Archives of Medical Research 33 (2002) 180185

ORIGINAL ARTICLE

Frequency and Determinants of Vitamin A Deficiency in Children Under 5 Years of Age with Pneumonia
Hortensia Reyes,a Salvador Villalpando,b Ricardo Prez-Cuevas,a Leticia Rodrguez,a Miriam Prez-Cuevas,c Irene Montalvob and Hctor Guiscafra
a

Unidad de Investigacin Epidemiolgica y Servicios de Salud, Centro Mdico Nacional Siglo XXI (CMN-SXXI), Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico b Unidad de Investigacin Mdica en Nutricin, Hospital de Pediatra, CMN-SXXI, IMSS, Mexico City, Mexico c Departamento de Medicina Familiar, Hospital General de Zona #1, IMSS, Pachuca, Hidalgo, Mexico Received for publication March 27, 2001; accepted August 27, 2001 (01/044).

Background. Vitamin A deficiency (VAD) has been closely related to acute respiratory infections (ARI), although information is still incomplete; for example, the frequency of VAD in children 5 years of age with pneumonia is not known, and the conditions associated with VAD have not been identified. This study was conducted to gain insight into the status of vitamin A in children with pneumonia. A secondary objective was to identify the sociodemographic, individual, and nutritional factors associated with VAD in these children. Methods. A cross-sectional study was conducted in the Mexican state of Hidalgo, one of the poorest in the country. Children with community-acquired pneumonia treated at nine public hospitals were included. Information was obtained by interviewing mothers, and ascertainment of vitamin A status was performed with relative-dose-response (RDR) test. Results. A total of 422 cases were included. VAD was identified in 17.8% of children; 50.3% showed normal results, 24.6% had liver reserve depletion, and 7.3% showed results attributable to the infectious process. Variables associated with VAD were as follows: age 2 months (OR 3.44, 95% CI: 1.849.24); children 6 months of age fed with formula (OR 0.37, 95% CI: 0.150.91), and affiliation with the Mexican Social Security Institute (IMSS) health system (OR 0.40, 95% CI: 0.220.72). Conclusions. The frequency of VAD in children with community-acquired pneumonia confirms that the problem of deficiency persists in Mexico. The associated factors for VAD found in this study can be taken into account when planning and evaluating vitamin A supplementation activities in populations with high risk for deficiency. 2002 IMSS. Published by Elsevier Science Inc.
Key Words: Vitamin A deficiency, Pneumonia, Children, Relative-dose-response test, Risk factors.

Introduction Vitamin A deficiency (VAD) has been extensively studied as a risk factor for childhood mortality (14). Xerophthalmia, a sign of severe vitamin A deficiency, has been identified as
Address reprint requests to: Hortensia Reyes, M.D., M.Sc., Unidad de Investigacin Epidemiolgica y Servicios de Salud, CMNSXXI, IMSS, Av. Cuauhtmoc #330, Col. Doctores, 06725 Mxico, D.F., Mxico. Tel.: ( 52) (55) 5627-6900, ext. 5407; FAX: ( 52) (55) 5761-0952; E-mail: reymh@ webtelmex. net.mx

an important determinant of child mortality (5). In communities with a high prevalence of xerophthalmia, vitamin A supplementation has successfully reduced both overall and specific mortality attributable to measles and diarrhea in children 5 years of age (68). However, no positive impact of vitamin A supplementation has been demonstrated either on mortality due to pneumonia or on the prevalence or incidence of this disease (9). Marginal vitamin A deficiency or subclinical deficiency is likewise in question. Subclinical deficiency has been related to increased overall

