Effect of vitamin A supplementation on diarrhoea and acute lower-respiratory-tract infections in young children in Brazil. Vitamin A supplementation fails to reduce incidence of acute respiratory illness and diarrhea in preschool-age Indonesian children. Randomized placebo-controlled clinical trial of the effect of a single high dose or daily low doses of vitamin A on the morbidity of hospitalized, malnourished children. Impact of massive dose of vitamin A given to preschool children with acute diarrhoea on subsequent respiratory and diarrhoeal morbidity. Supplementation with vitamin A reduces watery diarrhoea and respiratory infections in Mexican children. Vitamin A supplementation and increased prevalence of childhood diarrhoea and acute respiratory infections. Impact of large-dose vitamin A supplementation on childhood diarrhoea, respiratory disease and growth. The beneficial effects of weekly low-dose vitamin A supplementation on acute lower respiratory infections and diarrhea in Ecuadorian children. Effect of vitamin A on diarrhoeal and respiratory complications of measles.
A beneficial effect of periodic vitamin A supplementation on childhood mortality has been demonstrated, but the effect on morbidity is less clear. We investigated the effect of vitamin A supplementation on diarrhoea and acute lower-respiratory-tract infections (ALRI) in children from northeastern Brazil in a randomised, double-blind, placebo-controlled community trial. 1240 children aged 6-48 months were assigned vitamin A or placebo every 4 months for 1 year. They were followed up at home three times a week, and data about the occurrence and severity of diarrhoea and ALRI were collected. Any child with cough and respiratory rate above 40 breaths per min was visited by a paediatrician. The overall incidence of diarrhoea episodes was significantly lower in the vitamin-A-supplemented group than in the placebo group (18.42 vs 19.58 x 10(-3) child-days; rate ratio 0.94 [95% Cl 0.90-0.98]). The benefit of supplementation was greater as regards severe episodes of diarrhoea; the incidence was 20% lower in the vitamin A group than in the placebo group (rate ratio 0.80 [0.65-0.98]). With the standard definition of diarrhoea (> or = 3 liquid or semi-liquid stools in 24 h) the effect of vitamin A on mean daily prevalence did not reach significance, but as the definition of diarrhoea was made more stringent (increasing number of stools per day), a significant benefit became apparent, reaching for diarrhoea with 6 or more liquid or semi-liquid stools in 24 h a 23% lower prevalence. We found no effect of vitamin A supplementation on the incidence of ALRI. The reduction in severity of diarrhoea may be the most important factor in the lowering of mortality by vitamin A supplementation. Vitamin A supplementation of populations of vitamin A-deficient preschool-age children has been shown to reduce childhood mortality, but the primary preventive effects of such supplements on childhood infectious diseases have not been carefully evaluated. We conducted an individually randomized, placebo-controlled, double-masked trial among 1,407 Indonesian preschool-age children, to measure the effects of high dose vitamin A on acute respiratory and diarrheal illnesses. Signs and symptoms of morbidity were monitored using every other day home surveillance by trained interviewers. High dose vitamin A supplements increased the incidence of acute respiratory illnesses (ARI) by 8%, and acute lower respiratory illnesses (ALRI) by 39%. These detrimental effects on acute lower respiratory illnesses were most marked in children with adequate nutritional status (rate ratio 1.83, 95% confidence interval 1.257-2.669). In contrast, vitamin A tended to be protective of ALRI in chronically malnourished children (rate ratio 0.71, 95% confidence interval 0.375-1.331). There was no overall effect of high-dose vitamin A supplements on the incidence of diarrheal disease (rate ratio 1.06, 95% confidence interval 0.920-1.225). However, we found a significant interaction between supplementation and age: vitamin A increased the incidence of diarrhea in children < 30 mo of age, but tended to reduce the incidence in older children. The finding of a significant adverse effect of vitamin A supplements in adequately nourished children highlights the need to review the criteria for selecting populations of preschool-age children for vitamin A supplementation. The effect of high-dose vitamin A supplementation on recovery from morbidity and on recovery from nosocomial morbidity of hospitalized children has been poorly studied and results are conflicting. The effect of daily, low doses has never been assessed. We investigated the effect of a single high dose and daily, low doses of vitamin A on diarrhea, acute lower respiratory tract infections (ALRIs), and all-cause fevers in 900 hospitalized preschool-age children in the Democratic Republic of Congo in a randomized, double-blind, placebo-controlled clinical trial. The high-dose treatment group received 200,000 IU vitamin A (100,000 IU if aged <12 mo) orally on the day of admission, the low-dose treatment group received 5000 IU vitamin A/d until discharge. Data on all-cause morbidity were collected daily. Mortality rates were not significantly different among the 3 groups. High-dose vitamin A supplementation had no significant effect on the duration of moderate or severe diarrhea nor on the duration and incidence of ALRIs and all-cause fevers. Children in the high-dose group with no edema had an increased risk of severe nosocomial diarrhea (relative risk: 2.42; 95% CI: 1.15, 5.11). Low-dose vitamin A supplementation significantly reduced the incidence of severe diarrhea in severely malnourished children (relative risk: 0.21; 95% CI: 0.07, 0.62) but showed no significant effect on the duration of moderate or severe diarrhea or on the duration and incidence of ALRIs and all-cause fevers. Supplementation with high doses of vitamin A did not reduce morbidity in this population of malnourished and subclinically vitamin A-deficient children; daily, low doses appeared more beneficial for severely malnourished children. To assess the impact of vitamin A supplementation on morbidity from acute respiratory tract infections and diarrhoea.
