Fever

Fever is defined as a measured body temperature of at least 38℃ (100.4℉). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus. This process increases the physiologic “set-point” of body temperature. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin. Fever is a symptom of a wide array of diseases; therefore, an accurate history and review of other symptoms are crucial in finding the cause. The major etiologies of fever include infectious (most common), non-infectious, neurogenic, and drug-induced. High fever can have systemic effects that put the individual at risk of both short- and long-term dysfunction. In severe cases, fever may lead to death if untreated.

Last update:

Table of Contents

Share this concept:

Share on facebook
Share on twitter
Share on linkedin
Share on reddit
Share on email
Share on whatsapp

Definition

  • Fever is defined as a measured temperature of at least 38°C (100.4°F).
  • Normal body temperature fluctuates in a diurnal variation. Normal fluctuation is between 1°C and 1.3°C (1.8°F and 2.4°F) daily with:
    • Lowest-noted temperature between 2 am and 8 am
    • Highest-noted temperature between 4 am and 9 pm
  • Temperature varies based on the body site used for measurement (e.g., rectal is higher than oral)
  • Normal temperature elevations occur after:
    • Vigorous exercise
    • Eating
    • Ovulation

Etiology

Infection

  • Most common cause
  • Examples: influenza Influenza Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza, common cold, pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia, malaria Malaria Malaria is an infectious parasitic disease affecting humans and other animals. Most commonly transmitted via the bite of a female Anopheles mosquito infected with microorganisms of the Plasmodium genus. Patients present with fever, chills, myalgia, headache, and diaphoresis. Malaria, HIV, infectious mononucleosis Mononucleosis Infectious mononucleosis (IM), also known as "the kissing disease," is a highly contagious viral infection caused by the Epstein-Barr virus. Its common name is derived from its main method of transmission: the spread of infected saliva via kissing. Clinical manifestations of IM include fever, tonsillar pharyngitis, and lymphadenopathy. Mononucleosis, gastroenteritis Gastroenteritis Gastroenteritis is inflammation of the stomach and intestines, commonly caused by infections from bacteria, viruses, or parasites. Transmission may be foodborne, fecal-oral, or through animal contact. Common clinical features include abdominal pain, diarrhea, vomiting, fever, and dehydration. Gastroenteritis

Neurogenic

  • Caused by direct damage to the hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus from: 
    • Central nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System (CNS) trauma
    • Intracerebral bleeding
    • Increase in intracranial pressure
  • Characterized by a high temperature and resistance to antipyretic therapy; not associated with sweating

Drug-induced

  • Possible pathways: 
    • Interference with the physiological mechanisms of heat loss and central temperature regulation
    • Direct damage to tissues
    • Stimulation of an immune response
    • Pyrogenic properties of the drug
  • Common drug classes:
    • Anticonvulsants (carbamazepine, phenytoin, phenobarbital)
    • Antimicrobials (minocycline, beta-lactams, sulfonamides, nitrofurantoin)
    • Antidepressants ( serotonin syndrome Serotonin syndrome Serotonin syndrome is a life-threatening condition caused by large increases in serotonergic activity. This condition can be triggered by taking excessive doses of certain serotonergic medications or taking these medications in combination with other drugs that increase their activity. Serotonin Syndrome secondary to selective serotonin reuptake inhibitor (SSRI) intake)
    • Allopurinol
    • Heparin
    • Antihistamines Antihistamines Antihistamines are drugs that target histamine receptors, particularly H1 and H2 receptors. H1 antagonists are competitive and reversible inhibitors of H1 receptors. First-generation antihistamines cross the blood-brain barrier and can cause sedation. Antihistamines
    • Illegal drugs: amphetamines, cocaine

Other conditions

  • Endocrinopathies ( hyperthyroidism Hyperthyroidism Thyrotoxicosis refers to the classic physiologic manifestations of excess thyroid hormones and is not synonymous with hyperthyroidism, which is caused by sustained overproduction and release of T3 and/or T4. Graves' disease is the most common cause of primary hyperthyroidism, followed by toxic multinodular goiter and toxic adenoma. Thyrotoxicosis and Hyperthyroidism, pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma)
  • Pulmonary emboli
  • Neoplasms
  • Tissue damage ( myocardial infarction Myocardial infarction MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction, burns Burns A burn is a type of injury to the skin and deeper tissues caused by exposure to heat, electricity, chemicals, friction, or radiation. Burns are classified according to their depth as superficial (1st-degree), partial-thickness (2nd-degree), full-thickness (3rd-degree), and 4th-degree burns. Burns, surgery, hemorrhage, crush syndrome Crush Syndrome Crush syndrome encompasses the systemic manifestations that result from a crush (or traumatic compression) injury. Compartment syndrome and/or rhabdomyolysis can also occur in crush syndrome. Systemic effects include the development of renal failure due to toxins released from damaged muscles, hypovolemia, and acidosis. Crush Syndrome)
  • Autoinflammation (arthritis, irritable bowel syndrome Irritable bowel syndrome Irritable bowel syndrome (IBS) is a functional bowel disease characterized by chronic abdominal pain and altered bowel habits without an identifiable organic cause. The etiology and pathophysiology of this disease are not well understood, and there are many factors that may contribute. Irritable Bowel Syndrome ( IBS IBS Irritable bowel syndrome (IBS) is a functional bowel disease characterized by chronic abdominal pain and altered bowel habits without an identifiable organic cause. The etiology and pathophysiology of this disease are not well understood, and there are many factors that may contribute. Irritable Bowel Syndrome))

