Infection

Infections comprise the majority of identifiable causes of FUO in children, accounting for up to 50% of all final diagnoses. In most cases, the underlying diagnosis reflects an unusual presentation of a common illness rather than a typical presentation of an uncommon entity.

Collagen Vascular and Autoimmune Disorders

Fever may be a major presenting symptom in many noninfectious inflammatory conditions. Among these, the acute onset of fever occurs most commonly in systemic juvenile idiopathic arthritis and Kawasaki’s disease (KD) (see Chapters 26 and 28). The incidence of KD varies greatly with geography. In the United States, the average incidence ranges between 3.1 and 8.9 cases per 100,000 children per year. Apart from being the more common noninfectious inflammatory causes of fever among children, these disorders are important because they require early recognition and treatment to prevent long-term complications.

Systemic lupus erythematosus (SLE) accounts for a subset of patients with FUO, although this entity does not usually present with isolated fever but rather with multiorgan involvement. Apart from KD, other vasculitides may present with fever in addition to other organ involvement. Juvenile Behçet’s disease in children older than age 1 year may include fever as a symptom, and polyarteritis nodosa should be considered in older children with fever and muscle and skin involvement. Remaining identified vasculitides are either very rare in children or are unlikely to present with isolated fever, such as Henoch-Schönlein purpura (see Chapter 28).

Recurrent intermittent fevers may occur as part of a periodic fever syndrome. The most commonly encountered of these is periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis disease (PFAPA). The syndrome is rarely associated with fevers that last longer than 1 week. The hereditary fever disorders are far less common but are potential etiologies of recurrent fevers in children. One hereditary fever syndrome that may present with prolonged fever is tumor necrosis factor receptor–associated periodic syndrome (TRAPS). In young children and especially infants with persistent or recurrent fevers, an underlying immunodeficiency should be considered (see Chapter 21).

Inflammatory bowel disease (IBD), particularly Crohn’s disease, has become an important diagnostic consideration in children with FUO. Because this entity may be difficult to diagnose at an early age, patients may present with a history of prolonged isolated fever and growth failure with or without intestinal manifestations (see Chapter 110).

Malignancy

Malignancy remains an important diagnostic consideration for children with FUO, and early identification of oncologic processes allows for earlier initiation of directed therapy. In most cases, children with neoplastic processes present with other systemic symptoms or local findings, but it is possible that isolated fever is the only presenting sign. The oncologic processes most likely to present with fever depend on the age of the patient. The most common malignancies to present with isolated fever include leukemia, lymphoma, neuroblastoma, neoplasms of the bone, and Wilms’ tumor. Additionally, central nervous system (CNS) malignancies and metastases to the CNS may present with FUO if the thermoregulatory system of the hypothalamus is involved.

Miscellaneous

Other conditions are included in the differential diagnoses for FUO in children. Drug fevers are frequently overlooked as potential causes of FUO in children. Although a history of new medications is often elicited, chronic medications are commonly responsible for drug fevers, especially in drugs that are known to be sensitizing. Sulfa-containing drugs, antiseizure medications, antiarrhythmics, sleep medications, and narcotics are known causes of drug fevers.

Derangements of the thermoregulatory system may lead to prolonged fevers and present as FUO. In addition to malignancy, other noninfectious inflammatory entities that affect the CNS may lead to FUO in children, as can dysautonomia.

Finally, factitious fever is a diagnosis of exclusion and may enter the differential diagnosis only after a thorough investigation has been performed. In children, Munchausen by proxy syndrome is also a cause of factitious fevers. Hospitalization of the patient for close observation and measurement of body temperature can be instructive in the case that a concern exists for factitious fevers.

History

A careful fever history is of extreme importance. Although many parents initially report a history of daily fever for 2 weeks or more, it is important to distinguish one prolonged febrile episode from many serial illnesses. The height and pattern of fever should also be recorded.

The child’s overall state of health should be described, including activity level and appetite. A history of any localizing or coexisting symptoms should be elicited because they may help target the investigation (Table 86-2). The patient’s age and any underlying conditions may offer clues to the diagnosis and help to organize the differential diagnosis. A thorough medication history should be recorded, particularly when considering drug fever. A detailed family history should explore for family members with a history of rheumatologic conditions, malignancy, or IBD.

Table 86-2 Localizing Symptoms in Patients with Fever of Unknown Origin

The social history should include any exposure to ill contacts. Risk factors for TB exposure should be determined. A detailed travel history is important because tropical or exotic infections should be considered. Zoonotic exposures, including contact with livestock, cats, rodents, and reptiles, should be investigated. A dietary history should include consumption of unpasteurized dairy products.

Physical Examination

The physical examination has the highest yield when the child is comfortable in the presence of his or her parents. The child’s overall state of health should be noted, including a lethargic or wasted appearance, level of activity, hydration status, and the presence of irritability or inconsolability. Growth percentiles should be charted; stunted growth may point to a more chronic underlying disease process. If a rash is present, it is important to understand the history and evolution of the lesions. Oral lesions may coexist with a rash or occur independently.

The respiratory tract is a common source of infection in children. Vital signs will indicate tachypnea or hypoxia. The overall work of breathing should be noted. An examination of the upper respiratory tract may reveal cough, middle ear effusions, sinus tenderness, rhinorrhea, or stridor. Likewise, auscultation of the lower respiratory tract is important for identification of rales, rhonchi, wheezing, or decreased aeration.

The cardiovascular examination should include auscultation for murmurs and examination of the skin and extremities for signs of endocarditis, such as petechiae, Janeway’s lesions, Osler’s nodes, and splinter hemorrhages. These stigmata are often absent in younger children. The abdominal examination may reveal hepatosplenomegaly, localizing tenderness, or palpable masses. Suprapubic tenderness and costovertebral tenderness should be elicited. A rectal examination with guaiac smear for occult blood should be performed, particularly if a concern exists for IBD. Potential findings on the genitourinary examination include ulcerations or discharge.

An ophthalmologic examination should be performed; this may reveal uveitis, Roth spots, or signs of infection. The presence of adenopathy should be noted, as well as any tenderness or signs of adenitis. The musculoskeletal examination may help localize the source of fever. Any point tenderness, refusal to bear weight, or limited use of an extremity may suggest an underlying osteomyelitis or malignancy. The patient should be witnessed walking or bearing weight, if developmentally appropriate. All joints should be examined for effusions or arthritis. Muscle tenderness or weakness may suggest myositis. Any positive findings from the physical examination should be used to focus the diagnostic evaluation.

Diagnostic Testing

As the sensitivity and availability of laboratory tests and imaging modalities advance, the identifiable underlying causes of FUO in children continue to evolve (Fig. 86-1). Specifically, viral pathogens and fastidious bacteria that were formally difficult to isolate in culture are more easily detected with polymerase chain reaction (PCR) testing. Additionally, improvements in computed tomography (CT) and ultrasonography for imaging the abdominal cavity have virtually eliminated the need for exploratory laparotomy as a final resort in diagnosis in FUO. Finally, newer techniques in positron emission tomography (PET) scanning allow for identification of regions with increased metabolic activity, making it possible to find potential sources of FUO even in the absence of localizing clinical signs. Still, the diagnostic workup should proceed in a stepwise fashion, using the history and physical examination to guide the testing modalities selected for each patient.

Figure 86-1 Diagnostic considerations in fever of unknown origin.