Fever is elevated body temperature (> 37.8° C orally or > 38.2° C rectally) or an elevation above a person’s known normal daily value. Fever occurs when the body's thermostat (located in the hypothalamus) resets at a higher temperature, primarily in response to an infection. Elevated body temperature that is not caused by a resetting of the temperature set point is called hyperthermia.
Many patients use “fever” very loosely, often meaning that they feel too warm, too cold, or sweaty, but they have not actually measured their temperature.
Symptoms are due mainly to the condition causing the fever, although fever itself can cause chills, sweats, and discomfort and make patients feel flushed and warm.
Pathophysiology of Fever
During a 24-hour period, temperature varies from lowest levels in the early morning to highest in late afternoon. Maximum variation is about 0.6° C.
Body temperature is determined by the balance between heat production by tissues, particularly the liver and muscles, and heat loss from the periphery. Normally, the hypothalamic thermoregulatory center maintains the internal temperature between 37° and 38° C. Fever results when something raises the hypothalamic set point, triggering vasoconstriction and shunting of blood from the periphery to decrease heat loss; sometimes shivering, which increases heat production, is induced. These processes continue until the temperature of the blood bathing the hypothalamus reaches the new set point. Resetting the hypothalamic set point downward (eg, with antipyretic drugs) initiates heat loss through sweating and vasodilation.
The capacity to generate a fever is reduced in certain patients (eg, alcoholics, the very old, the very young).
Pyrogens are substances that cause fever. Exogenous pyrogens are usually microbes or their products. The best studied are the lipopolysaccharides of gram-negative bacteria (commonly called endotoxins) and Staphylococcus aureus toxin, which causes toxic shock syndrome. Fever is the result of exogenous pyrogens that induce release of endogenous pyrogens, such as interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), and IL-6 and other cytokines, which then trigger cytokine receptors, or of exogenous pyrogens that directly trigger Toll-like receptors.
Prostaglandin E2 synthesis appears to play a critical role.
Consequences of fever
Although many patients worry that fever itself can cause harm, the modest transient core temperature elevations (ie, 38 to 40° C) caused by most acute infections are well tolerated by healthy adults.
However, extreme temperature elevation (typically > 41° C) may be damaging. Such elevation is more typical of severe environmental hyperthermia but sometimes results from exposure to illicit drugs (eg, cocaine, phencyclidine), anesthetics, or antipsychotic drugs. At this temperature, protein denaturation occurs, and inflammatory cytokines that activate the inflammatory cascade are released. As a result, cellular dysfunction occurs, leading to malfunction and ultimately failure of most organs; the coagulation cascade is also activated, leading to disseminated intravascular coagulation Disseminated Intravascular Coagulation (DIC) Disseminated intravascular coagulation (DIC) involves abnormal, excessive generation of thrombin and fibrin in the circulating blood. During the process, increased platelet aggregation and coagulation... read more (DIC).
Because fever can increase the basal metabolic rate by about 10 to 12% for every 1° C increase over 37° C, fever may physiologically stress adults with preexisting cardiac or pulmonary insufficiency. Fever can also worsen mental status in patients with dementia.
Etiology of Fever
Many disorders can cause fever. They are broadly categorized as
Infectious (most common)
Inflammatory (including rheumatic, nonrheumatic, and drug-related)
The cause of an acute (ie, duration ≤ 4 days) fever in adults is highly likely to be infectious. When patients present with fever due to a noninfectious cause, the fever is almost always chronic or recurrent. Also, an isolated, acute febrile event in patients with a known inflammatory or neoplastic disorder is still most likely to be infectious. In healthy people, an acute febrile event is unlikely to be the initial manifestation of a chronic illness.
Virtually all infectious illnesses can cause fever. But overall, the most likely causes are
Upper and lower respiratory tract infections
Most acute respiratory tract and gastrointestinal infections are viral.
Specific patient and external factors also influence which causes are most likely.
Patient factors include health status, age, occupation, and risk factors (eg, hospitalization, recent invasive procedures, presence of IV or urinary catheters, use of mechanical ventilation).
