Pathophysiology of fever

2021-04-28 04:26 PM

Today it is known that there are many substances acting on the thermostat, causing fever, produced from many different types of cells, collectively called the fever-causing cytokines.


Fever is an increase in body temperature caused by a disturbance in the thermostat centre under the influence of harmful factors, usually infections.

Fever is common and has been studied for a long time. In 1943, Menkin announced that it had found a fever-causing substance called pyrexin which could cause fever when injected into rabbits, but it was later found to be tolerant and only a bacterial endotoxin.

In 1948, Beeson discovered a fever-causing agent extracted from polymorphonuclear leukocytes, recently discovered endogenous pyrogen, a protein with a molecular weight of 13000-15000 dalton. and it is known that reptiles also have a fever; hence fever was thought to be an adaptive phenomenon that should be retained through the evolution of the species.

It is known today that many substances acting on the thermostatic centre are produced from a variety of cells called pyrogenic cytokines.

Fever factors

Fever factors are also called exogenous pyrogens. Today it is well known that febrile factors act on phagocytes of bone marrow origin to produce endogenous fever-causing agents (blood and secretory neutrophils, mononucleosis, macrophages cells in the lungs, liver). The endogenous fever-causing agent acts on the thermostat center, altering the thermostat that causes fever.

Fever factors include:

Gram (+) bacteria and exotoxins, bacteria gram (-) and endotoxins which are essentially lipopolysaccharide (LPS). Tuberculosis bacteria with lipid-rich cell membranes (LAM: lipoarabinomannan) can trigger mononuclear BC to produce IL1, TNF, and IL6, causing prolonged fever.



Fever steroids (etiocholanolone).

Antigenic complexes.

Slow hypersensitivity antigens (according to Atkin) stimulate lymphocytes to release a non-fever-causing solute factor, which stimulates macrophages to produce endogenous fever-causing substances.

Substances from inflammatory and necrotic foci (polynuleic acids).


Endogenous fever-causing agents: (EP: Endogenous Pyrogen)

In 1977, it was known that endogenous fever (EP) is a protein with a molecular weight of 13000-15000 for every 35 ng that can cause an increase in body temperature to 0.6 0 C, inactivity when pH is alkaline, active. thanks to the free SH group, when oxidized or reduced, it will be inactivated.

We can incubate leukocytes from the inflammatory drive, white blood cells will produce fever-causing substances, if using leukocytes collected from the blood, they must incubate with bacterial endotoxins. In people with fever, by conventional biochemical methods, it cannot be detected because the concentration of endogenous fever-causing substances in the blood is too low. Author Dinarello has discovered fever-causing substances in people with fever by radioactive immunoassay.

In 1989, it was known that endogenous fever-causing substances similar to Interleukin I (IL1), abbreviated as EP / IL1, were derived from mononucleosis and macrophages. At first it was thought that there were two types of IL: IL-1α and IL-1β. They had a molecular weight of about 17.5 Da, only 26% of the amino acid sequence were the same and attached to the same specific type.

EP / IL1 in addition to its effects on the thermostat centre will be discussed in more detail in the following section, there are also biological effects:

EP / IL1 plays an important role in the immune response, it activates lymphoid cells that support Interleukin 2 (IL2) synthesis. IL2 stimulates a cell-mediated immune response because T lymphocytes reproduce IL2-dependent, and reproduce optimally in the presence of fever (39.5 ° C).

EP / IL1 stimulates B lymphocyte proliferation, and antibody synthesis is also enhanced by IL1.

EP / IL1 increases complement synthesis.

EP / IL1 contributes to bactericidal action, by reducing plasma Fe and Zn (Fe is essential for the growth of certain bacteria).

IL-1 causes the synthesis of IL-8, IL-8 is a very strong kinetic chemical for BCTT and DTB and stimulates enzyme release from BCTT.

EP / IL1 alter protein synthesis in the liver, decrease albumin, increase proteins in the acute phase including antiprotease, complement, fibrinogen, ceruloplasmin, ferritin, haptoglobin. C-reactive protein is a substance that attaches to necrotic cells and VK can increase a thousand times.

EP / IL1 moves amino acids from muscle through a proteolytic mechanism by cyclooxygenase, PGE1. These amino acids are used to power other cells. In the degenerative muscle fever with quite important amounts, in people with fever can lose weight up to 1 kg/day and muscle aches, if long-term fever makes the patient loss of appetite, weight loss, and weakness.

Today it is known that there are 11 types of fever-causing proteins that are derived from many types of cells, but the main source is still macrophages. These substances are collectively known as pyrogenic cytokines.

There are strong fever-causing cytokines including IL-1, TNFα (tumour necrosis factor α), INF, IL6 and IL-1 with strong fever-causing effects at doses of 1-10ng / kg that can cause fever up to 39o, at doses. 100ng / kg can cause a high fever accompanied by chills. TNFα has a fever-causing effect but at higher doses (50-100ng / kg). INF and IL6 have a weak fever-causing effect.

The cytokine antagonist and inhibitor that can act as a fever regulator is an IL-1Ra (IL-1Ra: IL-receptor antagonist) antagonist, a protein with a molecular weight of 23-25kDa. , which blocks the binding of IL-1 to the receptor.



