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www.elsevierhealth.com/journals/jinf
Drexel University College of Medicine, Section of Infectious Diseases, St. Christopher’s Hospital for
Children, Philadelphia, PA, USA
Available online - - -
KEYWORDS Summary The incidence and likely causes of fever of unknown origin (FUO) have changed
Chikungunka; over the last few decades, largely because enhanced capabilities of laboratory testing and im-
Vertebral osteomyelitis; aging have helped confirm earlier diagnoses. History and examination are still of paramount
Fatigue of importance for cryptogenic infections. Adolescents who have persisting nonspecific complaints
deconditioning; of fatigue sometimes are referred to Pediatric Infectious Diseases consultants for FUO because
Systemic exertion the problem began with an acute febrile illness or measured temperatures are misidentified as
intolerance disease; “fevers”. A thorough history that reveals myriad symptoms when juxtaposed against normal
Herpes simplex virus findings on examination and simple laboratory testing can suggest a diagnosis of “fatigue of de-
conditioning”. “Treatment” is forced return to school, and reconditioning. The management of
patients with acute onset of fever without an obvious source or focus of infection is dependent
on age. Infants under one month of age are at risk for serious and rapidly progressive bacterial
and viral infections, and yet initially can have fever without other observable abnormalities.
Urgent investigation and pre-emptive therapies usually are prudent. By two months of age,
clinical judgment best guides management. Between one and two months of age, a decision
to investigate or not depends on considerations of the height and duration of fever, the pa-
tient’s observable behavior/interaction, knowledge of concurrent family illnesses, and likeli-
hood of close observation and follow up. Children 6 monthse36 months of age with acute
onset of fever who appear well and have no observable focus of infection can be evaluated
clinically, without laboratory investigation or antibiotic therapy, unless risk factors elevate
the likelihood of urinary tract infection.
ª 2016 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
Unfocussed fever: Five cases, five approaches detailed history, physical examination and simple labora-
to diagnosis and management tory testing. The reader is challenged to choose the most
likely etiology or next step in management. The discussions
are focussed to highlight evidence from recent medical
Five cases are presented in which patients came to medical literature.
attention because of fever, yet had no clear cause after a
* St. Christopher’s Hospital for Children, 160 E. Erie Avenue, Section of Infectious Diseases, USA. Tel.: þ1 215 427 5204; fax: þ1 215 427
8389.
E-mail address: sarah.long@drexelmed.edu
http://dx.doi.org/10.1016/j.jinf.2016.04.025
0163-4453/ª 2016 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Long SS, Diagnosis and management of undifferentiated fever in children, J Infect (2016), http://
dx.doi.org/10.1016/j.jinf.2016.04.025
2 S.S. Long
Case 1: Fever and back pain in a returned the 1960s to 1990s, sporadic outbreaks sometimes involving
traveler >100,000 people occurred due to distinct clades in Africa
and Asia. Spread from a 2005 coastal Kenya epidemic to
the islands of the Indian Ocean was the harbinger of world-
Box 1 shows the principal data for this case together with a
wide distribution. In 2007, Italy had the first inter-tropical
question about the most likely diagnosis.
outbreak with indigenous transmission.
An outbreak beginning in late 2013 in the Caribbean led
Chikungunya to >1.5 million clinical cases of chikungunya transmission
documented by mid-2015, with spread to Latin America and
Chikungunya virus is an alphavirus of the family Togaviri- travel-associated cases confirmed in most U.S. states.
