Inflammatory Markers in Pediatrics

Inflammatory markers are substances in the blood that increase in response to inflammation, typically rising during infection, injury, rheumatoid and autoimmune conditions, malignancy, and chronic diseases. Inflammatory markers commonly used in pediatric practice include erythrocyte sedimentation rate (ESR), ferritin, C-reactive protein (CRP), procalcitonin (PCT), and calprotectin. The utility of these markers varies depending on the clinical indication and the acuity of the illness. This review article provides an overview of common inflammatory markers, including their biological origins, utility in certain conditions, normal ranges, and implications for real-time clinical decision-making.ESR measures how quickly red blood cells (RBCs) settle in a vertical sedimentation tube over 1 hour, expressed in millimeters per hour. Normally, RBCs repel each other due to the negative charge from sialic acid on their membranes. During inflammation, the liver produces fibrinogen, which is positively charged and reduces the negative charge on RBC membranes, causing them to adhere. This aggregation decreases resistance in the plasma, increasing the ESR. A higher ESR indicates faster RBC settling and inflammation. ESR typically rises within 1 to 2 days of inflammation onset but takes weeks to return to baseline due to fibrinogen’s half-life of about 7 days. Clinically, elevated ESR levels are seen in diverse conditions ranging from sickle cell vaso-occlusive crises to infection to systemic and localized inflammatory conditions.Kawasaki disease (KD) is a systemic vasculitis that usually affects children aged 5 years and younger and is a common cause of acquired heart disease in children. KD can cause moderate to severe elevations in ESR due to widespread systemic inflammation. Patients with KD treated with intravenous immunoglobulin therapy (IVIG) may have worsening ESR elevations after IVIG due to the aggregator effect of globulin on RBCs.Ferritin, an iron storage and transport protein, is a commonly used inflammatory marker. In the setting of bacterial infection, elevated ferritin levels play a pivotal role in sequestering iron, thereby impeding a pathogen’s access to the body’s iron stores. Ferritin levels typically rise within 1 to 2 days after the onset of inflammation or infection, peak within 5 to 7 days, and take weeks to normalize after an inflammatory response.Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are overlapping, life-threatening conditions characterized by excessive immune activation and inflammation leading to severe tissue damage. Hyperferritinemia is observed in HLH/MAS, along with a low ESR level (due to hypofibrinogenemia) and an elevated CRP level. Monitoring ferritin levels is crucial for diagnosing and managing HLH/MAS. Specialized biomarkers like soluble interleukin 2 receptor α, interleukin 18, and chemokine ligand 9 may be more specific for HLH/MAS; however, their results are not immediately available for early decision-making.Hyperferritinemia can also be seen in the settings of transfusion dependence, viral or bacterial infection, stem cell transplant, malignancy, and renal disease. In children who are critically ill, ferritin levels that exceed 1000 ng/mL, especially when accompanied by high CRP levels, indicate immune system hyperactivation and are associated with higher odds of pediatric intensive care unit admission and mortality.CRP is another commonly used inflammatory marker, predominantly synthesized by the liver in response to interleukin 6. CRP binds phosphocholine on the surface of bacteria and necrotic cells, enhancing opsonization and activating the classical complement cascade.CRP and ESR are often ordered in tandem under certain clinical circumstances, with their results interpreted in combination to provide a better understanding of the clinical situation. Compared with ESR, CRP exhibits a more rapid rise and fall, often rising within hours and peaking within 48 hours. This rapid response makes CRP particularly useful in detecting early acute infections or inflammation. Whereas ESR may take weeks to normalize due to the long half-life of fibrinogen, CRP levels typically return to normal shortly after effective therapy is initiated. This distinction between ESR and CRP can help differentiate between an acute insult and a chronic process.Infections are likely to cause both CRP and ESR elevations. The degree of CRP elevation may relate to the extent of infection. For instance, myositis is likely to cause higher CRP elevations compared with a superficial skin infection.CRP also has great utility in monitoring response to treatment for infectious conditions. In pediatric osteomyelitis, both ESR and CRP are typically elevated at admission. Whereas ESR generally peaks 2 days after effective treatment begins and declines slowly over weeks, CRP decreases more rapidly, within 2 to 3 days. Both CRP and ESR usually normalize by the end of the treatment course.Unlike ESR levels, CRP levels are not influenced by elevated plasma protein concentrations that may occur: for example, during treatment with IVIG.Of note, CRP is typically not elevated in patients with active systemic lupus erythematosus (SLE) disease (exceptions include cases of serositis and infection in a patient with active SLE disease). Active SLE disease is associated with elevated interferon alpha, which suppresses CRP.PCT is the precursor protein to calcitonin, predominantly produced by the thyroid gland. In healthy individuals, it is undetectable. PCT levels increase in response to bacterial toxins and cytokines including lipopolysaccharides from bacterial membranes. PCT exhibits a swift rise and fall, typically peaking around 24 to 48 hours. False elevations may occur within the first 48 hours after birth due to various maternal and perinatal factors.Because bacterial toxins and cytokines cause increased production of PCT, PCT levels are commonly used to differentiate between bacterial and nonbacterial processes in pediatric practice. Interferon gamma, commonly elevated during viral infections, inhibits PCT production. Thus, elevated PCT levels are typically associated with bacterial infections, particularly pneumonia, meningitis, and other invasive bacterial infections. Normal PCT results can occur in localized infections like tonsillitis, sinusitis, cellulitis, or abscess. In the right clinical setting, PCT has the potential to guide antibiotic use.Elevated PCT levels can also be seen in patients receiving immunomodulatory agents, those with severe liver disease, inflammatory disorders (including KD), and neuroendocrine tumors. Mild elevations may also be observed in patients with malaria, invasive candida, and pulmonary mold infections. Notably, immunocompromised status does not affect PCT production.Calprotectin is a complex of proteins that sequester metals such as calcium and zinc. It is located in the cytosol of neutrophils. During an inflammatory process of the gut, neutrophils migrate to the gastrointestinal tract, and calprotectin becomes detectable in the feces.Fecal calprotectin typically increases with an increasing degree of inflammatory activity in the gastrointestinal tract. Levels rise quickly and remain stable over weeks. Fecal calprotectin is used as a biomarker to distinguish inflammatory from noninflammatory gastrointestinal conditions. Fecal calprotectin has a high sensitivity and moderate specificity for inflammatory bowel disease in children compared to blood inflammatory markers. It also has a high negative predictive value; normal tests may prevent unnecessary gastroenterologist referrals and costly endoscopies. Fecal calprotectin can also be elevated in infectious diarrhea, with higher concentrations often observed in acute bacterial diarrhea compared with viral diarrhea.The clinical utility of inflammatory markers is tempered by limitations. Inflammatory markers can be influenced by a variety of factors, potentially leading to false-negative or false-positive results. Studies investigating inflammatory markers demonstrate variability in definitions, normal ranges, and methodology, making it difficult to directly compare these tests across different diseases and settings. Understanding limitations is crucial to prevent overreliance.Inflammatory markers are helpful tools in the diagnosis and management of inflammation, infections, injuries, autoimmune conditions, malignancies, and chronic diseases. Table 1 compares helpful features of inflammatory markers discussed in this article. Clinicians must be mindful of the implications of ordering these tests, with a clear understanding of pitfalls, timing, and potential causes of abnormal results. Interpretation of elevated inflammatory marker levels should always be made in conjunction with the patient’s overall clinical picture.Comments: Most of us will have reason to order inflammatory marker tests in the course of evaluating febrile infants. In the past, we relied on an elevated white blood cell (WBC) count as the best rapid-test indicator of possible occult bacteremia or other serious bacterial illness. Many primary care clinicians rued seeing a febrile but well-appearing 28- to 90-day-old infant with a WBC count barely over 15 000/mm3 since the next recommended step was to order a lumbar puncture and empirical antibiotics. Experience had taught us that while this WBC cutoff value had a high negative predictive value, it also had a very low positive predictive value given the rarity of serious bacterial infection. While we didn’t want to miss treating the rare case of serious bacterial infection, we knew that most of these infants would be just fine without our intervention.The widespread accessibility of rapid CRP testing and increasing availability of timely procalcitonin results have rendered this diagnostic dilemma obsolete. Ordering these tests when confronted with a febrile infant can save clinicians, our patients, and our patients’ families undue stress. At the same time, even though CRP is a better indicator than WBC of invasive bacterial disease, laboratory tests still cannot replace sound clinical intuition. Inflammatory marker testing should be adjunctive to clinical reasoning and ordered thoughtfully to minimize false-positive results and ensure responsible health care-cost stewardship.Linda Y. Fu, MD, MSAssociate Editor, In BriefThank you to Dr Anita Dhanrajani for her review of this article.