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Department of Nutrition, The Pennsylvania State University, University Park, PA 16802
1To whom correspondence should be addressed. E-mail: fxr5{at}psu.edu.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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0.36, indicative of marginal VA deficiency, 82 children were diagnosed as marginally VA deficient and 114 were diagnosed as VA sufficient. At baseline, marginally VA-deficient patients had significantly lower serum retinol and higher serum C-reactive protein concentrations than VA-sufficient children. At the 2-wk follow-up visit, serum retinol and the RBP/TTR ratio were significantly greater in marginally VA-deficient measles patients receiving VA supplements than in those receiving placebo; whereas in VA-sufficient measles patients, retinol increased in those receiving VA supplements or placebo. Concomitantly the odds ratio of unresolved pneumonia in marginally VA-deficient measles patients receiving VA supplements compared with those receiving placebo was 0.20 (95% confidence interval, 0.05–0.71). In conclusion, VA supplements during measles infection improved VA status of VA-deficient children and helped resolve MP, demonstrating the importance of determining VA status when assessing the efficacy of VA supplements.
KEY WORDS: • C-reactive protein • retinol • retinol-binding protein • transthyretin
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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), but there is less acceptance of the mechanism by which VA improves the survival of these patients. Recently Taylor and Higgs (2
) argued that this lack of knowledge might impede the general acceptance of VA supplements as standard treatment for measles patients in developing and developed countries.
The correction of low circulating retinol concentrations during measles infection with VA supplements has been suggested as a possible mechanism of the impact of VA. Hospital-based studies in developing and developed countries have demonstrated that measles severity is closely related to low serum retinol concentrations (3
,4
). Hussey and Klein (5
) suggested that measles infection impaired the distribution of VA to peripheral tissues through the reduction of serum retinol concentrations, and Coutsoudis et al. (6
) confirmed that supplementation increased serum retinol levels 8 d after two doses of 210 µmol of retinol. However, serum retinol also increased in children receiving placebo, raising the question of whether correcting serum retinol was necessary to reduce measles morbidity.
Others have suggested that it is the VA status before infection that determines the risk of morbidity and mortality during measles infection. A review of four community-based prophylaxis trials of VA supplements showed that measles-specific mortality rate was reduced by 50% (7
). However a community-based prophylaxis trial of VA supplements that directly examined acute measles case fatality in relation to premorbid VA supplementation found no effect (8
). A problem with these studies is that they used serum or plasma retinol as an indicator of VA status, which may not be indicative of VA status but rather of the effect of the acute phase response of inflammation (9
). Recently it was shown that the molar ratio of retinol-binding protein to transthyretin (RBP/TTR) can selectively detect those with marginal VA deficiency regardless of whether inflammation is present (10
,11
). In this a posteriori analysis, VA status was determined on the basis of the RBP/TTR ratio before and after VA supplementation or placebo administration, and the relationship between improved VA status and measles morbidity was examined.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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,13
). Briefly, a total of 200 acute measles patients, aged 5 mo to 17 y, not requiring hospitalization were enrolled in a randomized doubled-blinded placebo-controlled trial from March through September 1991 (13
). The study was conducted at urban health centers in Ndola, Zambia; children received by random assignment a single oral dose of 210 µmol retinol as retinyl esters or a placebo and were followed for 1 mo (13
). Blood samples (5 ml) were drawn at baseline and at the 2-wk evaluation for biochemical determinations of serum retinol, RBP, TTR, C-reactive protein (CRP) concentrations and measles antibodies (12
,13
). The samples were protected from light and placed inside a cool box at 8°C and allowed to coagulate. Within hours, serum was separated and stored at -20°C. Serum retinol levels were determined by HPLC at the Tropical Diseases Research Centre, Ndola, Zambia (12
). Serum RBP, TTR and CRP were determined at the time the study was conducted by radial immunodiffusion assays using commercially available kits (Kent Laboratory Inc., Redmond, WA for TTR and CRP and Behring Diagnostic Inc., Somerville, NJ for RBP). Vitamin A status was determined on the basis of the molar ratio of RBP/TTR determined in serum samples at baseline. A cutoff value of 0.36 was used, which previously has been shown to indicate marginal VA deficiency (11
). All procedures were approved by the Ethical Committee of the Tropical Diseases Research Centre in Ndola, Zambia, and by the Committee on Human Volunteers, The Johns Hopkins School of Hygiene and Public Health, Baltimore, Maryland. Statistical methods.
