Fever of unknown origin
Fever of unknown origin in children: a systematic review
Amy Chow, Joan L Robinson
Edmonton, Alberta, Canada
Background: There are no previous systematic reviews Key words: collagen vascular disease;
of published pediatric case series describing the etiology of fever of unknown origin;
fever of unknown origin (FUO). The purpose of collecting infection;
these data is to determine the etiologies for children with malignancy
FUO in both developing and developed countries.
Methods: The database Ovid Medline R (1950 to
Systematic review
Introduction
F
August 2009 week 4) and Ovid Embase (1980 to 2010 week
2) were used to conduct the search. Studies in any language ever of unknown origin (FUO) was firstly
were included if they provided the diagnosis in a series of 10 described in 1961 and defined as well-documented
or more children with FUO. The diagnosis of each child at fever of at least 3 weeks duration with no apparent
the time of publication of the study was recorded. source after 1 week of investigations. [1] I t is now
generally accepted that unexplained fever that persists
Results: There were 18 studies that met the inclusion
criteria, describing 1638 children. The diagnosis at the longer than 1 week in a child warrants preliminary
time of publication was malignancy for 93 children (6%), investigations as fever from viral infections generally
collagen vascular disease for 150 (9%), miscellaneous resolves within that time frame. Therefore, most recent
non-infectious conditions for 179 (11%), infection for 832 case series of pediatric FUO require persistence of
(51%), and no diagnosis for 384 (23%). There were 491 fever for only 1 or 2 weeks with negative preliminary
bacterial infections (59% of all infections) with common
investigations, and the investigations required varied by
diagnoses being brucellosis, tuberculosis, and typhoid
study.
fever in developing countries, osteomyelitis, tuberculosis,
This study summarized the literatures on pediatric
and Bartonellosis in developed countries, and urinary
FUO to determine the relative incidence of different
tract infections in both. For children with no diagnosis
etiologies, expecting that etiology will vary by
after investigations, most had fever that ultimately
geographical location related to the economy of the
resolved with no sequelae.
region, the presence of vectors of infection, and the
Conclusions: About half of FUOs in published case
availability of diagnostic tests.
series are ultimately shown to be due to infections with
collagen vascular disease and malignancy also being
common diagnoses. However, there is such a wide variety
Methods
of possibilities that investigations should primarily be
driven by the clinical story. Search methods for identification of studies
The database Ovid Medline R (1950 to August 2009
World J Pediatr 2011;7(1):5-10
week 4) and Ovid Embase (1980 to 2010 week 2) were
used to conduct the search. Key words and phrases used
to refine the search included "fever of unknown origin"
and "pyrexia of unknown origin", limited to children
0 to 18 years. The search was then further limited to
include clinical trials, meta-analysis, epidemiologic
studies, evaluation studies, validation studies, review
Author Affiliations: Department of Pediatrics and Stollery Children's
articles, retrospective and prospective studies. All
Hospital, University of Alberta, Edmonton, Alberta, Canada (Chow A,
Robinson JL)
abstracts were then reviewed.
Corresponding Author: Joan L Robinson, MD, FRCPC Room 8213,
Aberhart Centre One, 11402 University Avenue, Edmonton, AB Canada
Study characteristics
T6G 2J3 (Tel: 780-***-****; Fax: 780-***-****; Email: abqezq@r.postjobfree.com)
Studies were included if they provided the diagnosis
doi:10.1007/s12519-011-0240-5
in a series of 10 or more inpatients or outpatients of
Children's Hospital, Zhejiang University School of Medicine, China and
less than 18 years of age evaluated for FUO persisting
Springer-Verlag Berlin Heidelberg 2011. All rights reserved.
World J Pediatr, Vol 7 No 1 . February 15, 2011 . www.wjpch.com 5
World Journal of Pediatrics
for a minimum of one week duration. Because one had recurrent intussusception that may be due to the
initial fever.[6]
of the goals of the study was to look at the incidence
in different geographic areas, no language restriction The 18 included studies published from 1968 to
was applied. Studies were excluded if they included 2008 consisted of 8 studies (all more than a decade
only acute FUO (fever for less than one week) or old) from only 3 developed countries (Germany, USA
focused only on long-term follow-up of children with and Spain) and 10 studies from developing countries
(Table 1). [8-25] T he number of children in each case
unexplained FUO.
series varied from 10 to 221 (median 89.5) for a total of
1638 children (770 males; 628 females; 240 unknown).
