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Abstract

Objective: Since then, the reference intervals of serum hsCRP in apparently healthy Ethiopian children are unknown. Therefore, this study aimed to determine the reference intervals of serum hsCRP for apparently healthy children. Methods: In this cross-sectional study, a total of 492 apparently healthy children aged 5–17 years were recruited from residents of Addis Ababa. Well-trained professionals took anthropometric measurements. The biochemical analysis was performed with the automatic biochemical analyzer Cobas Integra 400 Plus from Roche. The 2.5th and 97.5th percentile limits were calculated using a non-parametric method as per the Clinical Laboratory Standard Institute (CLSI) guide. A box plot was used to show the distribution of hsCRP by age and gender. Furthermore, bivariate and multivariable logistic regression analyses were carried out to evaluate factors associated with elevated hsCRP levels. Percentiles were displayed by age subgroup and sex. p-values <0.05 were considered statistically significant. Results: The study included 245 boys and 247 girls. For the age group of 5–11 years, the combined 2.5th and 97.5th percentiles, which can be used as a reference interval for children in Addis Ababa, were 0.15–6.78 mg/L, while for the older age group (12–17 years), the determined percentile was 0.14–4.40 mg/L. Likewise, the current study shows that never or occasionally eating vegetables and/or fruits (AOR = 2.28, 95% CI, 0.84–4.97), and being obese (AOR = 3.63, 95% CI, 1.14–11.53) were independent risk factors for elevated serum hsCRP concentrations. Conclusion: This study is the first to determine the reference intervals of hsCRP concentrations among apparently healthy Ethiopian children. Notable differences were observed in the established percentiles of hsCRP in comparison with published literature.

Keywords

High sensitivity C-reactive protein children apparently healthy Ethiopia

Introduction

C-reactive protein (CRP) is an acute-phase protein of the pentraxin family that is primarily produced by liver hepatocytes and released into the bloodstream in response to inflammatory signals.¹ It’s a non-specific marker for a number of diseases, including infections and chronic inflammatory disorders. It is known that inflammatory factors, tumor necrosis factors, and interleukin-6 (IL-6) influence its level.^2–5 C-reactive protein is similar to high-sensitivity C-reactive protein (hsCRP), but hsCRP levels, as the name implies, are more sensitive.⁶ High-sensitive C-reactive protein is one of the simplest, most accurate, and least expensive inflammation markers.⁷ In healthy people, hsCRP levels are typically less than 10 mg/L. However, its concentrations rise rapidly in the days following an acute phase stimulation, reaching 1,000 mg/L, and then return to baseline with a half-life of 19 h when the stimulus is stopped.^3,8 In recent years, hsCRP has been used in a variety of applications, including cardiovascular disease, cancer, and tissue damage caused by various causes.^9–11

Slightly higher hsCRP levels are associated with a higher body mass index (BMI) in both adolescents and adults. In obese children, hsCRP rises due to macrophage invasion of enlarged adipose tissue, which emits inflammatory signals and cytokines. Furthermore, fragments of data suggested that slightly higher hsCRP levels were associated with obesity and cardiovascular risk markers such as hypertriglyceridemia and low HDL cholesterol levels.^12–18 Furthermore, hsCRP has a predictive value at all levels of serum lipids, blood pressure, the severity of the metabolic syndrome, and in those with or without subclinical atherosclerosis. For instance, even lower hsCRP levels were associated with a higher risk of cardiovascular disease. Pieces of evidence indicate that 1 mg/L, 1–3 mg/L, and 3 mg/L hsCRP levels are related to lower, moderate, and increased cardiovascular risks, respectively.¹⁹ The fact that the degenerative phase of atherosclerosis begins in childhood is now widely accepted.^20–22 As a result, hsCRP may be a useful biomarker for detecting and managing people who are at risk of various inflammatory disease conditions. The majority of existing African reference intervals for clinical laboratory parameters, including hsCRP, are based on foreign populations and may not be representative of population values elsewhere.^23,24 Because of lifestyle and genetic differences, it is inappropriate to employ Western reference values for Ethiopians. Moreover, there are no published hsCRP reference intervals for children in Ethiopia.²⁵ Therefore, the purpose of this study was to identify the reference intervals (2.5th and 97.5th percentiles) of serum hsCRP in children who appeared to be healthy. The reference intervals supplied could open the path for hsCRP to be used as a marker for early identification of any inflammatory condition in Ethiopia. Furthermore, the present study adds additional evidence to the existing data from several European, South Asian, and American countries on the distribution of hsCRP.

