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Clinical Chemistry 49: 1353-1357, 2003; 10.1373/49.8.1353
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(Clinical Chemistry. 2003;49:1353-1357.)
© 2003 American Association for Clinical Chemistry, Inc.


Lipids, Lipoproteins, and Cardiovascular Risk Factors

C-reactive Protein Concentration Distribution among US Children and Young Adults: Findings from the National Health and Nutrition Examination Survey, 1999–2000

Earl S. Ford1,a, Wayne H. Giles1, Gary L. Myers2, Nader Rifai4, Paul M. Ridker5 and David M. Mannino3

1 Division of Adult and Community Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, GA 30333.
Divisions of
2 Laboratory Sciences and
3 Environmental Hazards and Health Effects, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA 30341.

4 Department of Laboratory Medicine, Children’s Hospital, Harvard Medical School, Boston, MA 02115.

5 Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115.

aAddress correspondence to this author at: Centers for Disease Control and Prevention, 1600 Clifton Rd., MS K66, Atlanta, GA 30333. Fax 770-488-8150; e-mail esf2{at}cdc.gov.


   Abstract
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
 
Background: The distribution of C-reactive protein (CRP) concentrations among children and young adults in the US is not known at present.

Methods: We used data from 3348 US children and young adults 3–19 years of age who participated in the National Health and Nutrition Examination Survey, 1999–2000, to describe the distribution of CRP concentrations, based on results obtained with a high-sensitivity latex-enhanced turbidimetric assay.

Results: The range of CRP concentrations was 0.1–90.8 mg/L (mean, 1.6 mg/L; geometric mean, 0.5 mg/L; median, 0.4 mg/L). CRP concentrations increased with age. Females 16–19 years of age had higher concentrations than males in this age range (P = 0.003). Mexican Americans had the highest CRP concentrations among the three major race or ethnic groups (P <0.001).

Conclusions: For the first time, these data describe the CRP concentration distribution among US children and young adults, based on results obtained with a high-sensitivity assay.


   Introduction
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
 
Inflammation plays a role in many disease processes, and its contribution to the pathophysiology of cardiovascular disease has become better appreciated in the last decade. Many markers of inflammation exist, but C-reactive protein (CRP) concentrations are easily, accurately, and relatively inexpensively measured. CRP, an acute-phase reactant, is produced in the liver and belongs to the pentraxin family of proteins (1). This protein is very sensitive to inflammation, and its concentration can increase rapidly in response to a wide range of stimuli. In studies of adults, CRP concentrations have added to the predictive ability of more traditional risk factors for cardiovascular disease (2) and perform well when compared with other measures of inflammation.

The pathogenesis of cardiovascular disease often starts in childhood. Pathology studies of children have demonstrated the presence of early precursors of atherosclerosis, such as intimal thickening and fatty streaks (3)(4)(5). Immunologic-inflammatory cells are present in early atherosclerotic lesions of the aorta in people as young as 17 years (6). Risk factors for cardiovascular disease, such as smoking, hypertension, dyslipidemia, obesity, physical inactivity, and diabetes mellitus, also often start in childhood and track into adulthood for many (7)(8)(9). Less is known about the distribution and correlates of inflammatory markers that predict cardiovascular disease risk in children and young adults, however. CRP concentrations in children are associated with excess weight (10)(11)(12), as they are in adults. In addition, CRP is significantly related to various cardiovascular disease risk factors in children (10) and has been shown to be inversely related to antioxidant concentrations (13).

Because no studies using a high-sensitivity CRP assay have described the CRP concentrations among children and young adults in the US, our purpose was to examine data from the 1999–2000 National Health and Nutrition Examination Survey (NHANES). These data may serve as reference values for the US population 3–19 years of age.


   Materials and Methods
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
 
In 1999, the NHANES became a continuously operating survey (14). The data for this analysis are from the years 1999 and 2000. A representative sample of the noninstitutionalized civilian US population was selected by use of a stratified multistage sampling design. Trained interviewers, using a computer-assisted personal interview system, interviewed participants at home. Participants were asked to subsequently attend the mobile examination center where they were asked to complete additional questionnaires, undergo various examinations (audiometry, balance, blood pressure, body composition, body measurements, cardiovascular fitness, lower extremity disease, muscle strength, oral health, physician, and vision), and to provide biological specimens, including a blood sample. Many questionnaires and examinations were targeted at participants of different age groups. Low-income persons, adolescents 12–19 years of age, persons >=60 years, African Americans, and Mexican Americans were oversampled. For children <=15 years of age, a parent or guardian provided interview information. In the mobile examination center, children provided some of their own responses, depending on the component. The CDC gave human subjects approval to NHANES. Consent was obtained from a parent or guardian for children <18 years, and assent was also obtained from children 7–17 years of age.

