laboratory diagnosis in newborn infectious disease & neonatal sepsi
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Laboratory Diagnosisin Newborn InfectiousDisease
& Neonatal SepsisClinical Pathology Department,
Faculty of Medicine Universitas Gadjah Mada /
Dr. ardjito !ospital
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SCCM Consensus Denition
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Infection
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SCCM Consensus Denition
Sepsis
"nfection, plus # or more "$ criteria
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SCCM Consensus Denition
Severe Sepsis
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SCCM Consensus Denition
Septic Shock
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Infection
Parasite
irus
!ungus
"acteria
#rau$a
"urnsSepsis
"$
SevereSepsis
%dapted from CCM/%CCP Consensus Guidelines
shock
"SIPancreatitis
%thers
Multi
Organ
Dysfunction
syndrome
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Greg Martin, David mennino,et al.
& 'ngl ( Med, vol )*+, &o ) - ept #, ## - 000.nejm.or
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Mortality rate 1 increases 0ith increased severity
+2 in patients 0ith "$ 2 in patients 0ith epsis #2 in patients 0ith evere epsis *2 in patients 0ith eptic hoc3
$angel1Frausto, et al 4(%M% 5567
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Neonatal mortality ASEAN countries
Country Life birth(000)
Perinatalmortality
Earlyneonatal
death
Neonatalmortality
Singaore !" ! # #
Malaysia $!% " ! $
&runei ' % !
hailand #0'* *0 % #
Philiines *0*% * #* #$
+ietnam #$% " # #$
,ndonesia!$-! 0 #! #'
Laos #%$ $" *- $
Cambodia !-# -- # !0
Myanmar ##%! -$ 0 !0
WHO Data : Neonatal and perinatal mortality : country, regional and global estimates. 200
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Cause of neonatal death in SEA
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Neonatal Major Infection
!n"ection No. o" cases #ase $atality%ate &'( No. o" Deat)
*cute +ung!n"
2.00.000 -0 0.000
/etanusneonatal -1.000 1 -2.000
epsis 0.000 0 -00.000
Diar)ea 2.000.000 0. 30.000
Meningitis 32.000 0 0.00
Stoll BJ : The global impact of infection Clin Pernatol1997 24:1-21
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Diagnostic criteria for sepsis
"nfection, documented or suspected, and some of thefollo0ing8
General varia9les
Fever 4: );.) achypnea 4increased respiratory rate7%ltered mental statusigni?cant edema or positive @uid 9alance 4: # mA/3g over#* hrs7!yperglycemia 4plasma glucose :# mg/dA or +.+ mmol/A7 inthe a9sence of dia9etes
%CCP/CCM Consensus De?nition, Crit Care Med #)
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Ina$$atory variables
Leukocytosis '("C count ) *+,---.uL/
Leukopenia '("C count 0 1,---.uL/Nor$al ("C count with ) *-2 i$$ature for$s3levate4 plas$a C5reactive protein 'C6P/3levate4 plas$a procalcitonin 'PC#/
7e$o4yna$ic variables
8rterial hypotension 'S"P 0 9- $$7g, M8P 0 :-, or anS"P 4ecrease ) 1- $$7g in a4ults or 0 + SD belownor$al for age/Sv%+) :-2Car4iac In4e; ) $in5*M5+here is no speci?c pathognomonic clinicalor la9oratory parameter of sepsis
'arly detection and timely therapeuticintervention is crucial for improvedoutcome of patients 0ith sepsis
'arly diagnosis of sepsis is 3ey forimproved survival
>he diagnosis of sepsis is dicult and notrelia9le 9ased on general signs andsymptoms such as fever, tachycardia andtachypnea
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Laboratory tests i$portant in i4entifying the infectious agent
Infectious agent
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"n one recent, prospective study, positive9lood cultures 0ere found in8
+2 of patients 0ith sepsis, #62 0ith severe sepsis, 52 0ith septic shoc3.
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>0o major reasons8
>he patients are indeed septic 0ith9acteremia 9ut the organisms did not
gro0 under normal circumstances in theculture medium
>he septic state may have resulted notfrom 9acteremia 9ut from pyrogenic
cyto3ine activation
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Gram1negative organisms the mostcommon isolates from 9lood cultures
Echerichia coli,
!lebiella pne"moniae, Enterobacter cloacae,
the epidemiology of sepsis has changedin thelast # decades gram positive
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Gram1positive organisms accounted formore than 62 of all positive 9loodcultures from septic patients
Coagulase1negative staphylococci, Staph#lococc" a"re", Enterococc" faecali
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everal reasons for the increasing num9erof Gram1positive infections8 election of resistant Gram1positive organisms
from empiric anti9iotic therapy directed at
Gram1negative infections, "ncreased use of vascular access catheters and
implanta9le devices/prostheses, hared anti9iotic resistance 9et0een Gram1
positive organisms, and increased virulence ofGram1positive pathogens.
