Inflammatory Markers in Pediatrics

Introduction

• Inflammatory markers are blood substances increasing in response to inflammation.
• These markers typically increase during infection, injury, rheumatoid conditions, autoimmune conditions, malignancy, and chronic diseases.
• Common inflammatory markers in pediatrics include erythrocyte sedimentation rate (ESR), ferritin, C-reactive protein (CRP), procalcitonin (PCT), and calprotectin.
• The usefulness of these markers depends on the clinical situation and how severe the illness is.
• Common inflammatory markers, their biological origins, utility in certain conditions, normal ranges, and implications for real-time clinical decision-making are reviewed.

Erythrocyte Sedimentation Rate (ESR)

• ESR measures the speed at which red blood cells (RBCs) settle in a vertical tube in 1 hour.
• ESR is expressed in millimeters per hour.
• Usually, RBCs repel each other because of the negative charge from sialic acid on their membranes.
• During inflammation, the liver produces fibrinogen, which is positively charged
• Fibrinogen reduces the negative charge on RBC membranes, causing them to stick together.
• The aggregation of RBCs decreases resistance in the plasma, increasing the ESR.
• A higher ESR indicates faster RBC settling and more inflammation.
• ESR typically rises within 1 to 2 days of inflammation and takes weeks to return to baseline due to fibrinogen's 7-day half-life.
• Elevated ESR is seen in sickle cell crises, infection, and systemic/ localized inflammatory conditions.
• Kawasaki disease (KD) is systemic vasculitis affecting children aged 5 years and younger, and it commonly causes acquired heart disease.
• KD can cause moderate to severe ESR elevations due to widespread systemic inflammation.
• Patients with KD treated with intravenous immunoglobulin therapy (IVIG) may have worsening ESR elevations after IVIG because globulin aggregates on RBCs.

Ferritin

• Ferritin is an iron storage and transport protein, and a commonly used inflammatory marker.
• During bacterial infection, elevated ferritin levels sequester iron, impeding pathogen access to the body's iron stores.
• Ferritin levels usually rise within 1 to 2 days after inflammation or infection.
• Ferritin peaks within 5 to 7 days, and takes weeks to normalize afterward.

Hemophagocytic Lymphohistiocytosis (HLH) and Macrophage Activation Syndrome (MAS)

• HLH and MAS are life-threatening conditions of excessive immune activation and inflammation, leading to severe tissue damage.
• Hyperferritinemia is seen in HLH/MAS with a low ESR and high CRP level.
• Monitoring ferritin levels is critical for HLH/MAS diagnosis and management.
• Specialized biomarkers like soluble interleukin 2 receptor α, interleukin 18, and chemokine ligand 9 may be more specific for HLH/MAS, but results aren't immediately available.
• Hyperferritinemia can occur in transfusion dependence, viral/bacterial infection, stem cell transplant, malignancy, and renal disease.
• Critically ill children with ferritin levels of >1000 ng/mL, especially with high CRP, indicate immune system hyperactivation.
• Ferritin levels of >1000 ng/mL with high CRP is associated with higher odds of pediatric intensive care unit admission and mortality.

C-Reactive Protein (CRP)

• CRP is an inflammatory marker synthesized by the liver in response to interleukin 6.
• CRP binds phosphocholine on bacteria and necrotic cells, enhancing opsonization and activating the classical complement cascade.
• CRP and ESR are often ordered together and interpreted in combination for a better understanding of the clinical situation.
• CRP rises and falls more rapidly than ESR, often rising in hours and peaking in 48 hours.
• The rapid response makes CRP particularly useful in detecting early acute infections or inflammation.
• ESR may take weeks to normalize, CRP levels typically return to normal after effective therapy begins.
• The difference between ESR and CRP can differentiate between an acute insult and a chronic process.
• Infections likely cause both CRP and ESR elevations.
• The degree of CRP elevation may relate to the extent of infection.
• Myositis is likely to cause higher CRP elevations than a superficial skin infection.
• CRP monitors response to treatment for infectious conditions.
• In pediatric osteomyelitis, both ESR and CRP are typically elevated at admission.
• ESR generally peaks 2 days after effective treatment and declines slowly, while CRP decreases more rapidly within 2 to 3 days.
• Both CRP and ESR normalize by the end of the treatment course.
• Unlike ESR, CRP levels are not influenced by elevated plasma protein concentrations, such as during IVIG treatment.
• CRP is typically not elevated in patients with active systemic lupus erythematosus (SLE), except in cases of serositis and infection.
• Active SLE is associated with elevated interferon alpha, which suppresses CRP.

Procalcitonin (PCT)

• PCT is the precursor protein to calcitonin, predominantly produced by the thyroid gland.
• PCT is undetectable in healthy individuals.
• PCT increases in response to bacterial toxins and cytokines, including lipopolysaccharides from bacterial membranes.
• PCT exhibits a swift rise and fall, peaking around 24 to 48 hours.
• False elevations may occur within the first 48 hours after birth due to maternal and perinatal factors.
• PCT levels are commonly used to differentiate between bacterial and nonbacterial processes.
• Interferon gamma, commonly elevated during viral infections, inhibits PCT production.
• 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.
• PCT has the potential to guide antibiotic use.
• Elevated PCT 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.
• Immunocompromised status does not affect PCT production.

Calprotectin

• Calprotectin sequesters metals like calcium and zinc.
• It is located in the cytosol of neutrophils.
• During gut inflammation, neutrophils migrate to the gastrointestinal tract, and calprotectin becomes detectable in feces.
• Fecal calprotectin increases with an increasing degree of inflammatory activity in the gastrointestinal tract.
• Levels rise quickly and remain stable over weeks.
• Fecal calprotectin distinguishes inflammatory from noninflammatory gastrointestinal conditions.
• Fecal calprotectin has 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.
• Higher concentrations are often observed in acute bacterial diarrhea compared with viral diarrhea.

Limitations of Inflammatory Markers

• Clinical utility 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 direct comparisons difficult.
• Understanding limitations is crucial to prevent overreliance.

Conclusion

• Inflammatory markers are helpful in the diagnosis and management of inflammation, infections, injuries, autoimmune conditions, malignancies, and chronic diseases.
• Clinicians must be mindful of the implications of ordering these tests, understanding pitfalls, timing, and potential causes of abnormal results.
• Elevated inflammatory marker levels should always be interpreted with the patient's overall clinical picture.
• Rapid CRP testing and increasing availability of timely procalcitonin results have rendered diagnostic dilemma obsolete for febrile infants.
• Inflammatory marker testing should be adjunctive to clinical reasoning, ordered thoughtfully.
• Thoughtful testing minimizes false-positive results and ensures responsible health care-cost stewardship.