Journal of Microbiology, Immunology and Infection (2017) 50, 893e898

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ORIGINAL ARTICLE

Clinical approach to fever of unknown origin

in children
Ya-Li Chien a,b, Fang-Liang Huang a, Chung-Ming Huang a,
Po-Yen Chen a,*

a
Section of Pediatric Infectious Disease, Department of Pediatrics, Taichung Veterans General
Hospital, Taichung, Taiwan
b
Department of Pediatrics, Lin Shin Medical Corporation Lin Shin Hospital, Taichung, Taiwan

Received 29 April 2015; received in revised form 7 August 2015; accepted 20 August 2015
Available online 9 October 2015

KEYWORDS Abstract Background/purpose: Fever of unknown origin (FUO) can be caused by many clin-
children; ical conditions and remains a diagnostic challenge in clinical practice. The etiology of FUO var-
fever of unknown ies markedly among different age groups, geographic areas, and seasons. A four-stage
origin investigative protocol for FUO is widely applied in clinical practice. The aim of this study
was to evaluate the usefulness of this four-stage protocol for identifying the etiology of FUO
in children.
Methods: We enrolled children younger than 18 years of age who were admitted to the Tai-
chung Veterans General Hospital during the period from January 2006 to December 2014 with
FUO persisting for more than 3 weeks. The four-stage FUO investigative guideline was used to
evaluate the etiology of fever in all patients enrolled in the study.
Results: The etiology of FUO was identified in 79 (84.9%) of the 93 patients enrolled in the
study. The most common cause of FUO was infectious disease (37.6%), followed by malignancy
(17.2%), miscellaneous disease (16.1%), and collagen vascular disease (14.0%). With respect to
the four-stage survey of FUO, 36 of the 79 patients (45.6%) were identified in Stage 3, 28 pa-
tients (35.4%) in Stage 2, 13 patients (16.5%) in Stage 4, and only two patients (2.5%) in Stage 1.
Conclusion: A well-designed systemic review of the epidemiological information, medical his-
tory, physical examination, laboratory analysis, and adequate invasive procedures provide
adequate data to identify the most common causes of FUO in children.
Copyright ª 2016, Taiwan Society of Microbiology. Published by Elsevier Taiwan LLC. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).

* Corresponding author. Division of Infection, Department of Pediatrics, Taichung Veterans General Hospital, Number 1650, Section 4,
Taiwan Boulevard, Taichung 407, Taiwan.
E-mail address: pychen@vghtc.gov.tw (P.-Y. Chen).

