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Journal of Infection (2016) xx, 1e9

Diagnosis and management of

undifferentiated fever in children
Sarah S. Long*

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
E-mail address:
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://
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
History of presenting illness

 Progressive back pain over 1 month e flexion Fever of unknown origin

worse, supine & walking OK.
 2 months previously, had fever and back pain for 2 In a landmark publication by Petersdorf and Beeson in
weeks while in Dominican Republic. Dx of chikun- 1961,8 fever of unknown origin (FUO) was codified for pur-
gunya made. poses of clinical approach to require temperature >38.3  C
(101  F) documented on most days for >3 weeks, and no
Examination findings diagnosis after 1 week of hospitalization. In the 1990s, de-
Kleijn et al.9 modernized the definition by replacing stay in
 37  C, BMI 29 (97th centile), vital signs normal. hospital with non-diagnostic computed tomography, if any
Lying supine without pain. localizing sign or symptom was present. The availability
 No vertebral/paraspinal tenderness. Loss of of improved diagnostic tests and imaging aided earlier diag-
normal lordotic curvature. noses and led to dwindling cases of FUO and shuffling of eti-
 Straight leg raising causes pain in lumbar spine. ologies. Durack and Street in 199110 grouped FUO by
settings of occurrence, each having distinctive differential
Investigations diagnoses: neutropenic host, nosocomial onset, HIV-
associated, and classic (no clear predisposition). Horowitz11
 Hb 12.4 g/dL, Hct 35.8%, WBC 9800 (49% neutro- reviewed relative importance of categories of etiology re-
phils), Platelets 361,000. ported in FUO studies, primarily in adults, from 1961 to
 CRP 1.8 mg/dL, ESR 62 mm/h, protein 7.5 g/dL, 2007. Progressively over years, relative importance of
albumin 3.7 g/dL. infection fell from 36% to 16% and was replaced with “no
diagnosis” rising from 9% to 51%, and “noninfectious inflam-
Question 1. The most likely diagnosis is matory disease” exchanged place with “neoplasm” (each
accounting for 22% and 7%, respectively in 2007). The fall
A. Chikungunya in infectious etiologies likely reflects improving capability
B. Another infectious disease for earlier diagnosis rather than changes in disease
C. An oncologic diagnosis incidence.
D. A rheumatologic diagnosis Studies of FUO in children are limited. Jacobs and
E. Nonspecific musculoskeletal pain Schutze in 199812 reported 146 children with fever for >2
weeks. Diagnoses were made in 58%, with infectious

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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.

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4 S.S. Long

infection. The usual cause is Staphylococcus aureus or Es-

cherichia coli, and occasionally, Salmonella. Zimmerli Box 2. Case
2. A 15 year-old-girl referred for
et al.17 reviewed clinical and laboratory manifestations in prolonged fever and fatigue.
reported cases of vertebral osteomyelitis in adults
(Table 1). Insidious onset, lack of tenderness over the History of presenting illness
spine, and negative blood cultures in a substantial propor- 12 weeks ago: Acute 39.4  C, headache, myalgia,
tion of patients makes the diagnosis difficult until imaging sore throat, congestion
is performed. Vertebral osteomyelitis frequently is compli- Throat culture negative Group
cated by paravertebral (26%) or epidural (17%) extension, A Streptococcus
with resulting lower extremity weakness or paralysis in 38%. Following week: Fever and congestion abated
CT-guided aspiration of our patient’s paraspinal abscess Since then: Persisting temp (37.7  C every
(Fig. 1) revealed purulent material. Gram stain showed only 2e3 days)
WBCs, but Salmonella enterica, subspecies enterica sero- Headache, sore throat, weakness,
type Typhi was isolated from culture. Following a brief hospi- fatigue
talization, cefotaxime was administered intravenously (IV) Poor color and appetite
as an outpatient to complete 4 weeks, followed by ciproflox- 4 weeks ago: Attempted return school
acin orally for 2 weeks. Transition from IV to oral therapy was 2 h in: Reported to school nurse feeling
based on multiple studies of effectiveness, and a 6-week to- faint, chilly, sweaty, unable to
tal course on the 2014 report of a randomized controlled trial stay in class
in 359 French patients with vertebral osteomyelitis, which Since then: No return to school and now is
showed non-inferiority of 6-week versus 12-week therapy.18 home tutored
The patient has been symptom free for 12 months. With the Past history: No medical problems; “A” student;
knowledge of denouement, the patient’s febrile illness two Advanced science; Swim team;
months prior likely was typhoid fever and insidious progres- Church choir; Volunteer elder
sion of vertebral osteomyelitis was classic. The answer to center
Question 1 is B, cued by history of travel.
Question 2a. The most likely diagnosis is
Case 2: Prolonged fever and fatigue in an
A. Classic infectious disease of FUO
adolescent girl
B. Malignancy
C. Periodic fever syndrome
Box 2 shows the principal data for this case together with D. Rheumatologic syndrome
questions about the most likely diagnosis and the most E. None of these
appropriate further management. No diagnosis listed rises
to favored status with the information given (Question 2, Question 2b. What is your next diagnostic step?
Answer E), and obtaining more history is the next best
“diagnostic step” (Question 2a, Answer A). A. More history
Further history delineated these symptoms. Tempera- B. Referral to neurologist
ture peaks between 1600 and 2000 at <100  C. Headache is C. CT of the abdomen
diffuse, is relieved by acetaminophen and does not awaken D. MRI of the brain
her from sleep. Sore throat is only on awakening and is not E. Screening lab tests CBC, ESR, chemistries
worse with swallowing. Weakness has no pattern (e.g.,
Question 2c. The most likely diagnosis is

Table 1 Clinical & laboratory manifestations of vertebral A. Cryptogenic infection

osteomyelitis. B. Rheumatologic/autoinflammatory disease
Clinical findings C. Malignancy
Back pain 86% D. Fatigue of deconditioning
Fever 60% E. Psychiatric disorder
Weakness/sensory deficit/radiculo 30%
Tenderness over the spine 20%
Clinical course
Clinical picture dominated by back pain Most proximal, distal, truncal). She feels fatigued, yet retires at
Extravertebral source found 50% 2300, sleeps through the night, awakens at 0800 and does
Laboratory findings not sleep during the day. She has not lost weight, but rather
Time from onset of pain to diagnosis 42e59 days has gained 2 kg. The patient reports shooting pains (at
Elevated WBC or neutrophilia >80% multiple body areas lasting <10 s), eyes feeling “weird”,
Elevated sedimentation rate 98% heart “jumping”, stomach feeling “weird”, and feeling
Elevated C-reactive protein 100% faint upon arising. Mother has fibromyalgia, grandmother
Blood culture positive 30%e78% is in hospice after failing cancer therapy, and father works
at night. Parents work schedules have been changed to
Data from Zimmerli.17 accommodate the girl’s illness. Findings on complete

Please cite this article in press as: Long SS, Diagnosis and management of undifferentiated fever in children, J Infect (2016), http://
Undifferentiated fever in children 5

physical and neurologic examinations, including ophthal-

Table 3 Building the therapeutic alliance for manage-
moscopic examination, are normal. Height and weight are
ment of fatigue of deconditioning.
80e90th percentile, heart rate is 110, she is flushed,
animated and helpful with the examination. Complete For the patient: Validate symptoms as accurate
blood count, screening chemistry tests and urinalysis show Treatment:
normal results. Sedimentation rate is 9 mm/h. Incremental, forced return to school
The most likely diagnosis is fatigue of deconditioning Exercise program
(Question 2C, Answer D). The major clue is the remarkable Predict exacerbation of symptoms
mismatch of the long list of symptoms yet weight gain, No school absence is permitted without visit
normal findings on examination and normal laboratory test to medical provider
results 12 weeks into the problem. The only other possible No expectation of performance is allowed
differential diagnoses were abuse (excluded by open-ended Focus is to be back at school among classmates
private interview with the patient) and depression and friends
(excluded by the patient’s demeanor, expression of feeling For the family:
loved and supported, and interest in school, friends and the Validate their concern
future). Validate their medical pursuit
Table 2 summarizes typical findings in patients with fa- Justify your diagnosis and lack of need for further
tigue of deconditioning. Use of the operational “diagnosis” medical pursuit
of “deconditioning” is preferred by the author over Express confidence in the diagnosis and good prognosis
“chronic fatigue syndrome”, the latter which describes a Treatment:
serious, complex systemic condition with a guarded prog- Change focus to health
nosis in adults, and which would lead families to much Avoid asking “How do you feel?”
internet-based misinformation if applied to most patients No expectation of performance is allowed
referred to pediatric infectious diseases specialists. For the primary provider:
Indeed, the Institute of Medicine recently has proposed Take control and be firm on the rehabilitation plan
that the names for the adult conditions known as “chronic Discourage further subspecialist referrals
fatigue syndrome” and “myalgic encephalopathy” be aban- Encourage frequent visits/examinations and assure
doned and replaced with “systemic exertion intolerance continuous oversight
The diagnosis of fatigue of deconditioning would be
highly unlikely in a child <10 years of age, and this author
Any day that the patient “can’t go” or “must” be picked up
has not made the diagnosis unless the parents’ or patient’s
earlier than scheduled is coupled with a visit to the primary
pre-illness expectations of achievement were high. The
provider. Since patients truly are deconditioned, incremen-
operational dynamic may be that the patient’s
tal forced exercise also is key. Using a trainer is a highly suc-
achievement-based self-worth or valued place in the family
cessful approach, as this person is outside the family
is made impossible temporarily because of an acute illness
dynamic, and the patient usually responds to coach-
or injury. The patient loses self-esteem and fears that
ingeinterestepraise of such a person. Many deconditioned
declaration of health will lead to resumption of expecta-
patients have orthostatic intolerance. In a controlled study
tions, and meanwhile captures family and external atten-
of military recruits, exercise ameliorated symptoms,20 and
tion because of illness. Frequently there is a model of
in a small pediatric study of patients with orthostatic hypo-
illness or loss in the family, as in our patient’s case.
tension, static handgrip coupled with rising abolished symp-
In this author’ experience, the vast majority of affected
toms and minimized cardiovascular changes.21 Validating a
patients do well with management as summarized in Table 3.
real (not imaginary or contrived) problem, engaging parents
Incremental forced return to school is paramount, and
and the patient to promise “no expectation of performance”,
frequently is prescribed at graduating hours of attendance.
and re-focusing attention on health rather than illness are
essential parts of a therapeutic alliance.

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

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6 S.S. Long

infants 28 through 89 days of age. They favored full evalu-

Box 3. Case 3a. A 14-day-old infant with ation and if low risk criteria were met, administration of
fever for 6 h. Case 3b. A 6-week-old infant one dose of ceftriaxone, discharge from the Emergency
with fever for 6 h. Department (ED) and re-evaluation by a provider 24 h later.
These “guidelines” were not derived or vetted through
History of presenting illness formal processes as guidelines would be currently, and
were not endorsed by the American Academy of Pediatrics
 Born at term to 20-year-old mother by vaginal (AAP) or an Infectious Diseases Society. The approach was
delivery. adopted by Emergency Medicine physicians in the U.S. but
 No maternal complications during pregnancy or not by pediatricians practicing in the community. In 2004,
delivery. the AAP’s Pediatric Research in the Office Setting (PROS)
 Infant was well until acute onset fever 38.5  C and collaborative group published their case series using a clin-
decreased feeding. ical prediction model, and confirmed similar prevalence of
SBI/meningitis in the community as in the ED.25 PROS data
Examination findings showed an odds ratio for SBI/meningitis of 5.5 for age 30
days compared with 61e90 days, and incidence of 0.4% in
minimally ill appearing infants 25e60 days of age with tem-
 Examination is reassuring.
perature <38.6  C. Although only 46% of PROS practitioners
 No exanthem, rhinorrhea.
adhered to the 1993 “guidelines” for evaluation and hospi-
talization of all febrile infants 30 days of age, and only
Question 3. My management plan would be to/to
42% performed any testing of minimally ill appearing infants
31e90 days of age, their management choices had 97%
sensitivity (i.e., similar to ED’s testing approach) for treat-
A. Observe at home with follow up <24 h
ment of infants with SBI/meningitis at the first encounter.
B. Blood culture þ observe at home with follow up
The dichotomy of approach in EDs and practitioners’ offices
<24 h
has persisted in the U.S., and may be appropriate depend-
C. Blood, urine and CSF tests/cultures þ if reassur-
ing on age. There remains for this author urgent concern for
ing, ceftriaxone IM þ observe at home with follow
the febrile infant <28 days of age, who may have serious
up <24 h
infection but no other observable signs of illness. By 6
D. Blood, urine and CSF tests/cultures þ admit þ IV
weeks of age, the infant is able to smile meaningfully and
to show observable interest in the environment when
E. D above þ HSV PCR on CSF/plasma þ acyclovir
well. Such reassuring findings in a newly, modestly febrile
infant can permit safe management without testing or
treatment when constant family observation and repeated
control infection, and inability of parents and providers to medical evaluations can be performed. Although there is
determine degree of illness because of undeveloped behav- not a single correct answer, this author would choose hos-
ioral milestones. Although likeliness of a serious bacterial pitalization (D or E) for Case 3a and observation (A) for
or disseminated viral infection is predictable by high fever Case 3b. Remembering that a blood culture is not therapeu-
or hypothermia, ill appearance (e.g., poor color, tone, tic, and bacteremia is not benign in young infants, one
attention to a face) and abnormally high or low white blood should not be “observing” a patient at home with a blood
cell count, lack of such findings does not exclude serious culture in the laboratory (Cases 3a and 3b, answer B is
infection. Attempts to identify febrile young infants at low incorrect).
risk for serious bacterial infection (SBI) led to distillation of
infant characteristics/findings with high negative predic-
tive values (NPVs). The “Rochester criteria” published in Nonspecific presentation of perinatally acquired
1990 concluded a NPV of >95% if the infant was well herpes simplex virus infection
appearing with no risk factors other than age, had no
suspected site of infection, had a total WBC count >5000 Although perinatally acquired herpes simplex virus (HSV)
and <15,000 cells/mm3, urinalysis with 10 WBCs/hpf and infection is uncommon, and at least one-third of patients
stool (if diarrheal) with 5 WBCs/hpf.22 The “Pittsburgh have characteristic skin or mucous membrane lesions, HSV
criteria” published in 2001 concluded a NPV approaching must be considered in very young infants who appear ill or
100% by adding a negative CSF evaluation and enhanced uri- have fever alone. In a retrospective series of 5817 neonates
nalysis showing <10 cells/mm3 and negative Gram stain.23 without underlying conditions admitted to Texas Children’s
In 1993, several pediatric infectious diseases and emer- Hospital for any reason, 4.6% had serious bacterial infection
gency medicine subspecialists developed “practice guide- and 8.4% had viral infection confirmed (prior to availability
lines” for management of febrile infants <90 days of age of respiratory panel polymerase chain reaction (PCR)
who appeared well and had no source determined by exam- tests).26 For febrile neonates, 14.2% had bacterial infection
ination.24 Their consensus opinion was that all infants <28 and 0.3% had HSV confirmed. HSV infection was more
days of age should be evaluated (including blood, urine frequent than bacterial infection, however, among infants
and CSF tests and cultures) and hospitalized e with discre- 8e14 days of age (0.6% vs. 0.2%, respectively), in neonates
tionary use of empiric antibiotic therapy pending culture with hypothermia (1.1% vs. none) and in neonates with fe-
results. Options for management were proposed for febrile ver and CSF mononuclear pleocytosis (1.6% vs. 0.8%). In a

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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://
8 S.S. Long

