Open Access Research

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Diagnostic workup for fever of
unknown origin: a multicenter
collaborative retrospective study
Toshio Naito,1 Masafumi Mizooka,2 Fujiko Mitsumoto,3 Kenji Kanazawa,4
Keito Torikai,5 Shiro Ohno,6 Hiroyuki Morita,7 Akira Ukimura,8 Nobuhiko Mishima,9
Fumio Otsuka,10 Yoshio Ohyama,11 Noriko Nara,12 Kazunari Murakami,13
Kouichi Mashiba,14 Kenichiro Akazawa,15 Koji Yamamoto,16 Shoichi Senda,17
Masashi Yamanouchi,1 Susumu Tazuma,2 Jun Hayashi3

To cite: Naito T, Mizooka M, ABSTRACT

Mitsumoto F, et al. Strengths and limitations of this study
Objective: Fever of unknown origin (FUO) can be
Diagnostic workup for fever
caused by many diseases, and varies depending on ▪ This study is the first nationwide study of
of unknown origin: a
region and time period. Research on FUO in Japan has patients with fever of unknown origin in Japan.
multicenter collaborative
retrospective study. BMJ been limited to single medical institution or region, ▪ The present study identified diseases that should
Open 2013;3:e003971. and no nationwide study has been conducted. be considered in the differential diagnosis of
doi:10.1136/bmjopen-2013- We identified diseases that should be considered and fever of unknown origin.
003971 useful diagnostic testing in patients with FUO. ▪ The rate of ‘unknown’ in our study was relatively
Design: A nationwide retrospective study. small, but this retrospective study may have
▸ Prepublication history for Setting: 17 hospitals affiliated with the Japanese encountered bias because of the difficulty of
this paper is available online. Society of Hospital General Medicine. enrolling patients with an unknown cause after
To view these files please Participants: This study included patients ≥18 years undergoing tests.
visit the journal online diagnosed with ‘classical fever of unknown origin’
(http://dx.doi.org/10.1136/ (axillary temperature ≥38°C at least twice over a
bmjopen-2013-003971). INTRODUCTION
≥3-week period without elucidation of a cause
at three outpatient visits or during 3 days of Fever of unknown origin (FUO) can be
hospitalisation) between January and caused by many diseases, and causes can vary
December 2011. depending on region and time period. FUO
Results: A total of 121 patients with FUO were was first reported in the medical literature
enrolled. The median age was 59 years (range 80 years ago.1 Since then, the causative dis-
19–94 years). Causative diseases were infectious eases have greatly changed with changes in
disease in 28 patients (23.1%), non-infectious the social environment and widespread use
inflammatory disease in 37 (30.6%), malignancy in
of diagnostic imaging.2–6
13 (10.7%), other in 15 (12.4%) and unknown in
A few reports of FUO have also been pub-
28 (23.1%). The median interval from fever onset
to evaluation at each hospital was 28 days. lished in Japan, but have been limited to
The longest time required for diagnosis involved a case single-facility or limited-region studies7 8; no
of familial Mediterranean fever. Tests performed nationwide studies have yet been conducted.
included blood cultures in 86.8%, serum procalcitonin Moreover, few assessments of tests used in
in 43.8% and positron emission tomography in 29.8% the diagnostic evaluation of FUO have been
of patients. reported. In particular, few studies have
Conclusions: With the widespread use of CT, FUO assessed the clinical usefulness of tests such
due to deep-seated abscess or solid tumour is as serum procalcitonin or positron emission
decreasing markedly. Owing to the influence of the tomography (PET) in Japan, although these
ageing population, polymyalgia rheumatica was the tests are now frequently used.
most frequent cause (9 patients). Four patients had
We therefore conducted a multicenter col-
FUO associated with HIV/AIDS, an important cause of
laborative retrospective study of patients with
FUO in Japan. In a relatively small number of cases,
cause remained unclear. This may have been due to FUO at hospitals affiliated with the Japanese
For numbered affiliations see
bias inherent in a retrospective study. This study Society of Hospital General Medicine. This is
end of article.
identified diseases that should be considered in the the first nationwide study in Japan on dis-
differential diagnosis of FUO. eases causing FUO and the diagnostic
Correspondence to
workup, and identified diseases that should
Dr Toshio Naito;
naito@juntendo.ac.jp be considered when evaluating FUO in

Naito T, Mizooka M, Mitsumoto F, et al. BMJ Open 2013;3:e003971. doi:10.1136/bmjopen-2013-003971 1

Open Access

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Japan. In addition, we investigated the rate of perform-
ing various tests in the current diagnostic workup of
FUO.

