Carl J. Seashore, MD, is Assistant Professor of Pediatrics and Director, Pediatric Diagnostic Referral Service, Division of General Pediatrics and Adolescent Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC. Jacob A. Lohr, MD, is the Jacob A. Lohr, MD, Distinguished Professor of General Pediatrics, and Chief, Division of General Pediatrics and Adolescent Medicine, Division of General Pediatrics and Adolescent Medicine, University of North Carolina at Chapel Hill School of Medicine.
Dr. Seashore and Dr. Lohr have disclosed no relevant financial relationships.
Address correspondence to: Carl Seashore, MD, Division of General Pediatrics and Adolescent Medicine, Campus Box 7225, University of North Carolina, Chapel Hill, NC, 27599; or e-mail: firstname.lastname@example.org.
Fever of unknown origin (FUO) in children remains one of the most challenging clinical evaluations for the pediatric clinician. Evaluation of fever of unknown origin in children benefits from an understanding of the historical definition of this entity and how its definition has changed over time. Early literature from adults branded this diagnosis with associations of illnesses bearing high rates of morbidity and mortality (see Sidebar, page 28).
Serial histories and physical examinations are crucial in establishing a diagnosis.
A carefully performed and unremarkable physical examination is predictive of a benign outcome.
A diagnosis is most often reached using routine laboratory studies.
Early empiric antibiotics can obscure or delay making a specific diagnosis in children with FUO.
Three cardinal case series from the 1970s established the early definition of FUO, specifically in children, as the presence of documented, persistent fever in a child lasting 2 to 3 weeks without a clear etiology based upon history, physical examination, and initial screening laboratory studies.1–3 These case series, including 253 children total, found that roughly 30% to 50% of the patients had identifiable infectious diseases; 10% to 20% had collagen vascular disease; 10% had malignancy; and 10% remained undiagnosed.
Rare diseases made up a small proportion of diagnoses in all three series. Reported long-term morbidity and mortality were much lower than in similar series of adult patients.1–3 An additional common feature from these early case series was exposure to empiric antibiotics, often causing a delay in diagnosis. All children were admitted to the hospital for their definitive evaluation.
Among the infectious causes of FUO noted in these pediatric series, many familiar diagnoses populate the identified causes, but none predominates. Urinary tract infections, pneumonia, infectious enteritis, and bacteremia were all identified by history, physical examination, or simple laboratory studies. Tuberculosis was common and often was found only after a positive skin test prompted more focused evaluation. One case of cat scratch disease was identified, but numerous case reports since the 1970s have highlighted this disease as an important entity when evaluating FUO in children.4–10
Second-most common were categorically autoimmune diseases, such as juvenile inflammatory arthritis (JIA) or inflammatory bowel disease (IBD). Each series also identified a relatively small number of malignancies, most commonly leukemia and lymphoma. All three papers concluded that careful, serial history-taking and physical examinations, along with judicious, focused laboratory tests (see Figure, page 28), were the most useful tools in evaluating children with FUO. Although newer diagnostic modalities have emerged since the 1970s, leading to earlier diagnosis of specific illnesses, these tenets remain the foundation for evaluating children today.
Figure. Serial History-Taking and Physical Examinations, Along with Judicious, Focused Laboratory Tests Were the Most Useful Tools in Evaluating Children with FUO. The Flowchart Gives Recommendations on Which Screening Is Appropriate for Which Patients. Source: Seashore CJ.
In today’s practice, hospital admission is less common for a pediatric patient with a FUO unless a specific indication (eg, a ruptured appendix or malignancy) exists, so more evaluations are conducted in the outpatient setting. Fever without a source (FWS; see article, page 21) is a distinct entity with special considerations in the young infant and toddler populations and is approached differently from a FUO.
However, children presenting initially with FWS may progress to meet FUO criteria if the cause is not identified early and fever persists. Serial evaluation is critical for these children as well. Children with periodic fever syndromes (see article on Periodic Fevers, page 48) often are referred for a FUO evaluation. It is the characteristic recurring nature of fever in these children along with specific findings in the history and physical examination (see Table 1, page 29) that should prompt evaluation for one of these syndromes.11–13
Table 1. Associations with Periodic Fever Syndromes11–13
Most children presenting with fever have either an identifiable entity at presentation that directs treatment or further evaluation, or, more likely, have a self-limited viral illness that will “run its course,” with attention to symptomatic care and a watchful eye for secondary complications. Children in whom fevers persist beyond 10 days, despite reassuring findings initially, warrant more careful follow-up and are the focus of the rest of this article.
The Modern Office
The modern pediatric office is striving to resemble a primary care medical home and is often well equipped to begin the evaluation of a child with FUO. In many offices, sick children are seen by the first available provider rather than an identified primary care provider (PCP). Children with FUO ideally should be evaluated serially by the same provider, but modern record systems should optimize information sharing among partners and with outside providers when they are consulted.
