UNIVERSITATEA DE MEDICIN I FARMACIE "IULIU HAIEGANU" CLUJ-NAPOCA

CONTRIBUII LA STUDIUL ETIOLOGIEI, FORMELOR CLINICE, DIAGNOSTICULUI I TRATAMENTULUI ACTUAL AL MENINGITELOR ACUTE BACTERIENE LA COPIL

TEZA DE DOCTORAT PENTRU OBINEREA TITLULUI DE DOCTOR N MEDICIN SPECIALITATEA BOLI INFECIOASE

IUBU ROXANA OLIVIA MEDIC PRIMAR BOLI INFECIOASE SPITALUL CLINIC DE BOLI INFECIOASE CLUJ-NAPOCA

CONDUCTOR TIINIFIC: PROF. DR. VASILE GORGAN

- 2005 -

CUPRINS
INTRODUCERE /5

PARTEA I ACTUALITI ETIOPATOGENICE, DIAGNOSTICE, CLINICO - EVOLUTIVE I TERAPEUTICE N MENINGITELE ACUTE BACTERIENE LA COPIL / 8 CAPITOLUL 1. ACTUALITI N EPIDEMIOLOGIA I ETIOPATOGENIA MENINGITELOR ACUTE BACTERIENE LA COPIL / 9 1.1 Principalii ageni etiologici in meningitele acute bacteriene la copil. / 9 1.2 Date epidemiologice actuale n meningitele acute bacteriene la copil / 27 1.3 Factori predispozani in meningitele acute bacteriene la copil / 32 1.4 Patogenia meningitelor acute bacteriene la copil / 35 CAPITOLUL 2. ACTUALITI N DIAGNOSTICUL MENINGITELOR ACUTE BACTERIENE LA COPIL / 57 2.1 Diagnosticul clinic al meningitelor acute bacteriene al copil / 57 2.2 Diagnosticul etiologic al meningitelor acute bacteriene la copil / 61 2.3 Diagnosticul paraclinic al meningitelor acute bacteriene la copil / 68 CAPITOLUL 3. ACTUALITI N TRATAMENTUL MENINGITELOR ACUTE BACTERIENE LA COPIL / 71 3.1 Actualiti in tratamentul etiologic al meningitelor acute bacteriene la copil / 71 3.2 Actualiti in tratamentul patogenic al meningitelor acute bacteriene la copil / 85 3.3 Actualiti n profilaxia meningitelor acute bacteriene la copil / 88 PARTEA II CONTRIBUII LA STUDIUL ASPECTELOR ETIOPATOGENICE, CLINICO-EVOLUTIVE, DIAGNOSTICE I TERAPEUTICE ACTUALE N MENINGITELE ACUTE BACTERIENE LA COPIL / 93 CAPITOLUL 1. CERCETRI PERSONALE PRINCIPII GENERALE 1.1 Ipoteza de lucru / 94 1.2 Materialul cercetat i metoda de lucru / 95 / 94

CAPITOLUL 2. CONTRIBUII LA STUDIUL ETIOLOGIEI ACTUALE A MENINGITELOR ACUTE BACTERIENE LA COPIL / 100 2. 1 Scopul cercetrii / 100 2.2 Material i metod / 101 2.3 Rezultate / 102 2.4 Discuii / 116 2.5 Concluzii / 120 CAPITOLUL 3. CONTRIBUII LA STUDIUL DIAGNOSTICULUI ACTUAL AL MENINGITELOR ACUTE BACTERIENE LA COPIL / 122 3.1 Factori favorizani n meningitele acute bacteriene la copil / 122 3.2 Forme clinico-evolutive actuale n meningitele acute bacteriene la copil / 132 3.3 Importana examinrii LCR n diagnosticul etiologic al meningitelor acute bacteriene la copil / 165 3.4 Aspecte particulare in diagnosticul meningitelor acute bacteriene parial tratate al copil / 189 3.5 Studiul comparativ al valorii diagnostice a CRP, PCT i AL n diagnosticul meningitelor acute bacteriene la copil / 203 CAPITOLUL 4. CONTRIBUII LA STUDIUL TRATAMENTULUI ACTUAL AL MENINGITELOR ACUTE BACTERIENE LA COPIL / 220 4.1 Scopul cercetrii / 220 4.2 Material i metod ./ 221 4.3 Rezultate / 222 4.4 Discuii / 242 4.5 Concluzii / 247 CAPITOLUL 5. FACTORI DE PROGNOSTIC N MENINGITELE ACUTE BACTERIENE LA COPIL / 249 5.1 Scopul cercetrii / 249 5.2 Material i metod / 249 5.3 Rezultate / 250 5.4 Discuii / 259 5.5 Concluzii / 263 CAPITOLUL 6. CONCLUZII GENERALE LIST DE ABREVIERI /269 INDEX TABELE / 272 INDEX FIGURI / 275 BIBLIOGRAFIE / 279 / 265

REZUMAT
Cuvinte cheie: meningite bacteriene la copil, etiologie, meningococ, bacil Koch, factori favorizani, debut, oc infecios, cultura LCR, latex-aglutinare, pretratat, PCT, CRP, ceftriaxon, antibiogram, factori de prognostic INTRODUCERE Meningitele acute bacteriene (MAB), continu s reprezinte o problem clinic important i o preocupare mereu actual a patologiei infecioase pe plan mondial. Localizarea infeciei bacteriene la nivelul spaiului subarahnoidian se poate produce la orice vrst, dar sugarul i copilul mic sunt afectai preponderent, statisticile actuale indicnd o frecven mult mai mare (70 75%) a meningitelor bacteriene n perioada copilriei. Incidena MAB la copil se menine ridicat, n ciuda msurilor de imunoprofilaxie activ i chimioprofilaxie disponibile n prezent. n acelai timp, aplicarea de rutin, n unele ri, a vaccinrii mpotriva infeciei meningococice i cu H. influenzae tip b a condus la modificarea profilului etiologic al meningitelor bacteriene la copil n ultimii 20 de ani. Cu toate c n ultimele decenii s-au realizat progrese importante n domeniul diagnosticului etiologic i al terapiei, care au schimbat aspectul evolutiv al acestor afeciuni i au redus rata de letalitate de la 50 80% la 10 30% [1, 229, 242], o serie de probleme legate de incidena, modificarea permanent a profilului etiologic, sensibilitatea la antibiotice a germenilor implicai, mecanismele patogenice, particularitile tabloului clinic actual, abordarea terapeutic i factorii de pronostic, reprezint nc subiecte controversate. Afeciuni de o mare gravitate, MAB la copil constituie reale urgene medicale, necesitnd un diagnostic etiologic rapid i corect, n vederea instituirii ct mai precoce a unui tratament antibiotic intit, esenial pentru salvarea vieii bolnavului i vindecarea acestuia fr sechele. n contextul modificrii spectrului etiologic al meningitelor bacteriene i creterii numrului de germeni multirezisteni la antibiotice, apare necesitatea stabilirii unor noi scheme de tratament etiologic aplicabile n cazurile la care terapia se face pe criterii de probabilitate. PARTEA I. ACTUALITI ETIOPATOGENICE, DIAGNOSTICE, CLINICO - EVOLUTIVE I TERAPEUTICE N MENINGITELE ACUTE BACTERIENE LA COPIL Partea general este alctuit din trei capitole principale. Capitolul 1 cuprinde o sintez a datelor de ultim or din literatura de specialitate referitoare la etiologia i epidemiologia actual a MAB la copil, principalii factori favorizani i mecanismele patogenice implicate n declanarea bolii. n capitolul 2 sunt prezentate principalele elemente de diagnostic clinic i particularitile tabloului clinic al MAB la copil n funcie de vrst i agentul etiologic, precum posibilitile actuale de stabilire a diagnosticului etiologic. n capitolul 3 sunt trecute n revist principiile actuale, unanim acceptate pe plan mondial, referitoare la tratamentul etiologic, patogenic i profilaxia MAB la copil. PARTEA II. CONTRIBUII LA STUDIUL ASPECTELOR ETIOPATOGENICE, CLINICOEVOLUTIVE, DIAGNOSTICE I TERAPEUTICE ACTUALE N MENINGITELE ACUTE BACTERIENE LA COPIL

Capitolul 1. Cercetri personale principii generale prezint pe larg ipoteza de lucru, obiective
acestui studiu, materialul clinic cercetat i metoda de lucru. Scopul acestei cercetrii este de a aduce noi informaii referitoare la incidena i etiologia actual a meningitelor bacteriene la copil, de a analiza posibilitile i limitele diagnostice i terapeutice, de evaluare a unor factori de pronostic cu importan n practica medical i compararea rezultatelor obinute cu date de actualitate, din alte zone de pe glob, publicate n literatura de specialitate i cu date nregistrate i comunicate n urm cu 20 de ani pentru zona noastr geografic. Am analizat prospectiv i retrospectiv un numr de 141 cazuri de MAB la copil internate n Spitalul Clinic de Boli Infecioase Cluj-Napoca, pe o perioad de 6 ani (ian 1999 dec. 2004), care au fost mprii in mai multe loturi de bolnavi, n funcie de obiectivele urmrite. Menionez c am inclus n studiu i cazurile de meningit TBC la copil din mai multe considerente: cu toate c majoritatea autorilor ncadreaz meningitele TBC ntre infeciile cronice ale SNC[1,129], experiena personal ne-a artat c dei infecia bacilar cu localizare extraneural evolueaz cronic, n cazul determinrilor nervoase, mai

ales la copil, manifestrile clinice i evoluia sunt caracteristice unei boli infecioase acute; importana locului pe care meningita bacilar l ocup ntre infeciile sistemului nervos la copil, prin gravitatea deosebit, riscul mare de deces i incidena maxim a sechelelor neuromotorii i psihice [227,228]; creterea alarmant a incidena meningitei TBC n ultima perioad, n special n rndul populaiei infantile [242], ne-a determinat s analizm aceast afeciune important alturi de celelalte meningite bacteriene ale copilului, tocmai pentru a sublinia aspectele clinice particulare, importante n practica medical curent pentru orientarea diagnostic iniial. Diagnosticul de MAB s-a stabilit pe baza tabloului clinic tipic, n prezena modificrilor biochimice i citologice caracteristice ale LCR, corelate cu creterea probelor inflamatorii i modificri ale hemoleucogramei specifice pentru o infecie bacterian. Diagnosticul etiologic de certitudine s-a bazat pe izolarea agentului patogen prin cultivarea LCR (tehnica BacTAlert), hemocultur sau culturi din alte produse patologice (secreie otic), identificarea acestuia pe frotiu colorat Gram obinut prin centrifugarea LCR i/sau evidenierea antigenelor bacteriene specifice n LCR prin metode imunologice, respectiv testul latex-aglutinare (LA). Pentru diagnosticul etiologic al meningoencefalitei TBC s-a utilizat izolarea bacilului Koch din LCR prin cultivare pe mediul Lowenstein i/sau vizualizarea pe frotiu Ziehl-Nielsen sau prezena de modificri citologice i biochimice n LCR patognomonice pentru etiologia bacilar, coroborate cu ancheta epidemiologic pozitiv pentru tuberculoz, pozitivarea IDR la PPD, existena de leziuni active pleuro-pulmonare sau alte localizri extraneurale ale infeciei TBC, precum i valoarea diagnostic a probei terapeutice [274, 275]. Dup momentul apariiei i n funcie de mecanismul de producere, am clasificat complicaiile semnalate n complicaii imediate, tardive i prin mecanism imun-alergic. Cazurile au fost analizate statistic pe baza unei baze de date realizat n programul Fox Pro, care cuprinde date demografice, factorii favorizani, date clinice, date paraclinice, explorri imagistice, EEG, audiogram, consulturi interclinice de specialitate, date referitoare la tratament, date privind evoluia, durata spitalizrii, rezultate de la examenul anatomo-patologic, observaii de la controalele efectuate dup externare. S-au folosit teste de statistic descriptiv, analiz univariant i multivariant, furnizate de programele Epi Info, Statistica i Microsoft Excel (testul X2, testul Fisher, testul Student, testul MannWhitney i testul de regresie multipl).

Capitolul 2 - Contribuii la studiul etiologiei actuale a MAB la copil, cuprinde evaluarea

etiologiei generale i in funcie de grupele de vrst a MAB la copil n arealul nostru geografic, analiza modificrilor survenite n spectrul etiologic i referitor la datele demografice n ultimii 20 de ani, precum i compararea rezultatelor obinute cu date din literatura de specialitate. Vrsta medie a celor 141 de cazuri analizate a fost de 3,7 4,5 ani, cu limite ntre 2 zile i 16 ani, mai mult de 50% din cazuri (79) fiind nregistrate la grupa de vrst 3 luni 5 ani, 15 cazuri (10,63%) la grupa 0 3 luni i 47 cazuri (33,33%) la grupa de vrst 5 16 ani. Am remarcat tendina de deplasare a incidenei maxime a MAB spre vrste mai mari fa de studii anterioare [283 citat de 205], doar 10,63% din cazuri fiind diagnosticate la vrsta de nou-nscut i sugar mic, rezultate concordante cu date comunicate recent pe plan mondial (SUA, Marea Britanie, Europa occidental), care anun o scdere cu aproximativ 73% a incidenei generale a MAB la copil [79], concomitent cu creterea vrstei medii a cazurilor de meningit bacterian de la 15 luni n 1986, la 25 de ani n 1995. Incidena medie a cazurilor de MAB la copil a fost de 23 cazuri/10 000 internrii, cu o durat medie de spitalizare de 19,03 zile 16,34 zile. Incidena general a meningitelor bacteriene la copil s-a meninut constant comparativ cu perioada 1978 1983 [205], cu o medie anual de 34, respectiv 35,8 cazuri, dar spectrul etiologic s-a modificat prin creterea semnificativ a cazurilor de meningit TBC, (aproximativ de 10 ori mai multe n cadrul lotului studiat - 23 de cazuri (16,31%), fa de studiul anterior care menioneaz doar 2 cazuri (1,4%), p=0, 00002). Procentul mare de cazuri de etiologie specific pare s fie consecina direct a creterii incidenei generale a infeciei TBC n rndul populaiei infantile, n contextul scderii nivelului de via la anumite categorii sociale. Concomitent cu creterea marcat a cazurilor de meningit bacilar s-a remarcat scderea cu 16,9% a ponderii MAB nebacilare. Etiologia MAB la copil s-a caracterizat prin diversitatea agenilor patogeni implicai, cu o inciden diferit n funcie de vrst. La 99 cazuri (70,21%) etiologia meningitei s-a stabilit cu certitudine, n 18 cazuri (12,76%) etiologia a fost doar presupus cu mare probabilitate, pe baza unor semne clinice sugestive (6 cazuri de infecie meningococic) sau pe criterii indirecte (12 cazuri de meningit TBC), iar la 24 cazuri (17,02%) agentul etiologic nu a putut fi precizat. Datele obinute sunt

asemntoare cu cele din literatura de specialitate: Teindel Cl. i colab. [281] - 17,4%, Angelescu M. i colab. [242] - 34% (1988), Pun L. i colab [282] - 20,6% (1989) cazuri de etiologie neprecizat n MAB. Germenul cel mai frecvent izolat a fost Neisseria meningitidis (serogrupurile B si C) - (29,08%), cu inciden maxim la copilul mare, n scdere ns fa de perioada 1978 1983 (45,77%). Bacilul Koch a ocupat locul al doilea, cu incidena maxim la copilul sub 5 ani - 18 cazuri, dintre care 1 caz sub vrsta de 3 luni (fig. nr. 1), urmat de Str. pneumoniae 19 cazuri. Incidena global de izolare a Str. pneumoniae a crescut de la 4,92% la 13,47%, n ultimii 20 de ani, iar numrul de MAB la copil determinate de Hib s-a dublat (7,8% fa de 3,5%) ceea ce impune introducerea vaccinrii obligatorii antiHib.
Fig. nr. 1 Repartizarea cazurilor de MAB n funcie de agentul etiologic i grupa de vrst
25

23

20

17

17

15

10

9 5

9 6

10

11

1
0 Meningococ

3 1

Bacil Koch

Pneumococ

Hib

GBS

Stafilococ aureu

Bacili Gram negativ i

Etio dubla

Alti germeni

Etio neprecizata

0 - 3 luni

3 luni - 5 ani

5 ani - 16 ani

La nou-nscut i sugarul mic, bacilii Gram negativi au rmas principalii ageni etiologici, dei implicarea bacililor acestora n etiologia meningitei neonatale a fost mai mic (40%), fa de datele din literatur (Teindel i colab. 68,4%), p = 0,009. Am constatat ns o uoar cretere a frecvenei de izolare a bacililor Gram negativi per global (9 cazuri fa de 7) comparativ cu perioada 1978 1983, posibil prin creterea acurateei diagnosticului etiologic (fig. nr. 2).
Fig. nr. 2 Modificarea n timp a implicrii diferiilor ageni patogeni n etiologia MAB la copil
70 60 50 40 30 20

65 50 41

19 7

23 11 2 5 9 0
BK Hib Gram negativi

24

10 0

Meningococ

Pneum ococ

GBS

Stafilicoc aureu

Etio dubla

Alti germeni

NP

1973 - 1978

1999 - 2004

Capitolul 3. Contribuii la studiul diagnosticului actual al MAB la copil. 3.1 Factori favorizani n MAB la copil. In acest capitol s-a urmrit identificarea
principalilor factori favorizani in MAB la copil i stabilirea unei corelaii ntre acetia i agentul etiologic. La un numr mare de cazuri ( 82,26%) s-a depistat cel puin unul dintre factorii favorizani, citai n literatura de specialitate, n general la acelai caz, fiind prezeni mai muli factori predispozani concomitent, ceea ce probabil crete riscul de boal. Factorii de mediu, n special cei socio-economici, au fost mai frecvent depistai dect cei legai de organismul gazd: aglomeraia (68,97%), corelat mai ales cu etiologia meningococic (75,60%), bacilar (91,30%) i pneumococic (52,63%, condiiile socio-economice precare, asociate cu meningita meningococic (65,85%), bacilar (91,30%), pneumococic (73,68%) i stafilococic (100%) i proveniena din mediul rural 86 cazuri (60,99%), corelat cu infeciile meningococice (68,29%), bacilare (82,60%) i pneumococice (68,42%). Un rol important l-a avut fumatul pasiv asociat cu 51,77% din cazurile studiate, mai ales cele produse de meningococ (85,36%) i pneumococ (78,95%). Studii recente au artat c rata infeciei meningococice sistemice este de 3,5% n cazul n care mama este fumtoare, 3,2% pentru tat i 2,7% pentru fiecare 20 de igri fumate n medie pe zi n cas [107]. Factorii

favorizani legai de organismul gazd cel mai frecvent ntlnii au fost: vrsta mic, sub 5 ani (66,66% cazuri), asociat n principal cu meningita cu bacili Gram negativi (88,88%), streptococ de grup B (100%), Hib (81,81%), stafilococ (100%) i meningita bacilar (73,91%) - i existena unei IACRS n antecedentele recente ale copilului - 77 cazuri (54,60%), ntlnit cel mai frecvent la cazurile de etiologie meningococic (70,73%), pneumococic (73,68%) i cu Hib (72,72%). n meningitele neonatale, condiia socio-economic precar i nivelul de instruire sczut al mamei au fost regsite la 46,66% cazuri, de obicei asociate cu prematuritatea (26,66%) i greutatea mic la natere (33,33%), condiii unanim recunoscute ca favorizante pentru declanarea meningitei bacteriene la aceast vrst [286]. 3.2 Forme clinico-evolutive actuale n MAB la copil. Scopul cercetrii a fost analiza manifestrilor clinice actuale la cele 141 cazuri, modul de debut, simptomele i semnele clinice cele mai frecvente i evoluia acestora sub tratament, definirea formelor clinice actuale (gravitate, complicaii) i corelarea acestora cu vrsta pacientului i etiologia MAB. Debutul bolii a fost acut (1 2 zile) la 81 cazuri (57,44%), supraacut (sub 24 de ore) n 28 cazuri (19,85%), cele mai multe dintre acestea fiind infecii meningococice (19 cazuri) i subacut (3 14 zile) la 32 cazuri (22,69%), n majoritate de etiologie bacilar. Simptomul cel mai frecvent din perioada de debut au fost, vrsturile - 108 cazuri, (76, 59%) (tabelul nr.1). Semnele de iritaie meningian (68,7779%) i febra (66,67%) au fost manifestri inconstante, fiind absente mai ales in meningita neonatal i n meningita tuberculoas. Dintre semnele de afectare a SNC, simptomul cel mai frecvent a fost alterarea strii de contient (90,77%). Semnele neurologice de focar au mai frecvente n meningita TBC i n meningita pneumococic constatate n 60,86% i respectiv 26,31% din cazuri. Convulsiile, ca prim episod, s-au ntlnit la 52 cazuri (36,87%) i au reprezentat simptomul cel mai persistent n medie 7,2 zile, corelate cu o rat mare de letalitate i sechelaritate, n special n meningita neonatal i n meningita TBC.
Tabelul nr. 1 Principalele semne i simptome clinice n perioada de debut la cazurile analizate Semne i simptome febr >38C semne SNC t cefalee t fotofobie t sindrom meningian t obnubilare/agitaie t com t convulsii t semne neurologice de focar t bombarea fontanelei* vrsturi manifestri respiratorii erupie cutanat Nr. cazuri 94 61 41 97 63 65 52 44 26 108 43 33 Frecven 66,67% 43,26% 29,07% 68,79% 44,68% 46,09% 36,87% 31,20% 83,87% ** 76.59% 30,49% 23,40%