a positive blood culture, which was Streptococcus pneumo- Conflict of interest

niae in w80% of cases.32 Fever 39  C, age 7e18 months,
and WBC 15,000 cells/mm3 were associated with positive Dr. Long has no conflict of interest to disclose.
blood culture. Called “benign pneumococcal bacteremia”
because the vast majority of infections resolved spontane-
ously, the “practice guidelines” of 1993 and U.S. Pediatric
Emergency Medicine community, nonetheless, subscribed
to performance of WBC count in children 3e36 months of
age with unfocussed high fever, and if WBC was 1. Morens DM, Fauci AS. Chikungunya at the door e déja  vu all
15,000 cells/mm3, obtaining a blood culture and adminis- over again? N Engl J Med 2014;371:885e7.
tering a dose of ceftriaxone prior to ED discharge.24,33 2. [accessed 8.01.16].
“Glitches” in the “guidelines” were noted: variable 3. Weaver SC. Arrival of chikungunya virus in the new world: pros-
incidence of pneumococcal bacteremia and meningitis pects for spread and impact on public health. PLoS Negl Trop
across studies; knowledge that in the vast majority, Dis 2014;8:e2921.
bacteremia is self-limited; lack of evidence that the 4. Weaver SC, Osorio JE, Livengood JA, Chen R, Stinchcomb DT.
approach reduced meningitis; risk of entering ill children Chikungunya virus and prospects for a vaccine. Expert Rev Vac-
cines 2012;11:1087e101.
into the management pathway or potential dismissal from
5. Staples JE, Fischer M. Chikungunya virus in the Americas e
concern of children with WBC <15,000 (both typical of what a vectorborne pathogen can do. N Engl J Med 2014;
Haemophilus influenzae b); or consideration that >90% of 371:887e9.
patients given a parenteral antibiotic had no bacterial 6. Staples JE, Breiman RF, Powers AM. Chikungunya fever: an
infection but could have clinical follow up clouded, leading epidemiological review of a re-emerging infectious disease.
to additional testing.34 Finally, community practitioners Clin Infect Dis 2009;49:942e8.
did not pursue well-appearing febrile infants and toddlers 7. Jaffar-Bandjee MC, Ramful D, Gauzere BA, Hoarau JJ, Krej-
with testing or treatment e to no adverse outcome. bich-Trotot P, Robin S, et al. Emergence and clinical insights
Although this “practice guideline” also was not endorsed into the pathology of chikungunya virus infection: chronic
by the AAP or an Infectious Diseases Society, it was com- arthralgia, pain and arthritis post-CHIK. Expert Rev Anti Infect
Ther 2010;8:987e96.
mon practice in U.S. EDs for the next two decades.35
8. Petersdorf RG, Beeson PB. Fever of unexplained origin: report
With universal implementation of pneumococcal conjugate of 100 cases. Medicine (Baltimore) 1961;40:1e30.
vaccines (PCVs) such approach now seems indefensible. 9. deKleijn EM, van Lier HJ, van der Meer JWfor The Netherlands
The efficacy trial that led to licensure of PCV7 showed FUO Study Group. Fever of unknown origin (FUO) II: diagnostic
>97% reduction in cases of vaccine serotype pneumococcal procedures in a prospective multicenter study of 167 patients.
bacteremia. Early studies of impact of PCV13 in young chil- Medicine 1997;76:401e4.
dren across nine countries in the Americas, Europe and 10. Durack DT, Street AC. Fever of unknown origin e re-examined
Israel show substantial reduction of invasive disease due and redefined. Curr Clin Top Infect Dis 1991;11:35e51.
to the added vaccine serotypes as well as evidence of indi- 11. Horowitz HW. Fever of unknown origin or fever of too many or-
rect community protection.36e46 Pneumococcal bacter- igins? N Engl J Med 2013;368:197e9.
12. Jacobs RF, Schutze GE. Bartonella henselae as a cause of pro-
emia in a well appearing, previously healthy infant/
longed fever and fever of unknown origin in children. Clin
toddler in 2016 would be extremely rare. In fact, children Infect Dis 1998;26:80e4.
with invasive pneumococcal disease in the PCV13 era 13. Arisoy ES, Correa AG, Wagner ML, Kaplan SL. Hepatosplenic
rarely have occult illness or unfocussed fever, rather cat-scratch disease in children: selected clinical features and
they have underlying conditions and obvious tissue sites treatment. Clin Infect Dis 1999;28:778e84.
of infection.47 A UTI is the most relevant, treatable infec- 14. Chow A, Robinson JL. Fever of unknown origin in children: a
tion in young children with unfocussed fever. A danger of systematic review. World J Pediatr 2011;7:5e10.
continuing use of the WBC as pivotal to action in EDs is 15. Bottieau E, Clerinx J, van den Enden E, van Esbroeck M,
that infection due to non-pneumococcal pathogens, espe- Colebunders R, van Gompel A, et al. Fever after a stay in the
cially Gram-negative bacillary urinary tract pathogens tropics. Diagnostic predictors of the leading tropical condi-
tions. Medicine 2007;86:18e25.
and S. aureus, frequently is not associated with WBC count
16. Akpede GO, Abiodun PO, Sykes RM. Acute fevers of unknown
>15,000/mm3. origin in young children in the tropics. J Pediatr 1993;122:
The recent ability to detect many respiratory tract 79e81.
viruses by PCR testing of nasopharyngeal specimens (or 17. Zimmerli W. Vertebral osteomyelitis. N Engl J Med 2010;362:
plasma or both) confirms what was assumed. In a U.S. 1022e8.
prospective study of >200 children 2e36 months of age 18. Bernard L, Dinh A, Ghout I, Simo D, Zeller V, Issartel B, et al.
with acute onset of fever without a focus, 75% had virus Antibiotic treatment for 6 weeks versus 12 weeks in patients
detected. Somewhat surprisingly, approximately one-third with pyogenic vertebral osteomyelitis: an open-label, non-
of positive PCR tests were from plasma specimens only.48 inferiority, randomized, controlled trial. Lancet 2015;385:
Although the Case 5 boy has high fever, he is circumcised 875e82.
19. Institute of Medicine. Beyond myalgic encephalomyelitis/-
and lacks other risk factors for UTI. His risk of UTI is <1%.49
chronic fatigue syndrome: redefining an illness. Report Guide
The best answer to Question 5 is A. The patient had no tests for Clinicians. Institute of Medicine of the National Academies.
performed. Fever abated after three days, when a faint [accessed 8.01.16].
pinpoint macular, non-coalescent exanthem appeared on 20. Winker R, Barth A, Bidmon D, Ponocny I, Weber M, Mayr O,
the face and trunk, typical of roseola. et al. Endurance exercise training in orthostatic intolerance:
a randomized, controlled trial. Hypertension 2005;45:391e8.

