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Fever

Fever is defined as a measured body temperature Body Temperature The measure of the level of heat of a human or animal. Heatstroke of at least 38℃ (100.4℉). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E Prostaglandin E Three of the six naturally occurring prostaglandins. They are considered primary in that no one is derived from another in living organisms. Originally isolated from sheep seminal fluid and vesicles, they are found in many organs and tissues and play a major role in mediating various physiological activities. Eicosanoids2 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 Body Temperature The measure of the level of heat of a human or animal. Heatstroke. 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. Skin: Structure and Functions. 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 Infectious Febrile Infant (most common), non- infectious Infectious Febrile Infant, 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 updated: 25 Jan, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Definition

  • Fever is defined as a measured temperature of at least 38°C (100.4°F).
  • Normal body temperature Body Temperature The measure of the level of heat of a human or animal. Heatstroke 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 Ovulation The discharge of an ovum from a rupturing follicle in the ovary. Menstrual Cycle

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 Common cold A catarrhal disorder of the upper respiratory tract, which may be viral or a mixed infection. It generally involves a runny nose, nasal congestion, and sneezing. Rhinovirus, 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. Plasmodium/Malaria, HIV HIV Anti-HIV Drugs, infectious Infectious Febrile Infant 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. Nervous System: Anatomy, Structure, and Classification (CNS) trauma
    • Intracerebral bleeding
    • Increase in intracranial pressure Intracranial Pressure Idiopathic Intracranial Hypertension
  • Characterized by a high temperature and resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing to antipyretic Antipyretic Acetaminophen therapy; not associated with sweating

Drug-induced

  • Possible pathways: 
    • Interference with the physiological mechanisms of heat Heat Inflammation loss and central temperature regulation
    • Direct damage to tissues
    • Stimulation of an immune response
    • Pyrogenic properties of the drug
  • Common drug classes:
    • Anticonvulsants ( carbamazepine Carbamazepine A dibenzazepine that acts as a sodium channel blocker. It is used as an anticonvulsant for the treatment of grand mal and psychomotor or focal seizures. It may also be used in the management of bipolar disorder, and has analgesic properties. First-Generation Anticonvulsant Drugs, phenytoin Phenytoin An anticonvulsant that is used to treat a wide variety of seizures. The mechanism of therapeutic action is not clear, although several cellular actions have been described including effects on ion channels, active transport, and general membrane stabilization. Phenytoin has been proposed for several other therapeutic uses, but its use has been limited by its many adverse effects and interactions with other drugs. First-Generation Anticonvulsant Drugs, phenobarbital Phenobarbital A barbituric acid derivative that acts as a nonselective central nervous system depressant. It potentiates gamma-aminobutyric acid action on gaba-a receptors, and modulates chloride currents through receptor channels. It also inhibits glutamate induced depolarizations. First-Generation Anticonvulsant Drugs)
    • Antimicrobials ( minocycline Minocycline A tetracycline analog, having a 7-dimethylamino and lacking the 5 methyl and hydroxyl groups, which is effective against tetracycline-resistant staphylococcus infections. Tetracyclines, beta-lactams, sulfonamides Sulfonamides A group of compounds that contain the structure so2nh2. Sulfonamides and Trimethoprim, nitrofurantoin)
    • Antidepressants ( serotonin Serotonin A biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Receptors and Neurotransmitters of the CNS syndrome secondary to selective serotonin Serotonin A biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Receptors and Neurotransmitters of the CNS reuptake inhibitor (SSRI) intake)
    • Allopurinol Allopurinol A xanthine oxidase inhibitor that decreases uric acid production. It also acts as an antimetabolite on some simpler organisms. Gout Drugs
    • 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 Amphetamines Analogs or derivatives of amphetamine. Many are sympathomimetics and central nervous system stimulators causing excitation, vasopressin, bronchodilation, and to varying degrees, anorexia, analepsis, nasal decongestion, and some smooth muscle relaxation. Stimulants, cocaine Cocaine An alkaloid ester extracted from the leaves of plants including coca. It is a local anesthetic and vasoconstrictor and is clinically used for that purpose, particularly in the eye, ear, nose, and throat. It also has powerful central nervous system effects similar to the amphetamines and is a drug of abuse. Cocaine, like amphetamines, acts by multiple mechanisms on brain catecholaminergic neurons; the mechanism of its reinforcing effects is thought to involve inhibition of dopamine uptake. Local Anesthetics