9ecause of advances in medicaltechnology
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Gram1negative 9acteria
Microbial factors in sepsis
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Cohen, Nature: 2002 420:885
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Bhat microorganisms cause severeinfections and sepsis in 9a9iesE
Prenatal During Delivery %fter irth
$u9ella4German
measles7
Group
streptococcus4G7
$espiratory
syncytial virus4$7
Cytomegalovirus4CM7
'. Coli Candida
aricella1Hoster virus4chic3enpoI virus7
!erpessimpleI virus
!aemophilus in@uenHae type 94!i97
Aisteriamonocytogenes
1 'nterovirus
http://www.healthline.com/adamcontent/rubellahttp://www.healthline.com/adamcontent/acute-cytomegalovirus-cmv-infectionhttp://www.healthline.com/adamcontent/chickenpoxhttp://www.healthline.com/adamcontent/herpes-simplexhttp://www.healthline.com/adamcontent/herpes-simplexhttp://www.healthline.com/galecontent/haemophilus-influenzae-type-bhttp://www.healthline.com/galecontent/haemophilus-influenzae-type-bhttp://www.healthline.com/galecontent/haemophilus-influenzae-type-bhttp://www.healthline.com/galecontent/haemophilus-influenzae-type-bhttp://www.healthline.com/adamcontent/herpes-simplexhttp://www.healthline.com/adamcontent/herpes-simplexhttp://www.healthline.com/adamcontent/chickenpoxhttp://www.healthline.com/adamcontent/acute-cytomegalovirus-cmv-infectionhttp://www.healthline.com/adamcontent/rubella -
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Laboratory In4icators of Infection .Sepsis
Laboratory #est !in4ings Interpretation
Bhite 9lood cellcount
Aeu3ocytosis orleu3openia
'ndotoIemia maycause earlyleu3openia
Platelet count >hrom9ocytosis or
throm9ocytopenia
!igh value early
may 9e seen asacute1phaseresponseJ lo0platelet countsseen in overt D"C
Coagulation
cascade
Protein C
de?ciencyJantithrom9inde?ciencyJelevated D1dimerlevelJ prolonged P>and P>>
%9normalities can
9e o9served 9eforeonset of organfailure and 0ithoutfran3 9leeding.
Creatinine level 'levated from
9aseline
Dou9lingKindicates
acute renal injury
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Laboratory #est !in4ings Interpretation
Aactic acid level Aactic acid : *
mmol/A 4) mg/dA7
"ndicates tissue
hypoIiaAiver enHyme levels 'levated al3aline
phosphatase, %>,%A>, 9iliru9in levels
"ndicates acutehepatocellular injurycaused 9yhypoperfusion
erum phosphatelevel
!ypophosphatemia "nversely correlated0ithproin@ammatorycyto3ine levels4>&F, "A1, "A1#receptors7
C1reactive protein4C$P7 level
'levated %cute1phaseresponse
Procalcitonin level 'levated DiLerentiatesinfectious "$ fromnoninfectious "$
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Fast increaseto 9e present at the onsetor even 9efore the appearance of theclinical signs of infection/sepsis
>o 9e highly sensitive and speci?c forinfection/ sepsis4diLerentiation 9et0eeninfectious and non infectious causes ofin@ammation, organ dysfunction and
shoc37 "mprove accuracy of clinical diagnosis
>o indicate the eLectiveness of therapy
(hat is e;pecte4 fro$ such a$arker ??
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Recent Laboratory Marker :
1. Existing Marker: C-Reactive Protein (CRP)
2. Emerging Marker: Procalcitonin (PCT)
3. Promising Markers:
- Interleukin 6 (IL-6)
- Protein membran : CD 64 CD !!b
- Circulating protein:
"eo#terin $n%otok&in #rotein '* ! (+i,+-mobilit,rou#-bo. !) "T-#ro*"P ("-terminal #ro-brain natriuretic
#e#ti%e)
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CREAC!I"E #R$!EIN %CR#&: %'&
Intro%uce% in !/0 analitcal met+o%e +a&%evelo#e% &ince !/41 a& inection marker
Tec+nolo, 3+i,+ &en&itive ultra &en&itive
+a& analitcal &en&itivit: 001 u,mL (m,L)Pro#ert (!):
7: !20-!40 kDalton 206 #e#ti%a can not
#a&& t+e barrier #lacenta Pro%uce% in liver tri,erin, b IL6 IL! T"89
T8 I8";
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CREAC!I"E #R$!EIN %CR#&: %(&
Pro#ert (2): Reco,nation activation ca#abilit ma
reco,nieek in%icate& atreatment ailure or %i&ea&e comorbi%it
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(hat is PC#??
