ACUTE PHASE REACTANTS

MD Pediatrics Theory Examination Essay

INTRODUCTION

1. Assessing the extent and severity of an inflammatory process
2. Monitoring disease activity over time with serial measurements
3. Providing prognostic information

PATHOPHYSIOLOGY AND MECHANISM

Cytokine Cascade

• Interleukin-1 (IL-1)
• Tumor necrosis factor-alpha (TNF-alpha)
• Interferon-gamma (IFN-gamma)

• Induction of fever
• Leukocyte recruitment
• Muscle catabolism
• Shift in hepatic protein synthesis (increased APRs, decreased albumin, transferrin)

CLASSIFICATION OF ACUTE PHASE PROTEINS

A. Positive Acute Phase Reactants (Increase in Inflammation)

• Complement system: C3, C4, C9, Factor B, C1 inhibitor, C4b-binding protein, Mannose-binding lectin
• Coagulation/fibrinolytic system: Fibrinogen, Plasminogen, tPA, Urokinase, Plasminogen-activator inhibitor-1
• Anti-proteases: Alpha-1-protease inhibitor, alpha-anti-chymotrypsin, Inter-alpha-trypsin inhibitors
• Transport proteins: Ceruloplasmin, Haptoglobin, Hemopexin
• Mediators of inflammation: Secreted phospholipase A2, Lipopolysaccharide-binding protein (LBP), IL-1 receptor antagonist, G-CSF
• Others: CRP, Serum Amyloid A, Alpha-1-acid glycoprotein, Fibronectin, Ferritin, Angiotensinogen

B. Negative Acute Phase Reactants (Decrease in Inflammation)

• Albumin (most important clinically)
• Transferrin
• Transthyretin (Pre-albumin)
• Alpha-fetoprotein
• Thyroxine-binding globulin
• Insulin-like growth factor I (IGF-I)
• Anti-thrombin III
• Protein S
• Factor XII
• Apolipoprotein A-I

INDIVIDUAL ACUTE PHASE REACTANTS

1. C-REACTIVE PROTEIN (CRP)

• Undetectable in health (< 10 mg/L or < 1 mg/dL is normal)
• Begins to rise within 6-12 hours of the inflammatory stimulus
• Peaks within 2-3 days
• Returns to normal rapidly following successful therapy
• Half-life is approximately 19 hours (short, making it ideal for monitoring)
• Can rise up to 1000-fold above baseline in severe bacterial infection

1. Activates the classical complement pathway
2. Opsonization - binds phosphocholine on damaged cell membranes and microbial surfaces
3. Binds chromatin (important in autoimmunity)
4. Inhibits neutrophil adhesion to endothelial cells (via L-selectin shedding)
5. Scavenges cellular debris and directs phagocytic disposal

• Neonatal sepsis: CRP rises within 12-24 hours; serial values more useful than a single measurement. Normal at birth, rises in early-onset sepsis.
• Kawasaki disease: Very elevated CRP (often >100 mg/L); persistent elevation after Day 10 suggests incomplete response to IVIG or increased risk of coronary artery aneurysm.
• JIA/Systemic JIA: Markedly elevated CRP in systemic JIA; CRP in macrophage activation syndrome (MAS) may paradoxically fall while ferritin soars.
• Febrile neutropenia: CRP > 90 mg/L at 24-48 hours of fever predicts bacteremia.
• Bacterial vs. viral infection: CRP > 40-80 mg/L strongly favors bacterial etiology.
• Post-IVIG limitation: IVIG independently raises ESR; CRP is preferred for monitoring after Kawasaki IVIG treatment. (Red Book 2021, AAP)

2. ERYTHROCYTE SEDIMENTATION RATE (ESR)

• Fibrinogen (most important)
• Globulins (IgG, IgM, IgA)
• Alpha-2 macroglobulin
• Decreased albumin

• Children: < 10-20 mm/hr (age-dependent)
• Adult men: < 15 mm/hr (approximate: age/2)
• Adult women: < 20 mm/hr (approximate: (age+10)/2)
• ESR physiologically higher in women and increases with age
• ESR increases during pregnancy

• Rises within 24-48 hours of the inflammatory stimulus (slower than CRP)
• Remains elevated for weeks to months even after resolution (the "lag" effect)
• This slow normalization makes ESR useful for monitoring chronic inflammatory states but not acute fluctuations.

