Pathology chapters
Chronic and granulomatous inflammation, fever and ESR
What chronic inflammation is and its causes and cells, granulomatous inflammation and its causes, the systemic effects of inflammation (fever, acute-phase proteins, leucocytosis), how fever is produced by pyrogens, and what the ESR measures.
- Chronic inflammation lasts weeks to years, with mononuclear cells (macrophages, lymphocytes, plasma cells), tissue destruction and attempted repair (fibrosis, new vessels) going on together.
- A granuloma is a collection of epithelioid macrophages, often with multinucleated giant cells (Langhans type in TB), surrounded by lymphocytes; caseating granulomas suggest tuberculosis, non-caseating ones sarcoidosis, Crohn's disease or foreign bodies.
- Exogenous pyrogens (bacterial LPS) make leucocytes release endogenous pyrogens (IL-1, TNF, IL-6), which raise PGE2 in the hypothalamus and reset the temperature set point; the ESR rises mainly because fibrinogen makes red cells form rouleaux.
On this page
Overview
Chronic inflammation is inflammation of long duration (weeks, months or years) in which active inflammation, tissue destruction and attempts at repair happen at the same time. It may follow acute inflammation or start insidiously.
Causes
- Persistent infections: tuberculosis, leprosy, syphilis, fungi, some viruses and parasites.
- Immune-mediated diseases: autoimmune (rheumatoid arthritis, SLE), allergic (asthma), and inflammatory bowel disease.
- Prolonged exposure to toxic agents: silica (silicosis), lipids (atherosclerosis).
- Foreign bodies: sutures, splinters, talc.
Features
- Mononuclear cell infiltrate: macrophages, lymphocytes, plasma cells.
- Tissue destruction by the persistent cause and the inflammatory cells.
- Repair: new blood vessels (angiogenesis) and fibrosis.
Cells of chronic inflammation
| Cell | Role |
|---|---|
| Macrophages | The dominant cell. Derived from blood monocytes. Activated classically (M1) by microbial products and IFN-γ (kill microbes, cause inflammation) or alternatively (M2) by IL-4 and IL-13 (repair, fibrosis) |
| Lymphocytes | T cells activate macrophages (IFN-γ) and drive the response; B cells become plasma cells |
| Plasma cells | Make antibodies |
| Eosinophils | Parasitic infections and allergy (IgE) |
| Mast cells | Allergy; release mediators |
| Neutrophils | In some chronic infections (osteomyelitis) and repeated injury |
The macrophage is the central cell of chronic inflammation; T cells and macrophages stimulate each other (IFN-γ and IL-12) in a loop that keeps it going.
Granulomatous inflammation
A special form of chronic inflammation in which activated macrophages form small, compact collections: granulomas. It is the body's attempt to wall off something it cannot eliminate.
Structure of a granuloma
- Epithelioid cells: activated macrophages with pale, pink cytoplasm, looking like epithelial cells.
- Multinucleated giant cells: fused macrophages.
- Langhans giant cell: nuclei arranged in a horseshoe at the periphery (typical of TB).
- Foreign-body giant cell: nuclei scattered throughout.
- A collar of lymphocytes (and sometimes plasma cells).
- An outer rim of fibroblasts and connective tissue.
- Caseous necrosis in the centre in TB.
Types and causes
| Type | Mechanism | Examples |
|---|---|---|
| Immune granulomas | Persistent T cell response to an antigen | Tuberculosis (caseating), leprosy, syphilis (gumma), sarcoidosis, Crohn's disease, cat-scratch disease, schistosomiasis, fungal infections (histoplasmosis), berylliosis |
| Foreign-body granulomas | Inert material too large to be eaten | Sutures, talc (drug users), splinters, silica |
Caseating granuloma → tuberculosis. Non-caseating granulomas → sarcoidosis, Crohn's disease, tuberculoid leprosy, foreign bodies.
Not every granuloma is TB. In Pakistan, TB is so common that a caseating granuloma is treated as TB until proven otherwise, but sarcoidosis, fungi and others must be considered.
Systemic effects of inflammation (acute-phase response)
Cytokines (IL-1, TNF, IL-6) produce body-wide effects:
- Fever.
- Acute-phase proteins from the liver (driven by IL-6):
- C-reactive protein (CRP): rises within hours; a sensitive marker of inflammation and infection.
- Fibrinogen: raises the ESR.
- Serum amyloid A: can deposit as amyloid in long-term inflammation (secondary (AA) amyloidosis, for example in TB or rheumatoid arthritis).
- Hepcidin: reduces iron availability → anaemia of chronic disease.