PC> is the prohormone of the hormonecalcitonin 9ut are distinct proteins
Calcitonin is eIclusively produced 9y C1cells of the thyroid gland in response tohormonal stimuli, 0hereas
PC> can 9e produced 9y several cell types
and many organs in response to pro1in@ammatory stimuli, in particular 9y9acterial products
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#R$CALCI!$NIN %#C!&:
'i&tor: Intro%uce% in !/?4 a& a #ro+ormon #rotein
con&i&te% o !!6 a&am amino 7 !-!4
kDalton $ra !//0 : %evelo#e% a& a marker o bacterial
inection
Pro#ert (!): Pro%uction i& &timulate% b t+e #re&entation o
en%otok&in increa&e in 2 +r #eak in !2-24 +r
%ecrea&e &lo>l in 6-12 +r
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#R$CALCI!$NIN %#C!&: %(&
Pro#ert (2): Pro%uce% in C cell o tiroi% ,lan% un%er IL6
IL? T"89 re,ulation
"ormal con%ition : all PCT cleava,e% intocalcitonin
Inection : e.#re&&ion o ,ena Calc-! >ill
&timulate all t#e& o #arenc+m ti&&ue cell& torelea&e PCT
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#R$CALCI!$NIN %#C!&: %)&
Pro#erti :
=& &ecun%ar inlammation me%iator in+ibit
#ro&ta,lan%in trombok&an &inte&i& at
limo&it
Increa&in, level %e#an%& on t+e &ta,e o &e#&i&
"ormal: @ 005 n,mL (u,L) in bacterial
inection A 2 n,mL
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PC> reference rangesand "nterpretation of PC>serum or plasma levels
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Reeren& Level Ben&itivit B#e&ivicit
*en%er et al200? ("eonatalBettin,)
A 25 n,mL( IL 6 A 250
#,mL)
1! E ?? E
aini et al 2001(CommunitBettin,)
2!/ n,mL ?01 E 61?E
=n%reola et al2001($mer,encBettin,)
A 2 n, mL 11 F 5?4 E /? - /2 E
#erformance #C!
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$"DTJI" Li#o#ol&ac+ari%e com#onent o cell >all o
"e,ative ram *acillu& Btron, tri,,er to>ar% &e#&i& ca&ca%e
Detection:
! L=L (Limulu& =moebicte L&at):ver
&en&itive reliabel marker >it+ ,elatin L=L
%an c+romo,enic L=L
2 $== ($n%oto.in =ctivit =&&a): met+o%e
o C+emilumine&ent Level A 50 #,mL --- A
marker o ne,ative ,ram bacillu& inection
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Protein '* !: Cromo&omal nuklear #rotein 3late onset
proinflamatory cytokine. Secrete% bmakroa, culture >+ic+ &timulate% b
en%oto.in
Detection limit : 06 #,mL ($LIB=)
"$PT$RI": Derivat #teri%in in mono&itmakroa, culture
areker o inection (viral bacterial)
"T-#ro*"P:
Dierentiate : &urvivor v& non-&urvivor
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CD !!b: In ,ranula o ,ranuloct cito#la&mic --- A
e.ce&&ive activation >ill be mobilictometricCD 64: 8c-,amma rece#tor I unction to inte,rate t+e
innate a%a#tive immune reon&inection
ma up-regulation
arker netroil %etecte% b lo>ctometric
Bi&temik inectione.re&&i A2000
COMPARISON SEVERAL MARKERS
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ESR CBC CRP PCT
1 Specimen Wholeblood
(sitras)
Wholeblood
(EDTA)
Serum/Plasma
Serum/Plasma
2 Methode indirect(fibrinoen)
Directmanual
otomatic
Directmanual
otomatic
Directotomatic
! "ncreasin
Pattern
Slo#l$%
bac& tonormal in
#ee&s
'uic&%
muchinfluenced
b$ lots
conditions
'uic&%
bac& tonormal up
to no
stimuli
'uic&%
bac& tonormal up
to no
stimuli
Pea& leel s
normal
* 1%+,! * 1+,!- * . - ,
. 2-- *
Sepsis
COMPARISON SEVERAL MARKERS
ESR CBC CRP PCT
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ESR CBC CRP PCT
+ onfounder0
-se*
-ae-Plasma Protein
-Eritrosit
-etc
...
...
Tissue
necrosis
a Tiroid%
Plasmodium
3alciparum
4 AnaliticalPerform0
-Sensitiit$
-Spesifisit$
-Precisi
,Anal$tical time
Moderat
Moderat
Moderat
4- mnt
5ih
Moderat
5ih
1-,4-
mnt
5ih
5ih
5ih
6 !- mnt
5ih
5ih
5ih
6 !- mnt
7 ost lo# relatie relatie hih
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#hank @ou