• Anemia (decreased hematocrit allows faster fall)
• Obesity
• Hypercholesterolemia
• Female sex, older age
• Renal insufficiency
• Technical: tilted tube, prolonged standing, high room temperature

• Polycythemia, sickle cell disease (abnormal RBC shape)
• Chronic lymphocytic leukemia
• Congestive heart failure
• Extreme leukocytosis
• Hypofibrinogenemia
• Technical: short tube, air bubbles, low temperature

• ESR > 100 mm/hr strongly suggests: bacterial infection, malignancy (especially leukemia/lymphoma), autoimmune disease, or inflammatory bowel disease.
• JIA monitoring: ESR is a component of the JADAS (Juvenile Arthritis Disease Activity Score).
• Kawasaki disease: ESR elevated in acute phase; after IVIG, ESR may be unreliable (use CRP instead).
• Osteomyelitis/Septic arthritis: ESR rises within 2-3 days, remains elevated for weeks. Normalizes slower than CRP.
• Tubeculous disease: ESR often markedly elevated (> 60 mm/hr); useful for monitoring treatment response over months.
• Nephrotic syndrome: Elevated due to hyperfibrinogenemia and hypoalbuminemia.

3. PROCALCITONIN (PCT)

• Detectable within 3-4 hours of bacterial stimulus (faster than CRP)
• Peaks within 6-24 hours
• Half-life: 25-30 hours
• Normal: < 0.05 ng/mL

1. Rises faster (3-4 hours vs. 12-24 hours)
2. More specific for bacterial vs. viral infection
3. Better for distinguishing sepsis from non-infectious SIRS
4. More useful for antibiotic stewardship - rising PCT = continue antibiotics; falling PCT = can stop
5. Not elevated in non-infectious inflammatory states (IBD, polyarteritis nodosa, SLE, gout, polymyalgia rheumatica, temporal arteritis)

• Neonatal sepsis: PCT physiologically elevated in first 48-72 hours of life (normal up to 2-21 ng/mL on Day 1); falls by Day 3. Serial measurements essential.
• Febrile UTI/Pyelonephritis: PCT > 0.5 ng/mL is associated with high likelihood of pyelonephritis and renal scarring in children with UTI.
• Meningitis: PCT levels - both serum and CSF - have high diagnostic accuracy for bacterial meningitis.
• Kawasaki disease: PCT generally low (favors non-bacterial etiology), which helps distinguish from bacterial sepsis.
• Fever with petechiae: Children presenting with fever and petechiae - PCT > 0.5 ng/mL along with abnormal CRP and WBC increases risk of meningococcal disease. (Rosen's Emergency Medicine)
• Antibiotic stewardship in PICU: Serial PCT-guided protocols reduce antibiotic duration without adverse outcomes.

4. SERUM AMYLOID A (SAA)

• An apolipoprotein synthesized by hepatocytes; normal level < 10 mg/L
• Rises 1000-fold along with CRP during acute infection (peaks Day 2-3)
• Major role: Mobilizes cholesterol from macrophages and hepatocytes; acts as an opsonin
• In systemic JIA and MAS (Macrophage Activation Syndrome): SAA is markedly elevated and useful for monitoring disease activity
• In Familial Mediterranean Fever (FMF): SAA is the amyloidogenic precursor; persistently elevated SAA leads to AA amyloidosis - the main long-term complication. Serial measurement guides colchicine dosing to prevent amyloid deposition.

5. FERRITIN

• Iron storage protein; also an APR (moderate positive reactant)
• Normal: 12-150 ng/mL (varies by age and sex)
• Ferritin as a Pediatric Biomarker:
  • In Systemic JIA: markedly elevated (often > 10,000 ng/mL); a defining feature of systemic JIA
  • In Macrophage Activation Syndrome (MAS): ferritin > 500 ng/mL suggests MAS; levels between 5,000-10,000 ng/mL favor MAS diagnosis. A threshold of 13,405 microg/L optimizes diagnosis of hemophagocytic lymphohistiocytosis (HLH) with sensitivity 76% and specificity 79%.
  • In HLH: ferritin > 10,000 ng/mL (occasionally > 1,00,000 ng/mL)
  • May also occasionally rise > 20,000 ng/mL in other severe inflammatory states

6. HAPTOGLOBIN

• Binds free hemoglobin; transports the hemoglobin-haptoglobin complex to hepatocytes for recycling (conserves iron)
• Rises 2-4 fold as an APR
• Clinically falls in hemolysis (consumed), making it a marker of hemolytic states
• Used in neonatal hemolysis evaluation

