Lecture

Lecture FKUI 2012

Fever in Children
Sri Rezeki S Hadinegoro
Dept of Child Health
Faculty of Medicine, University of Indonesia
Fever
Normal body temperature
Definition of fever
Pathogenesis & pathophysiology of fever
Pattern of fever
Fever in the clinical setting
Treatment
Fever of unknown sources/ fever of
unknown origin (FUO)


Topics
Normal body temperature reached highest level
in early evening (5-7 p.m)
Young children: relatively high rectal temperature
predominate
Diurnal temperature
children have more fluctuated than adult
Gradually decreased towards adult levels beginning
at 2 years of age, trend stabilizes soon after puberty
Normal Body Temperature
Diurnal pattern of body temperature
Diurnal temperature in children more fluctuated
than in adults
N
o
r
m
a
l

b
o
d
y

t
e
m
p
e
r
a
t
u
r
e

3
6
.
2
-
3
7
.
5
o
C

Location Thermometer
Normal
temperature
Range, mean (
o
C)
Fever (
o
C)
Axilla Mercury, electronic 34.7 37.3; 36.4 37.4
Sublingual Mercury, electronic 35.5 37.5; 36.6 37,6
Rectal Mercury, electronic 36.6 37.9; 37.0 38.0
Ear Infra red emission 35.7 37.5; 36.6 37.6
Measurement of body temperature
Recommendation site of measurement
Age < 4 weeks: electronic thermometer axilla
Age >4 weeks to 5 years: electronic thermometer axilla,
mercury thermometer axilla, infrared tympanic thermometer
Fever is increased body temperature of 1
0
C
or greater above mean temperature
Clinical setting
Rectal temperature > 38.0
0
C
Oral temperature > 37.6
0
C
Axillary temperature > 37.4
0
C
Tympanic membrane > 37.6
0
C
Definition
E
n
d
o
g
e
n

p
y
r
o
g
e
n
,

c
y
t
o
k
i
n
e








Febrile response is
mediated by
endogenous
pyrogens (EP,
cytokines) in
response to
invading
exogenous
pyrogens,
primarily
microorganisms or
their product
(toxins)
H
y
p
o
t
h
a
l
a
m
u
s

c
e
n
t
r
e



Endogenous
pyrogen acts on
thermosensitive
neurons in
hypothalamus,
which upgrade
the set point via
prostaglandins
S
e
t

p
o
i
n
t
,

p
r
o
s
t
a
g
l
a
n
d
i
n



Body reacts by
increasing the
heat production
and decreasing
the heat loss until
the body
temperature
reaches this
elevated set point
Pathogenesis of Fever
Most common cause of fever in children
Fever
Hyper
sensitivity
reaction
Auto
immune
diseases
Malignancy
Infection
Mechanisms of Fever Production
Cytokine
Cytokines play a pivotal role in the
immune response by activation of the B
cells and T cell lymphocytes
Production of fever is strongly evidence as
a defence body mechanism
Fever become harmfull or fatal by
overproduction of cytokines or imbalance
between cytokine & their inhibitors
(severe infection and septic shock)
Pathogenesis of Fever
Fever is an interleukin-1 (IL-1) mediated
elevation of the thermoregulatory set
point of the hypothalamic centre
In response to an upward displacement
of the set points, an active process
occurs in order to reach the new set
point
Minimizing heat loss with
vasoconstriction and shivering
Pathophysiology of Fever
The regulation of body temperature
in the hypothalamic center
Behavioral means of raising body temperature
a warmer environment,
adding more clothing,
curling up in bed,
drinking warm liquids.
Fever is not dangerous
Fever is a body defence mechanism
Morbidity & mortality due to underlying disease
Fever does not damage the central nervous system
Fever controlled by a hypothalamic centre
Pathophysiology of Fever
Characterized by
discomfort

Result of
decreased heat loss
through
vasoconstriction &
increased heat
production through
shivering

Child feels cool,
skin feels cold to
the touch
New level of
thermoregulatoy set
point

