Curriculum Vitae

Prof. Dr. dr. Sri Rezeki S.Hadinegoro,Sp.A(K)

Staf pengajar Departemen Ilmu Kes Anak FKUI/RSCM Jakarta

• Pendidikan
– Dokter umum – FK.UNPAD 1972
– Spesialis anak – FK.UI 1983
– Doktor – FK.UI 1996
– Guru Besar – FK.UI 2000

• Organisasi
– Ketua Satuan Tugas Imunisasi Ikatan Dokter Anak Indonesia ( IDAI )
– Ketua KOMNAS PP KIPI - DEPKES
– Board member of Asian Society of Pediatric Infectious Disease ( ASPID )
– Chairman of Indonesian Immunization of Technical Advisory Group (TAG- MOH)
– Member of Asian Strategic Alliance for Pneumococcal Disease ( ASAP )
– Member of Asia-Pacific Board of Dengue Prevention
– Board member of WSPID
Antibiotic Usage in Children

Fever of Unknown Origin

Fever without Sources
Fever without localizing signs
UKK Infeksi Penyakit Tropis IDAI

Sri Rezeki S Hadinegoro

Topics

• Classification of fever
• Cause of fever of unknown origin
• Algorithmic approach of FUO
• Management of FUO
• Choose of antibiotics
• Evaluation of antibiotic therapy
• Conclusion
 Classification of Fever
Fever
without
localizing
signs
Fever with Fever of
localizing unknown
signs origin

Fever
 Classification of Fever
Classification Definition Most frequent Duration of
etiology fever

Fever with Acute febrile illness with focus Upper < 1 week
localizing signs infection which could be respiratory tract
diagnosed by anamnesis & infection (URTI)
physical examination

Fever without Acute febrile illness without Viral infection, < 1 week
localizing signs focus infection diagnosed after urinary tract
anamnesis & physical infection (UTI)
examination

Fever of Fever occured minimal 3 weeks, Infection, > 1 week

unknown no established diagnosis yet after juvenile
origin 1 week investigation at hospital idiopathic
arthritis
 Fever with Localized Signs
Common Causes

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

Acute febrile illness with focus of infection, which can be diagnosed

after history & physical examination
 Fever without localizing signs

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

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 >39.50C
 Fever without localized signs
Common causes

Etiology Causes Diagnostic tools

Infections Bacteremia/sepsis Ill looking, high CRP, leukocytosis
Most virus (HH-6) Well appearing, nomal CRP, WBC
UTI Urine dipsticks
Malaria In malarial area

FUO Juvenile idiopathic Pre-articular, rash, splenomegaly, high

arthritis 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
 Fever of Unknown Origin = FUO
Definition (Fever of Unknown Source)

 Fever occured minimal 3 weeks, no established

diagnosis yet after 1 week investigation at hospital

 Fever without localizing signs persists for one week

during which evaluation in hospital fails to detect the
cause
Common Causes Fever of Unknown Origin = FUO
(Fever of Unknown Source)
 Infection 60-70%, localized infections or systemic
infections

 Collagen diseases 20%

 Miscellenous 5-10%

 Neoplasma 2%
 Fever of Unknown Origin = FUO
Underlying cause (Fever of Unknown Source)

 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

 Principles causes of FUO
Causes Diseases Reasons of being a case of FUO

Infection (60%-70%) Repeated history taking & repeated physical

examination

Localized Sinusitis Sinus radiograph not performed or negative

Endocarditis Previously unsuspected of having cardiac

defect

Occult abscess Absence of clinical signs

Systemic Viral diseases Fever is the only sign of disease

TB Extrapulmonary, tuberculin test negative

Kawasaki disease Incomplete presentation, diagnosis not

considered
 Principles causes of FUO (cont’)
Causes Diseases Reasons of being a case of FUO
Collagen Juvenile Prearthritis presentation
(about 20%) rheumatoid
arthritis (JRA)
SLE Atypical manifestation
Neoplasma Leukemia Atypical presentation, blood tests negative

Lymphoma Unusual localization

Neuroblastoma Disseminated
Miscellaneous Drug fever Diagnosis not considered, suspected drug
(5%-10%) not stopped

