Evaluarea imunobiologică a inflamației la copil: proteina C-reactivă ultrasensibilă, procalcitonina și interleukina-6

Pediatric sepsis and organ failure

While inflammation is vital for fighting infections, a disrupted immune response can trigger a cascade of events, causing tissue damage, immune dysfunction, and systemic inflammatory response syndrome (SIRS). If uncontrolled, this intravascular inflammation may lead to distant organ failure and quickly progress to septic shock with multiple organ dysfunction^(1,2). The recognition of sepsis in pediatric patients is particularly challenging due to the high prevalence of common febrile infections, the low specificity of clinical features that distinguish sepsis from other conditions, and the ability of children’s physiological systems to compensate until the onset of advanced shock. The outcomes of pediatric sepsis are strongly influenced by the speed at which the condition is identified and appropriately managed. International campaigns and clinical guidelines emphasize the critical importance of early recognition and timely diagnosis, alongside the rapid initiation of empirical antimicrobial therapy and prompt escalation of care when necessary. Although such strategies have been shown to reduce mortality rates, sepsis-related mortality in high-income countries remains largely unchanged, highlighting the need for continued improvements in early detection and management practices⁽³⁾. The management of fever without a clear source in children aged 36 months old or younger continues to pose significant diagnostic challenges, as the underlying causes can range from self-limiting viral infections to more serious bacterial infections (SBIs). The use of biomarkers such as C-reactive protein (CRP), procalcitonin (PCT) and interleukin-6 (IL-6) has been explored in predicting the presence of SBIs, though their diagnostic thresholds vary. Several factors, including differences in the definitions of SBIs, the prevalence of these infections, patient-specific characteristics and the timing of the clinical presentation, influence these variations. This protocol outlines a systematic review and meta-analysis aimed at determining the optimal thresholds for CRP, PCT and IL-6 in distinguishing SBIs in children ≤36 months old. Furthermore, the review seeks to evaluate the performance of these biomarkers in the early detection of bacterial infections, specifically within the first 48 hours following the onset of fever⁽⁴⁾.

Clinical chemistry of inflammatory panel

Among the various biomarkers assessed, C-reactive protein and procalcitonin have consistently been shown to be reliable indicators for predicting serious bacterial infections in pediatric patients. These biomarkers are frequently used in clinical practice due to their ability to identify the presence of bacterial infections, providing valuable diagnostic information to guide treatment decisions⁽⁵⁾. Recent studies have highlighted the growing significance of cytokines, specifically interleukin-6, in the early prediction of sepsis in young children. While traditional biomarkers like C-reactive protein and procalcitonin have been widely used, emerging evidence suggests that cytokines, particularly IL-6, play a crucial role in the immune response during sepsis. IL-6 levels rise rapidly in response to infection and inflammation, making it a potential marker for diagnosing sepsis at an early stage in pediatric patients. This development underscores the evolving landscape of diagnostic tools, offering new avenues for more accurate and timely identification of sepsis in young children^(6,7). These biomarkers have been utilized for various diagnostic purposes in research related to serious bacterial infections (SBIs). In clinical practice, healthcare providers use these biomarkers with different threshold values depending on the goal of the diagnostic test – whether the aim is to confirm the presence of an SBI (rule in) or to exclude it as a potential diagnosis (rule out). Most studies and clinicians prefer thresholds that maximize sensitivity and negative predictive value. This approach is particularly important because it reduces the risk of overlooking an SBI, ensuring that pediatric patients do not miss potentially serious bacterial infections. Essentially, a higher sensitivity means that the test is more likely to correctly identify those with SBIs, while a higher negative predictive value ensures that those without the infection are accurately identified⁽⁸⁾.

1. High-sensitivity C-reactive protein

High-sensitivity C-reactive protein (hs-CRP) is a biomarker of inflammation that is a more sensitive version of the standard CRP test. It can detect lower levels of CRP in the blood, allowing for the identification of subclinical or low-grade inflammation. CRP is an acute-phase protein produced by the liver in response to inflammation, infection, or tissue injury.

• Interval reference
  • In children, normal hs-CRP levels are typically
  • Levels between 1 and 3 mg/L may indicate low-grade inflammation.
  • Levels above 3 mg/L suggest a higher inflammatory state, but the interpretation must consider the clinical context.
  • Role in inflammation in children: early detection of inflammatory conditions
  • High-sensitivity C-reactive protein is used to detect early or low-level systemic inflammation even when clinical signs are mild or absent. hs-CRP is helpful in identifying autoimmune diseases, infections, or chronic inflammatory conditions in children.
• Monitoring disease activity

In diseases such as juvenile idiopathic arthritis, systemic lupus erythematosus or Kawasaki disease, hs-CRP helps track disease progression or response to therapy.

• Differentiating between bacterial and viral infections: febrile/nonfebrile

Although hs-CRP is nonspecific, elevated levels may support the diagnosis of a bacterial infection over a viral one, especially when used alongside other markers (e.g., procalcitonin, WBC count).

