Chapter 228. Fever of Unknown Origin

The definition of FUO requires an immunologically normal host with oral or rectal temperature ⩾38.0°C (100.4°F) at least twice a week for more than 3 weeks, a noncontributory history and physical examination, and 1 week of outpatient investigation.6-9 Early diagnostic studies normally include a complete blood cell count; lactate dehydrogenase (LDH); uric acid; urinalysis and culture; chest roentgenogram; tuberculin skin test; erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP); and, in the older child, a titer of antinuclear antibodies. Management of patients with comorbidity factors such as acquired or congenital immunodeficiency, neutropenia, and occurrence of fever during prolonged hospital stays is not considered in the following discussion.

The greatest clinical concern in evaluating FUO is identifying patients whose fever has a serious or life-threatening etiology for whom a delay in diagnosis could jeopardize successful intervention. Cancer and severe bacterial infections are the causes most frequently discussed and most likely to influence diagnostic and management approaches. However, the vast majority of children with prolonged FUO resolve their illnesses without a diagnosis and do not exhibit long-lasting effects. Therefore, it appears appropriate for most children to delay extensive diagnostic evaluation until the child has remained febrile for at least 6 weeks.

Because of the ready availability of more sensitive serologic assays and more precise radiographic scanning procedures, the etiologies of FUO in children, as well as in adults, have changed over the past three decades (Table 228-1). The most striking change has been the virtual elimination of laparotomy as a final step in evaluation, a procedure routinely recommended in the 1970s, but now eliminated due to advances in radiologic imaging technology.

Three newly defined infectious diseases now account for a moderate number of cases: Epstein-Barr virus infection, cat-scratch disease, and Lyme disease. All three can be confirmed with serologic assays showing both IgM and, later, IgG antibodies to the respective pathogens. Cat-scratch disease can also be confirmed with compatible liver lesions documented by abdominal sonograms or CT scans.

Two-thirds of children who now present with fever of unknown origin resolve their fever without determination of a cause, in contrast to only 10% to 20% in a series published 20 to 30 years ago.7-12 In addition, a higher percentage of children with malignancies is now definitively diagnosed earlier in the course of illness, and such cases lead to an overall reduction in total cases of fever of unknown origin. A greater percentage of the remainder likely have viral illnesses that are more difficult to diagnose but more likely to resolve without intervention.

Infectious diseases now account for approximately 40% of identified etiologies with the most common being Epstein-Barr virus infection,7cat-scratch disease,11 and urinary tract infection.12All three can be confirmed with simple laboratory studies.

An oral or rectal temperature ⩾38°C (100.4°F) is two standard deviations above the average for normal children and most appropriately defines fever. Rectal recordings are preferred for younger children. Tympanic temperatures are so unreliable that they cannot be used to monitor febrile patients. Many parents believe that any temperature above the average—that is, 37°C (98.6°F)—is abnormal and seek consultation for these observations. Unless there are other clinical findings, either historically or during physical examination, reassurance is the only intervention warranted for temperatures <38°C (100.4°F).

For “subjective” fevers, usually meaning that the child feels warm to the parent or another caregiver, a diary recording of morning and afternoon rectal temperature measurements for at least 1 week should be obtained before initiating diagnostic evaluation. Children often feel warm, particularly when environmental temperatures are high enough to induce flushing or perspiration. Despite widespread public perceptions, few parents (or grandparents) can determine low-grade temperature elevations by simply touching their children’s forehead. However, core temperatures >39.4°C (103°F) consistently produce skin temperature changes that can be recognized by most caregivers.

The number of documented febrile recordings during a 21-day observation period considered abnormal is arbitrarily suggested as two per week. However, cases should be individualized. Well-defined events such as otitis media or limited viral illnesses can account for some febrile periods. Conversely, antipyretic therapy might mask significant temperature spikes. Occasionally, an observation period in the hospital is the only way to verify fever in children whose parents insist that fever exists, but in whom the observation cannot be confirmed. In cases of factitious fever (Munchausen syndrome by proxy), potential underlying family psychopathology should be assessed and managed with appropriate professional evaluation and counseling.

Although there is a natural tendency to consider unusual or exotic diseases when confronted with prolonged fever in children, common viral or bacterial pathogens that present atypically are much more frequent than exotic or unusual diseases. Therefore, epidemiologic information and history of exposure prior to illness are major components of the initial evaluation. Diagnoses quite common in one area of the United States might not even be considered in other locations. Examples include Lyme disease (Northeast and certain areas of the Midwest), tularemia (Midwest and far West), coccidioidomycosis (Southwest), and tuberculosis (urban).

Age is the next critical factor. Leukemia peaks in early childhood, whereas lymphomas are unusual before age 8 years. HIV infection presenting as fever of unknown origin is more prevalent during the first year of life or after adolescence. Most autoimmune disease is seen in school-age children and adolescents, so screening tests for this category would usually be limited to this older age group.