Factitious fever Diagnosis not considered, thermometer

left to patient
 Algorithmic approach to FUO
• Repeated anamnesis, physical examination &
laboratory examination
Step 1 • Evaluation: is there any specific signs &
symptoms

• Option 1: found the specific signs & symptom

examination additional specific lab
Step 2 • Option 2: no any specific signs & symptom
repeated WBC
• Evaluation option 1 & 2, go to step 3

• More comprehensive examination, consultation

Step 3 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

Heart sound (endocarditis)

Joint, lymph nodes, muscle
Detail (myalgia),
Pain of extrimities (SLE)
physical Special attention Icterus (hepatitis)
examinations are to certain part Skin rash (vascular-collagen
disease, Kawasaki disease)
needed Peritonsillar abscess
Mass intra abdominal
Blood stool
 Clinical illness severity in children
Parameter Green –low risk
Colour Normal colour of skin, lips,
tounge
Activity Respond normal to social
cues, smiles, stay awake or
awakens quiclky
Stronge normal crying
Respiratory Normal respiratory rate
Hydration Normal skin & eyes
Moist mucous membranes
Other None yellow or red signs
Yellow-intermediate Red – high risk
Pallor reported parents Pale, mottled, blue
Not responding normal No respond to social cues
social cues, wakes with Appear ill to health care
prolonged stimulation professional
Decreased activity, no smile Does not wake
Weak, high-piched crying
Nasal flaring, tachypnoea Grunting
Oxygen saturation <95% Tachypnoea
Crackles Moderate or severe chest
indrawing
Dry mucous membrane Reduced skin turgor
Poor feeding in infants Temperature:
CRT ≥ 3 seconds 0-3 mos≥ 380C
Reduced urine output 3-6 mos ≥ 390C
Fever ≥ 5 days Bulging of fontanel
Neck stiffness
Swelling limb or joint Local seizure
Neurological signs
Bile –stained vomiting
The Yale Observation Scale (YOS)
Diagnostic Test of Yale Observation Scale

National Collaborating Centre for Women’s and

Children’s 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%.
 Diagnostic Test of Yale Observation Scale

Pratiwi , Tumbelaka AR. dkk.

Departemen IKA FKUI/RSCM, RS Fatmawati, dan RS
Harapan Kita, 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 neg 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
 Laboratory examination

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
* Note: in serious case, lab procedure should be performed more rapidly
 Laboratory examination
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
 Management of child aged
0-< 3months without a focus of infection

Ill-looking or <1 month Yes

No

Outpatient clinic Hospital addmission

Blood culture
Option 1 Option 2
Urine examination
CBC , blood culture As in option 1
Complete blood count
Urine exam & culture + CSF
Chest x-ray
Chest x-ray
CSF
Stool micros & culture
IV antibiotic
(if indicated)

Abnormal labs or x-ray

Antibiotic
 Management of child aged 3-36 months
without a focus of infection

Ill-looking Not ill-looking Body temperature > 390C

child body temperature
<390C Evaluate for SBIs

Urine Option 1
Hospitalization Urine dipstick, CBC, blood
dipstick,
administer review if culture, CXR, consider
antibiotic antibiotic
condition
worsen
Option 2
Urine, no blood test,
evaluation if the condition
worsen

Option 3
CBC, if WBC > 15.000/mm3,
blood culture, consider
antibiotic
FUO case clinical
setting

ICU
Choose an Broad or
narrow
antibiotic spectrum

Bactericidal
Empiric or


or
definitive bacteriostatic

Intravenous Mono or
or oral combined

27
Antibiotic prescription in bacterial infection

Bacterial infection Guess

Culture
Cured (Gram stain)
Empirical
therapy
Narrow spectrum of Pathogen
antibiotic identification

Definitive
therapy
Confirmation
 Cara pemberian antibiotik
Apabila mungkin, pemberian antibiotik
Oral oral lebih disukai, oleh karena pemberian
lebih mudah dan ekonomis.

Kapan antibiotik diberikan secara intravena?