http://dx.doi.org/10.1016/j.jmii.2015.08.007
1684-1182/Copyright ª 2016, Taiwan Society of Microbiology. Published by Elsevier Taiwan LLC. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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894
Introduction
Fever is a common symptom of many clinical conditions,
and infection is the most common cause, especially in
children.1 “Fever of unknown origin (FUO)” in adults was
first described in 1961 and was defined as well-documented
fever of at least 3 weeks’ duration without an apparent
source after 1 week of investigation.2 Although there is no
standard definition of pediatric FUO, fever lasting any-
where from 10 days to 3 weeks is generally accepted as the
working definition of FUO in children.3e6
FUO is a challenging problem in clinical practice, and
patients who present with FUO are often subjected to un-
necessary over-the-counter laboratory tests and antimi-
crobial therapies. There is no gold “standard” process to
investigate the etiology of FUO. There are only a limited
number of reports on systemic surveys of the etiology of
FUO among children in Taiwan. In this study, we investi-
gated the four-stage protocol for FUO,7,8 and evaluated
which stage provides the most valuable information for
identifying the cause of FUO in children.
Methods
According to the classical Petersdorf and Beeson criteria,2
the working definition of FUO used in this study is well-
documented fever (>38.3 C) of at least 3 weeks’ duration
without an apparent source after 3 weeks of evaluation as
an outpatient or after a week of evaluation in hospital.
Children younger than 18 years of age who presented to
the Department of Pediatrics at the Taichung Veterans
General Hospital with prolonged or unrecognized source of
fever during the period from January 2006 to December
2014 and who fulfilled the FUO definition for children were
enrolled in this study. Exclusion criteria included any pre-
vious immunocompromised disease state [e.g., human im-
munodeficiency virus (HIV) infection, leukemia, lymphoma]
or chronic medical condition.
Children with FUO who fulfilled the inclusion criteria
were evaluated systemically based on the four-stage FUO
protocol.7,8 In brief, Stage 1 comprises the taking of a
detailed medical history, examination of medical records, a
physical examination, and performance of screening tests,
including measuring complete blood count/differential
count, C-reactive protein level, examination of peripheral
blood smear, urinalysis, routine biochemical analysis, cul-
ture of urine, stool and blood sample, and radiographic
examination of chest and sinus cavities. Stage 2 involves
collecting a more detailed history of travel, contact,
Table 1 Age distribution of different categories of fever of unknown origin in children.
Cause <1 y
Infectious disease 7 (77.8)
Malignancy 0 (0)
Collagen vascular disease 0 (0)
Miscellaneous 1 (11.1)
Undiagnosed 1 (11.1)
Total 9 (9.7)
Data presented as n (%).
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Y.-L. Chien et al.
environmental factors, and vaccinations, and conducting a
more detailed physical examination and assessment of
fever pattern, specific screening tests, and noninvasive
diagnostic tests, including cultures for viruses, serological
tests for bacteria and viruses (WeileFelix test, Widal test,
and serological tests for leptospiral and herpes group vi-
ruses), antinuclear antibody testing, complements 3 and 4
level, testing for cytoplasmic antineutrophil cytoplasmic
antibodies, measurement of immunoglobulin level, and ul-
trasonographic examination of tissue or organs (abdominal,
pelvic, chest, and lymph node). Stage 3 of the protocol
involves the undertaking of special diagnostic tests (for Q
fever, Lyme disease and Parvovirus, etc.), which can be
conducted at the reference laboratories of the Centers for
Disease Control, R.O.C. (Taiwan), radiological examinations
(computed tomography scan, magnetic resonance imaging,
and magnetic resonance angiography), nuclear medicine
(Gallium scan and bone scan), and tissue or bone marrow
biopsy. Further specific diagnostic examination includes
echocardiography, polymerase chain reaction for HIV and
cytomegalovirus (CMV), and molecular DNA analysis for
Fabry’s disease. Stage 4 investigation for FUO includes
therapeutic trials including empiric antimicrobial therapy
and administration of corticosteroids, intravenous immu-
noglobulins, and prostaglandin inhibitors.
The identified causes of FUO in children were divided
into the following five groups: infectious disease, collagen
vascular disease, malignancy, miscellaneous conditions,
and undiagnosed. Patients in whom the etiology of fever
was not identified and who recovered spontaneously were
assigned to the undiagnosed group.9
All statistical analyses were performed using the Statis-
tical Package for Social Science (SPSS Inc., Chicago, IL,
USA).
Results
A total of 93 children were enrolled in this study, including
58 boys (62.4%) and 35 girls (37.6%). The mean age was
7.3  5.5 years (range 2 mo to 18 y). Nine children (9.7%)
were younger than 1 year of age, 31 (33.3%) were in the age
range from 1 year to 5 years, 31 (33.3%) were in the age
range from 6 years to 12 years, and 22 (23.7%) were in the
age range from 12 years to 18 years. Infectious diseases
were the most common cause of FUO (n Z 35, 37.6%), fol-
lowed by malignancies (n Z 16, 17.2%), miscellaneous dis-
eases (n Z 15, 16.1%), and collagen vascular diseases
(n Z 13, 14.0%). Systemic investigation did not yield a
diagnosis in 14 (15.1%) patients (Table 1).
1e5 y 6e12 y >12 y Total
8 (25.8) 12 (38.7) 8 (36.4) 35 (37.6)
7 (22.6) 6 (19.4) 3 (13.6) 16 (17.2)
4 (12.9) 5 (16.1) 4 (18.2) 13 (14.0)
4 (12.9) 6 (19.4) 4 (18.2) 15 (16.1)
8 (25.8) 2 (6.4) 3 (13.6) 14 (15.1)
31 (33.3) 31 (33.3) 22 (23.7) 93 (100)
Fever of unknown origin in children 895