Balance heat
production & heat loss,
at a higher
hypothalamic set point

Flushed or pink face
appearance signifies
that fever has peaked

Child feels comfort
without shivering
Occur either by
lysis (falling
gradulally within 2-
3 days to a normal
level) or crisis
(falling within a
few hours to
normal level)
Phase of temperature
raise
Phase of temperature
stabilization (fastigium)
Phase of falling
temperature or
defervescence
Phase of Fever
Pattern Diseases
Continuous Typhoid fever, malignant malaria falciparum
Remittent Most viral or bacterial diseases
Intermittent Malaria, lymphoma, endocarditis
Septic or hectic Kawasaki disease, pyogenic infection
Quotidian Malaria (P.vivax)
Double quotidian Juvenile rheumatoid arthritis, some drug fever
(carbamazepine), Kalaazar, gonococcal
arthritis
Relapsing/periodic Quartana & tertiana malaria, brucellosis
Recurrent fever Familial Mediterranean fever
Pattern of Fever
Continuous Fever (sustained fever)
Typhoid fever, malignant malaria falciparum
Sustained increased body temperature with maximal
fluctuation 0,4
0
C for 24 hours periode
Diurnal body temperature does not significance appear
N
o
r
m
a
l

l
e
v
e
l

3
7
.
5
0

C

Remittent Fever
Most viral or bacterial diseases
Temperature decreased every day but never reach normal level with
fluctuation more than 0.5
0
C per 24 hours
The most frequent fever pattern in pediatric practice, no spesific for
certain diseases
Diurnal variation showed particularly if fever due to infection process
N
o
r
m
a
l

l
e
v
e
l

3
7
.
5
0

C

Intermitent Fever
Malaria, lymphoma, endocarditis

Every day body temperature reached normal level at the
morning and highest level at noon
This pattern is the second most frequent found in pediatric
practices
at noon
morning
Quotidian Fever
Malaria (P.vivax)

Body temperature
increased gradually within every four days
Periodic Fever
Pattern of Fever in Malaria
Recurrent fever
Borrelia (louse borne), ticks borne disease
Normal level of body temperature
Fever with rash (Acute Exanthema)

Measles, Rubeola
Skin rash (maculopapular rash) appeared when body
temperature reached the highest level
Biphasic Fever
Dengue fever, poliomyelitis, leptospirosis, yellow fever, Colorado tick fever,
spirillary rat-bite fever, African hemorrhagic fever (Marburg, Ebola, Lassa)
Camelback fever pattern or saddleback fever
Showed two fever episodes in one disease

T
e
m
p
e
r
a
t
u
r
e


0

C

Time of fever defervescence
9/2/2014
Fever with rash (Acute Exanthema)
Natural history of diseases
9/2/2014
Fever with rash (Acute Exanthema)
Rash distribution
Exanthemas
9/2/2014
9/2/2014
Varicella Zoster Infection
Presence of all stages of lesions in one area
Differential diagnosis Acute Exanthema
Maculopapular eruptions
Measles
Rubella
Scarlet fever
Meningococcemia
Toxoplasmosis
Cytomegalovirus infecton
Roseola infantum
Enteroviral infection
Drug eruptions
Miliaria
Kawasaki disease
others
9/2/2014
Differential diagnosis of Acute Exanthema
Papulovesicular eruptions
Varicella-zoster infection
Smallpox
Excema herpeticum
Coxsackie virus infection
Rickettsial pox
Impetigo
Insect bites
Drug eruptions
Molluscum contagiosum
Papular urticaria
others
9/2/2014
37
0
C
40
0
C
Complications
Day -15 Day 0 Day 7 Day 21
Incubation
period
Asymtomatic
Invasive phase
Intermitent fever
Headache
Fatique
Abdominal discomfort
Constipation
Diarrhoea
Toxic phase
Continuous fever
Bradycardia
Hepatomegaly
Splenomegaly
Constipation
Diarrhoea
Rose spot
Convalescence
period
Typhoid Fever, Typhus Abdominalis
History of illness
Symptoms
Chills (rigor), myalgia, headaches, anorexia, excessive
sleep, fatigue, thirst, delirium, scanty urine (oliguria)
Signs
Drowsiness, irritability, tachycardia, tachypnoea,
increased BP, flushed face, grunting, decrease in GFR<
proteinuria. Appearance of an innocent (functional)
murmur & third heart sound
ECG changes
Shortening QT-interval, increased in supraventricular
ectopic beats
Clinical changes noted during fever
Dehydration
Result of increased body temperature & therapeutic effect of drugs
that promoting sweating
Fever & infection increase the metabolic rate to >1.5 time the basal
metabolic rate (1 degree C = 10% increase of insensible water loss)
Prevent & treated by providing extra fluid to the

