- Clinical science
Inflammation is the body's response to harmful stimuli. Inflammatory processes lead to both local and systemic reactions and may be either acute or chronic. The five classic signs of local inflammation are redness, swelling, heat, pain, and loss of function. There are various signs of a systemic reaction, the most important of which is fever. In addition to identifying a systemic reaction, tracking temperature changes may also help to determine the cause of inflammation (e.g., when differentiating between different types of malaria). However, in some cases, the cause of the fever remains indeterminate (fever of unknown origin). Additionally, inflammatory processes lead to changes in the humoral and cellular immune responses, which can be measured in serum samples (with acute-phase reactants). Important inflammatory markers include leukocyte count, C-reactive protein (CRP), and the erythrocyte sedimentation rate (ESR). Procalcitonin can also be used for differentiating bacterial from viral infection as well as monitoring septic processes. An explanation of the immune system and all processes involving inflammation can be found in the learning card on the .
Acute local inflammation
- Classic signs of inflammation
Four steps leading to inflammation
- Tissue damage (e.g., infection, burn)
- Ischemic phase: (short-term) hypoperfusion of tissue
Edema formation (two mechanisms)
- Dilation of the arterioles and constriction of the venules → hyperemia → high intravascular pressure → leakage of blood plasma into the tissue
- Localized mast cell degranulation → ↑ histamine → separation of endothelial junctions → separation of endothelial cells → ↑ vascular permeability and ↑ paracellular movement of fluid
- Reduction of blood flow → adhesion of leukocytes to endothelium → diapedesis (extravasation) of leukocytes to the inflamed tissue
- Margination of neutrophils to the wall of blood vessels
- Rolling: expression of adhesion molecules on neutrophils (e.g., Sialyl-LewisX), other leukocytes (L-selectin) and endothelial cells (e.g., P-selectin, E-selectin, GlyCAM-1, CD34) → alternate binding and release of neutrophils
Adhesion: firm binding of leukocytes to endothelium
- On endothelial cells
- Intercellular adhesion molecule (ICAM, also called CD54)
- Vascular adhesion molecule (VCAM, also called CD106)
- On neutrophils and lymphocytes: leukotriene B4 (LTB4) and C5a → activation of integrins
- On endothelial cells
- Diapedesis: movement across the endothelial wall
- Migration of neutrophils to the site of infection (chemotaxis) mediated by chemoattractants, e.g.:
CD18 deficiency leads to .
Chronic local inflammation
Persistent acute inflammation due to non-degradable pathogens, prolonged exposure to toxic pathogens, or autoimmune reactions
- Cells involved: mononuclear cells (monocytes, macrophages, lymphocytes, plasma cells), fibroblasts
- Leads to necrosis and fibrosis (simultaneous destruction and formation of new tissue)
- May last for months to years
Granulomatous inflammation (distinctive pattern of chronic inflammatory reaction)
- Granuloma; : organized collection of activated macrophages (epithelioid histiocytes) that tries to wall off an offending antigen (e.g., infectious pathogen); may include other cells (e.g., lymphocytes, giant cells) that help in identifying the cause of granuloma
The pattern of fever may help with diagnosis, although it has limited value compared to more specific laboratory tests.
