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WN ORIGIN
The term fever of unknown origin (FUO) is best reserved for children with a fever documented by a
health care provider and for which the cause could not be identified after 3 wk of evaluation as an
outpatient or after 1 wk of evaluation in hospital. Patients with fever not meeting these criteria, and
specifically those admitted to the hospital with neither an apparent site of infection nor a noninfectious
diagnosis, may be considered to have fever without localizing signs. In most of these children, the
development of additional clinical manifestations over a relatively short period confirms the infectious
nature of the illness.
Etiology.
The principal causes of FUO in children, using these rigorous criteria, are infections and rheumatologic
(connective tissue or autoimmune) diseases ( Box 162–1 ). Neoplastic disorders should also be seriously
considered, although most children with malignancies do not have fever alone. The possibility of drug
fever should be considered if the patient is receiving any drug.
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Box 162-1. Diagnostic Considerations of Fever of Unknown Origin in Children
Abscesses: abdominal, brain, dental, hepatic, pelvic, perinephric, rectal, subphrenic
Diabetes insipidus (non-nephrogenic and nephrogenic)
Infections
Bacteria
Caused by specific organism
Actinomycosis
Bartonella henselae (cat-scratch disease)
Brucellosis
Campylobacter
Francisella tularensis (Tularemia)
Listeria monocytogenes (Listeriosis)
Meningococcemia (chronic)
Mycoplasma pneumoniae
Rat-bite fever (Streptobacillus moniliformis; streptobacillary form of rat-bite fever)
Salmonella
Tuberculosis
Yersiniosis
Localized infections
Abscesses: abdominal, brain, dental, hepatic, pelvic, perinephric, rectal, subphrenic
Cholangitis
Infective endocarditis
Mastoiditis
Osteomyelitis
Pneumonia
Pyelonephritis
Sinusitis
Spirochetes
Borrelia burgdorferi (Lyme disease)
Relapsing fever (Borrelia recurrentis)
Leptospirosis
Rat-bite fever (Spirillum minus; spirillary form of rat-bite fever)
Syphilis
Fungal diseases
Blastomycosis (extrapulmonary)
Coccidioidomycosis (disseminated)
Histoplasmosis (disseminated)
Chlamydia
Lymphogranuloma venereum
Psittacosis
Rickettsia
Ehrlichia canis
Q fever
Rocky Mountain spotted fever
Tick-borne typhus
Viruses
Cytomegalovirus
Hepatitis viruses
HIV
Infectious mononucleosis (Epstein-Barr virus)
Parasitic diseases
Amebiasis
Babesiosis
Giardiasis
Malaria
Toxoplasmosis
Trichinosis
Trypanosomiasis
Visceral larva migrans (Toxocara)
Rheumatologic diseases
Behçet's disease
Juvenile dermatomyositis
Juvenile rheumatoid arthritis
Rheumatic fever
Systemic lupus erythematosus
Hypersensitivity diseases
Drug fever
Hypersensitivity pneumonitis
Pancreatitis
Serum sickness
Weber-Christian disease
Neoplasms
Atrial myxoma
Cholesterol granuloma
Hodgkin's disease
Inflammatory pseudotumor
Leukemia
Lymphoma
Neuroblastoma
Wilms' tumor
Granulomatous diseases
Crohn's disease
Granulomatous hepatitis
Sarcoidosis
Familial-hereditary diseases
Anhidrotic ectodermal dysplasia
Fabry's disease
Familial dysautonomia
Familial Mediterranean fever
Hypertriglyceridemia
Ichthyosis
Sickle cell crisis
Miscellaneous
Chronic active hepatitis
Diabetes insipidus (non-nephrogenic and nephrogenic)
Factitious fever
Hypothalamic-central fever
Infantile cortical hyperostosis
Inflammatory bowel disease
Kawasaki disease
Kikuchi-Fujimoto disease
Pancreatitis
Periodic fever
Poisoning
Pulmonary embolism
Thrombophlebitis
Thyrotoxicosis
Recurrent or relapsing fever
See Box 161–1
Undiagnosed fever
Persistent
Recurrent
Resolved
Drug fever is usually sustained and not associated with other symptoms. Discontinuation of the drug is
associated with resolution of the fever, generally within 72?hr, although certain drugs, such as iodides,
are excreted for a prolonged period with fever that may persist for as long as 1 mo after drug
withdrawal .
Most fevers of unknown or unrecognized origin result from atypical presentations of common diseases.