The mean age of patients with FUO caused by infectious
disease, malignancy, collagen vascular diseases, and
miscellaneous diseases was 7.0  5.4 years, 8.9  5.2 years,
6.5  4.3 years, and 8.5  6.4 years, respectively. The mean
age of children for whom the etiology could not be deter-
mined was 5.6  6.2 years. The most common cause of FUO
in children aged younger than 1 year was infectious disease
(77.8%). All patients with FUO due to collagen vascular
disease or malignant disease in this study were older than 1
year of age. The age of children for whom the etiology
could not be determined mostly ranged from 1 year to 5
years (Table 1).
Following the protocol of systemic investigation for FUO,
36 of the 79 patients (45.6%) with FUO were identified in
Stage 3, 28 patients (35.4%) in Stage 2, 13 patients (16.5%)
in Stage 4, and two patients (2.5%) in Stage 1 (Table 2). For
those patients with FUO caused by infectious diseases, the
etiologies for 19 patients (54.3%) were found in Stage 2 by
reviewing additional medical history, careful physical ex-
amination, and common epidemiological screening testing
[WeileFelix test for Rickettsia disease, Widal test for Sal-
monella, Leptospiral test, and EpsteineBarr virus (EBV)
antibodies response, etc.]. All children with malignancy
needed an invasive procedure (bone marrow or tissue bi-
opsy) to make the diagnosis in Stage 3. Tissue biopsy in
Stage 3 was also useful for identifying hemophagocytosis
and KikuchieFujimoto lymphadenitis in the miscellaneous
group. Eight patients (61.5%) with collagen vascular disease
were identified in Stage 4 using the therapeutic trials of
prostaglandin inhibitor or corticosteroids, and in seven of
the patients FUO was laterally attributed to juvenile
rheumatoid arthritis (JRA; Table 3).
The identified causes of FUO in this study are listed in
Table 4. Leptospirosis (4 patients) and rickettsial disease (4
patients) were the most common infectious diseases in
children with FUO. Nonspecific presentations and inade-
quate history taking, physical examination, and empirical
antimicrobial therapies were the most common reasons for
delay in diagnosis.
Typhoid fever was the cause of FUO in two patients. The
mean duration of fever in those patients was 3 weeks. They
were aged 1 year and 2 years and neither patient presented
with relative bradycardia or rash. The laboratory studies
were all nonspecific. Blood culture was negative for the
organisms; however, the results of the Widal test were
confirmative of typhoid fever. Results of echocardiographic
examinations and blood cultures revealed infective endo-
carditis in two patients (Staphylococcus aureus in one and
Streptococcus parasanguinis in the other).
Of the malignant diseases causing FUO, acute leukemia
was the most common, followed by neuroblastoma and
lymphoma. Of the collagen vascular diseases causing FUO,
JRA was the most common, followed by systemic lupus
erythematosus, Sjögren’s syndrome, and sarcoidosis. The
miscellaneous causes of FUO among children included Ka-
wasaki disease (KD) and KikuchieFujimoto lymphadenitis.
A definitive diagnosis was not achieved using the four-
stage protocol in 14 of the 93 patients. Eleven of them were

Table 2 Etiologies of fever of unknown origin identified by the programmed four-stage investigation procedure among 79
children in Taichung Veterans General Hospital.
Stage Investigation procedure Measurement n %
1 History, physical examination, CBC/DC, CRP, peripheral blood smear, complete urine 2 2.5
screening test analysis, routine biochemistry, chest/sinus radiography,
urine/stool/blood culture
2 More detailed history, repeat Virus culture, ANA, C3/C4, C-ANCA, serological test 28 35.4
physical examination, specific for bacteria and virus, immunoglobulin level,
screening test abdominal/chest/lymph node ultrasonography
3 Specific diagnostic test, CT, MRI, gallium scan, bone marrow aspiration and 36 45.6
invasive test biopsy, biopsy of lymph nodes/mass, PCR for CMV and
HIV, echocardiography, lumbar puncture, molecular DNA
analysis for Fabry’s disease
4 Therapeutic trial Antimicrobial therapy, NSAID/steroid trial 13 16.5
ANA Z antinuclear antibody; C3/C4 Z complements 3 and 4; C-ANCA Z cytoplasmic antineutrophil cytoplasmic antibodies; CBC/
DC Z complete blood count/differential count; CMV Z cytomegalovirus; CRP Z C-reactive protein; CT Z computerized tomography;
HIV Z human immunodeficiency virus; MRI Z magnetic resonance imaging; NSAID Z nonsteroidal anti-inflammatory drug; PCR Z poly-
merase chain reaction.

Table 3 Value of the four-stage investigation procedure to establish the etiology of fever of unknown origin in children.
Etiology (n) Stage of diagnosis, n (%)
1 2 3 4
Infectious disease (35) 2 (5.7) 19 (54.3) 9 (25.7) 5 (14.3)
Malignancy (16) 0 (0.0) 0 (0.0) 16 (100.0) 0 (0.0)
Collagen vascular disease (13) 0 (0.0) 5 (38.5) 0 (0.0) 8 (61.5)
Miscellaneous (15) 0 (0.0) 4 (26.7) 11 (73.3) 0 (0.0)

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896 Y.-L. Chien et al.