External factors are those that expose patients to specific diseases—eg, through infected contacts, local outbreaks, disease vectors (eg, mosquitoes, ticks), a common vehicle (eg, food, water), or geographic location (eg, residence in or recent travel to an endemic area).
Evaluation of Fever
Two general issues are important in the initial evaluation of acute fever:
Identifying any localizing symptoms (eg, headache, cough): These symptoms help narrow the range of possible causes. The localizing symptom may be part of the patient’s chief complaint or identified only by specific questioning.
Determining whether the patient is seriously or chronically ill (particularly if such illness is unrecognized): Many causes of fever in healthy people are self-limited, and many of the possible viral infections are difficult to diagnose specifically. Limiting testing to the seriously or chronically ill can help avoid many expensive, unnecessary, and often fruitless searches.
History of present illness should cover magnitude and duration of fever and method used to take the temperature. True rigors (severe, shaking, teeth-chattering chills—not simply feeling cold) suggest fever due to infection but are not otherwise specific. Pain is an important clue to the possible source; the patient should be asked about pain in the ears, head, neck, teeth, throat, chest, abdomen, flank, rectum, muscles, and joints.
Other localizing symptoms include nasal congestion and/or discharge, cough, diarrhea, and urinary symptoms (frequency, urgency, dysuria). Presence of rash (including nature, location, and time of onset in relation to other symptoms) and lymphadenopathy may help.
Infected contacts and their diagnosis should be identified.
Review of systems should identify symptoms of chronic illness, including recurrent fevers, night sweats, and weight loss.
Past medical history should particularly cover the following:
Known conditions that predispose to infection (eg, HIV infection, diabetes, cancer, organ transplantation, sickle cell disease, valvular heart disorders—particularly if an artificial valve is present)
Other known disorders that predispose to fever (eg, rheumatologic disorders, systemic lupus erythematosus, gout, sarcoidosis, hyperthyroidism, cancer)
Questions to ask about recent travel include location, time since return, locale (eg, in back country, only in cities), vaccinations received before travel, and any use of prophylactic antimalarial drugs (if required).
All patients should be asked about possible exposures. Examples include unsafe food (eg, unpasteurized milk and milk products, raw or undercooked meat, fish, shellfish) or water, insect bites (eg, history of tick, mosquito, or other arthropod vector exposure), animal contact, unprotected sex, and occupational or recreational exposures (eg, hunting, hiking, water sports).
Vaccination history, particularly against hepatitis A and B and against organisms that cause meningitis, influenza, or pneumococcal infection, should be noted.
Drug history should include specific questions about the following:
Drugs that predispose to increased risk of infection (eg, corticosteroids, anti-tumor necrosis factor drugs, chemotherapeutic and antirejection drugs, other immunosuppressants)
Illicit use of injection drugs (predisposing to endocarditis, hepatitis, septic pulmonary emboli, and skin and soft-tissue infections)
Physical examination begins with confirmation of fever. Fever is most accurately diagnosed by measuring rectal temperature. Oral temperatures are normally about 0.6° C lower and may be falsely even lower for many reasons, such as recent ingestion of a cold drink, mouth breathing, hyperventilation, and inadequate measurement time (up to several minutes are required with mercury thermometers). Measurement of tympanic membrane temperature by infrared sensor is less accurate than rectal temperature. Monitoring skin temperature using temperature-sensitive crystals incorporated into plastic strips placed on the forehead is insensitive for detecting elevations in the core temperature. During the COVID-19 pandemic, use of infrared devices to measure skin temperature (eg, of the forehead) to screen people for fever prior to entry in public places has become common.
Other vital signs are reviewed for presence of tachypnea, tachycardia, or hypotension.
For patients with localizing symptoms, examination proceeds as discussed elsewhere in THE MANUAL. For febrile patients without localizing symptoms, a complete examination is necessary because clues to the diagnosis may be in any organ system.
The patient’s general appearance, including any weakness, lethargy, confusion, cachexia, and distress, should be noted.