7. FIBRINOGEN

• Clotting factor and major APR; rises 2-4 fold
• Central to ESR elevation (fibrinogen promotes rouleaux formation)
• In FMF attacks: fibrinogen along with CRP, SAA, ESR, and haptoglobin all rise markedly
• In Kawasaki disease: hyperfibrinogenemia contributes to thrombotic risk

8. CERULOPLASMIN

• Copper-transport protein; rises ~50% as an APR
• Falls in Wilson's disease, protein-losing states, malnutrition
• Role in inflammation: has ferroxidase activity; may serve as antioxidant

9. COMPLEMENT COMPONENTS (C3, C4)

• Both are positive APRs; rise in inflammation
• Important exception in SLE: Despite active inflammation, C3 and C4 are consumed by immune complex deposition, so they may be low or normal. This explains the phenomenon where CRP is also often low/normal in SLE (despite very high ESR) - a key discriminator.
• The SLE-ESR/CRP dissociation: In active SLE, ESR is markedly elevated while CRP remains normal. This is one of the most important discriminations in rheumatology.

10. ALPHA-1 ACID GLYCOPROTEIN (OROSOMUCOID)

• Rises 2-4 fold
• Has immunomodulatory functions; binds basic and neutral lipophilic drugs
• Can affect drug binding and pharmacokinetics during acute illness

COMPARISON TABLE: CRP vs. ESR vs. PCT

CLINICAL APPLICATIONS IN PEDIATRICS

1. Neonatal Sepsis

• CRP: Normal at birth; rises in early-onset sepsis after 12-24 hours. A single normal CRP does not exclude sepsis; serial measurements every 12-24 hours improve sensitivity (> 90% when measured at 12 and 24 hours combined).
• PCT: Physiologically elevated in healthy neonates in first 48-72 hours (up to 21 ng/mL on Day 1 of life). Values beyond this physiological peak, or a secondary rise, are concerning for late-onset sepsis.
• ESR: Limited value in neonates; blood volume constraints and high neonatal hematocrit affect results.

2. Fever Without Source (FWS) / Serious Bacterial Infection (SBI)

• CRP > 40-80 mg/L and PCT > 0.5 ng/mL together with ANC and WBC substantially improve sensitivity for detecting SBI in febrile children.
• The "Lab Score" (combining PCT, CRP, and urinalysis) is used in some centers.
• CRP alone has sensitivity ~88% and specificity ~75% for bacterial infection.

3. Urinary Tract Infection and Pyelonephritis

• PCT > 0.5 ng/mL predicts pyelonephritis (upper tract involvement) and future renal scarring in children with UTI.
• CRP > 20 mg/L suggests upper tract disease.
• ESR > 30 mm/hr also seen in pyelonephritis.
• However, ESR, CRP, and PCT alone are not sufficiently accurate to differentiate cystitis from pyelonephritis. (PIDS/PIDSP systematic review)

4. Acute Rheumatic Fever (ARF)

• Jones Criteria (Modified, WHO): Elevated APRs (CRP > 30 mg/L or ESR > 30 mm/hr) are included as minor criteria.
• APRs rise in virtually all cases of ARF except in pure chorea or erythema marginatum as sole manifestation - an important exception to know.
• Serial monitoring of CRP/ESR guides secondary prophylaxis and detection of carditis progression.
• ESR normalizes by 3 months in uncomplicated ARF. (Firestein & Kelley's Textbook of Rheumatology)

5. Juvenile Idiopathic Arthritis (JIA)

• Systemic JIA: CRP markedly elevated; ferritin very high; SAA elevated. The degree of ferritin elevation tracks disease activity.
• Oligoarticular/Polyarticular JIA: CRP and ESR elevated proportional to joint involvement.
• Macrophage Activation Syndrome (MAS): Paradoxical fall in ESR and CRP despite worsening clinical status, in contrast to soaring ferritin. This "falling CRP with rising ferritin" pattern is a red flag for MAS.
• JADAS score: Includes ESR as a component.
• CRP > 20 mg/L and ESR > 20 mm/hr as remission criteria (both must be normal for ACR/EULAR inactive disease definition in JIA).

