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FeverofUnknownOrigin:Evaluation
Pembimbing
Dr.DewiIriani,Sp.A.
Disusunoleh
AsherJuniar(112014288)
JAKARTA
The above definition of FUO is a reasonable working definition for clinical purposes.
However, an agreed-upon definition has not been used in published studies of FUO in
children [3-11]. The required duration of fever for inclusion in various case series has
ranged from five to seven days to three weeks [3-11]. Some series used different
durations depending upon the setting (inpatient versus outpatient) [4,5]. Several made a
distinction between FUO and "prolonged fever" [10,11].
FUO should be distinguished from FWS for three important reasons:
The differential diagnoses and most frequent causes of each entity are distinct
Children with FWS usually require immediate testing and evaluation, whereas those
with FUO generally do not need an emergency assessment
Expectant antibiotic therapy is not typically indicated in children with FUO, whereas
treatment generally is recommended in a select group of infants with FWS
(See "Evaluation and management of fever in the neonate and young infant (younger than
three months of age)" and "Fever without a source in children 3 to 36 months of age".)
ETIOLOGY The number of infectious and noninfectious etiologies of fever of
unknown origin (FUO) in children is extensive (table 1). FUO is usually caused by
common disorders, often with an unusual presentation. This has been illustrated in
several series of FUO in children, in which rare disorders (eg, Behet syndrome,
ichthyosis) are exceedingly uncommon [4-14]. (See "Etiologies of fever of unknown
origin in children".)
Infectious diseases and connective tissue diseases are the most common etiologic
categories of FUO in children; neoplastic disorders are less common and usually have
manifestations other than fever [4-14].
In many cases, a definitive diagnosis is never established and fever resolves. In more
recent series, there has been a trend toward an increasing proportion of undiagnosed cases
[10,13,14]. Many of the classic FUO case series in children were published before the
routine availability of sophisticated diagnostic testing methods that are currently available
[3-6,12]. With advances in diagnostic testing, children with diseases previously common
in FUO series are now diagnosed earlier in their course of illness, leaving increasing
numbers of children with difficult-to-diagnose conditions in FUO series [13-15].
DIAGNOSTIC APPROACH Unless the child appears acutely ill, the evaluation of
fever of unknown origin (FUO) usually begins as an outpatient. If outpatient
investigation fails to disclose a cause for the fever, admission to the hospital provides an
opportunity to review the detailed history, physical examination, and available laboratory
data, and to observe the child in a controlled setting.
Performing a detailed and thorough history and physical examination is the first and most
important component of the diagnostic evaluation of the child with FUO. Incomplete
histories, ignored physical findings, and failure to correctly interpret existing laboratory
data delayed accurate diagnoses in a number of series of pediatric FUO cases [4-6].
The clinician must be prepared to repeat the clinical assessment on multiple occasions to
reassess historical features or clinical findings that might have been missed previously. A
patient or parent eventually may recall information that was omitted, forgotten, or
deemed unimportant when the initial history was obtained. New physical findings can
appear, and subtle abnormalities not originally appreciated can become apparent. In one
of the pediatric FUO series, significant physical findings that were not present at the time
of admission developed in more than 25 percent of children during hospitalization [4].
We suggest that some basic tests be performed in the initial evaluation of all children with
FUO. Subsequent diagnostic testing is guided by "potential diagnostic clues" from the
serial clinical assessments and initial laboratory and radiographic evaluation [16,17]. (See
'Diagnostic testing' below.)
HISTORY Fever of unknown origin (FUO) is usually caused by common disorders,
often with an unusual presentation. Although it is important to ask questions related to
uncommon diseases, an uncommon presentation of a common entity always should be
entertained.
Fever It is essential to obtain as much detail about the fever as possible. Important
aspects include:
The duration, height, and pattern; parents can mistake normal variations in body
temperature (eg, temperature elevations after exercise or late in the afternoon) for febrile
episodes.
