r -=---

Fever in Children
Victor Nizet, MD, Robert J. Vinci, MD, and
Frederick H. Lovejoy, Jr, MDt

rogen called interleukin-1 (Fig. 1). result of the catabolism of phospho-

FOCUS QUESTIONS This compound (also known as lym- lipids in endothelial cells of the cen-
1. What is the mechanism of action phocyte-activating factor), in con- tral nervous system to arachidonic
of the antipyretic drugs most use- junction with interleukin-2, is acid, then by the enzyme cyclo-oxy-
ful for treating children?
responsible for increasing the number genase through endoperoxides, and
2. What nonpharmacologic measures
are helpful in the treatment of fe- of helper T cells and initiating the ultimately to prostacyclins, prosta-
ver in children? production of prostaglandins in the glandins, and thromboxanes (Fig. 3).
3. What is the epidemiology of occult hypothalamus. Helper T cells are in-
bacteremia?
strumental in fighting infections; Treatment
4. What is the differential diagnosis
of fever of unknown origin in in-
prostaglandins are responsible for
The febrile child may be treated with
fants, children, and adolescents? producing fever.
antipyretic drugs or by nonpharma-
Phagocytic leukocytes, when acti-
cologic adjunctive measures. The use
vated by leukotrienes, prostaglandins,
of antibiotics in the management of
and calcium, phagocytose the exoge-
Fever is the most common presenting patients who have suspected infec-
nous pyrogen and synthesize the en-
complaints in pediatric practice, ac- tious etiologies is discussed sepa-
dogenous pyrogen interleukin-1 (Fig.
counting for 10% to 20% of office rately in the sections on acute fever
2). Monocytes and macrophages are
and emergency room visits. and fever of unknown origin.
particularly productive of interleukin-
1, leukocytes and eosinophils less so,
Pathophysiology of Fever and lymphocytes not at all. ANTIPYRETICS

Three pathophysiologic bases exist Interleukin-1 acts on the arachi- How do prostaglandins and antipyret-
for fever. The first involves the rais- donic acid pathway, stimulating the ics affect body mechanisms so as to
ing of the hypothalamic set point in production of prostaglandins in the raise and lower body temperature?
the central nervous system. Infection, vascular endothelial cells of the hy- Current evidence suggests that mi-
collagen vascular disease, and malig- pothalamus. Prostaglandins form as a croinjections of prostaglandins in-
nancies are most commonly responsi-
ble. This type of fever is lowered by
antipyretics and physical removal of Exogenous Pyrogens
heat. A second type of fever is a re-
sult of heat production exceeding Viruses Endotoxin
heat loss as, for example, in salicy- Bacteria Ag-Ab complexes I
Fungi Drugs
late overdose, hyperthryroidism, ex-
cessive environmental temperature,
and malignant hyperthermia. The
third type of fever is caused by de- Antigen +

fective heat loss, as seen with ecto- Sensitized - Phagocytic Leukocytes

T-Cells __________
dermal dysplasia, heat stroke, and
poisoning via anticholinergic drugs. ( Monocytes
Antipyretics are ineffective for the
I Macrophages
Neutrophils
second and third types of fever.

Biologic Process of Fever lnterleukin-1 < - lnterleukin-1

Reduction
lymphocyte-activating) endogenous pyrogen)
Fever occurs as a result of a number
of complex
ogenous
biologic
pyrogens,
interactions.
including
Ex-
viruses, 4,
Interleukin-2 T-Cell
4,
Preoptic Anterior
bacteria, fungi, antigen-antibody -

Hypothalmic Nuclei
complexes, and drugs, are engulfed
by phagocytic
the production
leukocytes,
of an endogenous
leading to
py-
4,
Proliferation of 4,
Helper T-Cells Prostaglandins
*From
Children
Pediatrics,
the Department
s Hospital,
of Medicine,
and the Departments
Boston City Hospital, Harvard
The
of 4,
Fever
Medical School, and Boston University
School of Medicine, Boston MA. FIGURE 1: Mechanisms of fever production.

Pediatrics in Review Vol. 15 No. 4 April 1994 127

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 INFECTIOUS DISEASE

Fever of Unknown Origin

roidal agents have anti-inflammatory

Exogenous Pyrogens
activity.
+
Phagocytic Leukocytes NONPHARMACOLOGIC
ADJUNCTIVE MEASURES
Leukotrienes
Prostagiandins 4 4, 4, intracellular
Calcium
In addition
means
temperature,
to the pharmacologic
of lowering
adjunctive
elevated body
approaches
may be taken. Since the rate of fluid
Activated Leukocytes) loss may be increased as a result of
an elevated temperature, it is impor-

I,
tant for the febrile child to receive
de-repression
adequate hydration. In addition,
maintenance of adequate intravascu-
New DNA lar volume allows for better heat dis-
sipation. The child, however, should
transcription not be overhydrated, which can occur
when large volumes of water or non-
New RNA electrolyte-containing solutions are
administered, because this runs the
risk of hyponatremia. Sponging with