In some cases, the presentation as an FUO is characteristic of the disease, such as juvenile rheumatoid
arthritis (JRA), but the definitive diagnosis can be established only after prolonged observation because
initially there are no associated or specific findings on physical examination and all laboratory results
are negative or normal.
In the United States, the systemic infectious diseases most commonly implicated in children with FUO
(by the rigorous criteria) are salmonellosis, tuberculosis, rickettsial diseases, syphilis, Lyme disease, catscratch disease, atypical prolonged presentations of common viral diseases, infectious mononucleosis,
cytomegalovirus (CMV) infection, viral hepatitis, coccidioidomycosis, histoplasmosis, malaria, and
toxoplasmosis. Less common infectious causes of FUO include tularemia, brucellosis, leptospirosis, and
rat-bite fever. AIDS alone is not usually responsible for FUO, although febrile illnesses frequently occur
in patients with AIDS as a result of opportunistic infections.
JRA and systemic lupus erythematosus are the connective tissue diseases associated most frequently
with FUO. Inflammatory bowel disease, rheumatic fever, and Kawasaki disease are also commonly
reported as causes of FUO. If factitious fever (inoculation of pyogenic material or manipulation of the
thermometer by the patient or parent) is suspected, the presence and pattern of fever should be
documented in the hospital. Prolonged and continuous observation, which may include electronic
surveillance, of patients is imperative. FUO lasting more than 6 mo is uncommon in children and
suggests granulomatosis or autoimmune disease. Repeat interval evaluation, including history
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,physical examination, and roentgenographic studies, is required .
Diagnosis.
The evaluation of FUO requires a thorough history and physical examination supplemented by a few
screening laboratory tests, and additional laboratory and radiographic tests as indicated by the history or
abnormalities found on examination or initial screening.
HISTORY.
The age of the patient is helpful in evaluating FUO. Children younger than 6 yr of age often have a
respiratory or genitourinary tract infection, localized infection (abscess, osteomyelitis), JRA, or, rarely,
leukemia. Adolescent patients are more likely to have tuberculosis, inflammatory bowel disease,
autoimmune processes, and lymphoma, in addition to the causes of FUO found in younger children.
A history of exposure to wild or domestic animals should be solicited. Zoonotic infections in the United
States are increasing in frequency and are often acquired from pets that are not overtly ill. Immunization
of dogs against specific disorders such as leptospirosis may prevent canine disease but does not always
prevent the animal from carrying and shedding leptospires, which may be transmitted to household
contacts. A history of ingestion of rabbit or squirrel meat may provide a clue to the diagnosis of
oropharyngeal, glandular, or typhoidal tularemia. A history of tick bite or travel to tick- or parasiteinfested areas should be obtained.
Any history of pica should be elicited. Ingestion of dirt is a particularly important clue to infection with
Toxocara (visceral larva migrans) or Toxoplasma gondii (toxoplasmosis.)
A history of unusual dietary habits or travel as early as the birth of the child should be sought. Malaria,
histoplasmosis, and coccidioidomycosis may re-emerge years after visiting or living in an endemic area.
It is important to identify prophylactic immunizations and precautions taken by the individual against
ingestion of contaminated water or food during foreign travel. Rocks, dirt, and artifacts from
geographically distant regions that have been collected and brought into the home as souvenirs may
serve as vectors of disease.
A medication history should be pursued rigorously. This should include over-the-counter preparations
and topical agents, including eye drops, which may be associated with atropine-induced fever.
The genetic background of a patient also is important. Descendants of the Ulster Scots may have FUO
because they are afflicted with nephrogenic diabetes insipidus. Familial dysautonomia (Riley-Day
syndrome), a disorder in which hyperthermia is recurrent, is more frequent among Jews than other
population groups. Ancestry from the Mediterranean should suggest the possibility of familial
Mediterranean fever.
PHYSICAL EXAMINATION.
Sweating in a febrile child should be noted. The continuing absence of sweat in the presence of an
elevated or changing body temperature suggests dehydration due to vomiting, diarrhea, or central or
nephrogenic diabetes insipidus. It also should suggest anhidrotic ectodermal dysplasia, familial
dysautonomia, or exposure to atropine.
A careful ophthalmic examination is important. Red, weeping eyes may be a sign of connective tissue
disease, particularly polyarteritis nodosa. Palpebral conjunctivitis in a febrile patient may be a clue to
measles, coxsackievirus infection, tuberculosis, infectious mononucleosis, lymphogranuloma venereum,
and cat-scratch disease. In contrast, bulbar conjunctivitis in a child with FUO suggests Kawasaki disease
or leptospirosis. Petechial conjunctival hemorrhages suggest infective endocarditis. Uveitis suggests
sarcoidosis, JRA, systemic lupus erythematosus, Kawasaki disease, Behçet's disease, and vasculitis.