dae, which is arthropod-borne, classically transmitted by Indigenous transmission occurred in Florida, Puerto Rico
Aedes aegypti. Gene mutations in the virus envelope in and the U.S. Virgin Islands.2 The Caribbean virus appears to
certain clades have permitted adaptation to a different be an Asia lineage, so far unadapted to Ae. albopictus.3,4
mosquito vector, Ae. albopictus, and expansive transmissi- Ae. aegyptiacus, however, is an aggressive daytime-biting
bility. For chikungunya virus, the important step to sus- mosquito and with high levels of human viremia, transmis-
tained mosquitoehumanemosquito cycle appears to be sion to a na€ıve population occurs in rapid waves, typically
related to human behavior driving vector adaptation, and affecting more than one-third of a population.5
vector adaptation driving virus adaptation.1 In interepi- The majority (72%e97%) of people infected with chikun-
demic periods, chikungunya is maintained in animals, and gunya virus develop symptomatic disease e high fever and
in epidemic periods humans are the reservoir and ampli- bilateral, symmetrical and severe, debilitating arthralgia.6
fying host. Chikungunya virus appears to have originated Acute symptoms abate over 7e10 days, but >50% of pa-
and evolved into distinct clades over centuries in Africa, tients have relapsing or recurring polyarthralgia/arthritis
with a pandemic involving parts of the Western hemisphere or tenosynovitis that can persist for months to years.7
in the 1820s, and identification confirmed during a 1952 The patient’s clinical diagnosis of chikungunya made in
outbreak in southern Tanganyika (now Tanzania). From the Dominican Republic two months prior to admission
likely was correct, considering epidemic disease there at
the time. Recent progressive back pain and elevated
sedimentation rate make postinfectious arthritis a consid-
Box 1. Case 1. 12-year-old Hispanic girl with
eration, however, isolated non-incapacitating back pain
fever and back pain. was not a perfect fit and made further considerations
relevant.
History of presenting illness
Please cite this article in press as: Long SS, Diagnosis and management of undifferentiated fever in children, J Infect (2016), http://
dx.doi.org/10.1016/j.jinf.2016.04.025
Undifferentiated fever in children 3
diseases by far the leading diagnosis followed by autoim- autoimmune and inflammatory bowel disease in developed
mune diseases and then malignancy. Among infectious dis- countries, and Kawasaki disease and familial Mediterranean
eases, EpsteineBarr virus infection (EBV), osteomyelitis, fever in developing countries. Overall, 384 children (23%)
Bartonella infection (cat-scratch disease) and urinary tract had no diagnosis, but a new caveat was reported, i.e.
infection (UTI) were noteworthy. Description of an addi- that fever resolved spontaneously in 49% without a diag-
tional 19 cases of hepatosplenic cat-scratch disease in nosis by the time of series’ publication.
1999 solidified bartonellosis as a prominent cause of FUO Bottieau et al.15 prospectively enrolled 1962 adults who
in children.13 Enigmatic cases of osteomyelitis and UTI came to referral in Belgium for fever episodes within 1 year
would seem odd to have escaped more expeditious diag- after visiting a tropical or subtropical area. Malaria was the
nosis. However, delayed diagnosis of osteomyelitis can most common diagnosis. In studies of children with acute
occur when a subacute course is related to less virulent or- and classic FUO living in tropical areas, malaria and typhoid
ganisms (e.g. Kingella, Actinomyces), partial treatment, or fever were top diagnoses.14,16
involvement of flat bones. UTI can lead to FUO when Our patient had a tuberculin skin test placed, blood and
partially treated, complicated by perinephric infection or urine samples taken for culture, and serologic tests sent for
lobar nephronia, or when congenital anomalies (e.g. dupli- chikungunya, EBV and Bartonella antibodies. Blood smear
cated ureter) cause intermittent obstruction and recovery and antigen tests for Plasmodium were negative. Magnetic
in urine of no bacteria or non-enteric pathogens in low den- resonance imaging of her spine was performed. Images are
sity. In 2011, Chow and Robinson14 performed a systematic shown in Fig. 1. Osteomyelitis of lumbar 4e5 vertebrae with
review of 18 studies (1638 cases) of FUO in children across paravertebral abscess was diagnosed.