All of the skin should be inspected for rash, particularly petechial or hemorrhagic rash and any lesions (eg, eschar) or areas of erythema or blistering suggesting skin or soft-tissue infection. Neck, axillae, and epitrochlear and inguinal areas should be examined for adenopathy.
In hospitalized patients, presence of any IVs, nasogastric tubes, urinary catheters, and any other tubes or lines inserted into the body should be noted. If patients have had recent surgery, surgical sites should be thoroughly inspected.
For the head and neck examination, the following should be done:
Tympanic membranes: Examined for infection
Sinuses (frontal and maxillary): Percussed
Temporal arteries: Palpated for tenderness
Nose: Inspected for congestion and discharge (clear or purulent)
Eyes: Inspected for conjunctivitis or icterus
Fundi: Inspected for Roth spots (suggesting endocarditis)
Oropharynx and gingiva: Inspected for inflammation or ulceration (including any lesions of candidiasis, which suggests immunocompromise)
Neck: Flexed to detect discomfort, stiffness, or both, indicating meningismus, and palpated for adenopathy
The lungs are examined for crackles or signs of consolidation, and the heart is auscultated for murmurs (suggesting possible endocarditis).
The abdomen is palpated for hepatosplenomegaly and tenderness (suggesting infection).
The flanks are percussed for tenderness over the kidneys (suggesting pyelonephritis).
A pelvic examination is done in women to check for cervical motion or adnexal tenderness; a genital examination is done in men to check for urethral discharge and local tenderness.
The rectum is examined for tenderness and swelling, suggesting perirectal abscess (which may be occult in immunosuppressed patients).
All major joints are examined for swelling, erythema, and tenderness (suggesting a joint infection or rheumatologic disorder). The hands and feet are inspected for signs of endocarditis, including splinter hemorrhages under the nails, painful erythematous subcutaneous nodules on the tips of digits (Osler nodes), and nontender hemorrhagic macules on the palms or soles (Janeway lesions).
The spine is percussed for focal tenderness.
Neurologic examination Introduction to the Neurologic Examination The neurologic examination begins with careful observation of the patient entering the examination area and continues during history taking. The patient should be assisted as little as possible... read more is done to detect focal deficits.
The following findings are of particular concern:
Altered mental status
Headache, stiff neck, or both
Significant tachycardia or tachypnea
Temperature > 40° C or < 35° C
Recent travel to an area where serious diseases (eg, malaria) are endemic
Recent use of immunosuppressants
Interpretation of findings
The degree of elevation in temperature usually does not predict the likelihood or cause of infection. Fever pattern, once thought to be significant, rarely is helpful with the possible exceptions of tertian and quartan malaria Malaria Malaria is infection with Plasmodium species. Symptoms and signs include fever (which may be periodic), chills, rigors, sweating, diarrhea, abdominal pain, respiratory distress, confusion... read more and relapsing episodes (eg, brucellosis Brucellosis Brucellosis is caused by Brucella species, which are gram-negative bacteria. Symptoms begin as an acute febrile illness with few or no localized signs and may progress to a chronic stage... read more ).
Likelihood of serious illness is considered. If serious illness is suspected, immediate and aggressive testing and often hospital admission are needed.
Red flag findings strongly suggest a serious disorder, as in the following:
Headache, stiff neck, and petechial or purpuric rash suggest meningitis Overview of Meningitis Meningitis is inflammation of the meninges and subarachnoid space. It may result from infections, other disorders, or reactions to drugs. Severity and acuity vary. Findings typically include... read more .
Tachycardia (beyond the modest elevation normally present with fever) and tachypnea, with or without hypotension or mental status changes, suggest sepsis Sepsis and Septic Shock Sepsis is a clinical syndrome of life-threatening organ dysfunction caused by a dysregulated response to infection. In septic shock, there is critical reduction in tissue perfusion; acute failure... read more .
Malaria Malaria Malaria is infection with Plasmodium species. Symptoms and signs include fever (which may be periodic), chills, rigors, sweating, diarrhea, abdominal pain, respiratory distress, confusion... read more should be suspected in patients who have recently traveled to an endemic area.
