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PA3.3 | Chronic & Granulomatous Inflammation — SDL Guide (Part 4)

Systemic Effects of Inflammation

Diagram showing macrophage cytokines driving fever, acute-phase protein production, leukocytosis, and the clinical marker triangle of WBC count, CRP, and ESR. — **Panel A:** Microbes/LPS, tissue injury, activated macrophage, IL-1, IL-6, TNF-α cytokine release. **Panel B:** Exogenous pyrogens, endogenous pyrogens, prostaglandin E2, hypothalamic thermoregulatory centre, raised set-point, fever, aspirin/NSAIDs, COX inhibition. **Panel C:** Liver, IL-6 stimulation, CRP, fibrinogen, serum amyloid A, complement proteins, hepcidin, ferritin, opsonisation, complement activation, rouleaux formation, elevated ESR, decreased albumin, decreased transferrin. **Panel D:** Bone marrow, IL-1, TNF-α, G-CSF, leukocyte mobilisation, neutrophilia with left shift, lymphocytosis, eosinophilia, leukemoid reaction WBC >50,000/µL. **Clinical Marker Triangle:** WBC count, CRP, ESR as rapid inexpensive markers of inflammation intensity and type.

Both acute and chronic inflammation trigger a systemic response via cytokines (mainly IL-1, IL-6, TNF-α) released by activated macrophages.

1. Fever:
• Exogenous pyrogens (LPS, microbial products) → stimulate macrophages → endogenous pyrogens (IL-1, IL-6, TNF-α, prostaglandin E2)
• Prostaglandin E2 acts on the hypothalamic thermoregulatory centre → raises the thermostat set-point → fever
• Aspirin/NSAIDs reduce fever by inhibiting cyclooxygenase (COX) → reduced PGE2 synthesis

2. Acute-phase response:
• IL-6 stimulates the liver to produce acute-phase proteins: C-reactive protein (CRP), fibrinogen, serum amyloid A, complement proteins, hepcidin, ferritin
• CRP: Opsonises bacteria and activates complement; clinical marker of inflammation/infection
• Fibrinogen: Coats erythrocytes → increased rouleaux formation → elevated erythrocyte sedimentation rate (ESR)
• Albumin and transferrin are negative acute-phase reactants (decrease during inflammation)

3. Leucocytosis:
• IL-1, TNF-α, G-CSF → mobilise neutrophils from bone marrow
• Bacterial infections → neutrophilia (with left shift — band forms)
• Viral infections → lymphocytosis
• Parasitic/allergic conditions → eosinophilia
• Severe infections → leukemoid reaction (WBC >50,000/µL)

Clinical marker triangle: WBC count + CRP + ESR together give you a rapid, inexpensive window into the intensity and type of inflammation.

SELF-CHECK

A 60-year-old man with longstanding rheumatoid arthritis has a serum CRP of 85 mg/L, ESR of 110 mm/hr, and haemoglobin of 9.2 g/dL. Which acute-phase protein is MOST responsible for the elevated ESR?

A. C-reactive protein (CRP)

B. Serum amyloid A (SAA)

C. Fibrinogen

D. Albumin

Reveal Answer

Answer: C. Fibrinogen

Fibrinogen (elevated during inflammation under IL-6 stimulation) coats red blood cells, promoting rouleaux formation and increasing the rate at which they sediment — directly elevating ESR. CRP is an opsonin and clinical inflammation marker but does not directly affect ESR. Albumin is a negative acute-phase reactant.

Comparing Acute vs Chronic — A Clinico-Pathological Summary

A four-panel medical diagram comparing acute and chronic inflammation, highlighting chronic clinical clues, systemic mediator effects, and granuloma diagnostic questions. — **Panel A:** Acute inflammation with dilated vessels, edema, neutrophils, short duration; chronic inflammation with lymphocytes, plasma cells, macrophages, granuloma, fibroblasts, collagen fibrosis, duration >4-6 weeks.. **Panel B:** Clinical clues: duration >4-6 weeks, low-grade fever, weight loss, night sweats, elevated ESR/CRP/fibrinogen, normocytic normochromic anaemia, imaging fibrosis/cavitation/granulomas, lymphoplasmacytic infiltrate.. **Panel C:** Mediator pathways: macrophage IL-1 and TNF-alpha causing constitutional symptoms; liver acute phase response; hepcidin increase and reduced erythropoietin responsiveness causing anaemia of chronic disease.. **Panel D:** Granuloma workup: caseating versus non-caseating granuloma, ZN/GMS/PAS special stains, birefringent foreign material, narrowed differential diagnosis..

Synthesising both G1 and G2, the following framework anchors chronic inflammation in clinical practice:

When to suspect chronic (rather than acute) inflammation:
• Duration >4–6 weeks without resolution
• Constitutional symptoms dominate (low-grade fever, weight loss, night sweats) — driven by sustained IL-1/TNF-α
• Laboratory: elevated ESR, CRP, fibrinogen; normocytic normochromic anaemia (anaemia of chronic disease via hepcidin↑ + erythropoietin responsiveness↓)
• Imaging: fibrosis, cavitation, granulomas (CT/PET)
• Histology: lymphoplasmacytic infiltrate ± granulomas ± fibrosis

The three questions a pathologist asks at a granuloma:
1. Is it caseating or non-caseating?
2. Are special stains (ZN, GMS, PAS) positive?
3. Is there birefringent foreign material?

Answering these three questions narrows a granuloma differential from 30 diagnoses to 2–3.