I, translation tepid water has been shown

fective in lowering fever.
to be ef-
When this
(Endogenous Pyrogen measure is used by itself, however,
(Interleukin-1) J body temperature quickly returns to
its previous level as a result of shiv-
ering, which attempts to bring the
FIGURE 2: Mechanisms for the production of endogenous pyrogen.
body temperature back up to the un-
treated elevated set point. For these
crease the firing rate of cold-sensitive fever include: 1) situations where ad-
reasons, sponging is considered use-
cells in the preoptic anterior nuclei verse effects associated with the use
ful only as an adjunct to antipyretic
and decrease the activity of warm- of antipyretics outweigh the benefits
therapy; the combination of tepid
sensitive cells, resulting in shifting of of fever reduction; 2) situations
water sponging and an antipyretic
the set point to a higher temperature where reducing fever may obscure
may result in more rapid and effec-
setting. The body responds to a diagnostic or prognostic signs; 3) the
tive temperature lowering than anti-
colder peripheral skin temperature by generally recognized view that most
pyretic therapy alone, often
vasoconstriction, which decreases fever is short-lived and benign; and
decreasing patient discomfort and
heat loss, and through increased shiv- 4) an increasing body of information
allaying parental concern. Parents
ering, which increases heat genera- suggesting that fever may protect the
should be advised to use tepid water
tion. Antipyretics lower the central host.
because cold water will increase dis-
set point, resulting in the periphery It now is clear that aspirin, acet-
comfort. Finally, although alcohol
feeling hot at the skin surface. The aminophen, and nonsteroidal anti-
baths or sponging have been recom-
body lowers its temperature by vaso- inflammatory drugs exert their anti-
mended in the past, this measure has
dilation, which increases heat loss, pyretic effect through inhibition of
fallen out of favor because the alco-
and lying quietly, which minimizes the cyclo-oxygenase enzyme, thereby
hol can be absorbed through inhala-
heat generation. preventing synthesis of prostaglan-
tion and through the skin surface,
Arguments exist both for and dins from arachidonic acid (Fig. 3).
potentially leading to alcohol-induced
against lowering fever. Arguments Because they do not suppress inter-
hypoglycemia and even coma.
for include: 1) decreasing the dis- leukin-1, they do not diminish prolif-
Fever may occur as an acute event
comfort associated with fever and, eration of helper T cells and, thus,
or as a prolonged symptom in the pe-
often, settling an apprehensive home do not adversely affect the bodys
diatric patient. The following two
environment; 2) keeping extreme ability to fight infection. Corticoste-
sections will review the approach to
temperature elevations (>41#{176}Cto roids in vitro and in vivo, on the
the child whose fever is acute as well
41.6#{176}C[106#{176}Fto 107#{176}F])from caus- other hand, decrease interleukin-1 re-
as the child whose fever is of un-
ing permanent damage to the central lease from monocytes and macro-
known origin (FUO).
nervous system; and 3) decreasing, phages quantitatively. This activity
in theory, the likelihood of a febrile is, in fact, detrimental to the bodys
seizure in those who have such sei- ability to fight infection. Acute Fever and Bacteremla
zures, although no study has demon- Aspirin, acetaminophen, and non- The most vexing clinical question to
strated that treatment of fever steroidal anti-inflammatory agents all be answered in any febrile child is:
decreases the incidence of febrile sei- have excellent antipyretic and analge- Is this fever a marker for occult bac-
zures. Arguments against lowering sic activity. Only aspirin and nonste- teremia? As opposed to the term

128 Pediatrics in Review Vol. 15 No. 4 April 1994

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 INFECTIOUS DISEASE
Foyer of Unknown Origin

cus, and on rare occasions, enteric

lnterleukin-1
pathogens. Although the incidence of

4,
Phospholipids
bacteremia
constant,
various organisms
has remained
the relative
essentially
importance
has changed
of
con-
siderably. Previously, H influenzae
phospholipase A2 type b was reported as the responsi-
ble organism in 25% of bacteremic
children. Two recent studies have de-
Arachidonic acid Leukotrienes scribed an incidence of H influenzae
lipogenase
bacteremia of 2 of 27 (7.4%) and 9
cyclo-oxygenase
of 192 (4.7%).
Because infections due to H influ-
Endoperoxides enzae often are more severe than
those due to other organisms, chil-
dren who have H influenzae disease
often require hospitalization at the in-
4, itial visit. Other reasons for the de-
Prostacyclins Prostaglandins Thromboxanes dine of H injluenzae disease include
(PGE-2)
the effectiveness of the H influenzae

Fever
I, conjugate
the presence
community.
vaccine and a decline in
of the organism
The decline in H influ-
in the

enzae disease may be more signifi-

FIGURE 3: Catabolic pathway of arachidonic acid.
cant epidemiologically because the
rate of complications was higher with
sepsis, which should be used only children who were managed in the H inj7uenzae type b than with other
to describe the ill-appearing febrile ambulatory setting (Table 1). Most bacteria.
child, occult bacteremia refers to the studies have confirmed a 3% to 5%
relatively well-appearing child whose incidence of bacteremia in this age
blood culture is positive for a patho- group. Occult bacteremia occurs EVALUATION
genie organism. The primary clinical most commonly in the child 3 to 36 The differential diagnosis of the
concern in children who have occult months of age because of both im- acutely febrile child includes benign
bacteremia is the small but important munologic and epidemiologic factors. conditions such as viral upper respi-
percentage of those who develop sec- These include the normal decline of ratory tract infections and serious in-
ondary complications from invasive protective maternal antibodies, bacte- fections such as bacteremia and
bacterial disease-most notably, rial colonization of the nasopharynx, meningitis (Table 2). Distinguishing
meningitis, septic arthritis, and bacte- increased contact with other ill chil- between these entities requires the
rial sepsis. Therefore, the approach dren, and the virulence and invasive expertise of an experienced clinician
to the febrile child requires manage- nature of the organisms usually re- who is well-versed in the subtle pre-
ment strategies that can identify the sponsible for bacteremia. sentations of the diseases that under-
child at risk for bacteremia and use Although Streptococcus pneumo- lie the fever.
of treatment options that diminish the niae is the most common organism The history of any febrile child
risk of secondary complications. that produces occult bacteremia, should focus on the duration and
other bacterial pathogens remain im- height of the fever as well as on as-
EPIDEMIOLOGY portant, including Haemophilus influ- sociated symptoms such as vomiting
Numerous epidemiologic studies have enzae type b, Neisseria meningitidis, and diarrhea, respiratory symptoms,
delineated the causative organisms of Salmonella sp, group A Streptococ- and a history of rash (especially pete-
occult bacteremia. Early reports of
pneumococcal bacteremia in pediatric
Table I. Etiology of Occult Bacteremlat In Children who
patients in the ambulatory
peared in the medical
early 1970s. Subsequently,
setting ap-
literature in the
Klein and
I Have Bacteremia (N = 192)
ETIOLOGIC AGENT NUMBER OF CASES
colleagues reported their finding that
occult bacteremia occurred in 3.2% Streptococcus pneumoniae 167
of 600 consecutive febrile children Haemophilus influenzae type b 9
from the walk-in clinic at Boston
Salmonella 4
City Hospital. A more recent multi-
center study involving 6794 febrile Neisseria meningitidis 2
children (temperature >39.0#{176}Cand Other 10
ages 3 to 36 months) found a 2.9%
eMufticenter Occult Bacteremia Study Group
incidence of occult bacteremia in

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 INFECTIOUS DISEASE
Fever of Unknown Origin
-

ize a bacterial focus of infection such

Table 2. DIfferential Diagnosis of the Child Who Has as otitis media. Tachypnea out of
Acute Fever proportion to the degree of fever,
even in the absence of focal pulmo-
Upper Respiratory Tract Disease nary findings, suggests pneumonia.
Viral respiratory tract disease Sinusitis is supported by a history of
Otitis media chronic nasal discharge, especially if
Sinusitis mucopurulent. The presence of su-
Lower Respiratory Tract Disease prapubic or costal vertebral angle
Bronchiolitis tenderness suggests an acute urinary
Pneumonia tract infection. A detailed musculo-
skeletal examination, including a
Gastrointestinal Disorders careful examination of the childs
Bacterial gastroenteritis gait, may help uncover the some-
Viral gastroenteritis times elusive diagnoses of septic ar-
Musculoskeletal Infections thritis or osteomyelitis.
Cellulitis Finally, a detailed neurologic ex-
Septic arthritis amination, including mental status
Osteomyelitis changes, is required to diagnose the
child who may have a central ner-
Urinary Tract Infections vous system (CNS) infection.
Despite a careful assessment, the
Bacteremia
clinician frequently is faced with the
Meningitis dilemma of the febrile child who has
no discernible focus of infection. In
such a case, it may prove helpful to
chiae). Additionally, assessment of PHYSICAL EXAMINATION augment the clinical examination
neurologic functioning should include The first step in the physical exami- with laboratory data.
behavioral changes such as irritability nation of a febrile child should be a
and lethargy as well as parental esti- careful consideration of his or her LABORATORY EVALUATION