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morbidity and mortality, although information is not yet conclusive (10,11). Subclinical deficiency can be defined as low liver reserves of vitamin A without clinically evident manifestations and retinol serum levels between 0.35 and 0.70 mol/ L (1020 g/dL). Severe deficiency, usually associated with ocular signs, is more frequent in subjects showing serum retinol levels 0.35 mol/L (10 g/dL) (12). Assessing vitamin A status in sick children is difficult, mainly because serum retinol, the recommended indicator of vitamin A status, decreases during systemic infections such as pneumonia or septicemia regardless of the quantity of the tissue reserves; thus, under these conditions serum retinol does not reflect the actual vitamin A status (5). A suitable alternative is the relative-dose-response (RDR) test. This technique allows indirect estimation of the liver reserves of vitamin A, which are independent of circulating levels of retinol. RDR test is based upon the assumption that when liver reserves are depleted, release of stored vitamin A decreases, but synthesis of the retinol-binding-protein (RBP), the main transporter of vitamin A, continues. As a consequence, RBP is accumulated in the liver as hepatic apo-RBP. When exogenous retinol or retinyl is administered, accumulated apoRBP in the liver is released to circulation, increasing levels of circulating vitamin A. The proportional increment is assessed by measuring serum levels of retinol before and after exogenous retinol administration. An increment 20% is indicative of low liver reserves of retinol (13). RDR testing is useful for evaluating chronic deficiencies of vitamin A, even in patients in whom circulating levels are altered by an acute episode of infection (14). In Mexico, severe vitamin A deficiency has not been documented; however, the frequency of subclinical VAD in children with pneumonia is not known. Pneumonia is the main cause of death (15) and hospitalization in children 5 years of age. Furthermore, conditions that may increase the risk of developing VAD in this age groupor that may afford protection against ithave yet to be identified. This study was designed to assess the frequency and distribution of VAD in children 5 years of age with pneumonia. The main objective was to test the hypothesis that provided a reliable method is employed to measure vitamin A statusa high frequency of VAD and a significant number of cases with depletion of liver reserves among children with pneumonia can be shown to exist. Additionally, an ancillary objective was to identify sociodemographic, individual, and nutritional factors associated with VAD.

The study was carried out in the state of Hidalgo, one of the poorest in Mexico. In this state, 98% of communities have fewer than 2,500 inhabitants, and two thirds of the work force earns less than $4 U.S. dollars per day. The following three main public health care systems provide care to the people of Hidalgo: the Mexican Institute of Social Security (IMSS), which provides services to formally employed workers and their families; the Ministry of Health (SSA), which provides services to persons not enrolled in the IMSS (a principally poor population), and the IMSSSolidarity Program, which provides health care to people living in rural areas of extreme poverty. The SSA and IMSS-Solidarity Program cover roughly 70% of the population (16). Thus, affiliation with a particular health care system is synonymous with socioeconomic status, IMSS being the highest on the scale and IMSS-Solidarity the lowest. Sampling design. Children admitted to the participating hospitals with a diagnosis of community-acquired pneumonia were included. Nine hospitals participated in the study, three from IMSS, four from SSA, and two from the IMSSSolidarity Program. Pneumonia was defined (17) as fever, cough, and at least two respiratory distress signs, including the following: tachypnea (respiratory rate 60, 50, and 40 breaths/min in children 2 months of age, between 2 and 12 months of age, and 12 months of age, respectively), and nasal flaring or intercostal retractions with less than 72 h of evolution. Patients having major congenital malformations or neurologic damage were not included in the study. Selected children were enrolled within the first 6 h after admission once a participating physician confirmed the diagnosis clinically and radiologically. After explaining the goals and procedures of the project to parents or caregivers, a previously trained nurse obtained written informed consent to participate (Institutional Scientific Commission protocol approval, January 10, 1996). The nurse then interviewed the mother to obtain information concerning study variables, performed anthropometric measurements, and carried out the RDR test. One nurse per hospital and one supervising nurse who oversaw the entire process participated in the study. Study variables. The following variables were recorded: age; sex; birth weight; medical history; immunizations; parents literacy and work status; place of residence (urban or rural), and household characteristics. Anthropometric and dietary evaluation. Infants were weighed on a scale with 10 g precision; length was measured with an infant rod having a precision of 1 mm. Weight for height and height for age were calculated using as a reference the National Center for Health Statistics data (18). Values were expressed as Z scores and nutritional status classified according to the Waterlow criteria (19). Each mother gave information concerning whether on the last day before the child became illin her judgmenthe/she consumed breast

Materials and Methods A cross-sectional comparative study was conducted between October 1997 and September 1998 in children from 1 month to 5 years of age suffering from community-acquired pneumonia.

