Fever in the Adult Patient

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Chapter 12

Fever in the Adult Patient

Perspective

Epidemiology

Fever is a common presenting complaint in both pediatric and adult (aged 18-65 years) emergency department (ED) patients. Patients often confuse fever with a disease process itself, rather than a sign of an illness. Morbidity and mortality rates from febrile illnesses vary dramatically with age. Younger adults with fever usually have benign self-limited disease, with less than 1% mortality. The challenge in this group is to identify the rare meningitis or septic conditions when confronted with a predominance of self-limited viral and focal bacterial diseases. Patients older than 65 years, or those with chronic disease who have fever, represent a group at high risk for serious disease. Morbidity and mortality rates in this group are significant. From 70 to 90% are hospitalized, and 7 to 9% die within 1 month of admission.1 Infection is the most common cause of fever in these patients, and most of these infections are bacterial in nature. Three body systems—the respiratory tract, the urinary tract, and the skin and soft tissue—are the target for more than 80% of these infections.1,2 The relative mortality and morbidity for any given infection are much higher in the geriatric population. For example, elders are at 5 to 10 times greater risk for urinary tract infections and 15 to 20 times for appendicitis.1,3 Even viral illnesses that are generally not fatal, such as influenza, can be highly lethal in elder persons.

Pathophysiology

Body temperature is normally controlled within a narrow range by the preoptic area of the hypothalamus. This range is usually 36.0 to 37.8° C (96.8-100.0° F). There is a circadian rhythm within this range, with lower temperatures in the morning and higher temperatures in the late afternoon. Fever occurs when this normal range is reset to a higher value. Fever is defined by the Centers for Disease Control and Prevention as a core temperature greater than 37.8° C in the absence of fever-reducing medication. Fever should not be confused with hyperthermia. Hyperthermia is an elevation of the temperature related to the inability of the body to dissipate heat. Most cases of temperatures higher than 41.0° C (105.8° F) are a result of hyperthermia, but febrile illness also is considered.

In the anterior hypothalamus, neurons directly sense the blood temperature. Temperature is subsequently controlled by a combination of vasomotor changes, shivering, changes in metabolic heat production, and behavioral changes.

Fever may be produced by a number of endogenous and exogenous substances referred to as pyrogens. Endogenous pyrogens include a variety of cytokines released by leukocytes in response to infectious and inflammatory and neoplastic processes. Exogenous pyrogens include a large number of bacterial and viral products and toxins. Toxins induce fever by stimulating cells of the immune system to release endogenous pyrogens. These cytokines, such as interleukin-1 (IL-1), IL-6, tumor necrosis factor, and interferon, travel to the hypothalamus and induce the production of prostaglandin E2 (PGE2).

PGE2 raises the set point of the temperature range by a combination of effects, including peripheral vasoconstriction, increased metabolic heat production, shivering, and behavioral changes that conserve heat. Fever is maintained as long as the levels of endogenous pyrogens and PGE2 are high. Cyclooxygenase inhibitors, such as aspirin, decrease fever by blocking the production of PGE2. Age, malnutrition, and chronic disease may also blunt the febrile response.

Moderate elevations of the body temperature may serve to aid the host defense by increasing chemotaxis, decreasing microbial replication, and improving lymphocyte function. Elevated temperatures directly inhibit the growth of certain bacteria and viruses.4

Fever also results in certain increased physiologic costs to the host, including increased oxygen consumption, metabolic demands, protein breakdown, and gluconeogenesis. These costs are particularly problematic in elders, who typically have a smaller margin of reserve for any given body system. It is well established that the ability to develop fever in elders is somewhat impaired. Older individuals also are known to have lower baseline temperatures than younger adults.5 It has not been shown that treatment of fever with antipyretics has a beneficial effect on outcome or prevents complications; however, treatment to reduce the fever makes febrile patients more comfortable.4

