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Respiratory Symptoms in the First 7 Years of Life and Birth Weight at Term

The PIAMA Birth Cohort

¹ Department of Pediatrics/Respiratory Medicine, Erasmus University, Rotterdam, The Netherlands; ² Departments of Chronic Disease Epidemiology and Infectious Diseases Epidemiology, National Institute of Public Health and the Environment, Bilthoven, The Netherlands; ³ Institute for Risk Assessment Sciences, University of Utrecht, Utrecht, The Netherlands; ⁴ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands; ⁵ Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; ⁶ Centre for Pediatric Allergology, Wilhelmina Children's Hospital, Utrecht, The Netherlands; and ⁷ Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

Correspondence and requests for reprints should be addressed to Prof. dr. J.C. de Jongste, M.D., Ph.D., Erasmus MC/Sophia Children's Hospital, Department of Pediatric Respiratory Medicine, P.O. Box 2060, 3000 CB Rotterdam, The Netherlands E-mail: j.c.dejongste{at}erasmusmc.nl

	ABSTRACT

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Rationale: The relation between birth weight and respiratory symptoms and asthma in children remains unclear. Previous studies focused on a relation at separate ages. A longitudinal analysis may lead to a better understanding.

Objectives: To estimate the effect of birth weight on the development and course of respiratory symptoms and asthma in the first 7 years of life.

Methods: In a prospective birth cohort study, 3,628 children with a gestational age 37 weeks or more were monitored for 7 years. Parental questionnaires were used to assess respiratory health yearly. Associations of birth weight with respiratory symptoms (wheezing, coughing, respiratory infections) and doctor's diagnosis of asthma were assessed in a repeated-event analysis.

Measurements and Main Results: Lower birth weight was associated with more respiratory symptoms (odds ratio [OR] per kg decrease in birth weight, 1.21; 95% confidence interval [CI], 1.09–1.34). The effect of birth weight increased from age 1 to 5, but decreased thereafter and was no longer significant at the age of 7. The effect of birth weight on respiratory symptoms was significantly greater among children exposed to tobacco smoke in their home than among nonexposed children (OR at 5 yr: 1.21 [95% CI, 1.02–1.44] and 1.52 [95% CI, 1.23–1.87], respectively). Birth weight and a doctor's diagnosis of asthma were not related (OR, 1.06; 95% CI, 0.82–1.37).

Conclusions: A lower birth weight in children born at term is associated with a transiently increased risk of respiratory symptoms. This effect is enhanced by environmental tobacco smoke exposure.

Key Words: birth weight • environmental tobacco smoke • respiratory symptoms • longitudinal analysis • children

AT A GLANCE COMMENTARY TOP ABSTRACT AT A GLANCE COMMENTARY METHODS RESULTS DISCUSSION REFERENCES   Scientific Knowledge on the Subject Studies on the relationship between birth weight and asthma have shown contradictory results. Most effects have been documented in children born prematurely, and long-term follow-up studies on respiratory symptoms in children born at term are rare. What This Study Adds to the Field A low birth weight is associated with a transiently increased risk of respiratory symptoms before the age of 7 years, but not to an increased risk of a doctor's diagnosis of asthma. The effect on respiratory symptoms was enhanced by environmental tobacco smoke exposure.

 
Respiratory symptoms, such as wheezing, cough, and respiratory infections, are common in young children and put a serious burden on the affected children (1), their parents, and the health care system. In early childhood, these symptoms are related to a predisposition to asthma only in a minority of children (2). In the majority of children, symptoms will be transient and disappear during school age. Because the prevalence of these different phenotypes of symptoms changes rapidly during childhood, risk factors should be investigated using longitudinal data and analyses.

Size and maturity are major factors in the development of the lung. In children with diminished prenatal growth, and consequently low birth weight, a disturbed lung development is associated with a relatively small airway caliber (3). This might cause a decreased lung function and more respiratory symptoms later in life (2–4). Several studies have shown that prematurity is associated with lower lung function at birth and later, and a higher prevalence of respiratory symptoms in childhood (5–9). However, pathways leading to compromised lung development in premature and term infants are almost certainly not the same. The question remains whether the development of respiratory symptoms is influenced by birth weight in infants born at term.