I.V Sakit berat

Segera mencapai konsentrasi obat yang diharapkan
 Mencapai konsentrasi terapeutik lebih cepat
 Tidak bisa oral
 Kontraindikasi oral

29
Pergerakan antibiotik ke dalam
jaringan
• Inflamasi yang disebabkan
oleh infeksi mempermudah
penetrasi pada beberapa
antibiotik

• Penetrasi antibiotik ke dalam

likuor serebrospinalis harus
melampaui sawar darah-otak
(blood-brain barrier)

• Contoh: vancomycin akan

mudah masuk ke dalam likuor
serebrospinalis apabila terjadi
inflamasi pada meningen.
Effect of Inflammation or Abscess on Antibiotic
Penetration
 Mono Combined
therapy therapy of
only one two or more
antibiotic antibiotics

Antibiotic
therapy
 Antibiotics Therapy Serious Infection
Amino glycoside

Enterobacter or Ps.monas

Broad Spectrum
Clindamycin
Penicillin
or
Vancomycin or
Metroni
Broad Spectrum
dazol
Cephalosporin

Immunocompromize or Neutropenia

Aminoglycoside +
Vancomicyn
Antibiotic Combination Therapy

Initial therapy for serious infection with unknown

cause

Infectious disease caused by several bacteria which

failed by one antibiotic therapy

Reduced antibiotic resistance, reduced toxicity

Additive Action versus Synergy
Antibiotic Combination Therapy
Indication

Initial therapy for serious infection with unknown

cause

Infectious disease caused by several bacteria which

failed by one antibiotic therapy

Reduced antibiotic resistance, reduced toxicity

Incorrect-use of antibiotic
combination

Antagonistic
Increased price

Increased side effect

Super-infection

Kherallah M :Combination Antibiotics :2010

Sjabana D:Antibakteri (Farmakologi Klinik Antibakteri:2006
Redbook AAP 2006
Antibiotic Combination
Common used

-lactam &
Two (double) -lactam &
amino
-lactam quinolone
glycoside

38
 Evaluasi Pengobatan

Antibiotik Fever of
empiris defervescence
Suhu o C

Sadar, aktif
37.50 C Tidak ada komplikasi
Nafsu makan baik

Evaluasi
 klinis
 pem.penunjang

1 2 3 4 5 6 7 8 9 10
Hari sakit
Kegagalan pengobatan antibiotik

Pemilihan antibiotik
tidak tepat

Pemberian dosis
Salah diagnosis?
tidak tepat

Terdapat sumber infeksi lain

Terdapat daerah inflamasi
(misalnya saat antibiotik diberikan
V-P shunt dilepas terlebih dahulu) yang nekrotik
 Evaluasi Pengobatan
Compliance
Komplikasi
Antibiotik
o
Suhu C
empiris  Fokal infeksi lain
Resisten
Salah diagnosis

Pengobatan
37.50 C tidak berhasil
Leukosit
LED, CRP, PCT
Kesadaran Transaminase
Foto toraks
Deteksi komplikasi
LP, CT-scan, dll
Amati gejala lain
1 2 3 4 5 6 7 8 9 10
Hari sakit
Pengobatan Rawat Inap - Rawat Jalan
Switching therapy

Pengobatan Pengobatan Pengobatan

empiris definitif antibiotik
(patogen
(pengobatan awal)
diketahui) intravena

Switching therapy

Pulang rawat Antibiotik oral

42
Clinically unstable

A
Point of clinical stability

B Early Clinical Switch

Improvement therapy
Severity of disease

Intravena
antibiotic
Clearly Clinical Improvement
C
Out patient care
Oral
administration

Time of illness
Ramirez JA., 2002
 Conclusion

• Classification of fever based on causes: fever

with local source, fever without source (FWS),
and fever of unknown origin (FUO)
• To solve the difficulties in looked for the cause
of fever without source, stratification on
management is needed
• Attention should be paid to toddlers (below
three years of age) with high fever for detect
the serious bacterial infection.
 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
 Conclusion

• 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
 Conclusion

• Emergency case detection in children is quite

important
• History taking, physical examination, Yale
Observation Scale could help to detect the
serious infection
• Choosing empirical antibiotics based on
– The most common bacterial spectrum
– Done while waiting the culture’s result
• Evaluation of treatment is important part of
management of FWS