The initial step in the process of fever is the resetting of the thermostatic set point in the hypothalamus to a higher temperature while actual body temperature remains normal. This mismatch of the thermostat with the “sensed” body temperature causes the patient to feel chilled (chills). If the chills are reported to a caregiver and the temperature is taken, it is usually found to be normal or minimally elevated. To the examiner’s touch, the patient’s skin temperature will feel normal. The patient remains chilled until the body temperature rises to near the (elevated) hypothalamic set point. At this point, the patient feels euthermic (but may feel fatigued or ill), but to the caregiver the skin temperature or thermometer reading is now elevated. The sequence of chills followed by febrile illness is the basis of the (incorrect) popular belief that getting chilled leads to infection (classically pneumonia). When the thermostatic set point is reduced to normal, the patient suddenly feels hot and sweats until the body temperature falls to match the (now normal) set point.

Diagnostic Approach

Differential Considerations

The complete differential diagnosis for the patient in the ED with fever is extensive. The major infectious and noninfectious causes are summarized in Table 12-1 and Box 12-1, respectively. The vast majority of serious causes are infectious in origin. Immediate threats to life are from decompensated shock (usually septic), respiratory failure (related to shock or pneumonia), or central nervous system infection (meningitis). Some critical noninfectious causes of fever also exist (see Box 12-1), but these are relatively rare and frequently do not occur with fever as the primary symptom.

BOX 12-1   Differential Diagnosis—Noninfectious Causes of Fever

A primary medical decision in acute febrile illness is based on assessment of patient stability (Fig. 12-1). Patients with life-threatening signs and symptoms, including significant alterations in mental status, respiratory distress, and cardiovascular instability, may require rapid, vigorous treatment. Prompt airway management and initiation of monitoring, intravenous access, fluid resuscitation, supplemental oxygen, and respiratory support are often necessary despite incomplete information concerning the cause of the fever. Sustained temperatures above 41.0° C are rare but can be damaging to neural tissue and require rapid cooling (e.g., misting, fans, cooling blankets).

In the younger, otherwise healthy patient with fever, immediate threats to life such as toxic or septic shock, meningitis, meningococcemia, and peritonitis should be considered and treated empirically. In older, chronically ill patients with fever, most of the serious illnesses originate from infections in the respiratory tract, the genitourinary tract, and the skin and soft tissues.2 Meningitis, although less common, can also be a significant cause of morbidity and mortality in this group.

Pivotal Findings

Although the differential diagnosis of fever is broad, most of the treatable causes are of infectious origin. Most of these causes of fever may be diagnosed by careful history and physical examination alone.6 Age and the presence of underlying medical conditions can substantially influence the evaluation and subsequent decision-making regarding management.

An approach to diagnosis and management of the healthy, otherwise well, stable adult patient with acute febrile illness is shown in Figure 12-2. In younger and otherwise healthy adults, self-limited, localized bacterial infections or benign systemic viral infections are usually the cause of fever. The challenge with this group is to identify the rare life-threatening illness, such as meningococcemia, meningitis, or systemic methicillin-resistant Staphylococcus aureus (MRSA) infection.

In the older or chronically ill population, fever is frequently a sign of severe illness. Usually the cause is infectious. In addition to the most common infectious causes of illness (respiratory, urinary, or skin sources), infections such as meningitis, cholecystitis, appendicitis, and diverticulitis are considered and may cause atypical signs and symptoms in elders or immunosuppressed patients. In these populations, subtle changes in behavior may be the only sign of severe infection. Abnormal vital signs, especially significant tachypnea and hypotension, may portend a complicated and severe course. Seventy-five percent of the cases of functional decline in nursing home patients are a result of infection.1,2

Symptoms

The onset of the fever, its duration and magnitude, and any associated symptoms help identify possible causes and severity of illness. Localizing symptoms such as dysuria or productive cough are especially helpful. The timing of the fever and its patterns may implicate certain diseases (e.g., malaria). Recent or remote travel, chronic illnesses, past surgeries, hospitalizations, and treatment modalities may raise the suspicion of exotic or nosocomial infections. The presence of prosthetic heart valves or any indwelling device may be critical to the diagnosis. With the emergence of community-acquired MRSA, it is important to seek a history of skin infections in close family members or other close contacts. MRSA should also be considered in military personnel, prisoners, and persons involved in competitive sports that involve close contact.7,8

Also important in the medical history is a list of all the patient’s medications, including any antipyretic medications. Family members are frequently an important source of information in elder and very young patients.

