Q2 LONG ANSWER 10M ★ High-yield

Define chronic inflammation. Describe its causes and the cells involved. Describe granulomatous inflammation with its causes.

Pathology · 2nd Professional — Para-Clinical

Definition

Chronic inflammation is inflammation of prolonged duration, weeks to years, in which active inflammation, tissue destruction and attempts at repair proceed simultaneously.

Causes

Persistent infection by organisms of low toxicity that resist killing — Mycobacterium tuberculosis and leprae, Treponema, fungi
Prolonged exposure to a toxic agent — exogenous such as silica, or endogenous such as lipid in atherosclerosis
Immune-mediated (hypersensitivity) disease — autoimmune disease such as rheumatoid arthritis; allergic disease such as asthma
Following acute inflammation that fails to resolve
Foreign bodies — suture, talc, splinters

Cells of Chronic Inflammation

Cell	Role
Macrophage — the dominant cell	Derived from blood monocytes; phagocytosis, antigen presentation, and secretion of cytokines, growth factors and enzymes. Long-lived, and recruited continuously
Lymphocytes	T cells activate macrophages by IFN-gamma; macrophages present antigen and secrete IL-12 — a self-amplifying loop that perpetuates the reaction
Plasma cells	Produce antibody against the persistent antigen
Eosinophils	Parasitic infestation and IgE-mediated reactions; contain major basic protein
Mast cells	Both acute and chronic reactions
Neutrophils	May persist for months in some chronic lesions — chronic osteomyelitis, bronchiectasis

Macrophage activation

Pathway	Stimulus	Products	Effect
Classical (M1)	IFN-gamma, microbial products	Reactive oxygen species, NO, IL-1, IL-12, TNF	Microbicidal; inflammatory
Alternative (M2)	IL-4, IL-13	Growth factors, TGF-beta, IL-10	Tissue repair, fibrosis, anti-inflammatory

CLINICAL PEARL

The same cell both destroys the tissue and scars it. The classically activated macrophage causes the damage of chronic inflammation; the alternatively activated one lays down the fibrosis. This is why chronic inflammation and fibrosis are inseparable, and why a chronically inflamed organ ends up both damaged and scarred.

Granulomatous Inflammation

A granuloma is a focus of chronic inflammation consisting of a microscopic aggregation of activated macrophages transformed into epithelioid cells, usually surrounded by a collar of lymphocytes, often with multinucleate giant cells.

Epithelioid cell — an activated macrophage with abundant pink cytoplasm and an elongated vesicular nucleus, resembling an epithelial cell; it is secretory rather than phagocytic
Giant cells form by the fusion of 20 or more epithelioid cells

Type	Cause	Features
Immune granuloma	Persistent, poorly degradable antigen that induces a T cell response	Tuberculosis, leprosy, sarcoidosis, Crohn disease, fungal infection
Foreign body granuloma	Inert material too large to be phagocytosed; NO T cell response	Suture, talc, splinter; the material is often visible in the giant cell, and is birefringent under polarised light

Causes of Granulomatous Inflammation

Category	Diseases
Bacterial	Tuberculosis (caseating), leprosy, syphilis (gumma), cat-scratch disease
Fungal	Histoplasmosis, cryptococcosis, blastomycosis
Parasitic	Schistosomiasis
Inorganic	Silicosis, berylliosis
Unknown	Sarcoidosis (non-caseating), CROHN disease
Foreign body	Suture, talc, keratin

CLINICAL PEARL

The single most useful distinction is caseation. Caseating granulomas mean tuberculosis until proved otherwise, particularly in India. Non-caseating granulomas suggest sarcoidosis, Crohn disease, leprosy or a foreign body. Every granuloma must have a Ziehl–Neelsen stain performed on it.

Acute Compared with Chronic Inflammation

Feature	Acute	Chronic
Duration	Minutes to a few days	Weeks to years
Onset	Rapid	Insidious
Dominant cell	Neutrophil	Macrophage, lymphocyte, plasma cell
Vascular changes	Prominent — vasodilatation, exudation	Angiogenesis rather than exudation
Tissue injury	Usually mild and self-limited	Often severe and progressive
Fibrosis	Absent	Characteristic — proceeds alongside the inflammation
Local signs	The classical cardinal signs are prominent	Often inconspicuous
Systemic effect	Fever, neutrophilia	Low-grade fever, anaemia of chronic disease, weight loss, amyloidosis

Applied Aspects

Tuberculosis remains the commonest cause of granulomatous inflammation in India; diagnosis needs acid-fast staining, culture and molecular testing (CBNAAT), not histology alone
Sarcoidosis gives non-caseating "naked" granulomas with few lymphocytes; Schaumann and asteroid bodies may be seen but are not specific
Anti-TNF therapy reactivates latent tuberculosis, because TNF is required to hold the granuloma together — a striking demonstration that the granuloma is an active, maintained structure
Chronic inflammation predisposes to malignancy — chronic gastritis to gastric carcinoma, ulcerative colitis to colonic carcinoma, and chronic osteomyelitis sinuses to squamous carcinoma
Chronic inflammation causes secondary (AA) amyloidosis, which must be suspected if proteinuria appears in a patient with long-standing tuberculosis or rheumatoid arthritis
Anaemia of chronic disease — IL-6 induces hepatic hepcidin, which traps iron in macrophages; the anaemia is normocytic with a low serum iron but a high ferritin, distinguishing it from iron deficiency
Sinuses and fistulae are characteristic of chronic inflammation, since the persisting agent prevents closure — seen in chronic osteomyelitis, tuberculosis and Crohn disease
Systemic features of chronic inflammation are low-grade fever, weight loss, fatigue and a raised ESR, and they are often what brings the patient in
Corticosteroids and immunosuppressants control chronic inflammation but at the cost of reactivating latent infection, which is the central dilemma in treating it

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