Related videos

Pathophysiology

  • Body temperature is regulated by the CNS at the level of the hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus. 
  • Fever is a normal physiologic phenomenon caused by the release of either exogenous or endogenous pyrogens (any substance that causes fever). 
  • When a fever occurs, the hypothalamic thermoregulatory center shifts its set-point upward (similar to the thermostat in a home). 
  • This upward shift is due toprostaglandin E2 (PGE2)in the preoptic area of the hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus (increased PGE2 is caused by circulating pyrogens).
  • Endogenous pyrogens:
    • Produced by inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation, trauma, or antigen-antibody complexes
      • Interleukin-1 (IL-1)
      • IL-6
      • TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF)-?
      • Interferon-γ
    • Activates the arachidonic acid pathway, which releases PGE2 → activates the preoptic area of the hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus → increases temperature set-point
  • Exogenous pyrogens:
    • Primarily from microbes:
      • Lipopolysaccharides (LPS) of gram-negative bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview
      • Endotoxins
      • Exotoxins

Physiologic effects of fever

  • Heat conservation: vasoconstriction
    • Increases heat production in the periphery
    • Causes a subjective cold sensation in the hands and feet as blood is shunted from the periphery to internal organs
  • Heat production: thermogenesis of muscle and adipose tissue Adipose tissue Adipose tissue is a specialized type of connective tissue that has both structural and highly complex metabolic functions, including energy storage, glucose homeostasis, and a multitude of endocrine capabilities. There are three types of adipose tissue, white adipose tissue, brown adipose tissue, and beige or "brite" adipose tissue, which is a transitional form. Adipose Tissue 
    • Increased core temperature by release of adenosine triphosphate (ATP) 
    • Muscle heat production → shivering
    • Adipose tissue heat production → in neonates due to a higher percentage of brown fat
  • Once the hypothalamic set-point is reset downward, heat loss occurs through:
    • Vasodilation, sweating, and behavior changes; may be due to a reduction in pyrogenic cytokines or the use of antipyretics
Time course of a typical fever

Time course of a typical fever

Image by Lecturio.
Pathway of fever

Mechanisms of fever generation

A stressor of the body (e.g., infection, injury, trauma) incites lymphocytes Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes to release cytokines which, in turn, stimulate the hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus.
Within the hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus, the vascular organ of lamina terminalis, or supraoptic crest (OVLT) activates cyclooxygenases (COX), which catalyzes the formation of prostaglandins (PGE2).
These hormone-like substances produce fever by activating cold-sensitive (CS) neurons and inhibiting warm-sensitive (WS) neurons.

Image by Lecturio.

Clinical Presentation

Common symptoms

  • Rigors (shivering)
  • Sweats
  • Chills
  • Flushing of skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin
  • Tachycardia or palpitations
  • Lethargy

Types of fever patterns

Types of fever patterns

Types of fever patterns

Image by Lecturio.

Effects of Fever

Beneficial effects

  • Endogenous pyrogens:
    • Influence the recruitment and function of many types of immune cells
      • Enhance phagocytosis by neutrophils and macrophages
      • Enhance antigen presentation by macrophages and T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells
    • Decrease the levels of trace metals available (iron and zinc)
      • Helps to inhibit microbial reproduction
  • High temperatures (39°C41°C):
    • Directly inhibit the growth of some bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview
    • May also inhibit motility and capsule/cell wall formation
  • Increases antimicrobial activity of some antibiotics