Other conditions

  • Endocrinopathies ( hyperthyroidism Hyperthyroidism Hypersecretion of thyroid hormones from the thyroid gland. Elevated levels of thyroid hormones increase basal metabolic rate. 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 Neoplasms New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. Benign Bone Tumors
  • 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 Arthritis Acute or chronic inflammation of joints. Osteoarthritis, 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))

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Pathophysiology

  • Body temperature Body Temperature The measure of the level of heat of a human or animal. Heatstroke 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 Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology 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 to prostaglandin E Prostaglandin E Three of the six naturally occurring prostaglandins. They are considered primary in that no one is derived from another in living organisms. Originally isolated from sheep seminal fluid and vesicles, they are found in many organs and tissues and play a major role in mediating various physiological activities. Eicosanoids2 (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 Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination-antibody complexes
      • Interleukin-1 Interleukin-1 A soluble factor produced by monocytes; macrophages, and other cells which activates T-lymphocytes and potentiates their response to mitogens or antigens. Interleukin-1 is a general term refers to either of the two distinct proteins, interleukin-1alpha and interleukin-1beta. The biological effects of il-1 include the ability to replace macrophage requirements for t-cell activation. Interleukins (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)-𝛼
      • Interferon-γ
    • Activates the arachidonic acid Arachidonic Acid An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. Nonsteroidal Antiinflammatory Drugs (NSAIDs) 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 Lipopolysaccharides Lipid-containing polysaccharides which are endotoxins and important group-specific antigens. They are often derived from the cell wall of gram-negative bacteria and induce immunoglobulin secretion. The lipopolysaccharide molecule consists of three parts: lipid a, core polysaccharide, and o-specific chains (o antigens). When derived from Escherichia coli, lipopolysaccharides serve as polyclonal b-cell mitogens commonly used in laboratory immunology. Diarrheagenic E. coli (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
      • Endotoxins Endotoxins Toxins closely associated with the living cytoplasm or cell wall of certain microorganisms, which do not readily diffuse into the culture medium, but are released upon lysis of the cells. Bacteriology
      • Exotoxins Exotoxins Toxins produced, especially by bacterial or fungal cells, and released into the culture medium or environment. Bacteriology

Physiologic effects of fever

  • Heat Heat Inflammation conservation: vasoconstriction Vasoconstriction The physiological narrowing of blood vessels by contraction of the vascular smooth muscle. Vascular Resistance, Flow, and Mean Arterial Pressure
    • Increases heat Heat Inflammation 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 Heat Inflammation 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: Histology 
    • Increased core temperature by release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology of adenosine Adenosine A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. Class 5 Antiarrhythmic Drugs triphosphate (ATP) 
    • Muscle heat Heat Inflammation production → shivering Shivering Involuntary contraction or twitching of the muscles. It is a physiologic method of heat production in man and other mammals. Body Temperature Regulation
    • 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: Histology heat Heat Inflammation production → in neonates due to a higher percentage of brown fat
  • Once the hypothalamic set-point is reset downward, heat Heat Inflammation loss occurs through:
    • Vasodilation Vasodilation The physiological widening of blood vessels by relaxing the underlying vascular smooth muscle. Pulmonary Hypertension Drugs, sweating, and behavior changes; may be due to a reduction in pyrogenic cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response or the use of antipyretics
Time course of a typical fever

Time course of a typical fever

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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: Histology to release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response 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 Prostaglandins A group of compounds derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway. They are extremely potent mediators of a diverse group of physiological processes. Eicosanoids (PGE2).
These hormone-like substances produce fever by activating cold-sensitive (CS) neurons Neurons The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. Nervous System: Histology and inhibiting warm-sensitive ( WS WS Williams syndrome (WS), also known as Williams-beuren syndrome (WBS), is a genetic disease caused by a microdeletion on chromosome 7. Affected individuals have a characteristic elfin facies and short stature. Cognitive, developmental, and behavioral issues are common. Additionally, cardiovascular, connective tissue, endocrine, and renal anomalies may be present. Williams Syndrome) neurons Neurons The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. Nervous System: Histology.