mate of the degree of illness and the general appearance. In the hands of The laboratory evaluation can be
childs level of interaction. A careful an experienced clinician, this assess- used to identify the child who is at
review of any known exposures ment remains the most important as- increased risk for bacteremia as well
should include family illnesses and ill pect of the physical examination. as to diagnose infections that may
contacts with other children, espe- Observation scales such as the Acute not be apparent on clinical examina-
cially in settings such as child care Illness Observational Scale may help tion. Most studies seeking to identify
centers. The childs immunization to focus assessment of the ill child the child at risk have focused on
status and travel history may provide and predict the risk of significant ill- the utility of the peripheral white
valuable information. A history of ness. Using this scale, McCarthy and blood cell count. Because of an asso-
previous serious infections, such as colleagues found that children who ciation of peripheral white blood cell
bacteremia and meningitis; recurrent had scores greater than 10 were more counts > 15 000/mm3 with the pres-
bacterial infections; loss of splenic likely to have serious bacterial infec- ence of occult bacteremia, decision
function; or the presence of immuno- tions compared with children whose analysis studies have attempted to re-
logic disorders, such as human im- scores were less than 10. While there fine the approach to the febrile child.
munodeficiency virus (HIV) is no evidence of an improved out- A recent study by Jaffe et al, for ex-
infection, sickle cell disease, and hy- come in children who are evaluated ample, suggested that a white blood
pogammaglohulinemia and other im- via such observation scales, they re- cell count > 15 000/mm3 is an insen-
munodeficiency disorders, indicates main helpful as a mechanism to fo- sitive marker for occult bacteremia
an increased risk for bacterial dis- cus the examiner on the behavioral and suggested instead that a value of
ease. Finally, the use of antibiotics and interactive state of the child. > 10 000/mm3 be used when making
and antipyretics may have implica- Careful observation and analysis of decisions regarding presumptive anti-
tions for the evaluation of febrile vital signs, state of hydration, and microbial therapy. Other markers of
children; the former may alter the peripheral perfusion are required to acute inflammation, including the ab-
utility of diagnostic cultures and the assess the acuity of the illness as solute band count, increased sedi-
latter may affect the clinical evalua- well as the need for hospitalization. mentation rate, and elevated C-
tion of the patient. Recent studies The height of the fever, especially in reactive protein, also have not
have suggested that clinicians are children who have temperatures helped identify the bacteremic pa-
more likely to differentiate children >40#{176}C,
appears to be a marker for tient. Currently, no single laboratory
who have serious bacterial infections an increased risk of occult bactere- test can predict the likelihood of bac-
prior to the defervescence produced mia. teremia in febrile children with
by the use of antipyretics. A careful examination may local- certainty.

130 Pediatrics in Review Vol. 15 No. 4 April 1994

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 INFECTIOUS DISEASE
Fever of Unknown OrIgin

An important consideration in the decrease the incidence of focal bacte- faced with other management deci-
employment of laboratory studies is rial infections and to eradicate bacte- sions once the results of blood cul-
the search for other clinically si- rial pathogens from the blood of tures are known. All children who
lent infections, especially pneumo- bacteremic children compared with have a positive blood culture require
nia and urinary tract infections. The children receiving oral amoxicillin. a repeat clinical examination to deter-
child who has significant respiratory Other factors that need to be con- mine the presence of any focal com-
symptoms or any focal pulmonary sidered when contemplating antibiotic plication. This is especially true if
abnormality on examination warrants therapy include the overall assess- infection with the organism is associ-
a chest radiograph. Because of the ment of the child, the status of the ated with a high rate of complica-
