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THE FEBRILE PATIENT WITHOUT AN OBVIOUS SOURCE OF INFECTION

THE FEBRILE PATIENT WITHOUT AN OBVIOUS SOURCE OF INFECTION

Etiology
Management
Bibliography

Infection represents only one of several important groups of illnesses that can initially manifest with fever. Other examples include connective tissue disease, malignancy, and myocardial or pulmonary infarction. Certain medications may also be associated with fever. In addition to the broad differential diagnosis it entails, fever may be further confounded because it is sometimes absent in persons with significant infection. This consideration is especially important in elderly patients and those who are immunosuppressed. Moreover, neither the degree of fever nor the fever curve correlates with etiology or severity of disease. Finally, in numerous important infections, the source may not initially be obvious.
The likelihood that the acute onset of fever is caused by bacterial infection is statistically associated with advanced age, presence of indwelling urinary catheters, residence in a nursing home, and leukocytosis. Examples of diseases in which acute onset of fever may be unaccompanied by focal complaints or significant physical findings are given in Table 46-1. Identification of the source of acute fever may be complicated in circumstances in which the history and physical examination are difficult to obtain (e.g., elderly persons, severely debilitated or noncompliant patients, those with overwhelming illness or language barriers). Thus, the clinician must have a sound understanding of the potential causes of fever as well as a studied approach to the patient who presents with this complaint.

Table 46-1. Common acute febrile diseases that may be nonfocal

Etiology
The history and physical examination provide important initial clues on which to base management decisions. The history must be comprehensive and include questions concerning travel, pet exposures, similar illness in family members and colleagues, medications (prescribed, over-the-counter, and illicit), and duration of fever. The travel history may be the initial important clue toward consideration of diseases such as malaria, yellow fever, and dengue. If a patient has returned with fever from a malarious area, malaria should be considered until the diagnosis has been excluded. A history of animal and bird exposure may expand the differential diagnosis to include ornithosis, infection with Pasteurella multocida, plague, hantavirus infection, or tularemia.
In general, fevers of longer duration may be evaluated in a more relaxed fashion. Special attention should be paid to a review of systems because subtle complaints may be uncovered that will help target the physical examination and provide clues to management. The clinician should also assess patient age, length of illness, any underlying diseases, and gross severity. Information concerning immunosuppression should be elicited because selected processes may predispose to potentially life-threatening infections. Examples are splenectomy, neutropenia, infection with HIV, hypogammaglobulinemia, and intake of medications (e.g., corticosteroids) that may alter cell-mediated immunity.
In patients with HIV/AIDS, fever almost always accompanies the acute retroviral syndrome, and otherwise is generally noted as a component of opportunistic disease. In last-stage AIDS, fever may be the manifestation of disseminated infection with Mycobacterium avium complex. It is also noted as an adverse effect of certain drugs (e.g., trimethoprim-sulfamethoxazole) and may accompany lymphoma, tuberculosis, or pneumonia caused by Pneumocystis carinii.
The presence of foreign bodies, such as joint implants and prosthetic heart valves, should also be noted. A history of rigors is generally sought but does not provide information beyond the fact that the temperature became rapidly elevated; it does not imply a specific etiology.
The physical examination must be comprehensive. Vital signs provide an important initial clue to the severity of illness and may help with the decision of whether to hospitalize. In general, the degree of fever does not correlate with etiology. Nevertheless, fevers above 103°F generally are of more concern and often point to infection. Recent data suggest that for some infections, such as shigellosis, the degree of temperature elevation may correlate with the severity of illness. Adults with fevers above 105.6°F should be hospitalized for fever reduction; temperatures at this level may cause tissue damage. Contrary to the classic dictum, many patients with temperatures at this level have treatable bacterial disease and should be treated empirically with antimicrobials.
Hypothermia is associated with impending sepsis, hypothyroidism, environmental exposure, and diabetes mellitus with autonomic instability. In the hypothermia associated with infection, the systemic vascular resistance is likely to be statistically lower and the cardiac index higher than in the noninfectious conditions already listed.
The respiratory rate is an often overlooked sign. Elderly patients with rates above 25/min often have lower-respiratory infection, even in the absence of initial physical findings. In the setting of community-acquired pneumonia, rates above 30/min are associated with increased mortality. Low or unstable blood pressure may suggest impending septic shock and is an important reason for hospitalization. An elevated pulse is anticipated with temperature elevation. Physiologic elevation is 10 to 15 beats/min per degree rise in temperature.
Temperature-pulse dissociation is associated with beta blockade and intrinsic coronary disease. Infectious causes include viral influenza, Legionnaires’ disease, yellow fever, typhoid fever (or less commonly other gram-negative bacteremias), and other viral syndromes. Rash should be sought in all body areas; even if it is subtle, it can provide useful information both etiologically and diagnostically. Careful attention must be paid to physical examination of the mouth, sinuses, and rectum.
Management
Initial decision making focuses on requirements for hospitalization, empiric or targeted antimicrobial therapy, route of administration if a need for antimicrobials has been determined, and further testing. Hospitalization is indicated primarily for persons who are clinically unstable or believed to be at risk for rapid deterioration. The criteria are best determined for patients with community-acquired pneumonia. Recent studies in patients seen in emergency departments demonstrate that advanced age and leukocytosis (>15,000/mm3) correlate with serious disease and can help determine the need for hospitalization. Other reasons must be individualized; they can include the need for IV antimicrobials or other fluids, rapid evaluation likely to require sophisticated testing, and intense monitoring. Other potential reasons for hospitalization, such as lack of compliance, unfavorable home environment, and uncertain diagnosis, are less likely to be allowable under current reimbursement guidelines. In general, the acutely febrile elderly patient, especially if the fever is associated with underlying disease, is more likely to be infected and to require hospitalization. Similarly, the person with known major alterations of immunity should be hospitalized if significant infection cannot be rapidly ruled out. On the other hand, the younger, fit person is more likely to be treatable as an outpatient.
Management of the febrile patient without an obvious focus of infection will vary depending on the need for hospitalization. Basic laboratory data should be obtained from the hospitalized patient, including CBC count, urinalysis, and (generally) several sets of blood cultures. Decisions regarding other tests (e.g., chest x-ray films, further blood tests, and cultures from sites other than blood) will depend on clinical presentation and subtle clues obtained from the history and physical examination. The urgency of testing depends on the clinical status. Generally, acutely febrile patients, especially those who have high-grade fevers or are unstable, require more intensive evaluation. If hospitalization is not felt to be warranted, testing is generally more limited and based on symptoms and signs.
Antimicrobial needs are determined by the likelihood of treatable infection. Table 46-2 depicts conditions that usually warrant empiric antimicrobial therapy. This management strategy should be reserved for inpatients believed to have either a high probability of treatable infection or of significant adverse outcome if untreated. Antimicrobials should always be initiated after cultures have been obtained from appropriate sites, and the need should be reassessed after several days when more information is returned from the laboratory and clinical response has been evaluated. The choice of empiric antimicrobials is based on presumed site of infection and likely microbe(s) from that site. As an example, Pseudomonas aeruginosa is an unlikely pathogen in most patients with community-acquired infection. For most hospitalized patients requiring antimicrobials, therapy is initiated parenterally to ensure uniform absorption and attain high systemic levels quickly.

