1 Pediatric Infectious Disease Unit, Soroka University Medical Center, Beer Sheva, Israel
2 Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
3 S. Daniel Abraham International Center for Health and Nutrition, Beer Sheva, Israel
4 Current affiliation: Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD
5 Epidemiology and Health Services Evaluation Department, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
6 Department of Pediatrics, Soroka University Medical Center/Ben-Gurion University of the Negev, Beer Sheva, Israel
7 Department of Radiology, Hadassah University Medical Center, Jerusalem, Israel
Correspondence to Dr. Christian L. Coles, Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, 615 North Wolfe Street, E5545, Baltimore, MD 21205 (e-mail: ccoles{at}jhsph.edu).
Received for publication January 31, 2005. Accepted for publication June 14, 2005.
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ABSTRACT |
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anemia; diarrhea; micronutrients; nutritional status; pneumonia; risk factors
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INTRODUCTION |
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In the Negev region of southern Israel, Jews and Arab Bedouins live side by side. Unlike the more westernized Jewish population, the Bedouins are a minority population in transition from a seminomadic to a settled lifestyle. Overcrowding, low educational levels, low socioeconomic status, and high fertility rates are prevalent among the Bedouins (3). Pneumonia is an important cause of morbidity among Israeli-Bedouins and Jewish children under 5 years of age (4
, 5
), and rates of hospitalizations and severity of pneumonia among Bedouin children are significantly greater than those among Jewish children (5
). Both populations experience a winter peak in pneumonia; however, in Bedouins, a second peak occurs during the summer months (4
, 5
). Poor nutrition and diarrheal hospitalization rates are three times greater among Bedouins than among Jewish children (5
, 6
).
The synergistic effect of poor nutritional status and diarrhea on immunity to infection has been well described (7). Poor nutrition adversely affects a child's ability to resist or respond to infection, and infection adversely affects a child's appetite and ability to effectively use energy and nutrients obtained from the diet. The extent to which immunity is impaired is likely to vary with seasonal nutrient intake and distribution of infectious diseases. Low birth weight, underweight, and lack of breastfeeding have been identified as risk factors for pneumonia (8
, 9
). However, there is a paucity of data regarding the link between micronutrients that help regulate immune function and pneumonia.
Results of meta-analyses indicate that vitamin A supplementation has no beneficial impact on the incidence of clinically defined pneumonia (10, 11
). Yet, it has been shown that vitamin A supplementation delayed the age at which nasopharyngeal pneumococcal colonization occurred and reduced the risk of early carriage in children with vitamin A deficiency (12
). Low vitamin A status may result in greater bacterial adherence and colonization and therefore may increase the risk of bacterial infections, including pneumonia (13
). Vitamin A and zinc deficiencies can result as a consequence of the "malnutrition-diarrhea" cycle (14
, 15
), which is associated with increased risk of respiratory infections (15
, 16
). Seasonal patterns of diarrhea and pneumonia hospitalizations in Jewish and Bedouin children (4
, 5
) are consistent with this observation.
A finding that poor nutrition and/or diarrhea are independent risk factors for pneumonia could have important implications for the development of community-based pneumonia prevention programs, with the potential to provide cost-effective approaches to lowering pneumonia risk, serving as adjuncts to vaccination. Such an association may also suggest that vaccines developed to prevent diarrheal infections may also help protect children against pneumonia.
The PNEUMOVIT study was a population-based, prospective, case-control study designed to evaluate the influence of nutritional factors and prior diarrheal illness on the risk of community-acquired alveolar pneumonia (CAAP) in young Bedouin children living in southern Israel.
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MATERIALS AND METHODS |
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Currently, the best available method for diagnosing pneumonia is radiography. In general, the evidence supports the finding that an alveolar or lobar infiltrate with air bronchogram is an insensitive, but fairly specific indication of bacterial pneumonia, the predominant bacterial pathogen being S. pneumoniae (2, 18
, 19
). Therefore, we included only alveolar pneumonia cases in the study to maximize the probability of selection of bacterial pneumonia, in particular S. pneumoniae.
Identification and ascertainment of CAAP
All Bedouin children under 5 years of age visiting the pediatric emergency room of the Soroka University Medical Centers (the only hospital in the Negev region) with radiographically confirmed CAAP between November 4, 2001, and November 26, 2002, for whom a diarrheal history for the preceding 31 days could be obtained, were eligible. Therefore, the cases represent the general population of young Bedouin children with CAAP. The eligible population included all ambulatory and hospitalized Bedouins less than 5 years of age visiting the medical center with radiographically confirmed CAAP.
