of clinical vitamin A deficiency among 161,381 children admitted over a 13-year period, with no cases since 1985.
In view of the evidence that hyporetinemia may occur in the presence of adequate hepatic stores of vitamin A38 and in populations not known to be deficient in vitamin A,11 it would seem prudent to proceed on the assumption that previous nutritional adequacy may not ensure against the development of hyporetinemia in severe measles. For all children seriously ill with measles, vitamin A replacement should thus be provided at the dose given by Barclay et al.6 (400,000 IU), which proved effective and safe in our study. A lower dose (100,000 to 200,000 IU) is recommended by the World Health Organization,20 but its efficacy in measles has yet to be established.
It may be asked whether it is cost effective to advocate treatment with vitamin A for all children with severe measles. Clearly, children under two years of age are at highest risk of an adverse outcome and derive the most benefit from vitamin A. When resources are scarce, such children should be given priority. In our study, however, half the children over two years of age were at risk of xerophthalmia because of serum retinol levels below 0.35 μmol per liter (10 μg per deciliter),31 and hence they should have vitamin A prophylaxis. Thus, when resources permit, all children with severe measles should be given supplemental vitamin A.
We are indebted to many colleagues for constructive criticism; to Mr. R. Sayed, statistician to the Department of Community Health of the University of Cape Town for advice on study design and randomization procedures; to Ms. G. Joubert of the South African Medical Research Council, for assistance with data collection and preliminary analyses; to Glaxo (South Africa), for the donation of our computer; to the nursing staff of the City Hospital for Infectious Diseases for invaluable assistance and to the hospital's medical superintendent, Dr. P.J.W. Roux, for providing facilities; to Mr. A.F. Rodriques for searching the data base of patients of the Red Cross War Memorial Children's Hospital; to the medical superintendent, Dr. R.O. Simpson, for giving access to the data base; to the McCaul Bell Bequest of the Institute of Child Health, University of Cape Town, for a grant to Professor H. de V. Heese that provided funding for the assays of vitamins and retinol-binding protein; and to Ms. Frances Pocock for performing these assays in the Institute laboratory.
Source Information
From the Department of Paediatrics and Child Health. University of Cape Town, Cape Town, South Africa. Address reprint requests to Dr. Klein at the Red Cross War Memorial Children's Hospital, Rondebosch 7700, South Africa.
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