* bombarea fontanelei numai pentru sugar ** din numrul total de cazuri sub 1 an (31 cazuri)

n meningita neonatal tabloul clinic iniial a fost nespecific, fiind dominat de manifestri digestive (86,66%), i manifestri respiratorii (46,66%). Febra a fost prezent la mai puin de jumtate din cazuri (46,66%), concordant cu datele din literatur, care citeaz mai frecvent instabilitatea termic (hipotermie alternnd cu hipertermie), dect hiperpirexia [292,293]. Semnele de suferin ale SNC au fost decelate ntr-un procent mai mare dect datele din literatur (meningismul la 26,66% din cazuri, convulsiile la 80% i bombarea fontanelei la 73,33% din cazuri). Alterarea senzoriului, n diferite grade de la apatie, letargie sau agitaie psihomotorie pn la com a fost semnalat la toate cele 15 cazuri.
Fig. nr. 3 Principalele complicaii n MAB la copil la cazurile studiate
60 50 40 30 30 20 20 10 0 11 6 3 9 6 51

soc inf.

IRA

CID

abces cloazonarenecroze extinse compl. tardive

nevrite perif

artrite miocardita compl. IA

compl. imediate

n cursul evoluiei, 79 de cazuri (56,03%) au prezentat una sau mai multe complicaii (fig. nr. 3) ocul infecios, cea mai frecvent complicaie imediat (36,17%), a fost asociat mai ales cu vrsta mic (40,42% dintre copii sub 5 ani) i cu etiologia meningococic (51,21% din cazuri) i pneumococic (73,68% din cazuri). Incidena complicaiilor tardive a fost mai mare n meningita bacilar (43,47%), meningita

pneumococic (26,31%) i n meningita neonatal (33,33%). Formele cele mai severe de boal s-au ntlnit n meningita neonatal (60%), cazurile de etiologie bacilar (78,29%), pneumococic (73,61%) i cu etiologie dubl (60%). Rata cea mai mare de letalitate s-a nregistrat n meningitele cu etiologie dubl (20%) i cu H. Influenzae (18,18%). O rat mare a letalitii, peste media general (10,63%), s-a constatat i n cazurile de etiologie bacilar (17,39%) i cele produse de Str. pneumoniae (15,78), n timp ce pentru infecia meningococic i la cazurile de etiologie neprecizat s-au obinut cele mai mici valori (7,3% i respectiv 4,16%). De remarcat c n cadrul meningitelor cu bacili Gram negativi nu s-a nregistrat nici un deces pe cazuistica cercetat. 3.3 Importana examinrii LCR n diagnosticul etiologic al MAB la copil. Scopul acestui studiu a fost evaluarea importanei diferitelor examinri de laborator din LCR, disponibile n prezent pentru stabilirea diagnosticului etiologic al MAB la copil, precum i limitele acestora. Din cele 141 cazuri de MAB la copil luate n studiu, identificarea agentului etiologic s-a realizat n 99 cazuri (70,21%). Identificarea agentului patogen s-a realizat prin utilizarea combinat a mai multor metode: examinri bacteriologice din LCR (cultur + frotiu Gram) la 77 pacieni (77,77%), numai prin testul LA la 15 pacieni (15,15%), prin hemocultur la 3 cazuri de infecie meningococic (3,03%) i prin alte examinri bacteriologice (secreie otic, examen anatomopatologic) la cte 2 pacieni (2,02%) (fig. nr. 4).
Figura nr. 4 Metodele de determinare a etiologiei la cazurile de MAB la copil studiate
71.71% 2.02% 2.02% 3.03% 15.15% 6.06% 77.77%

Testul LA Examen AP

Hemocultura . Cultura

Secrectie otica . Frotiu

Pentru cazurile de MAB nebacilar (n = 118) etiologia s-a stabilit n procent de 74,57%. Procentul relativ mic de izolare a agentului patogen, comparativ cu alte studii, este consecina includerii n lotul studiat a unui numr considerabil de cazuri pretratate cu antibiotice cel puin 3 zile naintea recoltrii LCR (26,24% din cele 141 analizate). Pentru cazurile de meningit specific (n = 23), bacilul Koch a fost identificat n 11 cazuri (47,82%). Identificarea bacilului Koch prin metodele bacteriologice clasice este deosebit de dificil [229,277], diagnosticul stabilindu-se mai ales pe criterii clinice i paraclinice de probabilitate [274,275,299], situaie ntlnit i n studiul de fa. Testul LA a fost pozitiv la 65 pacieni din lotul de 83 la care s-a efectuat aceast determinare, demonstrnd o sensibilitate de 78,31% pentru determinarea Ag bacteriene specifice din LCR. Utilizarea testului LA a crescut procentul de identificare a agentului etiologic cu 26,5%. Cele mai multe rezultate pozitive au fost obinute la cazurile determinate de Str. pneumoniae (89,47%) i N. meningitidis (82,92%), pentru acesta metoda avnd un rol important n mbuntirea diagnosticului etiologic i n precizarea serogrupului. Germenul cel mai frecvent izolat prin cultivarea LCR a fost H. influenzae tip b (81,81%), dei este cunoscut c acest microorganism este deosebit de pretenios, necesitnd medii speciale, mbogite cu factori de cretere; procentul mare de culturi pozitive ar putea fi explicat prin utilizarea mediilor de cultur BacT/Alert, care sunt medii speciale, de o calitate superioar. Procentele mai mici de identificare a N. meningitidis prin metode bacteriologice (60,97% prin cultur, 56,09% pe frotiu), confirm nc o dat rezistena sczut a acestui microorganism n mediu extern i necesitatea utilizrii testului LA, care a mbuntit semnificativ diagnosticul etiologic (p = 0,001). Pentru Str. pneumonie examenul bacteriologic al LCR a constituit principala metod de identificare. Din cele 74 hemoculturi recoltate, 26 (35,14%) au fost pozitive, majoritatea (22) fiind infecii meningococice. Hemocultura are valoare diagnostic mic n stabilirea etiologiei MAB la copil, cu excepia meningitelor meningococice asociate cu meningococemie, la care n condiiile unui tablou clinic sugestiv, ar putea nlocui puncia lombar, fr a prejudicia conduita terapeutic [232] i a meningitelor neonatale, care evolueaz frecvent n cadrul sepsisului neonatal. Scheld i colab. recomand recoltarea hemoculturii ca prima manevr de diagnostic n meningitele neonatale.

Examinarea parametrilor biochimici i citologici din LCR permite n contextul clinic ncadrarea rapid ntr-o anumit categorie etiologic [1,12,229,242,288], n cazurile la care agentul patogen nu a fost identificat, fcnd posibil alegerea imediat a unei scheme terapeutice corespunztoare i ofer totodat informaii preioase despre gravitatea infeciei i rspunsul la tratamentul aplicat. Rspunsul inflamator local la cazurile studiate a fost diferit n funcie de etiologie, vrsta pacientului i statusul imun, cu o valoare medie a numrului de celule din LCR de 3 331/mm3 i limite cuprinse ntre 10 elem/mm3 i 15 000/mm3. La 46,80% din cazuri (o parte din meningitele meningococice asociate cu meningococemie, cu evoluie fulminant, cazurile de meningit TBC i o parte din cazurile pretratate) numrul de celule din LCR a fost < 500 elem/mm3. O celularitate sczut este caracteristic i n meningitele neonatale la prematuri (pn la 15% din cazuri) [229,318], dar un numr sczut de leucocite la nivelul LCR, nu exclude diagnosticul de MAB la copil. Albuminorahia a depit valoarea normal de 40 mg% la majoritatea a pacienilor (93,60%), cu o valoare medie de 194 mg%; valorile medii cele mai ridicate s-au constatat la cazurile de meningit tuberculoas (297 mg%, cu limite ntre 61 mg% i 650 mg%), fr a se semnala ns valorile extreme ale albuminorahiei i scderea accentuat a glicorahiei, consemnate in tratatele clasice. Concentraia foarte sczut a glicorahiei este mai tipic pentru stadiile avansate ale bolii; n absena terapiei specifice se observ o scdere progresiv a acesteia [274]. n cazurile de etiologie nebacilar valorile glicorahiei au prezentat variaii mari (5 mg% 105 mg%), inclusiv valori normale, mai sugestiv pentru etiologia bacterian a meningitei fiind raportul glicorahie/glicemie, care a avut o valoare < 0,31 n 86 cazuri (60,99%).