Febrile convulsion
Mostly has a familial history of febrile convulsion
Genetically hypothalamic center susceptible to high body
temperature (imbalance of thermoregulator)
Incidence in 6 months to 4 years of ages
Prevent & treated by antipyretic & anticonvulsion drug


Potential Complication (1)
Hyperpyrexia (by Dubois)
Imbalance between heat production and loss
, not controlled centrally
Rectal temp 41.1
0
C or higher or axillary/
tympanic temp >40
0
C
Young infants with hyperpirexia suggested to
have severe infection (serious bacterial
infection)

Potential Complication (2)

Classification

Definition

Most frequent
etiology

Duration of
fever

Fever with
localizing signs

Acute febrile illness with
focus infection which could
be diagnosed by anamnesis &
physical examination

Upper respiratory
tract infection
(URTI)

< 1 week

Fever without
localizing signs

Acute febrile illness without
focus infection diagnosed
after anamnesis & physical
examination

Viral infection,
urinary tract
infection (UTI)

< 1 week

Fever of
unknown
origin

Fever occured minimal 3
weeks, no established
diagnosis yet after 1 week
investigation at hospital

Infection, juvenile
idiopathic arthritis

> 1 week
Classification of Fever
Organ system Diseases
Upper airway infections Viral URTI, otitis media,tonsillitis,
laryngitis, herpetic stomatitis
Pulmonary Bronkhiolitis, pneumonia
Gastrointestinal Gastroenteritis, hepatitis, appendicitis
CNS Meningitis, encephalitis
Exanthems Campak, chicken pox
Collagen Rheumathoid arthritis, Kawasaki disease
Neoplasma Leukemia, lymphoma
Tropics Kala azar, cickle cell anemia
Main causes of
fever due to disease of localized signs
Acute febrile illness with focus of infection, which can be diagnosed
after history & physical examination
About 20% all febrile episodes demonstrate no localizing signs
Most common cause is a viral infection
Most occuring during the first few years of life




Fever without localizing signs

Serious infections occured in 1% cases:
serious bacteriemic infections (SBIs)
Children 3-24 months have the highest incidence (3-4%),
aged 7-12 months demonstrating twice incidence
association with high fever >39.5
0
C

Etiology Causes Diagnostic tools
Infections Bacteremia/sepsis
Most virus (HH-6)
UTI
Malaria
Ill looking, high CRP, leukocytosis
Well appearing, nomal CRP, WBC
Urine dipsticks
In malarial area
FUO
Juvenile idiopathic
arthritis
Pre-articular, rash, splenomegaly, high
antinuclear factor, CRP
Post vaccination DTwP, measles Time of fever onset in relation to the time
of vaccination
Drug fever Most drug History of drug intake, diagnosis of
exclusion
Usual causes of fever without localized signs
Fever of Unknown Origin = FUO
(Fever of Unknown Source)
FUO defined when fever without localizing
signs persists for one week during which
evaluation in hospital fails to detect the
cause

Cause of FUO
Infection 60%-70%
Localized infections
Systemic infections
Collagen diseases 20%
Neoplasma 2%
Miscellenous 5%-10%

Lack of laboratory facilities
No experience to certain cases (rare case)
Not do the history on travel abroad, animal exposure,
prior use antibiotics
Repeated physical examinations are more helpful
Causes Diseases Reasons of being a case of FUO
Infection (60%-70%)
Repeated history taking & repeated
physical examination

Localized

Sinusitis

Endocarditis

Occult abscess

Sinus radiograph not performed or
negative
Previously unsuspected of having cardiac
defect
Absence of clinical signs

Systemic


Viral
TB
Kawasaki disease

Fever is the only sign of disease
Extrapulmonary, tuberculin test negative
Incomplete presentation, diagnosis not
considered
Principles causes of FUO
Causes Diseases Reasons of being a case of FUO

Collagen
(about 20%)

