Fever without a discernible cause is always difficult for clinicians because fever suggests disease. The inability to identify the cause of the fever can undermine the physician's credibility and can affect rapport with patients. The longer the fever persists, the more concern is raised by the parents. A fever of only a few days' duration that is not associated with any localizing signs or symptoms frequently does not even come to a physician's attention unless the child also appears ill. Fever that continues beyond 5 to 7 days, or one that occurs repeatedly, usually alarms parents enough to prompt a medical consultation. This discussion focuses on these prolonged fevers and their evaluation.

In 1961 the classic definition for a fever of unknown origin (FUO) was proposed: fever that is higher than 38.3°C (101°F) on several occasions, that is present for more than 3 weeks, and that has a cause that is still unexplained after 1 week of evaluation in the hospital.[1] More recently, researchers have suggested that the criteria are inappropriate for immunocompromised patients and that the third criterion—evaluation—be changed either to reflect the increased emphasis on ambulatory assessment (unexplained fever after 3 days of in-hospital evaluation or 3 ambulatory visits) or to make the evaluation more qualitative by requiring specific tests that should have been performed before applying the label of an FUO.[2] [3] The latter definition is closer to one accepted by most primary care physicians, who usually prefer not to delay evaluation for 3 weeks or require a week of hospitalization. An FUO in children has been defined as a daily rectal temperature greater than 38.3°C (101°F), lasting for at least 2 weeks, the cause of which has not been determined by simple diagnostic tests, including a complete history and thorough physical examination.[4] Some experts would add that 1 of the 2 weeks of fever should be documented in the hospital.

Careful documentation of fever is necessary before diagnosing FUO. A thorough explanation of the range of normal core body temperature for age, with its diurnal variation, may help to exclude patients who are not truly febrile but who instead have a high normal body temperature. The physician should instruct the parents in the technique of taking a rectal temperature and define a day of fever as a 24-hour period in which a temperature greater than 38.3°C (101°F) occurs at least once. All medications taken, the various activities in which the child has participated, and the environmental temperature during this time should be recorded because each of these may affect body temperature.

Although much importance has been attached to fever patterns in the past (ie, remittent, intermittent, sustained), detailing them may not be useful because they are rarely diagnostic of a specific disease.[5] Nevertheless, some inflammatory diseases do have recognizable fever patterns (eg, double quotidian fever of systemic idiopathic juvenile arthritis). In addition, whether even 1 or 2 days of normal temperature are interspersed between days of fever needs to be carefully determined. These children may have a series of rapidly sequenced brief febrile illnesses, which are masquerading as a single febrile illness. Careful documentation of fever should also help exclude the so-called pseudo-FUO.[6] Children who have a pseudo-FUO not only do not have a true fever if their body temperature is measured accurately and consistently (sometimes this needs to be done under hospital supervision), but also exhibit a specific constellation of findings that is recognizable and often diagnostic (BOX 182-1). In addition to the inability to corroborate fever, and in the setting of a completely normal physical examination, the parents may relate a previous serious illness and their concerns about its possible recurrence or lasting effect on the child (vulnerable child syndrome). Their child may have missed an excessive amount of school, given the general degree of illness described; school absence is often prompted by the presence of fatigue, abdominal pain, and headache in the morning—symptoms that are conspicuously absent during the rest of the day. Others have noted a similar pattern of findings and called it deconditioning syndrome, which occurs after an acute, easily definable febrile illness and usually occurs in children who are older than 12 years and who have frequently been previously ill.[7]

In addition to the single episode of prolonged fever, some children have shorter than normal episodes of fevers that recur in a regular (periodic) fashion, along with a predictable constellation of symptoms. Patients with these types of fevers are said to have periodic fever syndromes. [7] Many of these periodic fevers are now known to be genetically based and can be diagnosed by sophisticated genetic testing.

• Absence of documented, persistent fever
• Lack of objective, abnormal physical findings
• History of significant or near-fatal illness
• Parental fear of malignant or crippling disease
• Frequent environmental exposure to illness
• Absence of persistent weight loss
• Normal erythrocyte sedimentation rate and platelet count
• Many missed school days because of subjective morning complaints
• Discordance of fever and pulse rate
• Medical or paramedical family background
• One or more of mild self-limited diseases, behavioral problems, parents who have misconceptions concerning health and disease, or families under stress

¹From Kleiman MB. The complaint of persistent fever. Pediatr Clin North Am. 1982;29(1):201-208. Copyright © 1982, Elsevier, with permission.