Chorioretinitis suggests CMV, toxoplasmosis, and syphilis. Proptosis suggests orbital tumor,
thyrotoxicosis, metastasis (neuroblastoma), orbital infection, Wegener's granulomatosis, or
pseudotumor.
The ophthalmoscope should also be used to examine nailfold capillary abnormalities that are associated
with connective tissue diseases such as juvenile dermatomyositis and systemic scleroderma (see Fig.
149–3 ). Immersion oil or lubricating jelly is placed on the skin adjacent to the nailbed, and the capillary
pattern is observed with the ophthalmoscope set on +40.
FUO is sometimes due to hypothalamic dysfunction. A clue to this disorder is failure of pupillary
constriction due to absence of the sphincter constrictor muscle of the eye. This muscle develops
embryologically when hypothalamic structure and function also are undergoing differentiation.
Fever resulting from familial dysautonomia may be suggested by lack of tears, an absent corneal reflex,
or by a smooth tongue with absence of fungiform papillae. Tenderness to tapping over the sinuses or the
upper teeth suggests sinusitis. Recurrent oral candidiasis may be a clue to various disorders of the
immune system.
Fever blisters are common findings in patients with pneumococcal, streptococcal, malarial, and
rickettsial infection. They also are common in children with meningococcal meningitis (which usually
does not present as FUO) but rarely are seen in children with meningococcemia. Fever blisters also are
rarely seen with Salmonella or staphylococcal infections.
Hyperemia of the pharynx, with or without exudate, suggests infectious mononucleosis, CMV infection,
toxoplasmosis, salmonellosis, tularemia, Kawasaki disease, or leptospirosis.
The muscles and bones should be palpated carefully. Point tenderness over a bone may suggest occult
osteomyelitis or bone marrow invasion from neoplastic disease. Tenderness over the trapezius muscle
may be a clue to subdiaphragmatic abscess. Generalized muscle tenderness suggests dermatomyositis,
trichinosis, polyarteritis, Kawasaki disease, or mycoplasmal or arboviral infection.
Rectal examination may reveal perirectal lymphadenopathy or tenderness, which suggests a deep pelvic
abscess, iliac adenitis, or pelvic osteomyelitis. A guaiac test should be obtained; occult blood loss may
suggest granulomatous colitis or ulcerative colitis as the cause of FUO.
Repetitive chills and temperature spikes are common in children with septicemia (regardless of cause),
particularly when associated with renal disease, liver or biliary disease, infective endocarditis, malaria,
brucellosis, rat-bite fever, or a loculated collection of pus. The general activity of the patient and the
presence or absence of rashes should be noted. Hyperactive deep tendon reflexes may suggest
thyrotoxicosis as the cause of FUO.
LABORATORY FINDINGS.
Ordering a large number of diagnostic tests in every child with FUO according to a predetermined list
may waste time and money. Alternatively, prolonged hospitalization for sequential tests may be more
costly. The tempo of diagnostic evaluation should be adjusted to the tempo of the illness; haste may be
imperative in a critically ill patient, but if the illness is more chronic, the evaluation can proceed more
slowly and deliberately and, usually, in an outpatient setting. If there are no clues in the patient's history
or on physical examination that suggest a specific infection or area of suspicion, it is unlikely that
diagnostic studies will be helpful.
A complete blood cell count with a differential WBC count and a urinalysis should be part of the initial
laboratory evaluation. An absolute neutrophil count less than 5,000/µL is evidence against indolent
bacterial infection other than typhoid fever. Conversely, patients with polymorphonuclear leukocytes
greater than 10,000/mL or nonsegmented polymorphonuclear leukocytes greater than 500/mL have a
high likelihood of having a severe bacterial infection. Direct examination of the blood smear with
Giemsa or Wright stain may reveal organisms of malaria, trypanosomiasis, babesiosis, or relapsing
fever.
An erythrocyte sedimentation rate (ESR) greater than 30?mm/hr indicates inflammation and the need for
further evaluation for infectious, autoimmune, or malignant diseases. An ESR greater than 100?mm/hr
suggests tuberculosis, Kawasaki disease, malignancy, or autoimmune disease. A low ESR does not
eliminate the
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possibility of infection or JRA. C-reactive protein is another acute phase reactant that becomes elevated
and returns to normal more rapidly than the ESR. Although experts may prefer use of one over the other,
there is no evidence that there is value in measuring both the ESR and C-reactive protein in the same
patient .
