86 Fever of Unknown Origin
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
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).
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).
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