                Double blind randomised placebo controlled field trial.
                An urban slum area in New Delhi, India.
                900 children aged 12-60 months attending a local health facility for acute diarrhoea of less than seven days' duration randomly allocated to receive vitamin A 200,000 IU or placebo.
                Incidence and prevalence of acute lower respiratory tract infections and diarrhoea during the 90 days after termination of the enrolment diarrhoeal episode measured by twice weekly household surveillance.
                The incidence (relative risk 1.07; 95% confidence interval 0.92 to 1.26) and average number of days spent with acute lower respiratory tract infections were similar in the vitamin A supplementation and placebo groups. Among children aged 23 months or less there was a significant reduction in the incidence of measles (relative risk 0.06; 95% confidence interval 0.01 to 0.48). The incidence of diarrhoea was also similar (relative risk 0.95; 0.86 to 1.05) in the two groups. There was a 36% reduction in the mean daily prevalence of diarrhoea associated with fever in the vitamin A supplemented children older than 23 months.
                Results were consistent with a lack of impact on acute lower respiratory tract related mortality after vitamin A supplementation noted in other trials and a possible reduction in the severity of diarrhoea. Previous clinical vitamin A trials have found no consistent effect on diarrhoeal disease and respiratory tract infection. These inconsistent results may be due to the distinct effects vitamin A supplementation has among children stratified by factors related to socio-economic status, nutritional status and season. We evaluated the effect of supplementation on the overall incidence of diarrhoeal disease and respiratory tract infections and on the incidence among children stratified by these factors. A total of 188 children, aged 6-15 months, from periurban, marginalized communities of Mexico City were assigned to receive vitamin A ( < 12 months of age, 20,000 IU retinol; >or= 12 months, 45,000 IU retinol) or a placebo every 2 months, and were followed for up to 15 months. Project personnel visited households twice a week to determine the onset and duration of diarrhoeal disease and respiratory tract infections. Vitamin A supplementation had no significant effect on risk of overall diarrhoeal disease but reduced mild watery diarrhoea (incidence rate ratio (RR) 0.69; 95 % CI 0.50, 0.93) and cough with fever (RR 0.69; 95 % CI 0.48, 0.98). Vitamin A supplementation decreased diarrhoeal disease during the summer (RR 0.74; 95 % CI 0.57, 0.94), among non-stunted children (RR 0.69; 95 % CI 0.52, 0.93) and among children from households with better socio-economic measures. Heterogeneity in the response to vitamin A supplementation may reflect heterogeneity in the aetiology and epidemiology of diarrhoeal disease and respiratory tract infections and the impact that supplementation has on the immune response. There is uncertainty over whether vitamin A supplementation reduces morbidity among children with subclinical deficiency of the vitamin. Hence a double-blind, placebo-controlled trial of the effect of vitamin A supplementation on childhood morbidity was conducted among 11,124 children aged 6-83 months in the northwest of Haiti. After a random start, children were sequentially assigned by household units to receive either megadose vitamin A or placebo in three distribution cycles 4 months apart. 2 to 8 weeks after each administration of the vitamin A and placebo capsules, indicators of childhood morbidity were reassessed through interviews conducted in the homes of participating families. The vitamin A group was found to have an increased 2-week prevalence of all symptoms and signs of childhood morbidity assessed, including diarrhoea (rate ratio [RR] = 1.09, 95% confidence interval 1.05-1.14), rhinitis (RR = 1.02, 95% confidence interval 1.00-1.04), cold/flu symptoms (RR = 1.04, 95% confidence interval 1.01-1.06), cough (RR = 1.07, 95% confidence interval 1.03-1.11), and rapid breathing (RR = 1.18, 95% confidence interval 1.09-1.27). The study shows an increased 2-week prevalence of diarrhoea and the symptoms of respiratory infections after vitamin A supplementation. One hundred and seventy-two 0.5-3.0-year-old children in a mountainous area of northern Hebei Province of China were randomly assigned to a vitamin A supplementation group (n = 98) or a control group (n = 74) for a 1 year double-blind study. Capsules containing 200,000 IU vitamin A and 40 IU vitamin E were given to the children in the experimental group 3 and 9 months after baseline examination. During the 12 month study period, there was a significant reduction in the incidence of diarrhoea (P < 0.01) and respiratory disease (P < 0.01) in the children of the experimental group compared to the control. Risk of diarrhoea and respiratory disease were respectively 2.5 and 3.4 times higher in the control children. Serum retinol and IgA levels of the treatment group were significantly higher than that of control group (P < 0.01) 7 weeks after first supplementation. There was no significant difference in saliva IgA level between groups. No significant differences in growth were observed. It was concluded that supplementation with large doses of vitamin A decreased the incidence and severity of diarrhoea and respiratory disease in these children, possibly through enhanced activity of the immune system, but had no effect on growth over 1 year. Previous studies of large-dose vitamin A supplementation on respiratory morbidity have produced conflicting results in a variety of populations. The influence of malnutrition has not been examined in the majority of these trials. We hypothesized that weekly low-dose vitamin A supplementation would prevent respiratory and diarrheal disease morbidity and that malnutrition might influence the efficacy of vitamin A supplementation.