Materials and methods

Study population and eligibility criteria

The current cross-sectional study was conducted from April 2019 to October 2019 in Addis Ababa, Ethiopia. Addis Ababa is the capital city of Ethiopia and a seat for the African Union. The city was divided into 10 subcities (currently 11) during the study period. A multistage random sampling procedure based on the selection of sub-cities and woredas (the smallest administrative unit) was used to choose study participants. The probability proportionate to size (PPS) sampling method was used, with the size of the sample based on the number of people in the sub-city. Accordingly, four subcities were selected with the help of the Central Statistical Agency of Ethiopia. Then, using a practical sampling strategy, study participants were recruited from randomly selected woredas (the smallest administrative units under subcities) through both school and village-to-village mobilization by health extension workers and well-trained data collectors. Volunteers were requested to come to the mobile specimen collection sites. The study population’s socio-demographic and behavioral characteristics (cigarette smoking, alcohol use, fruit and vegetable consumption, and physical activity), history and physical examination, and anthropometric measurements (blood pressure, weight, and height) were taken. Both the study participants and their parents/guardians, as applicable, provided medical history information. Apparently healthy children living in Addis Ababa for at least 6 months, aged between 5 and 17, who voluntarily participated in the study, were included. Participants with viral (HIV, HBV, and HCV) or bacterial infections (syphilis), intestinal parasites, any acute or chronic health concern, or who were on medication were excluded from participating in the study. Likewise, participants experiencing an acute illness and having chronic diseases like diabetes mellitus, heart disease, anaemia, thyroid disease, liver disease, and cancer of any type were excluded from the study. Participants were partitioned by age into groups of 5–11 years and 12–17 years because of pubertal differences in serum analytes of hsCRP and lipid profile. Based on Clinical Laboratory Standard Institute (CLSI) guidelines, a minimum of 120 samples is needed to establish the 2.5th and 97.5th percentiles with 95% CI by using a non-parametric method. A total of 492 apparently healthy children (ages 5–17 years) participated in the study.

Anthropometric measurements

Well-trained professionals took anthropometric measurements such as body weight and height. Each subject’s weight and height were assessed, and their BMI was computed by dividing their weight (kg) by their height squared (m²). Height was measured in a standing position using well-placed stadiometers without shoes to the nearest 0.1 cm. A digital balance was used to measure the weights to the nearest 0.1 kg. Weights were taken in a standing position with the children barefoot, with no shoes, phones, or other materials in their pockets. After a 5-min break, an electronic sphygmomanometer was used to take blood pressure in the right upper arm, and three measures were averaged to get the final result. The study excluded children with a systolic or diastolic blood pressure of more than 120/80 mmHg. According to the Centres for Disease Control (CDC) recommendations,²⁶ study participants’ weight status was classified as underweight (5th percentile), healthy weight (5th to 85th percentile), overweight (85th to 95th percentile), and obese (95th percentile).

Sample collection, processing, and biochemical measurements

From 8:30 a.m. to 11:00 a.m., 5 mL of fasting blood samples were taken from the median cubital vein using serum separator tubes (SST) after all children and their families were informed of the study’s purpose. The blood samples were centrifuged at 3000 revolutions per minute for 5 min. The serum was isolated and stored at −80°C until analysis. During the biochemical analysis process, serum samples were exposed to a single freeze-thaw cycle. Serum hsCRP levels were measured in the clinical chemistry laboratory of the Ethiopian Public Health Institute (EPHI) using an immune-turbidimetric test with a Cobas Integra 400® Plus automatic biochemical analyzer (Roche Diagnostics, GmbH, Mannheim, Germany). The amounts of TC, LDL-c, and TG were measured using colorimetric assays. The amino groups of HDL-c were identified enzymatically by cholesterol esterase and cholesterol oxidase, which were combined with polyethylene glycol (which specifically forms complexes with chylomicrons, LDL-c, and VLDL-c). Infectious disease screening tests were conducted at the Ethiopian National Blood Bank Services (NBBS) using enzyme-linked immunosorbent assay (ELISA) testing technologies. All of the samples were frozen and thawed once during the testing process. All of the tests were done in a nationally authorized laboratory, with a measurement uncertainty of 1.4% for TC, 1.3% for LDL-c, 1.8% for TG, 1.9% for HDL-c, and 1.5% for hsCRP at the time of analysis.

Data quality assurance and quality control

The questionnaire was pilot-tested on 10% of the sample size to ensure its completeness, consistency, and applicability, and it was modified as needed. Following the completion of each questionnaire, data collectors and the principal investigator cross-checked the information gathered to ensure its accuracy. The test tube label and the questionnaire’s unique identification number were also compared for similarity. The clinical chemistry analyzer was tested for accuracy using normal and pathological controls after checking the expiration dates of both the reagents and the controls. Furthermore, prior to processing the study participant’s sample, dual quality controls (normal and pathological) and pooled serum samples were always performed, and the study participant’s sample was then analyzed. In general, all pre-analytical, analytical, and post-analytical precautions were taken to ensure the accuracy and precision of the test results.

Statistical analysis

Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS Statistics, IBM Corporation USA), version 23.0. Histograms and box plots were used to show the distribution of serum hsCRP by age and gender. The skew distribution of hsCRP was represented by the median and 95% Confidence Intervals (CI). Because the data were not normally distributed, a non-parametric Spearman correlation coefficient was used for correlation analysis. Furthermore, bivariate and multivariable logistic regression analyses were performed to assess factors associated with elevated hsCRP levels. The crude and adjusted odds ratios and their corresponding 95% CI were computed. For the purpose of performing regression analysis, the values of hsCRP are classified as normal (hsCRP values <3 mg/L) and high (hsCRP values >3 mg/L). According to sex and age subgroup, the 2.5th, 5th, 10th, 25th, 50th, 75th, 90th, 95th, and 97.5th percentiles were displayed. p-values <0.05 were considered statistically significant.

Result

Characteristics of study population

The study comprised a total of 492 children (245 boys and 247 girls). Of them, 163 (33.13%) and 329 (66.87%) were between the ages of 5 and 11, and 12 and 17 years, respectively. According to the CDC standards, 396 (80.48%), 22 (4.48%), 50 (10.16%), and 24 (4.88%) participants in this study were classified as healthy weight, underweight, overweight, and obese, respectively. About 490 (99.60%) of the study participants had neither smoked cigarettes nor chewed khat; 477 (97%) had never consumed alcohol; 302 (61.40%) had occasionally consumed fruits and vegetables; 289 (58.74%) had consumed coffee or tea more than once per day; and 339 (68.90%) and 335 (68.10%) had the habits of physical exercise and fasting, respectively. Although more than 95% of the study participants had normal total cholesterol and triglyceride levels, the majority of 291 people (59.10%) had excessively low serum HDL cholesterol levels (Table 1).

Table 1.

Socio-demographic characteristics of children aged 5–17 years in Addis Ababa, Ethiopia.

Variables		Number (%)
Sex	Male	245 (49.80)
Sex	Female	247 (50.20)
Age group (years)	5–11	163 (33.13)
Age group (years)	12–17	329 (66.87)
BMI (kg/m²)	Healthy weight	396 (80.48)
	Underweight	22 (4.48)
	Overweight	50 (10.16)
	Obesity	24 (4.88)
Alcohol drinking	Once/day (regular)	None
	2–3 times/week	4 (0.8)
	Once per week	2 (0.4
	Occasionally (holiday, special ceremony)	9 (1.8)
	Never	477 (97.00)
Consume/use khat	2–3 times/week	1 (0.2)
	Once per week	1 (0.2)
	Occasionally (holiday, special ceremony)	None
	Never	490 (99.60)
Cigarette smoking	More than once/day	1 (0.2)
	Once per week	1 (0.2)
	Never	490 (99.60)
Habit of fasting	Yes	335 (68.1)
Habit of fasting	No	157 (31.9)
Habit of physical exercise	Yes	339 (68.9)
Habit of physical exercise	No	153 (31.1)
Eating roots and tuber (potato, sweet potato, Enset, cassava)	More than once/day	38 (7.70)
	Once/day	14 (2.80)
	2–3 times/week	199 (40.40)
	Occasionally (e.g., holidays, special ceremonies)	225 (45.70)
	Never	12 (2.40)
Eating legumes (beans, peas, chicken pea, etc.)	More than once/day	81 (16.50)
	Once/day	175 (35.60)
	2–3 times/week	88 (17.9)
	Occasionally (e.g., holidays, special ceremonies)	130 (26.40)
	Never	18 (3.70)
Eating fruits/vegetables	More than once/day	39 (7.9)
	Once/day	10 (2.00)
	2–3 times/week	136 (27.60)
	Occasionally (e.g., holidays, special ceremonies)	302 (61.4)
	Never	5 (1.00)
Consuming meat and other animal products	More than once/day	14 (2.84)
	Once/day	8 (1.63)
	2–3 times/week	75 (15.25)
	Occasionally (e.g., holidays, special ceremonies)	366 (74.39)
	Never	29 (5.89)
Drinking of tea and/or coffee	More than once/day	289 (58.74)
	Once/day	100 (20.32)
	2–3 times/week	59 (12.00)
	Occasionally (e.g., holidays, special ceremonies)	25 (5.08)
	Never	19 (3.86)
Total cholesterol level (mg/dL)	<200	478 (97.20)
Total cholesterol level (mg/dL)	≥200	14 (2.80)
Triglyceride level (mg/dL)	<150	465 (94.50)
Triglyceride level (mg/dL)	≥150	27 (5.50)
Low-density lipoprotein cholesterol level (mg/dL)	<130	476 (96.70)
Low-density lipoprotein cholesterol level (mg/dL)	≥130	16 (3.30)
High-density lipoprotein cholesterol level (mg/dL)	≥40	201 (40.90)
High-density lipoprotein cholesterol level (mg/dL)	<40	291 (59.10)

High-sensitive C-reactive protein level distribution

Figure 1 depicts the non-normally distributed hsCRP distribution among study populations. Observation from the figure shows that the values of serum hsCRP were skewed to the right and compacted between 0.00-2 mg/L for both sexes (Figure 1). Moreover, the visual inspection of the box plots shows that the upper whisker values of hsCRP in all study populations were found to be less than 2 mg/L. Meanwhile, a number of outlier values of hsCRP were observed, as indicated in the figure below (Figure 2).