Adverse effects

  • Direct cellular damage by cytokines and inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation: causes both local and systemic effects (summarized below)
  • May provoke sepsis Sepsis Organ dysfunction resulting from a dysregulated systemic host response to infection separates sepsis from uncomplicated infection. The etiology is mainly bacterial and pneumonia is the most common known source. Patients commonly present with fever, tachycardia, tachypnea, hypotension, and/or altered mentation. Sepsis and Septic Shock syndrome
  • Very high fevers (> 41°C): increase host metabolic demands → may result in congestive heart failure Congestive heart failure Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Congestive Heart Failure ( CHF CHF Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Congestive Heart Failure) and ischemia
Table: Adverse effects of cytokines
Cellular Local Systemic
  • Membrane, mitochondrial, and DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure damage
  • Stimulation of excitotoxic mechanisms
  • Protein denaturation
  • Cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death
  • Cytokine stimulation
  • Inflammatory response
  • Vascular stasis
  • Extravasation
  • Edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
  • Endotoxemia
  • Gut bacterial translocation

Clinical Relevance

The following conditions are associated with elevated body temperature:

  • DRESS (drug rash with eosinophilia and systemic symptoms) syndrome: a delayed, severe hypersensitivity reaction to drugs. Often caused by allopurinol, anticonvulsants, and sulfonamides. Besides fever, symptoms include eosinophilia, diffuse rashes Rashes Rashes are a group of diseases that cause abnormal coloration and texture to the skin. The etiologies are numerous but can include irritation, allergens, infections, or inflammatory conditions. Rashes that present in only 1 area of the body are called localized rashes. Generalized rashes occur diffusely throughout the body. Generalized and Localized Rashes, lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy, atypical lymphocytosis Lymphocytosis WBCs develop from stem cells in the bone marrow and are called leukocytes when circulating in the bloodstream. Lymphocytes are 1 of the 5 subclasses of WBCs. Lymphocytosis is an increase in the number or proportion of the lymphocyte subclass of WBCs, often as a result of an immune response to infection (known as reactive lymphocytosis). Lymphocytosis, thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia, and hepatitis. Treated by withdrawal of the causative agent. The case fatality rate is 10%.
  • Malignant hyperthermia Malignant hyperthermia An important complication of anesthesia is malignant hyperthermia, an autosomal dominant disorder of the regulation of calcium transport in the skeletal muscles resulting in a hypermetabolic crisis. Malignant hyperthermia is marked by high fever, muscle rigidity, rhabdomyolysis, and respiratory and metabolic acidosis. Malignant Hyperthermia: a rare genetic condition characterized by the sudden appearance of life-threatening symptoms, such as fever > 40°C with muscle rigidity and hemodynamic instability, in response to certain drugs used for anaesthesia. Diagnosis is based on clinical presentation in an acute event or through genetic testing following the diagnosis in a relative. Treatment is with intravenous dantrolene.
  • Neuroleptic malignant syndrome Neuroleptic malignant syndrome Neuroleptic malignant syndrome (NMS) is a rare, idiosyncratic, and potentially life-threatening reaction to antipsychotic drugs. Neuroleptic malignant syndrome presents with ≥ 2 of the following cardinal symptoms: fever, altered mental status, muscle rigidity, and autonomic dysfunction. Neuroleptic Malignant Syndrome (NMS): a life-threatening condition in response to antipsychotic Antipsychotic Antipsychotics, also called neuroleptics, are used to treat psychotic disorders and alleviate agitation, mania, and aggression. Antipsychotics are notable for their use in treating schizophrenia and bipolar disorder and are divided into 1st-generation antipsychotics (FGAs) and atypical or 2nd-generation antipsychotics. First-Generation Antipsychotics and neuroleptic drugs. Presents with high fever, muscle rigidity, altered mental status, and dysautonomia. Treatment includes withdrawal of the drug and antidotes such as dantrolene and amantadine.
  • Serotonin syndrome: a condition in response to serotonergic drugs, e.g., antidepressants such as SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors Monoamine oxidase inhibitors Monoamine oxidase inhibitors are a class of antidepressants that inhibit the activity of monoamine oxidase (MAO), thereby increasing the amount of monoamine neurotransmitters (particularly serotonin, norepinephrine, and dopamine). The increase of these neurotransmitters can help in alleviating the symptoms of depression. Monoamine Oxidase Inhibitors (MAOIs). Presents with agitation, confusion, hyperthermia, autonomic hyperactivity, and rigidity. Treatment consists of discontinuation of the causative agent.

Learn even more with Lecturio:

Complement your med school studies with Lecturio’s all-in-one study companion, delivered with evidence-based learning strategies.

Study on the Go

Lecturio Medical complements your studies with evidence-based learning strategies, video lectures, quiz questions, and more – all combined in one easy-to-use resource.

¡Hola!

Esta página está disponible en Español.

🍪 Lecturio is using cookies to improve your user experience. By continuing use of our service you agree upon our Data Privacy Statement.

Details