The association between birth weight and asthma has been extensively studied, and the results are inconsistent. This may in large part be due to different periods of follow-up and to different definitions of asthma and (low) birth weight. In addition, not all studies took pregnancy duration into account in the analysis, thereby studying the combined effect of prematurity and birth weight (5). It has been postulated that the inverse association between birth weight and asthma as found in some studies might be explained by misclassification of transient respiratory symptoms as asthma (10).

The aim of this study was to investigate birth weight as a predictor of respiratory symptoms and doctors' diagnosis of current asthma longitudinally in children born at term. The prospective Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort data gave us the opportunity to investigate the effect of birth weight on the development and course of respiratory symptoms in children 1 to 7 years. We hypothesized that reduced intrauterine growth could lead to more respiratory symptoms as a result of smaller airways, which improve with increase in body size during childhood. We also investigated other factors that could possibly modify the effect of birth weight, such as sex, parental smoking, and allergic predisposition.

	METHODS

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Study Population
The study population consisted of 3,628 children who participated in the PIAMA birth cohort study. Details of this study have been published earlier (11) and are described in the online supplement. Briefly, recruitment took place by means of a validated screening questionnaire (12), distributed to 10,232 pregnant women visiting 1 of 52 prenatal clinics in the Netherlands. On the basis of this screening, 8,033 woman were invited to participate in the study; approximately 50% (n = 4,146) agreed and gave informed consent. Their children were monitored for 8 years. Standardized questionnaires for self-completion (according to the ISAAC [International Study of Asthma and Allergies in Childhood] guidelines [13]) were sent to participating parents at the third trimester of pregnancy, at the ages of 3 months and 1 year, and yearly thereafter. The present study analyzes the data up to the age of 7 years. We excluded all children with a gestational age of less than 37 weeks to avoid possible confounding effects of prematurity. In our final analyses, 3,628 children were included (88%).

Definition of Variables
Birth weight was obtained from the child's delivery chart, and reported in the 3-month questionnaire. Birth weight was considered as a continuous variable.

We defined the following six (dichotomous) outcomes, each of which were obtained at the ages of 1 to 7 years, and which pertain to the previous 12 months:

1. Wheezing: at least one episode of wheezing
   
2. Frequent wheezing: four or more episodes of wheezing (subgroup of "wheezing")
   
3. Cough: at least one episode of cough at night, not associated with a cold
   
4. Lower respiratory tract infection (LRTI): parental report of a doctor's diagnosis of pneumonia, bronchitis, or pertussis
   
5. Respiratory symptoms: a compound score with at least one positive score on the outcomes "wheezing," "cough," or "LRTI." If medication was prescribed for asthma, this score is considered positive, because symptoms may have been suppressed.
   
6. Doctors' diagnosis of current asthma: parental report of asthma ever diagnosed by a doctor in combination with symptoms of asthma in previous 12 months
   

Statistical Analysis
Locally-weighted regression (LOESS) smoothing curves (14) of the crude relationship between birth weight and the different outcomes were created using S-Plus 6.0 software (Insightfull, Seattle, WA) (see Figure E3 of the online supplement for "Wheeze"). We compared smoothed curves with linear fits by testing for a difference between the linear fit and the smooth fit that includes both linear and smooth terms. Because no significant difference was found between linear and smooth fit (except at age of 3 years), linearity of the association between birth weight and the logit of the outcome were assumed in all subsequent analyses.

Further analyses were performed with SAS 9.1.3 statistical software (SAS Institute, Cary, NC). Analyses of crude birth weight effect on all outcomes were first performed by logistic regression at every age separately (cross-sectional). Variables that meaningfully changed the univariate point estimate on one or more of the outcomes were included in the longitudinal models. General estimating equations (GEEs) were used to investigate the longitudinal effects of birth weight on all six outcomes from age 1 to 7 years, taking into account the serial relations between repeated measurements in the same individual. To test for effect modification, we calculated terms for interactions between birth weight and the variables age (time trend), parental smoking, sex, and maternal allergy in the GEE model.

