Fever – Body Temperature, Pathogenesis, Stages, Symptoms

Pathophysiology deals with the changes or processes that occur in the human body in response to the presence of disease or injury. Fever is the elevation of the body temperature above the normal level. Fever pathophysiology, therefore, is the rise in the body’s temperature due to the changes caused by a disease. The normal temperature of the human body is 37 degrees Celsius (98.6 degrees Fahrenheit). Fever pathophysiology generally occurs inside the body when the body’s temperature rises above the normal level for several hours or days. It is often considered significant when the body’s temperature rises above 38 degrees Celsius (100.4 degrees Fahrenheit). One way to take the body temperature is through the use of a digital thermometer. A digital thermometer is a device that is capable of reading the body temperature when inserted under the axilla, in the mouth or in the anus.

Regulation and control of body temperature

In a healthy individual, body temperature is kept constant in a very small range despite of big differences in temperature of the surroundings and also those in physical activity. Very perfect regulation of body temperature, necessary for optimal progress of enzymatic reactions, is developed in all homoeothermic animals. It doesn’t apply to poikilothermic animals. During the most variable changes in human organism, the body temperature may increase. Fever is a natural reaction during a number of illnesses. In several cases, absence of the natural reaction is more alarming sign than the presence of fever itself. Fever is usually accompanied by different general symptoms, such as sweating, chills, sensation of cold, and other subjective sensason. Missing of these symptoms during high temperature may be a sign of a serious illness.

The main task in heat production has thermogenesis caused by the effect of thyroid hormones. Hormones of thyroid gland stimulate Na+-K+ATP-ase found in cytoplasmic membranes. Increased production of heat is achieved by increasing the metabolic processes in which energy is released in the form of heat. The greatest importance is splitting of ATP when 54kJ are released from one mole of ATP. Skeletal muscles, liver, splanchnic organs, and brain are the biggest producer of heat in an organism. In the heat production the muscles have especially important role. Because of their weight, they are able to produce very large amount of heat very quickly. Increased production of heat takes place in skeletal muscles during increased physical activity. During the digestion, an increased production of heat occurs also in the GIT. Constant body temperature is achieved by perfect nervous regulation. Nervous system maintains the optimal intensity of metabolism and at the same time regulates amount of heat loss. In early postnatal development, the thermoregulation is inadequate because of immature CNS. Fever is always achieved by reset the center thermoregulation to higher values. Hyperthermia means overheating of an organism caused only by exogenic causes (e.g. hot environment, hot bath). In this case the center of thermoregulation doesn’t change its setting up.

Heat is lost from an organism in several ways. The biggest loss is by conduct It depends on the gradient between the body temperature and the temperature of the surrounding environment. The second way is by radiation. The third way is by evaporation. It is used especially during increased production of heat. Distribution of heat is done by blood circulation. Heat goes from each cell to the surrounding liquid and afterwards to the circulated blood. Modulating factor of heat loss is the amount of blood that circulates through the body surface. The big flow through the subcutaneous us area and the skin secures the income of heat that may be given to the environment through the body surface. Sweating helps in delivering the heat. Sweat glands are controlled by cholinergic impulses through the sympathetic fibers. During intensive sweating, up to one liter of sweat may be formed. When the humidity of the enenvironment is higher, a loss of heat by sweating is easier. When necessary to accumulate the heat in an organism, adrenergic stimuli cause reduction of the blood flow through the skin. The skin becomes an isolator decreasing the heat loss to minimum. Control mechanisms regulate the production of heat and its loss. Production and handover (loss) of heat are controlled from the center in the hypothalamus.

It works on the principle of negative feedback control and includes:

1.       Receptors registration central temperature.

2.       Effector mechanisms composed of vasomotors, metabolic effectors, and controls of sweat glands.

3.       Structures recording whether the actual temperature is not too high or too low,

Increased central temperature activates mechanisms enabling the heat loss. Low central temperature activates mechanisms enabling the accumulation of heat. These mechanisms work as the thermostat

In healthy individuals, the body temperature (oral temperature) is somewhere between 36.5 °C and 37.5 °C. It slightly increases during the day since the morning (from 6:00 a.m.). The peak is reached at 6:00 to 10:00 p.m. The lowest temperature is between 2:00 and 4:00 a.m. Diurnal variation depends on the activity throughout the day. Diurnal variation don’t change in persons that work at night and sleep during the day. Such a diurnal variation is also kept when fever occurs. Fever reaches the peak in the evening, and in the morning even a very sick patient may have almost normal temperature. Body temperature changes are more intensive in young person than in old people. The temperature may slightly or temporarily increase in hot environment. Physical activity may also increase the body temperature. In extreme effort, the increase may be very high. The temperature in marathon runners may increase to 39 °C to 41 °C. The temperature may increase slightly if vasodilatation, hyperventilation, and other compensation mechanisms fail. Small increase in temperature may occure, if the surrounding temperature is lower or the jogging is done early in the morning.