3.4 Aspecte particulare n MAB parial tratate la copil. n acest studiu efectuat pe 118 copii cu MAB nebacilar, dintre care 37 (31,35%) primiser un tratament antibiotic cu o durat de minim 48 ore naintea internrii, ne-am propus s analizm efectul terapiei antibiotice asupra caracteristicilor clinice, de laborator, asupra acurateei diagnosticului etiologic i consecinele asupra evoluiei ulterioare a acestor cazuri. Administrarea de antibiotice n ambulator a prelungit perioada de instalare definitiv a simptomelor clinice iniiale i implicit intervalul de timp de la debutul primelor semne de boal pn la prezentarea la medicul specialist. Debutul subacut al bolii a fost mai frecvent ntlnit - 24,32% (9 cazuri) la pacienii pretratai dect la cei 81 pacieni fr tratament antibiotic anterior internrii - 3,70% (3 cazuri). Tabloul clinic tipic de MAB a fost mai atenuat la cazurile pretratate comparativ cu cele netratate, cu o frecven mai mic a semnelor de gravitate n momentul internrii (com 16, 21% vs. 51,85%, convulsii 13,5% vs. 38,27%), retrocedarea mai rapid, n medie cu 1 zi, a principalelor semne i simptome dup instituirea unei terapii corespunztoare i o inciden mai mic a complicaiilor imediate, oc infecios (24, 32% vs. 51,85%), IRA (13,51 vs. 30,86%), CID (3,40% vs. 11,11%). Parametrii biochimici i citologici din LCR nu au fost influenai semnificativ de administrarea antibioticelor naintea efecturii punciei lombare, cu excepia albuminorahiei pentru care s-a constatat o valoare medie mai sczut, 125 mg% n cazurile de meningit pretratate fa de 228 mg% n meningitele netratate (p <0,05). Procentul de rezultate bacteriologice pozitive din LCR a fost ns semnificativ mai mic la cazurile pretratate (13,51% vs. 74,83% pentru Fig. nr. 5 Identificarea agentului patogen prin culturi, respectiv 8,11% vs. 61,72%, pentru frotiu - fig. diverse metode la cazurile pretratate comparativ nr. 5). cu cele netratate. Identificarea Ag bacteriene specifice din LCR 100% prin testul LA nu a fost n schimb influenat 80.70% 74.83% 73.07% 80% semnificativ de administrarea de antibiotice: 73,07% 61.72% rezultate pozitive din totalul probelor efectuate pentru 60% 48.07% cazurile pretratate i 80,70% n cazurile netratate, 40% confirmnd aportul important al determinrilor 13.51% imunologice din LCR n diagnosticul etiologic al 8.11% 20% 4.54% MAB la copil, n mod special la pacienii crora li s-a 0% administrat un tratament antibiotic nainte de Cultura Frotiu HC Test LA recoltarea LCR prin puncie lombar. LCR Gram Stabilirea diagnosticului etiologic a fost MAB PT MAB NT influenat n sens negativ de administrarea antibioticelor nainte de internare: 43,24% cazuri cu etiologie precizat pentru lotul de meningite pretratate n comparaie cu 88,89% pentru cazurile netratate (p < 0, 003). Pentru cazurile pretratate etiologia s-a stabilit n principal prin metode imunologice (56,25%), n timp ce la cazurile fr tratament antibiotic, metoda principal a fost examenul bacteriologic al LCR, culturi i frotiu colorat Gram (76,54% ).

3.5 Studiul comparativ al valorii diagnostice a CRP, PCT i AL n MAB la copil.

Studii relativ recente au demonstrat c PCT este nedetectabil n sngele periferic al persoanelor sntoase, dar nivelul acesteia crete n timpul infeciilor severe, cnd este eliberat n snge fr a mai forma calcitonina [334]. Obiectivul acestui studiu a fost de a analiza comparativ importana CRP, PCT i AL n diagnosticul pozitiv al MAB la copil i n diferenierea acestora de meningitele acute virale (MAV) la un lot de 77 copii internai cu suspiciunea de meningit acut (36 diagnosticai cu MAB i 41 cu MAV). PCT a fost msurat prin metoda semicantitativ Brahms PTC-Q, - test imunocromatografic. Valoarea PCT n ser a fost mult crescut, > 10 ng/ml la toate cele 36 cazuri de MAB (excepie - 3 pacieni, care primiser tratament antibiotic naintea internrii i care au avut nivele detectabile, dar mai sczute ale PCT n ser). La cele 41 de cazuri de MAV studiate comparativ, nivelul PCT n ser a fost sub valoarea de detecie de 0,5 ng/ml. Pentru CRP, dei au existat diferene semnificative statistic (p < 0,05) ntre cele 2 grupuri (MAB vs. MAV), s-a constatat o zon larg n care att valorile serice i din LCR au fost superpozabile. In concluzie, nivelul seric al PCT este un marker mai bun n diferenierea MAB de MAV la copil, dect valoarea CRP serice. Fig. nr. 6 Corelaia dintre valoarea PCT n LCR PCT seric > 0,5 ng/ml a avut o sensibilitate de i vrst n MAB la copil pentru cazurile studiate 91,66%, la valori > 2 ng/ml sensibilitatea a fost de 12 97,22%, iar la valori > 10 ng/ml sensibilitatea este 10 practic de 100%. Specificitatea este de 100% de la o valoare > 0,5mg/ml. 8 CRP seric > 5 mg% a avut o sensibilitate de 6 72,22% i o specificitate de 83,87% n diferenierea MAB de MAV la copil. n LCR proteina C reactiv la o 4 valoare > de 5 mg% a avut o sensibilitate de 58,33% i o 2 specificitate mare, de aproape 100%. O valoare negativ a CRP n LCR a exclus practic n totalitate etiologia 0 0 20 40 60 80 bacterian a meningitei. varsta (luni) La 33 copii cu MAB s-a determinat concomitent i valoarea PCT n LCR. La 16 dintre acetia (48,48%) am gsit nivele detectabile ale PCT n LCR.(5 cazuri > 0,5 ng/ml, 7 cazuri cu gsit valori ntre 2 ng/ml 10 ng/ml i 4 cazuri > 10 ng/ml). Valori ale PCT din LCR > 2 ng/ml (11 cazuri), au fost asociate cu forme severe de boal: 2 cazuri cu evoluie letal, 4 pacieni cu complicaii tardive i 5 cazuri s-au vindecat cu sechele neuropsihice severe. De asemenea valorile PCT > 2 ng/ml la nivelul LCR au fost corelate cu vrsta mic (media de vrst - 2,2 ani) (fig. nr. 6).

Capitolul 4. Contribuii la studiul tratamentului actual al MAB la copil. In acest capitol sunt prezentate cele mai eficiente scheme terapeutice utilizate, importana antibiogramei, corelaia dintre rezultatele terapiei i momentul instituirii ei i rolul tratamentului patogenic n scderea mortalitii i morbiditii la cele 118 cazuri de MAB monitorizate. Tratamentul antibiotic de prim intenie s-a fcut cu monoterapie la 60 pacieni (50,85%) i cu terapie asociat la 58 pacieni (49,15%) - la 52 (44,06%) cu biterapie i la 6 (5,08%) cu triterapie. Antibioticul cel mai frecvent utilizat n monoterapie a fost ceftriaxona (73,33%) datorit spectrului larg i sensibilitii la aceasta a principalilor ageni etiologici ai MAB la copil n zona noastr geografic [242, 245], fapt confirmat i de rezultatele antibiogramei. Penicilina G, fa de care s-a constat o cretere a numrului de tulpini rezistente de N. meningitidis i Str. pneumoniae , a fost folosit ca unic antibiotic doar la 4 pacieni (6,66%), n condiiile actuale, utilizarea acesteia n monoterapie n tratamentul MAB la copil, n absena antibiogramei, fiind contraindicat. Meropenemul, ca antibiotic de rezerv, s-a administrat doar n monoterapie, la 5 cazuri (8,33%), n conformitate cu antibiograma, care a evideniat germeni rezisteni la celelalte antibiotice. Utilizarea terapiei asociate a fost impus de absena antibiogramei i de prezena condiiilor agravante n momentul internrii. Una dintre cele mai folosite asocieri (29 pacieni 41,38% dintre cei care au beneficiat de biterapie) a fost penicilina G plus ampicilina, folosit i n trecut n trecut n clinica noastr, avnd n vedere efectul bactericid aditiv al celor 2 antibiotice, care acioneaz prin mecanisme diferite i n locuri diferite asupra celulei bacteriene. Tratamentul antibiotic n tripl asociere a fost indicat doar n cazurile de meningit neonatal de etiologie neprecizat (3 cazuri), pentru care s-au respectat recomandrile Academiei Americane de Pediatrie, acceptate pe plan mondial, care indic folosirea asocierii ampicilin + cfs III + aminoglicozid.

PCT (ng/ml)

n funcie de etiologie, monoterapia (Cfs III) a fost indicat cel mai frecvent la cazurile de meningit meningococic (63,41%), iar terapia asociat la cazurile de etiologie neprecizat (biterapie 66,66% i triterapie 20,83%) (fig. nr. 16).
Fig. nr. 7 Monoterapia i terapia antibiotic asociat n funcie de etiologie la cazurile de MAB la copil studiate

