CAUSE OF PROLONGED FEVER

1. Cho CY, Lai CC, Lee ML, Hsu CL, Chen CJ, Chang LY, Lo CW, Chiang SF, Wu KG.
Clinical analysis of fever of unknown origin in children: A 10-year experience in a
northern Taiwan medical center. Journal of Microbiology, Immunology and Infection.
2017 Feb 1;50(1):40-5.

Background: Fever of unknown origin (FUO) was first described in 1961 as fever >38.3C for at
least 3 weeks with no apparent source after 1 week of investigations in the hospital. Infectious
disease comprises the majority of cases (40-60%). There is no related research on FUO in
children in Taiwan. The aim of this study is to determine the etiologies of FUO in children in
Taiwan and to evaluate the relationship between the diagnosis and patient’s demography and
laboratory data.
Methods: Children under 18 years old with fever >38.3_C for >2 weeks without apparent source
after preliminary investigations at Taipei Veterans General Hospital during 2002-2012 were
included. Fever duration, symptoms and signs, laboratory examinations, and final diagnosis were
recorded. The distribution of etiologies and age, fever duration, laboratory examinations, and
associated symptoms and signs were analyzed.
Results: A total of 126 children were enrolled; 60 were girls and 66 were boys. The mean age
was 6.7 years old. Infection accounted for 27.0% of cases, followed by undiagnosed cases
(23.8%), miscellaneous etiologies (19.8%), malignancies (16.6%), and autoimmune disorders
(12.7%). Epstein-Barr virus (EBV) and cytomegalovirus (CMV) were the most commonly found
pathogens for infectious disease, and Kawasaki disease (KD) was the top cause of miscellaneous
diagnosis.
Conclusions: Infectious disease remains the most common etiology. Careful history taking and
physical examination are most crucial for making the diagnosis. Conservative treatment may be
enough for most children with FUO, except for those suffering from malignancies.

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2. Chien YL, Huang FL, Huang CM, Chen PY. Clinical approach to fever of unknown
origin in children. Journal of Microbiology, Immunology and Infection. 2017 Dec
1;50(6):893-8.

Background/purpose: Fever of unknown origin (FUO) can be caused by many clinical

conditions and remains a diagnostic challenge in clinical practice. The etiology of FUO varies
markedly among different age groups, geographic areas, and seasons. A four-stage 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
Taichung 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
patients (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
history, physical examination, laboratory analysis, and adequate invasive procedures provide
adequate data to identify the most common causes of FUO in children.

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3. Tezer H, Ceyhan M, Kara A, Cengiz AB, Devrim I, Seçmeer G. Fever of unknown
origin in children: the experience of one center in Turkey. Turk J Pediatr. 2012 Nov
1;54(583):9.

Knowledge about the etiology of fever of unknown origin (FUO) has been changed under the
influence of new advances in diagnostic techniques in both adulthood and childhood. Seventy-
seven patients with the diagnosis of FUO were evaluated retrospectively. Forty-six (60%) of the
patients were male and 31 (40%) were female, with ages ranging from 4 months to 16 years
(mean: 4.5 years). Physical findings were absolutely normal in 33 (42.9%) patients, and the most
common findings were hepatosplenomegaly (15.5%) and lymphadenopathy (15.5%). The
etiologies were determined in 69 patients with FUO. The most common diagnoses were
infectious diseases (50.7%), malignancy (14.4%), collagen vascular disorders (7.2%), and
miscellaneous conditions (27.5%). With the development of diagnostic tools, the etiologies in a
considerable number of patients with FUO were diagnosed. A detailed history and physical
examination are required for accurate diagnosis, and if indicated, invasive procedures should be
instituted.

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4. Latupeirissa D. Demam Berkepanjangan pada Anak di RSUP Fatmawati Tahun 2008-2010.
Sari Pediatri. 2016 Nov 17;14(4):241-5.

Latar belakang. Demam berkepanjangan merupakan penyebab penting morbiditas dan

mortalitas pada anak, terutama di negara-negara tropis dan sedang berkembang. Diagnosis sering
sulit ditentukan sehingga perlu diteliti etiologi dan karakteristik demam berkepanjangan pada
anak, khususnya di RSUP Fatmawati, Jakarta.
Tujuan. Mengetahui karakterisrik penyebab demam berkepanjangan pada anak di RSUP
Fatmawati. Metode. Penelitian deskriptif retrospektif dilakukan untuk melihat karakteristik dan
etiologi pasien demam berkepanjangan yang dirawat di SMF Kesehatan Anak RSUP Fatmawati.
Populasi anak dengan diagnosis demam berkepanjangan diambil dari data rekam medis sejak
Januari 2008 hingga Desember 2010.
Hasil. Angka kejadian pasien demam berkepanjangan di SMF Kesehatan Anak RSUP Fatmawati
0,68% (60/8808 pasien), sebagian besar laki-laki. Rerata usia adalah 7,28±3,91 tahun. Penyebab
terbanyak penyakit infeksi 97%, yaitu demam tifoid, tuberkulosis paru dan infeksi saluran
kemih. Sebagian besar pasien berusia > 6 tahun, memiliki status gizi kurang. Kuman terbanyak
ditemukan pada biakan darah dan urin yaitu Salmonella typhi dan E.coli.