BOX 182-2 lists the common causes of FUO in children. The causes are subdivided into 4 categories: (1) infectious diseases, (2) autoimmune diseases, (3) malignancies, and (4) miscellaneous. This list shows that most FUOs are eventually found to be caused by common pediatric illnesses that are either self-limited or treatable.

An infectious illness is the most common cause for an FUO in children, comprising between 40% and 60% of the reported cases[4] [8] [9] [10]; the second most common cause is autoimmune disease, comprising between 7% and 20% of the cases. Children younger than 6 years are most likely to have FUO resulting from an infection; autoimmune diseases start to become more common after 6 years, although infection remains the most frequent cause of FUO (Table 182-1).[9]

Although most infections that exhibit themselves as an FUO are an atypical or incomplete manifestation of a common infectious disease, several other types of infections should be considered. Epstein-Barr virus is the most common infectious cause of FUO,[8] [11] followed by osteomyelitis and bartonellosis. The advent of serologic testing (indirect immunofluorescent antibodies) for Epstein-Barr virus and Bartonella infections has made these diagnoses easier to make. Although bartonellosis (caused by Bartonella henselae) usually exhibits as classic cat-scratch disease, it may also show as atypical cat-scratch disease, producing prolonged fever and hepatosplenic abscesses,[12] lymphadenopathy, or central nervous system disease.[13] Thus, when exposure to kittens and cats can be documented, serologic testing for Bartonella should be obtained; if positive, then an abdominal ultrasound should be considered.

Osteomyelitis, particularly of the axial skeleton (intervertebral disk space and vertebral body) and the pelvis, should also be strongly considered.

The appearance during the 1980s and subsequent increased incidence of HIV infection and AIDS should encourage primary care physicians to assess children thoroughly for the presence of the characteristic physical signs and symptoms, as well as known risk factors, including parental intravenous drug abuse, parental sexual contact with individuals who may be HIV positive, an HIV-positive mother, and hemophilia requiring transfusion of blood products. Fever is not usually the sole manifestation of HIV infection. However, HIV infection should be strongly considered and the appropriate laboratory tests performed if the fever has been present for more than 2 months and is associated with one or more of the following:

• Failure to thrive or a weight loss of more than 10% from baseline
• Hepatomegaly
• Splenomegaly
• Generalized lymphadenopathy (lymph nodes measuring at least 0.5 cm in 2 or more sites, with bilateral site involvement counting as one site)
• Parotitis
• Persistent or recurrent diarrhea[14]

Of the autoimmune diseases, systemic idiopathic juvenile arthritis (formerly known as systemic juvenile rheumatoid arthritis) is the most common. Fever is almost always associated with this illness, and it frequently precedes the joint manifestations by weeks or months. The typical double quotidian fever (2 fever spikes in 24 hours with a normal temperature in between) is a helpful clue to this diagnosis. Other common autoimmune diseases that should be considered are lupus erythematosus and chronic regional enteritis. The latter condition is more common among children older than 6 years than those in other age groups.

Malignancy, the diagnosis that provokes the most anxiety, is present in only a small percentage of patients in most studies (1.5% to 6%).[4] [8] [9] [11] This circumstance is in contrast to adults with FUO, of whom between 7% and 16% have a neoplastic process.[3] [15] The most common malignancy in children is leukemia, although solid tumors such as lymphoma, neuroblastoma, hypernephroma, and hepatoma have been reported to present as FUO. The exact reason for fever in these diseases is unclear but may be related to endogenous pyrogen and other cytokines produced by the neoplastic cells. A large spectrum of miscellaneous diseases may cause prolonged fevers (see BOX 182-2). However, a clear diagnosis is never obtained in 25% to 67% of patients who have persistent fever.[8] [11] [16] These fevers are the genuine FUOs. Most of these patients appear to do well, and the fever eventually disappears after months or even years.[17]

Some patients have fevers that do not satisfy the classic definition of FUO. Instead, they have recurrent fevers that are associated with a well-defined constellation of symptoms each time. The most common of these periodic fever syndromes is PFAPA (periodic fever, aphthous stomatitis, pharyngitis, and cervical adenopathy).[7] This nonhereditary autoinflammatory syndrome has its onset before the age of 3 years, is associated with a sudden fever to 39°C to 40°C (102°F to 104°F) lasting 3 to 5 days. Also present are anorexia, mild oral ulcerations with pharyngitis, cervical lymphadenopathy, an increased white blood cell count, and an increased erythrocyte sedimentation rate (ESR). This constellation of symptoms returns every 3 to 6 weeks. A single dose of corticosteroids may quickly resolve the symptoms of individual episodes.[18]

Other periodic fever syndromes include cyclic neutropenia, familial Mediterranean fever, hyperimmunoglobulinemia D and periodic fever syndrome (HIDS, or mevalonate kinase deficiency) and tumor necrosis factor receptor–associated periodic syndrome (TRAPS). These syndromes are found in various populations around the world and are associated with known gene mutations.[7] [19] The primary care physician should therefore know the patients' race, ethnicity, and country of origin because these factors may provide clues to a specific periodic fever syndrome.