Data extraction
Definitions of FUO varied widely. The values for the
Data were recorded on the demographics and diagnosis
definition of fever varied from minimum 37.5 degrees
at the time of publication for enrolled children. The data
Celsius to minimum 38.9 degrees Celsius. The duration
were separated for studies from advanced economies
of fever ranged from 1 week to 3 weeks with the
(developed countries) versus emerging or developing
Systematic review
majority of the papers requiring a minimum of 2 to 3
economies (developing countries) using International
weeks duration. In terms of the site of investigation,
Monetary Fund classification from 2008 (Imf-
1316 children were inpatients during at least part of
advanced-un-least-developed-2008.svg).
their investigation, 209 were outpatients and for 113 it
was not specified.
Data analysis
The total number of patients with a diagnosis of
This was purely a descriptive study so it was not possible
malignancy was 93 (6%), of which 41 had leukemia,
to report study quality or risk of bias. The etiologies
16 had lymphoma, 23 had other types of malignancy
of fever were classified into the following groups: a)
i n c l u d i n g n e u r o b l a s t o m a, Wi l m s t u m o u r, a n d
infectious diseases, b) malignancy, c) collagen vascular
myeolodysplastic syndrome, and 13 had an unspecified
disease (CVD), d) miscellaneous diseases including
malignancy. The number of patients with a diagnosis of
hemophagocytic lymphohistiocytosis, inflammatory
collagen vascular disease was 150 (9%), of which 90
bowel disease, and any other conditions with a proven
had juvenile idiopathic arthritis, 22 had systemic lupus
etiology, and e) no etiology established at the time of
erythematosis, 27 had some other forms of CVD and 11
publication. Infectious diseases where classified as
patients had an unspecified type of CVD. One hundred
bacterial, fungal, parasitic, or as infectious syndromes
and seventy-nine patients had a miscellaneous non-
with no specified pathogen.
infectious etiology for their fever (11%) (Table 2) with
nonspecified autoimmune disease and inflammatory
bowel disease predominating in developing countries and
Results Kawasaki disease in developed countries.
The search revealed 643 abstracts of which 18 studies Infection was by far the most commonly identified
met the inclusion criteria (13 in English, 2 in French, etiology of FUO in all studies. In total, 832 patients
2 in Spanish and 1 in Polish). Six other studies were (51%) had a final diagnosis of infection with bacterial
excluded as they included children up to 21 years of i nfections followed by infectious syndromes being
age, [1] the duration of fever was less than 1 week in the most common etiologies. There were 491
some children,[2,3] there were less than 10 patients in bacterial infections (59% of all infections) with
the study,[4] or the study was limited to children with common diagnoses of brucellosis, tuberculosis, and
unexplained FUO following a full evaluation. [5,6] typhoid fever in developing countries, osteomyelitis,
Only the latter two studies provided data on a long- tuberculosis, and Bartonellosis in developed countries,
term follow-up of children with FUO. One study and urinary tract infections in both (Table 3). There
looked at children referred to a rheumatology clinic were 58 patients with viral infections (7% of all
with a mean follow-up of 5 years: 32 of 37 children infections) with Epstein-Barr virus (EBV) accounting
had resolution of their fever with no diagnosis, 3 for over half of cases. Another 193 patients (23%
had persistent periodic fever, and 2 had a diagnosis of those with infections) had infectious syndromes
of Crohn's disease. [7] A nother study from Chicago associated with pneumonia accounting for fully one-
reported follow-up of 19 children for a mean of 3.5 quarter of these in developing countries. Fungal
years after assessment: 16 had resolution of their infection was diagnosed in only 3 of the 832 patients,
fever with no established etiology, 2 were eventually but 86 had parasitic infections (10%), predominantly
diagnosed with juvenile idiopathic arthritis, and 1 leishmaniasis in developing countries.