Table 4 Identified causes of fever of unknown origin in children.

Etiology (n) Diagnosis (n) n
Infectious disease (35) Viral (9) HIV 1
Coxsackievirus B4 1
CMV 2
Parvovirus B19 1
HSV type 1 1
Parainfluenza type 3 1
Influenza type B 1
EBV 1
Bacterial (26) Infective endocarditis 2
TB meningitis 1
TB lymphadenopathy 1
Leptospirosis 4
Rickettsiae disease 4
Typhoid fever 2
Pulmonary actinomycosis 1
Toxoplasmosis 1
Pneumonia 1
Pharyngotonsillitis 2
Acute otitis media 1
Acute sinusitis 1
Osteomyelitis 1
Perivertebral abscess and diskitis 1
Atypical infection 3
Malignancy (16) Acute lymphoblastic leukemia 9
Acute myelogenous leukemia 1
Anaplastic large cell lymphoma 2
Peripheral T-cell lymphoma 1
Neuroblastoma 3
Collagen vascular disease (13) Juvenile rheumatoid arthritis 8
Sjögren’s syndrome 1
Sarcoidosis 1
SLE 1
Undifferentiated connective tissue disease 2
Miscellaneous (15) KikuchieFujimoto lymphadenitis 4
Kawasaki disease 5
Hemophagocytosis 2
Fabry’s disease 1
Hypohidrotic ectodermal dysplasia 1
Lymphadenopathy 1
Hypogammaglobulinemia 1
Undiagnosed 14
Total 93
CMV Z cytomegalovirus; EBV Z EpsteineBarr virus; HIV Z human immunodeficiency virus; HSV Z herpes simplex virus; SLE Z systemic
lupus erythematosus; TB Z Mycobacterium tuberculosis.

afebrile without any sequelae at follow up. The other three
patients remained febrile but were lost to follow up.
Four patients died during the study period. One of them
died due to the complication of infective endocarditis, two
died due to neuroblastoma, and one died due to acute
leukemia.
Discussion
Fever in pediatric patients causes considerable anxiety to
their parents, while FUO is a source of confusion and
frustration for the attending physician, and leads to un-
necessary and additional over-the-counter laboratory tests
and medications (including antimicrobial agents), subse-
quently increasing the burden on both the National Health
Insurance system and the patient’s family. A well-designed
systemic investigation protocol conducted according to
local epidemiological information may save time and
reduce unnecessary medical costs and disease sequelae.
There are few available data on children with FUO in
Taiwan. Based on the four-stage procedure to investigate
the etiology of FUO among children, most cases were
identified in Stage 2.