Tratamentul etiologic de prim intenie a fost concordant n 88,57% din cazuri cu tratamentul 30 27 antibiotic intit indicat dup obinerea rezultatelor 25 bacteriologice i imunologice din LCR. 20 n urma efecturii antibiogramei (la 75 16 14 15 dintre tulpinile bacteriene izolate) am remarcat i 10 9 10 pentru zona noastr apariia de tulpini de 7 7 5 4 4 3 3 3 3 meningococ rezistente la penicilina G, dar n procent 5 2 1 mai mic (6,89%) fa de alte ri i un procent mare 0 de tulpini rezistente la biseptol (79,31%). Pentru Str. pneumoniae dintre tulpinile izolate 25% au fost rezistente la cloramfenicol i biseptol, 12,5% rezistente la penicilina G i ampicilin (6,25%) i 1 tulpin (6,25%) a prezentat rezistent multipl la antibioticele uzuale. Utilizarea terapiei antibiotice asociate i prezena n schema terapeutic a unei cfs III a scurtat durata medie de spitalizare la 15,2 zile la pacienii cu terapie asociat, fa de 23,7 zile la pacienii cu monoterapie (p = 0,001), respectiv la 16,1 zile la cei tratai cu cfs III, comparativ cu 21,4 zile pentru cei tratai cu alte antibiotice (p = 0,04). Perioada pn la afebrilizare i remisia principalelor manifestri clinice a fost de asemenea mai mic pentru cazurile cu terapie asociat sau /i tratate cu cfs III. Instituirea tratamentului etiologic corect n primele 12 ore de la debut, a crescut semnificativ eficiena acestuia i a sczut riscul de apariie al complicaiilor tardive. La 10 din cele 11 cazuri cu evoluie letal terapia antibiotic corect s-a introdus la mai mult de 12 ore de la debutul bolii. Toate cazurile analizate au beneficiat de tratament cortizonic (HHC -10 mg/kgcorp/zi la 6 ore n primele 24 48, apoi dexametazon - 0,5 mg/kgcorp/zi la 8 12 ore), cu o durat medie de 6,2 zile. Pentru cele 118 cazuri tratate cu preparate cortizonice am constatat un indice mai sczut al sechelelor de tip surditate la cazurile de meningit cu H. influenzae i Str. pneumoniae (3,33% vs. 12,5% respectiv 15,5%) i o rat de letalitate semnificativ mai mic n meningita pneumococic (15,78% vs. 28,7% , respectiv 15,78% vs. 40,25%) , fa de procentele comunicate de ali autori pentru loturi de copii care nu au fost tratai cu dexametazon [1,229,344,345, 346,347], p = 0,005 i p = 0,001) . Pentru cazurile de meningit TBC (n = 23) rata de letalitate a fost de aproximativ 2 ori mai mare la pacienii la care tratamentul specific a fost introdus la peste 7 zile de la debut, comparativ cu cei la care tratamentul etiologic a fost administrat n prima sptmn (23,07% vs. 10%), dar fr a se constata o diferen semnificativ statistic (p > 0,05). Din punct de vedere al sechelelor, ntre cele 2 grupuri s-au nregistrat diferene semnificative statistic (p = 0,03); dintre cazurile la care tratamentul s-a instituit tardiv, la nici unul nu s-a obinut vindecarea complet.
monoterapie biterapie triterapie
g e u du bl ne au re tid za on i ct et ra m in gi um nf lu Et io ga S. en pn e N .m H S.

Capitolul 5. Factori de prognostic n MAB la copil. In acest capitol am evaluat datele

demografice, clinice i paraclinice la cele 141 de cazuri studiate care ar putea reprezenta parametrii unui scor prognostic n MAB la copil. Dintre factorii de prognostic care in de organismul gazd, vrsta mic (< 3luni) a constituit un factor de prognostic nefavorabil, crescnd semnificativ riscul de deces (p = 0,01), fapt consemnat n majoritatea tratatelor de specialitate i n numeroase studii publicate [1,12,205,229,242,288]. Statusul imun deficitar, prezent la 5,67% din cazuri, a crescut semnificativ rata de mortalitate, constatndu-se diferene semnificative statistic (p = 0,03) ntre grupul de supravieuitori (126 cazuri) i grupul de nesupravieuitori (15 cazuri). Urmtoarele modificri ale echilibrului acido-bazic i hidro-electrolitic au fost corelate cu riscul de deces, constatndu-se diferene semnificative statistic ntre valorile medii nregistrate la cazurile cu evoluie letal comparativ cu grupul de supravieuitori : scderea pH-ului sanguin (7,27 0,12 vs. 7,38 0,08, p = 0,003), scderea rezervei alcaline (13,9 3,1 mEq/l, vs. 17,4 3,5 mEq/l, p = 0,001), creterea concentraia acidului lactic n sngele arterial (46,2 2,4 mg% vs. 37,5 6,3 mg%, p = 0,005) hiponatremia (128,2 2,2 mEq/l vs. 137,4 7,3 mEq/l, p = 0,002), hiperpotasemia (4,1 1,4 mEq/l vs. 3,4 0,6 mEq/l, p = 0,001), fiind puternic corelat cu valorile sczute ale pH-ul arterial

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(rs = - o,46; p < 0,001). Hipocalcemia (< 8 mg%), detectat la 119 de pacieni (84,36%), nu a fost corelat cu evoluia letal (p = 0,2) , dar a fost asociat cu prezena convulsiilor la internare, p = 0,03). Valorile serice ale CRP la nesupravieuitori au fost semnificativ mai mici dect la cei cu evoluie bun i intens corelate cu intervalul de timp scurs de la debutul simptomatologiei pn la recoltarea probelor de laborator (r = 0,62, p < 0,001 i respectiv r = 0,54, p < 0,001). Celularitatea redus la nivelul LCR (< 20 elem./mm3) a fost corelat cu decesul n meningitele meningococice (p = 0,01). La grupul de nesupravieuitori s-au nregistrat valori semnificativ mai sczute ale raportului glicorahie/glicemie (0,22 0,09) dect la cazurile cu evoluie favorabil (0,30 0,05), cu o valoare p pentru riscul de deces de 0,03. Detectarea PCT n LCR pare s constituie un factor de risc pentru vindecarea cu sechele neuropsihice (45,45% din pacienii cu valori ntre 2 10 ng/ml s-au vindecat cu sechele neuropsihice, fa de doar 4,54% dintre cei care au prezentat valori mai mici sau nedetectabile ale PCT n LCR; p = 0,009). De asemenea prezena PCT n LCR a fost puternic corelat cu vrsta mic, sub 2 ani (r = 0,42; p = 0,005). Manifestrile clinice corelate cu evoluia spre deces au fost: coma (p = 0,01) i hiperpirexia (p = 0,01). CONCLUZII
1. Inciden general n MAB copil s-a meninut constant n ultimii 20 de ani, dar cu deplasarea spre dreapta a incidenei maxime n funcie de vrst. 2. Spectru etiologic al meningitele bacteriene la copil s-a modificat semnificativ n ultimii 20 de ani, prin creterea important a incidenei meningitelor TBC, mai ales la copilul mic i scderea implicrii altor ageni patogeni. 3. Principalii ageni patogeni etiologici ai MAB la copil, n prezent, n ordinea frecvenei, sunt: N. meningitidis, bacilul Koch, S. pneumoniae, H. influenzae tip b i bacilii Gram negativi. Frecvena de izolare a Haemophilus influenzae tip b este n cretere pentru zona noastr geografic, ceea ce impune introducerea vaccinrii obligatorii anti-Hib. 4. Factorii favorizani care in de mediu sunt mai frecvent depistai dect cei legai de organismul gazd n MAB la copil. 5. Vrsturile sunt simptomul cel mai frecvent n perioada de debut n MAB la copil. Semnele de iritaie meningian i febra pot fi absente n special n meningita neonatal i n meningita bacilar. Convulsiile persistente i semnele neurologice de focar sunt mai frecvente n meningita bacilar, pneumococic i n meningita neonatal. 6. ocul infecios, ca i complicaie imediat, este asociat cu vrsta mic i cu etiologia meningococic, iar complicaiile tardive sunt mai frecvente n meningita bacilar, pneumococic i meningita neonatal. 7. Evoluia cea mai sever a bolii se ntlnete n meningita neonatal, pneumococic, bacilar i la cazurile cu etiologie dubl. Meningita meningococic i meningitele cu bacili Gram negativi au n prezent o evoluie favorabil n condiiile unui tratament adecvat. 8. Determinarea antigenelor bacteriene specifice din LCR prin testul latex-aglutinare crete procentul de identificare a agentului etiologic cu 26,5% i este superioar ca eficien fa de examinrile bacteriologice din LCR. 9. Prin metodele diagnostice uzuale actuale precizarea diagnosticului etiologic n MAB la copil se realizeaz n procent de 75%. 10. Diagnosticul de meningit bacilar la copil se stabilete n principal pe criterii clinice, epidemiologice i paraclinice indirecte, identificarea bacilului Koch din LCR prin metode bacteriologice realizndu-se n procent de doar 47,82%. Examinrile citologice i biochimice ale LCR au o valoare diagnostic orientativ important n meningita bacilar la copil. 11. Hemocultura poate contribui la mbuntirea diagnosticului etiologic n meningita meningococic asociat cu meningococemie i n meningita neonatal. 12. Incidena MAB parial tratate la copil este n cretere n ultimii 20 de ani. Tratamentul antibiotic anterior internrii modific tabloul clinic de debut al bolii i reduce semnificativ procentul de rezultate pozitive obinute la examenul bacteriologic al LCR, ceea ce ntrzie diagnosticul clinic i influeneaz negativ diagnosticul etiologic, dar nu modific semnificativ parametrii biochimici i citologici din LCR i rezultatele testelor imunologice. 13. PCT seric este un marker mai bun dect CRP pentru diferenierea meningitelor acute bacteriene de cele virale la copil i la o valoare peste 0,5 ng/ml are sensibilitate i specificitate maxim.