	RESULTS

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Participants
From the 4,146 included women, 187 (4.5%) dropped out before returning the first postnatal questionnaire due to various reasons (e.g., perinatal death, language barrier, not interested, moved). The children who dropped out were more likely to have an allergic mother (50 vs. 31% based on screening questionnaire). Of the 3,959 remaining children, those without a recorded birth weight (n = 45) or gestational age (n = 9), those with no data on the specified outcomes at any of the 7 years (n = 82), and those with missing data on multiparity (n = 9) were excluded from analysis. These excluded children (n = 145) were more likely than the children with complete data (n = 3,814) to have an allergic mother (51 vs. 30%), to have both parents with a low level of education (32 vs. 13%), to have a mother who smoked during pregnancy (27 vs. 17%), and to have been exposed to environmental tobacco smoke (ETS) at 3 months (43 vs. 28%). After exclusion of all children who were born prematurely (n = 186), 3,628 children remained in the final analyses.

General Characteristics
Birth weights were normally distributed, even after adjustment for gestational age. Table 1 shows the general characteristics of the study population. Male sex, higher gestational age at birth, overweight of the mother, and presence of older siblings were strongly related with a higher birth weight. Maternal smoking during pregnancy was clearly associated with a reduced birth weight. A considerable proportion of children were exposed to tobacco smoke in utero (13.5%) and/or after birth (28.3%).

View larger version (20K): [in this window] [in a new window]   Figure 1. Prevalence of wheeze (of available cases) at different ages. Bars show infrequent (1–3 times, light gray) and frequent (4 or more, dark gray) wheezing episodes per year. Total height of each bar is prevalence of wheezing at least once. Number in each bar is the absolute number of children that reported infrequent wheezing or frequent wheezing.

View larger version (18K): [in this window] [in a new window]   Figure 2. Prevalence of self-reported doctors' diagnosis of current asthma at different ages. Total height of each bar represents the prevalence; the number in each bar represents the absolute number of children with doctors' diagnosis of current asthma.

To account for the serial correlations among outcomes of the same individual, we used GEE models to perform longitudinal analyses on all outcomes. For crude estimates on all outcomes, see Tables E2–E7. Figure 3 shows the adjusted odds ratios (ORs) from the longitudinal multivariate analysis for all outcomes. The overall effect of birth weight over 7 years was calculated, but the effect at every age separately from models with interaction term (age) is also presented. After multivariate adjustment, a lower birth weight remained significantly associated with more wheezing (OR, 1.17 per kg decrease in birth weight; 95% confidence interval [CI], 1.01–1.35), cough (OR, 1.21; 95% CI, 1.07–1.36), and respiratory infections (OR, 1.20; 95% CI, 1.05–1.38) overall. In addition, the association with the compound score for respiratory symptoms was significant over the whole 7-year period (OR, 1.21; 95% CI, 1.09–1.34). We investigated the ORs of birth weight at different ages by allowing interaction of the effect with age. The inverse relation between birth weight and wheezing remained significant at the ages 2 to 5 years, with the highest OR at age 4 (OR, 1.36; 95% CI, 1.08–1.71). For the outcome LRTI, the OR was also highest at the age of 4 (OR, 1.45; 95% CI, 1.13–1.86). The OR increased from age 1 to 4, and decreased to zero by the age of 7. Tests for this interaction between birth weight and age (time trend) in the GEE model reached significance for wheezing and LRTI (p value = 0.03 and 0.05, respectively). The association between birth weight and wheezing could not be explained by the relation between birth weight and LRTI. The OR of birth weight on cough was more stable over the years, ranging between 1.34 (95% CI, 1.10–1.62) and 1.13 (95% CI, 0.92–1.39). The compound score for respiratory symptoms was significantly associated with birth weight at the ages of 2 to 6 years. To assess the relative impact of children with an extreme birth weight, we performed a sensitivity analysis by excluding the 2% of the lightest and 2% of the heaviest children. ORs on the different outcomes became somewhat smaller at certain ages, but the overall pattern of the associations remained the same.

View larger version (9K): [in this window] [in a new window]   Figure 3. Odds ratios (ORs) and confidence intervals per kilogram decrease in birth weight for all outcomes, from a longitudinal general estimating equation model. ORs given for the overall effect and (allowing for a time trend) for each year of age separately. *Estimates are adjusted for sex, multiparity, body mass index of mother, smoking of mother during pregnancy, and gestational age at birth. The following outcomes are depicted: (A) Wheezing at least once; (B) lower respiratory tract infections (LRTI), including pneumonia, bronchitis, and pertussis; (C) cough in absence of a cold; (D) compound score "respiratory symptoms"; (E) doctors' diagnosis of current asthma.

