Fever of Unknown Origin

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86 Fever of Unknown Origin

Elizabeth E. Foglia

Fever is one of the most common signs that prompt parents to seek medical attention for their children, accounting for up to 15% of office visits to pediatricians. Although most pediatric febrile illnesses have an easily identifiable source, a small percentage of children have prolonged fevers with no clear etiology. In children, fever of unknown origin (FUO) has classically been defined as a 2-week history of daily fevers >38.3°C with no identifiable etiology after a thorough physical examination and an initial screening diagnostic evaluation have been performed.

Differential Diagnosis

The differential diagnosis for FUO can be broadly divided into the following categories: infection, collagen vascular or autoimmune, and malignancy. A number of case series have followed children who were evaluated for FUO to determine the underlying etiology of fever in these patients (Table 86-1). Many of these reports are decades old and may not comprise the underlying infectious etiologies of FUO because of the advancement of clinical microbiologic laboratory and diagnostic imaging modalities, as well as the emergence of novel pathogens. Nonetheless, these studies are informative in that the most commonly identified etiologies for FUO have remained stable through time.

Table 86-1 Underlying Diagnosis in Fever of Unknown Origin in 545 Patients from Compiled Case Reports

Diagnosis	Total (n)	Established Diagnoses (%)
*Infectious*	*262*	62
Epstein-Barr virus	26	6
Viral syndrome	22	5
Urinary tract infection	22	5
Pneumonia	19	4
Osteomyelitis	18	4
Viral meningitis or encephalitis	17	4
Bacterial meningitis	14	3
Pharyngitis or tonsillitis	14	3
Viral upper respiratory infection	12	3
Streptococcosis	9	2
Otitis media	8	2
Bartonellosis	8	2
Bacterial enteritis	7	2
Viral gastroenteritis	7	2
Sinusitis	6	1
Subacute bacterial endocarditis	5	1
Tuberculosis	5	1
Rickettsial infection	5	1
Cytomegalovirus	5	1
Tularemia	4	1
Other Infections	29	7
*Collagen Vascular or Autoimmune*	65	15
Juvenile idiopathic arthritis	28	7
Inflammatory bowel disease	11	3
Rheumatic fever	7	2
Other collagen vascular	19	4
*Malignancy*	27	6
Leukemia	14	3
Lymphoma	4	1
Other malignancy	9	2
*Other*	65	17
Drug reaction	8	2
Factitious fever	6	1
Miscellaneous	51	14
*Total established diagnoses*	*426*	78
*Diagnosis unknown*	*119*	22

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.

Bacterial Infections

Identification of bacterial sources of FUO is important because early diagnosis can lead to prompt initiation of antimicrobial therapy and fewer long-term consequences. The most common bacterial infections causing FUO in children are upper and lower respiratory tract infections (including otitis media, sinusitis, and pneumonia), urinary tract infections (UTIs), and osteomyelitis. Although the history and physical examination often point to these diagnoses, many of these infections may present with isolated fever. In particular, UTI should be considered in all patients with FUO because physical examination findings are not reliable in patients with UTIs, and in younger, nonverbal children, the history may not suggest UTI.

Soft tissue infections of the head and neck (including tonsillopharyngitis, peritonsillar abscess, and cervical adenitis) can also lead to prolonged fevers, although localizing symptoms usually prompt earlier diagnosis of these entities. Endocarditis is an important cause of FUO in patients with congenital or acquired heart disease; this entity can also occur in patients without an underlying structural heart anomaly, particularly in the case of infections with Staphylococcus aureus. Although isolated prolonged fever rarely occurs in bacterial meningitis, it should be considered in the differential diagnosis of all febrile patients. The incidence of occult bacteremia has decreased in recent years after the introduction of Streptococcus pneumoniae and Haemophilus influenza type B vaccines. Still, it should be considered in the case of isolated fevers, particularly in young children who are not fully immunized or who have not received vaccinations.

Bartonellosis, or cat scratch disease, is an increasingly identified etiology of FUO in children and should especially be considered in patients with marked regional adenopathy or a history of exposure to cats or kittens. Enteric infections, such as salmonellosis and yersiniosis, have also been identified as sources of FUO; a history of gastrointestinal (GI) complaints is suggestive in these cases. Returned travelers or recent immigrants may present with typhoid (Salmonella typhi or Salmonella paratyphi) or typhoidal rickettsial infections. Both pulmonary and extrapulmonary tuberculosis (TB) must be included in the differential diagnosis in every patient with FUO because isolated prolonged fever is often the only presenting sign. Zoonotic infections are less common, but still identifiable, causes of FUO. Among these are tularemia, brucellosis, and Q fever, and they should be considered with the appropriate exposures. Ehrlichiosis, anaplasmosis, and Rocky Mountain spotted fever are tickborne infections and may present with prolonged fever; the incidence of these infections varies greatly with geography and season.

Viral Infections

Viral infections are frequent causes of FUO in children. Although these infections are generally self-limited, their identification can help avoid further testing and imaging in patients in whom a diagnosis has not been established. Epstein-Barr virus (EBV) remains one of the most common causes of FUO in children. Other systemic viral infections responsible for FUO include systemic cytomegalovirus (CMV), enterovirus, and adenovirus. Viruses in the herpes family, particularly human herpesvirus-six (HHV-6), are commonly found in children and may present with prolonged isolated fever. Newer molecular techniques for identification of parvovirus have demonstrated its prevalence in children with fever. Finally, HIV is a possible source of FUO, both acutely and chronically, in association with opportunistic infections (see Chapter 95).

Other Infections

In patients with an appropriate travel history, malaria is a potential source of FUO in children. Similarly, fungal infections, such as blastomycosis and histomycosis, may present with prolonged fever in children who live in or have traveled to endemic regions.

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

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