inability of the child to localize com- childs immunologic functioning, the tions, such as in H influenzae type b
plaints specific to the urinary tract ability of the parents or caretakers to and N meningitidis, or if the organ-
and the nonspecific nature of the observe for the subtle manifestations ism is an unusual pathogen, such as
symptoms of urinary tract infections, of bacterial sepsis, and the ease of Escherichia coli or any of the patho-
a careful examination of freshly ob- obtaining follow-up within the first gens associated with urinary tract dis-
tamed urine is necessary in the evalu- 24 hours after initial presentation. ease. If the follow-up clinical
ation of the febrile child. Urinary Clinicians will need to individualize assessment finds the child to be afe-
tract infections occur in 1% to 4% of their approach to the febrile child: bnile and clinically improved, outpa-
febrile children and are suggested by No single parameter can be used to tient antimicrobial therapy should be
the presence of a positive reaction of determine the most appropriate initiated for 5 to 7 days. Sensitivity
assays for leukocyte esterase or un- therapy. patterns of the organism can be used
nary nitrites on the presence of pyu- to guide the selection of antibiotics,
na, bacteniunia, or both on wet COMPLICATIONS although amoxicillin (40 mg/kg per
mount examination of the urine. Al- Complications from occult bactere- day) or penicillin VR (25 000 to
though more time-consuming, a urine mia have been reported to occur in 50 000 U/kg per day) generally is
Gram stain demonstrating bacteria 4% to 20% of patients. These usually sufficient for the treatment of pneu-
under oil immersion microscopy has are due to the development of a see- mococcal infections, and third-gener-
been shown to correlate with positive ondary focus, in particular, meningi- ation cephalosponins or combination
urine culture results. tis, pneumonia, septic arthritis, therapy with amoxicillin/clavulanic
Examination of the stool for the pneumonia, or persistent bacteremia. acid will maximize the coverage for
presence of white blood cells may of- The incidence of complications cur- beta-lactamase-producing organisms
fer evidence of invasive bacterial rently is organism-specific and has such as H influenzae type b. If on re-
gastroenteritis. A lumbar puncture been reported to occur in 2% to 4% peat examination the child is febrile
certainly is not required in all febrile of children who have S pneumoniae or exhibits other manifestations of fo-
children, but should be reserved for bacteremia, 7% of children who have cal bacterial infection, he or she re-
those in whom there is any clinical H inJluenzae bacteremia, and 25% of quires a complete evaluation,
suspicion of CNS involvement. This those who have N meningitidis bacte- including lumbar puncture and hospi-
becomes critically important in chil- remia. talization for intravenous antibiotic
dren less than 12 months of age, as therapy and assessment for any focal
even an experienced clinician may THE CHILD WHO HAS complications (Table 3).
have difficulty localizing the signs of BACTEREMIA
CNS infections in this age group. Because 3% of children will have PROGNOSIS
positive blood cultures for a true bac- The prognosis for most children who
TREATMENT terial pathogen, clinicians will be have bacteremia remains excellent.
The presence of a focal bacterial in-
fection on examination warrants anti-
microbial treatment aimed at the Table 3. Algorithm for Child Who Has Known
most common
However,
bacterial
controversy
etiologies.
continues to
[ Bacteremia
surround the question of the utility of Child who has bacteremia
antimicrobial therapy in the febrile
child who has no source of infection. Repeat
Early studies suggesting an improved clinical
outcome for bacteremic patients who evaluation
received oral antimicrobial therapy at
Afebrile/Appears well
their initial visit prior to obtaining
the results of blood cultures have not Yes No
been corroborated by more recent $
1) Continue outpatient management 1) Complete mediCal evaluation
randomized clinical trials. The results
2) Consider a repeat blood culture 2) Consider lumbar puncture
of a recent multicenter trial suggest
3) Treat with oral antibiotics 3) Hospitalize for parenteral
that treatment with intramuscular cef-
antibiotics
tniaxone (50 mg/kg) is more likely to