Subtle changes in the history or physical examination or different ways of phrasing the same basic questions often help elucidate subtleties that might otherwise be overlooked. Consulting a colleague to lend a fresh pair of eyes can be beneficial and is preferable to the child simply seeing a different provider on serial visits when FUO is the chief complaint. Method of temperature assessment at home should be reviewed with the parent and its accuracy verified. It is sometimes helpful to plot the occurrence of fever over time and its diurnal variation.
Offices using mid-level providers should promote a culture of collegiality in which a physician can be readily consulted for assistance in guiding evaluation when needed. Reflex referral of a child with FUO before beginning a thoughtful evaluation may lead to a delay in diagnosis, depending on the availability of specialists in different areas and the range of expertise these colleagues possess.
After a careful history and physical examination (see Table 2, page 29), initial screening laboratory studies should be obtained.
Table 2. Cardinal Elements in the History and Physical Examination of Children with FUO
As in the early case series, a complete blood count (CBC), with manual differential, erythrocyte sedimentation rate (ESR), blood culture, urinalysis, and urine culture, universally should be obtained. Serum chemistries, including liver enzymes, protein and albumin, lactate dehydrogenase (LDH) and uric acid, should be considered. C-reactive protein, a marker of acute inflammation, is helpful to delineate acute versus chronic inflammation when obtained with the ESR. A tuberculin skin test is indicated for most patients. A chest radiograph can be helpful if pneumonia or lymphoma is considered, and more directed studies should be obtained based upon the history and physical examination.
Extensive serologic testing should be reserved for those patients whose history supports the diagnosis: A recent summer vacation in Connecticut makes Lyme disease much more likely, whereas a newly acquired kitten should prompt consideration of Bartonella infection. Imaging of the abdomen for occult infection or malignancy, useful at times in adults with FUO, has not been shown to be of benefit in children with FUO. A series of 109 patients in whom diagnostic imaging was performed concluded that without localizing clinical findings, these tests were generally not useful.14 Admission to the hospital for expedited evaluation should be considered for children with localizing findings, progressive symptoms, clinical deterioration, or concern for maltreatment (eg, Munchausen’s syndrome, by proxy).
What to Suspect
In the young child with fever alone without localizing findings, the clinician should have a high index of suspicion for Still’s disease (systemic-onset JIA). The classic evanescent rash would further support this diagnosis but is not always observed when the child is being seen in the office.
In adolescents, IBD is more likely to be found and can often present in an indolent fashion. Anemia, decreased height velocity, or delayed sexual maturation and elevated inflammatory markers should draw attention to and necessitate a more focused evaluation of the intestines.
Review of complete growth charts should be part of the physical examination. The growth charts should always be included when patients are referred for specialty evaluation or a second opinion, along with relevant office notes, laboratory results, and other clinical information.
In certain circumstances, evaluation of fever and FUO warrants a more careful eye. Children with chronic diseases, such as cystic fibrosis and sickle cell anemia, are prone to specific infections and other complications of their diseases and treatments. Children receiving medications must be considered for drug fever, and adjustment of these medicines should be made in consultation with the person who is prescribing them.
Certain children, such as those with tracheotomy tubes, gastric tubes, or cochlear implants, for example, have additional diagnostic considerations, such as infections of their sites or portals of entry for systemic infection. Children receiving or who have received chemotherapy abide by different rules. For the most part, these patients are under the care of a subspecialist, but such chronic conditions are far more common today than they were 40 years ago and should not be overlooked when the child presents to the PCP.
Since the three cardinal articles on FUO were published in the 1970s, there have been only a small number of case series on which to base a more modern approach, and the lessons from history suggest a new approach may not be needed. Most modern references cite at least 10 days of fever without a clear diagnosis as the definition of FUO in children.10,15–17 Talano and Katz reported on 19 children with FUO followed after more than 1 year had passed and only included those in whom a diagnosis was not made at initial presentation.18 Only two of these children went on to have chronic illness (JIA in both), while the remaining children were well.
Miller et al. described long-term follow-up of 40 children with FUO 5 years after an initial diagnosis was not reached.19 In their series, this undiagnosed group had a high incidence of periodic fever (29 of 40), predominantly among younger patients, and 23 of these children’s symptoms had resolved at follow up. Of the 11 with initial daily fevers, one patient had inflammatory bowel disease, and another had uveitis, while the remainder had recovered. They also noted that 29% of the children having initial periodic fevers were noted to have neurologic problems of varying significance at 5-year follow up. Cogulu et al.20 reported on 80 children in Turkey identified between 1996 and 2001.
