a. Normal body temperature. Body temperature varies throughout the day. The nadir is usually in the early morning and peak at 4–6 p.m. This variation in temperature is called the Circadian rhythm. The normal oral temperature is 36° C–37.4° C (average = 36.7° C).
i. In adults 18–40 years of age, the upper limit of normal temperature should be considered 37.2° C at 6 a.m. and 37.7° C overall.
ii. The average rectal temperature is 0.5° C higher, and the average axillary temperature is 0.5° C lower, than the oral temperature.
b. The term “fever” reflects an upward shift in the body’s temperature set point triggered by release of pyrogens. In contrast, “hyperthermia” is the term that reflects the body’s inability to lower temperature by the usual mechanisms because of overheating or other mechanisms.
c. Causes of fever. Not all fever is due to infection. Fever may be a manifestation of malignancy, connective tissue disorders, drug reactions, central nervous system (CNS) disorders, inflammatory diseases, or other diseases. However, fever should be presumed to be secondary to an infection until proven otherwise because infections cause most fevers and can be life-threatening.
B. Approach to the patient. In many cases, the etiology of the fever is clinically obvious; other times, fever can be the initial manifestation of an elusive illness. This chapter provides a way to approach patients with recent onset of fever from an obscure source. If the fever persists for weeks without a diagnosis, a fever of unknown origin (FUO) may be present (see Chapter 51).
• Patients who are older adults, immunocompromised, or taking steroids or nonsteroidal antiinflammatory drugs (NSAIDs) may not mount a fever, even in the presence of a severe infection.
• The degree of fever is of little predictive value in assessing the severity of an underlying illness.
• Hypothermia may signal the presence of an overwhelming infection and should therefore be evaluated just as thoroughly as hyperthermia.
a. Patient history
i. Immune status. Is the patient immunocompromised (e.g., as a result of leukemia, chemotherapy, steroid use, HIV infection, or liver disease)?
ii. Medical history. Patients with a known illness may have a fever caused by their underlying illness (e.g., tumor fever from lymphoma or a fever from a lupus flare). However, these are diagnoses of exclusion because infectious causes must first be considered and ruled out. Relatedly, some illnesses predispose patients to infectious complications (e.g., abdominal abscess as a complication of Crohn’s disease, endocarditis in a patient with an aortic valve replacement).
iii. Medication history. Is the patient taking prescription or over-the-counter medications? The medication history should be aimed at discovering drugs that cause immunosuppression (e.g., steroids) or those that may result in drug fever (e.g., neuroleptics, anticholinergics, anesthetics, antibiotics).
iv. Social history. What is the patient’s travel history? Is there a history of injection drug use or other HIV risk factors? What is the patient’s sexual history? Does the patient have pets or frequent animal contact? What are his or her occupation and hobbies? This information may lead to expanding the differential diagnosis to include diseases common in the developing world, HIV-related infections, sexually transmitted infections, tick-borne illnesses, endemic fungal disease, complications such as endocarditis that are common in injection drug users, and so on.
Fever should be presumed to be secondary to an infection until proven otherwise.
b. Top-to-bottom approach. One way of determining the cause of a fever is to start at the patient’s head and work your way down. Characteristic signs and symptoms (shown in parentheses) may increase your suspicion for the following disorders:
i. Meningitis (headaches, neck stiffness, photophobia)
ii. Sinusitis (sinus tenderness)
iii. Otitis (ear pain, diminished hearing)
iv. Pharyngitis (sore throat, lymphadenopathy)
v. Pneumonia (cough, pleurisy, dyspnea)
vi. Endocarditis (recent dental or other invasive gastrointestinal or genitourinary procedure, back pain, new skin lesions)
vii. Abdominal processes (pain, change in bowel habits, nausea, vomiting)
viii. Urinary tract infection (UTI) or pyelonephritis (dysuria, frequency, suprapubic or costovertebral angle tenderness)
ix. Pelvic infection (discharge, dysuria)
x. Prostatitis (lower abdominal pain, tender prostate)
xi. Perirectal abscess (pain, tenderness, swelling)
xii. Cellulitis (erythema, pain, swelling)
xiii. Joint infections (pain, warmth, swelling)
xiv. Local intravenous catheter site infection (pain, pus)
If a patient develops diarrhea and leukocytosis after antibiotic treatment, consider Clostridium difficile colitis.
c. Physical examination. A complete physical examination is critical and should cover all the areas mentioned in the review of systems.
Often overlooked portions of the physical include a complete skin examination, a dental examination, evaluation of the joints (particularly the hips), a rectal and perirectal evaluation, and a pelvic examination. Each may provide critical clues that lead to the correct diagnosis.
d. Laboratory studies. The history and physical examination may provide enough information to make a diagnosis. Quite commonly, however, you may remain unsure about the etiology of the fever. The following laboratory tests will help you assess the likelihood of an infection and may also help to localize the source.
i. Complete blood count (CBC) with platelets
1. Neutropenia with fever is a medical emergency and requires hospitalization and broad-spectrum antibiotics.
2. A leftward shift in white blood cell (WBC) count often implies significant or overwhelming bacterial infection.
3. A low WBC count may be just as worrisome as a high one; the WBC count may not be elevated in alcoholic patients, the older adult patients, HIV-infected patients, and other immunocompromised patients in the presence of a serious infection. Overwhelming infection can cause bone marrow suppression and a reduced WBC, which may be manifest before the presence of hemodynamic compromise. Many indolent infections may not be associated with elevations in the WBC count. On the other hand, individuals of African descent often have WBC counts slightly below the given “normal” range.
