High/Low Dose Vit A in Diarrhea/ALRI in Severe PEM
High/Low Dose Vit A in Diarrhea/ALRI in Severe PEM
Vitamin A deficiency is an important health problem globally including Bangladesh. The
 problem is greater among under-five children, particularly in malnourished. Vitamin A
 supplementation reduces morbidity from diarrhoeal diseases and also prevents future diarrhoea
 episodes. However, there are conflicting reports on the role of vitamin A supplementation on
 morbidity from acute lower respiratory infections (ALRI) including pneumonia. In
 non-malnourished children supplementation has been reported to be associated with increased
 incidence and morbidity of ALRI. The WHO committee[1] has reviewed both the risk and benefit
 of mega dose (200,000 IU) vitamin A supplementation during acute illness particularly
 diarrhoea, irrespective of the nutritional status of under-5 children and recommended vitamin
 A supplementation in areas where vitamin A status is low. In Bangladesh mega dose (200,000
 IU) of vitamin A is routinely supplemented to under-5 children every 6 months. Absorption of
 vitamin A precursors from the GI tract is reduced in severely malnourished children, who are
 also lacking in retinol binding protein (RBP), required for transportation of retinol to
 target tissues. Thus it is established that a significant portion of the supplemented vitamin
 A is excreted in feces and urine of malnourished children. The excretion of vitamin A
 increases substantially during acute infections including diarrhoeal diseases. On the other
 hand, due to reduced RBP, concentration of free vitamin A increases in the body resulting in
 the possibility of adverse events including "pseudotumor cerebri". It has recently been
 observed that low-dose daily supplementation of vitamin A to malnourished children produces a
 better effect on recovery from acute illness and also in preventing infectious diseases among
 under-five children. However, the limitations of those studies included a small sample size,
 delayed assessment of retinol after supplementation among the others. Thus WHO felt that the
 issue needs to be addressed in a well-designed clinical trial. We hope that our proposed
 study will enable us to compare the efficacy of low-dose daily administration of vitamin A
 with that of initial mega dose followed by daily low dose of vitamin A in malnourished
 children presenting with acute diarrhoeal diseases with or without ALRI. If the results of
 this study indicate that the daily low-dose has similar efficacy to that of the currently
 recommended mega dose followed by daily low-dose of vitamin A, would have important
 programmatic implications.
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].

 The reports on mortality and morbidity from diarrhoea and pneumonia in severely malnourished
 children in association with vitamin A supplementation are conflicting. In the 21st IVACG
 meeting three papers were reviewed. They observed no significant difference in mortality (8%
 vs. 8.4% and 8.8%) in high and low dose of vitamin A and placebo group [15]. Yet another
 study also failed to show any significant reduction (16.8 vs. 12.4%) in the mortality in
 patients receiving high or low dose of vitamin A [43]. However, in sub-group analysis deaths
 were significantly lower among oedematous children who received low dose vitamin A on
 admission [44]. A meta-analysis observed substantial reduction in mortality in association
 with vitamin A supplementation in population where at least low-level deficiency state was
 prevalent, and the effect was independent of dose, sex and age, and the effect was more
 pronounced for incidence of diarrhoea than for respiratory diseases [45]. However, no
 difference in morbidity (frequency, duration, or prevalence) from diarrhoeal or respiratory
 diseases was noted (Ghana VAST Study Team) [46] among stunted children in Ghana.

 Malnourished children are deficient in RBP, facilitating excretion of the resultant free,
 unbound form of vitamin A either through urine or faces, a situation that is aggravated
 during acute infections. Vitamin A, when administered in a single high dose, presumably
 circulates in free form in the extra cellular fluids before being taken up by the liver. This
 free form of vitamin A perhaps affects sodium and water metabolism causing 'pseudotumor
 cerebri', an adverse event of hypervitaminosis A [47]. Thus a mega dose supplementation may
 not be yielding any better effect in the severely malnourished children.

 Rationale

 Vitamin A supplementation is beneficial in the management of clinical and sub-clinical
 deficiencies of this important micronutrient, and has been observed to improve outcomes from
 certain illnesses, particularly diarrhoeal diseases and in preventing infectious diseases.
 The beneficial effect of vitamin A supplementation in ALRI including pneumonia is not that
 clear. WHO currently recommends single high dose of vitamin A supplementation to malnourished
 children with diarrhoea because of low cost with high participation rate for improving health
 status of children. The WHO recommendation is based on studies in communities that showed
 benefit of the cheapest intervention, which is quicker to implement into health programmes.
 The programmes for vitamin A capsule distribution reduced risk of vitamin A deficiency among
 participating children. Interpretation of the three studies done in the Democratic Republic
 of Congo and Senegal, as mentioned earlier, in relation to the existing guidelines on vitamin
 A supplementation was considered difficult and their validity was doubted in a meeting
 convened by WHO in September 2004. It was, however, recognized that the question of vitamin A
 dosage remains an important one and there is scope for further research. The meeting proposed
 that the high dose only be given if the interval is at least 6 months from the last previous
 high dose.