Immunocompromise, whether caused by a known disorder or use of immunosuppressants or suggested by examination findings (eg, weight loss, oral candidiasis), is also of concern, as are other known chronic illnesses, injection drug use, and heart murmur.
Older adults, particularly those in nursing homes, are at particular risk of serious bacterial or viral (eg, COVID-19 COVID-19 COVID-19 is an acute, sometimes severe, respiratory illness caused by the novel coronavirus SARS-CoV-2. COVID-19 was first reported in late 2019 in Wuhan, China and has since spread extensively... read more ) infection (see Geriatrics Essentials: Fever Geriatrics Essentials: Fever Fever is elevated body temperature (> 37.8° C orally or > 38.2° C rectally) or an elevation above a person’s known normal daily value. Fever occurs when the body's thermostat... read more ).
Localizing findings identified by history or physical examination are evaluated and interpreted (see elsewhere in THE MANUAL). Other suggestive findings include generalized adenopathy and rash.
Generalized adenopathy may occur in older children and younger adults who have acute mononucleosis Infectious Mononucleosis Infectious mononucleosis is caused by Epstein-Barr virus (EBV, human herpesvirus type 4) and is characterized by fatigue, fever, pharyngitis, and lymphadenopathy. Fatigue may persist weeks or... read more ; it is usually accompanied by significant pharyngitis, malaise, and hepatosplenomegaly. Primary HIV infection Human Immunodeficiency Virus (HIV) Infection Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more or secondary syphilis Syphilis Syphilis is caused by the spirochete Treponema pallidum and is characterized by 3 sequential clinical, symptomatic stages separated by periods of asymptomatic latent infection. Common... read more should be suspected in patients with generalized adenopathy, sometimes accompanied by arthralgias, rash, or both. HIV infection develops 2 to 6 weeks after exposure (although patients may not always report unprotected sexual contact or other risk factors). Secondary syphilis is usually preceded by a chancre, with systemic symptoms developing 4 to 10 weeks later. However, patients may not notice a chancre because it is painless and may be located out of sight in the rectum, vagina, or oral cavity.
Fever and rash have many infectious and drug causes. Petechial or purpuric rash is of particular concern; it suggests possible meningococcemia Meningococcal Diseases Meningococci (Neisseria meningitidis) are gram-negative cocci that cause meningitis and meningococcemia. Symptoms, usually severe, include headache, nausea, vomiting, photophobia, lethargy... read more , Rocky Mountain spotted fever Rocky Mountain Spotted Fever (RMSF) Rocky Mountain spotted fever (RMSF) is caused by Rickettsia rickettsii and transmitted by ixodid ticks. Symptoms are high fever, severe headache, and rash. (See also Overview of Rickettsial... read more (particularly if the palms or soles are involved), or, less commonly, some viral infections (eg, dengue fever Dengue Dengue is a mosquito-borne disease caused by a flavivirus. Dengue fever usually results in abrupt onset of high fever, headache, myalgias, arthralgias, and generalized lymphadenopathy, followed... read more , hemorrhagic fevers). Other suggestive skin lesions include the classic erythema migrans rash of Lyme disease Lyme Disease Lyme disease is a tick-transmitted infection caused by the spirochete Borrelia species. Early symptoms include an erythema migrans rash, which may be followed weeks to months later by... read more , target lesions of Stevens-Johnson syndrome Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) Stevens-Johnson syndrome and toxic epidermal necrolysis are severe cutaneous hypersensitivity reactions. Drugs, especially sulfa drugs, antiseizure drugs, and antibiotics, are the most common... read more , and the painful, tender erythema of cellulitis Cellulitis Cellulitis is acute bacterial infection of the skin and subcutaneous tissue most often caused by streptococci or staphylococci. Symptoms and signs are pain, warmth, rapidly spreading erythema... read more and other bacterial soft-tissue infections. The possibility of delayed drug hypersensitivity Drug Eruptions and Reactions Drugs can cause multiple skin eruptions and reactions. The most serious of these are discussed elsewhere in THE MANUAL and include Stevens-Johnson syndrome and toxic epidermal necrolysis, hypersensitivity... read more (even after long periods of use) should be kept in mind.
