Identifying laboratory parameters that can quickly guide our diagnosis of a child with signs of acute illness has always been of great interest to pediatricians. One such marker, discovered as early as 1930, is the C-reactive protein (CRP)¹ and has proven useful in assessing the severity of acute infectious disease or in the diagnosis and follow-up of patients with inflammatory diseases.¹

Synthesized in the liver, CRP reaches the bloodstream in response to inflammation. It is an acute phase reactive protein that is induced primarily (but not only)² by interleukin-6 (IL-6) during an acute inflammatory or infectious process.^1,3 Among its main roles, CRP has both pro-inflammatory and anti-inflammatory properties, playing an important part in recognizing and eliminating exogenous pathogens.¹ Serum CRP values begin to rise about 6 hours after stimulus onset and its plasma half-life is approximately 19 hours. Its half-life is constant across health and disease, thus, the only factor driving the circulating CRP level is its rate of synthesis.⁴

Since its discovery, numerous studies have evaluated the role of this biomarker in the diagnosis and management of a wide array of conditions. Altered CRP values can be found in both acute and chronic diseases, in infectious or non-infectious diseases, as well as in mental illness or trauma.⁵ Although the specificity for a clear diagnosis is low, the utility of CRP in clinical practice is now increased for two reasons: 1) CRP levels rise and fall rapidly with the onset and elimination of the inflammatory stimulus¹ and 2) determination of CRP values is quick, within minutes, and can easily be done from both whole blood and serum.⁶

Given the clinical importance of CRP, but also the dynamics of published studies on this topic, we set out to perform a critical review of the most recent data on the usefulness of CRP in the diagnosis and monitoring of the pediatric patient.

We conducted a systematic literature search to identify the most recently published articles on the clinical utility of CRP in pediatric practice. The data search was performed using PubMed. We used the following two-word combinations to identify articles: "C-reactive protein” and "children”, and "CRP” and "children”. In order to present data as current as possible, the search period was defined as 1 January 2016 to 30 September 2021.

Inclusion criteria were: (i) original articles or reviews; (ii) articles published in English; (iii) articles whose content could be accessed in extenso; (iv) studies that assessed the importance of CRP in the management and diagnosis of the pediatric patient.

Exclusion criteria were: (i) case report or opinion articles; (ii) articles whose abstract or full-text content was not available; (iii) articles published in a language other than English; (iv) studies that did not provide data for the intended purpose.

After initial evaluation of the abstracts, relevant data were extracted by 2 reviewers by critically reading each article. A total of 7510 articles were identified from the primary search. After applying the inclusion and exclusion criteria and critical reading of the studies we retained 64 eligible articles to be presented in this review.

Literature review

Newborns

Newborn care requires great attention from the clinician, as the prevalence of early and late-onset neonatal sepsis is still high in this age group and can be life-threatening. An abundance of studies have evaluated laboratory markers in the diagnosis of neonatal sepsis. In clinical practice, CRP is the most widely used laboratory biomarker for the detection of early-onset sepsis in particular.⁷ Recent studies, however, caution that CRP may be physiologically increased in term or preterm infants.⁸ The type of delivery may also influence the value of this biomarker, thus mean CRP values have been shown to be significantly higher in infants born by vaginal delivery (3.80 mg/L) and emergency caesarean section (3.60 mg/L) than in infants born by elective caesarean section (2.10 mg/L).⁷ At the same time increased CRP on day 4 of life could reflect early production and secretion of IL-6 rather than actual infection. Therefore, serial measurement of IL-6 could aid in the diagnosis of sepsis and reduce unnecessary antibiotic consumption in infants.⁹ Overall, all recent studies identified showed that CRP alone is not a good indicator for early-onset sepsis.^10-14 Serial determinations at 24-48 hours¹¹ along with other markers of inflammation such as procalcitonin^15,16 or IL-6⁹ are needed to support the diagnosis of early neonatal sepsis.