 In Bangladesh, high potency (200,000 IU) vitamin A is routinely supplemented to under-five
 children every 6 months. There are at least three large studies that failed to observe any
 effect of mega dose of vitamin A on the incidences and duration of diarrhoea and respiratory
 tract infections. In recent studies it has been shown that daily low-dose supplementation of
 vitamin A to malnourished under-five children produces similar or better effect, compared to
 high dose, during acute illness and also in preventing infectious diseases. Studies have
 observed higher mortality in high dose vitamin A supplemented group compared to the low dose
 group. However, they were done in smaller number of children [15, 44]. In serum, vitamin A
 remains saturated with RBP in a 1:1 ratio. Therefore, the amount of vitamin A in excess of
 this ratio, as would be expected in mega-dose supplementation of vitamin A to severely
 malnourished children with low serum RBP, would be non-functional at best, at least
 theoretically [19]. Two trials in Asia that used high dose vitamin A observed conflicting
 results. One study reported that, capsule distribution was not universal and probably vitamin
 A deficient children would be missed, and the response of the high dose was unlikely to be
 due to non-specific changes. In the other study, vitamin A supplementation alone failed to
 show any expected improvement of child survival in demographic data but they did not deny the
 importance of vitamin A supplementation in improving nutritional status [48, 49]. On the
 other hand, weekly supplement of 8,333 IU of vitamin A was reported to reduce mortality by
 54% [50]. There thus is a need for a carefully designed study with adequate sample size to
 address the effect of low dose vitamin A on morbidity and mortality among severely
 malnourished children with diarrhoea and pneumonia- the basis of our proposed study. We hope
 that the results of this study will enable us to compare the cure rates of low-dose daily
 administration of vitamin A with that of the initial mega dose followed by daily low dose of
 vitamin A. Daily basal requirements (estimated amount which is needed to prevent signs of
 deficiency) for 0-1 and 2-6 years old children are 600 and 650 IU respectively, and the
 normal requirement (which is sufficient to maintain desirable levels of tissue store) for the
 same age group are 1200 and 1300 IU respectively [51]. It is estimated that malnourished
 children will lose 0.1µmol of retinol /day (97 IU) through urine during acute illness [24].

 The national coverage rate (percentage of target age children who received vitamin A capsules
 during the past six months, according to information provided by the mothers) of vitamin A in
 rural areas was 45% in 1982-83[52]. The rate gradually decreased to 37% in 1987-88 and 35% in
 1989 respectively [53], [54]. However, the Nutritional Surveillance Project reported in
 December 1995, that the coverage of vitamin A capsule distribution increased substantially-
 83.6% in rural and 73.7% in the urban areas [54]. It is noteworthy that night blindness is
 considered as the marker of vitamin A deficiency, and when that exceeds 1%, is considered as
 a significant public health problem [55]. In Bangladesh, the proportion of children aged
 18-59 months having night blindness in rural areas and urban slums were 0.23% and 0.12%
 respectively [52]. These figures are well below the cut-off for public health significance of
 vitamin A deficiency. Anecdotal observations of doctors working at the ICDDR, B Hospital,
 Dhaka, indicate a significant decrease in the number of children with clinical vitamin A
 deficiency seeking treatment in the hospital. Further more, according to a report of the
 surveillance system of Dhaka Hospital of ICDDR, B 84 children presented with conjunctival
 xerosis and only three had keratomalacia/corneal ulcer out of the total of 11,605 under-5
 children who attended the hospital during the period 1996-2004. Children to be enrolled in
 our proposed study will receive 5000 IU of vitamin A. That amounts to be an additional 1000
 IU during the acute phase and 800 IU during the nutritional rehabilitation phase of severe
 malnutrition from various diets provided to them during their hospital stay. We thus estimate
 that the total amount of vitamin A received from these sources, even after adjusting for
 urinary excretion and the retinol level, will not fall below the basal and normal
 requirements. We feel that once we are able to maintain the daily optimal level of vitamin A
 stores in the body the sudden development of keratomalacia can be averted. However, we will
 remain vigilant, through performing careful clinical examination (of eye and skin), to
 exclude children with any form of clinical vitamin A deficiency from enrollment. Children
 with clinical vitamin A deficiency disease (conjunctival xerosis, Bitot's spots,
 keratomalacia, or dermatosis suggestive of vitamin A deficiency) will not be eligible for
 enrollment and will be provided with the currently recommended treatment with vitamin A
 supplementation as is routinely followed in this hospital. It may also be noted that a couple
 of studies did not observe development of an overt sign of vitamin A deficiency in children
 not receiving vitamin A (placebo group) [15, 41]. Additionally, serum retinol concentrations
 were not significantly changed after 7 days of hospitalization both among children receiving
 the high dose and children receiving the low dose or placebo [15].

 Clinical failure rates in the first 48 hours for the Dhaka hospital for shigellosis, cholera
 and pneumonia were 31%, 35% and 40% respectively. Thus we postulate that the clinical failure
 from diarrhoea and pneumonia will be reduced at least by 15% from the current rate, if
 vitamin A can be supplemented at lower daily dose to malnourished children attending the
 Dhaka Hospital of ICDDR, B
Inclusion Criteria:

 1. Age 6-59 months

 2. Either sex

 3. Severe malnutrition as defined by the presence of any of the followings:

 -  Bipedal oedema

 -  Weight (measured after correction of dehydration) for height Z score <-3 of the
 National Center for Health Statistics (NCHS) reference

 -  Written informed consent of respective parents/ guardians for participation of
 the children in the study.

 4. Children having diarrhoea (watery or invasive) or cough and cold or both for the last
 48 hours.

 Exclusion Criteria:

 1. Failure to obtain consent

 2. Received a dose of vitamin A within the last three months

 3. History of night blindness or eye signs of vitamin A deficiency

 4. Measles or history of measles within last 8 weeks [56]

 5. Clinical suspicion of TB (evening rise of temperature, loss of appetite, gradual loss
 of weight, cough, night sweating) after applying modified Kenneth Jones criteria [57],
 shock other than due to hypovolaemia or hypoglycaemia, congestive cardiac failure,
 severe sepsis (hypothermia, tachycardia, tachypnea, hypotension) [58], and seizure
 disorders

 6. Trisomy-21

 7. Cerebral palsy

 8. Any other known chronic disease (e.g. hepatic, renal or congenital disorder) or
 malignant condition.