Interaction with Sex, Maternal Allergy, and ETS Exposure on Respiratory Symptoms
Modification of the effect of birth weight on respiratory symptoms by sex, atopic constitution, gestational age (wk) at birth, and ETS was investigated. The effect did not differ between boys and girls, between children with and without an allergic mother, or between children with a lower and children with a higher gestational age range at birth. Separate analysis of the results of the participants who were exposed and who were not exposed to ETS in their home after birth revealed a greater effect of birth weight in the exposed group. In the GEE model, interaction with ETS exposure at 3 months reached significance for the outcomes wheezing (p = 0.03) and respiratory symptoms (p = 0.04). In Figure 4, the predicted probabilities of respiratory symptoms for children with different birth weights (2.5, 3.5, and 4.5 kg) are shown in the presence and absence of ETS exposure, to visualize the effect of birth weight in children of smoking and nonsmoking parents. Probabilities were calculated with given values for all confounders, as specified in the figure legend. A comparison of Figure 4A with 4B reveals the interaction effect of ETS exposure at 3 months in children who were not exposed prenatally. The difference between Figures 4A and 4C could be interpreted as the combined effect of pre- and postnatal ETS exposure. In the presence of ETS exposure (Figure 4B), a child with a birth weight of 2.5 kg has an approximately 45% chance each year of having respiratory symptoms between the ages 1 and 5 years, compared with 25% in a child with a birth weight of 4.5 kg. In absence of ETS exposure (Figure 4A), the difference in prevalence of respiratory symptoms between a 2.5- and a 4.5-kg newborn child is much smaller, about 6%. As can also be seen from Figure 4, a child of low birth weight (2.5 kg) has an additional 6% chance of respiratory symptoms if exposed to ETS postnatally. When exposed to ETS both pre- and postnatally, the additional risk of symptoms mounts to 12%. Figure 5 shows the predicted probabilities of the outcome wheezing for children from both smoking and nonsmoking parents. Clearly, the effect of birth weight is larger in the children exposed to ETS, especially in the first year of life. The isolated effect of postnatal exposure appears limited after adjustment for prenatal smoking; however, 87.2% of the children exposed to tobacco smoke during pregnancy were also exposed at 3 months after birth. Of the children exposed to cigarette smoke in their home more than once a week, about half (48%) had a mother who smoked for at least 4 weeks during pregnancy.

View larger version (14K): [in this window] [in a new window]   Figure 4. Predicted probabilities of any respiratory symptom (wheezing, cough, or lower respiratory tract infection) for a male child, 40 weeks gestational age at birth, with a nonoverweight mother, and with older sibling(s). Probabilities are predicted for a child with a birth weight of 2,500 g, 3,500 g, and 4,500 g (A) for children whose mother did not smoke during pregnancy, and who were not exposed to environmental tobacco smoke (ETS) at 3 months (67.3% of study population); (B) for children whose mother did not smoke during pregnancy, but who were exposed to ETS ( once/wk) at 3 months (14.4% of study population); and (C) for children whose mother did smoke during pregnancy, and who were exposed to ETS ( once/wk) at 3 months (11.9% of study population).

View larger version (13K): [in this window] [in a new window]   Figure 5. Predicted probabilities of wheeze for a male child, 40 weeks gestational age at birth, with a nonoverweight mother, and with older sibling(s). Probabilities are predicted for a child with a birth weight of 2,500 g, 3,500 g, and 4,500 g (A) for children whose mother did not smoke during pregnancy, and who were not exposed to environmental tobacco smoke (ETS) at 3 months. (67.3% of study population); (B) for children whose mother did not smoke during pregnancy, but who were exposed to ETS ( once/wk) at 3 months (14.4% of study population); and (C) for children whose mother did smoke during pregnancy, and who were exposed to ETS ( once/wk) at 3 months (11.9% of study population).