Faisal Khan¹⁰ published a report in 2019 showing that CRP has better sensitivity and positive predictive value in distinguishing late- versus early-onset sepsis: sensitivity=17.16%, specificity=58.33%, positive predictive value=72.72% and negative predictive value=9.81% – for early-onset sepsis vs. sensitivity=77.45%, specificity=57.14%, positive predictive value=92.94% and negative predictive value=25.80 – for late-onset sepsis).¹⁰

Viral vs. bacterial infections

Acute infections, viral or bacterial, are the main reasons for children’s presentation to the hospital. Clinical differentiation between these etiologies is sometimes difficult and laboratory investigations are used to guide diagnosis. A complete blood count coupled with inflammatory markers are most often used for this purpose. Fever, a quasi-present element in acute infectious diseases, occurs as a result of a proinflammatory cytokine response, which will also lead to increased serum CRP. In addition, as mentioned above, this biomarker has a rapid synthesis and a short half-life, which is why CRP is most often used in clinical practice in viral-bacterial differentiation in febrile children.^17,18 Verbakel et al.¹⁹ published in 2018 a study of 5517 Belgian children with acute illness showing that CRP can be used in their primary assessment for stratification and emergency management. The study also showed that in one third of acutely ill children a serious infection could be excluded.

A French study of 1060 children with fever without an identified source reported a low prevalence of bacterial etiology, and CRP and procalcitonin were more sensitive in their identification than absolute white blood cell or neutrophil counts.²⁰

Keitel et al.²¹ in a study of 1726 children showed that determining CRP in children with respiratory infections substantially reduced antibiotic prescribing. Similar results were reported by a study conducted in Vietnam, where antibiotic consumption was reduced by 14% by following CRP measurement in children with respiratory tract infections,²² and Verbakel et al.²³ in a meta-analysis published in 2019, recommend using CRP in outpatients to reduce antibiotic prescribing.

Influenza has long been the most important epidemic virus during the cold season and is responsible for an increased rate of hospitalization among children.^24,25 Bacterial superinfections can often occur²⁶ and early identification reduces morbidity, mortality, and unnecessary or inadequate antibiotic consumption in such cases. Recent studies show that simultaneous tracking of CRP and procalcitonin evolution curves in children with influenza can lead to early identification of bacterial co-infections.²⁷ In infants under 3 months with influenza-like illness a CRP value above 30.5 mg/L should raise suspicion of possible bacterial superinfection.²⁸

In terms of differentiating the etiology of pneumonia in pediatric patients Bhuiyan et al.²⁹ in a study of 230 children with pneumonia showed that combining increased CRP with the patient's clinical and radiological features differentiated much better between a viral or bacterial etiology of infection than CRP used alone, regardless of its value. Similarly, Higdon et al³⁰ show a positive association between the diagnosis of bacterial pneumonia and elevated CRP (above 100 mg/L), but the data must be interpreted in the clinical context.

CRP is also used in the diagnosis of sepsis in pediatric patients, and recent data show that serial assessment of CRP is useful in the early identification of patients with poor outcomes on antimicrobial therapy.³¹ Tracking this biomarker may reduce mortality especially among infants with sepsis by allowing timely intervention and personalized adjustments of the treatment regimen.³¹

In febrile pediatric patients without an established source of infection, CRP has been positively associated with urinary tract infections (UTI).³² In children under 2 years of age, positive CRP is suggestive of an UTI due to Gram-negative enteric bacteria.³²

CRP can also be measured in the urine. A significant urinary CRP excretion in children with transient non-renal infectious disease could be attributed to CRP synthesis in renal epithelial cells.³³ In contrast, in nephrotic syndrome although there is urinary protein loss, there is no significant CRP loss in the urine.³³

COVID-19

Coronavirus disease-2019 (COVID-19) is characterized by a well-known proinflammatory phase and CRP along with other inflammatory markers, especially IL-6, show elevated values.^34,35 Numerous studies in adults have shown a negative association between disease progression and CRP values (especially above 100 mg/L).^34-37 Among children less data are available, in a meta-analysis published by Ma et al.³⁸ 17% of children with COVID-19 had elevated CRP values, but their prognosis was good. However, CRP is a criterion in the diagnosis and prognosis of multisystem inflammatory syndrome in children (MIS-C).^39-43 Therefore, in children who have experienced COVID-19 and at 4-6 weeks present with an acute episode of illness with fever, it is necessary to dynamically follow CRP values.