World J Pediatr, Vol 7 No 1 . February 15, 2011 . www.wjpch.com
6
Fever of unknown origin
Table 1. Case series of fever of unknown etiology in children, divided into developed and developing countries and listed in order of the year of publication
n
Study (country, Definition of fever of unknown origin Malignancy Collagen Miscellaneous Infection No diagnosis
year of vascular non-infectious at time of
publication) diseases diagnosis publication
Developed countries
[8]
Fever >39 C, WBC 15 103/ L, duration of fever
Germany 1998 30 0 5 (17%) 5 (17%) 15 (50%) 5 (17%)
minimum 2 weeks and with minimum 1 week of
inpatient evaluation
[9]
USA 1998 Documented daily fever 38 C for at least 14 days 146 4 (3%) 0 16 (11%) 64 (44%) 62 (42%)
without diagnostic signs or symtoms
[10]
Spain 1994 Fever >1 week with rectal temperatures >38.5 C 32 1 (3%) 7 (22%) 0 23 (72%) 1 (3%)
[11]
USA 1991 Fever 38 C at least twice a week for 3 weeks with 109 2 (2%) 8 (7%) 4 (4%) 22 (20%) 73 (67%)
a normal urinalysis and chest X-ray
[12]
Spain 1978 Rectal temperature >38.9 C on multiple occasions for 79 10 (13%) 7 (9%) 3 (4%) 52 (66%) 7 (9%)
minimum 3 weeks outpatient evaluation or minimum
1 week of inpatient evaluation
[13]
USA 1977 Fever >38.3 C with unknown souce after 3 weeks evaluation 54 7 (13%) 8 (15%) 11 (20%) 18 (33%) 10 (19%)
Systematic review
as an oupatient or 1 week inpatient evaluation
[14]
USA 1975 Rectal temperature >38.5 C on >4 occasions for at 100 6 (6%) 16 (16%) 14 (14%) 52 (52%) 12 (12%)
least a 2 week period
[15]
USA 1972 Rectal temperature >38.9 C for a minimum of 3 99 8 (8%) 11 (11%) 19 (19%) 29 (29%) 32 (32%)
weeks outpatient evaluation or minimum 1 week of
inpatient evaluation
Total developed 649 38 (6%) 62 (10%) 72 (11%) 275 (42%) 202 (31%)
countries
Developing countries
[16]
India 2008 Fever >2 weeks with unknown source after history, 49 6 (12%) 1 (2%) 2 (4%) 34 (69%) 6 (12%)
physical exam, and screening lab tests
[17]
Poland 2007 Rectal temperature >38.3 C for duration of 3 weeks 10 0 0 5 (50%) 5 (10%) 0
with no source on initial investigation
[18]
Tunisia 2006 Fever >17 days for kids between 2 and 15 yrs 110 3 (3%) 8 (7%) 9 (8%) 64 (58%) 26 (24%)
[19]
Serbia 2006 Fever >3 weeks with temperature >38.3 C & no 185 12 (6%) 24 (12%) 25 (14%) 70 (38%) 54 (29%)
diagnostic signs or symptoms
[20]
Georgia 2006 Fever >38 C for at least 3 days per week, lasting 52 2 (4%) 2 (4%) 1 (2%) 40 (77%) 7 (13%)
for more than 3 weeks and failure to diagnoze using
complete blood count, urinalysis and chest X-ray
[21]
Tunisia 2004 Fever for 2 weeks with unknown source 67 2 (3%) 14 (21%) 0 38 (57%) 13 (19%)
[22]
Turkey 2003 Fever >37.5 C for greater than 2 weeks with an 80 2 (3%) 5 (6%) 16 (20%) 47 (59%) 10 (13%)
unknown source
[23]
Turkey 2003 Fever >38.3 C for minimum of 3 weeks after 1 week 102 12 (12%) 7 (7%) 26 (25%) 45 (44%) 12 (12%)
intensive investigation
[24]
Argentina 1994 Fever 38.3 C for at least 3 weeks including 1 week 113 11 (10%) 16 (14%) 23 (20%) 41 (36%) 22 (19%)
of intensive investigation
[25]
Kuwait 1990 Rectal temperature 38.3 for a minimum 2 weeks as 221 5 (2%) 11 (5%) 0 173 (78%) 32 (14%)
an outpatient or >1 week investigation as an inpatient
Total developing 989 55 (6%) 88 (9%) 107 (11%) 557 (56%) 182 (18%)
countries
Total all countries 1638 93 (6%) 150 (9%) 179 (11%) 832 (51%) 384 (23%)
In total, 384 patients had FUO with no diagnosis at
Table 2. Miscellaneous diagnoses in children with fever of unknown origin
the time of publication (23%). Resolution of fever by
Developed Developing
Miscellaneous diagnosis
the time of publication in the absence of a diagnosis was
countries* countries
reported in 190 of these 384 patients (49%). Another 25
Autoimmune, non-specified 11 0
Drug-induced 7 1
patients had persisting fever, while the outcome was not
Toxins 2 0
reported for the remaining 169 patients.
Inflammatory bowel disease 12 6
Other than differences in the types of infections
Kawasaki disease 0 27
Factitious fever 2 9
as outlined above, the distribution of etiologies was
Hemophagocytic syndrome 0 10
similar in developed versus developing countries.
Immunodeficiency 1 9
Familial mediterranean fever 0 10
Others 37 35
Total 72 107
Discussion
*: USA, Germany, and Spain; : Tunisia, India, Turkey, Poland,
In the published case series, just over half of cases
Argentina, Serbia, Georgia, and Kuwait.
World J Pediatr, Vol 7 No 1 . February 15, 2011 . www.wjpch.com 7
World Journal of Pediatrics
of cases never have an established diagnosis, and it
Table 3. Infectious etiologies identified in children with fever of
unknown origin
appears the majority of these children eventually have
Developed* Developing resolution of the fever.