|Type of fever||Course||Associated diseases|
|Continuous fever||Temperature permanently over 38°C (100.4°F); daily fluctuations < 1°C (1.8°F)||Viral and bacterial infections (e.g., lobar pneumonia),|
|Remittent fever||Temperature permanently over 38°C (100.4°F); daily fluctuations ≥ 1°C (1.8°F)||Viral infections,|
|Intermittent fever||High spike and rapid defervescence||Pyogenic infection, ,|
|Relapsing fever||Days of fever followed by an afebrile |
period of several days and then a relapse into additional days of fever, usually after 14–21 days
|Tick-borne relapsing fever and louse-borne relapsing fever .|
|Fever lasting 1–2 weeks followed by an afebrile period of 1–2 weeks|
|Periodical fever||Fever that recurs over months or years in the absence of associated viral or bacterial infection or malignancy||Periodic fever syndromes (e.g., hyper-IgD syndrome)|
|Others||malaria ( , ), drug fever, factitious fever, , , relapsing|
|Biphasic fever||A fever that breaks and returns once more||,|
|Undulant fever||Temperature rises gradually and falls like a wave over days to weeks||Brucellosis|
|Has a highly variable course and many different causes; discussed in the learning card on|
- Causes: infection, autoimmune disease, and malignant neoplasm
- Fever ≥ 3 weeks
- Repeated temperature > 38.3°C (101°F)
- No definitive diagnosis despite thorough clinical investigation
- Nosocomial FUO: newly occurring fever in patients that have been admitted to the hospital at least 24 hours ago
- HIV-associated FUO
Immune-deficient FUO (neutropenic fever)
- Neutropenic patient with fever and a neutrophil count ≤ 500/μL (severe risk of bacterial infection)
- Neutropenic fever is often chemotherapy-induced.
- Other common causes: bacterial infections, aspergillosis, candidiasis, herpes virus
- Management: Even without a determinant source of infection, broad-spectrum antibiotics must be administered without delay to avoid sepsis and life-threatening complications.
Severe febrile neutropenia is life-threatening because of an impaired neutrophil-mediated inflammatory response to bacterial infections. After drawing blood and urine cultures, immediate empiric antibiotic therapy should be initiated.
Familial Mediterranean fever (FMF) is a hereditary disorder. Patients suffer from recurring, self-limiting fever attacks with chest and abdominal pain. The attacks are sometimes accompanied by arthritis and skin reactions. Patients do not experience any symptoms between attacks.
- Epidemiology: mostly limited to eastern Mediterranean ; most common inherited fever syndrome
- Genetics: mutation in the MEFV gene on chromosome 16; autosomal-recessive disorder
- Clinical presentation
- Complication: AA amyloidosis
- Therapy: Prevention of AA amyloidosis through inhibition of granulocyte function: colchicine, TNF inhibitors
Further hereditary fever syndromes
- Hyper-IgD syndrome
- TNFα reception associated periodic syndrome
Inflammatory markers are of great diagnostic value because their plasma concentration changes in different ways depending on the underlying cause.
- The test measures the distance that erythrocytes have fallen after one hour in a vertical tube of anticoagulated blood.
- Normal values: ♀ 0–20 mm/h and ♂ 0–15 mm/h
Factors that increase ESR
- Elevated fibrinogen level (infection, inflammation, malignancy)
- Pregnancy (↑ fibrinogen)
- Old age
- Anemia, macrocytosis
- Multiple myeloma, Waldenström's macroglobulinemia
- Autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis, giant cell arteritis, polymyalgia rheumatica, de Quervain's thyroiditis)
- Factors that decrease ESR
- Other factors (e.g., dilution problems, clotting of the blood) may influence the result.
- The acute phase reaction is the initial response of the organism to systemic or local disturbances (e.g., operation, trauma, inflammation, infection, malignancy).
- It provides rapid protection for the host by destroying pathogens and promoting healing processes. Part of this response is the release of more than 30 acute-phase reactants, which are produced in the liver.
- Acute-phase reactants are mainly part of the alpha-1 and alpha-2 zones in serum protein electrophoresis, causing an increase in these zones during acute inflammation .
Important acute phase reactants
- C-reactive protein (CRP): opsonization of pathogens
- Ferritin: protein that stores and releases iron
- Fibrinogen → coagulant → wound healing
- α1-Antitrypsin → protection from protease activity
- Antioxidative properties
- Antimicrobial properties
- Decreases in hemolysis
- pneumonia, and sepsis: sensitive parameter for following the progression of bacterial infections, especially for
- Interleukin-6 (IL-6)
- Negative acute phase reactants; : The most notable are albumin, transferrin, and antithrombin.