Bacterial Infectious Diseases

• Bacterial endocarditis
• Bartonellosis
• Brucellosis
• Chlamydia
  • Lymphogranuloma venereum
  • Psittacosis
• Leptospirosis
• Liver abscess
• Mastoiditis (chronic)
• Osteomyelitis
• Pelvic abscess
• Perinephric abscess
• Pyelonephritis
• Salmonellosis
• Sinusitis
• Subdiaphragmatic abscess
• Tuberculosis
• Tularemia

Viral Infectious Diseases

• Cytomegalovirus
• Epstein-Barr virus (infectious mononucleosis)
• Hepatitis viruses
• Q fever
• Rickettsial diseases
  • Q fever
  • Rocky Mountain spotted fever

Fungal Infectious Diseases

• Blastomycosis (nonpulmonary)
• Histoplasmosis (disseminated)

Parasitic Infectious Diseases

• Malaria
• Sarcoidosis
• Toxoplasmosis
• Visceral larva migrans
• Visceral leishmaniasis

Autoimmune Diseases

• Polyarteritis nodosa
• Systemic idiopathic juvenile arthritis
• Systemic lupus erythematosus

Malignancies

• Hodgkin disease
• Leukemia or lymphoma
• Neuroblastoma

Periodic Fever Syndromes

• Cyclic neutropenia
• Familial Mediterranean fever
• Hyperimmunoglobulinemia D and periodic fever syndrome (HIDS)
• Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenopathy (PFAPA)
• Tumor necrosis factor receptor–associated periodic syndrome (TRAPS)
• Other periodic fever syndromes

Miscellaneous Causes

• Central diabetes insipidus
• Drug fever
• Ectodermal dysplasia
• Familial dysautonomia
• Granulomatous colitis
• Infantile cortical hyperostosis
• Münchausen by proxy
• Nephrogenic diabetes insipidus
• Pancreatitis
• Pseudo-fever
• Sarcoidosis
• Serum sickness
• Thyrotoxicosis
• Ulcerative colitis

²Modified from Feigin RD, Cherry JD. Textbook of Pediatric Infectious Diseases. 5th ed. Philadelphia, PA: WB Saunders; 2004. Copyright © 2004, Elsevier, with permission.

Diagnosis	Age
	<6 Years	>6 Years	Total
Infection
Viral	14 (27%)	7 (15%)	21
Nonviral	20 (38%)	11 (23%)	31
Other
Collagen	4 (8%)	16 (33%)	20
Malignancy	4 (8%)	2 (4%)	6
Miscellaneous	7 (13%)	3 (6%)	10
No diagnosis	3 (6%)	9 (19%)	12
Total	52	49	100

From Pizzo PA, Lovejoy FH, Smith DH. Prolonged fever in children: review of 100 cases. Pediatrics. 1975;55(4):468-473.

Whether the child has a true FUO or a pseudo-FUO cannot be determined without a precise history and thorough physical examination, with the physician paying close attention to behavioral, social, familial, and environmental factors. Information regarding travel, patient residence if outside the United States, animal exposure, frequency of exposure to other persons who have common febrile illnesses, previous illness, hospitalizations, medications, family history of disease, race and ethnicity, and the precise course of the exhibiting symptoms must be obtained methodically and efficiently. Meticulous documentation of dates is especially important. To this end, having the family record on a calendar, both the daily time and height of the fever along with associated symptoms, is usually helpful.

For children older than 11 to 12 years, a separate interview should be conducted alone with the child to obtain the child's perspective on the illness and to elicit information that may be difficult to express in the presence of parents. School, peer relationships, family functioning, and sexual identity and activity should be explored.