The present analysis included clinical and biochemical determinations at baseline and the 2-wk evaluation to assess the relationship between VA status and MP. MP was diagnosed on the basis of the presence of cough and a respiratory rate above an age-specific rate using criteria established by the World Health Organization (14
); children with cough alone and a normal age-specific respiratory rate were considered not to have MP (13
,14
). The two-sample test for binomial proportions and 
2 tests were used to assess treatment differences by VA status for dichotomous variables, and the Mann-Whitney or Kruskal-Wallis test was used when necessary for continuous variables (15
). A longitudinal analysis was carried out using a first-order Markov chain procedure, which described the distribution of individual changes in MP from baseline to the 2-wk evaluation (16
). This consisted of creating a 2 x 2 table, with rows being morbidity at baseline (i.e., no pneumonia versus pneumonia) and columns being morbidity at the 2-wk evaluation. The transients (i.e., those who moved along the rows and across the columns of the 2 x 2 table) described the proportion of acute measles patients with unresolved MP from baseline to 2-wk evaluation and the proportion of those without MP during this period. From this table, the odds ratio (OR) was calculated that contrasted the probability of unresolved MP versus no pneumonia. Then a logistic regression model was developed to adjust the OR for VA status at baseline and treatment allocation. Other possible covariates such as age, gender, nutritional status (e.g., stunting) and inflammatory status (i.e., serum CRP > 10 mg/L at the 2-wk evaluation) were evaluated. Indicator variables were created for each of these covariates, and their selection in the model and the goodness of fit of the model were based on a significant change in the log likelihood of the model (e.g., -2 LL) (17
). Only variables with a significant change are reported, and the probability of MP was calculated from the estimated OR after comparison with the observed probability. Differences were considered significant at P < 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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0.36, representing marginal VA deficiency.2 Half were allocated to receive VA supplements. At baseline, marginally VA-deficient measles patients had significantly lower serum retinol concentrations and RBP/TTR ratios and significantly higher serum CRP concentrations than VA-sufficient children. However the VA and placebo treatment groups did not differ (Table 1
).
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). At the 2-wk evaluation, marginally VA-deficient measles patients receiving VA supplements had significantly higher serum retinol concentrations than those receiving placebo (Fig. 1
A). In VA-sufficient children, the treatment groups did not differ (Fig. 1
A) but serum retinol concentrations increased from baseline to 2-wk evaluation. Serum CRP concentrations decreased by >50% from the baseline to the 2-wk evaluation; however, the distribution of CRP at 2-wk did not differ due to treatment or baseline VA status (Fig. 1
B). The distribution of RBP/TTR values among the groups paralleled those of serum retinol concentrations (Fig. 1C)
.
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). In VA-sufficient measles patients, the proportion of patients with MP was significantly lower in those receiving placebo compared with those receiving VA supplements. A longitudinal analysis showed that the probability of unresolved MP in marginally VA-deficient children receiving VA supplements was 30% (n = 20), and for those receiving placebo, 68% (n = 19) with an OR of 0.20 [95% confidence interval (CI), 0.05–0.71]. On the other hand, the probability of unresolved pneumonia in VA-sufficient children receiving VA supplements was 58% (n = 19), and in those receiving placebo, 32% (n = 19), with an OR of 3.0 (95% CI, 0.80–11.2).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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). In other areas of the world, however, an estimated 30 million cases and 875,000 deaths are attributed to measles infection yearly, representing 10% of all deaths in children under the age of 5 y (18
). In Zambia, measles infection is one of the five major causes of morbidity and mortality among children <5 y, and the measles case-fatality rate is still high at 2%, even though there is high rate of vaccination (72–93%) (19
). In March 2001, the World Health Organization (WHO)/United Nations Children’s Fund Global Strategy Plan established specific goals for reducing global measles deaths that included improving measles case management. This is important because prophylactic efficacy of antibiotics to reduce mortality has not yet been determined (20
), whereas the efficacy of VA supplements was demonstrated more than a decade ago (5
), although its mechanism of action is not yet known.
A recent review suggested that both VA deficiency and measles virus reduce synergistically the host’s immune system and thus might enhance the risk of secondary infection (21
). The author cautioned that no definitive conclusion could yet be reached because the inflammatory response of measles infection makes it difficult to confirm the effects of VA supplements on serum retinol. Therefore it is not possible to confirm the VA status of infected children (21
).