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 INFECTIOUS DISEASE
Fever of Unknown Origin

Table 4. Causes of Fever of Unknown Origin (FUO) In 1 and neoplastic diseases. Second, the
Childhood
I vast majority of patients have a dis-
Ii ease process seen commonly in gen-
eral pediatrics. Thus, rather than an
Infectious Diseases (localized) Infectious Diseases (systemic) exhaustive search for rare or exotic
Endocarditis Viral: Cytomegalovirus
diagnoses, attention should be fo-
Mastoiditis Ebstein-Barr virus cused on recognizing subtle or atypi-
Meningitis Hepatitis viruses cal presentations of common
Occult abscesses HIV disorders. Finally, although roughly
Hepatic Bacterial: Brucellosis 20% of cases (presumed viral infec-
Pelvic Cat-scratch disease tions) will resolve spontaneously, a
Peninephric Leptospirosis larger percentage will have infections
Subdiaphragmatic Lyme disease requiring specific therapy. Up to
Osteomyelitis Salmonellosis 40% of patients will have a serious
Pneumonia/empyema Tuberculosis disorder or lasting sequelae; mortality
Pyelonephritis/urinary tract infection Tularemia rates of 6% to 17% have been re-
Septicemia Other: Histoplasmosis ported in studies of pediatric FUO.
Sinusitis Malaria Therefore, prolonged fever in child-
Tonsillitis/peritonsillar abscess Rickettsial infections hood cannot be approached casually.
Toxoplasmosis Perhaps the most important lesson
to be learned from the pediatric FUO
Collagen-Inflammatoty Diseases Miscellaneous disorders literature is that there is no substitute
Henoch-Schoenlein purpura CNS dysfunction for a complete and detailed history
Juvenile rheumatoid arthritis Drug fever and careful, repeated physical exami-
Rheumatic fever Factitious fever nation. The final diagnosis in the ma-
Systemic lupus erythematosis Immunodeficiency jority of patients was indicated or
Inflammatory bowel disease suggested by history or physical find-
Neoplastic diseases Kawasaki syndrome ings rather than by specific labora-
Histiocytosis Sarcoidosis tory investigations or imaging
Leukemia/lymphoma Subdural hematoma/effusion studies.
Neuroblastoma Thyroiditis
Solid tumors (eg, hepatoma) EVALUATION
When a child presents having FUO,
For many, occult bacteremia will be known origin (FUO). Because fever the history should include a meticu-
a transient phenomenon requiring is a primary manifestation of many bus review of any relevant symp-
outpatient antibiotic treatment. How- diseases (Table 4), including benign, toms. Significant weight loss or
ever, clinicians should be aware of self-limited infections, chronic multi- linear growth impairment suggests
the risks of focal infections, espe- system inflammatory processes, and long-standing chronic conditions such
cially life-threatening events such as life-threatening malignancies, the pe- as inflammatory bowel disease. The
meningitis and bacterial sepsis, even diatnician is faced with an important first appearance of symptoms such as
in the well-appearing febrile child. and challenging diagnostic dilemma. fatigue, malaise, and diminished ap-
Although studies designed to de- An organized framework for the petite (which commonly accompany
crease the risk of bacterial complica- evaluation of children who have FUO acute fever in children) should be
tions do not, as of yet, support is essential: 1) to facilitate early di- documented because these may pre-
routine antimicrobial treatment of the agnosis, 2) to ensure that thorough date the onset of fever. Other symp-
febrile child, other factors, including attention is given to excluding seri- toms, such as abdominal pain,
the clinical assessment of an experi- ous disease, and 3) to avoid a fish- cough, headache, or dysuria, may be
enced physician, the ability and ease ing expedition involving expensive a clue to localized infection. Joint
of obtaining follow-up, and the ob- or invasive tests of low diagnostic pain and rashes are characteristic of
servational abilities of the parent or yield. collagen-inflammatory diseases and
caretaker, remain important consider- of infections such as hepatitis B virus
ations in management. EPIDEMIOLOGY and Lyme disease. A medical history
Although published series of FUO in of recurrent fevers or infections may
Fever of Unknown Origin children differ substantially in their indicate an immune defect such as
(FUO) inclusion criteria, certain important cyclic neutropenia or IgG subclass
Although precise definitions vary, considerations emerge. First, infec- deficiency. Recent surgical proce-
when a child has a significant fever tions are the most common identified dures could provide a nidus for oc-
(>38.5#{176}C) lasting more than 2 weeks source of FUO in children (approxi- cult infection, while transfusion of
and the diagnosis remains uncertain mately 50% of cases), followed in blood products carries a small risk of
despite a careful history and physical order by collagen-inflammatory dis- hepatitis virus or HIV transmission.
examination, it is appropriate to con- orders (more common in females and Drug fevers may occur as a reaction
sider the patient to have fever of un- children greater than 6 years of age) to a medication the child has been