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Fever of unknown origin in children
In this study, we found that the most common cause of
FUO was infectious disease (37.6%) followed by malignancy,
miscellaneous diseases, and collagen tissue disease. Similar
findings have been reported previously.10e13 A recent study
of children with FUO conducted by Cho et al14 in northern
Taiwan, in which FUO was defined as fever for more than 2
weeks, found that infectious diseases accounted for 27% of
FUO in children, followed by malignancies (16.6%), and
collagen vascular disease (12.7%). Cho et al14 also found
that upper respiratory infections (URIs) were the most
common cause of infectious disease, followed by CMV and
EBV infections; leptospirosis or scrub typhus rarely caused
FUO in their study. There were more urban cases in Taipei
(Northern Taiwan), whereas there were more rural cases in
Central Taiwan, and the criterion for duration of fever in
northern and central Taiwan was 2 weeks and 3 weeks,
respectively. Viral URI usually caused fever for 3e5 days,
and was rarely longer than 10 days, except in cases with
adenovirus/influenza infection or complication with otitis
media or bronchopneumonia/pneumonia. CMV and EBV in-
fections in children usually presented with mononucleosis-
like syndrome15; they were easily reactivated in patients
with immunocompromised status,16 and their possible roles
in prolonged fever should be carefully interpreted. Chin
et al17 reported that infection was the most common eti-
ology of FUO in adults in Taiwan, which was similar to the
rate in children. Tuberculosis was the most common in-
fectious etiology in their study. That finding is compatible
with the higher annual incidence rate of tuberculosis in
adults (3.04/100,000 population and 82.60/100,000 popu-
lation for children and adults, respectively) reported by
Tsai et al.18
Malignancies were previously found to be the third most
common cause of FUO in children, following infectious and
collagen vascular disease. However, malignancies were
slightly more common than collagen vascular diseases in
this study. Most cases of FUO due to collagen vascular dis-
eases had been intensively surveyed in a local hospital, and
were referred to medical centers for further investigation.
The percentage of FUO in children who remained unrec-
ognized was similar to previously reported rates, which
ranged from 12% to 24%.10e13
The four-stage protocol used in this study to investigate
the etiology of FUO provides for a reasonably accurate
establishment of a diagnosis. Stage 2 of the protocol was
sufficient to establish a diagnosis of infectious disease as
the cause of FUO in most patients in this study. Clinicians
who encounter children with FUO need to collect a detailed
record of disease and medical history, including vaccination
history, growth and developmental milestones, and body
weight changes. Cough contact history with elders with TB
is an indicator for tuberculosis, and poor weight gain or
failure to thrive is suggestive of an autoimmune or immu-
nodeficiency disorder. Some common endemic infectious
diseases (leptospirosis and rickettsial diseases) are easily
overlooked in clinical practice.19e21 A detailed evaluation
of travel, occupation, contact, and cluster may help to
establish whether the patient lives in a rural area or has
recently visited a mountainous area.
A more detailed physical examination is needed for all
patients with FUO. Skin rashes or lesions are important
clues for diagnosing some infectious diseases. Eschar is
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897
presented in 44e86% of patients with scrub typhus.22,23 In
our study, approximately 25% of patients with scrub typhus
presented with eschar. Rose spots are commonly seen in
patients with typhoid fever24 and conjunctival suffusion is
commonly noted in patients with leptospirosis.20 Limping
gait and sternal tenderness may indicate the presence of
malignant invasion of the bone marrow.25
Serological tests for atypical bacteria (WeileFelix test
and leptospiral antibody) have been shown to have low
sensitivity and specificity. Leptospirosis is an important
endemic zoonotic disease in Taiwan. Culture and micro-
scopic agglutination tests are the gold standard methods for
establishing a diagnosis of leptospirosis; however, they are
only available from reference laboratories of the Centers
for Disease Control, R.O.C (Taiwan). Whole-cell-based
rapid serological tests have been shown to have a low
sensitivity for early phase leptospirosis and a low specificity
in highly endemic areas.26 For patients with high clinical
suspicion of leptospirosis, empirical therapeutic trial should
be initiated (Stage 4).
Investigation studies for FUO in Stage 3 include invasive
procedure. Clinical suspicion of acute leukemia/lymphoma
and malignancy always requires bone marrow studies.
There were four cases of KikuchieFujimoto disease in this
study, and all were definitely diagnosed by lymph node
biopsy.27
Infective endocarditis is commonly found in pediatric
patients.28 Echocardiography should be arranged based on
clinical suspicion, especially for those with positive blood
cultures.29 Echocardiography is also very helpful when KD is
suspected, even in young children with FUO who did not
meet the typical criteria of KD.30,31 In five KD patients in
this study, four were diagnosed with incomplete-type KD,
based on echocardiographic finding and laboratory
characteristics.32
Gallium scanning is capable of identifying inflammatory
lesions and tumors throughout the entire body. However,
this modality was not commonly used in our study. A pre-
vious study also found that gallium scanning was rarely
useful in most children with FUO.33 Magnetic resonance
imaging was the imaging modality of choice for establishing
the diagnosis of osteomyelitis and arthritis or to delineate
the location and extent of bone and soft-tissue
involvement.34,35
Therapeutic trial with anti-inflammatory medications or
antibiotics should be generally avoided as empirically
diagnostic measures in children with FUO, except for chil-
dren with suspected JRA for whom nonsteroidal agents are
administered, but this is a diagnosis of exclusion.36 How-
ever, it is always delayed since the onset of fever and the
progression to arthritis. All the cases of JRA diagnosed in
our study had a good response to treatment with nonste-
roidal anti-inflammatory drugs.
Empirical treatment with broad-spectrum antibiotics
will mask or delay the diagnosis of some infectious dis-
eases; however, broad-spectrum antibiotics are the most
commonly applied medication in children to treat the
infection. Diseases that cannot be routinely tested include
Lyme disease, leptospirosis, and nonscrub typhus rickettsial
diseases. Empirical antimicrobial therapy after blood/tis-
sue sampling for these diseases may provide a diagnostic
clue.
898
In conclusion, children with FUO should be evaluated
using the four-stage protocol. Epidemiological data, con-
tact history, previous medical history, fever pattern,
detailed physical examination, and screening tests provide
adequate information to establish a diagnosis. Stage 3
procedures should be reserved for special consideration.
Conflicts of interest
None declared.
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