	DISCUSSION

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The effect of birth weight on respiratory symptoms has been examined in several other birth cohorts. Our findings are in concordance with results from a large birth cohort (15) that showed an association between birth weight and wheezing at 3 years, but not at 6 months. Another study in term infants did report an association in the first year of life (16). A separate analysis on the same cohort at the age of 6 years no longer showed a significant association (17), in line with our findings. Some other studies reported no association between birth weight and respiratory symptoms (18, 19). The discrepancy might be explained by the fact that symptoms in these studies were assessed only after the age of 5. Our yearly longitudinal analysis over a period of 7 years extends our knowledge on the time trend of the association. We found an increase of the OR until the age of 5 and a decrease thereafter, suggesting an association between birth weight and transient symptoms in preschool- and early elementary school–aged children. It is clear from previous publications that prematurity is associated with a decreased lung function and more asthmalike symptoms (6–9). Unlike previous studies investigating the effect of birth weight on respiratory symptoms (5, 18–20), we excluded all premature infants from our analyses. This enabled us to separate the effect of a low birth weight in children born at term from the sequelae of prematurity, and to investigate the independent effect of birth weight. The association between birth length and respiratory symptoms was investigated, but was not significant after adjustment for birth weight. The increased risk of symptoms in term children of a lower birth weight can be due to small airways relative to lung size (dysanapsis) (3), as a result of diminished prenatal growth (2). Although the impact of impaired fetal growth surely is related to its timing, we have no data on the timing of any possible adverse prenatal conditions. As the airways grow in absolute size with age, such children may become less apt to have symptoms, which would explain the transient nature of the increased risk. Lung function in the low-birth-weight children might remain suboptimal, even after these children become asymptomatic, as was found in children who wheezed between the ages of 1 and 6 years (2). This is important because it has been speculated that these children may be at increased risk of respiratory morbidity when lung function decreases in later life (21). One could also argue that disorders of fetal growth affect the immune function, thereby leading to a higher rate of respiratory symptoms.

This study does not support an effect of birth weight on the risk of a doctor's diagnosis of current asthma in children born at term. Because objective tests, including lung function, bronchial hyperresponsiveness, or allergy tests, are either difficult to perform in young children or not informative, a diagnosis of asthma in children younger than 5 is mainly based on respiratory symptoms (22, 23). As the diagnosis becomes more reliable with increasing age, one would expect less misclassification at later ages. This would lead to less dilution bias and more precise estimates of the association between birth weight and an asthma diagnosis. Our results show a decrease of the association at ages 6 and 7 years. Previous studies on the association between birth weight and asthma in children have shown contradictory results, with some reporting a positive association (24–26), some a negative association (5, 27–30), and some no association (8, 17, 18). Only a few of these studies excluded premature children (17, 24). The increased risk of asthma in low-birth-weight children reported by some studies might therefore be confounded by the effect of prematurity and/or bronchopulmonary dysplasia. Further inconsistencies in the results might appear because varying definitions of asthma were used in the different studies. Our longitudinal data suggest a negative association between asthma and birth weight only at the ages of 4 and 5 years. Possibly, this association is caused by misdiagnosis of transient wheezing syndromes (10). This is supported by the fact that our study showed a strong association between birth weight and (transient) wheezing, especially at the ages of 4 and 5 years.

This study reports for the first time an interaction between birth weight and ETS exposure in infancy on respiratory symptoms. To asses ETS exposure, we used reported smoking in the child's home, as this is the most important single location for exposure in children. We observed a stronger effect of low birth weight in the group with ETS exposure at 3 months. The interaction with ETS could not be explained by the correlation of ETS with the level of education of the parents, which we used as a proxy of socioeconomic status. Both in groups with high and low socioeconomic status, the interaction between ETS and birth weight remains present. On the basis of our longitudinal models, we estimated that, in the presence of ETS exposure, a child with a birth weight of 2.5 kg suffers a nearly doubled risk of having respiratory symptoms compared with a 4.5-kg child until the age of 5 years. In a 2.5-kg child, we estimated that ETS exposure pre- and postnatally is associated with a 12% increase in prevalence of wheezing and respiratory symptoms. Although several other factors, such as prematurity, other environmental pollutants, and a history of allergy, were previously reported to possibly influence the susceptibility for the effects of ETS (31), a low birth weight was not. A possible explanation for our finding is that the lungs of a child with lower birth weight are more vulnerable to the irritating effects of ETS. Many epidemiologic studies have demonstrated that children are more sensitive to the respiratory effects of ETS exposure than adults (32). In low-birth-weight children, a disturbed lung development could lead to immature lungs and therefore a higher susceptibility to the effects of ETS. We investigated interaction with ETS exposure established at the age of 3 months, because this variable had no missing values and it prevents bias caused by a change of parental smoking behavior due to their child's later symptoms. Tests for interaction between birth weight and ETS exposure at later ages showed similar results as ETS exposure at 3 months. This finding might suggest that ETS exposure is especially harmful for children of low birth weight, regardless of the child's age. However, another explanation is that ETS exposure at young ages has a long-lasting harmful effect in low-birth-weight children and that tracking of parental smoking behavior is responsible for the association with ETS exposure at later ages.