Organism uses simple mechanism for temperature regulation. It is the blood through the skin and subcutaneous area. Vasoconstriction allows the increased accumulation of heat, and vasodilation secures its quick loss. Changes in temperature up to 3oC don’t cause an interruption of physiological functions. Spasms may occur during high fever in children, If the body temperature is increased over 42.2 °C, irreversible changes in the brain occur. In humans the temperature usually doesn’t overcome 41.1 °C. Uncontrolled decrease in temperature below 32.8 °C is accompanied by confusions and gradual loss of consciousness. If the decrease continues under 30 the fibrillation of ventricles occur that is the sign of fatal termination of this condition.

Brown fat that differs from the white one in structure and sites of location has an important function in thermogenesis in newborns and children. It is found between scapula, on the neck, in axils, around the aorta and the kidneys. It is highly vascularised and it has large mitochondria in its cells. One could say that while the white fat acts as feather-bed, the brown one is an electrical pillow. Receptors of cold conduct the information to the center of thermoregulation. From this center the impulses run in the sympathetic nerve fibers and lead to the release of norepinephrine in the brown fat. Norepinephrine activates the enzyme lipase. Activated lipase splits the fat to glycerol and free fatty acids (FFA) and the heat is released. Glycerol and FFA remain in the cell and can perform the re-synthesis after some time, An adult person has little brown fat.

 

Pathogenesis of fever

If the body temperature is above 37.2C and is associated with sweating, hyperventilation, and vasodilatation in the skin, we speak of fever. At the beginning, gradual increase in body temperature is observed together with muscle shivering and vavasoconstriction in the skin. This situation is called chills. Increased body temperature is achieved by lowered loss of heat. Vasoconstriction in the skin and subcutaneous tissue is the cause of pale color and dryness, the affected person has a feeling of coldness. At the same time the production of heat in the organism increases. The muscle tonus increases, the spasms occur. Spasms may occur mainly in children. When the vasodilatation starts in the skin, the feeling of warmth and sweating occurs.

Fever may be proved by many stimuli. Most often, they are bacteria and their endotoxins, viruses, yeasts, spirochetes, protozoa, immune reactions, several hormones, medications, and synthetic polynucleotides. These substances are commonly called exogenic pyrogens. Cells stimulated by exogenic pyrogens form and produce cytokines called endogenous pyrogens. Endogenous pyrogens centrally affect the thermosensitive neurons in the preoptic area of the hypothalamus increase the production of heat and decrease in heat loss. The body temperature increases until it reaches the set point. This information is transferred by temperature of blood that flows around the hypothalamus. The decrease of temperature is controlled by activation of mechanisms regulating increased outcomes of heat to the surrounding area. Increased outcome continues in favorable case until the new equilibrium is achieved.

The most important endogenous pyrogens are IL-1, IL-6 and cachectin also called the tumour necrosis factor-α (TNF-α). These are glycoproteins that also have other important effects. They are produced especially by monocytes and macrophages but also by endothelial cells and astrocytes. Also the interferons α, β and γ display the pyrogenic activity.

After Administration an endotoxin in an experiment, the level of plasmatic TNF-α increases and fever occurs. Increased concentrations of IL-1 and TNF-α are also found in sepsis. The production of these cytokines is regulated by the positive feedback mechanism. Besides this, macrophages activated by IFN-γ may increase the production of IL-1 and TNF-α primary induced by other stimuli. On the other hand, glucocorticoids and prostaglandins of group E may display inhibitory effect on the production of IL-1 and TNF-α. Released IL-1 and TNF-α are transported by blood. They affect the target cells in the close proximity or in distant sites. The target cells have secific receptors for IL-1 and TNF-α. In the hypothalamus, IL-1 and TNF-α trigger the synthesis of prostaglandins of group E from the arachidonic acid of cyto-plasmic membranes of target cells. Precise mechanism by which prostaglandin PGE2 reset the central thermostat, is not known. Aspirin and the non-steroidal antiphlogistics display antipyretic activity by inhibiting the cyclooxygenase, an enzyme responsible for the synthesis of PGE2 (these antipyretics don’t inhibit the production of TNF-α or IL-1). Glucocorticoids work antipyretic ally by inhibiting the production of IL-1 and TNF-α, and by inhibiting the metabolic processes of arachidonic acid.