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Kesimpulan. Penyakit infeksi masih merupakan penyebab utama demam berkepanjangan pada
anak.

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5. Chow A, Robinson JL. Fever of unknown origin in children: a systematic review. World
Journal of Pediatrics. 2011 Feb 1;7(1):5-10.

Background: There are no previous systematic reviews of published pediatric case series
describing the etiology of fever of unknown origin (FUO). The purpose of collecting these data
is to determine the etiologies for children with FUO in both developing and developed countries.
Methods: The database Ovid Medline R (1950 toAugust 2009 week 4) and Ovid Embase (1980
to 2010 week 2) were used to conduct the search. Studies in any language were included if they
provided the diagnosis in a series of 10 or more children with FUO. The diagnosis of each child
at the time of publication of the study was recorded.
Results: There were 18 studies that met the inclusion criteria, describing 1638 children. The
diagnosis at the time of publication was malignancy for 93 children (6%), collagen vascular
disease for 150 (9%), miscellaneous non-infectious conditions for 179 (11%), infection for 832
(51%), and no diagnosis for 384 (23%). There were 491 bacterial infections (59% of all
infections) with common diagnoses being brucellosis, tuberculosis, and typhoid fever in
developing countries, osteomyelitis, tuberculosis, and Bartonellosis in developed countries, and
urinary tract infections in both. For children with no diagnosis after investigations, most had
fever that ultimately resolved with no sequelae.
Conclusions: About half of FUOs in published case series are ultim ately shown to be due to
infections withcollagen vascular disease and malignancy also being common diagnoses.
However, there is such a wide variety of possibilities that investigations should primarily be
driven by the clinical story.

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6. Hassan RH, Fouda AE, Kandil SM. Fever of unknown origin in children: a 6 year-
experience in a tertiary pediatric Egyptian hospital. International journal of health
sciences. 2014 Jan;8(1):13.

Background: Fever of unknown origin (FUO) is among the most conditions which poses
challenge in diagnosis. The presence of information on regional patterns of FUO will shorten the
time for diagnosis and reduces health services costs. There are almost no previous studies
describing the etiology of FUO in children of Egypt or nearby countries.
Aim of the Study: To determine different causes of FUO and the possible diagnostic
procedures.
Methods: Data of patients with FUO, presented to the Infectious Diseases Unit of Mansoura
University Children Hospital, were retrospectively collected in a 6 year-period from May 2006 to
May 2011. The study included children with a fever of 38.3° C or more documented by a health
care provider and for which the cause could not be identified after 3 weeks of evaluation as an
outpatient or after a week of evaluation in hospital. Patients were then categorized into 5 groups.
Results: 127 patients met the diagnostic criteria. Infectious diseases were the commonest causes
of FUO in 46 cases (36.22%) followed by the miscellaneous causes in 38 cases (29.9%).
Meanwhile, collagen vascular diseases and malignancy were diagnosed in 13 cases (10.2%) and
10 cases (7.87%) respectively. While, 20 cases (15.75%) remained undiagnosed.
Conclusions: Infectious diseases are the commonest cause of FUO. The delay in diagnosis was
due to atypical presentationsor inappropriate use of antibiotic prior to the referral. Non infectious
causes, malignancy and collagen or vascular disorders were diagnosed in rest of the patients.
However, about 15% of our patients remained undiagnosed. The diagnosis was established by
non-invasive means in more than two-third of the cases.

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Figure 1: Final diagnosis in 1٢٧ children with FUO. *Others: Hyper IgD syndrome,
Kawasaki disease, Crohn’s disease, Diabetes insipidus, Sinus histiocytosis, Factitious fever,
Oesinophilic gastritis, Chronic granulomatous disease (one patient for each diagnosis)

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Figure 3: Comparison of the patterns of FUO in different developing countries.

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 7. Niehues T: The febrile child: diagnosis and treatment. Dtsch Arztebl Int 2013;
110(45): 764−74. DOI: 10.3238/arztebl.2013.0764

Background: Fever accounts for 70% of all consultations with pediatricians and family
physicians. Fever without an identifiable cause (<7 days’ duration) and fever of unknown origin
(FUO, ≥ 7 days’ duration) are particularly challenging clinical situations.
Methods: This article is based on a selective literature search for publications containing the
term “pediatric fever management,” with special attention to meta-analyses and systematic
reviews.
Results: The mainstay of diagnosis is physical examination by a physician who is experienced in
the care of children and adolescents. The frequency of severe bacterial infection (SBI) is about
10% in neonates, 5% in babies aged up to 3 months, and 0.5% to 1% in older infants and
toddlers. The mortality of SBI in neonates is about 10%. Both the degree of the parents' and the
physician’s concern are important warning signs for SBI. Clinical signs of SBI include cyanosis,
tachypnea, poor peripheral perfusion, petechiae, and a rectal temperature above 40°C.
Antipyretic drugs should only be used in special, selected situations. More than 40% of cases of
FUO are due to infection; in more than 30% of cases, the cause is never determined.
Conclusion: Aspects of central importance include the repeated physical examination of the
patient, and parent counseling and education of medical and nursing staff pertaining to the
warning signs for SBI. Research is needed in the areas of diagnostic testing and the development
of new vaccines.

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