There are some limitations of this study that should be considered in the interpretation of the results. First, the presence of respiratory symptoms was based on parental reporting, which may lead to misclassification. We assume that this misclassification is nondifferential (independent of a child's birth weight), which may lead to dilution of the effect estimate. Especially at age 1 to 2 years, this could have caused some underestimation, because the ISAAC questionnaires that were used were originally designed and validated for the age category of 6 to 7 years. Misclassification of parental reports of ETS exposure is less likely because previous analyses showed that ETS exposure correlated well with nicotine concentrations measured in living-room air (33). Second, in our analyses, we adjusted for the confounding effects of smoking during pregnancy. The mechanisms by which smoking leads to more respiratory symptoms include a lower birth weight (2), which would imply that smoking is an antecedent rather than a confounder. Hence, adding prenatal smoking to our models might have caused some overadjustment and conservative estimates of the effect. Third, a problem encountered by many investigators studying the independent effect of in utero and household exposure to ETS is the strong correlation between the two factors (34). Although in our study we were able to adjust these factors for each other without the problem of colinearity, it remains difficult to prove that the interaction with birth weight found in this study is attributable to either in utero or postnatal exposure. Our data do suggest (especially for the compound score of respiratory symptoms) that the household ETS exposure is the actual effect modifier, but we base our conclusion largely on pathophysiologic reasoning.

Our study shows that low birth weight is an important risk factor for development and persistence of respiratory symptoms during preschool and early elementary school age. The effect of birth weight was greater in children exposed to ETS. Hence, it seems that the increased risk of symptoms in a low-birth-weight child might be considerably reduced by prevention of postnatal ETS exposure. In recent years, passive smoking has been reported in numerous studies to have harmful effects on a child's health (32). Our findings contribute to the knowledge that exposure to tobacco smoke is a public health problem with a substantial impact on respiratory health in children, especially in those with a low birth weight. Despite growing public awareness, the prevalence of smoking during pregnancy and frequent ETS exposure in the first years of life has remained high (35). An active policy to reduce in utero and ETS exposure on infants is desirable for all new parents. Our study suggests that significant extra health benefit can be gained by focusing on parents of newborns with a low birth weight.

Conclusions
We conclude that a low birth weight is an important risk factor for respiratory symptoms in young children born at term, independent of other characteristics at birth. This association showed a time trend with the strongest effect at 4 years and no effect after the age of 6. We also demonstrated potentiation of the effect of birth weight by exposure to ETS. All parents should be strongly encouraged to stop smoking because it has clear health benefits for their offspring. Our data suggest that focusing on parents of low-birth-weight children is of specific interest because their children may be especially vulnerable to the effects of ETS.

	FOOTNOTES

 
The PIAMA study is supported by The Netherlands Organization for Health Research and Development; The Netherlands Organization for Scientific Research; The Netherlands Asthma Fund; The Netherlands Ministry of Spatial Planning, Housing, and the Environment; and The Netherlands Ministry of Health, Welfare, and Sport.

This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org

Originally Published in Press as DOI: 10.1164/rccm.200610-1441OC on February 8, 2007

Conflict of Interest Statement: D.C. has received funding for a research project on HIV/TB in Cameroon in 2003 from GlaxoSmithKline (a500), Boehringer Ingelheim (a250), and Abbott (a225). A.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. U.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. H.A.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. B.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.C.d.J. participated in a scientific advisory board for GlaxoSmithKline in 2006 and received 1,500. Speaker's fees for J.C.d.J were paid to the Erasmus MC (AstraZeneca: 3,100; GlaxoSmithKline: 1,150; both 2005). The Erasmus MC–Sophia Children's Hospital received project funding in the past 3 years from the following companies: Roche (2004: 153,585; 2005: 221,850), Friesland Nutrition (2004: 65,200; 2005: 175,241; 2006: 21,150), Aerocrine (2004: 1,680; 2005: 45,960), Chiron (2005: 15,200), Transave (2005: 31,700), Pfizer (2005: 61,200).

Received in original form December 22, 2006; accepted in final form February 8, 2007

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