Overweight and metabolic syndrome

Childhood obesity is a growing problem among the pediatric population worldwide.⁴⁴ In addition to problems related to physical appearance, overweight has numerous metabolic implications, including the association with chronic and subclinical inflammation due to an imbalance of inflammatory mediators.⁴⁵ A 2018 study supports earlier data showing that adipose tissue is an extrahepatic source of CRP.⁴⁶ Another study points out that adipose tissue is an important secretor of several proinflammatory markers.^47,48 Thus, obese people tend to have high concentrations of CRP and IL-6,^45,48-52 tumor necrosis factor α,⁴⁸ apolipoprotein A-1, haptoglobin⁴⁹ and leptin⁵² compared to normal weight subjects. Moreover, the association between obesity and type 1 diabetes mellitus was further associated with an increase in serum CRP levels.^51,53,54 This subclinical inflammation maintained by overweight, whether or not associated with other metabolic changes increases cardiovascular risk in these children.^53-55 In contrast, Abreu et al.⁵⁶ showed that normotensive adolescents had lower levels of IL-6, CRP and leptin than overweight or obese counterparts.

Diet and sedentary lifestyles are proven risk factors for childhood obesity. But both parameters are also implicated in a pro-inflammatory status. Thus, in 2018, Gonzalez-Gil et al.⁵⁷ showed that frequent consumption of sugar and processed products in the detriment of consumption of vegetables and fruits is independently associated with inflammation (elevated CRP values) in children. In addition, Khayyatzadeh et al.⁵⁸ conducted a study on 670 Iranian adolescent girls and observed a positive association of elevated CRP values and adherence to the Western dietary pattern. Therefore, improving diet quality in childhood may prevent to a certain extent future diseases related to chronic inflammation.^57,59

Physical activity has been shown in numerous recent studies to be inversely associated with an increase in CRP.^60-64 Adolescents with an activity of more than 300 minutes/week had lower serum CRP values compared to sedentary adolescents,⁶¹ regardless of gender,⁶⁴ but abrupt cessation of active behavior will lead to negative feedback on CRP values, especially in pubertal children.^60,64 Overall, physical activity helps prevent obesity, limit the pro-inflammatory status and reduce cardiovascular risk among children and adolescents.

Neuro-psychological state

Evidence of an association between depression and inflammation in adults has already been reported in the literature, but in children these issues have recently begun to be studied. Tabatabaeizadeh et al.⁶⁵ showed that there is a significant association between increased CRP and depression score in adolescents. Moreover, serum CRP had elevated values in adolescents who were resistant to antidepressant treatment.^66,67 In addition, it was shown that in patients with functional neurological symptom disorder elevated CRP levels suggest activation of the immune-inflammatory component of the brain's stress system.⁶⁸ It has also been shown that adolescents who have experienced recent stressful events have increases in inflammatory activity (increased CRP).^69,70

Slopen et al.⁷¹ in a study of 502 Tanzanian children showed that healthy children whose mothers experienced domestic violence had a marginally increased median CRP level compared to children whose mothers did not report domestic violence (0.41 mg/L vs. 0.35 mg/L; p=0.13). This difference became significant between the two groups if the child showed signs of acute illness (4.06 mg/L vs. 3.09 mg/L; p=0.03).

Bernard et al.⁷² demonstrated increased CRP in children in social care who did not receive an optimal and safe developmental environment, thus suggesting a link between a pro-inflammatory status and a sense of attachment that is formed from birth and depends on the degree of security the child feels within the family. Similar findings were presented by Measelle et al.⁷³ who reported that family stress, maternal depression and attachment security were directly associated with infant inflammation.

CRP has been and remains according to the latest literature data the biomarker most used by pediatricians for the diagnosis and follow-up of children with acute illnesses but also to identify a subclinical inflammatory profile in individual patients. It is an easy and reliable marker, but its value must be integrated into the patient's clinical context and medical judgement must take precedence, the ultimate goal being not to normalize CRP but to improve the patient's clinical outcome.

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