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Clinical Presentation

Common symptoms

  • Rigors ( shivering Shivering Involuntary contraction or twitching of the muscles. It is a physiologic method of heat production in man and other mammals. Body Temperature Regulation)
  • 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. Skin: Structure and Functions
  • Tachycardia Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children or palpitations Palpitations Ebstein’s Anomaly
  • Lethargy Lethargy A general state of sluggishness, listless, or uninterested, with being tired, and having difficulty concentrating and doing simple tasks. It may be related to depression or drug addiction. Hyponatremia

Types of fever patterns

Types of fever patterns

Types of fever patterns

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Effects of Fever

Beneficial effects

  • Endogenous pyrogens:
    • Influence the recruitment Recruitment Skeletal Muscle Contraction and function of many types of immune cells
      • Enhance phagocytosis Phagocytosis The engulfing and degradation of microorganisms; other cells that are dead, dying, or pathogenic; and foreign particles by phagocytic cells (phagocytes). Innate Immunity: Phagocytes and Antigen Presentation by neutrophils Neutrophils Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. Innate Immunity: Phagocytes and Antigen Presentation and macrophages Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood monocytes. Main types are peritoneal macrophages; alveolar macrophages; histiocytes; kupffer cells of the liver; and osteoclasts. They may further differentiate within chronic inflammatory lesions to epithelioid cells or may fuse to form foreign body giant cells or langhans giant cells. Innate Immunity: Phagocytes and Antigen Presentation
      • Enhance antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor by macrophages Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood monocytes. Main types are peritoneal macrophages; alveolar macrophages; histiocytes; kupffer cells of the liver; and osteoclasts. They may further differentiate within chronic inflammatory lesions to epithelioid cells or may fuse to form foreign body giant cells or langhans giant cells. Innate Immunity: Phagocytes and Antigen Presentation and T cells T cells Lymphocytes responsible for cell-mediated immunity. Two types have been identified – cytotoxic (t-lymphocytes, cytotoxic) and helper T-lymphocytes (t-lymphocytes, helper-inducer). They are formed when lymphocytes circulate through the thymus gland and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen. T cells: Types and Functions
    • Decrease the levels of trace metals available ( iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements and zinc Zinc A metallic element of atomic number 30 and atomic weight 65. 38. It is a necessary trace element in the diet, forming an essential part of many enzymes, and playing an important role in protein synthesis and in cell division. Zinc deficiency is associated with anemia, short stature, hypogonadism, impaired wound healing, and geophagia. It is known by the symbol zn. Trace Elements)
      • 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
    • May also inhibit motility Motility The motor activity of the gastrointestinal tract. Gastrointestinal Motility and capsule Capsule An envelope of loose gel surrounding a bacterial cell which is associated with the virulence of pathogenic bacteria. Some capsules have a well-defined border, whereas others form a slime layer that trails off into the medium. Most capsules consist of relatively simple polysaccharides but there are some bacteria whose capsules are made of polypeptides. Bacteroides/ cell wall Cell wall The outermost layer of a cell in most plants; bacteria; fungi; and algae. The cell wall is usually a rigid structure that lies external to the cell membrane, and provides a protective barrier against physical or chemical agents. Cell Types: Eukaryotic versus Prokaryotic formation
  • Increases antimicrobial activity of some antibiotics

Adverse effects

  • Direct cellular damage by cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response 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 Systemic inflammatory response syndrome with a proven or suspected infectious etiology. When sepsis is associated with organ dysfunction distant from the site of infection, it is called severe sepsis. When sepsis is accompanied by hypotension despite adequate fluid infusion, it is called septic shock. Sepsis and Septic Shock syndrome
  • Very high fevers (> 41°C): increase host metabolic demands → may result in congestive heart failure Heart Failure A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction. Total Anomalous Pulmonary Venous Return (TAPVR) ( 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 Ischemia A hypoperfusion of the blood through an organ or tissue caused by a pathologic constriction or obstruction of its blood vessels, or an absence of blood circulation. Ischemic Cell Damage
Table: Adverse effects of cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response
Cellular Local Systemic
  • Membrane, mitochondrial, and DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure damage
  • Stimulation of excitotoxic mechanisms
  • Protein denaturation Denaturation Disruption of the secondary structure of nucleic acids by heat, extreme ph or chemical treatment. Double strand DNA is ‘melted’ by dissociation of the non-covalent hydrogen bonds and hydrophobic interactions. Denatured DNA appears to be a single-stranded flexible structure. The effects of denaturation on RNA are similar though less pronounced and largely reversible. Polymerase Chain Reaction (PCR)
  • 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 Body Temperature The measure of the level of heat of a human or animal. Heatstroke:

  • DRESS (drug rash Rash Rocky Mountain Spotted Fever with eosinophilia Eosinophilia Abnormal increase of eosinophils in the blood, tissues or organs. Autosomal Dominant Hyperimmunoglobulin E Syndrome and systemic symptoms) syndrome: a delayed, severe hypersensitivity reaction to drugs. Often caused by allopurinol Allopurinol A xanthine oxidase inhibitor that decreases uric acid production. It also acts as an antimetabolite on some simpler organisms. Gout Drugs, anticonvulsants, and sulfonamides Sulfonamides A group of compounds that contain the structure so2nh2. Sulfonamides and Trimethoprim. Besides fever, symptoms include eosinophilia Eosinophilia Abnormal increase of eosinophils in the blood, tissues or organs. Autosomal Dominant Hyperimmunoglobulin E Syndrome, 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 Case fatality rate Defined as the number of deaths of individuals with a certain disease or condition divided by the total number of people diagnosed with that same disease or condition over a specific time period. Measures of Health Status 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 Muscle rigidity Continuous involuntary sustained muscle contraction which is often a manifestation of basal ganglia diseases. When an affected muscle is passively stretched, the degree of resistance remains constant regardless of the rate at which the muscle is stretched. This feature helps to distinguish rigidity from muscle spasticity. Motor Neuron Lesions and hemodynamic instability, in response to certain drugs used for anaesthesia. Diagnosis is based on clinical presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor in an acute event or through genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies following the diagnosis in a relative. Treatment is with intravenous dantrolene Dantrolene Skeletal muscle relaxant that acts by interfering with excitation-contraction coupling in the muscle fiber. It is used in spasticity and other neuromuscular abnormalities. Although the mechanism of action is probably not central, dantrolene is usually grouped with the central muscle relaxants. Spasmolytics.
  • 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 NMS 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): 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 Muscle rigidity Continuous involuntary sustained muscle contraction which is often a manifestation of basal ganglia diseases. When an affected muscle is passively stretched, the degree of resistance remains constant regardless of the rate at which the muscle is stretched. This feature helps to distinguish rigidity from muscle spasticity. Motor Neuron Lesions, altered mental status Altered Mental Status Sepsis in Children, and dysautonomia. Treatment includes withdrawal of the drug and antidotes such as dantrolene Dantrolene Skeletal muscle relaxant that acts by interfering with excitation-contraction coupling in the muscle fiber. It is used in spasticity and other neuromuscular abnormalities. Although the mechanism of action is probably not central, dantrolene is usually grouped with the central muscle relaxants. Spasmolytics and amantadine Amantadine An antiviral that is used in the prophylactic or symptomatic treatment of influenza A. It is also used as an antiparkinsonian agent, to treat extrapyramidal reactions, and for postherpetic neuralgia. The mechanisms of its effects in movement disorders are not well understood but probably reflect an increase in synthesis and release of dopamine, with perhaps some inhibition of dopamine uptake. Antivirals for Influenza.
  • Serotonin Serotonin A biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Receptors and Neurotransmitters of the CNS syndrome: a condition in response to serotonergic drugs, e.g., antidepressants such as SSRIs SSRIs Serotonin Reuptake Inhibitors and Similar Antidepressants, serotonin Serotonin A biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Receptors and Neurotransmitters of the CNS norepinephrine Norepinephrine Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers, and of the diffuse projection system in the brain that arises from the locus ceruleus. Receptors and Neurotransmitters of the CNS reuptake inhibitors ( SNRIs SNRIs Serotonin Reuptake Inhibitors and Similar Antidepressants), and monoamine oxidase Oxidase Neisseria inhibitors ( MAOIs MAOIs 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). Presents with agitation Agitation A feeling of restlessness associated with increased motor activity. This may occur as a manifestation of nervous system drug toxicity or other conditions. St. Louis Encephalitis Virus, confusion, hyperthermia, autonomic hyperactivity Hyperactivity Attention Deficit Hyperactivity Disorder, and rigidity Rigidity Continuous involuntary sustained muscle contraction which is often a manifestation of basal ganglia diseases. When an affected muscle is passively stretched, the degree of resistance remains constant regardless of the rate at which the muscle is stretched. This feature helps to distinguish rigidity from muscle spasticity. Megacolon. Treatment consists of discontinuation of the causative agent.

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