METHODS
Among 99 hospitals affiliated with the Japanese Society
of Hospital General Medicine that were asked to partici-
pate in this study, 17 hospitals participated. The hospi-
tals participated in our study had a wide geographic
distribution throughout Japan, including 7 hospitals in
Eastern Japan and 10 hospitals in Western Japan. These
17 hospitals included 13 university hospitals and 4 com-
munity hospitals. Data were collected by these participat-
ing hospitals from patients ≥18 years who were Figure 1 Age and sex distribution of fever of unknown origin
diagnosed with ‘classical fever of unknown origin’ patients.
between 1 January and 31 December 2011. The data
were recorded on standardised case report forms and
disease (NIID) in 37 (30.6%), malignancy in 13
were collected by fax.
(10.7%), other in 15 (12.4%) and unknown in 28
Classical FUO was diagnosed based on the definition
(23.1%; figure 2). The most common causative disease
by Durack et al9 in patients meeting all of criteria 1–4
was polymyalgia rheumatica (PMR; 9 patients), followed
below.
by malignant lymphoma (8 patients) and adult Still’s
1. Fever with axillary temperature ≥38°C at least twice
disease (7 patients). Among the nine patients with PMR,
over a ≥3-week period.
coexisting giant cell arteritis was ruled out by PET in
2. Unknown cause after three outpatient visits or during
four patients and temporal artery biopsy in one patient.
3 days of hospitalisation.
In the remaining four patients, symptoms and the
3. Not diagnosed with immunodeficiency before fever
success of treatment with low-dose steroids suggested
onset.
PMR alone. Table 1 lists the frequent causative diseases.
4. No confirmed HIV infection before fever onset.
The prognosis in patients with undiagnosed FUO has
Axillary temperature is usually measured in Japan, so
been reported as relatively good.10 In our study as well,
fever was defined as a temperature ≥38°C.
among 28 patients with undiagnosed FUO, only 3 died
The data described below were collected. No add-
(10.7%). Among the three patients who died with
itional testing was performed in this study due to insuffi-
undiagnosed FUO, one was a 72-year-old man who
cient data.
developed disseminated intravascular coagulation (DIC)
▸ Patient characteristics: sex, age, concomitant disease,
2 months after fever onset and died. Another was an
medical history and medication history.
82-year-old man who similarly developed DIC of
▸ Clinical findings: subjective symptoms and objective
unknown cause 1 month after fever onset and died. The
physical findings.
other was a 63-year-old woman in whom the cause of
▸ Blood tests: blood count, biochemical examination
FUO remained unknown despite PET and random skin
and inflammatory markers (C reactive protein (CRP),
biopsies. This patient developed respiratory failure
erythrocyte sedimentation rate (ESR), procalcitonin).
about 6 months after fever onset and died.
▸ Results of blood cultures if performed.
▸ Results of imaging studies and endoscopy if
performed.
▸ Results of cytology, histology, genetic testing or
autopsy findings if performed.
▸ Final diagnosis, day of diagnosis and outcome.

RESULTS
A total of 121 patients with FUO were enrolled at the 17
participating hospitals. There were 52 women (43.0%),
and the median patient age was 59 years (range 19–
94 years). The most frequent age group was patients in
their 70s (figure 1). There were 112 patients from 13
university hospitals and 9 patients from 4 community
hospitals.
Causative diseases for FUO were infectious disease in Figure 2 Causative disease in fever of unknown origin. NIID,
28 (23.1%) patients, non-infectious inflammatory non-infectious inflammatory disease.