Figure 1.

Histograms showing sex disaggregated distribution of serum hsCRP concentrations (mg/L) among children in Addis Ababa, Ethiopia.

Figure 2.

Box plots showing the age and sex specific distribution of hsCRP among children in Addis Ababa, Ethiopia.

The age group of 12–17 years had the highest median serum hsCRP concentration. For girls aged 5–11 and 12–17 years, median hsCRP values were 0.55 mg/L (95% CI, 0.48–0.65) and 0.58 mg/L (95% CI, 0.51–0.64), respectively. Male equivalents aged 5–11 and 12–17 years old had median hsCRP levels of 0.52 (95% CI, 0.48–0.64) and 0.55 (95% CI, 0.50–0.68) mg/L, correspondingly. The determined median levels of hsCRP for male subjects were 0.54 (95% CI, 0.50–0.60), and for females, 0.57 (95% CI, 0.52–0.64) (Table 2).

Table 2.

Serum hsCRP concentration (mg/L) levels of children in Addis Ababa, Ethiopia.

Age in year	Serum hsCRP concentration among male				Serum hsCRP concentration among female				For both sexes
Age in year	Mean	Range	Median	95% CI of median	Mean	Range	Median	95% CI of median	Mean	Range	Median	95% CI of median
Combined	1.02	0.05–9.05	0.54	0.50–0.60	1.02	0.00–8.41	0.57	0.52–0.64	1.02	0.00–9.05	0.56	0.15–5.01
5–11	0.94	0.05–9.05	0.52	0.48–0.64	1.21	0.07–8.41	0.55	0.48–0.65	1.08	0.05–9.05	0.53	0.50–0.62
12–17	1.05	0.10–9.05	0.55	0.50–0.68	0.93	0.00–8.08	0.58	0.51–0.64	1.00	0.00–9.05	0.57	0.52–0.61

Correlation between hsCRP and predictors

Table 3 displays the Spearman correlation analysis between predictors and hsCRP levels. The current study found that LDL-c, TC, and mean upper arm circumference all had a moderately positive relationship with hsCRP concentrations (p < 0.05). Likewise, BMI had a strong positive correlation with serum hsCRP concentrations. Other indicators, such as triglycerides, HDL-c, and age, had no correlations with hsCRP levels (Table 3).

Table 3.

Spearman correlation analysis of hsCRP with predictors among study participants in Addis Ababa, Ethiopia.

Predictors	High sensitive C-reactive protein (hsCRP)
Predictors	Correlation coefficient (r)	p-value
Age	0.014	0.761
Body mass index	0.61	<0.001*
Mean upper arm circumference	0.54	0.007*
Low density lipoprotein cholesterol	0.51	0.023*
High density lipoprotein cholesterol	0.053	0.245
Total cholesterol	0.49	0.028*
Triglycerides	0.070	0.124

Note: *p-value less than 0.05.

Factors associated with elevated hsCRP levels among children

The hsCRP concentration of >3 mg/L may reflect an acute-phase response to infectious diseases or disorders characterized by acute inflammation. Here, we have provided the regression analysis for participants with a concentration of hsCRP >3 mg/L in Table 4. The bulk of the study subjects (92.68%) had serum hsCRP levels below 3 mg/L. Only 36 children (7.32%) had serum hsCRP levels greater than 3 mg/L (22 healthy weights, 1 underweight, 5 overweight and 8 obese). Twenty-seven (5.49%) of the children with abnormal lipid profiles had blood hsCRP levels greater than 3 mg/L (one high TC, two high TG, one high LDL-c, and 23 low HDL-c). Stepwise multivariate analysis was used by including factors that had significant relationships (p-value <0.25) in the bivariate analysis. The hsCRP was shown to have significant relationships with BMI, eating vegetables and/or fruits, and eating roots and tubers (p < 0.05), but none of the other factors, including a lipid profile, were associated with the serum hsCRP. Likewise, the current study shows that never or occasionally eating vegetables and/or fruits (AOR = 2.28, 95% CI, 0.84–4.97) and being obese (AOR = 3.63, 95% CI, 1.14–11.53) were independent risk factors for elevated serum hs-CRP concentrations (Table 4).

Table 4.

Factors associated with high hsCRP levels among children in Addis Ababa, Ethiopia.