Blood cultures should be obtained aerobically. Anaerobic blood cultures have an extremely low yield
and should be obtained only if there are specific reasons to suspect anaerobic infection. Multiple or
repeated blood cultures may be required to detect bacteremia associated with infective endocarditis,
osteomyelitis, or deep-seated abscesses. Polymicrobial bacteremia suggests factitious self-induced
infection or gastrointestinal (GI) pathology. The isolation of leptospires, Francisella, or Yersinia may
require selective media or specific conditions not routinely used. Urine culture should be obtained
routinely.
Tuberculin skin testing should be performed with intradermal placement of 5 units of purified protein
derivative (PPD) that has been kept appropriately refrigerated.
Radiographic examination of the chest, sinuses, mastoids, or GI tract may be indicated by specific
historical or physical findings. Radiographic evaluation of the GI tract for inflammatory bowel disease
may be helpful in evaluating selected children with FUO and no other localizing signs or symptoms.
Examination of the bone marrow may reveal leukemia; metastatic neoplasm; mycobacterial, fungal, or
parasitic diseases; and histiocytosis, hemophagocytosis, or storage diseases. If a bone marrow aspirate is
performed, cultures for bacteria, mycobacteria, and fungi should be obtained.
Serologic tests may aid in the diagnosis of infectious mononucleosis, CMV infection, toxoplasmosis,
salmonellosis, tularemia, brucellosis, leptospirosis, cat-scratch disease, Lyme disease, rickettsial disease,
and, on some occasions, JRA. As serologic tests for more diseases become available through
commercial laboratories, it is important to ascertain the sensitivity and specificity of each test before
relying on these results to make a diagnosis. For example, serologic tests for Lyme disease outside of
reference laboratories have been generally unreliable.
Radionuclide scans may be helpful in detecting abdominal abscesses as well as osteomyelitis, especially
if the focus cannot be localized to a specific limb or multifocal disease is suspected. Gallium citrate (67
Ga) localizes in inflammatory tissues (leukocytes) associated with tumors or abscesses. 99m Tc
phosphate is useful for detecting osteomyelitis before plain roentgenograms demonstrate bone lesions.
Granulocytes tagged with indium (111 In) or iodinated IgG may be useful in detecting localized
pyogenic processes. Echocardiograms may demonstrate the presence of vegetation on the leaflets of
heart valves, suggesting infective endocarditis. Ultrasonography may identify intra-abdominal abscesses
of the liver, subphrenic space, pelvis, or spleen.
Total body CT or MRI permits detection of neoplasms and collections of purulent material without the
use of surgical exploration or radioisotopes. CT and MRI are helpful in identifying lesions of the head,
neck, chest, retroperitoneal spaces, liver, spleen, intra-abdominal and intrathoracic lymph nodes,
kidneys, pelvis, and mediastinum. CT or ultrasound-guided aspiration or biopsy of suspicious lesions
has reduced the need for exploratory laparotomy or thoracotomy. MRI is particularly useful for
detecting osteomyelitis if there is concern about a specific limb. Diagnostic imaging can be very helpful
in confirming or evaluating a suspected diagnosis but rarely leads to an unsuspected cause.
Biopsy is occasionally helpful in establishing a diagnosis of FUO. Bronchoscopy, laparoscopy,
mediastinoscopy, and GI endoscopy may provide direct visualization and biopsy material when organspecific manifestations are present.
Treatment.
Fever and infection in children are not synonymous; antimicrobial agents should not be used as
antipyretics, and empirical trials of medication should generally be avoided. An exception may be the
use of antituberculous treatment in critically ill children with suspected disseminated tuberculosis.
Empirical trials of other antimicrobial agents may be dangerous and can obscure the diagnosis of
infective endocarditis, meningitis, parameningeal infection, or osteomyelitis. Hospitalization may be
required for laboratory or radiographic studies that are unavailable or impractical in an ambulatory
setting, for more careful observation, or for temporary relief of parental anxiety. After a complete
evaluation, antipyretics may be indicated to control fever and for symptomatic relief (see Chapter 161.)
Prognosis.
Children with FUO have a better prognosis than do adults. The outcome in a child is dependent on the
primary disease process, which is usually an atypical presentation of a common childhood illness. In
many cases, no diagnosis can be established and fever abates spontaneously. In as many as 25% of cases
in which fever persists, the cause of the fever remains unclear, even after thorough evaluation.