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milk, formula, or cows milk, and whether other foods in addition to milk had been introduced into their diets. RDR procedure and interpretation. A venous blood sample was drawn by venipuncture within the first 24 h after hospital admission. The child immediately was given orally 450 g retinol equivalents such as retinol palmitate in oil. Five hours after dosing, a second blood sample was drawn. Blood samples were centrifuged and serum separated and stored in amber tubes to protect it from light. The samples were then refrigerated at 4 C during a period no longer than 4 h and subsequently frozen at 17 C. All-trans-retinol concentration was determined in serum samples by high performance liquid chromatography, using a Bondapok C18 column with a mobile phase of ethanol/water 95/5 after extraction with ethanol/hexane, and adding an internal standard of retinol palmitate of a known concentration (20). The results of the RDR test were obtained by using the following formula: RDR = A 5 A 0 A 5 100, where A0 basal concentration of retinol A5 retinol concentration in the sample obtained 5 h after dose A result to or 20% was considered positive for retinol depletion (21). Vitamin A nutritional status was graded as follows: normal baseline retinol or 20 g/dL and negative RDR test result; deficiency baseline retinol 20 g/dL and positive RDR test result; liver reserve depletion baseline retinol within normal parameters and positive RDR test result; and modification secondary to the infectious process baseline retinol 20 g/dL and negative RDR test result. Statistical analysis. Descriptive statistics were used to ascertain the frequency of vitamin A deficiency. To analyze the risk factors for VAD, comparisons were made between the deficiency group and the normal group. To avoid the risk of misclassification (see previously mentioned classification), the remainder of the groups was not taken into account. Bivariate analysis was conducted to estimate the relative risk for deficiency. This was done by calculating odds ratio (OR) and corresponding 95% confidence interval (95% CI). Subsequently, an unconditional logistic regression model was constructed. Variables found to be statistically significant in bivariate analysis were included in the model. Correlation and interaction terms were also calculated. The purpose of logistic regression analysis was to obtain an explanatory model for vitamin A deficiency (22). Analysis was conducted using the statistical packages SPSS (SPSS Professional Statistics 7.5, SPSS, Inc., 1997) and STATA (STATA statistical software; Release 5.0, Stata Corporation, 1997).

Results During the study period, 422 cases met the inclusion criteria; vitamin A determination and RDR test were available for them. Some characteristics of the sample are presented in Table 1. Approximately one half of the children in the sample were 1 year of age. A discrete predominance of male children was observed and birth-weight mean was 3 kg. Sixty percent of children 1 year of age were breast-fed; the same proportion had had solid food introduced into their diet. Forty percent were formula-fed, either exclusively or in combination with breast milk. Nutritional status was assessed on the basis of weight for height. This was found to be inadequate in 24% of cases; the same proportion of children was stunted according to the height-for-age indicator. With regard to the type of hospital to which the children were admitted, 47% were affiliated/registered with the IMSS, while the remainder received care from the SSA or IMSS-Solidarity. One third of the children came from communities having 2,500 inhabitants. Parents average schooling was reported as 6 years. Thirty-nine percent of children had a previous history of acute upper respiratory infections (ARI) and 67% had received the full immunization scheme according to age. RDR test results showed that 17.8% of children had VAD, 50.3% were normal, 24.6% had liver reserve depletion, and 7.3% showed results that could be attributable to the infectious process (Table 2). According to RDR test, it

Table 1. Characteristics of children with pneumonia % 422

Characteristic Age 1 2 months 2 12 months 13 24 months 24 months Gender Male Birth weight Mean (SD) Type of feeding Formula Breastfeeding (children 1 year of age) Weaning (children 1 year of age) Nutritional status Weight for height Normal Wasting Height for age Normal Stunting History of acute upper respiratory infections Complete immunization scheme Type of hospital in which the child received care Mexican Institute of Social Security Ministry of Health or IMSS-Solidarity Residence in rural community ( 2,500 inhabitants) Parents schooling (years) median (interval)

10.0 45.0 27.5 17.5 59.2 2,935.4 g (766.7) 40.0 60.9 56.0

75.2 24.8 76.1 23.9 38.6 67.0 46.7 53.3 37.9 6 (018)