2 Naito T, Mizooka M, Mitsumoto F, et al. BMJ Open 2013;3:e003971. doi:10.1136/bmjopen-2013-003971

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Table 1 Frequent causes
Causes Number (%)
Infection 28 (23.1)
Infectious endocarditis 4
HIV/AIDS 4
Tuberculosis 3
Other 17
NIID 37 (30.6)
Polymyalgia rheumatica 9
Still’s disease 7
Sarcoidosis 3
ANCA-associated vasculitis 3
Rheumatoid arthritis 3
Other 12
Malignancy 13 (10.7)
Malignant lymphoma 8
Castleman’s disease 2
Other 3
Other 15 (12.4)
Drug fever 3
Fraudulent fever 3
Other 9
Unknown 28 (23.1)
ANCA, anti-neutrophil cytoplasmic antibody; NIID, non-infectious
inflammatory disease;.

In patients ≥65 years (51 patients), malignancy as the

causative disease was twice as common as in patients
<65 years, and the cause remained unknown in only a Figure 3 (A) Causative disease in patients <65 years
few of these patients (figure 3). (70 patients). (B) Causative disease in patients ≥65 years
The median duration from fever onset to evaluation at (51 patients).
each hospital was 28 days. Among the 24 patients requir-
ing ≥100 days from fever onset until diagnosis, 10
patients (41.7%) had malignancy, exceeding the of FUO, accounting for 10% of cases.7 The present
number with infection (7 patients, 29.2%; figure 4). study identified NIID as the most common cause.
Among patients with malignancy, 60% had malignant Infections, including tuberculosis, were diagnosed based
lymphoma. The longest time required for diagnosis was on appropriate culture or serological tests, before
a case of familial Mediterranean fever, which required meeting the definition of classical FUO.
≥2 years from the time of fever onset for diagnosis. On the basis of the results of a survey conducted by
Tests performed for diagnostic evaluation included the Organisation for Economic Cooperation and
blood cultures in 86.8%, serum procalcitonin in 43.8%, Development (OECD) in 30 member countries, Japan
gallium scintigraphy in 31.4% and PET in 29.8% of has 92.6 CT scanners and 40.1 MRI scanners per million
patients (figure 5). However, only 1 of 17 patients population, the highest among OECD member coun-
(5.9%) with a serum procalcitonin level ≥0.25 ng/mL tries.11 Because CT and MRI tend to be performed early
showed bacterial infection and 3 patients (11.5%) with a after fever onset, FUO due to deep-seated abscess and
value <0.25 ng/mL also had bacterial infection. solid tumours has decreased markedly. Among our 121
Nine deaths occurred among all 121 patients. The most patients, the only deep-seated abscess was an ovarian
common cause was malignant lymphoma, in four patients. abscess found in one patient, and the solid tumours
Pathological autopsy was performed on a small proportion were renal carcinoma in one patient and anal canal car-
of the patients who died (n=2; 22.2%). The diagnosis was cinoma in one patient only.
malignant lymphoma in both of these autopsied cases. PMR was the most common disease causing FUO
(9 patients) in the present study. This was probably influ-
enced by the ageing of the Japanese population.
DISCUSSION According to data from the Ministry of Internal Affairs
Causative diseases underlying FUO vary by region and and Communications Statistics Bureau, among the total
time period, and evaluation of these causes over a wide population in Japan of 127.34 million, 31.4 million
area using recent data is important. A previous study in (24.7%) are elderly persons ≥65 years, the highest
Japan reported tuberculosis as the most common cause number ever.12 In our study, 42.1% of patients were

Naito T, Mizooka M, Mitsumoto F, et al. BMJ Open 2013;3:e003971. doi:10.1136/bmjopen-2013-003971 3

