Fever of Unknown Origin
Martin I. Lorin
Ralph D. Feigin
The definition of fever of unknown origin (FUO) in children has evolved during the past few decades; a prolonged period of documentation of fever and in-hospital workup no longer are required for use of this term. These rigid criteria arose from studies of adults performed at a time when our understanding of this entity was relatively primitive and modern diagnostic techniques were unavailable. The length of time a child must be febrile before being labeled as having an FUO varies among different authors and investigators. Here, we use the term FUO to describe the condition of a child who is febrile for 8 or more days and in whom a careful history, physical examination, and preliminary laboratory evaluation (inpatient or outpatient) fail to reveal a probable cause for the fever. Youngsters who have been febrile without explanation for fewer than 8 days should be considered as having fever without source (FWS), which carries a different set of diagnostic probabilities and requires a different diagnostic approach (see Chapter 132). The causes of fever of unknown origin in children are shown in Table 133.1.
GENERAL PRINCIPLES
Most children with FUO do not have rare or exotic diseases, which has been shown to be true even in series from major pediatric referral centers. For example, in a series of 100 children evaluated at the Children’s Hospital Medical Center in Boston, only three patients had diseases that would be considered rare (undefined vasculitis, Behçet syndrome, and ichthyosis).
Although the relative frequencies are somewhat different, the three causes of FUO most commonly identified in children are the same as those in adults: infectious diseases, rheumatologic disorders, and malignancies. The prognosis in children is somewhat better than that in adults, but FUO often represents a serious condition even in children. The mortality rate was 9% in the series of Pizzo and colleagues and 17% in that of Lohr and Hendley. McClung reported that 40% of the children in his study had “serious or lethal diseases.” Infection, the leading cause of FUO at all ages, accounts for an even greater percentage of cases in children (more than 50% in some reports) than in adults. Rheumatologic diseases occur with approximately the same frequency in pediatric and adult series, whereas neoplasms are a less common cause of FUO in children than in adults.
The percentages of specific causes in different reports vary with factors such as criteria for inclusion in the study, availability of diagnostic expertise, and classification of patients with probable but uncertain diagnoses. In many cases of FUO in children, a specific diagnosis never is established and the condition eventually resolves spontaneously.
INITIAL APPROACH TO CLINICAL EVALUATION
The clinical approach to the child with FUO should be individualized for each patient. For most patients, diagnostic evaluation may be initiated in the office or the clinic. However, young infants, children who appear toxic or chronically ill, and children who have been febrile for a prolonged period of time with associated findings such as weight loss should be hospitalized for evaluation. Hospitalization is useful not only for expediting laboratory tests, but also for providing an opportunity to document fever, explore the history further, repeat the physical examination, and maintain constant observation.
The child’s age affects both the probability of various disorders and the urgency with which the workup is undertaken. Young infants present a pressing problem; bacteremia and meningitis are more difficult to recognize than in the older child. Neonates and young infants also are susceptible to certain organisms such as group B streptococci and Listeria monocytogenes, which are rare findings in older patients. On the other hand, Neisseria gonorrhoeae as a cause of prolonged fever usually is seen in adolescents. Rheumatologic diseases occur more commonly in older children. Pizzo and colleagues reported an incidence of connective tissue disease approximately four times greater in children older than 6 years of age with
FUO than in those younger than 6 years. The patient’s gender also is relevant. Autoimmune disease occurs more commonly in girls, and certain immunologic deficiencies, such as Bruton agammaglobulinemia, Wiskott-Aldrich syndrome, and Chédiak-Higashi syndrome, are restricted to boys. Pelvic inflammatory disease, of course, occurs only in girls.
FUO than in those younger than 6 years. The patient’s gender also is relevant. Autoimmune disease occurs more commonly in girls, and certain immunologic deficiencies, such as Bruton agammaglobulinemia, Wiskott-Aldrich syndrome, and Chédiak-Higashi syndrome, are restricted to boys. Pelvic inflammatory disease, of course, occurs only in girls.