Variables		High sensitive C-reactive Protein concentration (hsCRP)		Unadjusted OR (95% CI)	p- Value	Adjusted OR (95% CI)	p- Value
Variables		≤3 mg/dL n (%)	>3 mg/dL n (%)	Unadjusted OR (95% CI)	p- Value	Adjusted OR (95% CI)	p- Value
Sex	Female	229 (46.54)	18 (3.66)	0.99 (0.50–1.95)	0.98
Sex	Male	227 (46.14)	18 (3.66)	1
Age group (years)	5–11	149 (30.28)	14 (2.85)	1
Age group (years)	12–17	307 (62.40)	22 (4.47)	0.45 (0.38–1.53)	0.447
BMI (kg/m²)	Healthy weight	374 (76.02)	20 (4.06)	1
	Underweight	21 (4.27)	1 (0.20)	0.67 (0.09–5.18)	0.701
	Overweight	45 (9.14)	5 (1.02)	1.71 (0.62–4.71)	0.297
	Obesity	18 (3.66)	10 (2.03)	5.14 (1.87–14.14)	0.002	3.63 (1.14–11.53)	0.029*
Habit of fasting	Yes	312 (63.41)	23 (4.68)	1
Habit of fasting	No	144 (29.27)	13 (2.64)	1.22 (0.60–2.49)	0.575
Habit of physical exercise	Yes	319 (64.84)	20 (4.06)	1
Habit of physical exercise	No	137 (27.85)	16 (3.25)	1.86 (0.94–3.70)	0.76
Eating roots and tuber (potato, sweet potato, enset, cassava)	More 2–3 times/week	219 (44.51)	18 (3.66)	1		1
	Occasionally (e.g., holidays, special ceremonies)	211 (42.89)	18 (3.66)	0.77 (0.21–2.83)	0.699
Eating vegetables and/or fruits	More 2–3 times/week	166 (33.74)	19 (3.86)	1		1
Eating vegetables and/or fruits	Never or occasionally (e.g., holidays, special ceremonies)	283 (57.52)	24 (4.88)	5.23 (1.92–11.91)	0.001	2.28 (0.84–4.97)	0.026*
TC level (mg/dL)	<200	443 (90.04)	35 (7.11)	1
TC level (mg/dL)	≥200	13 (2.64)	1 (0.20)	0.649 (0.14–3.01)	0.581
TG level (mg/dL)	<150	431 (87.60)	34 (6.91)	1
TG level (mg/dL)	≥150	25 (5.08)	2 (0.41)	0.870 (0.25–3.02)	0.827
LDL-c level (mg/dL)	<130	441 (89.63)	35 (7.11)	1
LDL-c level (mg/dL)	≥130	15 (3.05)	1 (0.20)	0.770 (0.17–3.52)	0.736
HDL-c level (mg/dL)	≥40	188 (38.21)	13 (2.64)	1
HDL-c level (mg/dL)	<40	268 (54.47)	23 (4.68)	0.789 (0.43–1.45)	0.445

Note: BMI, body mass index; TC, total cholesterol; TG, triglycerides; HDL-c, high density lipoprotein cholesterol; LDL-c, low density lipoprotein cholesterol.

*p-value less than 0.05.

The percentile distributions of serum hsCRP concentrations in apparently healthy children

The distribution of percentiles of serum hsCRP concentrations in study participants is shown below (Table 5). For the age group of 5–11 years, the combined 2.5th and 97.5th percentiles were 0.15–6.78 mg/L, while for the older age group (12–17 years), the determined percentile was 0.14–4.40 mg/L. Female participants in the lower age subgroup had a higher level of hsCRP (0.13–7.07 mg/L). For overweight and obese children, the established 2.5th and 97.5th percentiles of hsCRP concentrations were 0.15–7.43 mg/L and 0.16–8.08 mg/L, respectively (Table 5).

Table 5.

Percentile distributions of serum hsCRP levels (mg/L) among children in Addis Ababa, Ethiopia.