Infectious etiologies Total
countries
countries
When comparing data between developed and
Bacterial infections
developing nations, infection is consistently the most
Brucellosis 7 97 104
common cause of FUO but the types of infections
Urinary tract infection 21 40 61
Tuberculosis 22 39 61 vary. With regards to bacterial infections, Bartonella
Typhoid fever 7 47 54
infections were more commonly diagnosed in
Abscess 3 33 36
developed countries while brucellosis, typhoid fever,
Septicemia 9 23 32
tuberculosis, rickettsial infections, and abscesses
Osteomyelitis 25 4 29
Endocarditis 6 14 20 were more common in the developing nations. Viral
Pyelonephritis 11 8 19
etiologies for FUO were more commonly identified
Bartonellosis 10 5 15
in the developed countries, particularly EBV. When
Rickettsiae 0 12 12
looking at infectious syndromes, pneumonia was far
Systematic review
Mycoplasma 0 4 4
Lyme disease 2 0 2 more common in developing nations, presumably
Others 30 12 42
as diagnosis can be delayed because of poor access
Total bacterial 153 338 491
to oximetry or a chest radiography. Some of the
Viral Infections
differences are undoubtedly related to a higher
EBV 31 7 38
Enterovirus 4 0 4 incidence of infections such as tuberculosis or parasitic
CMV 4 3 7
disease in developing countries but other differences
HIV 1 2 3
may relate more to the availability of diagnostic tests.
HSV 1 2 3
The main limitation of the current study is that the
Hepatitis 1 2 3
published case series of FUO over the decades may not
Total viral 42 16 58
Infectious syndromes
be representative of FUO in general in 2010. There is no
Pneumonia 16 32 48
reliable way to judge the quality of the heterogeneous
Respiratory non-specified 6 32 38
descriptive studies included in this review. The data
Viral syndromes non-specified 17 12 29
are biased by inclusion of only limited geographic
Infectious mononucleosis 5 18 23
Meningitis 9 9 18 areas in the 18 studies with only one study from each
Sinusitis 7 3 10
of Asia, Africa, and South America. It is difficult to
Encephalitis 2 0 2
know if this is because clinicians from these continents
Others 9 16 25
did not submit manuscripts or because of publication
Total infectious syndromes 71 122 193
Fungal infections bias favoring studies from North America and Europe.
Blastomycosis 1 0 1
Some conditions such as Kawasaki disease were not yet
Histoplasmosis 1 0 1
recognized when the earliest studies were conducted
Fungal non-specified 0 1 1
while criteria for other diagnoses and the sensitivity
Total fungal 2 1 3
Parasitic infections of diagnostic tests changed over time. The incidence
Leishmaniasis 5 61 66
of vaccine-preventable diseases will have decreased
Malaria 1 10 11
in some countries. Many of the cases classified as
Infected hydatid cysts 1 6 7
" autoimmune" in older studies were likely CVDs.
Toxoplasmosis 0 2 2
Total parasitic 7 79 86 Furthermore, the definition of FUO varied widely in
Unknown infections 0 1 1
the studies, and even were it uniform, the etiology of
Total infections 275 557 832
FUO for minimum one week likely differs from that of
*: USA, Germany, and Spain; : Tunisia, India, Turkey, Poland,
FUO for minimum three weeks. It is disappointing that
Argentina, Serbia, Georgia, and Kuwait. EBV: Epstein-Barr virus;
long-term outcome data are not available for the large
CMV: cytomegalovirus; HIV: human immunodeficiency virus; HSV:
herpes simplex virus.
number of children who had no diagnosis established
for their FUO. This review did not look specifically at
nonclassic FUO (nosocomial, human immunodeficiency
if FUO in children are eventually proven to be from v irus related, or FUO in the immunocompromised
infectious diseases. The majority of these infections are host).[26]
bacterial in origin. A wide variety of malignancies and A recent study from Greece demonstrated that
CVDs account for 6% and 9% of cases respectively, over 85% of adults with FUO had infection if they had
while a broad range of miscellaneous non-infectious two of the following: 1) serum ferritin
diagnoses comprise 11% of cases. About one-quarter eosinophils 60
World J Pediatr, Vol 7 No 1 . February 15, 2011 . www.wjpch.com
8
Fever of unknown origin
mg/L. [27] T here is a great need for large prospective Disclaimers: T his study was presented as a poster at the
Association of Medical Microbiology and Infectious Disease
pediatric studies in developed and developing countries,
Canada Annual Meeting in Edmonton, Alberta Canada May 6-8,
ideally validating this simple predictive scheme and
2010.
testing an algorithm for management.
Based on the current study, limited investigations
should be performed routinely in previously well
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for FUO persisting
Springer-Verlag Berlin Heidelberg 2011. All rights reserved.