14. Ca tratament de prim intenie, n absena diagnosticului etiologic sau a antibiogramei i n prezena factorilor agravani, n MAB la copil terapia antibiotic asociat este superioar monoterapiei. 15. Antibioticul cel mai indicat pentru monoterapie n tratamentul MAB la copil este ceftriaxona. Utilizarea penicilinei G n monoterapie n absena antibiogramei este contraindicat. Meropenemul este un antibiotic de rezerv, indicat n monoterapie n MAB la copil determinate de germeni rezisteni la alte antibiotice. 16. Asocierea de 3 antibiotice n terapia meningitelor acute bacteriene la copil este indicat n meningitele plurietiologice i n tratamentul meningitelor neonatale de etiologie neprecizat. 17. Numrul de tulpini de N. meningitidis i S. pneumoniae rezistente la penicilina G este n cretere n zona noastr geografic. 18. Instituirea unui tratament etiologic adecvat n MAB la copil n primele 12 ore de la debut, crete semnificativ eficiena acestuia i scade riscul de apariie al complicaiilor tardive. n meningita bacilar introducerea tratamentului tuberculostatic n primele 7 zile de la debutul simptomatologiei neurologice crete ansa de supravieuire i scade riscul de sechele neuropsihice definitive. 19. Asocierea cortizonului n tratamentul MAB la copil este benefic n cazurile care evolueaz cu semne de afectare encefalitic, oc infecios i n formele fulminate nsoite de sindrom de CID i reduce riscul de sechele neuropsihice definitive. 20. Vrsta mic, deficitele imunologice, prezena bolilor asociate, coma n momentul internrii i hiperpirexia cresc semnificativ riscul de deces n meningitele acute bacteriene la copil. 21. Hiperpotasemia, hiponatremia, acidoza metabolic i valorile serice sczute ale proteinei C reactive reprezint factori de prognostic negativi n meningitele acute bacteriene la copil. 22. Prezena procalcitoninei la nivele detectabile n LCR la copii de vrst mic crete semnificativ riscul de sechelaritate n meningita acut bacterian. 23. Valoarea potasiului , CRP, AL i pH-ului n sngele periferic i detectarea PCT n LCR, ar putea constitui parametrii unui scor prognostic n MAB la copil, cu valoare predictiv pentru riscul de deces i util pentru clasificarea pacienilor n funcie de gravitatea bolii i aprecierea evoluiei sub tratament. Abv: AL acid lactic, AP anatomo-patologic, Cfs cefalosporin, CID coagulare intravascular diseminat, CRP proteina C reactiv, IA imun alergice, IRA - insuficien renal acut, MAB meningite acute bacteriene, MAV meningit acut viral, NP neprecizat, PCT procalcitonina, TCC - traumatism craniocerebral

BIBLIOGRAFIE SELECTIV 1. Mandell L. G., Bennett J., Dolin R., Principles and Practice of Infectious Diseases 5th, Churchill Livingstone,
Philadelphia, 2000, vol. I, pg. 961 63, 964 70, 972 74, 974 76, 980 85. 4. Nasiemnto-Carvalho C., Etiology of bacterial meningitis among children aged 2-59 months in Salvador, Northeast Brazil, before and after routine use of Haemophilus influenzae type b vaccine, Arq. NeuroPsiquiatr. Vol.62 no.2a So Paulo June 2004). 11. Peter W Fowlie William, McGuire Linda, Clerihew, Infection in the preterm infant BMJ 2004; 329:12771280 (27 November) 12. Chiotan M., Boli Infecioase, Ed. Naional, Bucureti, 1999, pg. 375 397, 414 444, 447 454. 20. Nancy E. Rosenstein, M.D., Bradley A. Perkins, M.D., David S. Stephens, M.D., Tanja Popovic, Ph.D., M.D., and James M. Hughes, M.D, Meningococcal Disease, The New England Journal of Medicine, 3 may 2001, vol. 344, pg. 1378 1388. 67. Tan, T. Q. 2002. Prevention of pneumococcal meningitis. Curr. Infect. Dis. Rep. 4:317-323 71. Stnescu D. Meningitele acute n Boli infecioase sub redacia rebedea I., Ed Medical, Bucureti, 2000, pg. 300 301, 304 306 72. Fuller DG, Duke T, Shann F, Curtis N. Antibiotic treatment for bacterial meningitis in children in developing countries. Ann. Trop. Paedriatr. 2003 Dec; 23(4); 255-7 79. Heikki Peltola, Eeva Salo, Harri Saxn. Incidence of Haemophilus influenzae type b meningitis during 18 years of vaccine use: observational study using routine hospital data BMJ. 2005 January 1; 330(7481): 1819). 87. Connolly M, Noah N. Is group C meningococcal disease increasing in Europe? A report of surveillance of meningococcal infection in Europe 1993-6. Epidemiol Infect 1999; 122:41-49. 89. Linger G, Chin Cn, Beyene J., et al. Predicting the outcome of neonatal bacterial meningitis. Pediatrics 2000; 106: 477-82 100. Yogev, MD and Sheldon L. Kaplan,MD, Streptococcus pneumoniae Infections in the Neonate, PEDIATRICS Vol. 112 No. 5 November 2003, pp. 1095-1102 103. Klein JO. Bacterial sepsis and meningitis. In: Remington JS, Klein JO, eds. Infectious Diseases of the Fetus and Newborn Infant. Philadelphia, PA: WB Saunders; 2001:943998

107. Kriz P, Bobak M, Kriz B, Parental smoking, socio-economic factors, and risk of invasive meningococcal disease in children: a population based case-control study, Arch Dis Child 2000; 83:117-121 (August) 111. Nico Stollenwerk , Martin C. J. Maiden an Vincent A. A. Jansen, Diversity in pathogenicity can cause outbreaks of meningococcal disease, POPULATION BIOLOGY, PNAS, July 6, 2004, vol. 101, no. 27,10229-10234 115. Michael R. Jacobs MD, PhD., Streptococcus pneumoniae: Epidemiology and patterns of resistance, American Journal of Medicine, Supplement Volume 117, Issue 3, Supplement 1 , 2 August 2004, Pages 3-15, 135. A J Kvalsvig and D J Unsworth The immunopathogenesis of meningococcal disease, Journal of Clinical Pathology 2003; 56:417-422. 149. Sunil K. Sukumaran, Suresh K. Selvaraj, and Nemani V. Prasadarao, Inhibition of Apoptosis by Escherichia coli K1 Is Accompanied by Increased Expression of BclXL and Blockade of Mitochondrial Cytochrome c Release in Macrophages. Infection and Immunity, October 2004, p. 6012-6022, Vol. 72, No. 10 174. Imler, J. L., and J. A. Hoffmann. 2001. Toll receptors in innate immunity. Trends Cell Biol. 11:304-311. 193. Sunil K. Sukumaran, Hiroyuki Shimada, and Nemani V. Prasadarao, Entry and Intracellular Replication of Escherichia coli K1 in Macrophages Require Expression of Outer Membrane Protein A Infection and Immunity, October 2003, p. 5951-5961, Vol. 71, No. 10 205. Petcu (ulescu) D., Probeme actuale de diagnostic n meningitele infecioase, Tez pentru obinerea titlului de doctor n medicin, 1985, UMF Cluj Napoca, 42 60. 229. Scheld W. Michael; Whitley J. Richard; Durack T. David. Infections of the central nervous system, LippincottRaven 1997, pg. 313 315, 321 324, 325 329, 366 370, 377 378,422 - 426, 434 435. 232. Riordan FAI, Cant AJ. When to do a lumbar puncture. Arch Dis Child 2002; 87:2357. 238. Lise E. Nigrovic, MD, Nathan Kuppermann, MD, MPH and Richard Malley, MD. Development and Validation of a Multivariable Predictive Model to Distinguish Bacterial From Aseptic Meningitis in Children in the Post-Haemophilus influenzae Era. PEDIATRICS Vol. 110 No. 4 October 2002, pp. 712-719. 242. Angelescu M., Terapia cu antibiotice. Ed. Med., Bucureti, 1998, pg. 471 500. 244. Cupa A, Principii de tratament n bolile infecioase n Boli Infecioase sub redacia Ileana Rebedea, Ed. Medical, Bucureti, 2000, 52 65. 245. Crstina D. Antibioticele utilizarea lor n tratamentul infeciei, Ed. Medical Universitar Iuliu Haieganu Cluj Napoca, 2001, 57 64, 67 68, 111 115. 246. Schwartz C. Bacterial Meningitis - A View of the Past 90 Years. NEJM Volume 351:1826-1828 October 28, 2004 256. Kirsten Mller, Peter Skinhj, Guidelines for managing acute bacterial meningitis BMJ 2000; 320:1290 (13 May) 257. ulescu D. Boli Infecioase, Ed. Medical Universitar Iuliu Haieganu, Cluj-Napoca, 2002, 10 1; 10 13. 261. Molyneux EM, Walsh AL, Forsyth H, et al. Dexamethasone treatment in childhood bacterial meningitis in Malawi: a randomised controlled trial. Lancet 2002; 360:21117. 267. Bocan IS. Epidemiologie Practic. Editura Medical Universitar Iuliu Haieganu 1999. pg. 407 424. 273. Moore MR, Schrag SJ, Schuchat A. Effects of intrapartum antimicrobial prophylaxis for prevention of group-Bstreptococcal disease on the incidence and ecology of early-onset neonatal sepsis. Lancet Infect Dis 2003; 3:201-13. 281. Teindel Cl, Predescu I, et al. Meningite i encefalite acute umane. 1983. Ed. Medical, Bucureti, 305 312. 282. Pun L, Tratamentul infeciilor acute severe, Ed. Medical, Bucureti, 1985, 123 127. 286. Cupa A, Patogeneza bolilor infecioase n Boli Infecioase sub redacia Rebedea I., Ed. Medical Bucureti, 2000, 19 36. 288. Voiculescu M, Boli Infecioase, vol.I, Ed. Medical, Bucureti 1989, 403 420 304. Porkert MT, Sotir M, Parrott-Moore P, et al. Tuberculous meningitis at a large inner city medical center. Am J Med Sci, 1997; 313: 325 331. 312.Bhisitkul DM, Hogan AE, Tanz RR. The role of bacterial antigen detection tests in the diagnosis of bacterial meningitis. Pediatr Emerg Care 1994; 10: 67 71. 334.Chan YL, Tseng CP, Tsay PK, Chang SS, Chiu TF, Chen JC; Procalcitonin as a marker of bacterial infection in the emergency department: an observational study; Crit Care, 2004; 8(1): R12-R20. 335.Castelli GP, Pognani C, Meisner M, Stuani A, Bellomi D, Sgarbi L; Procalcitonin and C-reactive protein during systemic inflammatory response syndrome, sepsis and organ dysfunction; Crit Care. 2004; 8(4): R234-R242. 353. Kaojarrern S, Supmonachai K, Phuapradit P, Mokkhavesa C, Krittiyanunt S. Effect of steroids on cerebrospinal fluid penetration of antituberculous drugs in tuberculous meningitis Clin Pharm Ther 1991; 49: 6 12. 355.Kumarvelu S, Prasad K, Khosla A, Behari M, Ahuja GK. Randomized controlled trial of dexamethasone in tuberculous meningitis. Tubercle Lung Dis. 1994; 75: 203 207. 358. Kornelisse R, hazelzet J, Hop W, Spanjaard L, Suur M, Voort E, Groot R. Meningococcal Septic Shock in Children: Clinical and Laboratory Features, Outcome, and Development of a Prognostic Score. Clin Infect Dis 1997; 25: 640 646.

