Inflammation: A High-Yield USMLE Pathology Review

Inflammation is the body's response to injury—it exists to eliminate the cause of injury, clear debris, and initiate repair. It can also do all three poorly: linger, scar, or destroy. On the exam, inflammation is a process to be read (acute vs. chronic vs. granulomatous), not a disease in itself, and its systemic effects (leukocytosis, acute-phase reactants, anemia) generate classic diagnostic traps.

Presentation

• Cardinal signs of acute inflammation described by Celsus: rubor (redness) and calor (warmth) from vasodilation, tumor (swelling, in the Celsus sense of edema—not neoplasm), and dolor (pain); functio laesa (loss of function) was later added by Virchow
• Acute inflammation shows a neutrophil-rich tissue infiltrate; a neutrophil-rich infiltrate on biopsy signals an acute process with predictable outcomes (resolution, abscess, or fibrosis)
• Chronic inflammation shows a different cellular cast—lymphocytes, plasma cells, and macrophages—over a time course of weeks to years, with simultaneous tissue destruction and attempted repair often producing fibrosis
• Reactive leukocytosis, particularly neutrophilia, accompanies inflammatory states such as surgery, burns, MI, and pancreatitis
• Granulomatous inflammation presents as epithelioid macrophages, sometimes fused into multinucleated giant cells, walling off an antigen that could be phagocytosed but not destroyed

Diagnosis

• CBC with differential: reactive neutrophilia (>7,500/µL) supports inflammation; a 'left shift' (increased immature band forms) indicates acute demand exceeding marrow capacity, as in severe infection or sepsis
• Tissue biopsy to identify the process—neutrophil-rich infiltrate (acute) vs. lymphocyte/plasma cell/macrophage infiltrate (chronic) vs. granuloma; in granulomatous inflammation, the presence or absence of caseous necrosis at the center is the discriminating feature (caseation suggests mycobacteria or fungi; non-caseating points toward sarcoidosis, Crohn's, berylliosis, or foreign body)
• Iron studies in suspected anemia of chronic disease: low serum iron, LOW TIBC, and HIGH (or normal) ferritin, with an inappropriately blunted EPO response
• Recognize that inflammation systemically distorts labs—ferritin is an acute-phase reactant that rises with inflammation independent of iron stores

Management

• Determine whether a leukocytosis is reactive (an appropriate response to infection, inflammation, drugs, or stress) or neoplastic (uncontrolled clonal proliferation)—reactive changes are managed by addressing the trigger
• For chronic inflammation, the key move is to identify and treat the persistent stimulus (unresolved infection, autoimmunity, toxic exposure, or foreign body); control of the underlying inflammatory disease addresses the downstream anemia of chronic disease

High-yield

• Cardinal signs of Celsus (the classic tetrad) = rubor, calor, tumor (swelling, not tumor as in neoplasm), and dolor—the macroscopic signature of acute inflammation; functio laesa was added later by Virchow
• Neutrophil recruitment cascade: margination → rolling on selectins → firm adhesion on integrins → transmigration through PECAM-1
• 'Left shift' = increased band (immature neutrophil) forms, indicating acute demand exceeding marrow capacity in severe infection/sepsis
• Chronic inflammation → IL-6 → hepcidin → ferroportin degradation → iron trapped in macrophages → anemia of chronic disease with LOW iron, LOW TIBC, HIGH ferritin
• In granulomatous inflammation, the necrosis pattern inside the granuloma—caseating (infectious: mycobacteria, fungi) vs. non-caseating (sarcoidosis, Crohn's, berylliosis, foreign body)—is the discriminating feature, not the granuloma itself
• Necrosis is cell death with leakage of contents and an inflammatory response, unlike apoptosis, which is contained and does not provoke inflammation

Pitfalls

• Assuming a 'normal' ferritin excludes iron deficiency in an inflamed patient—ferritin is an acute-phase reactant that rises with inflammation independent of iron stores; because serum iron (and thus transferrin saturation) also falls with IL-6/hepcidin in chronic inflammation, use soluble transferrin receptor (or the sTfR/log-ferritin index), which is relatively unaffected by inflammation, to detect concurrent iron deficiency
• Calling the granuloma itself diagnostic—it is the caseating vs. non-caseating necrosis pattern that discriminates the cause
• Mislabeling reactive leukocytosis as malignancy; suspect neoplasm only with very high counts (>50,000) without obvious infection, immature cells (blasts, promyelocytes), associated cytopenias, or unexplained splenomegaly
• Applying healthy-population lab thresholds to a sick, inflamed patient—inflammation shifts biology off the reference distribution