• Clinical science

Fever and systemic inflammatory responses


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 immune system.

Local inflammatory reactions

Acute local inflammation

  • Classic signs of inflammation
    • Rubor = redness
    • Calor = heat
    • Tumor = swelling
    • Dolor = pain
    • Functio laesa = loss of function
  • Four steps leading to inflammation
    1. Tissue damage (e.g., infection, burn)
    2. Ischemic phase: (short-term) hypoperfusion of tissue
    3. Edema formation (two mechanisms)
      • Dilation of the arterioles and constriction of the venuleshyperemia → 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
    4. Reduction of blood flow → adhesion of leukocytes to endotheliumdiapedesis (extravasation) of leukocytes to the inflamed tissue

Chemotaxis and leukocyte extravasation

Within inflamed tissue, leukocytes (mainly neutrophils in early infection) interact with the vascular endothelium and leave the blood vessels to migrate to the site of infection.

  1. Margination of neutrophils to the wall of blood vessels
  2. 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
  3. Adhesion: firm binding of leukocytes to endothelium
    1. On endothelial cells
      • Intercellular adhesion molecule (ICAM, also called CD54)
      • Vascular adhesion molecule (VCAM, also called CD106)
    2. On neutrophils and lymphocytes: leukotriene B4 (LTB4) and C5a → activation of integrins
  4. Diapedesis: movement across the endothelial wall
  5. Migration of neutrophils to the site of infection (chemotaxis) mediated by chemoattractants, e.g.:

CD18 deficiency leads to leukocyte adhesion deficiency type 1.

Chronic local inflammation

Persistent acute inflammation due to non-degradable pathogens, prolonged exposure to toxic pathogens, or autoimmune reactions


Types of fever

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., typhoid fever, lobar pneumonia)
Remittent fever Temperature permanently over 38°C (100.4°F); daily fluctuations ≥ 1°C (1.8°F) Viral infections, acute bacterial endocarditis
Intermittent fever High spike and rapid defervescence Pyogenic infection, TB, juvenile idiopathic arthritis

Recurrent fever

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 .
Pel-Ebstein fever Fever lasting 1–2 weeks followed by an afebrile period of 1–2 weeks Hodgkin lymphoma
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., familial Mediterranean fever, hyper-IgD syndrome)
Others Still's disease, Crohn's disease, Behcet's disease, relapsing malaria (tertian malaria, quartan malaria), drug fever, factitious fever
Biphasic fever A fever that breaks and returns once more Dengue fever , leptospirosis
Undulant fever Temperature rises gradually and falls like a wave over days to weeks Brucellosis
Postoperative fever Has a highly variable course and many different causes; discussed in the learning card on perioperative management


Fever of unknown origin (FUO)

  • Classical FUO
    • Causes: infection, autoimmune disease, and malignant neoplasm
    • Fever ≥ 3 weeks
    • Repeated temperature > 38.3°C (101°F)
    • No definitive diagnosis despite thorough clinical investigation
  • Immune-deficient FUO (neutropenic fever)

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.


Inherited fever syndromes

Familial Mediterranean fever

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.

Further hereditary fever syndromes

  • Hyper-IgD syndrome
  • TNFα reception associated periodic syndrome


Inflammatory markers

Inflammatory markers are of great diagnostic value because their plasma concentration changes in different ways depending on the underlying cause.

Erythrocyte sedimentation rate (ESR)

Acute phase reaction

  • 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