	n	P_2.5	P₅	P₁₀	P₂₅	P₅₀	P₇₅	P₉₀	P₉₅	P_97.5
Age both sexes (Years)
5–11	163	0.15	0.23	0.29	0.40	0.40	0.53	0.93	2.57	6.78
12–17	329	0.14	0.21	0.30	0.41	0.41	0.57	0.93	2.24	4.40
Male
5–11	82	0.19	0.25	0.30	0.41	0.41	0.52	1.02	2.01	4.87
12–17	163	0.14	0.18	0.31	0.42	0.42	0.55	1.01	2.36	4.43
Female
5–11	81	0.13	0.18	0.25	0.40	0.40	0.55	0.90	3.66	7.07
12–17	166	0.11	0.23	0.30	0.40	0.40	0.58	0.90	2.02	3.82
BMI kg/m²
Healthy weight	396	0.14	0.23	0.28	0.40	0.54	0.87	1.99	3.36	4.43
Underweight	22	0.13	0.14	0.25	0.40	0.50	0.73	2.14	3.52	3.75
Overweight	50	0.15	0.25	0.35	0.47	0.68	1.21	3.27	5.10	7.43
Obesity	24	0.16	0.20	0.36	0.59	1.70	3.06	7.01	7.34	8.08
Eating vegetables and/or fruits
More than once/day	40	0.00	0.12	0.17	0.40	0.61	1.05	3.71	4.86	6.60
Once/day	10	0.00	0.26	0.28	0.66	1.26	3.35	4.30	NA	NA
2–3 times/week	136	0.16	0.26	0.33	0.46	0.57	1.12	2.09	3.71	4.96
Occasionally (e.g., holidays, special ceremonies)	302	0.16	0.24	0.30	0.40	0.53	0.86	1.98	3.27	6.94
Never	5	0.12	0.12	0.12	0.23	0.92	2.04	NA	NA	NA
Consuming meat and other animal products
More than once/day	14	0.08	0.10	0.22	0.42	0.50	0.71	1.22	NA	NA
Once/day	8	0.44	0.44	0.44	0.53	0.92	2.01	NA	NA	NA
2–3 times/week	75	0.15	0.16	0.27	0.41	0.66	1.20	3.54	5.28	6.94
Occasionally (e.g., holidays, special ceremonies)	366	0.14	0.23	0.30	0.41	0.56	0.92	2.61	3.71	5.03
Never	29	0.09	0.10	0.29	0.36	0.48	0.51	0.92	NA	NA
Drinking tea and/or coffee
More than once/day	289	0.13	0.18	0.27	0.40	0.55	0.86	2.16	3.73	4.36
Once/day	100	0.16	0.25	0.34	0.44	0.60	1.11	2.82	5.03	6.52
2–3 times/week	59	0.19	0.19	0.29	0.40	0.53	0.76	2.01	3.21	3.71
Occasionally (e.g., holidays, special ceremonies)	25	0.28	0.29	0.33	0.40	0.54	0.84	1.64	2.45	2.56
Never	19	0.22	0.32	0.33	0.46	0.84	1.33	3.06	NA	NA
Habit of physical exercise
Yes	339	0.18	0.25	0.31	0.42	0.57	0.90	2.00	3.42	4.30
No	153	0.17	0.15	0.26	0.39	0.53	1.08	3.21	5.93	7.07
Habit of fasting
Yes	335	0.26	0.25	0.33	0.41	0.58	0.93	2.11	3.60	3.81
No	157	0.14	0.18	0.25	0.39	0.51	0.89	2.30	5.00	6.81
TC level (mg/dL)	<200	478	0.15	0.23	0.23	0.41	0.56	0.93	2.16	3.71	4.36
TC level (mg/dL)	≥200	14	0.27	0.27	0.30	0.38	0.68	1.96	3.12	NA	NA
TG level (mg/dL)	<150	465	0.16	0.24	0.31	0.41	0.56	0.93	2.25	3.69	5.03
TG level (mg/dL)	≥150	27	0.16	0.07	0.09	0.35	0.59	1.55	2.17	4.43	4.86
LDL-c level (mg/dL)	<130	476	0.16	0.23	0.30	0.41	0.56	0.93	2.17	3.71	4.73
LDL-c level (mg/dL)	≥130	16	0.25	0.27	0.28	0.36	0.56	1.78	2.86	NA	NA
HDL-c level (mg/dL)	≥40	201	0.13	0.24	31	0.42	0.58	0.86	2.22	3.64	3.71
HDL-c level (mg/dL)	<40	291	0.29	0.20	0.28	0.40	0.53	0.95	2.26	3.81	6.52

Note: BMI, body mass index; TC, total cholesterol; TG, triglycerides; HDL-c, high density lipoprotein cholesterol; LDL-c, low density lipoprotein cholesterol; P, percentile; NA, not applicable due small sample size.

Discussion

Feyissa Challa et al. recently described the distribution and risk factors of serum hsCRP levels in a 15–69-year-old Ethiopian population. However, children under the age of 15 were not included in the previous study, and participants were not tested for non-infectious or infectious disorders such as the human immunodeficiency virus, hepatitis B, hepatitis C, syphilis, or malaria.²⁵In cardiovascular illnesses and diabetes, hsCRP has recently been identified as a sensitive marker of low-grade inflammation.^7,27,28 Based on a large data set, the US CDC and the American Heart Association concluded that hsCRP is a useful marker for predicting the risk of future cardiovascular disease and diagnosing and treating patients with acute coronary syndrome.^29,30 A high serum hsCRP level has been linked to obesity and poor lipid metabolism in children in a number of studies.^31,32 The distribution of hsCRP concentrations in children has been established in several studies from various countries.^33–38 However, little was known about the distribution of hsCRP concentrations in apparently healthy Ethiopian children, and no data on the distribution of hsCRP in apparently healthy Ethiopian children had been published. In Ethiopia, manufacturer provided values that are determined for other populations are being utilized in clinical practice. As a result, this is the first study to characterize the distribution of serum hsCRP concentrations in children who appear to be healthy. Children in our study did not have any infectious diseases (such as HIV, HBV, HCV, syphilis, or malaria), and the percentile modelling took into account non-hypertension, non-diabetes, and the absence of any other known chronic diseases. However, fifty (10.16%) of the study participants were overweight, and twenty-four (4.88%) were obese.

