Calprotectin is a cytoprotective protein predominantly expressed by neutrophils, monocytes, and activated macrophages. The measurement of serum calprotectin has emerged as a novel biomarker of systemic inflammation, reflecting activation of the innate immune system. Unlike fecal calprotectin, which indicates localized intestinal mucosal inflammation, serum calprotectin provides insight into systemic inflammatory activity.
The analysis of serum calprotectin is now being applied across a wide range of diseases, particularly rheumatologic, autoimmune, inflammatory, and infectious conditions. It is also being investigated as a prognostic marker in malignancies and in critical situations, such as sepsis and COVID-19. Although it is a non-specific marker, it is a sensitive and functionally relevant tool that can be incorporated into broader inflammatory panels and enhance clinical interpretation, especially in cases where traditional markers (such as CRP or ESR) may be insufficient.
Pathophysiological Insight
Calprotectin is not a single protein, but rather a heterodimeric complex of two proteins, specifically S100A8 (also known as MRP8) and S100A9 (also known as MRP14). Together, they form the S100A8/A9 complex, commonly referred to as calprotectin. The S100 protein family comprises small calcium-binding proteins that regulate cellular processes, inflammation, and the immune response. These proteins are primarily intracellular but are released extracellularly when neutrophils or macrophages are activated, such as during inflammation or infection. When inflammation is present, the S100A8/A9 complex (calprotectin) is actively secreted into the extracellular space. There, it functions as a damage-associated molecular pattern (DAMP) or “alarmin,” amplifying the immune response by acting as both a chemoattractant and a pro-inflammatory modulator through interactions with specific cell-surface receptors.
In plasma or serum, calprotectin levels reflect systemic activation of the innate immune system, typically due to the presence of activated neutrophils or monocytes in circulation. Elevated levels are observed in inflammatory, autoimmune, and infectious conditions and may also be associated with oxidative stress or tumor activity through mechanisms involving angiogenesis and metastatic signaling. Calprotectin correlates closely with the severity of inflammatory activity and is considered relatively unaffected by immunosuppressive or anti-inflammatory treatments, making it particularly valuable for monitoring subclinical or residual inflammation. However, it is not disease-specific, and results should always be interpreted in the context of the broader clinical and laboratory context.
Clinical Relevance
Serum calprotectin is increasingly being evaluated as a sensitive marker of systemic inflammation across a wide range of clinical contexts. Although it is not specific to a single disease, its presence indicates activation of the innate immune system and an elevated inflammatory burden.
The test is particularly used in rheumatologic and autoimmune disorders, including rheumatoid arthritis, vasculitides, systemic lupus erythematosus (SLE), and inflammatory myopathies. Calprotectin levels often correlate with disease activity, even when conventional inflammatory markers such as CRP or ESR remain within normal limits. Furthermore, serum calprotectin is being studied as a prognostic marker in infections (such as severe COVID-19 or sepsis) and as a supportive oncologic biomarker in various malignancies. Persistent elevation after treatment or during clinically quiescent phases may indicate subclinical inflammation or incomplete immunologic remission.
Due to its biological stability and its direct release from activated inflammatory cells, serum calprotectin serves as a valuable tool for monitoring and risk stratification, particularly within the frameworks of functional and personalized medicine.
Diagnostic Value
Serum calprotectin is emerging as a valuable laboratory marker of systemic inflammation, with broad applicability across inflammatory, autoimmune, and infectious diseases. Its measurement provides functional insight into neutrophil activation and the presence of inflammatory activity in tissues and organs, regardless of localization. Serum calprotectin is a complementary tool to classical markers such as CRP, ESR, and IL-6, particularly when those markers fail to fully reflect the intensity or persistence of inflammation.
Its utility is enhanced in subclinical inflammation, non-specific symptomatology, or when monitoring therapeutic response is required. While not a standalone diagnostic marker, calprotectin integrates effectively into risk stratification protocols, disease activity assessments, and chronic inflammatory burden evaluation.
Technical and Practical Advantages
- Sensitivity to early inflammation: Detects neutrophil activation even when other inflammatory markers remain within normal limits.
- Suitable for chronic inflammatory conditions: Well-suited for monitoring autoimmune or rheumatologic disorders, where fine assessment of inflammatory activity is required.
- Functional insight: Reflects actual cellular activation rather than just static protein presence, offering a dynamic view of the inflammatory process.
- Applicable in high-risk infections: Can be used for prognosis and risk stratification in severe cases of COVID-19 or sepsis.
- Relative stability: Calprotectin levels are not significantly influenced by food intake or mild pharmacologic treatments, facilitating sample collection, especially during therapeutic monitoring.
- Complementary use: Easily combined with CRP, IL-6, ferritin, and other biomarkers for comprehensive inflammatory evaluation in both functional and clinical protocols.
Diagnostic Applications and Target Populations
- In autoimmune and rheumatologic diseases: For assessing inflammatory activity in conditions such as rheumatoid arthritis, systemic lupus erythematosus (SLE), vasculitis, or inflammatory myopathies.
- When classical inflammatory markers are insufficient: In cases where CRP and ESR are within normal limits but there is persistent clinical suspicion of active inflammation.
- For prognosis in high-risk infections: In sepsis and severe bacterial or COVID-19 infections, where calprotectin levels correlate with disease severity.
- In chronic, non-specific inflammatory conditions: Such as unexplained fatigue, low-grade systemic inflammation, or subclinical inflammation related to metabolic syndrome.
- For monitoring therapeutic response: During immunosuppressive or biologic therapy, to assess for residual inflammatory activity.
- In potential neoplastic inflammatory activity: As a supportive indicator of immune activation in certain cancers, such as pancreatic or lung carcinoma.
- In personalized inflammation stratification: For high-risk individuals or as part of preventive functional medicine assessments, enabling early detection of subclinical inflammation.
Last update: 27/11/2025