JIA
SLE

Prearthritis presentation
Atypical manifestation

Neoplasma
(<5%)


Leukemia
Lymphoma
Neuroblastoma

Atypical presentation, blood tests neg
Unusual localization
Disseminated

Miscellaneous
(5%-10%)

Drug fever

Factitious fever

Diagnosis not considered, suspected drug
not stopped
Diagnosis not considered, thermometer
left to patient
Principles causes of FUO
Algorithmic approach to FUO
Step 1
Repeated anamnesis, physical examination &
laboratory examination
Evaluation: is there any specific signs & symptoms
Step 2
Option 1: found the specific signs & symptom
examination additional specific lab
Option 2: no any specific signs & symptom repeated
FBC
Evaluation option 1 & 2, go to step 3
Step 3
More comprehensive examination, consultation to
other specialist, including invasive procedure


Anamnesis
Age
Age < 6 years: UTI, local infection (abcess, osteomyelitis), JRA
Children > 6 years: TB, collitis, autoimmune disease, neoplasma

Characteristic of fever
When, duration, and type of fever
Non-specific symptoms (fatique, headache, stomac-ache, chill)

Epidemiological data
Animal exposure
Travel aboard
Genetic
Drugs used
Physical examinations
Detail physical examinations are needed
Special attention to certain part
Heart sound (endocarditis)
Joint, lymph nodes, muscle (myalgia),
Pain of extrimities (SLE)
Icterus (hepatitis)
Skin rash (vascular-collagen disease, Kawasaki disease)
Peritonsillar abscess
Mass intra abdominal
Blood stool

Green low risk Yellow-intermediate Red high risk
Colour Normal colour of skin, lips,
tounge
Pallor reported parents Pale, mottled, blue
Activity Respond normal to social
cues, smiles, stay awake or
awakens quiclky
Stronge normal crying
Not responding normal
social cues, wakes with
prolonged stimulation
Decreased activity, no smile
No respond to social cues
Appear ill to health care
professional
Does not wake
Weak, high-piched crying
Respiratory Normal respiratory rate Nasal flaring, tachypnoea
Oxygen saturation <95%
Crackles
Grunting
Tachypnoea
Moderate or severe chest
indrawing
Hydration Normal skin & eyes
Moist mucous membranes
Dry mucous membrane
Poor feeding in infants
CRT 3 seconds
Reduced urine output
Reduced skin turgor
Temperature:
0-3 mos 38
0
C
3-6 mos 39
0
C
Other None yellow or red signs Fever 5 days Bulging of fontanel
Neck stiffness
Swelling limb or joint Local seizure
Neurological signs
Bile stained vomiting
Clinical illness severity in children
The Yale Observation Scale (YOS)
The Yale Observation Scale
National Collaborating Centre for Womens and Childrens
Health:
Skor YOS + anamnesis + pemeriksaan fisik: sensitifitas 89%-93%
dan NPV 96%-98%.
Nilai total skor 6 pada kelompok umur 3 bulan-3 tahun, dapat
mendeteksi occult bacteriemia dengan NPV 97,4%.

Pratiwi , Tumbelaka AR. dkk. dalam penelitiannya di
Departemen IKA FKUI/RSCM, RS Fatmawati, dan RS
Harapan Kita di Jakarta, 2010
256 kasus demam dengan skor 8 : sensitivitas 69,35%,
spesifisitas 90,2%, PPV 69,35%, NPV 90,2%, rasio kemungkinan
positif 7,08, dan rasio kemungkinan negative 0,34.



Laboratory examination
Laboratorium examination as a tools for
looking to the cause
An important part to established the
diagnosis
Recommend done gradually, not at the
same time for many examinations
Depend on severity of the disease
Step 1
FBC, blood smear, blood cell morphology
Chest x-ray
Tick blood smear
BSR, CRP
Urine analysis
LCS, other body fluid depend on indication
Blood, urine, stool, nasopharyngeal swab culture
Tuberculin test
Liver function test
Laboratory examination
* Note: in serious case, lab procedure should be performed more rapidly
Step 2
Serological test: Salmonella, toxoplasma, leptospira,
mononucleosis, CMV, histoplasma
Ultrasonography: abdominal, skull
Step 3
Bone marrow puncture
Intravenous pyelography
Paranasal sinus photography
Antinuclear antibody (ANA)
Barium enema examination
Scanning examination
Liver biopsy
Laparatomy diagnostic
Laboratory examination
Ill-looking or <1 month
Outpatient clinic
Option 1
CBC , blood culture
Urine exam & culture
Chest x-ray
Stool micros & culture
(if indicated)