In the process of fever, IL-1 and TNF-a play the central role. Except introduced activity in fever, they interfere with many mechanisms in an organism. Some of their effects are executed with the participation of metabolites of arachidonic acid. IL-1 and TNF-α affect myelopoiesis, release of neutrophils and enhancement of their functions. They cause vasodilatation and the increase the adhesivity of cells, increase the production of PAF and thrombomodulin by endothelial cells, proteolysis and glycogenolysis in muscles, mobilization of lipids from adipocytes, proteosynthesis and glycogenolysis in the liver, induce proliferation of fibroblasts, activate osteoclasts and the release of collagenase from chondrocytes, induce slow wave sleeping activity in the brain, the release of ACTH, beta endorphins, growth hormone and vasopressin, the release of insulin, cortisol, and catecholamines. TNF-α and partially also IL-1 in long-lasting operation may cause cachexia mainly by decreasing the appetite. It is so in chronic infections, inflammatory processes, and in neoplastic processes.

Besides that, TNF and IL-1 significantly increase the immune response by activation of T-cells and stimulation of IL-2 production. IL-1 enhances β-cells proliferation. It is interesting that these processes have the temperature optimum at 39,5C. It follows that the fever can be supposed as a positive factor. Fever and specific effects of IL-1 and TNF-α form together highly integrated processes that are involved in the response to infection and acute inflammation processes.

Interferons and especially IFN-y (formed by T lymphocytes and NK cells) may enhance this response. Several parts of this complex response have protective and the others may have malignant consequences. Septicemia or septic shock is an overshot response of the organism. In this complicated reaction of the organism, it is not easy to decide whether fever should be treated by antipyretics or not. By antipyretics the symptoms of fever may be suppressed but it is uncertain if it is reasonable to suppress also the positive effects of fever and everything that is connected with it. This complex process (fever) mobilizes not only the immune system but also those processes that improve the nutrition of cells and have protective importance on their activity.

In the majority of diseases, fever is caused by pyrogens. There are situations when fever may be caused directly by changes in the center of thermoregulation without the participation of exogenic and may be also endogenous pyrogens. This occurs in brain tumours, intracranial bleeding, and thrombosis.

 

Stages of the fever and accompanying symptoms

Typical fever runs in certain stages that may be called phases. As first phase is entitled prodromal phase or pre-report phase that occurs for about 15 to 90 minutes In this stage, the release of endogenous pyrogen occurs on the basis of exogenic pyrogen’s effect. Endogenic pyrogen mediated through PGE2 affects the thermosensitive neurons of thermoregulatory center in hypothalamus. In this stage, the resetting of thermoregulatory center for a different temperature takes place.

The second stage is called the phase of increase (stadium incrementi). It is thought that in this stage the thermoregulatory center is reset. The thermoregulatory center has probably two compartments. The impulses from the sympathetic compartment that are sent by sympathetic fibers to the whole organism are operating in this stage. In cutaneous and subcutaneous vessels, they cause vasoconstriction, thus they decrease the heat outcome. On the other hand, muscles, liver, and heart, under the influence of sympathetic compartment, increase production of heat that forms, together with decreased outcome of heat, the optimal situation for heat accumulation in an or organism. Body temperature increases, but the sick person has a feeling of cold. Thermogenesis participates in this process through thyroxin and tri-iodothyronine. In consequence of thyroxin thermogenesis and the activation of sympathetic nervous system, the effect of cardiovascular and respiratory systems increases together the basal metabolism. These changes may be measured by increased utilization of oxygen in the organism.

The third stage is called the climax phase (stadium acme). Climax means that the body temperature culminates. At culmination of fever, such a temperature is achieved to which the thermoregulatory center is reset. The center is washed by blood that has the temperature originally adjusted. Because of this, the activation of sympathetic compartments stops. However, the parasympathetic compartment of the other more regulatory enter is activated. Subsequently, the impulses cause vasodilatation of skin vessels and the decrease in peripheral vascular resistance. These changes are the reason of decreased blood pressure and increased pressure in the pulmonary artery. The pressure in the pulmonary artery increases because of vasoconstriction of pulmonary arterioles. The patient has warm and red skin; he sweats, and loses heat by conduction, radiation, and evaporation.