• Predicting cardiovascular risk

In older children, especially those with obesity or metabolic syndrome, elevated hs-CRP may indicate endothelial dysfunction and future cardiovascular risk⁽⁹⁾.

• Evaluating nonspecific symptoms

High-sensitivity C-reactive protein can help guide further testing in children with fever of unknown origin, fatigue, or other nonspecific complaints.

2. Procalcitonin

Procalcitonin (PCT) is a precursor of the hormone calcitonin, normally produced by the thyroid gland. Under healthy conditions, PCT levels in the blood are very low. However, during systemic bacterial infections, PCT is produced in large amounts by various tissues throughout the body.

It is considered a highly specific biomarker for bacterial infections and sepsis.

• Interval reference
  • 0.05-0.5 ng/mL: possible local infection or early systemic infection.
  • >0.5 ng/mL: suggestive of systemic bacterial infection or sepsis.
  • >2 ng/mL: strong indication of severe bacterial sepsis or septic shock.
• Role in inflammation in children: distinguishing between bacterial and viral infections

PCT is significantly elevated in bacterial infections, but usually remains low in viral infections, helping clinicians decide on antibiotic use.

This is especially useful in febrile children where the source of infection is unclear.

• Diagnosing and monitoring sepsis

In neonates and children with signs of systemic illness, elevated PCT levels help in the early diagnosis of sepsis. Serial measurements can monitor the response to treatment or disease progression.

• Guiding antibiotic therapy

PCT-guided protocols can help reduce unnecessary antibiotic use, especially in respiratory infections and febrile illnesses, by determining when it is safe to withhold or stop antibiotics⁽⁹⁾.

• Evaluating inflammatory diseases

It helps differentiate between inflammatory conditions such as Kawasaki disease or systemic inflammatory response syndrome (SIRS) of noninfectious cause, where PCT is typically not as elevated as in bacterial infections.

• Advantages over CRP:
  • More specific for bacterial infections.
  • It rises faster (within 2-4 hours) after infection and peaks around 12-24 hours.
  • Falls more quickly as infection resolves, making it useful for monitoring.
• Limitations

May be elevated in: major trauma or surgery, severe burns, prolonged cardiogenic shock.

Less sensitive in localized infections (e.g., otitis media, tonsillitis).

Newborns may have transiently elevated PCT levels in the first 48 hours of life without infection⁽⁹⁾.

3. Interleukin-6

Interleukin-6 (IL-6) is a proinflammatory cytokine, a type of signaling protein that plays a central role in the body’s immune and inflammatory response. It is produced by various cells, including macrophages, T cells, endothelial cells and fibroblasts, in response to infection, tissue injury or immune activation.

• Interval reference in children

A level below 7 pg/mL is generally considered normal, although the reference ranges may vary depending on age, lab and clinical setting.

• Role in inflammation in children

Early inflammatory marker:

• IL-6 levels rise rapidly (within 1-2 hours) in response to infection or tissue damage, often earlier than CRP or other acute-phase reactants.
• It stimulates the liver to produce CRP, fibrinogen and other acute-phase proteins.
• Indicator of infection severity:
• Elevated IL-6 is associated with systemic bacterial infections, sepsis and cytokine storms, especially in critical pediatric illnesses.
• In neonates, IL-6 is a sensitive marker for early-onset sepsis.

Role in autoimmune and chronic inflammatory diseases

IL-6 contributes to chronic inflammation seen in conditions like:

• Juvenile idiopathic arthritis (JIA)
• Systemic lupus erythematosus (SLE)
• Kawasaki disease.

It promotes T cell activation, B cell maturation and autoantibody production.

• COVID-19 and pediatric inflammatory syndromes

IL-6 is elevated in multisystem inflammatory syndrome in children (MIS-C) and severe pediatric COVID-19 cases, reflecting hyperinflammation or cytokine storm.

• Therapeutic target

Drugs that block IL-6 (e.g., tocilizumab) treat severe inflammatory diseases, including JIA and COVID-19-associated hyperinflammation⁽⁹⁾.

Early identification of bacterial infections in patients with fever is crucial for appropriate therapy. However, laboratory parameters such as CRP levels and leukocyte counts have less value for early diagnosis. Many previous studies have shown that procalcitonin (PCT) levels can be used to identify bacterial infections in patients with sepsis and those admitted to intensive care units (ICUs) or the emergency department (ED).

Conclusions

Assessing the inflammatory process, whether febrile or nonfebrile, in a child is very important, following correlation with the complete blood count (CBC), to detect an infection. The inflammatory syndrome of obscure/unspecified etiology may present with elevated levels of acute-phase reactants. It is essential that, after a thorough examination, we have clear and conclusive clinical evidence to justify the interpretation of these inflammation markers within the clinical context.

However, the combination of these biomarkers could provide a significant benefit in the prognosis of pediatric sepsis. Further studies are needed to demonstrate the effectiveness of combining these biomarkers in sepsis prognosis and confirmation of an infection.

 

Autor corespondent: Bogdan-Marius Istrate E-mail: istratem.bogdan@yahoo.com

 

 

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

This work is permanently accessible online free of charge and published under the CC-BY.