CURRICULUM VITAE
I. DATE PERSONALE Nume: Prenume: Prinii: Data i locul naterii: Starea civil: Domiciliu: Telefon: E-mail: IUBU ROXANA OLIVIA tatl: Iubu Traian; mama: Iubu Letiia Lucia 26.08.1962 Craiova, Romnia divorat, 1 copil (13 ani) str. Observatorului, nr.140, ap.20, Cluj-Napoca 0740189197, 0264/522781 [email protected] engleza, franceza

Limbi strine cunoscute:

Studii:
Gimnaziale i liceale: Liceul de Matematic-Fizic Fraii Buzeti - Craiova, 1973 1981; Universitatea de Medicin Craiova, promoia 1988, media general 9,96; Doctorand n stadiul final, de susinere a tezei, pentru obinerea titlului de doctor n medicin la Universitatea de Medicin i Farmacie Iuliu Haieganu Cluj-Napoca, din 01.11.1999, cu titlul Contribuii la studiul etiologiei, formelor clinice, diagnosticului i tratamentului actual al meningitelor acute bacteriene la copil, conductor tiinific prof. dr. Gorgan Vasile. - medic primar boli infecioase - director general medical adjunct Spitalul Clinic de Boli Infecioase Cluj-Napoca

Situaia profesional actual: Locul de munc:

II. ACTIVITATE PROFESIONAL - 01.03.1999 i n prezent - medic primar boli infecioase (examen de primariat din sesiunea 05 12. 06.1998, cu media 9,77), n Secia Respirator Copii, Spitalul Clinic de Boli Infecioase, Cluj-Napoca. Atribuii: diagnosticarea i tratamentul pacienilor internai n secia Respirator copii, cu infecii respiratorii acute, boli eruptive, infecii ale sistemului nervos central (meningite, encefalite); diagnosticarea, evaluarea i tratamentul copiilor cu infecie HIV din Centrul Regional de Lupt AntiSIDA Cluj; - 18.02.1994 01.03.1999 medic specialist boli infecioase (examen de specialitate din 17.01.1994, media 9,76), la Spitalul Clinic de Boli Infecioase Cluj-Napoca, Secia Respirator Copii i Digestiv Copii.

- 01.02.1991- 18.02.1994 medic secundar boli infecioase (n urma promovrii concursului de secundariat sesiunea 27 28.10.1990), la Spitalul Clinic de Boli Infecioase Cluj-Napoca
- 21.11.1988 01.02.1991 medic stagiar, Clinica Pediatrie II i Clinica Medical III, ClujNapoca;

- din 02. 06 2004 dein i funcia de director general medical adjunct al Spitalului Clinic de Boli Infecioase Cluj-Napoca.
III. ACTIVITATE TIINIFIC 1). Am elaborat un numr de 31 lucrri tiinifice, 11 n calitate de autor principal, 10 ca al doilea autor i 10 ca i coautor. Dintre acestea: a). 7 lucrri au fost publicate in extenso n reviste medicale de specialitate: Clujul Medical, Viaa Medical, Terapeutic, farmacologie i toxicologie clinic: - ROXANA IUBU: Particulariti etiopatogenice ale meningitei neonatale, Viaa Medical, nr. 19 (749) anul XVI 7 mai 2004, pg 1 2. - ROXANA IUBU, DOINA ULESCU, C. JIANU, C. MARCU, . TOMESCU: Actualiti terapeutice n meningita neonatal. Terapeutic, farmacologie i toxicologie clinic, vol. VIII, nr. 1, martie 2004, pg. 73 79.

- ROXANA IUBU, DOINA ULESCU, C. JIANU, C. MARCU: Orientri actuale n tratamentul antibiotic de prim intenie al meningitelor acute bacteriene la copil. Clujul Medical, vol. LXXVII 2004, nr. 1, pg. 25 32. - ROXANA IUBU, DOINA ULESCU, C. JIANU, C. MARCU: Aspecte clinico-etiologice actuale n meningitele acute bacteriene la copil. Clujul Medical, vol. LXXVII 2004, nr. 1, pg. 61 69. - ROXANA CSIKOS (IUBU), C. MARCU, V. NEAGA, LIDIA NANULESCU: Aspecte clinicoevolutive ale infeciei meningococice la copil. Clujul Medical, vol. LXXIV, nr. 1-2, 2001, pg. 105 111. - V. NEAG, C. MARCU, NORA BUCOV, ROXANA CSIKOS (IUBU), LIDIA NANULESCU - Consideraii n legtur cu epidemia de enteroviroze din vara anului 1999. Clujul Medical, vol. LXXIV, nr. 1-2, 2001, pg. 66-74. - LIDIA NANULESCU, ROXANA CSIKOS (IUBU), C. MARCU: Claritromicina (Klacid) n tratamentul infeciilor bacteriene la copil. Terapeutic, farmacologie i toxicologie clinic, vol. IV, nr. 1, martie 2000 b). 24 lucrri au fost comunicate la diverse manifestri tiinifice, naionale i internaionale i publicate n volume de rezumate : - ROXANA IUBU, C. JIANU, DOINA ULESCU, C. MARCU, LIGIA URSU: The prognostic value of cerebrospinal fluid procalcitonin in acute bacterial meningitis in children, prezentare poster la al 15th European Congress of Clinical and Infectious Diseases, Copenhagen, Denmark, 2 5 Aprilie 2005, publicat n volumul de rezumate (P 1671) pg 547. - ROXANA IUBU, C. JIANU, DOINA ULESCU: Outcome of invasive pulmonary aspergillosis under highly antiretroviral therapy n a HIV-infected patient without appropriate antifungal drugs: case report, prezentat la 15th European Congress of Clinical and Infectious Diseases, Copenhagen, Denmark, 2 5 Aprilie 2005, publicat n volumul de rezumate (R 2196) pg 728. - ROXANA IUBU, DOINA ULESCU, C. JIANU, C. MARCU: Terapia actual a meningitelor acute bacteriene la copil, comunicat la al XI-lea Congres Naional de Boli Infecioase, Craiova, 22 25 septembrie 2004, publicat n volumul de rezumate, pg 127, Craiova Medical, 2004, 6 (3): 127 - ROXANA CSIKOS (IUBU), V. NEAGA, LIDIA NANULESCU, C. JIANU, C. MARCU: Aspecte clinico-evolutive actuale ale meningitelor acute bacteriene la copil; comunicat la Conferina a V-a a infecionitilor din Republica Moldova "Probleme actuale n patologia infecioas", Chiinu, 4-5 Octombrie, 2001, publicat n volumul de rezumate pg.150. - CSIKOS (IUBU) ROXANA, MARCU C., NEAGA V, NANULESCU LIDIA - Aspecte clinicoevolutive actuale ale infeciei meningococice la copil, comunicat la al VIII-lea Congres Naional de Boli Infecioase, Mangalia, 17-20 mai 2000, publicat n volumul de rezumate, pg. 129. - ROXANA IUBU Rezultatele cercetrii imunoglobulinelor n LCR n scleroza multipl Lucrare de diplom, comunicat la Sesiunea de comunicri tiinifice studeneti, Craiova, Romnia, mai 1988 - C. JIANU, ROXANA IUBU, I. CIUTIC: Meningo-enecephalo-mielo-polyradiculonevritis with Mycobacterium tuberculosis: case report, prezentat la 15th European Congress of Clinical and Infectious Diseases,Copenhagen, Denmark, 2 5 Aprilie 2005, publicat n volumul de rezumate (R 2132) pg. 708. - C. JIANU, CORINA ITU, DOINA ULESCU, ROXANA IUBU: Immune reconstitution without antiretroviral therapy n patient with AIDS and tuberculosis, prezentat la 14 th European Congress of Clinical and Infectious Diseases Prague, Czech Republic 1 4 May 2004, publicat n volumul de rezumate (R 2258) pg. 648 - C. MARCU, ROXANA IUBU, D. CRSTINA: Experiena Centrului regional Cluj n terapia cu Amprenavir la copii. Simpozionul Rezistena viral; locul i rolul Agenerase n terapia cu inhibitori de proteaz, Timioara, 27 martie 2004, publicat n volumul de rezumate. - DOINA ULESCU, CORINA ITU, ANGELA BUTNARIU, C. JIANU, ROXANA IUBU, C. MARCU, D. CRSTINA - Importana testrii HIV la gravid. Zilele Universitii de Medicin i Farmacie "Iuliu Haieganu" Cluj-Napoca, 2-5 Decembrie 2003, publicat n vol. de rezumate pg. 87. - C. MARCU, D. CRSTINA, ROXANA IUBU, ADRIANA SLAVCOVICI, DOINA ULESCU, CORINA ITU, C. JIANU - Manifestri clinico-evolutive n infecia HIV la copii. Zilele Universitii de Medicin i Farmacie "Iuliu Haieganu" Cluj-Napoca, 2-5 Decembrie 2003, publicat n volumul de rezumate pg. 90.