ii. Electrolytes with blood urea nitrogen (BUN) and creatinine. The presence of anion gap acidosis may indicate the presence of sepsis.
iii. Prothrombin time (PT) and partial thromboplastin time (PTT). Abnormal coagulation studies may indicate disseminated intravascular coagulation (DIC), which may accompany serious infection.
iv. Liver tests (e.g., bilirubin, alkaline phosphatase, and transaminase levels) help evaluate the possibility of hepatobiliary disease (e.g., cholecystitis, ascending cholangitis, liver abscess, hepatitis).
v. Amylase levels may be helpful if pancreatitis is suspected.
vi. Urinalysis should always be done to evaluate the possibility of UTI.
vii. Urine pregnancy test. A pregnancy test should be considered in all women of childbearing age.
1. Blood cultures are the gold standard for diagnosing bacteremia. A minimum of two sets of blood cultures should be drawn. Depending on the organism, determining whether a single positive blood culture represents true infection or skin contamination can be difficult. Patients at higher risk for endocarditis, such as those with prosthetic valves or a history of injection drug use, should always have multiple sets of blood cultures drawn from different sites and at different times.
Persistently positive blood cultures or multiple positive sets of cultures suggest an intravascular infection such as endocarditis, infectious aortitis, septic thrombophlebitis, or a vascular graft infection.
2. Urine culture should be obtained if urinalysis is suggestive of a UTI; bacteriuria in the absence of pyuria is unlikely to be the cause of fever.
3. Sputum evaluation may be useful for patients with respiratory tract symptoms.
5. Cerebrospinal fluid (CSF) analysis and culture are necessary in patients with meningeal symptoms or signs, altered mental status, or HIV infection and an unexplained fever.
6. Body fluid analysis and culture. Patients with a fever accompanied by ascites, a pleural or joint effusion, or any other type of fluid collection need a diagnostic tap.
7. Stool culture for patients with fever and diarrhea. Testing for C. difficile infection should be performed in the setting of diarrhea and recent antibiotic use.
Consider skin biopsy in patients who present with fever and rash to rule out vasculitis, unless the diagnosis is apparent or straightforward.
i. Chest. Posterior-anterior (PA) and lateral views should be taken on all patients with unexplained fever.
ii. Abdomen. Flat and upright views may be useful when the patient has a fever and abdominal pain. Be sure to look for air-fluid levels, bowel distention, kidney stones, and free air.
f. Ancillary studies. At this point, you have systematically ruled out most of the possible infections from head to toe. If a diagnosis still has not been made, you need to consider the easiest place for an infection to hide—which is often the abdomen and pelvis.
i. Computed tomography (CT). CT is the best radiographic test in this situation. It provides a thorough evaluation of the intra-abdominal organs and is more sensitive than ultrasound for detecting occult abscesses.
ii. Ultrasound. Abdominal ultrasound is often inadequate for ruling out intra-abdominal abscesses and other pathology but may be better than a CT scan for evaluating the gallbladder and bile ducts specifically (e.g., cholecystitis or ascending cholangitis). Ultrasound also has the advantage of avoiding radiation and contrast but is operator-dependent.
iii. Other tests (e.g., bone marrow biopsy, liver biopsy, indium or positron emission tomography [PET] scans, bone scans) may be obtained if the cause of the fever is still in question (see Chapter 51).
C. Treatment. If a potentially dangerous infection is suspected, or close follow-up is uncertain, admission to the hospital is warranted. Older adults, patients that are immunocompromised, or patients with other organ system disease may also require admission.
a. General measures
i. Fluids need to be administered to keep up with increased insensible losses.
ii. Discontinuing medications that may be responsible for a fever can be both diagnostic and therapeutic.
b. Empiric antibiotic therapy
i. Nontoxic patients who are otherwise stable may be closely watched without antibiotics, until a diagnosis is made.
ii. Patients hospitalized for fever and neutropenia, suspected meningitis, or who are critically ill should be treated empirically pending culture results.
iii. A low threshold for giving empiric antibiotics should also be used for patients who are immunocompromised, including those with HIV infection, diabetes, alcoholism, or liver or renal disease, and patients who are asplenic or taking steroids or immunosuppressants. In such patients, delaying antibiotics can become life-threatening.
iv. Empiric antibiotic coverage should be appropriately narrowed after a source of infection has been identified or should be discontinued if infection is excluded.
c. Antipyretic therapy
i. Acetaminophen (325–650 mg every 4 hours as needed) is given initially to provide symptomatic relief. It should preferentially be administered in response to fever rather than around-the-clock so that the temperature curve can be monitored.
ii. Ibuprofen (400–800 mg every 8 hours) and cold sponge baths may be useful for persistent fevers.
iii. Evaporative cooling is often used for patients with a temperature greater than 41° C. In this technique, the patient is sprayed with cool water while fans move ambient air across the body. Electric cooling blankets can be used as well.
Suggested Further Readings
Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 2011;52:e56–e93.Find this resource:
James J, Kaul DR, Goldberger ZD, Saint S, Skerrett SJ. Back to nature. N Engl J Med 2015;373:2271–6.Find this resource:
O’Grady NP, Barie PS, Bartlett JG, et al. Guidelines for evaluation of new fever in critically ill adult patients: 2008 update from the American College of Critical Care Medicine and the Infectious Diseases Society of America. Crit Care Med 2008;36.Find this resource: