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Fever

by Allan R. Tunkel, MD, PhD

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. Elevated body temperature that is not caused by a resetting of the temperature set point in the hypothalamus is commonly 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 discomfort.

Pathophysiology

During a 24-h 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. Exogenous pyrogens usually cause fever by inducing release of endogenous pyrogens (eg, IL-1, tumor necrosis factor [TNF]-α, interferon-γ, IL-6), which raise the hypothalamic set point. Prostaglandin E 2 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°) caused by most acute illnesses 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.

Because fever can increase the BMR 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.

Fever in healthy children can cause febrile seizures (see Febrile Seizures).

Etiology

Many disorders can cause fever. They are broadly categorized as

  • Infectious (most common)

  • Neoplastic

  • 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.

Infectious causes

Virtually all infectious illnesses can cause fever. But overall, the most likely causes are

  • Upper and lower respiratory tract infections

  • GI infections

  • UTIs

  • Skin infections

Most acute respiratory tract and GI 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).

Some causes appear to predominate based on these factors (see Some Causes of Acute Fever).

Some Causes of Acute Fever

Predisposing Factor

Cause

None (healthy)

Upper or lower respiratory tract infection

GI infection

UTI

Skin infection

Hospitalization

IV catheter infection

UTI (particularly in patients with an indwelling catheter)

Pneumonia (particularly in patients using a ventilator)

Atelectasis

Surgical site infection (postoperatively)

Deep venous thrombosis or pulmonary embolism

Diarrhea ( Clostridium difficile–induced)

Drugs

Hematoma

Transfusion reaction

Decubitus ulcers

Travel to endemic areas

Malaria

Viral hepatitis

Diarrheal disorders

Typhoid fever

Dengue fever (less common)

Vector exposure (in US)

Ticks: Rickettsiosis, ehrlichiosis, anaplasmosis, Lyme disease, babesiosis, tularemia

Mosquitoes: Arboviral encephalitis

Wild animals: Tularemia, rabies, hantavirus infection

Fleas: Plague

Domestic animals: Brucellosis, cat-scratch disease, Q fever, toxoplasmosis

Birds: Psittacosis

Reptiles: Salmonella infection

Bats: Rabies, histoplasmosis

Immunocompromise

Viruses: Varicella-zoster virus or cytomegalovirus infection

Bacteria: Infection due to encapsulated organisms (eg, pneumococci, meningococci), Staphylococcus aureus, gram-negative bacteria (eg, Pseudomonas aeruginosa), Nocardia sp, or Mycobacteria sp

Fungi: Infection due to Candida, Aspergillus, Zygomycetes, Histoplasma, or Coccidioides sp or Pneumocystis jirovecii

Parasites: Infection due to Toxoplasma gondii, Strongyloides stercoralis, Cryptosporidium sp, microsporidia, or Cystoisospora (previously Isospora) belli

Drugs that can increase heat production

Amphetamines

Cocaine

Methylenedioxymethamphetamine (MDMA, or Ecstasy)

Antipsychotics

Anesthetics

Drugs that can trigger fever

β-Lactam antibiotics

Sulfa drugs

Phenytoin

Carbamazepine

Procainamide

Quinidine

Amphotericin B

Interferons

Evaluation

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

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:

  • Recent surgery

  • Known disorders 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, SLE, 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 (eg, via unsafe food or water, insect bites, animal contact, or unprotected sex).

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 known to cause fever ( Some Causes of Acute Fever)

  • Drugs that predispose to increased risk of infection (eg, corticosteroids, anti-TNF 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

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.

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 or areas of erythema or blistering suggesting skin or soft-tissue infection. Axillae and epitrochlear and inguinal areas should be examined for adenopathy. In hospitalized patients, presence of any IVs, NGTs, 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).

Red flags

The following findings are of particular concern:

  • Altered mental status

  • Headache, stiff neck, or both

  • Petechial rash

  • Hypotension

  • Dyspnea

  • Significant tachycardia or tachypnea

  • Temperature> 40° C or < 35° C

  • Recent travel to malaria-endemic area

  • 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, is not.

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. Headache, stiff neck, and petechial or purpuric rash suggest meningitis. Tachycardia (beyond the modest elevation normally present with fever) and tachypnea, with or without hypotension or mental status changes, suggest sepsis. Malaria 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.

The elderly, particularly those in nursing homes, are at particular risk (see Fever : Geriatrics Essentials).

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; it is usually accompanied by significant pharyngitis, malaise, and hepatosplenomegaly. Primary HIV infection or secondary syphilis should be suspected in patients with generalized adenopathy, sometimes accompanied by arthralgias, rash, or both. HIV infection develops 2 to 6 wk 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 wk later.

Fever and rash have many infectious and drug causes. Petechial or purpuric rash is of particular concern; it suggests possible meningococcemia, Rocky Mountain spotted fever (particularly if the palms or soles are involved), and, less commonly, some viral infections (eg, dengue fever, hemorrhagic fevers). Other suggestive skin lesions include the classic erythema migrans rash of Lyme disease, target lesions of Stevens-Johnson syndrome, and the painful, tender erythema of cellulitis and other bacterial soft-tissue infections. The possibility of delayed drug hypersensitivity (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 ( 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

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 or HIV infection: Serologic testing

  • Rocky Mountain spotted fever: Biopsy of skin lesions to confirm the diagnosis (acute serologic testing is unhelpful)

  • Bacterial or fungal infection: Blood cultures to detect possible bloodstream infections

  • Meningitis: 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

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, BUN, creatinine, lactate, and liver enzymes. CBC is typically done, but sensitivity and specificity for diagnosing serious bacterial infection are low. However, WBC count is important prognostically for patients who may be immunosuppressed (ie, a low WBC count may be associated with a poor prognosis).

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 CBC; 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.

Febrile elderly patients often require testing (see Fever : Geriatrics Essentials).

Treatment

Specific causes are treated with anti-infective therapy; empiric anti-infective therapy 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 po q 6 h

  • Ibuprofen 400 to 600 mg po q 6 h

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 NSAIDs (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

In the frail elderly, 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 or UTI.

In spite of their less severe manifestations of illness, the febrile elderly 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 UTI, but in the elderly, skin and soft-tissue infections are among the top causes.

Focal findings are evaluated as for younger patients. But unlike younger patients, elderly patients probably require urinalysis, urine culture, and chest x-ray. Blood cultures should be done to exclude septicemia; if septicemia is suspected or vital signs are abnormal, patients should be admitted to the hospital.

Key Points

  • Most fevers in healthy people are due to viral respiratory tract or GI infections.

  • Localizing symptoms guide evaluation.

  • Consider underlying chronic disorders, particularly those impairing the immune system.

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • No US brand name
  • DILANTIN
  • TEGRETOL
  • OZURDEX
  • ADVIL, MOTRIN IB
  • ALEVE, NAPROSYN
  • TYLENOL

* This is a professional Version *