Vitamin A Deficiency in Children with Pneumonia Table 2. Vitamin A status according to serum levels of retinol and relative-dose-response (RDR) test in children with pneumonia Vitamin A status Baseline serum levels 20 g/dL, and Positive RDR testa (marginal vitamin A deficiency) Negative RDR test (modification secondary to infectious process) Baseline serum levels 20 g/dL or higher, and Positive RDR testa (liver reserve depletion) Negative RDR test (normal)
a

183

Table 4. Variables associated with vitamin A deficiency in children with pneumonia, multivariate analysisa % 25.1 17.8 7.3 74.9 24.6 50.3 Variable Age 2 months Affiliation with IMSS Children 6 months of age fed with formula
a

n 106 75 31 316 104 212

Odds ratio 3.44 0.40 0.37

95% CI 1.84 9.24 0.220.72 0.250.91

p value 0.001 0.002 0.03

Unconditional logistic regression analysis.

Serum levels of retinol 20% of 450 g of retinol.

baseline levels, after 5 h of administration

was possible to define as deficient 71% of children having low baseline retinol levels. In addition, 33% of children with normal baseline retinol levels were identified as depleted. To ascertain the risk of VAD, patients found to have a deficiency (75) were compared with patients considered normal (212). The power of this sample was 80%, with a 90% CI to detect a minimum risk of 2.4 (23). Table 3 shows the variables and their corresponding crude risks (statistically significant) for VAD, as follows: age 2 months of age; using formula to feed children 6 months; being affiliated with the IMSS; father being a subsistence farmer, and being unweaned. Neither correlation nor interaction was found among these variables. Table 4 shows the best-fit explanatory model for risk of vitamin A deficiency. The final model included the following covariates: age 2 months (OR 3.44, 95% CI: 1.84 9.24); children 6 months of age fed with formula (OR 0.37, 95% CI 0.150.91), and being IMSS-affiliated (OR 0.40, 95% CI: 0.220.72).

Discussion The role of vitamin A in the pathophysiology of respiratory tract infections has been extensively studied; nevertheless, methodologic and technical obstacles to ascertaining vitamin A status under such conditions still remain to be overcome. An important weakness in the process of classifying VAD in children with pneumonia has been the use of serum retinol or plasma retinol binding protein (RBP) as indicator.

The rationale behind this statement is that during an acute infection, serum levels of vitamin A and RBP can decrease; thus, this measure overestimates deficiency. There are several hypotheses that seek to explain why vitamin A serum levels decrease in children with acute infections, including the following: 1) vitamin A is closely related to the restoration of the tracheo-bronchial epithelium during the infectious process and its consumption is increased; 2) during the infectious process, vitamin A absorption decreases even with an adequate dietary supply; 3) infection causes an increase of urinary excretion of vitamin A; 4) acute circulatory changes due to systemic stress cause an increase in vitamin A consumption and a reduction of liver mobilization rather than depletion of reserves (24,25), and RBP synthesis declines, thus limiting mobilization of vitamin A. Some authors have suggested RBP production may be reduced during infection, acting similar to albumin as a negative acute-phase reactant (26,27). RDR testing appears more reliable as a means of assessing vitamin A status because it relies on a relative accumulation of RBP that is less affected by the infectious process. When liver reserves are adequate prior to acute infections, it is unlikely that an RBP store has accumulated; thus, the RDR test would be negative. If stores were inadequate prior to acute infection, preformed RDR might be present and available to be mobilized when an external challenge is given, thus resulting in a positive RDR. Therefore, this test conducted on a one-time basis makes it possible to identify the true deficiency regardless of the underlying process. Repeat testing is not valid if done within a short interval that has not allowed RBP to again accumulate in the liver. This study was conducted only in children with pneumonia; thus, this group is not representative of healthy children in the area. However, because most cases consisted of un-

Table 3. Variables associated with vitamin A deficiency in children with pneumonia, bivariate analysis Deficient children n 75 % 20.0 29.3 29.3 34.7 75.0 Normal children n 212 % 7.1 51.9 16.0 22.2 90.8