If no localizing findings are present, healthy people with acute fever and only nonspecific findings (eg, malaise, generalized aches) most likely have a self-limited viral illness, unless a history of exposure to infected contacts (including a new, unprotected sexual contact), to disease vectors, or in an endemic area (including recent travel) suggests otherwise.
Patients with significant underlying disorders are more likely to have an occult bacterial or parasitic infection. Injection drug users and patients with a prosthetic heart valve may have endocarditis. Immunocompromised patients are predisposed to infection caused by certain microorganisms (see Table: Some Causes of Acute Fever Some Causes of Acute Fever ).
Drug fever (with or without rash) is a diagnosis of exclusion, often requiring a trial of stopping the drug. One difficulty is that if antibiotics are the cause, the illness being treated may also cause fever. Sometimes a clue is that the fever and rash begin after clinical improvement from the initial infection and without worsening or reappearance of the original symptoms (eg, in a patient being treated for pneumonia, fever reappears without cough, dyspnea, or hypoxia).
Testing depends on whether localized findings are present.
If localizing findings are present, testing is guided by clinical suspicion and findings (see also elsewhere in THE MANUAL), as for the following:
Mononucleosis Diagnosis Infectious mononucleosis is caused by Epstein-Barr virus (EBV, human herpesvirus type 4) and is characterized by fatigue, fever, pharyngitis, and lymphadenopathy. Fatigue may persist weeks or... read more or HIV infection Diagnosis Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more : Serologic testing
Rocky Mountain spotted fever Diagnosis Rocky Mountain spotted fever (RMSF) is caused by Rickettsia rickettsii and transmitted by ixodid ticks. Symptoms are high fever, severe headache, and rash. (See also Overview of Rickettsial... read more : Biopsy of skin lesions to confirm the diagnosis (acute serologic testing is unhelpful)
Bacterial or fungal infection Diagnosis Fungal infections are often classified as either Opportunistic Primary Opportunistic infections are those that develop mainly in immunocompromised hosts. Primary infections can develop in immunocompetent... read more : Blood cultures to detect possible bloodstream infections
Meningitis Diagnosis Meningitis is inflammation of the meninges and subarachnoid space. It may result from infections, other disorders, or reactions to drugs. Severity and acuity vary. Findings typically include... read more : Immediate lumbar puncture and IV dexamethasone and antibiotics (head CT should be done before lumbar puncture if patients are at risk of brain herniation; IV dexamethasone and antibiotics must be given immediately after blood cultures are obtained and before head CT is done)
Specific disorders based on exposure (eg, to contacts, to vectors, or in endemic areas): Testing for those disorders, particularly a peripheral blood smear for malaria
Respiratory infection: Rapid molecular tests (nucleic acid–based identification Nucleic Acid–Based Identification Methods for Infectious Disease Nucleic acid–based (molecular) identification has become commonplace in clinical settings; the resulting rapid identification allows the patient to be placed on specific antimicrobial therapy... read more ) for common viral and bacterial community-acquired respiratory tract infections
If no localizing findings are present in otherwise healthy patients and serious illness is not suspected, patients can usually be observed at home without testing. In most, symptoms resolve quickly; the few who develop worrisome or localizing symptoms should be reevaluated and tested based on the new findings.
If serious illness is suspected in patients who have no localizing findings, testing is needed. Patients with red flag findings suggesting sepsis require cultures (urine and blood), chest x-ray, and evaluation for metabolic abnormalities with measurement of serum electrolytes, glucose, blood urea nitrogen, creatinine, lactate, and liver enzymes. Complete blood count is typically done, but sensitivity and specificity for diagnosing serious bacterial infection are low. However, white blood cell (WBC) count is important prognostically for patients who may be immunosuppressed (ie, a low WBC count may be associated with a poor prognosis). C-reactive protein elevation is a sensitive but nonspecific indicator of sepsis. An elevated procalcitonin level is indicative of a bacterial process but lacks sufficient sensitivity to warrant routine use.