How was the fever assessed (eg, by touch, forehead strip, or measured with a
thermometer; if measured with a thermometer, which type was used)? Rectal temperature
is most accurate; however, in an older child, temperature recorded with an oral
thermometer is usually adequate.
Was the fever confirmed by someone other than the caregiver?
Are there specific circumstances that precede the temperature elevation?
Does the child appear ill or develop any signs or symptoms during the febrile episode?
Absence of malaise or other generalized signs in a child with a history of high fevers can
signal factitious fever.
Whether and how quickly the fever responds to antipyretic drugs and whether other
constitutional symptoms (eg, myalgias, headache, malaise, etc.) persist when the fever
abates; the persistence of constitutional symptoms is more worrisome. Lack of response
4
Associated complaints It is important to ask, and ask again, about past or current
abnormalities or complaints. As examples:
Red eyes that resolved spontaneously may suggest Kawasaki disease (see "Kawasaki
disease: Clinical features and diagnosis")
Nasal discharge may suggest sinusitis (see "Acute bacterial rhinosinusitis in children:
Clinical features and diagnosis", section on 'Acute bacterial rhinosinusitis')
Recurrent pharyngitis with ulcerations may suggest the periodic fever with aphthous
stomatitis, pharyngitis, and adenitis syndrome (PFAPA) (see "Periodic fever with
aphthous stomatitis, pharyngitis and adenitis (PFAPA syndrome)")
Gastrointestinal complaints may suggest Salmonellosis, an intraabdominal abscess,
hepatosplenic cat scratch, or inflammatory bowel disease
Limb or bone pain may suggest leukemia, osteomyelitis, or infantile cortical
hyperostosis (see "Overview of the presentation and diagnosis of acute lymphoblastic
leukemia in children and adolescents" and "Differential diagnosis of the orthopedic
manifestations of child abuse", section on 'Infantile cortical hyperostosis (Caffey disease)'
and "Hematogenous osteomyelitis in children: Clinical features and complications",
section on 'Clinical features')
Exposures It is important to ask specifically about the following exposures:
Contact with infected or otherwise ill persons.
Exposure to animals, including household pets, domestic animals in the community, and
wild animals (table 2). (See "Zoonoses from cats" and "Zoonoses from dogs" and
"Zoonoses from pets other than dogs and cats" and "Microbiology, epidemiology, clinical
manifestations, and diagnosis of cat scratch disease".)
Travel history (including place of residence), extending back to birth. A number of
diseases acquired in endemic areas can reemerge years after departure (eg,
histoplasmosis, coccidioidomycosis, blastomycosis, malaria). The travel history should
include:
The site(s) of travel
Prophylactic medications and immunizations before travel
Measures taken to prevent exposure to contaminated food and water
Whether artifacts, rocks, or soil from other geographic areas were brought into the home
Exposure to other persons with a recent history of travel
6
Tick bites can be a clue to Rocky Mountain spotted fever, ehrlichiosis, tularemia, tickborne relapsing fever, or Lyme disease. North American mosquitoes and some ticks carry
a variety of arboviruses. (See appropriate topic reviews).
Consumption of game meat, raw meat, or raw shellfish may be a clue to brucellosis,
toxoplasmosis, tularemia, or hepatitis.
A history of pica, specifically eating dirt, may be associated with diseases such as
visceral larva migrans and toxoplasmosis.
Exposure to medications (including prescription, topical, and nonprescription drugs)
and nutritional supplements. (See "Drug fever".)
History of surgical procedures; patients with a history of abdominal surgery have an
increased risk of developing an intraabdominal abscess.