Patient history should be more detailed than that obtained for acute illnesses, carefully examining family history, previous illnesses, recent symptoms, current medications, travel, and exposure to pets or humans with potential communicable pathogens. Weight loss, failure to thrive, or decreased activity during afebrile periods are more ominous systemic signs that will usually require a more rapid diagnostic evaluation. Prolonged fever and bone pain may be the only manifestations of bone tumors, leukemia, osteomyelitis, syphilis, cat-scratch disease, tuberculosis, or Langerhans cell histiocytosis. In the presence of documented fever and constitutional symptoms, a history of abdominal pain necessitates evaluation for autoimmune diseases, pyelonephritis, Crohn disease, and hepatitis, as well as abdominal abscesses and tumors.

Of all symptoms, the presence of pain is the single finding that is likely to suggest specific laboratory studies. Therefore, pain should be completely characterized by its severity, location, periodicity, precipitating factors, and response to attempted therapy.

Physical examination occasionally provides the first diagnostic clue, especially when directed toward areas where abscesses or solid tumors are less apparent. Thorough abdominal and rectal exams are essential because the abdomen and pelvis represent the largest area for such masses. Bones and joints can be adequately evaluated if the child is cooperative. Transillumination of sinuses is only useful in the older child and adolescent; younger children require selective CT scans to diagnose sinusitis.

Diagnostic evaluation should begin with basic studies done during outpatient observation, as summarized in Table 228-2. The complete blood count accomplishes three goals: (1) it is a screen for leukemia, anemia, and neutropenia; (2) it identifies some acute phase reactant changes by quantitating polymorphonuclear leukocytes, immature granulocytes, and platelets; and (3) it helps eliminate some specific, although unusual, diagnostic considerations, such as eosinophilia (present in some parasitic diseases), Howell-Jolly bodies (congenital or functional asplenia), or pathogens on blood smear (malaria, relapsing fever). Additional screening for leukemia is achieved with a serum lactate dehydrogenase and uric acid. Urinalysis and urine culture should be obtained because urinary tract infection is the second most commonly identified infectious cause of fever of unknown origin. Remember that fever is second only to abdominal pain as a symptom of pyelonephritis. Chest roentgenograms may identify an unexpected pneumonia, but they are also important in screening for tumors, particularly lymphomas, and for tuberculosis. A tuberculosis skin test (TST) using 5 tuberculin units injected intradermally (Mantoux method), rather than a multiple puncture device, should be placed to rule out tuberculosis. In older children, an antinuclear antibody (ANA) determination is beneficial for diagnosing systemic lupus erythematosus, although no single test consistently identifies autoimmune processes. Patients with systemic juvenile rheumatoid arthritis (JRA) are most likely to present with fever alone, but JRA is rarely associated with a positive ANA response.

The greatest clinical concern in evaluating fever of unknown origin (FUO) is identifying patients whose fever has a serious or life-threatening etiology for whom a delay in diagnosis could jeopardize successful intervention. However, the majority of children with prolonged FUO resolve their illnesses without a diagnosis and do not exhibit long-lasting effects. Therefore, it appears appropriate for most children to delay extensive diagnostic evaluation until the child has remained febrile for at least 6 weeks. The initial outpatient evaluation (Table 228-2) generally requires 1 week for completion of laboratory testing and for reporting of final results. After this time, the physician must decide whether continued observation or progressive laboratory investigation is more appropriate. Decisions are based primarily on the clinical status of the child and the results of the initial evaluation. For most patients, observation is the most prudent course of action6,13-15 because the majority of patients will become afebrile by 6 weeks. If a decision is made to pursue testing beyond the initial screen, selection of subsequent studies is guided primarily by knowledge of the more common etiologies. This approach takes into consideration patient age, epidemiologic and geographic information, and any positive findings from a detailed history and physical examination. In addition, testing for some less common etiologies should be included for diseases known to progress in severity if diagnosis and treatment are delayed.13-16 Examples of the latter category include abdominal tumors, Lyme disease, and Crohn disease.

Table 228-3 summarizes a practical approach to a step-wise, yet systematic, evaluation. Earlier studies can be accomplished during continued outpatient evaluation, although hospitalization is required for those more invasive (and costly) procedures suggested during later phases of investigation. The rationale for each test should be apparent. Individual circumstances will certainly modify selection of tests to the extent that any two patients are unlikely to have the same studies ordered. More invasive and expensive testing is not recommended unless there is a clear clinical indication. Such tests might include bone marrow examination, sonograms, CT, indium and gallium scans, or other imaging studies.7,16,17 When done in a routine fashion for all patients with FUO, they rarely offer useful information.7,15,16

Finally, patience on the part of the physician is required. The best test to arrive at a final etiologic diagnosis remains repeated careful clinical assessment with interim histories and physical examinations. Even under these conditions, fever will often resolve before specific causes have been delineated.