Cachectin (TNFα)

Lymphotoxin (TNFβ)

IL1 α, IL1β

Interferon (INF α, β, γ)

Interleukin 6 (IL6)

Macrophage inflammatory protein 1 alpha (MIF-1α), MIF-1β

Interleukin 8 (IL8)


Lymphocyte B,T

Macrophages and other cells


From a variety of cells



Table: Endogenous fever-causing substances.

Mechanism of fever

Mechanism of action of endogenous fever-causing agents: EP → Centre of thermostats → thermoregulatory setpoint change → hyperthermia, reduction in heat excretion → fever.

When the thermostat is changed, the body temperature becomes cold, the patient feels cold, shivering, chills, tremors, peripheral vasoconstriction, the body temperature starts to rise, and does not perspire until fever began to recede.

Mechanism of thermostatic change: The authors all mention the role of arachidonic acid products, synthesized from the endothelial cells of blood vessels when fever-causing cytokines attach to the receptors on the surface. cells in the hypothalamus. It is now thought that a large amount of endogenous fever-causing agents from endothelial cells (most importantly PGE2 and other arachidonic products) causes a second signalling system alteration, cyclic AMP (cAMP). ), cAMP causes an increase in the thermostat.


Figure: Diagram of the Rosendoff fever generation mechanism.

There is evidence that a CRF (Corticotropin-Releasing Factor) release initiates heat production under the action of at least one cytokine, IL-1.

When there is a change in the thermostat point, the signals follow the centrifugal nerves, especially the sympathetic wires to the peripheral blood vessels, causing vasoconstriction, reducing heat excretion, and the signals propagate to the shell The brain changes behaviours such as blankets, warm clothes ...

Standing fever: (steady-state fever), when the body temperature has reached the temperature of the new thermostat, there will be vasodilation and perspiration so that the body temperature can be balanced.

Defervescence When the endogenous fever-causing agent naturally decreases or due to the antipyretic drug, the heat-sensitive neurons return to normal, the thermostat to normal, the fever recedes and the body temperature to normal again.

Metabolic disorders in fever

Energy metabolism disorder: When the temperature increases, the energy metabolism also increases, oxygen consumption also increases (when the temperature increases by 10 0 C, metabolism increases by 3.3%, oxygen consumption increases 13 %).

Glucid metabolism disorders: When fever increases glucide metabolism, decreased glycogen stores, increased blood sugar, increased lactic acid.

Disorders of lipid metabolism: when fever is prolonged, glycogen stores decrease, lipid use increases, ketones increase in blood.

Protide metabolism disorder: increase in muscle protein degradation, decrease in protein synthesis, negative nitrogen balance. Protide metabolism can be increased by up to 30%.

Increased need for vitamins, especially vitamins of groups B and C.

During the fever flare-up phase, there is an increase in hormones such as Aldosterone and ADH, which decrease urinary excretion. When fever subsides, there is an increase in urinary excretion, sweating to increase heat excretion.

Dysfunction in fever

Neurological disorders: When fever, there can be disorders in the nervous system with manifestations such as headache, dizziness, general aches, delirium, in children may have seizures. Manifestations depend on the causative agent and the body reactivity.

Circulatory disorders: The heart rate increases, usually the body temperature increases 10C, the heart increases 10 beats. At the onset of fever increases due to peripheral vasoconstriction, when fever decreases in blood pressure due to vasodilation.

Respiratory disorders: Hyperventilation occurs in cases of fever due to increased oxygen demand

Gastrointestinal disturbances: Usually there are symptoms such as bitterness, loss of appetite, dryness of the oral mucosa, decreased secretion and peristalsis of the gastrointestinal tract, causing indigestion, constipation.

In addition, the endocrine system has been shown to increase the secretion of ACTH, Cortisol.

As for liver function, there is a metabolic increase of 30-40%.

The biological significance of fever

Fever is a beneficial phenomenon for the body.

The fever phenomenon has existed for millions of years. Fish, reptiles and amphibians all have fever, fever is a phenomenon that persists in the evolutionary process, so it is a beneficial phenomenon.

When the body temperature increases, it inhibits the activity of bacteria and can kill the bacteria. There is a lot of evidence to suggest that the ability to kill bacteria when body temperature increases: the average lethal dose of a white drain purifier with endotoxin injection increases if hypothermia is caused by drugs or chemicals. Desert Igwana, when infected with Aerobacter hydrophyla, is a type of gram (-) bacteria; if given at a temperature of 40-41 0 C, most of them live, if at lower temperatures most will die. This is an application when it is known that fish, reptiles and birds also have a fever, when they need to increase their temperature, they just need to look for a high temperature; This makes it easier to study fever phenomena. People also have similar results if they experiment with the reptile Diprosaurus dorsalis.

When there is a fever, the body's resistance system increases due to increased activity of the immune system, increased phagocytosis, increased antibody synthesis ...

Fever reduces the amount of iron in the serum due to increased iron absorption by the phagocytic mononuclear system, reducing the absorption of iron from the intestine, preventing bacteria from reproducing. Grigler and Kluger studied in reptiles, found that when a fever, serum iron levels decrease, if iron is added to the death rate will be high.

Thus, fever is a beneficial phenomenon for the body, it is necessary to be cautious in finding ways to reduce fever quickly. However, it is necessary to intervene at the right time in some cases such as myocardial anaemia, pregnant women, with a history of epilepsy, and fever over 41 0 C.



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