Abnormal labs or x-ray
Antibiotic
Option 2
As in option 1
+ CSF
Hospital addmission
Blood culture
Urine examination
Complete blood count
Chest x-ray
CSF
IV antibiotic
Management of child aged
0-< 3months without a focus of infection
No
Yes
Management of child aged 3-36 months
without a focus of infection
Ill-looking
child
Hospitalization
administer
antibiotic
Not ill-looking
body temperature
<39
0
C
Urine
dipstick,
review if
condition
worsen
Body temperature > 39
0
C
Evaluate for SBIs
Option 1
Urine dipstick, CBC, blood
culture, CXR, consider
antibiotic
Option 2
Urine, no blood test,
evaluation if the condition
worsen
Option 3
CBC, if WBC > 15.000/mm
3,
blood culture, consider
antibiotic
ICU
FUO case clinical
setting
Antipyretic act centrally by lowering the
thermoregulatory set point of the hypothatalamic
center

Inhibition of cyclooxygenase, the enzyme responsible
for the conversion of arachidonic acid to prostaglandin
Antipyretic
The main indication for prescribing an antipyretic is not
to reduce body temperature but to relieve the childs
discomfort & reduced parents anxiety
Give rapid result and be effective in reducing fever by
at least 1
0
C
Be available in liquid and suppository form
Have low rate of side effect in theurapeutic doses
Have low incidence of interaction with other
medications and rarely contraindication in pediatric
doses
Be safe
Be cost effective
Characteristic of an ideal antipyretic
Para-aminophenols
Paracetamol
Propionic acid derivates
Ibuprofen
Naproxen
Salicylates
Aspirin
Other NSAIDs
Diclofenac
Endogenous antipyretic
Arganine vasopressin
Physical measures
Bed rest
Tepid sponging
Medications & Physical Measures
Antipyretic Oral Rectal Intravenous
Paracetamol Tablet
500 mg
Liquid
120mg/5ml or
250mg/5ml
Suppository
60, 125, 500mg
Infusion 10mg
Children
10-15 mg/kg at 4-6 hrs or
60-75mg/kg per day
Same as oral 15mg/kg
Ibuprofen Tablet
500 mg
Liquid
120mg/5ml or
250mg/5ml
Suppository
60, 125, 500mg

Children
5mg/kg at 3-4 hrs, dose 10mg/kb more
potent & has longer lasting fever
suppression than PCT
Same as oral

Doses of antipyretics
58
Broad or
narrow
spectrum
Bactericidal
or
bacteriostatic
Mono or
combined
Intravenous
or oral
Empiric or
definitive

Choose an
antibiotic
Antibiotic
prescription in
bacterial infection
59
Bacterial
infection
Culture
(Gram stain)
Pathogen
identification
Definitive
therapy
Narrow
spectrum of
antibiotic
Cured
Empirical therapy
Guess
Fever is a body defence mechanism, controlled by a
hypothalamic centre
Fever does not damage the central nervous system
Morbidity & mortality due to underlying disease
Fever become harmful by overproduction of cytokines or
imbalance between cytokine & their inhibitors (hyperthermia)
The main indication of giving antipyretic is not to reduce body
temperature but to relieve the childs discomfort & reduced
parents anxiety


Conclusions
Conclusions
FUO defined when fever without localizing signs persists
for one week during which evaluation in hospital fails to
detect the cause
60%-70% cause of FUO is infection
Reasons of being a case of FUO
Lack of laboratory facilities
No experience to certain cases (rare case)
Not do the history on travel abroad, animal exposure,
prior use antibiotics
Repeated physical examinations are more helpful




Conclusions
Antibiotic only used for bacterial infections
Culture should be done to confirmed the
etiology of infectious disease
Susceptibility test done together with
bacterial culture
Empirical antibiotic therapy should be
confirmed by definitive therapy