continents. Separating reports from developed and devel-
oping countries, infection was diagnosed frequently in
both settings (42% and 56%, respectively). However, compli- Vertebral osteomyelitis
cations of pneumonia, brucellosis, tuberculosis and typhoid
fever dominated in developing countries versus EBV infec- Vertebral osteomyelitis represents <2% of cases of osteo-
tion, osteomyelitis, tuberculosis, cat-scratch disease and myelitis in children. Inoculation of bone occurs hematoge-
UTI in developed countries. Miscellaneous diagnoses were nously (or through rich local plexus draining the gut),
confirmed in 11% in both settings, predominantly directly (e.g., spinal surgery) or from adjacent soft tissue
Figure 1 Sagittal and axial (at level shown by white bar on sagittal image) magnetic resonance images of Case 1 on fluid atten-
uated inversion recovery (FLAIR), and pre and post contrast sequences. Images demonstrate osteomyelitis with lytic lesions and
contrast-enhancing inflammation of lumbar bodies 4 and 5, and enhancing paravertebral soft tissue abscess (arrows). Lower right
image shows CT-guided site of aspiration.
Please cite this article in press as: Long SS, Diagnosis and management of undifferentiated fever in children, J Infect (2016), http://
dx.doi.org/10.1016/j.jinf.2016.04.025
4 S.S. Long
Please cite this article in press as: Long SS, Diagnosis and management of undifferentiated fever in children, J Infect (2016), http://
dx.doi.org/10.1016/j.jinf.2016.04.025
Undifferentiated fever in children 5
Table 2 Typical findings in patients with fatigue of Cases 3: Acute febrile illness in a 14-day-old
deconditioning. and a 6-week-old infant without clinical focus
Age >12 years. Girls > boys of infection
Pre-illness achievement high
Family expectations high
Onset easily dated to an acute febrile illness/injury Box 3 shows the principal data with questions about the
Escalated family and outside attention most likely diagnosis and the appropriate further manage-
Lengthy list, but vague complaints ment of fever in two cases: a 14-day-old infant and a 6-
Odd complaints (e.g., “shooting” pains, 30-s “blindness”, week-old infant.
stereotypic jerks, “paralysis”)
No daytime sleep
Preserved weight Bacterial infection in very young infants
Normal physical and neurologic examination
Normal results of screening lab tests Management of the very young febrile infant must take into
consideration the infant’s limited ability to localize and
Please cite this article in press as: Long SS, Diagnosis and management of undifferentiated fever in children, J Infect (2016), http://
dx.doi.org/10.1016/j.jinf.2016.04.025
6 S.S. Long
Please cite this article in press as: Long SS, Diagnosis and management of undifferentiated fever in children, J Infect (2016), http://
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Undifferentiated fever in children 7
case series of 32 infants in Philadelphia brought for illness Seattle infants with HSV diagnosis in whom plasma PCR
confirmed to be perinatally acquired HSV, 50% had only testing was performed at diagnosis. Overall, 83% had HSV
nonspecific symptoms or signs at presentation (i.e., absent DNA detected in plasma: 100% of those categorized with
skin or mucous membrane lesions or neurologic signs/sei- disseminated disease, 64% with CNS disease and 78% with
zures), which was fever in 75%.27 Of the 32 infants, 75% skin or mucous membrane disease. It is our practice to
had CNS HSV confirmed (predominantly by CSF PCR testing); perform PCR testing for HSV (and other viruses as appro-
CNS HSV was confirmed in 40% of infants presenting with priate) on CSF and plasma samples and to administer
mucocutaneous lesions, 83% with seizures, and 94% with acyclovir empirically to infants with onset of illness at
only nonspecific symptoms/signs. Importantly, 94% with 21 days of age (Case 3a, E) but not for hospitalized infants
HSV diagnosis who presented with nonspecific symptoms/ 28 days of age (Case 3b) because of extreme rarity of
signs had onset of illness at 21 days of age. A similarly nonspecific presentation of HSV in the latter group. With re-
collected case series from St. Louis and Salt Lake City re- striction of empiric use to infants <28 days of age with
ported 49 infants with HSV diagnosed before 6 weeks of nonspecific illness, number-needed-treat to treat one in-
age. Sixteen percent (8 patients) had only nonspecific fant with HSV might be 300e400 infants.