Cases were identified prospectively. On a daily basis, all pediatric chest radiographs (anteroposterior and lateral) from children less than 5 years of age in the pediatric emergency room, pediatric wards, and pediatric intensive care unit were stored electronically for reading through a computerized, high-resolution radiograph screen. Radiographs were initially read by two study pediatric infectious disease physicians and were classified as indicating either alveolar pneumonia, nonalveolar pneumonia, or no pneumonia according to the World Health Organization criteria for standardization of interpretation of chest radiographs for the diagnosis of pneumonia (20).
For each radiograph identified as exhibiting alveolar pneumonia by at least one of the pediatric infectious disease physicians, the next radiograph classified by the pediatricians as "pneumonia free" was added (control radiograph). Radiographs for all cases and controls were mixed, and the study pediatric radiologist read all radiographs unaware of the pediatricians' diagnosis. Only cases of alveolar pneumonia confirmed by the radiologist were included in the analysis. Cases were excluded from the study if the radiograph was lost or unreadable, if the radiograph was performed more than 48 hours after the case was hospitalized (to be consistent with community-acquired infection), or if a diagnosis other than infectious pneumonia explained the endpoint consolidation (e.g., kerosene ingestion, tumor).
Selection of controls
Controls were healthy Bedouin children less than 5 years of age seen for a regular checkup examination who had not been diagnosed or treated for pneumonia in the previous 28 days. These children were from two maternal/child health clinics in the Negev and were matched on age (±3 months) and month of enrollment. An attempt was made to individually match at least one control per case. The clinics for enrollment of controls were selected to represent the distribution of births from established settlements and rural encampments.
Ethical review
The research protocol was approved by the Institutional Review Board of the Soroka University Medical Center/Ben-Gurion University of the Negev, Beer Sheva, Israel. Provision of written informed consent from a parent or guardian was required for enrollment in the study.
Data collection
Following enrollment, trained interviewers used a standardized questionnaire to elicit information from parents/guardians on the child's diarrhea and respiratory illness history, health status, socioeconomic status, demographic data, and household/environmental exposures. Birth weight was obtained from birth certificates or hospital records. A child's weight and height, as well as mid-upper arm and head circumference, were measured by trained staff members. Anthropometric techniques were standardized according to the World Health Organization procedures. For cases, we used weight measurement from the convalescent visit 24 weeks after enrollment in the analyses because it was more likely to reflect the child's normal weight.
Blood samples
Blood hemoglobin, serum retinol, and plasma zinc levels were measured. Specimens were obtained from controls at enrollment and from cases 24 weeks after enrollment to limit the effect of acute-phase reactions on several of the biochemical indicators (21). For hemoglobin determination, specimens were processed within 6 hours of collection. For vitamin A determination, blood was collected into amber-colored tubes, spun at 3,0004,000 rpm for 10 minutes and transported to the laboratory on ice (04°C), and then frozen at 70°C until further processing. Plasma zinc determination specimens were drawn into trace-element-free, heparinized tubes and centrifuged within 2 hours of collection to prevent leaching of zinc from the red blood cells into the plasma, and they were then frozen at 70°C until processed.
Laboratory assessment
Hemoglobin was measured by using a standard spectrophotometric procedure. Retinol and plasma zinc levels were assessed by using high-pressure liquid chromatography and atomic absorption spectrometry, respectively (22, 23
).
Definitions
Diarrhea was defined as three or more liquid or semiliquid stools per day. A new episode was preceded by three diarrhea-free days. Dichotomous variables were also created to indicate the presence or absence of diarrhea 7 or fewer days and 831 days prior to enrollment. Anemia was defined as a hemoglobin concentration of less than 11.0 g/dl. Children weighing less than 2,500 g at birth were classified as "low birth weight." Subclinical vitamin A deficiency was defined as a serum retinol concentration of less than 20 µg/dl and zinc deficiency as a plasma zinc concentration of less than 60 µg/dl. We calculated z scores for stunting, wasting, and underweight by using World Health Organization/National Center for Health Statistics reference population data, and z scores were calculated for anthropometric measures (EpiInfo 6.04; Centers for Disease Control and Prevention, Atlanta, Georgia). Stunting was defined as a z score 2 standard deviations below the mean for length or height for age, wasting was defined as a z score
2 standard deviations below the mean for weight for height, and underweight was defined as a z score
2 standard deviations below the mean for weight for age.
Statistical analysis
We aimed to enroll 380 or more cases and 380 or more controls for a total of 760 children. The sample size had the power to detect an odds ratio of 1.7 or more to test the null hypothesis that nutritional status is not associated with lobar pneumonia ( level = 0.05 (two sided), power = 0.85, estimated correlation coefficient of exposure between cases and controls = 0.2, and estimated prevalence of nutritional deficiency in controls = 20 percent). The estimates were also valid for testing the null hypothesis that diarrhea is not associated with CAAP, assuming diarrhea prevalence among controls to be 20 percent.