                In a randomized, double-blind, placebo-controlled field trial of 400 children, 6 to 36 months of age in a high Andean urban slum, half of the children received 10 000 IU of vitamin A weekly and half received placebo for 40 weeks. Children were visited weekly at home by physicians and assessed for acute diarrheal disease and acute respiratory infections.
                Acute diarrheal disease and acute respiratory infection did not differ globally or by severity between supplement-treated and placebo groups. However, the incidence of acute lower respiratory infection (ALRI) was significantly lower in underweight (weight-for-age z score [WAZ] <-2 SD) supplement-treated children than in underweight children on placebo (8.5 vs 22.3 per 10(3) child-weeks; rate ratio: 0.38 [95% CI: 0.17-0.85]). ALRI incidence was significantly higher in normal-weight (WAZ >-2 SD) supplement-treated children than in normal-weight children on placebo (9.8 vs 4.4 per 10(3) child-weeks; rate ratio: 2.21 [95% CI: 1.24-3.93]). By logistic regression analysis the risk of ALRI was lower in underweight supplement-treated children than in underweight children on placebo (point estimate 0.148 [95% CI: 0.034-0.634]). In contrast, risk of ALRI was higher in normal-weight supplement-treated children (WAZ >-1 SD to mean) than in normal-weight children on placebo in the same WAZ stratum (point estimate: 2.51 [95% CI: 1.24-5.05]). The risk of severe diarrhea was lower in supplement-treated children 18 to 23 months of age than in children on placebo in this age group (point estimate: 0.26 [95% CI: 0.06-1.00]).
                Weekly low-dose (10 000 IU) vitamin A supplementation in a region of subclinical deficiency protected underweight children from ALRI and paradoxically increased ALRI in normal children with body weight over -1 SD. Protection from severe diarrhea was consistent with previous trials. Additional research is warranted to delineate potential beneficial and detrimental interactions between nutritional status and vitamin A supplementation regarding ALRI. A randomized placebo-controlled trial of high dose vitamin A in acute measles was performed in Nairobi, Kenya to determine if it reduced the incidence or severity of diarrhoeal and respiratory complications. On enrollment laryngotracheobronchitis (LTB) pneumonia, diarrhoea and otitis media were each found in 45-80% of children in the treatment and placebo groups. While 4 of 119 cases of LTB in the placebo group progressed to grade III (loud stridor, markedly diminished air entry, chest indrawing, cyanosis), none of 116 in the vitamin A group did. Episodes of diarrhoea, but not pneumonia, resolved faster and were less severe in the vitamin A group. There were no differences in the incidences of pneumonia, LTB or diarrhoea during hospitalization, but children treated with vitamin A had a lower rate of developing otitis media. The overall case fatality rate was 2.7% and did not differ by group. These findings, along with those from three other trials in Africa, suggest that high dose vitamin A reduces the severity of complications during measles.
This unexpected result is outside our current understanding of the use of vitamin A for preventing acute LRTIs. Accordingly, vitamin A should not be given to all children to prevent acute LRTIs. Despite its benefits in preventing diarrhoeal illnesses, vitamin A supplementation has only a limited effect in preventing acute LRTIs. Positive effects appear limited to populations with acute and chronic under nutrition. Low-dose vitamin A appears to have fewer side effects and at least equal benefit to a high dose of vitamin A.