The fourth stage is called the descent stage (stadium decrementi). This stage starts from the peak of fever and is characterized by the decrease of the body temperature. The decrease of fever may be critical. Critical decrease means the situation when the fever decreases to normal temperature in 1 or 2 hours. With the decrease of fever, also the frequency of pulse and respiration is decreased. Sudden decrease especially of long-lasting fever may cause temperature crisis. Expressive decrease of fever, decreased pulse, and decrease in peripheral vascular resistance may cause the failure of circulation. This is especially dangerous for persons with cardiovascular disease and for old persons.

 

Some diseases are characterized by certain stereotypic consequence of tempernature changes. According to the temperature curve, we may distinguish several types of fever.

1.       Febris continua is fever in which the temperature changes are less than 1 °C in 24 hours.

2.       Febris septica-hectica is fever in which the swings are 3 to 5C.

3.       Febris remittens is fever with big temperature swings.

4.       Febris intermittens is fever characterized by several hours lasting apyretic periods.

5.       Febris recurrens is fever that recurs after several days.

6.       Febris undulans is fever in which the halwave lasts several days.

7.       Fever inversa means that fever is higher in the morning than in the evening.

This is typical for patients suffering from tuberculosis.

In fever, important changes occur in the function of organism. As a direct consequence, tachycardia is observed. Increased frequency in heart beats by 10 to 15 beats means the increased in the body temperature by 1 °C. Except tachycardia, extra systoles may also occur during fever. These may have toxic or infectious origin or may be the sign of myocardial degeneration at long-lasting fever. The blood pressure increases in the period of increasing fever. In the period of decreasing fever, the blood pressure decreases because of the decrease of peripheral vascular resistance and the simultaneously present bradycardia.

Oligemia, caused by evaporation and sweating, may participate in worsening of cardiovascular functions. In initial stages of fever, up to its culmination, the frequency of breathing increases. During the fever, or after its finish, pathological components- proteins, hyaline casts, and creatinine are present in the urine. Probably, this is caused by the direct damage to the kidneys by the fever itself. Experimentally it was observed that warm water bath of 40C lasting for several hours doesn’t causes similar changes in urine and general condition as fever. Fever has unfavorable influence on the function of the digestive tract. The defect in secretion of digestive juices is observed. This is associated with motor disorder and the disorder of absorption. Such changed functions of GIT may cause the constipation with catastrophically effects especially in old people. Hypoptyalism is the part of decreased secretory function of the gastrointestinal tract. At hypoptyalism, inflammation of buccal mucosa and the tongue is present as well. In general, the patient loses appetite what is caused by direct activity of TNF-a but also by functional changes in the digestive tract.

Oxidative processes speed up during the fever what may be demonstrated by the increased utilization of oxygen. During the fever or after its finish, hyperglycemia may be ascertained. In general, the catabolism of proteins with negative nitrogen balacne increases leading to the losses of protein that may reach 300 to 400 grams per day, Decreased diuresis associated with increased protein catabolism often leads to the rise in metabolic acidosis. These metabolic changes may be improved in the phase of polyuria that starts after the decrease of fever.

When the body temperature increases by 60C a situation not compatible with life is formed. Subjective feeling of fever is highly variable. Some persons perceive already a small increase in body temperature; others don’t feel even the increase of temperature to high values. This occurs in persons with long-lasting increase of body temperature. A patient with tuberculosis sometimes doesn’t even feel the temperature of 39°C. In most cases, the fever is associated with subjective discomfort such as uncertain headache, arthralgia, and pain in muscles and in the back. The cause of thesesymptoms is not completely clear.

 

Chills may accompany any fever. It is typical for pyogenic infections associated with bacteremia. It may also occur in noninfectious diseases such as vasculitis or lymphoma. Chills may be proved by antipyretics that cause sudden decrease of body temperature. This effect of antipyretics is seen especially if they are given in the phase of increasing temperature.

Sweating: Diffuse sweating usually occurs in culmination of fever. It may be very unpleasant for some persons. However, it is the natural reaction at the process of fever.

Changes in mental condition: are present in very young and very old persons. They may be very mild. Expressive changes in mental condition may be sometimes observed in alcohol drinkers, cardiovascular patients, and senile persons. TNF-α and IL-1 cause the release of beta-endorphins in the brain that may participate on changed mental condition.

Spasms are present in children to 5 years of age. Most often they develop in the phase of increasing body temperature.

Herpes labialis: Increased body temperature may activate latent virus of herpes simplex. From unclear reasons, it often occurs in pyogenic bacterial infections (pneumococcal, streptococcus, and meningococcal), in malaria, and in rickettsioses. Herpes labialis to some extent a sign of suppressed cellular immunity.