Atypical symptoms of illness are common in elder patients. Pneumonia or urinary tract infection in the older patient may be heralded by only a change in mental status, difficulty ambulating, or some other functional decline. Dysuria, frequency, and flank pain often are absent entirely in elders with urinary tract infection. Patients with pneumonia may inconsistently demonstrate productive cough or shortness of breath. Other frequent but nonspecific symptoms include anorexia, weight loss, weakness, lethargy, nausea, and recurrent falls.1,2 A history of cancer with recent chemotherapy or radiation therapy may be a clue to leukopenia or other immunodepressed states. Assessment of the patient’s baseline mental and physical function often relies on the reports of others who know the patient well.

Signs

The presence and magnitude of fever are important elements of the examination, but the elder, very young, or chronically ill patient may not mount a febrile response to significant infection. Temperatures may fluctuate, and rechecks may be necessary.

Although the most accurate measure of core body temperature is thought to be via the thermistor of a pulmonary artery catheter, in the ED, rectal temperature measurements or, when a Foley catheter is indicated, bladder thermistors are the most practical and accurate.9 Axillary and tympanic temperatures often are unreliable. Oral temperatures may be transiently distorted by recent ingestion of hot or cold liquids, smoking, or hyperventilation. For example, rectal temperatures are typically 0.7 to 1.0° C higher than oral temperatures.9

Fever is inconsistently associated with tachycardia and tachypnea. The heart rate may increase by 10 beats/min for each 0.55° C (1° F) degree rise in temperature. Relative bradycardia may be caused by medication such as beta-blockers, but it also can suggest factitious or drug-related fevers, typhoid fever, brucellosis, or leptospirosis. Frank bradycardia may occur with rheumatic fever, Lyme disease, viral myocarditis, and endocarditis. The respiratory rate may increase 2 to 4 breaths/min per degree Celsius. More significant tachypnea may be caused by respiratory infection or the acidosis related to shock.

In many patients the examination is directed by the patient’s localization of symptoms. The head and neck examination focuses on treatable foci of infection, such as otitis media, sinusitis, pharyngitis, peritonsillar abscess, retropharyngeal abscess, and dental infections. A muffled, “hot potato” voice with severe sore throat may be a clue to adult epiglottitis or upper airway abscess. Fundoscopy rarely may reveal evidence of disseminated candidiasis, miliary tuberculosis, endocarditis, toxoplasmosis, or leukemia.

The neck is examined for lymphadenopathy, masses, or thyroid pathology (thyromegaly or mass). Nuchal rigidity or pain on flexion of the neck is a useful sign for meningismus if present but may not be prominent in many patients, particularly the very young or debilitated patient, even if meningitis is present. Conversely, cervical arthritis or Parkinson’s disease may cause preexisting nuchal rigidity.

The lungs are examined for rales, pleural rubs, or dullness to percussion. Localized rales or rhonchi may be subtle clues to the presence of pneumonia. The presence of concomitant chronic obstructive pulmonary disease or congestive heart failure, as well as poor respiratory effort, may hamper the diagnosis of pneumonia in elders. The heart is examined for pericardial rubs or new murmurs.

The abdominal examination may be deceptively benign in older patients, patients with diabetes, or patients taking immunosuppressive drugs or steroids. When indicated by history or other findings, a rectal examination should be performed to check for evidence of enteritis, perirectal abscess, or prostatitis. The external genitalia examination may reveal evidence of Bartholin’s abscess, urethral or vaginal discharge, or evidence of epididymitis or orchitis. In women, symptoms of lower abdominal pain, vaginal discharge, and dyspareunia suggest the need for a pelvic examination to evaluate for pelvic inflammatory disease or tubo-ovarian abscess.