- Leucocytosis: neutrophilia in bacterial infections, lymphocytosis in viral infections, eosinophilia in parasites and allergy. A very high count resembling leukaemia is a leukaemoid reaction. (Some infections such as typhoid cause leucopenia.)
- Raised pulse and blood pressure, chills, sweating, loss of appetite, sleepiness, malaise.
- In severe infection, sepsis and septic shock (see oedema and shock).
- In chronic inflammation: weight loss and cachexia (TNF).
Mechanism of fever
- Exogenous pyrogens: substances from outside the body, mainly microbial products such as lipopolysaccharide (LPS) (endotoxin) of Gram-negative bacteria.
- They stimulate macrophages and other leucocytes to release endogenous pyrogens: IL-1 and TNF (and IL-6).
- Endogenous pyrogens act on the hypothalamus (thermoregulatory centre), increasing cyclo-oxygenase activity and producing PGE2.
- PGE2 raises the temperature set point.
- The body conserves and produces heat (vasoconstriction, shivering) until body temperature reaches the new set point.
NSAIDs and aspirin reduce fever by blocking PGE2 synthesis.
Exogenous pyrogen (LPS) → endogenous pyrogens (IL-1, TNF) → PGE2 in the hypothalamus → raised set point.
Erythrocyte sedimentation rate (ESR)
The ESR is the distance red cells fall in a vertical tube of anticoagulated blood in one hour (Westergren method).
Why it rises in inflammation: acute-phase proteins, especially fibrinogen (and immunoglobulins), reduce the negative charge (zeta potential) that keeps red cells apart, so they stack into rouleaux, which sink faster.
| ESR raised | ESR lowered |
|---|---|
| Infection, inflammation, TB | Polycythaemia |
| Autoimmune disease (RA, SLE), temporal arteritis, polymyalgia rheumatica | Sickle cell disease, spherocytosis (abnormal shapes prevent rouleaux) |
| Multiple myeloma (very high) | Low fibrinogen; heart failure |
| Malignancy, anaemia, pregnancy, older age, women |
Normal values rise with age and are higher in women. A rough upper limit: men age ÷ 2, women (age + 10) ÷ 2 mm/hour.
Man aged 60 → upper limit ≈ 60 ÷ 2 = 30 mm/hour
Woman aged 60 → upper limit ≈ (60 + 10) ÷ 2 = 35 mm/hour
An ESR of 90 mm/hour in a 60-year-old is clearly raised: think of myeloma, temporal arteritis, TB or other serious inflammation
Significance: the ESR is non-specific (does not tell the cause) but useful for monitoring disease activity (TB, rheumatoid arthritis, temporal arteritis, polymyalgia rheumatica). CRP rises and falls faster and is better for acute infection.
A normal ESR does not exclude disease, and a raised ESR is never a diagnosis on its own.
Outcomes of chronic inflammation
Fibrosis and scarring (cirrhosis, lung fibrosis), loss of function, amyloidosis, or resolution if the cause is removed.
Expect: causes and cells of chronic inflammation, the macrophage-T cell loop, the structure of a granuloma, Langhans vs foreign-body giant cells, caseating vs non-caseating causes, acute-phase proteins, the mechanism of fever, why ESR rises (fibrinogen, rouleaux), causes of high and low ESR, and the ESR rule of thumb.
Quick revision
- Chronic inflammation: macrophages, lymphocytes, plasma cells; destruction and repair together.
- Granuloma: epithelioid cells, giant cells, lymphocyte cuff.
- Langhans (TB): horseshoe nuclei; foreign-body: scattered nuclei.
- Caseating: TB. Non-caseating: sarcoidosis, Crohn's, leprosy, foreign body.
- Acute-phase: CRP, fibrinogen, SAA, hepcidin (IL-6).
- Fever: LPS → IL-1, TNF → PGE2 → raised set point.
- ESR: fibrinogen → rouleaux; very high in myeloma; low in polycythaemia and sickle cell.
Written by The House Job from standard pathology references (Robbins and Cotran Pathologic Basis of Disease is the book named in the UHS PGET syllabus).
FAQ
What is the main cell in chronic inflammation?
The macrophage.
What is a granuloma?
A focal collection of activated (epithelioid) macrophages, often with giant cells, surrounded by lymphocytes.
What causes fever in infection?
Microbial products (exogenous pyrogens) make leucocytes release IL-1 and TNF (endogenous pyrogens), which raise prostaglandin E2 in the hypothalamus and reset the temperature set point.
Why is the ESR raised in inflammation?
Increased fibrinogen and globulins make red cells stack into rouleaux, which settle faster.