TABLE 133.1. CAUSES OF FEVER OF UNKNOWN ORIGIN IN CHILDREN | |||||||||
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The patient’s history should be searched carefully for any possible clues, however trivial or remote. A history of transfusion or the use of blood products would raise the possibility of a variety of transmittable viral and parasitic agents, including human immunodeficiency virus (HIV). Animal contact always is important. Dogs can harbor brucellosis or leptospirosis, and cats are vectors for cat-scratch disease and toxoplasmosis. Birds are a source of ornithosis and histoplasmosis. Rodents carry tularemia, leptospirosis, Spirillum minus, and Streptobacillus moniliformis. A history of travel, even in the distant past, is notable. Endemic diseases in Africa, India, and Asia include malaria, amebiasis, and schistosomiasis, which may manifest months to years after the person returns from an endemic area. Leprosy endemics even in parts of the United States and coccidioidomycosis endemics in the southwestern portion of the United States are examples of other diseases that may not become apparent clinically until months or years after initial exposure to the causative organism.
EVALUATION
After a careful and thorough history and physical examination have been completed, evaluation of the child with FUO should proceed along three lines: follow-up of all diagnostic clues, screening tests, and continued observation and reexamination.
Follow-Up of Diagnostic Clues
The most important aspect of the evaluation of a youngster with FUO is meticulous and complete follow-up of all potential clues, however insignificant they may appear to be. The results of the history and physical examination and all available laboratory data must be scrutinized closely for any abnormalities or positive features. Pizzo and colleagues found that in one-half of their cases, failure to use existing laboratory data correctly was a major reason for not establishing the proper diagnosis before the patient was hospitalized. A history of abdominal pain or diarrhea, even weeks before the onset of the fever, may be a clue to an enteric infection or an intraabdominal abscess. The slightest tenderness over the sinuses or mastoid area may be indicative of an underlying chronic infection. Even a mild peripheral eosinophilia may be a clue to a parasitic infection, immunodeficiency, or occult malignancy.
Screening Tests
When no clues exist to guide the workup or when follow-up of such clues fails to yield an answer, the physician must rely on an initial battery of screening tests. Even when clues are present, proceeding with some preliminary screening tests while following up on specific clues is not unreasonable. Basic screening tests include a complete blood count, erythrocyte sedimentation rate and C-reactive protein, chest roentgenography, urinalysis and culture, tuberculin skin test, blood culture, analysis of levels of hepatic enzymes and alkaline phosphatase, and analysis of blood urea nitrogen and creatinine. Further tests would include those for serum antibody titers against brucellosis, tularemia, rickettsial diseases, Epstein-Barr virus, HIV,
and cytomegalovirus. Testing for antinuclear antibody titers may be useful, especially in the older child with prolonged fever. Serum rheumatoid factor results usually are negative in patients with the acute systemic form of juvenile rheumatoid arthritis (JRA). If these tests fail to yield a diagnosis, a gallium scan should be considered to look for a focus of inflammation. Other imaging studies such as bone scan, radiographic skeletal survey, roentgenography of the sinuses and mastoids, and abdominal ultrasound or computed tomographic (CT) examination generally should be performed only if specific clues or indications are present or if fever persists for an inordinate period of time. Bone marrow aspiration generally is most useful in diagnosing or ruling out hematologic disorders such as leukemia and hemophagocytic syndrome, but it may yield an unexpected organism on culture or may permit visualization of a viral or rickettsial agent by electron microscopy. Lumbar puncture usually is necessary only in young infants or in the child with meningeal or neurologic signs or symptoms, including mental status changes.
and cytomegalovirus. Testing for antinuclear antibody titers may be useful, especially in the older child with prolonged fever. Serum rheumatoid factor results usually are negative in patients with the acute systemic form of juvenile rheumatoid arthritis (JRA). If these tests fail to yield a diagnosis, a gallium scan should be considered to look for a focus of inflammation. Other imaging studies such as bone scan, radiographic skeletal survey, roentgenography of the sinuses and mastoids, and abdominal ultrasound or computed tomographic (CT) examination generally should be performed only if specific clues or indications are present or if fever persists for an inordinate period of time. Bone marrow aspiration generally is most useful in diagnosing or ruling out hematologic disorders such as leukemia and hemophagocytic syndrome, but it may yield an unexpected organism on culture or may permit visualization of a viral or rickettsial agent by electron microscopy. Lumbar puncture usually is necessary only in young infants or in the child with meningeal or neurologic signs or symptoms, including mental status changes.
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