The skin and extremities should be evaluated for rash, petechiae, joint inflammation, or evidence of soft tissue infection. In the absence of trauma, tenderness over the long bones or the spine may be evidence of osteomyelitis or neoplastic processes. Elders and bedridden patients should be checked for the presence of pressure sores or decubitus ulcers.2

Ancillary Testing

Ancillary testing is directed by the history and physical examination. The two most useful ancillary tests, especially in elder patients, are urinalysis and chest radiography. Chest radiographs are often helpful in the diagnosis of pulmonary infection but may be difficult to interpret in the patient with concurrent chronic obstructive pulmonary disease, congestive heart failure, dehydration, or other chronic lung disease. The urinalysis, although not foolproof, is highly accurate for urinary tract infection, especially in men. Although the white blood cell count is almost universally used in the evaluation of febrile patients, it lacks the sensitivity and specificity to be of discriminatory value. The white blood cell count may incorrectly indicate serious infection when none is present or may be normal in the presence of life-threatening infection.10 Other indirect tests of infection and inflammation, such as the erythrocyte sedimentation rate, are also plagued with irregular sensitivity and poor specificity. Gram’s stain of appropriate specimens may be helpful, and cultures may be ordered, although the results do not often influence emergency evaluation and treatment. With the emergence of MRSA, it has become increasingly important to obtain cultures from soft tissue skin abscesses in patients considered at risk for MRSA infection. In elder or chronically ill patients with acute fever of unknown source, blood and urine cultures are frequently appropriate. Outpatient blood cultures should rarely, if ever, be done. A patient ill enough to require blood cultures from the ED generally requires hospitalization and empirical antibiotic coverage. Cerebrospinal fluid evaluation should be considered when mental status changes are evident, or if headache, meningismus, or other unexplained neurologic symptoms are present and cannot be clearly accounted for by infection outside the central nervous system. Thyroid function studies may be helpful when thyroid storm is suspected. Arterial or venous blood gas studies may help identify patients with critical disease who require prompt treatment.

Plain films of the abdomen are rarely indicated or helpful unless perforation or obstruction is suspected. Abdominal computed tomography (CT) is helpful if appendicitis, diverticulitis, cholecystitis, or intra-abdominal abscess is suspected. Ultrasonography may be helpful in the patient with potential cholecystitis.

Cranial CT scanning may be indicated before lumbar puncture in patients with focal neurologic findings or an embolic source, such as suspected endocarditis, to exclude mass lesions such as tumor or brain abscess. This test should not delay antibiotics in patients with suspected meningitis.

Differential Diagnosis

The differential diagnoses of infectious causes of fever are summarized in Table 12-1. The differential diagnoses of noninfectious causes of fever are listed in Box 12-1. However, differences in patient characteristics can cause different manifestations of the same illness. For example, pneumonia or a urinary tract infection manifests in and is tolerated by an 80-year-old very differently compared with a young adult. A careful history and physical examination, along with strategic ancillary testing, will allow the practitioner to identify when a critical condition is present and will determine the operational tempo of subsequent evaluation and treatment.

Empirical Management

Patients with temperatures greater than 41.0° C require prompt and vigorous treatment with antipyretics and possibly external cooling measures. Temperatures above this range can result in damage to neuronal tissue. There is no evidence for improved outcome by routine use of antipyretic therapy, such as acetaminophen, in patients without extreme temperature elevation, but it is not harmful, and patients often feel better when their temperature declines.4 Recent studies have shown that intravenous acetaminophen is as effective as oral acetaminophen and may be used in patients who are unable to take oral medication.11

Patients with signs and symptoms of septic shock require prompt and vigorous treatment. Patients with evidence of respiratory failure from either shock or pneumonia require ventilatory support. Soft tissue infections of the head and neck may compromise the airway because of mechanical obstruction. These may require acute intervention to provide a secure airway.