Utility of fever: Fever slightly increases immune reactions, increases chemitactic, phagocytic, and bactericidal activity of polymorphonuclear leucocytes. Up to certain value, it stimulates the processes of antibody production.

 

Concomitantly, it slows down the proliferation of microorganisms. Increased body temperature causes a decrease in the amount of plasmatic iron, zinc, and copper. This decrease is not favorable for the growth of microbes. High temperature causes destruction of lysosomes and the whole cells. This is a way by which the body defends itself against microbes but also against replication of viruses. The increase production of interferons also acts against viruses. In general, fever is considered to be a pathological reaction. However, longs to compensatory mechanisms and has important role in defense processes. Therefore, medication of actual fever can’t be the target of treatment. Infectious disease without fever means a prognostically bad medical finding. Harmful effects of fever: They may come into consideration at high temperatures, if fever lasts too long, and especially if the patients are suffering from an additional disease, too. Increased basal metabolism, minute heart volume, and water and salt loses may complicate other basic illnesses. Very high temperature suppresses immune mechanisms. Long-lasting fever causes dysfunctions of parenchymal organs. It is so in malignant (extreme) fever, febrile spasms, epilepsy, cardiac problems, and the disease of the central nervous system. Fast decrease of fever may endanger the patient by fast lowering of the blood pressure.

 

Hyperthermia

 

Hyperthermia is elevated body temperature due to failed thermoregulation that occurs when a body produces or absorbs more heat than it dissipates. It is because of the increase temperature in the surrounding medium but in contrast fever occurs because of disorder inside the body which irritate thermoregulatory center. Hyperthermia occurs when the body temperature rises without a change in the heat control centers. Extreme temperature elevation then becomes a medical emergency requiring immediate treatment to prevent disability or death.

The most common causes include heat stroke and adverse reactions to drugs. The former is an acute temperature elevation caused by exposure excessive heat, or combination of heat and humidity, that overwhelms the heat-regulating mechanisms. Hyperthermia differs from fever in that the body’s temperature set point remains unchanged. The opposite is hypothermia, which occurs when the temperature drops be low that require maintaining normal metabolism.

Signs and symptoms: Hot, dry, skin is typical as blood vessels dilate in an attempt to increase heat loss. An inability to cool the body through perspiration may cause the skin to feel dry.

Other signs and symptoms vary. Accompanying dehydration can produce nausea, vomiting, headaches, and low blood pressure and the latter can lead to fainting or dizziness, especially if the standing position is assumed quickly.

In severe heat stroke, there may be confused, hostile, or seemingly intoxicated behavior. Heart rate and respiration rate will increase (tachycardia and tachypnea) as blood pressure drops and the heart attempts to maintain adequate circulation. The decrease in blood pressure can then cause blood vessels to contract reflexly, resulting in a pale or bluish skin color in advanced cases. Young children, in particular, may have seizures. Eventually, organ failure, unconsciousness and death will result.

Pathophysiology: There is scientific support for the concept of a temperature set point that is. maintenance of an optimal temperature for the metabolic processes that life depends on. Nervous activity in the preoptic-anterior hypothalamus of the brain triggers heat losing (sweating, etc.) or heat generating (shivering and muscle contraction, etc.) activities through stimulation of the autonomic nervous system. The pre-optic anterior hypothalamus has been shown to contain warm sensitive, cool sensitive, and temperature insensitive neurons, to determine the body’s temperature set point. As the temperature that these neurons are exposed to rises above 37°C, the rate of electrical discharge of the warm-sensitive neurons increases progressively. Cold-sensitive neurons increase their rate of electrical discharge progressively below 37°C.

 

Hyperpyrexia

Hyperpyrexia is a fever with an extreme elevation of body temperature greater than or equal to 41.5 °C (106.7 °F). Such a high temperature is considered a medical emergency as it may indicate a serious underlying condition or lead to significant side effects. The most common cause is an intracranial hemorrhage. Other possible causes include sepsis, Kawasaki syndrome, neuroleptic malignant syndrome, drug effects. serotonin syndrome, and thyroid storm. Infections are the most common cause of fever, however as the temperature raises other causes become more common. Infectiontions commonly associated with hyperpyrexia include: roseola, rubeola and entero viral infections. Immediate aggressive cooling to less than 38.9 °C (102.0 °F) has been found to improve survival. Hyperpyrexia differs from hyperthermia in that in hyperpyrexia the body’s temperature regulation mechanism sets the body temperature above the normal temperature, and then generates heat to achieve this temperature, while in hyperthermia the body temperature rises above its set point due to an outside source.