The current work revealed that there were no significant differences in the distribution of hsCRP with age subgroups or sexes in this investigation. This finding was supported by a study done by Rodoo P et al.,³⁹ Blaha MJ et al.,⁴⁰ and Colantonio DA et al.⁴¹ In contrast, the studies conducted by H Schlenz et al.,⁴² Thierfelder W et al.,⁴³ and Soldin OP et al.⁴⁴ discovered sex differences in serum hsCRP distribution. However, in the present study, the serum hs-CRP levels among females were slightly but not significantly higher than their male counterparts. This could be because the girls had high levels of fat storage, which causes inflammation and raises hsCRP. This finding contradicted the prior two studies done by Tang YB et al.³⁴ and Raitakari M et al.⁴⁵ Thirty-six (7.32%) of the total study participants had a serum hsCRP of >3 mg/L, which was lower than the earlier Ethiopian study by Feyissa et al., which found 18%.²⁵ Because the prior study included adult participants who were at high risk for numerous factors that could cause blood hsCRP elevation, the discrepancy was expected.

Male children had a median hsCRP value of 0.54 mg/L, while female children had a median hsCRP value of 0.57 mg/L. The present median readings for both sexes were lower than those found in a study by Tang Yan Bin et al. in China, which found that the average hsCRP concentration in the urban population was 0.68 mg/L for males and 0.65 mg/L for females.³⁴ Adult participants in the China study may be more exposed to traditional risk factors, including cardiovascular disease and smoking, which could explain the differences. On the other hand, the current median value of hsCRP is higher than in several previous studies.^46–49 Another comprehensive study done by H Schlenz et al. observed that the median hsCRP values in eight European nations (Sweden, Germany, Hungary, Italy, Cyprus, Spain, Belgium, and Estonia) varied from 0.2 to 0.3 mg/L, with the exception of Italy, where the median hsCRP levels were 0.5 mg/L.⁴²

For the age groups 5–11 and 12–17 years, the established 2.5th and 97.5th percentiles for combined sexes were 0.15–6.78 mg/L and 0.14–4.40 mg/L, respectively. For 5–11 and 12–17 years, the derived 2.5th and 97.5th percentiles were 0.19–4.87, 0.14–4.43 mg/L for males, and 0.13–7.07, 0.11–3.82 mg/L for females, respectively. A study done by Soldin et al.⁴⁴ reported slightly higher 97.5th percentiles of hsCRP, which varied from 7.9 mg/L in males to 10.0 mg/L in females. Likewise, H Schlenz et al.⁴² reported 97.5th percentiles of hsCRP 2.8 and 6.3 mg/L in males and females, respectively. Moreover, the highest 97.5th percentile of 11.3 mg/L hsCRP was reported in Swedish children.⁴¹ The hsCRP concentrations reported by Ford ES et al. ranged from 0.1 to 90.8 mg/L,⁴⁷ which was extremely higher in the upper limit than the current reports of 0.00–9.05 mg/L. This variability may be explained by the difference in the study population and the applied exclusion criteria.

In this study, the 95th percentiles of hsCRP were 0.15 and 5.01 mg/L for 5–17-year-old males and females, respectively. This range is slightly different from the one reported by the large European cohort study.⁴² The 97.5th percentiles of hsCRP in the current study ranged from 2.56 to 8.08 mg/L, which is comparable with other previous findings (2.8–6.3 mg/L).^45,50. In contrast to the above reports, a Canadian study⁴¹ revealed the lowest 97.5th hsCRP percentile of 1 mg/L for both sexes. The discrepancy in hsCRP concentrations may be due to differences in health status (such as the presence of chronic and acute illness conditions), other behavioral habits, differences in methodologies, or the number of study participants.

According to the current findings, children who never eat vegetables and/or fruits and those who are obese were more than three times more likely to have elevated serum hsCRP concentrations. Obese children also had lower 2.5th hsCRP values of 0.16 mg/L and higher 97.5th hsCRP values of 8.08 mg/L. A number of studies^{13–15,42,51–54} found a link between childhood obesity and high hsCRP levels. Previous studies have revealed that adipose tissue is a secondary source of hsCRP, with hsCRP mRNA expression in human adipose tissue.^55–57 In the regression analysis, the hsCRP levels were found to be directly related to not consuming fruit and/or vegetables. Fruits and vegetables’ antioxidant effects may be mediated by changes in fat mass and decreased adipocyte IL-6 production.^58,59 Previous studies^25,35 discovered a direct link between hsCRP and physical activity. In contrast, no association was found between hsCRP and physical activity, fasting behaviors, meat and/or animal product consumption, or coffee and/or tea consumption in this study. There was no clear explanation for these findings; as the data was self-reported, there could be some bias. Children who did not fast had higher upper-limit hsCRP levels (6.81 mg/L) than those who did (3.81 mg/L). Similarly, those who did not engage in regular physical activity had higher upper limit hsCRP levels (7.07 mg/L) than those who did (4.30 mg/L). Participants who were overweight or obese had significantly higher levels of hsCRP, implying that physical activity and fasting could accelerate peripheral fat oxidation, resulting in less fat deposition and weight loss.^60,61