Ethnic or genetic background Certain conditions associated with fever tend to occur
among members of certain ethnic groups. As examples:
Nephrogenic diabetes insipidus in Ulster Scots [19] (see "Diagnosis of polyuria and
diabetes insipidus")
Familial Mediterranean fever in those of Sephardic Jewish, Armenian, Turkish, and
Arab descent (see "Clinical manifestations and diagnosis of familial Mediterranean
fever")
Familial dysautonomia in those of Ashkenazi Jewish decent (see "Hereditary sensory
and autonomic neuropathies", section on 'HSAN3 (Familial dysautonomia)')
EXAMINATION
General assessment The patient with fever of unknown origin (FUO) should be
evaluated while febrile. This is necessary to assess how ill the patient appears, to
determine the effect of fever on sweating and the heart and respiratory rates, and to
document any accompanying symptoms (eg, malaise or myalgias) or signs. The rash of
juvenile idiopathic arthritis (JIA) is characteristically evanescent and may be present only
during fever (picture 1).
The physical examination should begin with a general assessment of the patient's
appearance, activity, vital signs, and growth parameters. Although it is important to
evaluate the patient for weight loss, this is a nonspecific finding. Certain chronic diseases,
such as inflammatory bowel disease (IBD), or endocrine abnormalities, such as pituitary
gland impairment related to an intracranial lesion, characteristically result in
disproportionate deceleration of linear growth or short stature. (See "Causes of short
stature", section on 'Systemic disorders with secondary effects on growth'.)
Eyes The eye examination may provide a number of potential diagnostic clues,
including:
Palpebral conjunctivitis: Infectious mononucleosis, Newcastle disease (a viral infection
associated with exposure to chickens or other birds)
Bulbar conjunctivitis: Leptospirosis, Kawasaki disease (picture 11)
Phlyctenular conjunctivitis (with small, white, elevated lesions): Tuberculosis (TB)
Ischemic retinopathy with hemorrhages and retinal detachment, ischemic optic
neuropathy: Polyarteritis nodosa [20,21]
Absence of the pupillary constrictor response: Hypothalamic or autonomic dysfunction
Absent tears and corneal reflexes: Familial dysautonomia (Riley-Day syndrome)
Abnormal funduscopic examination: Miliary TB (choroid tubercles) (image 1),
toxoplasmosis (raised yellow-white, cottony lesions in a nonvascular distribution)
(picture 12), vasculitis (picture 13)
Sinuses The sinuses should be palpated in patients with purulent or persistent nasal
discharge; tenderness may suggest a diagnosis of sinusitis.
Oropharynx Abnormalities of dentition and other lesions in the oropharynx may
provide important clues to the underlying cause of fever. As examples:
Pharyngeal hyperemia without exudate occasionally can be the only sign of infectious
mononucleosis caused by Epstein-Barr virus (EBV) or cytomegalovirus (CMV),
toxoplasmosis, tularemia, or leptospirosis.
Dental abscess and other oral or facial infections can cause persistent fever [22-25].
Oral infections also can be associated with other infections (eg, sinusitis, brain abscess,
mediastinal abscess).
Anomalous dentition (hypodontia, adontia, or conical "peg teeth") is a characteristic of
anhidrotic ectodermal dysplasia. (See "The genodermatoses", section on 'Ectodermal
dysplasias'.)
A smooth tongue that lacks fungiform papillae or excessive salivation may suggest
familial dysautonomia. (See "Hereditary sensory and autonomic neuropathies", section on
'HSAN3 (Familial dysautonomia)'.)
Patients with leukemia or Langerhans cell histiocytosis can have gingival hypertrophy
or inflammation and loosening or loss of teeth. (See "Overview of the presentation and
diagnosis of acute lymphoblastic leukemia in children and adolescents" and "Clinical
9
performed to evaluate the patient for perirectal tenderness or a mass, which can indicate a
pelvic abscess or tumor. Stool should be examined for occult blood.
DIAGNOSTIC TESTING The laboratory and imaging evaluations for fever of
unknown origin (FUO) should be directed toward the likely causes of fever based upon
the patient's age, duration of fever, and findings from the history and physical
examination. In a review of 40 children with FUO referred to a pediatric rheumatology
clinic (presumably after the more common causes of FUO had been ruled out), results of
laboratory, radiologic, and pathologic studies were occasionally abnormal, but none of
the tests resulted in a specific diagnosis [28].