Table 46-2. Acute febrile conditions often warranting empiric antimicrobial treatment

In febrile patients not sufficiently ill to be hospitalized, especially those with a subacute or chronic onset, antimicrobials should not be overused. Overuse of oral antibiotics for viral infections has been identified as a major problem in the United States, and one that may be associated with emerging antibiotic resistance of common bacteria. Persons with neither focal abnormalities nor significant underlying disease may often be observed. However, all patients should be followed regularly for changes in clinical status that either point to improvement or a more focused process.
The need for further testing is based on the presence of ongoing fever. Although no clear guidelines can be presented, blood tests that determine the CBC count (with differential), liver function, sedimentation rate, antinuclear antibody, and renal function are often warranted. Early in the evaluation, posteroanterior and lateral chest x-ray images should be obtained. The need for other blood, radiographic, microbiologic, and invasive tests for tissue must be individualized. (R.B.B.)
Bibliography
Gallagher EJ, Brooks F, Gennis P. Identification of serious illness in febrile adults. Am J Emerg Med 1994;12:129–133.
The authors conducted a prospective observational study within a cohort of approximately 600 adults who presented to an emergency department with fever above 100°F. Serious disease was defined as (a) associated with bacteremia or (b) fatal. Twelve percent of febrile patients met the criteria for serious illness. By regression analysis, only advanced age (50 years or more) and leukocytosis (>15,000/mm3) were associated with serious disease. The authors concluded that approximately one third of adults exhibiting both these parameters will be seriously ill. However, the absence of the two parameters does not preclude serious disease as defined.
Leibovici L, Cohen O, Wysenbeek AJ. Occult bacterial infection in adults with unexplained fever. Arch Intern Med 1990;150:1270–1272.
This investigation of more than 100 patients admitted to a hospital with unexplained fever depicted a strategy to determine the likelihood of bacterial infection. Patients who were of advanced age, had indwelling urinary catheters, resided in nursing homes, or had elevated WBC counts were more likely to harbor bacterial infection.
Mackowiak PA, et al. Concepts of fever: recent advances and lingering dogma. Clin Infect Dis 1997;25:119–138.
This round-table discussion on a variety of issues related to fever covers pathogenesis, fever patterns, and fever in the HIV/AIDS population. The authors describe situations likely to be associated with fever and discuss selected tests of value. Fever is most commonly noted during the acute retroviral (mononucleosis-like) syndrome and accompanies many opportunistic processes. Fever is unlikely to resolve spontaneously in advanced disease.
McFadden JP, et al. Raised respiratory rate in elderly patients: a valuable physical sign. Br Med J 1982;284:626–627.
A normal respiratory rate in elderly patients was 16 to 25/min. Higher rates were noted in those with acute lower respiratory infection. The observation of an increased rate preceded diagnosis. An elevated respiratory rate was not seen in other infections.
Pinson AG, et al. Fever in the clinical diagnosis of acute pyelonephritis. Am J Emerg Med 1997;15:148–151.
Adult women who had pyuria with or without fever were studied as two groups to determine the presence of acute pyelonephritis. They were further stratified by need for hospitalization. Among both the hospitalized women and those treated as outpatients, the absence of fever predicted alternative diagnoses that included pelvic inflammatory disease and cholecystitis. The authors conclude that fever is associated with pyelonephritis in patients with pyuria.
Sioson PB, Brown RB. Hyperpyrexia in a large community hospital: etiologies, features, and outcomes. South Med J 1993;86:773–776.
Within a defined population of 39 patients with fever above 105.6°F, potentially treatable bacterial infections were commonly noted. This finding differs from observations reported in earlier literature and has important implications for management. The authors feel that most patients with hyperpyrexia warrant empiric antibiotic therapy pending results of cultures and other assessments for treatable infection.

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