In the current study, no significant association was found between lipid profiles (such as TC, TG, LDL-c, and HDL-c) and hsCRP levels. In line with the current study, several other previous studies have shown that hsCRP has no association with serum triglyceride levels^25,31,36,62 or LDL cholesterol.²⁵ In contrast, prior cross-sectional and longitudinal investigations have found that high hsCRP levels are associated with low HDL-c levels,^36,63–65 and other studies have found an association with triglyceride levels.^66–68 Even though HDL-c levels were not significantly related to hsCRP, participants with low HDL-c had greater hsCRP concentrations (6.52 mg/L) at the upper limit than those with normal HDL-c (3.71 mg/L). We recruited apparently healthy children for this study. For instance, more than 95% of the participants had normal serum lipid levels, with only a tiny percentage of children having aberrant serum lipid levels, which could explain the absence of connections. The study has some limitations, such as those under-five-year-old children, non-native Ethiopian children, and migrants were not taken into account due to resource constraints, and the study was limited only to Addis Ababa. Furthermore, the sample size was determined only using the CLSI guidelines; no power calculations were done.

Conclusion

This study is the first to determine the reference intervals of serum hsCRP among apparently healthy Ethiopian children. The study detected no significant differences in hsCRP distribution across age groupings or sexes in this investigation. Meanwhile, notable differences were observed in the established reference intervals of hsCRP in comparison with published literature. The hsCRP levels were found to be linked to increased BMI and never or occasionally eating vegetables and/or fruits. Furthermore, we confirmed that the serum hsCRP concentration in obese children was considerably greater than in non-obese children. Since hsCRP has recently been identified as a sensitive marker of low-grade inflammation, this finding highlights the importance of improving weight status in childhood. Moreover, based on our findings, we suggest using these population-based hsCRP reference values as a screening tool for the early detection of a variety of inflammatory diseases.

Supplemental Material

Supplemental Material - Determination of high-sensitivity C-reactive protein reference intervals for apparently healthy children in Addis Ababa, Ethiopia

Supplemental Material for Determination of high-sensitivity C-reactive protein reference intervals for apparently healthy children in Addis Ababa, Ethiopia by Ousman Mohammed, Melkitu Kassaw, Endalkachew Befekadu, Letebrhan G/Egzeabher, Abebaye Mekonen, Demiraw Bikila, Feyissa Challa, Abiy Belay, Mistire Wolde, Kassu Desta and Aster Tsegaye in European Journal of Inflammation

Footnotes

Acknowledgements

We appreciate the study participants’ tolerance during the study period. We would especially like to express our gratitude and appreciation to the data collectors.

Authors contribution

All authors made significant contributions to the manuscript. All authors have read and given their final approval of the version of the manuscript submitted for publication.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Ethiopian Public Health Institution and the Ministry of Innovation and Technology, which were the sources of the budget.

Ethical consideration

The study was granted permission by the Department of Medical Laboratory Science’s departmental research and ethical review committee (DRERC), with protocol number DRERC/439/2019/MLS, in accordance with the Declaration of Helsinki. Moreover, written informed consent was obtained from all subjects and/or their legal guardian(s). An information sheet was distributed to all study participants and their parents or guardians to explain the purpose of the study. The names of the participants were kept confidential, and only codes were used on the questionnaire and biological sample containers to maintain confidentiality.

Availability of data and materials

All the datasets used and/or analyzed during the current study are available in the manuscript.

Informed consent

Written informed consent was obtained from all subjects and/or their legal guardian(s). Likewise, the author obtained written informed consent from the legally authorized representative of the subjects for the publication of this study.

ORCID iD

Ousman Mohammed

Supplemental Material

Supplemental material for this article is available online.

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Determination of high-sensitivity C-reactive protein reference intervals for apparently healthy children in Addis Ababa,Ethiopia

Abstract

Keywords

Introduction

Materials and methods

Study population and eligibility criteria

Anthropometric measurements

Sample collection, processing, and biochemical measurements

Data quality assurance and quality control

Statistical analysis

Result

Characteristics of study population

High-sensitive C-reactive protein level distribution

Correlation between hsCRP and predictors

Factors associated with elevated hsCRP levels among children

The percentile distributions of serum hsCRP concentrations in apparently healthy children

Discussion

Conclusion

Supplemental Material

Supplemental Material - Determination of high-sensitivity C-reactive protein reference intervals for apparently healthy children in Addis Ababa, Ethiopia

Footnotes

Acknowledgements

Authors contribution

Declaration of conflicting interests

Funding

Ethical consideration

Availability of data and materials

Informed consent

ORCID iD

Supplemental Material

References

Supplementary Material