HCP'S CORNER

BASICS OF FEVER

Fever is defined as an oral temperature of >100.0°F or a
rectal temperature of >100.8°F or a temperature higher
than an individual’s known normal daily value.

BASICS OF FEVER

Body temperature refers to the temperature in the hypothalamus and the vital intense organs. The hypothalamus regulates the body temperature. It checks the current temperature and compares it with the normal temperature of about 98.6°F. If the temperature is too low, the hypothalamus ensures that the body generates and maintains heat. If, on the other hand, the current body temperature is too high, heat is given off, or sweat is produced to cool the skin. People develop fever due to an increase in the hypothalamic set point as an adaptive response of the body to a pathological state. Hyperthermia on the other hand, is an abnormally high temperature (above 104°F) also known as overheating. Hyperthermia occurs without an increase in the hypothalamic set point and the body temperature becomes elevated due to thermoregulation failure.

Body temperature Condition
99.1–100.4°F Mild/low-grade fever
100.6-102.2°F Moderate grade fever
102.2-105.8°F High-grade fever
>105.8°F Hyperpyrexia

Reference: InformedHealth.org [Internet]. Cologne, Germany: Institute for Quality and Efficiency in Health Care (IQWiG); 2006-How does the urinary system work?2009 Nov 25 [Updated 2018 Apr 5]

Pathogenesis of fever

Fever is “a physiologic response characterized by an elevation of body temperature above normal daily variation”. Below are the pathophysiologic bases of fever:

  • Fever due to the rise of the hypothalamic set point in the CNS.
  • Fever due to heat production exceeding heat loss.

Fever is the result of a physiological process triggered by an external stimulus. Pyrogens (exogenous and endogenous) are substances which may be infectious microorganisms, toxins released by microorganisms, or pyrogenic cytokines that prompt fever.

The major fever causing cytokines are IL-1β, IL-1α, IL-6, TNF-α and INF-α. These cytokines can be produced in the periphery and brain and have a pyrogenic effect directly affecting the production of PGE2, which resets the thermoregulatory set point.

An early rapid phase (peripheral prostaglandin E2 [PGE2]-dependent) and a delayed late phase (central PGE2) mark the febrile response. Hence, while peripheral PGE2 may act to initiate the febrile response, central PGE2 may be mostly involved in its sustenance.

The humoral pathway is directed by circulating pyrogenic cytokines (IL-1β, IL-6, tumor necrosis factor [TNF]-α). They send fever indicators to the thermoregulatory network through indirect and direct routes. The indirect pathway includes binding cytokines outside the brain and stimulating the cytokine receptors located on the capillaries of the circumventricular organ resulting in PGE2 release. The direct pathway involves disruption of the blood-brain barrier by the circulating cytokines giving direct access to cytokine receptors present on vascular, glial, and neuronal structures of the brain.

While PGE2 is essential in the febrile response, certain cytokines, such as IL-6, may also trigger the febrile response independent of PGE2.

In the neuronal pathway, peripheral nerves such as the cutaneous sensory and vagus nerve are involved. Localized PGE2 synthesized at inflammation sites may activate cold-sensitive cutaneous nerves, transmitting fever signals to the brain.

Reference: Gambhir A, Tamboli S, Prasad S, Inamdar NR. Pyrogenic cytokines mediated pathophysiology of fever and role of Mefenamic Acid in pediatric practice. Indian Journal of Clinical Practice. 2021; 32: 229-236.

NLRP3 inflammasome activation

The Nod-like receptor protein-3 (NLRP3) inflammasome has been implicated in several acute and chronic human diseases. The NLRP3 inflammasome is known to sense disturbances in cellular homeostasis for its activation. Multiple cellular signals that have divergent molecular characterization can trigger NLRP3 activation.

Two signals activate NLRP3 inflammasome; one is via activation of nuclear factors-κβ by Pathogen assisted molecular pattern (PAMPs) and Damage associated molecular patterns (DAMPs)and formation of pro-IL1β.

NLRP3 induces ionic flux events in treated cells, including K+ efflux, Ca2+ mobilization, Cl-1 efflux, and Na+ influx, which are implicated in activating the NLRP3 inflammasome. Activation of NLRP3 inflammasome leads to the release of IL-1β and other pyrogenic cytokines. These pyrogenic cytokines act in the brain to augment the synthesis of cyclooxygenase enzyme increasing the production of PGE2s thus causing fever.

Reference: Kelley N, Jeltema D, Duan Y, He Y. The NLRP3 inflammasome: an overview of mechanisms of activation and regulation. Int J Mol Sci. 2019; 20: 3328.

Aberrant activation of the microglial/NLRP3 inflammasome/IL-1 axis has been implicated in the febrile illness epilepsy syndrome (FIRES), which creates a pro-inflammatory and pro-convulsive milieu

Ref: Kasture P, Mehta K, Gowda A. Inflammasome, inflammation, infection and Mefenamic Acid. JAPI. 2022; 70.

Types and causes of fever

Classification of acute febrile illness

Fever patterns

Clinically described fever patterns can be helpful in indicating the possible causes of infections.

  • Remittent fevers: Fever with daily fluctuations exceeding 35.6°F but at no time touches normal. E.g., infective endocarditis, rickettsiae infections, and brucellosis.
  • Intermittent fevers:Temperature remains 98.6°F during the day but rises during the night. E.g., malaria, abscess, and cholangitis.
  • Sustained or continuous fever: Fever that does not fluctuate more than 33.8°F during the day. E.g., pneumococcal pneumonia and typhoid fever.
  • Relapsing fever: Fever characterized by recurrent acute episodes of fever followed by an intervening afebrile period)-. E.g., Hodgkin’s disease, P. vivax malaria, Borrelia infection, and rat-bite fever.

Other Sections to view

Pediatric Fever
Management of Fever