The tempo of the evaluation is dictated by the appearance of the patient. The pace should
be rapid if the child appears severely ill. It can be more deliberate if the child is less ill
appearing. Sometimes the fever resolves without explanation before invasive diagnostic
testing is undertaken.
Initial tests We recommend the following tests for all children with FUO:
Complete blood count (CBC) and careful examination of the peripheral smear
Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)
Aerobic and anaerobic blood cultures (anaerobic blood cultures may be helpful in
isolating fastidious organisms such as Streptobacillus moniliformis as well as facultative
aerobes)
Urinalysis and urine culture
Chest radiograph
Tuberculin skin testing
Serum electrolytes, blood urea nitrogen (BUN), creatinine, and hepatic enzymes
HIV serology
Additional tests may be indicated depending upon the presence of clues from the history,
examination, or initial tests. (See 'Additional tests' below.)
CBC, differential, and smear The CBC and smear are to evaluate the child for anemia
and thrombocytosis or thrombocytopenia. Anemia may be a clue to malaria, infective
endocarditis, IBD, SLE, or tuberculosis [29]. Thrombocytosis is a nonspecific acute
phase reactant, but it can be a clue to Kawasaki disease. (See "Kawasaki disease: Clinical
features and diagnosis".)
The total white blood cell count (WBC) and the differential generally are less helpful,
11
13
14
when there is suspicion of localized infection but is unlikely to be helpful in those with
only systemic signs [41].
Other imaging techniques A number of other imaging techniques, including
radiographic bone survey, technetium bone scan, and liver-spleen scan can be employed
in selected cases when a thorough evaluation has failed to reveal the cause of FUO and
suspicion for a source that could be revealed by these tests exists.
PET scans Positron emission tomography (PET) scanning is another technique that
may be helpful in patients with persistent FUO who remain without a diagnosis after
initial evaluation. In a review of prospective studies, (18)F-FDG PET contributed to the
diagnosis in 25 to 69 percent of cases of FUO [42]. (18)F-FDG PET was more sensitive
than Ga-citrate SPECT in detecting tumors, infection, and inflammation.
Studies of PET scans in the evaluation of FUO in children are limited. One group studied
PET in 11 children with FUO awaiting liver transplant [43]. The scans were positive in
five, all of whom had positive bacterial cultures and/or histologic evidence of infection in
the excised liver; other scanning procedures in these children had been negative. PET
scans were negative in the other six children, none of whom had evidence of infection in
the liver at the time of transplant.
Immunoscintigraphy Immunoscintigraphy is another technique that may be helpful in
certain patients with persistent FUO who remain without a diagnosis after initial
evaluation. In 30 neonates and infants with FUO, immunoscintigraphy with labeled
antigranulocyte antibody had a sensitivity and specificity of 72 and 95 percent,
respectively, for detection of infection (as verified by conventional radiography, MRI,
CT, biopsy, blood culture, and clinical follow-up) [44].
Whole-body MRI Whole body MRI is used to evaluate the extent of multisystemic
disease in pediatric oncology patients. In a retrospective study, whole body MRI was
found to influence the decisional process and clinical management in 42 children with
inflammatory disorders such as chronic recurrent multifocal osteomyelitis, juvenile
idiopathic arthritis, chronic granulomatous disorder, and Langerhans cell histiocytosis
[45]. The utility of whole-body MRI in the routine evaluation of children with persistent
FUO who remain without a diagnosis after initial evaluation has not been established.