6. Kawasaki Disease (KD)

• CRP and ESR markedly elevated in acute phase; CRP often > 100 mg/L.
• Prolonged CRP elevation after Day 10 of illness suggests incomplete KD or predicts increased coronary artery aneurysm risk.
• After IVIG treatment: ESR is unreliable (IVIG independently elevates ESR). CRP is preferred for post-treatment monitoring.
• Platelet count (thrombocytosis, typically > 4,50,000/microL) is also elevated from Day 7-10. (Red Book 2021, AAP)

7. Osteomyelitis and Septic Arthritis

• CRP rises within 6-12 hours; most sensitive early marker (rises before X-ray changes).
• ESR rises within 2-3 days.
• Serial CRP monitoring guides duration of antibiotic therapy: switch from IV to oral when CRP normalizes (< 20 mg/L), typically by Days 5-7.
• PCT levels are generally low in non-bacteremic osteomyelitis (limited value).

8. Tuberculosis

• ESR markedly elevated (often > 60 mm/hr); correlates with disease burden.
• CRP elevated; normalizes with anti-TB therapy (within 2-4 months).
• Useful for monitoring treatment response in pediatric TB.

9. Inflammatory Bowel Disease (IBD)

• CRP and ESR elevated in active Crohn's disease and ulcerative colitis.
• Fecal calprotectin (a direct mucosal marker) is superior to serum CRP for assessing gut inflammation.
• PCT is typically low in IBD (despite active inflammation) - an important distinction from infection.

10. Malignancy

• Markedly elevated CRP (> 100 mg/L) and ESR > 100 mm/hr may be the first clue to lymphoma or leukemia.
• In ALL: leukocytosis + elevated ESR/CRP; CRP > 90 mg/L in febrile neutropenia predicts bacteremia.

LIMITATIONS AND PITFALLS

When APRs May Be Falsely Normal Despite Active Disease:

1. SLE with active nephritis: CRP often normal; ESR markedly elevated (ESR/CRP dissociation)
2. Pure chorea or erythema marginatum in ARF: APRs may be normal
3. Congenital deficiencies of individual APR proteins
4. Newborns: Lower baseline levels of many APRs; physiological PCT elevation
5. Immunocompromised/immunosuppressed patients: Especially those on IL-6 receptor antagonists (tocilizumab, sarilumab) - CRP may be completely suppressed despite active infection

When APRs May Be Falsely Elevated (Non-inflammatory):

1. Obesity: CRP chronically elevated (low-grade metabolic inflammation)
2. Pregnancy
3. Smoking
4. Strenuous exercise
5. Minor trauma, surgery, post-procedural state

ESR-CRP Discordance:

• Up to 12% of hospitalized patients show discordant ESR and CRP
• ESR high + CRP normal: SLE, renal insufficiency, transient ischemic attacks, hypergammaglobulinemia, anemia
• CRP high + ESR normal: Early acute infection, post-myocardial infarction, after IVIG administration

HIGH-SENSITIVITY CRP (hsCRP)

• Childhood obesity and metabolic syndrome
• Kawasaki disease-related cardiovascular risk
• Familial hypercholesterolemia

NEGATIVE ACUTE PHASE REACTANTS - CLINICAL UTILITY

Albumin:

• Falls rapidly in acute severe illness; unreliable as nutritional marker during acute illness
• Hypoalbuminemia in nephrotic syndrome, malnutrition, liver failure, protein-losing enteropathy
• Serum albumin < 2.5 g/dL: significant hypoalbuminemia

Pre-albumin (Transthyretin):

• Half-life of 2-3 days (much shorter than albumin's 21 days)
• More sensitive and faster nutritional marker
• Also a negative APR; falls in infection/inflammation even without malnutrition
• Useful for monitoring nutritional repletion when inflammation has resolved

Transferrin:

• Half-life 8-9 days
• Negative APR + also falls in iron deficiency (misleading in mixed states)

SUMMARY TABLE: ACUTE PHASE REACTANTS AT A GLANCE

CONCLUSION

• Firestein & Kelley's Textbook of Rheumatology (Chapter 57: Acute Phase Reactants)
• Henry's Clinical Diagnosis and Management by Laboratory Methods (Chapter: Acute-Phase Reactants, p.333)
• Rheumatology, 2-Volume Set (Elsevier, 2022 - Chapter on Acute Phase Reactants)
• Red Book 2021: Report of the Committee on Infectious Diseases (AAP) - Kawasaki Disease, IVIG
• Nelson Textbook of Pediatrics (Systemic JIA, ARF, Sepsis chapters)
• IAP Guidelines: Fever without source, Neonatal Sepsis protocols
• Basic Medical Biochemistry - A Clinical Approach, 6th edition
• Pediatric Infectious Diseases Society of the Philippines: APRs in Pediatric Infections (Systematic Review, 2016)