In an earlier analysis of these data, no effect of VA supplements was found based on the concentration of serum retinol (13
). More important, cross-sectional and longitudinal analyses showed no efficacy of VA-supplements in reducing MP by the 2-wk evaluation (13
). In the present analysis, only marginally VA-deficient children receiving placebo did not have increased serum retinol concentrations at the 2-wk evaluation. In the remaining groups, an increase in serum retinol was not attributed to a reduction of inflammation alone because serum CRP concentrations did not differ among the four groups (Fig. 1B)
. Therefore these results indicate that VA supplements increased serum retinol concentrations of marginally VA-deficient measles patients, whereas in VA-sufficient measles patients, an increase in serum retinol was most likely because of amelioration of inflammation. The response of circulating retinol to VA from supplements or diet has been demonstrated to depend on hepatic VA stores (22
). In VA deficiency, absorbed VA is immediately (i.e., within 5–6 h postprandial) transferred from the liver into plasma for utilization by peripheral tissues, whereas during VA sufficiency, most VA absorbed is stored in the liver (22
).
Cross-sectional and longitudinal analyses indicated that marginal VA deficiency increased the likelihood of unresolved MP from baseline to the 2-wk evaluation. Among children receiving placebo, the OR between marginally VA-deficient and -sufficient children was 2.5 (95% CI, 1.1–5.7), and VA supplementation of deficient children reduced it. In VA-sufficient measles patients, however, VA supplements increased the likelihood of unresolved MP compared with those receiving placebo. Although this difference did not remain significant in the longitudinal analysis, this finding is of public health importance. An increase in cough or pneumonia in well-nourished or healthy children receiving VA supplements has been reported in Indonesia, Peru, Ecuador and Tanzania (23
–26
). It has been shown that lung tissue has an independent capacity to store VA due to the presence of lecithin:retinol acyltransferase (27
). The activity of this enzyme decreases during chronic VA deficiency, but it can be restored within 18 h of receiving VA from the diet or supplements (27
). In VA-sufficient rats, lung tissue retinyl ester concentrations increased up to twofold after a large dose of VA (28
), indicating that VA status regulates the amount of VA in lung tissue. Whether an increase in retinyl esters enhances the risk of cough or pneumonia requires further research; however, these observations emphasize the need to determine the VA status of populations to effectively provide VA supplements. In summary, the present analysis indicates that marginal VA deficiency at the time of measles effervescence determined the efficacy of VA supplements.
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FOOTNOTES |
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Manuscript received 24 May 2002. Initial review completed 5 July 2002. Revision accepted 21 September 2002.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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1. Fawzi, W. W., Chalmers, T. C., Herrera, M. G. & Mosteller, F. (1993) Vitamin A supplementation and child mortality. A meta-analysis. J. Am. Med. Assoc. 269:898-903.
2. Taylor, C. E. & Higgs, E. S. (2000) Micronutrients and infectious diseases: thoughts on integration of mechanistic approaches into micronutrient research. J. Infect. Dis. 182:S1-S4.
3. Markowitz, L. E., Nzilambi, N., Driskell, W. J., Sension, M. G., Rovira, E. Z., Nieburg, P. & Ryder, R. W. (1989) Vitamin A levels and mortality among hospitalized measles patients, Kinshasa, Zaire. J. Trop. Pediatr. 35:109-112.
4. Frieden, T. R., Sowell, A. L., Henning, K. J., Huff, D. L. & Gunn, R. A. (1992) Vitamin A levels and severity of measles. New York City. Am. J. Dis. Child. 146:182-186.
5. Hussey, G. D. & Klein, M. (1990) A randomized, controlled trial of vitamin A in children with severe measles. N. Engl. J. Med. 323:160-164.[Abstract]
6. Coutsoudis, A., Coovadia, H. M., Broughton, M., Salisbury, R. T. & Elson, I. (1991) Micronutrient utilisation during measles treated with vitamin A or placebo. Int. J. Vitam. Nutr. Res. 61:199-204.[Medline]
7. Sommer, A. (1997) Vitamin A prophylaxis. Arch. Dis. Child. 77:191-194.
8. Dollimore, N., Cutts, F., Blinka, F. N., Ross, D. A., Morris, S. S. & Smith, P. H. (1997) Measles incidence, case fatality, and delayed mortality in children with or without vitamin A supplementation in rural Ghana. Am. J. Epidemiol. 146:646-654.