Other evaluations
Electrocardiography and echocardiography should be obtained in patients with positive
blood cultures and suspicion for infective endocarditis [46] (see "Infective endocarditis in
children")
Ophthalmologic examination by slit lamp is useful in some patients with FUO to
evaluate the presence of uveitis or leukemic infiltration
15
Biopsy (eg, of lymph nodes or liver) should be reserved for children with evidence of
involvement of specific organs
Sophisticated abdominal imaging procedures largely have eliminated the need for
exploratory laparoscopy or laparotomy in the evaluation of children with FUO
EMPIRICAL TREATMENT Empirical treatment with antiinflammatory medications
or antibiotics generally should be avoided as diagnostic measures in children with fever
of unknown origin (FUO). Exceptions include nonsteroidal agents in children with
presumed juvenile idiopathic arthritis (JIA) and antituberculous drugs in critically ill
children with possible disseminated tuberculosis (TB).
Antiinflammatory drugs do not help to distinguish fevers of infections from those of
noninfectious causes. Empirical trials of broad-spectrum antibiotics can mask or delay the
diagnosis of important infections, such as meningitis, parameningeal infection, infectious
endocarditis, or osteomyelitis. Use of empirical antibiotics also can hamper the ability to
isolate an organism from the blood or a specific site if further culturing is warranted as
the evaluation proceeds.
OUTCOME In contrast to adults, most children with fever of unknown origin (FUO)
have treatable or self-limited diseases. The fever resolves over time in most cases, and a
specific diagnosis eventually can be made in others [8,9,12,47].
Despite this fact, the overall prognosis is far from benign. In two series from the 1970s,
mortality was 9 percent in one group of 100 children with FUO and 6 percent in another
group of 54 children [4,6]. In more recent series, mortality is less frequent [8,9].
Curiously, the prognosis may be better when a diagnosis cannot be established after
extensive evaluation [5,28,47]. Of those without a definitive diagnosis, many appear to
do well, although episodes of fever may recur [5,47].
In long-term follow-up (median 3.5 years, range 1.2 to 5.3 years) of 19 children with
FUO for at least two weeks and in whom no diagnosis was established, 16 of 19 (82
percent) were afebrile and completely well [47]. Two patients were subsequently
diagnosed with juvenile idiopathic arthritis (JIA), one shortly after discharge and one 1.5
years later. One child, who had presented with abdominal pain and fever, had two
episodes of intussusception (8 and 14 months after discharge), and the authors speculate
that her initial episode might have been intussusception that spontaneously reduced.
Among 40 children who were referred for pediatric rheumatology evaluation with FUO
of at least one month's duration and in whom no diagnosis was established, 37 were
available for follow-up at a mean of 60.5 months [28]. Two children developed
inflammatory bowel disease (IBD) (one 7 months and one 3.5 years after initial
evaluation); in both cases, fever resolved after initiation of appropriate therapy for IBD.
16
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GRAPHICS
Causes of fever of unknown origin in children
Infectious disease
Collagen vascular disease
Bacterial
Juvenile idiopathic arthritis
Bacterial endocarditis
Polyarteritis nodosa
Bartonella henselae
Systemic lupus erythematosus
Brucellosis
Malignancies
Leptospirosis
Hodgkin disease
Liver abscess
Leukemia/lymphoma
Mastoiditis (chronic)
Neuroblastoma
Osteomyelitis
Miscellaneous
Pelvic abscess
Central diabetes insipidus
Perinephric abscess
Drug fever
Pyelonephritis
Ectodermal dysplasia
Salmonellosis
Factitious fever
Sinusitis
Familial dysautonomia
Subdiaphragmatic abscess
Granulomatous colitis
Tuberculosis
Hemophagocytic lymphohistiocytosis
Tularemia
Infantile cortical hyperostosis
Viral
Kawasaki disease
Adenovirus
Kikuchi-Fujimoto disease
Arboviruses
Nephrogenic diabetes insipidus
Cytomegalovirus
Pancreatitis
Hepatitis viruses
Periodic fever
Enteroviruses
Serum sickness
Epstein-Barr virus (infectious mononucleosis) Thyrotoxicosis
Chlamydial
Ulcerative colitis
Lymphogranuloma venereum
Psittacosis
Rickettsial
Q fever
Rocky Mountain spotted fever
Fungal
Blastomycosis (nonpulmonary)
Histoplasmosis (disseminated)
Parasitic
Malaria
Toxoplasmosis
21
A salmon-pink rash is characteristic of this juvenile idiopathic arthritis (JIA) subtype. The
rash is brought out by heat and often can be found in the axillae and around the waist, but
may be present anywhere on the body.