They found that 47 of 80 had identifiable infections while a smaller number were diagnosed with collagen vascular disease (5 of 80) or malignancy (2 of 80). These results suggest that these diagnoses currently might be made more quickly than in previous decades because they have become better understood. Importantly, this group also noted lack of a diagnosis in 10 of 80 patients despite the availability of more modern diagnostic tools. Periodic fevers and specific immune deficiencies were described in several patients, highlighting the success of newer diagnostic tools and a better understanding of certain disease entities.
More recent case series from Tunisia, 21 Kuwait,22 and another from Turkey23 all found similar incidences of infectious diseases, collagen vascular disease, and malignancy.21–23 The Kuwait study had a higher overall rate of infectious diseases, possibly reflecting significant geographic variation in disease patterns.
A caveat must be stated if the definition of FUO is altered to include patients with only 10 days of fever. A concern is that this shortened period may allow for inclusion of more potentially life-threatening or debilitating acute or subacute infectious or inflammatory disorders (aggressive sinusitis complicated by intracranial spread; prolonged Rocky Mountain spotted fever or Ehrlichia infection; Kawasaki disease; EBV-associated hemophagocytic syndrome; systemic lupus erythematosis complicated by sepsis; and others) that call for a prompt diagnostic approach. On the other hand, these disorders are likely to be accompanied by an abnormal physical examination and/or suspicious initial laboratory studies, which should compel the diagnostician to promptly pursue additional studies that could lead to an accurate diagnosis.
FUO in children remains a puzzle each time pediatricians are faced with the challenge its evaluation presents. Initially, children can be managed competently by the generalist in the outpatient setting, using time as a diagnostic tool with frequent re-evaluation and simple laboratory testing. Severity of presentation should direct a faster evaluation or earlier referral for admission or outpatient specialty evaluation. A general pediatric referral service, if available, is often a good starting point if a clear diagnosis, such as malignancy, is not evident. Hospital admission is also indicated when the patient is unstable or there is concern for maltreatment or factitious fever.24
In the 40 years since the first three case series describing FUO in children, this entity has remained one of the more challenging diagnostic dilemmas for pediatric clinicians. Although newer diagnostic modalities have likely hastened the diagnosis of malignancy and collagen vascular diseases, and a better understanding of periodic fever syndromes has allowed identification of these patients, the challenge still remains about how to approach the child with an FUO when the child first presents. Once the child is identified as having FUO, serial physical examinations, careful reviews of the history, and a basic workup should be started. Careful attention should be paid to follow-up, referral, and further evaluation.
Consistency in provider, communication within the medical home among providers, and thoughtful further workup and referral are all important in optimizing the likelihood of a prompt and accurate diagnosis.
- Lohr JA, Hendley JO. Prolonged fever of unknown origin: a record of experiences with 54 childhood patients. Clin Pediatr (Phila). 1977;16(9):768–773. doi:10.1177/000992287701600905 [CrossRef]
- Pizzo PA, Lovejoy FH, Smith DH. Prolonged fever in children: review of 100 cases. Pediatrics. 1975;55(4):468–473.
- McClung HJ. Prolonged fever of unknown origin in children. Am J Dis Child. 1972;124(4):544–550.
- Weinspach S, Tenenbaum T, Schonberger S, et al. Cat scratch disease — heterogeneous in clinical presentation: five unusual cases of an infection caused by Bartonella henselae. Klinische Padiatrie. 2010;222(2):73–78. doi:10.1055/s-0029-1233488 [CrossRef]
- Loeckx I, Tuerlinckx D, Jespers S, Marchant AS, Bodart E. A clinical case of spontaneous involution of systemic cat scratch disease. Revue Med Liege. 2010;65(2):78–80.
- Abdel-Haq N, Abuhammour W, Al-Tatari H, Asmar B. Disseminated cat scratch disease with vertebral osteomyelitis and epidural abscess. South Med J. 2005;98(11):1142–1145. doi:10.1097/01.SMJ.0000163305.50078.63 [CrossRef]
- Ridder-Schroter R, Marx A, Beer M, Tappe D, Kreth HW, Girschick HJ. Abscess-forming lymphadenopathy and osteomyelitis in children with Bartonella henselae infection. J Med Microbiol. 2008;57(Pt 4):519–524. doi:10.1099/jmm.0.47438-0 [CrossRef]
- Tsujino K, Tsukahara M, Tsuneoka H, et al. Clinical implication of prolonged fever in children with cat scratch disease. J Infect Chemother. 2004;10(4):227–233. doi:10.1007/s10156-004-0320-8 [CrossRef]
- Hipp SJ, O’Shields A, Fordham LA, Blatt J, Hamrick HJ, Henderson FW. Multifocal bone marrow involvement in cat-scratch disease. Pediatr Infect Dis J. 2005;24(5):472–474. doi:10.1097/01.inf.0000160993.52059.3a [CrossRef]
- Gartner JC. Fever of unknown origin. Adv Pediatr Infect Dis. 1992;7:1–24.