CRP was measured by latex-enhanced nephelometry (N High Sensitivity CRP assay) on a BN II nephelometer (Dade Behring Inc.) at the University of Washington Medical Center (Seattle, WA). The lower limit of detection for this assay was 0.1 mg/L. Participants who had a CRP concentration below this limit were assigned a value of 0.1 mg/L. Two levels of control materials from Bio-Rad Laboratories were used for quality-control purposes, and day-to-day CVs were 4.9–7.8%. The means for the control materials were 1.67 and 3.82 mg/L for samples analyzed during an initial 9-month period and 1.84 and 3.95 mg/L for a subsequent 12-month period. The performance of this assay has been shown to be good (15).

We limited our analyses to participants who attended the mobile examination center. For this analysis, we examined the CRP concentration distribution by age, sex, and race or ethnicity (white, African-American, Mexican-American). To examine whether sex or racial or ethnic differences in CRP concentrations were independent of age, body mass index percentiles, total cholesterol concentration, systolic blood pressure (for participants >=8 years of age), and smoking behavior (for participants >=12 years of age), we performed multiple linear regression analysis after log-transforming the CRP concentrations and calculated adjusted least-square means. We used SAS 8.02 to generate percentiles of the CRP concentration distribution, using the weight obtained at the mobile examination center, and SUDAAN 8.0 to test for differences of log-transformed CRP concentration between men and women and among the three major race or ethnic groups (16).


   Results
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
 
A total of 5085 persons whose ages ranged from 0 to 19 years participated in NHANES 1999–2000. Of these, 3348 participants 3–19 years of age with a CRP value were included in the analyses. CRP concentrations ranged from 0.1 to 90.8 mg/L. The distribution of CRP is highly skewed. Almost 33% of participants had a CRP concentration of 0.1 mg/L.

The distributions of CRP concentration by age, sex, and race or ethnicity are presented in Table 1 . In addition, because CRP concentrations >10 mg/L may reflect an acute-phase response to infectious diseases or disorders characterized by acute inflammation, we have provided details about the CRP concentration distribution for participants with a concentration <10 mg/L in Table 2 . Generally, the geometric mean concentration of CRP increased gradually with age among both male and female participants (Fig. 1 ). Geometric mean CRP concentrations were similar among male and female participants through ~15 years of age (age 3–9 years, P = 0.304; age 10–15 years, P = 0.407), after which female participants tended to have higher geometric mean concentrations than male participants 16–19 years of age (P = 0.003). To examine whether the differences in CRP concentrations between males and females 16–19 years of age were different after adjusting for age, body mass index percentiles, total cholesterol, systolic blood pressure, and smoking behavior, we performed multiple linear regression analysis with log-transformed CRP concentration as the dependent variable and calculated least-squares-adjusted means for males and females. The least-squares-adjusted geometric mean for males was 0.5 mg/L, and that for females was 0.9 mg/L (P = 0.001).


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Table 1. Percentiles of CRP concentration (mg/L) among US children and young adults 3–19 years of age, NHANES 1999–2000.


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Table 2. Percentiles of CRP concentration (mg/L) among US children and young adults 3–19 years of age after exclusion of participants with concentrations >10 mg/L, NHANES 1999–2000.



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Figure 1. Geometric mean CRP concentration among US children and young adults after adjustment for race or ethnicity, body mass index percentile, and total cholesterol concentration, by sex and age, NHANES 1999–2000.

{blacksquare}, males; {blacktriangleup}, females. CRP concentrations >10 mg/L were excluded.

In addition, race or ethnic differences were apparent as well. Although white and African-American participants tended to show similar CRP concentrations through the 90th percentile, Mexican-American participants showed the highest concentrations from the 50th through the 99th percentiles. Mexican Americans had the highest CRP concentrations among the three major race or ethnic groups (P <0.001). Among participants 3–19 years of age, the least-squares geometric means adjusted for age, body mass index percentiles, and total cholesterol concentration were 0.5 mg/L for Mexican-American males vs 0.4 mg/L for white males (P = 0.001) and 0.7 mg/L for Mexican-American females vs 0.5 mg/L for white females (P = 0.001). Further adjustment for systolic blood pressure among participants 8–19 years of age did not change the results.