Courtesy of Robert Sundel, MD.
Graphic 62959 Version 7.0
Rocky mountain spotted fever rash
23
Child with Rocky Mountain spotted fever has the rash that is characteristic but typically
does not appear until several days after fever onset.
From: Fatal Cases of Rocky Mountain Spotted Fever in Family Clusters --- Three States,
2003. MMWR Morb Mortal Wkly Rep 2004;
53(19):407. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5319a1.htm.
Graphic 58061 Version 3.0
Typical papular lesion on the finger of a child with cat scratch disease
24
25
Erythema migrans lesion with uniform erythema. Note that the lesion is not a perfect
circle.
Courtesy of Eugene D Shapiro, MD, FAAP.
Graphic 57414 Version 1.0
Erythema migrans-like rash of STARI
Circular erythema migrans-like lesion with central clearing on the lower leg of a patient
with STARI. The central papule was the site of a recent tick bite.
STARI: Southern tick-associated rash illness.
Courtesy of Edwin Masters, MD.
Graphic 60256 Version 4.0
Acute cutaneous lupus erythematosus
26
Malar erythema and subtle edema are present in this patient with systemic lupus
erythematosus.
Reproduced with permission from: www.visualdx.com. Copyright Logical Images, Inc.
Graphic 75781 Version 3.0
Acute cutaneous lupus erythematosus
27
An erythematous, edematous eruption is present on the malar area. Note the sparing of
the nasolabial folds.
Reproduced with permission from: www.visualdx.com. Copyright Logical Images, Inc.
Graphic 55875 Version 3.0
Leucocytoclastic vasculitis
28
Leukocytoclastic vasculitis appearing as raised purpura. This lesion can occur with any
vasculitic syndrome and in the collagen vascular diseases.
Courtesy of Marvin I Schwarz, MD.
Graphic 78697 Version 1.0
Serum sickness of the hands and feet
Reproduced with permission from: Bielory L, Gascon P, Lawley TJ, et al. Human serum
sickness: a prospective analysis of 35 patients treated with equine anti-thymocyte
globulin for bone marrow failure. Medicine 1988; 67:40. Copyright 1988 Lippincott
Williams and Wilkins.
Graphic 61556 Version 10.0
Erythema nodosum
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Miliary choroids (tubercles) appear as ill-defined nodules varying in size from pinpoint to
several disc diameters on funduscopic examination.
Reprinted with permission. Copyright American Society of Contemporary
Ophthalmology. Annals of Ophthalmology 1989.21(6);226.
Graphic 61826 Version 5.0
Toxoplasma chorioretinitis
30
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http://www.lww.com
Graphic 80056 Version 5.0
Conjunctivitis in Kawasaki disease
Courtesy of Robert Sundel, MD.
Graphic 78898 Version 2.0
Choroidal tuberculosis
Miliary choroids (tubercles) appear as ill-defined nodules varying in size from pinpoint to
several disc diameters on funduscopic examination.
Reprinted with permission. Copyright American Society of Contemporary
Ophthalmology. Annals of Ophthalmology 1989.21(6);226.
Graphic 61826 Version 5.0
Toxoplasma chorioretinitis
Chorioretinitis characteristic of toxoplasmosis. A pigmented scar is seen with an adjacent
area of active chorioretinitis. The diagnosis of toxoplasmosis is based primarily on the
appearance of the chorioretinal lesion rather than serologic studies.
Courtesy of James T Rosenbaum, MD.
Graphic 69853 Version 2.0
Perivascular sheathing of retinal vasculitis
Funduscopic examination shows perivascular sheathing.
Courtesy of M Reza Dana, MD, MPH.
Graphic 54347 Version 2.0
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