9. Rosales, F. J. & Kjohede, C. L. (1992) Low vitamin A during measles. Am. J. Dis. Child. 146:1133-1134.
10. Rosales, F. J. & Ross, A. C. (1998) A low molar ratio of retinol binding protein to transthyretin indicates vitamin A deficiency during inflammation: studies in rats and a posteriori analysis of vitamin A-supplemented children with measles. J. Nutr. 128:1681-1687.
11. Rosales, F. J., Chau, K., Haskell, M. J. & Shankar, A. H. (2002) Determination of a cutoff value for the molar ratio of retinol-binding protein to transthyretin (RBP:TTR) in Bangladeshi patients with low hepatic vitamin A stores 2002(accepted, J. Nutr., August 2002).
12. Rosales, F. J. & Kjohede, C. L. (1994) A single 210-mmol oral dose of retinol does not enhance the immune response in children with measles. J. Nutr. 124:1604-1614.
13. Rosales, F. J., Kjolhede, C. & Goodman, S. (1996) Efficacy of a single oral dose of 200,000 IU of oil-soluble vitamin A in measles-associated morbidity. Am. J. Epidemiol. 143:413-422.
14. World Health Organization (1990) Acute Respiratory Infections in Children: Case Management in Small Hospitals in Developing Countries. Programme for the Control of Acute Respiratory Infections 1990 World Health Organization Geneva, Switzerland.
15. Rossner, B. (1986) Fundamental of Biostatistics 1986:278-293 Duxbury Press Boston .
16. Ware, J. H., Lipsitz, S. & Speizer, F. E. (1988) Issues in the analysis of repeated categorical outcomes. Stat. Med. 7:95-107.[Medline]
17. Hosmer, D. W. & Lemeshow, S. (1989) Applied Logistic Regression 1989 John Wiley and Sons New York.
18. Papania, M. & Redd, S. (2002) Measles United States (2000). M.M.W.R. 51:120-123.[Medline]
19. Mtoga, A., Nyrenda, J. & Banda, M. (2001) Measles incidence before and after supplementary vaccination activities–Lusaka, Zambia, 1996–2000. M.M.W.R. 50:513-517.[Medline]
20. Chalmers, I. (2002) Why we need to know whether prophylactic antibiotics can reduce measles-related morbidity. Pediatrics 109:312-315.
21. West, C. E. (2000) Vitamin A and measles. Nutr. Rev. 58:S46-S54.[Medline]
22. Blomhoff, R., Green, M. H., Green, J. B., Berg, T. & Norum, K. R. (1991) Vitamin A metabolism: new perspectives on absorption, transport, and storage. Physiol. Rev. 71:951-990.
23. Dibley, M. J., Sadjimin, T., Kjolhede, C. L. & Moulton, L. H. (1996) Vitamin A supplementation fails to reduce incidence of acute respiratory illness and diarrhea in preschool-age Indonesian children. J. Nutr. 126:434-442.
24. Stephensen, C. B., Franchi, L. M., Hernandez, H., Campos, M., Gilman, R. H. & Alvarez, J. O. (1998) Adverse effects of high-dose vitamin A supplements in children hospitalized with pneumonia. Pediatrics 101:E3.
25. Sempértegui, F., Estrella, B., Camaniero, V., Betancourt, V., Izurieta, R., Ortiz, W., Fiallo, E., Troya, S., Rodriguez, A. & Griffiths, J. K. (1999) The beneficial effects of weekly low-dose vitamin A supplementation on acute lower respiratory infections and diarrhea in Ecuadorian children. Pediatrics 104:E1.
26. Fawzi, W. W., Mbise, R., Spiegelman, D., Fataki, M., Hertzmark, E. & Ndossi, G. (2000) Vitamin A supplements and diarrheal and respiratory tract infections among children in Dar es Salaam, Tanzania. J. Pediatr. 137:660-667.[Medline]
27. Zolfaghari, R. & Ross, A. C. (2002) Lecithin-retinol acyltransferase expression is regulated by dietary vitamin A and exogenous retinoic acid in the lung of adult rats. J. Nutr. 132:1160-1164.
28. Nagy, N. E., Holven, K. B., Roos, N., Senoo, H., Kojima, N., Norum, K. R. & Bloomhoff, R. (1997) Storage of vitamin A in extrahepatic stellate cells in normal rats. J. Lipid Res. 38:645-658.[Abstract]
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