Data were analyzed with Stata 8 software (Stata Corporation, College Station, Texas). Tests for significance were performed on selected variables between cases and controls by using t tests, the two-tailed 2 test, or Fisher's exact test. We were unable to individually match controls to cases on age and month of enrollment for logistic reasons and therefore chose frequency matching. Thus, we used logistic regression models, adjusted for age (in months) and calendar month of enrollment, to evaluate at the univariate level potential risk factors, covariates, and confounders. Variables implicated in the literature or statistically significant at the level of p < 0.1 in the univariate analyses were included in the multivariate logistic regression models. Potential risk factors of interest were then entered into multivariate logistic regression models, adjusting for effects of age at and month of enrollment and corrected for the influence of other significant covariates and confounders. Odds ratios and 95 percent confidence intervals were used to measure the association between exposures and disease status. A p value of <0.05 was considered statistically significant in multivariate analyses.
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RESULTS |
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Univariate analyses
We evaluated the association between CAAP and nutritional status indicators (breastfeeding, low birth weight, stunting, underweight and wasting, and concentrations of hemoglobin, serum retinol, and plasma zinc) and history of diarrhea in the month before enrollment. The analyses included continuous and categorical variables and were controlled for age and month of enrollment. Children never breastfed had a twofold greater risk of CAAP compared with children who had been breastfed (table 4). Similarly, the odds of CAAP for low-birth-weight children were more than 2.5 greater than those for children of normal birth weight. Stunting also increased CAAP risk by approximately 2.5 times. In addition, underweight children had double the risk of developing CAAP. The relative odds of CAAP was approximately three times greater for anemic children than for children whose hemoglobin values were normal. Vitamin A deficiency status showed no significant association with alveolar pneumonia. Yet, when analyzed as a continuous variable, higher serum retinol concentrations were associated with an increased risk of CAAP (adjusted odds ratio (AOR) = 1.02 per µg/dl, 95 percent confidence interval (CI): 1.01, 1.04; p = 0.001). Neither zinc deficiency status nor plasma zinc concentration was associated with the risk of CAAP. The CAAP risk was doubled for children who had one or more diarrhea episodes between 8 and 31 days before the day of enrollment compared with those children who were diarrhea free. The strongest association between diarrhea and CAAP was during the winter months (AOR = 3.90, 95 percent CI: 1.00, 15.23; p = 0.05), when the frequency of CAAP cases peaked. There was no significant association between diarrhea occurring within 7 days of enrollment and risk of CAAP.
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DISCUSSION |
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Anemia significantly increased the risk of CAAP in Bedouin children. Few studies have evaluated anemia; of these, several found that anemia was a risk factor for lower respiratory tract infections including pneumonia (25, 26
). Determining the cause of anemia in this setting is important for the development of effective strategies for reducing anemia, which may subsequently decrease the risk of pneumonia in this population.
Several studies conducted in developing countries have identified poor zinc and vitamin A status as risk factors for lower respiratory tract infections and pneumonia (15, 16
). Our results indicate that zinc status did not influence the risk of CAAP. This finding may be due to the relatively low prevalence of zinc deficiency in the Bedouin community. Surprisingly, we found that elevated serum retinol concentrations were significantly associated with increased risk of pneumonia. This risk was greatest in the quartile of children with the highest serum retinol concentration. Observational studies conducted in the 1980s and 1990s reported that children with clinical vitamin A deficiency were at increased risk of clinically diagnosed lower respiratory tract infection (16
, 27
). However, we used radiologic definition supplemented by clinical signs and symptoms, unlike the previous studies, raising the possibility that the role of vitamin A in the risk of pneumonia may depend on the outcome definition and on whether retinol concentration is outside of some as-yet-undetermined critical range.
Currently, there is little information on the impact of vitamin A on bacterial infections. Laboratory studies suggest that vitamin A deficiency results in impaired antibody-mediated immunity and barrier defenses (28). Yet, other than the clear impact of vitamin A supplementation on the prevention of measles-related pneumonia (29
, 30
), there is general agreement from clinical trial data that vitamin A supplements have no beneficial effect on the prevention of clinical pneumonia (10
, 11
). Moreover, results from several recent trials showed that vitamin A supplementation significantly increased the risk of lower respiratory tract infection in children with adequate retinol stores (31
33
). In addition, adjunctive therapy with high-dose vitamin A supplements for children with pneumonia has been found to have no effect or adverse effects on disease severity (34
37
). These findings raise the possibility that high serum retinol concentrations may directly increase the inflammatory response to infection to inappropriate levels (38
, 39
), or indirectly by amplifying the adverse effects associated with childhood vaccines (40
). Given the low prevalence of vitamin A deficiency and high vaccination coverage in our study population, it is plausible that our observation could represent an analogous situation.