Variable Age 2 months Affiliated with IMSS Father (farmer/peasant) No weaning Children older than 6 months fed with formula

Odds ratio 3.28 0.38 2.17 1.86 0.38

95% CI 1.517.10 0.210.67 1.714.03 1.043.31 0.240.60

p value 0.005 0.001 0.05 0.05 0.0001

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complicated pneumonia, we can consider that the childrens vitamin A status could not be too different from the status of children residing in the same area. Recently, a national representative survey carried out in Mexico reported that the prevalence of VAD in children 5 years of age is approximately 24% based on serum levels of retinol being slightly higher in poor rural populations (28). Additionally, this survey ascertained the intake of a variety of micronutrients in children 5 years of age by means of a 24-h dietary recall questionnaire; results revealed that the percentage of appropriate intake of vitamin A was 86.3% at the national level, while for the region in which the state of Hidalgo is located it was 63.5% (29). Although our findings showed a lower frequency of VAD, inadequate vitamin A status based on positive RDRs was 40%. Our ascertainment of VAD risk factors highlighted that being 2 months of age was the most important factor when compared with children older than 2 months. This issue has been scarcely analyzed. The majority of studies addressing risk factors for vitamin A deficiency have been conducted in children 6 months of age (30,31). Furthermore, there has been insufficient evidence of the effect of supplementing children 2 months of age with vitamin A, only a few reports documenting a positive impact on morbidity or mortality (32,33). It is possible to assume that the risk of developing VAD in children 2 months of age may be an expression of maternal vitamin A deficiency, especially at the end of pregnancy. Low maternal retinol serum levels have been shown to bear a positive correlation with newborn plasma retinol concentrations, as well as with fetal growth (34,35). This finding has been principally observed in women of low socioeconomic status (36). The recommendation that pregnant women in high-risk populations be supplemented with vitamin A from the early stages of pregnancy, as soon as the risk of teratogenesis is passed, could enjoy theoretical support under this assumption (37). The group of children 6 months of age fed with formula was found to have a lower risk for VAD. Industrialized milk, which is routinely supplemented with vitamins, was the main source of vitamin A in children 1 year of age, even if they had been weaned. In addition, we found no association between duration of breast-feeding or weaning with VAD, despite previous reports that found a protective effect for prolonged breast-feeding (38). Other studies have documented VAD in breast-fed children 6 months of age (39) not receiving sufficient intake of vitamin A from other sources (40,41). This would support the recommendation of strengthening nutrition programs, emphasizing the promotion of vitamin A-rich food farming for self-consumption. Similar strategies have been successful in developing countries (42,43) and are currently part of some Mexican health programs (44). Another strategy could be infant supplementation with vitamin A in addition to other micronutrients frequently deficient in Mexico such as iron, zinc, and vitamin C (26).

In our study, enrollment in the IMSS health care system was identified as a protective factor for VAD. In Mexico, the IMSS system is mainly intended for workers in the formal sector and their families; enrollment in this system is thus associated with a regular income. People with low socioeconomic status are not usually enrolled in the IMSS; they principally receive care from the SSA. Thus, lack of enrollment is regarded as synonymous with poverty. Since 1993, the Mexican government has implemented a highdose vitamin A supplementation program, carried out on a twice-yearly basis, directed at children from 6 months to 5 years of age. This program has been continuous and is focused on deprived areas (45). According to Ministry of Health estimates, by 1999 52% of children living in these areas had received at least one dose of vitamin A (46). We may assume, according to our own findings, that vitamin A supplementation coverage in some communities of the state of Hidalgo is still insufficient and that it would be advisable to strengthen the program. In conclusion, frequency of inadequate status in children with community-acquired pneumonia can be considered an indicator that the problem of deficiency persists in Mexico, particularly in relation to depletion of liver reserves. Furthermore, some of the associated factors for VAD found in this study could well be taken into account when planning and evaluating vitamin A supplementation activities in populations with high risk in terms of marginal deficiency. Acknowledgments
We wish to thank the Public Health Care Institutions of the State of Hidalgo for authorization to obtain information from children and from hospital records. This research was funded by National Council of Science and Technology of Mexico (CONACYT) grant number 0874P-M9506.

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