A full physical examination must be performed. Rectal temperature, respiratory rate, heart rate, and blood pressure measurements should be obtained. Any discrepancy between heart rate and temperature implies factitious fever. A thorough examination of the respiratory tract is indicated. Inspection of the pharynx for hyperemia and exudate, of the tympanic membranes for chronic otitis media, transillumination of the sinuses for sinusitis, a search for a purulent nasal discharge, and auscultation of the chest for localized wheezing are all important. In the older child, an examination of the teeth to exclude dental caries and periodontal disease should be included. A new cardiac murmur may be a clue to rheumatic fever or infective endocarditis. Lymphadenopathy, especially if generalized, may suggest a viral infection, such as infectious mononucleosis, cytomegalovirus infection, toxoplasmosis, or HIV infection. Joints must be examined meticulously for swelling, restricted range of motion, and tenderness. Skin rashes may suggest a viral disease or an autoimmune disease such as juvenile idiopathic arthritis. The absence of sweating and the presence of a smooth tongue are consistent with familial dysautonomia, a rare genetic disorder of thermoregulation. Finally, a rectal examination in the older child and a stool guaiac test are imperative; finding pararectal lymphadenopathy may suggest a pelvic infection, and a positive stool guaiac test may be consistent with inflammatory bowel disease.

If the history and physical examination disclose no specific findings and growth is normal, then only simple diagnostic tests are indicated. Routine blood counts and urinalysis have not been shown to be particularly useful, although no one advocates their elimination from the work-up. A purified protein derivative tuberculin skin test should be given to detect tuberculosis, although anergy may occur in active tuberculosis infection. Negative blood, urine, and throat cultures exclude infections of these areas.

Probably the most useful laboratory tests are the ESR, C-reactive protein (CRP), and the albumin-globulin ratio. If the ESR is more than 30, the CRP is elevated, or the albumin-globulin ratio is inverted, then a higher probability of serious disease exists, particularly an autoimmune vascular disease or a malignancy. Further evaluation should be vigorously pursued.

The remainder of the evaluation should be individualized based on historical and clinical findings. Because infectious causes are the most common, pursuing specific serological tests for such diseases as hepatitis A and B, Epstein-Barr virus infection (infectious mononucleosis), bartonellosis, toxoplasmosis, and cytomegalovirus infection would be reasonable. A radioactive gallium scan may be useful in detecting occult abscesses and infections, although this scan has been found to be less useful in children than in adults.[20] Total body computed tomographic scans may help find tumors, although if the abdomen is of primary concern, then an abdominal ultrasound will also detect significant abnormalities.[16] Radiologic studies of the sinuses, the gastrointestinal tract, and the chest all may be appropriate in certain individuals but should not be routine. A bone marrow examination may occasionally help in the diagnosis of tuberculosis, leukemia, metastatic cancer, or fungal infections but should be considered only in children who either have a clinical or laboratory finding suggestive of malignancy or who are immunocompromised.[21] Finally, if the child is not visibly deteriorating, a period of observation may be necessary until new findings appear that can give more direction to the investigation.

If the ESR, CRP, and the albumin-globulin ratio are normal and no signs and symptoms are present that are specific to a particular disease, little can be gained from any of the tests previously mentioned. Observation and periodic evaluation are the only measures that are required while remaining alert for the occurrence of new symptoms or signs that might lead the investigation in a specific direction. Fortunately, most FUOs for which a cause cannot be found will resolve over time.

Since it is likely that the parents and patient will be anxious about an undiagnosable problem, the primary care physician must be ready to provide all family members with a clear explanation of the evaluative process, any normal results, and reassurance. Referrals to pediatric infectious disease specialists, rheumatologists, specialized diagnosticians, or any combination of these professionals may occasionally be necessary for additional assistance in determining a diagnosis.

The evaluation of the child who has FUO must be individualized to accommodate the history, the physical examination, and the particular social environment in which the child and family live. An intensive examination of all these factors is the physician's responsibility and is the first stage of managing the patient. Whether hospitalization is part of this approach ultimately depends on the amount of parental anxiety, the necessity to document fever, and the performance of diagnostic tests that cannot be done on an outpatient basis.

The health care professional must continue to assess these children frequently to detect new findings early and to maintain the confidence of the family while the fever continues. However, children with FUO generally do well, even though the fever may last for weeks or months.

• Fever and Your Child (brochure), American Academy of Pediatrics (patiented.aap.org).

• Red Book: 2006 Report of the Committee on Infectious Diseases, 27th edition (book), American Academy of Pediatrics (www.aap.org/bookstore).

• Long SS. Fever of unknown origin. In: Long SS, Pickering LK, Prober CG, eds. Principles and Practice of Pediatric Infectious Diseases. 2nd ed. New York, NY: Churchill Livingstone; 2003.

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