   Discussion
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
 
This is the first study to describe the CRP concentration distribution, based on results obtained with a high-sensitivity CRP assay, in US children and young adults. Therefore, these data provide reference intervals for US children and young adults. Children and young adults have much lower CRP concentrations than adults. As in adults, the CRP concentration distribution in children and young adults is highly positively skewed.

CRP concentration varied by age, sex, and race or ethnicity. The median CRP concentration increased with age, perhaps a little more slowly among participants <=15 years than among participants >15 years of age. CRP concentrations were similar among girls and boys except for participants 16–19 years of age, among whom females had significantly higher CRP concentrations than males. Furthermore, Mexican-American children and young adults had higher CRP concentrations than whites and African Americans. Some of these demographic differences in CRP concentrations may be attributable to differences in health status (such as the presence of disease) and presence of known correlates of CRP concentration; we therefore calculated geometric mean concentrations of CRP that were adjusted for several correlates. Although some variables were collected for all participants 3–19 years of age, other sets of variables were collected for participants 8–19 years (e.g., blood pressure) and 12–19 years (e.g., smoking behavior). In addition, other potentially relevant variables, such as socioeconomic status and oral contraceptive use among female participants 12–19 years of age were not available at the time that we conducted our analyses. Developmental stage was not assessed in the survey. We thus were unable to adjust for all relevant variables, but we did adjust for age, body mass index percentiles, smoking status, systolic blood pressure, and total cholesterol concentration and examined the differences in the adjusted geometric mean CRP concentrations among racial or ethnic groups and between males and females.

Relatively little was known about the CRP concentration distribution in children. In healthy newborns, CRP concentrations range from 0 to 4 mg/L, with a median concentration of 2 mg/L (17). Among 699 British children 11 years of age, the median CRP concentration, measured with an in-house ELISA, was 0.15 mg/L (interquartile range, 0.06–0.47) (10). In NHANES III, CRP concentrations ranged from <3.0 to 93.5 mg/L as measured with an immunoassay with limited sensitivity <3.0 mg/L intended for assessing acute inflammation (11).

The utility of measuring CRP concentration in children and young adults to assess cardiovascular disease risk remains open to speculation. Recently, researchers demonstrated that CRP concentration was associated with endothelial dysfunction and carotid intima-media thickness in children (18). A previous study of 699 British children showed that CRP concentration was associated with systolic blood pressure, diastolic blood pressure, pulse, fibrinogen concentration, factor VIIc, HDL-cholesterol concentration, triglyceride concentration, apolipoprotein B concentration, and postload insulin concentration after adjustment for age, sex, ethnicity, and town (10). Further adjustment for ponderal index (kg/m3) attenuated most of the Pearson correlation coefficients to some degree and caused some of the previously significant associations (systolic blood pressure, factor VIIc, triglyceride concentration, apolipoprotein B, and postload insulin concentration) to lose their statistical significance. Other studies have also demonstrated that excess weight is strongly associated with CRP concentration in children (10)(11). Thus, children with abnormal values for cardiovascular disease risk factors are likely to have increased CRP concentrations as well but whether useful differences in CRP concentrations to assess cardiovascular disease risk can be defined remains to be established.

CRP concentration shows substantial intraindividual variability (19). Consequently, more than one measurement may be needed to better assess a person’s true CRP status. In a recent scientific statement, the American Heart Association and CDC recommended that two CRP determinations should be made 2 weeks apart in persons who are metabolically stable and free from obvious inflammatory or infectious conditions to provide a better estimate of CRP concentration (20). Several high-sensitivity assays are in commercial use. Comparisons of some of these tests have been conducted (21)(22).

In conclusion, our results show that the median CRP concentrations in children and young adults are low, far below those that have been associated with cardiovascular disease risk among adults. In addition, little is known about how CRP concentrations may track from childhood into adulthood. In adults, Rifai and Ridker (23) have proposed that CRP concentration may be especially valuable for identifying individuals at higher risk for cardiovascular disease who have lipid concentrations within reference values. Extending this proposition to children and young adults warrants further investigation.


   References
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
 

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