Please cite this article in press as: Long SS, Diagnosis and management of undifferentiated fever in children, J Infect (2016), http://
Undifferentiated fever in children 9

21. Clarke DA, Medow MS, Taneja I, Ocon AJ, Stewart JM. Initial of invasive pneumococcal disease in Norway. Vaccine 2013;
orthostatic hypotension in the young is attenuated by static 31:6232e8.
handgrip. J Pediatr 2010;156:1019e22. 37. Guevara M, Ezpeleta C, Gil-Setas A, Torroba L, Beristain X,
22. Powell KR. Evaluation and management of febrile infants Aguinaga A, et al. Reduced incidence of invasive pneumococcal
younger than 60 days of age. Pediatr Infect Dis J 1990;9: disease after introduction of the 13-valent conjugate vaccine
153e7. in Navarre, Spain, 2001e2003. Vaccine 2014;32:2553e62.
23. Herr SM, Wald ER, Pitetti RD, Choi SS. Enhanced urinalysis im- 38. Tam P-YI, Madoff LC, Coombes B, Pelton SI. Invasive pneumo-
proves identification of febrile infants ages 60 days and coccal disease after implementation of 13-valent conjugate
younger at low risk of serious bacterial illness. Pediatrics vaccine. Pediatrics 2014;134:210e7.
2001;108:866e71. 39. Harboe ZB, Dalby T, Weinberger DM, Benfield T, Mølbak K,
24. Baraff LJ, Bass JW, Fleisher GR, Klein JO, McCracken Jr GH, Slotved HC, et al. Impact of 13-valent pneumococcal conjugate
Powell KR, et al. Practice guideline for the management of in- vaccination in invasive pneumococcal disease incidence and
fants and children 0 to 36 months of age with fever without a mortality. Clin Infect Dis 2014;59:1066e73.
source. Ann Emerg Med 1993;22:1198e210. 40. Moore CE, Paul J, Foster D, Mahar SA, Griffiths D, Knox K, et al.
25. Pantell RH, Newman TB, Bernzweig J, Bergman DA, Reduction of invasive pneumococcal disease 3 years after the
Takayama JI, Segal M, et al. Management and outcomes of introduction of the 13-valent conjugate vaccine in the Oxford-
care of fever in early infancy. JAMA 2004;291:1203e12. shire region of England. J Infect Dis 2014;210:1001e12.
26. Caviness AC, Demmler GJ, Almendarez Y, Selwyn BJ. The prev- 41. Lepoutre A, Varon E, Georges S, Dorléans F, Janoir C,
alence of neonatal herpes simplex virus infection compared Gutmann L, et al. Impact of the pneumococcal conjugate vac-
with serious bacterial illness in hospitalized neonates. J Pe- cines on invasive pneumococcal disease in France, 2001e2012.
diatr 2008;153:164e9. Vaccine 2015;33:359e66.
27. Long SS, Pool TE, Vodzak J, Daskalaki I, Gould JM. Herpes sim- 42. Camacho-Badilla K, Falleiros-Arlant LH, Brea J, Avila-Aguero ML.
plex virus infection in young infants during 2 decades of Challenges in the surveillance of invasive pneumococcal disease
empiric acyclovir therapy. Pediatr Infect Dis J 2011;30: in the postvaccination era. J Pediatr 2015;4:91e3.
556e61. 43. Moore MR, Link-Gelles R, Schaffner W, Lynfield R, Lexau C,
28. Curfman A, Glissmeyer EW, Ahmad FA, Korgenski EK, Bennett NM, et al. Effect of use of 13-valent pneumococcal
Blashke AJ, Byington CL, et al. Initial presentation of neonatal conjugate vaccine in children on invasive pneumococcal dis-
herpes simplex virus infection. J Pediatr 2016;172:121e6. ease in children and adults in the USA: analysis of multisite,