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 INFECTIOUS DISEASE
- FeverofUnknownOrlgki j
prescribed. Family history should be of fever spikes. A perineal rash may spirochetal infections. Thrombocyto-
screened for autoimmune disease, in- aid in the diagnosis of Kawasaki syn- 515 is common in Kawasaki syn-
flammatory bowel disease, and tuber- drome, a seborrheic rash in histiocy- drome. Leukocytosis with a left
culosis. tosis, and petechiae or purpura in shift increases the likelihood of
Any contact with infected or other- bacterial endocarditis or a systemic bacterial infection, whereas atypical
wise ill individuals should be investi- vasculitis. lymphocytes are characteristic of sys-
gated thoroughly. Child care centers Generalized adenopathy or hepato- temic viral infections. Immature leu-
can be a source of exposure to corn- splenomegaly suggests viral infec- kocyte forms or pancytopenia suggest
municable diseases, such as Ebstein- tions (eg, infectious mononucleosis) leukemia.
Barr Virus (EBV), cytornegalovirus and collagen vascular disease (eg, Aerobic and anaerobic blood cul-
(CMV), hepatitis, or salmonellosis. JRA, drug reactions, leukemia, or tunes, urinalysis, tuberculin skin test
Animal exposure may result in trans- HIV-related immunodeficiency). Re- (with controls), liver chemistries,
mission of leptospirosis (dogs), toxo- gional adenopathy indicates a local- serum protein analysis, and chest and
plasmosis (cats), rat-bite fever (rats), ized bacterial infection, cat-scratch sinus radiographs are appropriate mi-
psittacosis (birds), or salmonellosis disease, or malignancy. tial screens for children who have
(turtles). A detailed history could Conjunctivitis is found with Kawa- FUO. In older children, a heterophil
raise the possibility of endemic dis- saki syndrome, leptospirosis, tulane- antibody test and antinuclear anti-
ease such as malaria, hepatitis, mia, and systemic lupus erytherna- body titer could be added to the list.
enteric fever, tuberculosis, histoplas- tosis. Fundoscopic examination may Erythrocyte sedimentation rate or C-
mosis, or coccidiomycosis. One reveal papillederna (brain tumor, sub- reactive protein level are of little di-
should inquire about visits to wooded dural hematoma, meningoencephali- agnostic value, but as indicators of
areas, tick bites (Lyme disease, tis), Roth spots (infective endo- significant illness (bacterial infection,
Rocky Mountain spotted fever, re- carditis), or granulomatous changes tumor, collagen vascular disease),
lapsing fever), and mosquito bites (tuberculosis, sarcoidosis). A slit they can be useful to follow disease
(arboviruses). The dietary history lamp examination is useful in identi- activity and guide the need for fur-
should focus on consumption of raw fying uveitis (JRA, Crohn disease, ther evaluation.
meat (brucellosis, toxoplasmosis), toxoplasmosis).
game meat (tularemia), raw fish Joints, including the hips, should DIAGNOSTIC APPROACH
(hepatitis, salmonellosis), and unpas- be examined for arthropathy associ- A schematic approach to the evalua-
teurized milk (brucellosis, salrnonel- ated with collagen inflammatory dis- tion of the child who has FUO is
losis). Children who have pica may orders, toxic synovitis, or septic shown in Figure 4. The algorithm
expose themselves to infectious dis- arthritis. Reactive arthritis is seen emphasizes an essential feature in the
eases such as visceral larva migrans with brucellosis, bacterial enteric in- evaluation: the painstaking pursuit of
or toxoplasmosis. fections such as shigellosis, and hep- every diagnostic lead uncovered, no
High spiking fevers suggest tran- atitis virus infection. Bony tenderness matter how insignificant it may ap-
sient bacteremia associated with py- could indicate osteomyelitis or neo- pear at first.
ogenic infections. This pattern also is plastic marrow invasion. The sinuses History or physical findings pro-
seen in juvenile rheumatoid arthritis and mastoid area should be palpated vide the clue to the final diagnosis in
(JRA). Typhoid fever classically is carefully and transilluminated. Mus- the majority of patients. Potential ex-
sustained. Relapsing fevers are seen cle soreness is seen with underlying posure to infectious agents via sick
in malaria, Borrelia infections, rat- abscesses. contacts, travel to endemic areas, or
bite fever, and lymphomas. Recur- Every patient who has FUO should dietary intake should guide serologic
rent fevers separated by several afe- receive a rectal examination to look studies and special cultures. A his-
brile days may represent a series of for tenderness or adenopathy indica- tory of repeated infections may signal
different infections (pseudo-FUO), tive of abdominal or pelvic abscesses the need for a more elaborate immu-
perhaps as a result of an underlying or tumors. nologic evaluation or HIV serology.
immunodeficiency state. The height Stools should be examined for oc- Abdominal symptoms or linear
or pattern of fever itself has not been cult blood loss (guaiac test), charac- growth impairment indicate barium
shown to predict the ultimate diagno- teristic of inflammatory bowel studies to rule out inflammatory
sis or prognosis in the larger pedia- disease. A pelvic examination is indi- bowel disease. Unusual cutaneous
tric FUO series. cated in adolescent females to rule findings or enlarged lymph nodes
out inflammatory disease or abscess. may yield a diagnosis on biopsy.
PHYSICAL EXAMINATION
Failure to use existing laboratory
The physical examination of a child LABORATORY EVALUATION
data appropriately also has been
who has FUO must be both thorough All who have FUO should
patients shown to contribute significantly to
and repeated, for studies suggest that have a complete blood count with delayed diagnosis of FUO. Abnormal
25% of patients develop key findings differential taken. Anemia is seen in findings in the peripheral blood may
at some point after their initial pre- inflammatory bowel disease, JRA, be an indication for bone marrow ex-
sentation. malaria, and parvovirus B19 infec- amination. Eosinophilia is seen in
A careful dermatologic examina- tion. Low platelet counts are associ- parasitic infections, drug reactions,
tion may demonstrate the evanescent ated with EBV infection, toxo- and malignancy. Sterile pyuria is a
rash of JRA, which recurs at the time plasmosis, tuberculosis, and common overlooked diagnostic clue

