The connection between fever and immunological reactions (for medical specialists)

Elevation of body temperature is closely tied to a number of immunological reactions.

For approx. 600 million years evolution has been “polishing” the immunologic process in vertebrates to develop a complexly regulated system that integrates fever and in which the entire body is involved (149). This was preceded by an even longer evolutionary process. See our separate article „The Meaning and Evolution of Fever” for more on this topic.

Fever synchronously exerts its immunological action through several mechanisms:

1) by thermal effects (9)

2) humoral production of antibodies (10) and

3) through several cellular (11) mechanisms:

  • by activation (148), proliferation and maturation of leukocytes,
  • by stimulating neutrophil and monocyte motility (a4 integrins, 148), migration, phagocytosis, -pinocytosis,
  • T cell activity—including faster activation and faster growth (higher cytotoxic activity),
  • accelerated antibody production,
  • accelerated the processing and presentation of antigens by dendritic cells,
  • antigen presentation onT cells as well as migration to lymph nodes (FAK-RhoA, 148).

NF-kB and A20 proteins, which activate the cell clock of immune cells, are more active at higher temperatures.

The activity of heat shock proteins (such as Heat Shock Protein 90) and a4 integrins is closely related to T cell activity (148).

It is probably through this mechanism, that fever increases the anti-bacterial effect of antibiotics (7-10). Thus, when antiviral and antibacterial drugs are indicated, they tend to be more effective if the patient also has an optimum fever.

This means that routinely reducing fever without a clear clinical indication, or inhibiting a fever reaction just for convenience, also suppresses these immune mechanisms.

The administration of antibiotics to a patient in good general condition is not indicated for three days (124).


Fever-causing pyrogens:

1) Exogenous pyrogens (these activate the production of endogenous pyrogens during infections)

  • Gram negative endotoxins
  • G positive toxins
  • other infectious agents

2) Endogenous pyrogens

  • cytokines: IL-1α, IL-1β, IL-6, IL-11, TNF-α, IFN-α, -β and γ, oncostatin M, LIF, prostaglandins
  • they are produced by a wide variety of cells, most notably monocytes and macrophages, mesangial cells, keratinocytes and other epithelial cells at the site of infection
  • these triggered a set-point rise when reaching the hypothalamus

Multiple serum reactant changes can be detected during infection (135):

Positive acute phase reactants: procalcitonin (PCT), C-reactive protein, complements, cytokines, coagulation proteins, alpha-1-antitrypsin, alpha-1-chymotrypsin, haptoglobin, haemopexin, ceruloplasmin, ferritin, cytokines.

Negative acute phase reactants: albumin, transferrin, serum iron, fibronectin.

Because serum iron levels will test low during an infection common mistake in this case is oral substitution of iron. We do not recommend routine administration for a period of two weeks after a simple infection, unless justified later, based on a detailed lab results.


You can find the corresponding numbered references here: References

Version update: 1 March 2024