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