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ESR of 100 mm/h, including 5 with unknown cause, 2
with PMR and 2 with ANCA-associated vasculitis.
When evaluating FUO, performing differential diag-
nosis for bacterial infections is important, given the
need for prompt antibiotic therapy. It goes without
saying that blood cultures are essential. In patients with
bacteraemia given inappropriate treatment without per-
forming blood cultures, the mortality rate has been
reported as 3.18 times higher compared with patients
with initial appropriate treatment. However, if treatment
is switched based on blood culture results, the mortality
rate is only 1.27 times higher.15
In recent years, the usefulness of serum procalcitonin in
the differential diagnosis of bacterial infections has increas-
Figure 4 Causative disease in patients requiring ≥100 days ingly been reported, and serum procalcitonin is now in
until diagnosis (24 patients). wide use in Japan. Simon et al reported that for differential
diagnosis of bacterial infection from non-infectious disease,
≥65 years. A diagnosis of PMR, which occurs with a rela- serum procalcitonin offers higher sensitivity (88%) and spe-
tively high incidence in elderly patients, must thus be cificity (81%) than CRP (75% and 67%, respectively).16 In
considered for FUO. Moreover, this trend should also be our study, serum procalcitonin was measured in 43.8% of
considered in Western countries, where ageing of the patients. Although use of this test is widespread in Japan,
population is also expected. PMR had an influence, and 5.9% of patients with a serum procalcitonin level ≥0.25 ng/
when participants ≥65 and <65 years were compared, mL showed bacterial infection, and 11.5% of patients with
rates of NIID as a cause of FUO were similar (figure 3). a value <0.25 ng/mL also had bacterial infection. It is,
In Japan, 1529 new HIV infections were reported therefore, difficult to conclude that serum procalcitonin
during 2011,13 and this increase in HIV-infected persons is a superior test for the differential diagnosis of bacterial
is continuing. Our study also found four patients with infection in patients with classical FUO. Serum procalci-
FUO caused by HIV/AIDS. The importance of HIV/ tonin testing is also more expensive than CRP or ESR
AIDS as a cause of FUO will probably continue to testing, so indiscriminate measurement of serum procal-
increase in Japan. In our study, patients already diag- citonin in febrile patients should be avoided.
nosed with HIV infections before meeting the definition PET appears promising as a useful test to evaluate
of classical FUO were excluded. FUO. Many studies have been performed using this
Evaluations vary regarding the usefulness of ESR to modality in patients with FUO, all showing a percentage
diagnose FUO.6 Well-known diseases associated with ESR helpfulness that exceeds that of CT, MRI or other diag-
>100 mm/h include PMR, tuberculosis, multiple nostic possibilities.17–20 However, the fact that PET is not
myeloma and osteomyelitis (vertebral discitis), but malig- covered by National Health Insurance in Japan for
nancies have also been reported in about 60% of such patients with FUO is problematic. A previous Japanese
cases.14 In our study, 18 of 121 patients (14.9%) had an study about PET included patients with FUO evaluated
by radiology departments.21 In the present study, it was
interesting to see the frequency of PET use in general
medical settings, mainly for evaluating FUO.
Previous studies have reported increasing rates of
FUO in which the cause remains unknown.22 23 A pro-
spective study from the Netherlands reported that the
cause of FUO remained unknown in 51% of cases.6 The
rate of ‘unknown’ in our study was relatively small, but
this retrospective study may have encountered bias
because of the difficulty enrolling patients with an
unknown cause after undergoing tests. Furthermore,
retrospective studies also encounter the problem that
there may be no follow-up observation of patients until a
final diagnosis has been obtained. We are planning a
prospective study of patients who are enrolled at the
time when criteria for FUO are fulfilled, to perform
Figure 5 Frequency of tests performed for diagnostic periodic follow-up observations. Only 17 hospitals parti-
evaluation. WCC, white blood cells count; CRP, C reactive cipated in this study, so the results may not be generalis-
protein; ESR, erythrocyte sedimentation rate; Ga, gallium; able to the overall situation in Japan. We hope that
PET, positron emission tomography. more hospitals will participate in future studies.

4 Naito T, Mizooka M, Mitsumoto F, et al. BMJ Open 2013;3:e003971. doi:10.1136/bmjopen-2013-003971

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CONCLUSION non-commercially, and license their derivative works on different terms,
We conducted the first nationwide study of patients with provided the original work is properly cited and the use is non-commercial.
See: http://creativecommons.org/licenses/by-nc/3.0/
FUO in Japan. Our study identified diseases that should
now be considered in the differential diagnosis for FUO.
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