29. Shah SS, Aronson PL, Mohamad Z, Lorch SA. Delayed acyclovir population-based surveillance. Lancet 2015;15:301e9.
therapy and death among neonates with herpes simplex virus 44. Ben-Shimol S, Greenberg D, Givon-Laevi N, Schlesinger Y,
infection. Pediatrics 2011;128:1153e60. Somekh E, Aviner S, et al. Early impact of sequential introduc-
30. Aronson PL, Thurm C, Alpern ER, Alessandrini EA, Williams DJ, tion of 7-valent and 13-valent pneumococcal conjugate vac-
Shah SS, et al. Variation in care of the febrile young infant <90 cine on IPD in Israeli children <5 years: an active prospective
days in US pediatric emergency departments. Pediatrics 2014; national surveillance. Vaccine 2014;32:3452e9.
134:667e76. 45. Farnham AC, Zimmerman CM, Papadouka V, Konty KJ,
31. Melvin AJ, Mohan KM, Schiffer JT, Drolette LM, Magaret A, Zucker JR, Nattanmai GV. Invasive pneumococcal disease
Corey L, et al. Plasma and cerebrospinal fluid herpes simplex following the introduction of 13-valent conjugate vaccine in
virus levels at diagnosis and outcome of neonatal infection. J children in New York City from 2007 to 2012. JAMA Pediatr
Pediatr 2015;166:827e33. 2015;169:646e52.
32. Teele DW, Pelton SI, Grant MJA, Herskowitz J, Rosen DJ, 46. Kaplan SL, Barson WJ, Lin PL, Romero JR, Bradley JS, Tan TQ,
Allen CE, et al. Bacteremia in febrile children under 2 years et al. Early trends for invasive pneumococcal infections in chil-
of age: results of cultures of blood of 600 consecutive febrile dren after the introduction of the 13-valent pneumococcal
children seen in a “walk-in” clinic. J Pediatr 1975;87:227e30. conjugate vaccine. Pediatr Infect Dis J 2013;32:203e7.
33. Fleisher GR, Rosenberg N, Vinci R, Steinberg J, Powell K, 47. Yildirim I, Shea KM, Little BA, Silverio AL, Pelton SI. Vaccina-
Christy C, et al. Intramuscular versus oral antibiotic therapy tion, underlying comorbidities, and risk of invasive pneumo-
for the prevention of meningitis and other bacterial sequelae coccal disease. Pediatrics 2015;135:495e503.
in young, febrile children at risk for occult bacteremia. J Pe- 48. Colvin JM, Muenzer JT, Jaffe DM, Smason A, Deych E,
diatr 1994;124:504e12. Shannon WD, et al. Detection of viruses in young children
34. Long SS. Antibiotic therapy in febrile children: “best-laid with fever without an apparent source. Pediatrics 2012;130:
schemes.”. J Pediatr 1994;124:585e8. e1455e62.
35. Jhaveri R, Byington CL, Klein JO, Shapiro ED. Management of 49. Roberts KB, Subcommittee on Urinary Tract Infection, Steering
the non-toxic-appearing acutely febrile child: a 21st century Committee on Quality Improvement and Management.
approach. (Medical Progress). J Pediatr 2011;159:181e5. American Academy of Pediatrics. Urinary tract infection: clin-
36. Steens A, Bergsaker MA, Aaberge IS, Ronning K, Vestrheim DF. ical practice guidelines for the diagnosis and management of
Prompt effect of replacing the 7-valent pneumococcal conju- the initial UTI in febrile infants and children 2 to 24 months.
gate vaccine with the 13-valent vaccine on the epidemiology Pediatrics 2011;128:595e610.

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