- Gattorno M, Caorsi R, Meini A, et al. Differentiating PFAPA syndrome from monogenic periodic fevers. Pediatrics. 2009;124(4):e721–728. doi:10.1542/peds.2009-0088 [CrossRef]
- Steichen O, van der Hilst J, Simon A, Cuisset L, Grateau G. A clinical criterion to exclude the hyperimmunoglobulin D syndrome (mild mevalonate kinase deficiency) in patients with recurrent fever. J Rheumatol. 2009;36(8):1677–1681. doi:10.3899/jrheum.081313 [CrossRef]
- Padeh S, Livneh A, Pras E, et al. Familial Mediterranean Fever in the first two years of life: a unique phenotype of disease in evolution. J Pediatr. 2010;156(6):985–989. doi:10.1016/j.jpeds.2009.12.010 [CrossRef]
- Steele RW, Jones SM, Lowe BA, Glasier CM. Usefulness of scanning procedures for diagnosis of fever of unknown origin in children. J Pediatr. 1991;119(4):526–530. doi:10.1016/S0022-3476(05)82399-6 [CrossRef]
- McCarthy P. Fever without apparent source on clinical examination. Curr Opin Pediatr. 2005;17(1):93–110. doi:10.1097/00008480-200502000-00019 [CrossRef]
- Steele RW. Fever of unknown origin: a time for patience with your patients. Clin Pediatr (Phila). 2000;39(12):719–720. doi:10.1177/000992280003901206 [CrossRef]
- Tolan RW. Fever of unknown origin: a diagnostic approach to this vexing problem. Clinical Pediatr (Phila). 2010;49(3):207–213. doi:10.1177/0009922809347799 [CrossRef]
- Talano JA, Katz BZ. Long-term follow-up of children with fever of unknown origin. Clin Pediatr (Phila). 2000;39(12):715–717. doi:10.1177/000992280003901205 [CrossRef]
- Miller LC, Sisson BA, Tucker LB, Schaller JG. Prolonged fevers of unknown origin in children: patterns of presentation and outcome. J Pediatr. 1996;129(3):419–423. doi:10.1016/S0022-3476(96)70075-6 [CrossRef]
- Cogulu O, Koturoglu G, Kurugol Z, Ozkinay F, Vardar F, Ozkinay C. Evaluation of 80 children with prolonged fever. Pediatr Int. 2003;45(5):564–569. doi:10.1046/j.1442-200X.2003.01793.x [CrossRef]
- Chouchane S, Chouchane CH, Ben Meriem CH, et al. Prolonged fever in children. Retrospective study of 67 cases. Archives de Pediatrie: Organe Officiel de la Societe Francaise de Pediatrie. 2004;11(11):1319–1325.
- Mouaket AE, el-Ghanim MM, Abd-el-Al YK, al-Quod N. Prolonged unexplained pyrexia: a review of 221 paediatric cases from Kuwait. Infection. 1990;18(4):226–229. doi:10.1007/BF01643393 [CrossRef]
- Ciftci E, Ince E, Dogru U. Pyrexia of unknown origin in children: a review of 102 patients from Turkey. Ann Trop Paediatrics. 2003;23(4):259–263. doi:10.1179/027249303225007833 [CrossRef]
- Kleiman MB. The complaint of persistent fever. Recognition and management of pseudo fever of unknown origin. Pediatr Clin North Am. 1982;29(1):201–208.
Associations with Periodic Fever Syndromes11–13
|Familial Mediterranean Fever||Pediatric Fevers, Aphthous Stomatitis, Pharyngitis and Adenitis (PFAPA)||Hyper IgD Syndrome|
|Mediterranean or Middle Eastern descent; painful episodes with fever (abdominal pain, arthritis, myalgia, general malaise); fever alone if younger than 2 years old||Age typically younger than 5 years; aphthous stomatitis; pharyngitis; cervical adenitis; abdominal pain, diarrhea; rash, arthralgia||Age typically younger than 1 year; abdominal pain, vomiting, diarrhea; lymphadenopathy +/− splenomegaly; arthralgias; rash|
Cardinal Elements in the History and Physical Examination of Children with FUO
|Symptoms at onset of fever; relevant travel history; pet or other animal exposures; immunization history; current or recent medications; allergies (drug or others); pattern of fever since onset; pattern of additional symptoms; accuracy of fever assessment; past medical, social, family history||Growth parameters (including trends): HEENT: oral ulcers, thyroid contour, conjunctiva, ears, lymph nodes, scalp; CVR: murmur, tachycardia, tachypnea, rales, dullness, work of breathing; ABD: focal tenderness, guarding; EXT/SKIN: joint tenderness, chronic changes, effusions, rashes, bites, nails; GU: stool guaiac, urethral discharge, ulcers|