High/Low Dose Vit A in Diarrhea/ALRI in Severe PEM

Globally An estimated 140-250 million under-five children are deficient in vitamin A, which is associated with increased mortality and morbidity among this population. A relationship between the severity of vitamin A deficiency and childhood mortality has also been reported. In 2002, the United Nations held a special session to examine ways to eliminate this problem through various approaches including breast-feeding, food fortification, improved diet and supplementation. Periodic supplementation of a mega dose of vitamin A has been recommended to be a suitable intervention at the community level which is likely to improve the over all vitamin A status. This is also cost effective and patient compliant. This approach has resulted in reduction in all-causes of deaths among under-five children by 23% in areas where vitamin A deficiency is a major public health problem [3] (http://www.who.int/vaccines/en/vitamina.shtml accessed on 26 May, 2005 at 1300 hrs). In view of the public health importance of vitamin A nutriture, the Government of Bangladesh recommends the administration of 200,000 IU of vitamin A every six months to all children aged 12-59 months irrespective of their nutritional and vitamin A status (Institute of Public Health Nutrition. Field guide for National Vitamin A Plus Campaign, 2005).

Vitamin A is required for maintenance of integrity of epithelial cells and its growth and differentiation, visual function, and the immune system [4]. Vitamin A deficiency leads to patchy keratinization of epithelial lining of the respiratory, genitourinary and gastrointestinal tracts [5], which acts as protective barriers against infections. The loss of intestinal epithelial integrity increases the likelihood of bacterial colonization and incidence of infections and septicemia, and it has also been shown that vitamin A supplementation in smaller or higher doses help repair the damaged mucosa during the convalescence stage [6-10]. Vitamin A deficiency state is worsened during acute infections that reduces the dietary intake and absorption, and increases excretion of vitamin A in urine [11]. The mortality in vitamin A deficiency is also related to reduced immune function [12], [13]. Vitamin A improves wound healing by mediating early inflammatory responses associated with influx of macrophages, enhanced fibroblast differentiation, and collagen accumulation [14].

About half of the absorbed vitamin A ingested is oxidized and excreted in the feces and urine, and the remainder is stored in the liver as retinol ester. It is released into the plasma for transportation to peripheral tissues after binding with specific protein known as retinol binding protein (RBP). Protein deficiency in severe malnutrition reduces the hepatic synthesis of RBP [15], [16] which is the likely to be the reason for low serum retinol level observed in such children [17-19]. Infectious diseases such as diarrhoea and acute lower respiratory infections including pneumonia are common in malnourished children, which worsen the vitamin A level [20]. Acute infections are also associated with acute phase response and a transient decrease in serum retinol level [21]. This is due to reduced transcription of messenger RNA for RBP, resulting in decreased release of RBP from the liver into the blood [22], [23]. It is likely that liver utilizes all of its available resources for rapid synthesis of proteins that are required for the host defense in acute infection, thereby limiting the synthesis of relatively lesser important ones such as RBP. In severe infection, the increased urinary loss of retinol contributes to the lower serum retinol concentration [24]. Thus the utilization of vitamin A in the peripheral tissue is adversely affected in systemic infections and in protein- energy malnutrition leading to development of features of vitamin A deficiency.

Acute lower respiratory infections (ALRI) including pneumonia, and diarrhoeal diseases are the two most common illnesses that affect the under-five children. Earlier studies have observed beneficial role of high dose vitamin A as an adjunct therapy in the treatment of both watery and invasive diarrhoeas [25, 26]. It was observed that an increase of 1 mmol/liter of retinol reduces proportion of patients with diarrhoea and respiratory disease by 50% and 80% respectively [9]. A more recent study had observed supplementation of vitamin A to under-five children to be associated with reduced frequency of diarrhoea and ALRI, and subsequent malnutrition [27]. In another study 85% of the infants attending a diarrhoea treatment centre in Bangladesh were found to have depleted vitamin A stores, as measured by relative dose response test, and 61% of them remained deficient despite receiving high dose of vitamin A [24, 28]. Healthy children receiving high dose of vitamin A may experience higher incidences of adverse manifestations such as nausea, vomiting and higher incidence of diarrhoeal episode [29], while low dose vitamin A is associated with reduced incidence of severe diarrhoea in malnourished children [15]. In India studies examined the effect of an intermediate dose (8.7 mmol; 2500 mgm), administered weekly, and did not observe any difference in the incidence, severity and or duration of diarrhea in vitamin A deficient children [30]. In another community based study, infants aged 2-15 months receiving 16700 IU vitamin A or placebo weekly for 8 weeks experienced enhanced gut repair as indicated by improved lactulose-mannitol (L:M) ratio, as compared to the hospitalized infants who received high dose. The results suggest impaired gut permeability during convalescent period. There is every possibility that the low vitamin A level during the infectious state and the low retinol concentration in malnourished children aggravates the already existing compromised gut mucosa thus necessitating the vitamin A supplementation among the hospitalized malnourished children [10].

There are conflicting reports on the role of high dose of vitamin A supplementation in the management of ALRI and pneumonia in malnourished children [31], [15]. Even sub-clinical vitamin A deficiency in non-malnourished children is associated with increased risk of ARI [32], [33]. Meta-analysis of community-based studies of high dose vitamin A supplementation to children aged 6 months to 5 years did not observe any protective or detrimental effects of vitamin A supplementation on pneumonia-specific mortality according to the vitamin A and pneumonia working group [34]. In fact, some studies have reported an increase in the incidence of ALRI in children with adequate nutritional status receiving vitamin A supplementation [35]. In a placebo-controlled study, high dose vitamin A supplementation did neither influence recovery nor the duration of hospitalization in Guatemalan children with ALRI [31]. A higher dose of vitamin A was evaluated in studies in Brazil [36], Vietnam [37], Chile [38] and Tanzania [39], and none of them had observed any beneficial effect, and in fact had observed a negative effect in adequately nourished children [40]. Another clinical trial conducted in Peru not only observed high dose vitamin A supplements to be ineffective in improving recovery from pneumonia in hospitalized children, but actually observed prolonged duration of the clinical signs, higher requirements of oxygen support, and higher nursing time and patient care cost in high-dose supplemented group [41]. On the other hand, in a population based, controlled clinical trial in Ecuadorian urban slum children, weekly supplementation of low dose vitamin A (10,000 IU) for 40 weeks was associated with a strong protective effect on ALRI in malnourished under-five children [42].