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 INFECTIOUS DISEASE
Fever of Unknown OrIgin

technetium bone scan may reveal an

(Persistent fever > 38.5 for more than 2 week
occult osteomyelitis. Spinal fluid
1 analysis
tients who have
should be considered
headache or neuro-
in pa-

Detailed History

I
logic symptoms. Bone marrow
Complete review of systems; PMH of recurrent examination is indicated to rule out
infections, surgery, or transfusion; exposures to
sick contacts; travel and dietary history; family hematologic malignancies or neuro-
history of autoimmune disease or IBD; fever pattern blastoma; the marrow also should be
cultured for mycobacteria and salmo-
Thorough Physical Examination nella. Abdominal ultrasonography,
body computed tomography, or mag-
Attention to skin findings, lymphadenopathy,
optho exam, joint exam, palpatation of sinuses, bones netic resonance imaging may identify
and muscles, rectal exam with stool guaiac, pelvic masses, deep lymph nodes, or ab-
exam in adolescent females
scesses. Studies suggest that explora-
: tory laparotomy is not useful unless
Screening Laboratory Studies 1cuIous indicated by imaging studies.

I
CBC with differential, blood cultures, urine analysis I Follow-Up of I
and culture, PPD and controls, liver chemistries,
>1 Any andAll
TREATMENT
chest and sinus x-rays, serum protein analysis.
I Diagnostic
l\.%___Leads
In older children, monospot and ANA. A child in whom JRA is suspected
should receive a trial of nonsteroidal
. Special Studies
(Is child systemically ill, failing to thrive, or very young?)
anti-inflammatory agents. Empiric
trials of broad-spectrum antibiotics
Serologies for systemic
viral and bacterial generally are without diagnostic or
infections; lumbar therapeutic benefit and may mask or
puncture; stool culture
and 0 & P; gallium WBC delay the diagnosis of infections such
scan; technetium bone as endocarditis, meningitis, or osteo-
scan; abdominal or
cardiac ultrasound; CT myelitis. The high incidence of infec-
(Follow outpatient with frequent
scan or MRI of body; tious processes emphasizes the need
bone marrow biopsy
visits and careful follow-up of and culture; lymph for bacterial cultures before antibiot-
diagnostic studies
node biopsy; needle ics are started.
biopsy of liver

( Documentation of fever
Fever itt Conclusion
(ipecific cause may \ Fever curve, repeated examination
never be determ,,J < resolves I1pIi,sical findings
for development of J persists The wise evaluation and treatment of
fever in children tests the skills of
the best pediatrician. This article of-
FIGURE 4: Diagnostic approach to the child who has FUO.
fers an approach that we hope simpli-
fies that process and will result in a
to Kawasaki syndrome or tuberculo- indicated for very young children or higher degree of accuracy in diagno-
sis. Evidence of liver inflammation, for those who have severe systemic sis and treatment.
biochemical dysfunction, or choles- symptoms. An advantage to admit-
tasis should be pursued with appro- SUGGESTED READING
ting children who have FUO is the
Alario AJ, Nelson EW, Shapiro ED. Blood
priate serologies (hepatitis screen, opportunity for careful, repeated his-
cultures in the management of febrile
EBV/CMV, leptospirosis) and ultra- tory-taking and physical examination. outpatients later found to have bacteremia. J
sonographic imaging. Constant observation may unveil sub- Pediatr. 1989;! 15:196-199
tle clinical features (eg, the rash of Atkins E. Fever. The old and the new. J lnfect
Dis. 1984; 149:339-348
IS HOSPITAL ADMISSION iRA). A parents misinterpretation of
Baker RC, Tiller T, Bauscher JC, et al.
NECESSARY? several unrelated febrile illnesses as Severity of disease correlated with fever
If a child who has FUO is not sys- persistent fever (pseudo-FUO) and reduction in febrile infants. Pediatrics.

temically ill, if thorough history tak- factitious fevers (eg, Munchausen 1989;83: 1016- 1019
syndrome by proxy) sometimes is Baraff LI, Bass JW, Fleisher GR, et al.
ing, physical examination, and Practice guideline for the management of
screening laboratory studies have clarified only by hospital admission.
infants and children 0-36 months of age
been performed, and if all diagnostic with fever without cause. J Pediatr.
leads have been pursued, it is appro- MORE ELABORATE TESTING 1993;92: 1-12
Burg i, Etzwiler L, Petrychi 5, et al. Outcome
priate to follow the patient over time If fever persists beyond a month or if
in highly febrile non-bacteremic children.
in the outpatient setting. Studies sug- the child is systemically ill or failing Ped Emerg Care. 1989;5:282
gest that up to 20% of fevers will re- to thrive, more elaborate testing is Dascombe Mi. The pharmacology of fever.
solve spontaneously, with the justified. A gallium white blood cell Progress in Neuro-Biology. 1985;25:328-
373
specific cause never determined. Im- scan may help to localize abscesses,
Davis AT, Fleisher 0, Jaffe DM, et al.
portant physical findings or labora- granulomatous foci (eg, tuberculosis, Antibiotic administration to treat possible
tory abnormalities may develop later. sarcoidosis), and certain malignancies occult bacteremia in febrile children. N Engi
Hospital admission, however, is (lymphomas, many solid tumors). A JMed. 1987;317:1175-1180

34 Pediatrics
Downloaded from http://pedsinreview.aappublications.org/ by guest in Review
on January 15, 2016 Vol. 15 No. 4 April 1994
 -. INFECTIOUS DISEASE

Fever of Unknown OrigIn

Dinarello CA, Wolff SM. Molecular basis of

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D. Hyperthyroidism.
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C. Juvenile rheumatoid arthritis.
D. Leptospirosis.
E. Sarcoidosis.

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 Fever in Children
Victor Nizet, Robert J. Vinci and Frederick H. Lovejoy, Jr
Pediatrics in Review 1994;15;127
DOI: 10.1542/pir.15-4-127

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 Fever in Children
Victor Nizet, Robert J. Vinci and Frederick H. Lovejoy, Jr
Pediatrics in Review 1994;15;127
DOI: 10.1542/pir.15-4-127

The online version of this article, along with updated information and services, is located on
the World Wide Web at:
http://pedsinreview.aappublications.org/content/15/4/127

Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1979. Pediatrics in Review is owned, published, and
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