In many cases, early empirical antibiotic therapy is appropriate. The choice of antibiotics is based on the likely cause of the fever as well as concomitant conditions such as absolute neutropenia and end-stage renal disease. If a specific infection is subsequently identified, antibiotic therapy should be specific to that infection. In the absence of a clear source of infection, broad-spectrum coverage of gram-positive and gram-negative aerobic and anaerobic bacteria is indicated. In acutely ill febrile patients, especially those who are immunocompromised, antiviral and antifungal treatment should also be considered.

Disposition

Localized bacterial infections can most frequently be treated with outpatient oral antibiotics. Relatively young, healthy patients with systemic viral illness can be treated as outpatients. These illnesses are often accompanied by vomiting and poor oral intake, and treatment in the ED with antipyretics, antinausea medications, and intravenous hydration may help prepare the patient for a successful outpatient course.

When no clear infection is identified in older patients or those with chronic illness, such as diabetes or chronic renal failure, admission to the hospital often is necessary to further elucidate the possible causes of the presentation. In this subset of patients, a diligent search for evidence of bacterial infection is required. Also, admission to an inpatient unit or ED observation unit may be advisable when fever or other systemic symptoms accompany a suspected MRSA infection. In patients with unexplained severe febrile illness, blood and urine cultures and broad-spectrum antibiotics are indicated to treat possible life-threatening infection, until a specific disease process or pathogen is identified. Indwelling devices, such as percutaneous intravenous access ports, frequently require culture and may need to be removed. Neutropenic patients with fever require prompt treatment with broad-spectrum parenteral antibiotics, pending results of cultures. Patients with unstable vital signs or life-threatening infections may require admission to a special care unit if they cannot be adequately stabilized in the ED before admission.

References

1. Angus, DA, et al. Epidemiology of severe sepsis in the United States: Analysis of the incidence, outcome and associated costs of care. Crit Care Med. 2011;29:1303–1310.

2. High, KP, et al. Clinical practice guideline for the evaluation of fever and infection in older adults residents of long term care facilities: 2008 update by the Infectious Disease Society of America. Clin Infect Dis. 2009;48:149–171.

3. Tal, S, Guller, V, Gurevich, A, Levi, S. Fever of unknown origin in the elderly. J Intern Med. 2002;252:295–304.

4. Greisman, LA, Mackowiak, PA. Fever: Beneficial and detrimental effects of antipyretics. Curr Opin Infect Dis. 2002;15:241–245.

5. Roghhmann, MC, Warner, J, Mackowiak, PA. The relationship between age and fever magnitude. Am J Med Sci. 2001;322:68–70.

6. Tolan, RW, Jr. Fever of unknown origin: A diagnostic approach to this vexing problem. Clin Pediatr (Phila). 2010;49:207–210.

7. Aiello, AE, Lowy, FD, Wright, LN, Larson, EL. Meticillin-resistant Staphylococcus aureus among U.S. prisoners and military personnel: Review and recommendations for future studies. Lancet Infect Dis. 2006;6:335–341.

8. Turbeville, SD, Cowan, LD, Greenfield, RA. Infectious disease outbreaks in competitive sports: A review of the literature. Am J Sports Med. 2006;34:1860–1865.

9. O’Grady, N, et al. Guidelines for the 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;36:1330–1353.

10. Furer, V, Raveh, D, Picard, E, Goldberg, S, Izbicki, G. Absence of leukocytosis in bacteraemic pneumococcal pneumonia. Prim Care Respir J. 2011;20:276–281.

11. Peacock, WF, Breitmeyer, JB, Pan, C, Smith, WB, Royal, MA. A randomized study of the efficacy and safety of intravenous acetaminophen compared to oral acetaminophen for the treatment of fever. Acad Emerg Med. 2011;18:360–366.

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