Patients with certain underlying disorders may need testing even if they have no localizing findings and do not appear seriously ill. Because of the risk and devastating consequences of endocarditis, febrile injection drug users are usually admitted to the hospital for serial blood cultures and often echocardiography. Patients taking immunosuppressants require complete blood count; if neutropenia is present, testing is initiated and chest x-ray is done, as are cultures of blood, sputum, urine, stool, and any suspicious skin lesions. Because bacteremia and sepsis are frequent causes of fever in patients with neutropenia, empiric broad-spectrum IV antibiotics should be given promptly, without waiting for culture results.
Treatment of Fever
Specific causes of fever are treated with anti-infective therapy; empiric anti-infective therapy that is based on the most likely anatomic site and the pathogens involved is required when suspicion of serious infection is high.
Whether fever due to infection should be treated with antipyretics is controversial. Experimental evidence, but not clinical studies, suggests that fever enhances host defenses.
Fever should probably be treated in certain patients at particular risk, including adults with cardiac or pulmonary insufficiency or with dementia.
Drugs that inhibit brain cyclooxygenase effectively reduce fever:
Acetaminophen 650 to 1000 mg orally every 6 hours
Ibuprofen 400 to 600 mg orally every 6 hours
The daily dose of acetaminophen should not exceed 4 g to avoid toxicity; patients should be warned not to simultaneously take nonprescription cold or flu remedies that contain acetaminophen. Other nonsteroidal anti-inflammatory drugs (eg, aspirin, naproxen) are also effective antipyretics. Salicylates should not be used to treat fever in children with viral illnesses because use has been associated with Reye syndrome.
If temperature is ≥ 41° C, other cooling measures (eg, evaporative cooling with tepid water mist, cooling blankets) should also be started.
Geriatrics Essentials: Fever
In frail older adults, infection is less likely to cause fever, and even when elevated by infection, temperature may be lower than the standard definition of fever. Similarly, other inflammatory symptoms, such as focal pain, may be less prominent. Frequently, alteration of mental status or decline in daily functioning may be the only other initial manifestations of pneumonia Overview of Pneumonia Pneumonia is acute inflammation of the lungs caused by infection. Initial diagnosis is usually based on chest x-ray and clinical findings. Causes, symptoms, treatment, preventive measures, and... read more or urinary tract infection Introduction to Urinary Tract Infections (UTIs) Urinary tract infections (UTIs) can be divided into upper tract infections, which involve the kidneys (pyelonephritis), and lower tract infections, which involve the bladder (cystitis), urethra... read more .
In spite of their less severe manifestations of illness, the febrile older adults are significantly more likely to have a serious bacterial illness than are febrile younger adults. As in younger adults, the cause is commonly a respiratory infection or urinary tract infection, but in older adults, skin and soft-tissue infections are among the top causes. Older adults with respiratory virus infections such as influenza Influenza Influenza is a viral respiratory infection causing fever, coryza, cough, headache, and malaise. Mortality is possible during seasonal epidemics, particularly among high-risk patients (eg, those... read more and COVID-19 COVID-19 COVID-19 is an acute, sometimes severe, respiratory illness caused by the novel coronavirus SARS-CoV-2. COVID-19 was first reported in late 2019 in Wuhan, China and has since spread extensively... read more are also more likely to have serious manifestations.
Focal findings are evaluated as for younger patients. But unlike younger patients, older patients probably require urinalysis, urine culture, and chest x-ray. Blood cultures should be done to exclude bacteremia Bacteremia Bacteremia is the presence of bacteria in the bloodstream. It can occur spontaneously, during certain tissue infections, with use of indwelling genitourinary or IV catheters, or after dental... read more ; if bacteremia is suspected or vital signs are abnormal, patients should be admitted to the hospital.
Most fevers in healthy people are due to viral respiratory tract or gastrointestinal infections.
Localizing symptoms guide evaluation.
In the absence of localizing symptoms, limiting testing to patients who appear seriously or chronically ill can help avoid many unnecessary evaluations.
Consider underlying chronic disorders, particularly those impairing the immune system.
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