symptoms/signs on admission; 7 patients had fever, 7 Case 3a was evaluated fully and treated with acyclovir
were <28 days of age at presentation, and 7 had positive as well as antibiotics empirically. CSF examination showed:
CSF PCR test.28 Among w7000 febrile infants 60 days of WBCs 7/mm,3 RBCs 13/mm,3 glucose 56 mg/dL, protein
age evaluated in Salt Lake City from 2004 to 2015, 0.3% 92 mg/dL; PCR testing was positive for HSV. The infant
had HSV; incidence was 0.9% in those 14 days and 1.6% developed seizures on hospital day 3, but had negative
in those with CSF pleocytosis.28 CSF PCR on day 5, an otherwise uncomplicated 3-week
Nonspecific/febrile manifestations of perinatally ac- course of therapy and normal magnetic resonance imaging
quired HSV likely are early presentations of CNS infection. study of the brain at discharge.
Differences across studies may be related to differences in
incidence of HSV and use of EDs for acute care, where
complete testing and hospitalization of mildly ill neonates Case 4: Fever in a 6-month-old infant
is standard. Shah et al.29 reviewed an administrative data-
base of 41 freestanding children’s hospitals, collected 1098 Box 4 shows the principal data for this case together with a
cases of confirmed perinatal HSV infection treated with question about the appropriate further management.
acyclovir, and found odds ratio of death of 2.63 (95% CI, In a prospective study of 620 infants 4 weeks to 24 months
1.36e5.08) for infants in whom commencement of acyclovir of age with rectal temperature of 38.3 C evaluated at the
was delayed until hospital day 2 or 3 compared with hospi- Boston City Hospital in 1973 and 1974, 3.2% unexpectedly had
tal day 1. In a 2011e2013 retrospective cohort study of ED
management of 35,000 febrile infants at 37 U.S. children’s
hospitals, 32% of 7712 infants 28 days of age were given
acyclovir empirically.30 Universal empiric acyclovir therapy Box. 4. Case 4. A 6-month-old boy with fever
has not been recommended by any official body in the U.S. for 36 h.
as standard of care at this time.
Table 4 shows this author’s approach to management of History of presenting illness
young infants who appear well and have fever without a
focus of infection. Melvin et al.31 published findings on 63 A previously healthy infant boy was well until
acute onset of high fever.
Except for decreased feeding there are no other
Table 4 An approach to management of the well- symptoms or signs.
appearing young infant with unfocussed fever.
Examination findings
“All” infants <28 days should be hospitalized
e Perform usual tests and cultures plus CSF/plasma
for PCR testing for HSV EV, HPeV (depending Temperature is 39 C.
on season, seizures) Physical examination is reassuring.
e Administer acyclovir 60 mg/kg/day IV if onset The boy is circumcised.
illness 21 days of age, or for clarity of algorithms,
admission <28 days of age Question 5. My management plan would be to/to
Infants 60 days of age can be evaluated clinically perform
Individualize management for infants 28e59 days of age
e Consider family illness, height and duration of
A. Observe at home with follow up <24 h
fever, sex, circumcision
e Use laboratory tests, hospitalization, antibiotics
B. Urinalysis with further management pending
selectively results
e Minimize use of pathway of full evaluation C. CBC with further management pending results
followed by administration of ceftriaxone and D. CBC, urinalysis & culture, blood
observation at home for those meeting low-risk criteria culture þ ceftriaxone IM and observe at home
e Do not pursue HSV as etiology of unfocussed fever with follow up <24 h
E. Tests of D above þ CSF þ admit to hospital
Please cite this article in press as: Long SS, Diagnosis and management of undifferentiated fever in children, J Infect (2016), http://
dx.doi.org/10.1016/j.jinf.2016.04.025
8 S.S. Long
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dx.doi.org/10.1016/j.jinf.2016.04.025
Undifferentiated fever in children 9
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Please cite this article in press as: Long SS, Diagnosis and management of undifferentiated fever in children, J Infect (2016), http://
dx.doi.org/10.1016/j.jinf.2016.04.025