On the basis of the malnutrition-infection cycle described by Scrimshaw and SanGiovanni (7), we had hypothesized that increased frequency of diarrhea would result in poor nutritional status, which in turn might predispose children to pneumonia. Our results indicate that children with diarrhea are at increased risk of CAAP, a finding consistent with our hypothesis. This finding suggests that interventions designed to reduce the risk and severity of diarrhea may have the added benefit of decreasing the risk of severe pneumonia, which may have important implications for the cost-benefit of new diarrheal vaccines, such as the rotavirus vaccines, because their use may potentially reduce the risk of severe pneumonia.
Given that our study was hospital based, one of its potential limitations is that, by including only those cases seen at the pediatric emergency room, our cases are not representative of pediatric CAAP in Bedouin children living in southern Israel. This possibility is unlikely, however, because Soroka University Medical Center serves as the only medical center for southern Israel to which all pneumonia cases are referred. Furthermore, Israel has a centralized health reporting system and there are no financial barriers to receiving health care, facilitating the capture of most, if not all, severe cases of pediatric pneumonia occurring during the study period. In addition, the fact that we conducted a hospital-based study is likely to have resulted in a bias favoring the inclusion of severe pneumonias, which were the focus of our study. The ineligibility of 102 CAAP cases along with the loss of 40 percent of enrolled cases to follow-up may have biased our results and threatened the internal validity of the study. However, our analyses show that the characteristics of the cases included in our analyses were similar to those of the cases who were ineligible or lost to follow-up, with the exception of breastfeeding status and age. Therefore, it is unlikely that these losses would have a significant impact on internal validity. That excluded cases were younger and less likely to be breastfed than the included cases may suggest that the excluded cases were less healthy. If this suggestion is correct, then our results may possibly have underestimated the impact of nutritional status on the risk of CAAP.
Recall bias related to recording of diarrhea histories is another potential limitation. It is possible that parents of cases were more likely to remember an episode of diarrhea than were parents of healthy children, yet our data show that while the monthly prevalence of diarrhea was significantly higher in CAAP children, the prevalence of diarrhea in the week prior to enrollment was comparable between groups. In contrast, the weekly prevalence of other recorded symptoms of illness (e.g., cough, fever) was higher in the CAAP group while the monthly prevalence of these symptoms was similar in the two groups. Therefore, our findings are unlikely to have been influenced by differential recall bias.
We have identified potentially modifiable factors that may contribute to the high incidence of alveolar CAAP in the Bedouin children living in southern Israel: anemia, stunting, and low birth weight. Development and implementation of effective antenatal and nutritional intervention programs for children and community-based educational programs for mothers are likely to improve all three factors, decreasing the risk of pneumonia. More research is needed on the causes of anemia in this community to determine whether they are amenable to nutritional intervention. Furthermore, more research is needed to delineate the effect of elevated vitamin A concentrations on the risk of CAAP. In addition, our results suggest that interventions designed to control diarrhea, including vaccines to address the causes of diarrhea, may help to reduce the risk of severe pneumonia.
Although poor nutrition is a major problem for Bedouin children, the problem is much less severe than what is often observed in less developed countries. However, our findings underscore the fact that even poor nutrition or marginal malnutrition can predispose children to alveolar pneumonia. While this information has important implications for children in transitional populations, it also suggests that children with more severe forms of malnutrition and diarrhea are at greater risk of alveolar pneumonia.
Conjugate Haemophilus influenzae b vaccines prevent the occurrence of pneumonia, and the recently introduced pneumococcal conjugate vaccines may further prevent invasive pneumococcal disease in children under the age of 3 years (41, 42
). However, the expensive pneumococcal conjugate vaccines are not expected to be widely used in developing countries, at least not in the next decade. Furthermore, recent evidence from clinical trials indicates that the pneumococcal conjugate vaccines prevent less than 20 percent of the cases of alveolar pneumonia in children under 2 years of age and may not lower the rate in older children, presumably because of the limited number of pneumococcal serotypes included in the vaccines and potential replacement disease with serotypes not included in the vaccines (43
, 44
). Therefore, although their use may potentially impact morbidity, a considerable disease burden associated with pneumonia will still prevail in developing countries. Universal measures such as improving general health, improving nutrition, and providing health education and vaccination against enteric infections should be emphasized as potentially important measures to reduce the burden of pneumonia in children.
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ACKNOWLEDGMENTS |
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References |
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