- LIDIA NANULESCU, ROXANA IUBU, C. MARCU. Efecte secundare controlabile n tratamentul cu inhibitori de proteaz Indinavir (IDV), comunicat la al III-lea Congres Naional HIV/SIDA, cu participare internaional, Bucureti, Romnia, 15 18 mai, 2002, publicat n volumul de rezumate pg. 46. - LIDIA NANULESCU, ROXANA CSIKOS (IUBU), C. MARCU, ANCA BUTNARIU, L. NEGRU - Manifestri neurologice n infecia cu HIV la copil; comunicat la al III-lea Congres Naional HIV/SIDA, cu participare internaional, Bucureti, Romnia, 15 18 mai, 2002, publicat n volumul de rezumate pg. 37. - LIDIA NANULESCU, ROXANA IUBU, C. MARCU. Tratamentul cu tripl asociere IndinavirStocrin Epivir n infecia HIV/SIDA la copil; comunicat la al III-lea Congres Naional HIV/SIDA, cu participare internaional, Bucureti, Romnia, 15 18 mai, 2002, publicat n volumul de rezumate pg. 48. - LIDIA NANULESCU, ROXANA CSIKOS (IUBU), C. MARCU: Asocierea Indinavir/Efavirenz n tratamentul infeciei HIV la copii. Rezultate de etap; comunicat la Simpozionul "Probleme actuale n terapia antiretroviral n infecia HIV", 23 Martie 2001, Cluj-Napoca - C. MARCU, MONICA TURDEANU, CRISTINA CISMARU, D. CRSTINA, C. JIANU, ROXANA CSIKOS (IUBU): Evaluarea statistic a elementelor de diagnostic clinic ale hepatitei acute virale; comunicat la Conferina a V-a a infecionitilor din Republica Moldova "Probleme actuale n patologia infecioas", Chiinu, 4-5 Octombrie, 2001, publicat n volumul de rezumate, pag.54. - NANULESCU LIDIA, MARCU C., CSIKOS (IUBU) ROXANA: Sindromul ocului toxic (TSS) - Particulariti clinico-evolutive la copil; comunicat la al VIII-lea Congres Naional de Boli Infecioase, Mangalia, 17-20 mai 2000, publicat n volumul de rezumate pg. 186. - C. MARCU, ROXANA CSIKOS (IUBU), V. NEAGA, LIDIA NANULESCU: Coinfecia cu virusurile hepatitice B i C la copiii cu infecie HIV/SIDA, comunicat la al VIII-lea Congres Naional de Boli Infecioase, Mangalia, 17-20 mai 2000, publicat n volumul de rezumate pg. 72 - LIDIA NANULESCU, A. ERBAN, ROXANA CSIKOS (IUBU): Markeri seroimuni nespecifici n formele grave de hepatit acut viral la copil; comunicat la al VII-lea Congres Naional de Patologie Infecioas Tg-Mure, Romnia, octombrie 1995, publicat n volumul de rezumate. - LETIIA IUBU, ROXANA CSIKOS (IUBU), MARIANA APU, IOAN STOICA: Consideraii asupra studierii proteinelor i imunoglobulinelor din LCR n scleroza multipl; comunicat la Conferina Anual de Neurologie din cadrul Zilele Academiei Clujene , Cluj-Napoca, Romnia, octombrie1994, publicat n volumul de rezumate pg 89. - LETIIA IUBU, O. LASCU, MARIANA MODORAN, ROXANA IUBU: Aspecte epidemiologice n atacurile ischemice tranzitorii cerebrale repetate; comunicat la Conferina Anual de Neurologie, Sibiu, Romnia, iunie 1989, publicat in volumul de rezumate. - LETIIA IUBU, O. LASCU, ROXANA IUBU: Valoarea semiologic a suflurilor din regiunea cervical; comunicat la Conferina Anual de Neurologie, Sinaia, Romnia, iunie 1988, publicat n volumul de rezumate. - LETIIA IUBU, O. LASCU, ROXANA IUBU: Aspecte evolutive n scleroza multipl; comunicat la Simpozionul Epidemiologia sclerozei multiple n Romnia , Piatra-Neam, iunie 1987, publicat n volumul de rezumate. - EISABETA STANCIU, ROXANA IUBU, ROXANA CRUCE: Frecvena neuropatiilor periferice n diabetul zaharat juvenil insulino-dependent; comunicat la Simpozionul Epidemiologia sclerozei multiple n Romnia , Piatra-Neam, Romnia, iunie 1987, publicat n volumul de rezumate. 2. Am participat la numeroase manifestri tiinifice din ar i strintate: - Al 15-lea Congres European de Microbiologie Clinic i Boli Infecioase, 2 5 aprilie 2005, Copenhaga, Danemarca; - Al XI-lea Congres Naional de Boli Infecioase, 22 25 septembrie 2004, Craiova, Romnia; - Al 14-lea Congres European de Microbiologie Clinic i Boli Infecioase, 1 4 mai 2004, Praga, Republica Ceh; - Simpozionul Naional Actualiti n patologia infecioas, 21 24 mai 2003, Iai, Romnia; - Al III-lea Congres Naional HIV/SIDA 15 18 mai 2002, Bucureti, Romnia; - Conferina a V-a a infecionitilor din Republica Moldova Probleme actuale n patologia infecioas, 4 5 octombrie 2001, Chiinu, Republica Moldova;

- Al VIII-lea Congres Naional de Boli Infecioase, 17 20 mai 2000, Mangalia, Romnia; - Al VII-lea Congres Naional de Patologie Infecioas, octombrie 1995, Trgu-Mure; - Conferina Anual de Neurologie din cadrul Zilele Academiei Clujene, 27 28 octombrie 1994 Cluj-Napoca; - Conferina Anual de Neurologie, Sibiu, Romnia, iunie 1989 - Conferina Anual de Neurologie, Sinaia, Romnia, iunie 1988 - Simpozionul Epidemiologia sclerozei multiple n Romnia , Piatra-Neam, Romnia, iunie 1987. 3. Domeniile de interes n care mi-am desfurat activitatea tiinific, dup cum reiese i din materialele publicate i/sau comunicate, au fost: infeciile sistemului nervos central; infecia HIV/SIDA la copil: studiul hepatitelor acute virale la copil; studiul sclerozei multiple; diabetul zaharat la copil a. 4. n perioada 1998 2005 am absolvit 5 cursuri de perfecionare postuniversitar n cadrul UMF Cluj-Napoca: - Actualiti n bolile infecioase, 04.05.1998 - 12.06.1998, Catedra Boli Infecioase, UMF ClujNapoca, promovat cu nota 10; - Capcane de diagnostic n pediatrie, 01.10.1999 - 30.06.2000, Catedra Pediatrie II, UMF ClujNapoca, promovat cu nota 10; - Urgene pediatrice, 06.04.200 08.06.2000, Catedra Pediatrie III, promovat cu nota 10; - Ecografie pentru competen (partea I Ecografie general), 01.03.2004 09.04.2004, Catedra Medical I i centrul de pregtire n ultrasonografie al UMF Cluj-Napoca, afiliat al Jefferson Ultrasound Research and Educational Institute Philadelphia, promovat cu nota 9,83. - Managementul serviciilor de sntate, 01.10.2004 20.03.2005, Catedra Sntate Public i Management a facultii de Medicin, promovat cu media 9,80. 5. Din 01.11.1999 sunt nscris la doctorat, n prezent n stadiul final, de susinere a tezei. n cadrul stagiului de pregtire pentru doctorat: Am promovat cele 3 examene: Boli Infecioase aprilie 2000, Microbiologie octombrie 2000 i Epidemiologie februarie 2001, apreciate cu calificativul Foarte bine Am susinut cele 3 referate: Actualiti etiopatogenice i de diagnostic n meningitele acute bacteriene la copil- iunie 2000, Forme clinico-etiologice actuale ale meningitelor acute bacteriene la copil noiembrie 2001 i Tratamentul actual al meningitelor acute bacteriene la copil martie 2003, apreciate cu calificativul Foarte bine Am publicat i/sau comunicat 7 lucrri tiinifice cu tematic referitoare la teza de doctorat, 5 n calitate de prim autor i 2 ca i co-autor. IV. ACTIVITATE DIDACTIC : Am desfurat activitate didactic n calitate de colaborator n cadrul : - Catedrei de Boli Infecioase a UMF Cluj-Napoca, n cursul anilor universitari 1994/95, 1995/96, 1996/97, 1997/98 i 1998/99, 2004/2005. - Catedrei de Farmacie Clinic a Facultii de Farmacie UMF Cluj, n cursul anilor universitari 1996/97, 1997/98, 1998/99 i 1999/2000. n perioada 2002 2005 am participat la introducerea i raportarea n sistem informatizat a datelor legate de pacienii HIV/SIDA din centrul regional Cluj-Napoca, solicitate de DSP Cluj-Napoca i Comisia Naional de Lupt Anti-SIDA. De asemenea dein cunotine necesare pentru operare PC (Windows, Microsoft Office).

UNIVERSITY OF MEDICINE AND PHARMACY IULIU HAIEGANU CLUJ-NAPOCA

CONTRIBUTION OF THE STUDY OF ACTUAL ETIOLOGY, CLINICAL MANIFESTATIONS, DIAGNOSIS AND TREATMENT OF ACUTE BACTERIAL MENINGITIS IN CHILDREN

GRADUATION PAPER FOR OBTAIN THE TITLE OF DOCTORS DEGREE IN MEDICINE THE SPECIALITY OF INFECTIOUS DISEASES - 2005

AUTHOR: ROXANA IUBU PRIMARY PHYSICIAN OF INFECTIOUS DISEASES CLINICAL HOSPITAL OF INFECTIOUS DISEASES CLUJ-NAPOCA

SCIENTIFIC SUPERVISOR: PROF. DR. VASILE GORGAN

- 2005-

CONTENTS
INTRODUCTION /5

PART I ETIOPATHOGENIC, DIAGNOSIS, CLINICAL-EVOLUTION AND THERAPEUTIC PRESENTS IN ACUTE BACTERIAL MENINGITIS IN CHILDREN / 8
..

CHAPTER 1. PRESENT- DAY TOPICS IN EPIDEMIOLOGY AND ETIOPATHOGENESIS OF ACUTE BACTERIAL MENINGITIS IN CHILDREN / 9 1.1 Major etiologic agents in acute bacterial meningitis in children. / 9 1.2 Actual epidemiological datum in acute bacterial meningitis in children. / 27 1.3 Predisposed factors in acute bacterial meningitis in children. / 32 1.4 Pathogenesis of acute bacterial meningitis in children. / 35 CHAPTER 2. PRESENT-DAY TOPICS IN DIAGNOSIS OF ACUTE BACTERIAL MENINGITIS IN CHILDREN / 57 2.1 Clinical diagnosis of acute bacterial meningitis in children. / 57 2.2 Etiological diagnosis of acute bacterial meningitis in children / 61 2.3 Laboratory diagnosis of acute bacterial meningitis in children / 68 CHAPTER 3. PRESENT-DAY TOPICS IN ACUTE BACTERIAL MENINGITIS TREATMENT IN CHILDREN 3.1 Present-day topics in etiological treatment of acute bacterial meningitis in children / 71 3.2 Present-day topics in pathogenic treatment of acute bacterial meningitis in children / 85 3.3 Present-day topics in prophylaxis of acute bacterial meningitis in children / 88 PART II CONTRIBUTIONS TO THE STUDY OF ETIOPATHOGENIC, CLINICAL-EVOLUTION, DIAGNOSIS AND THERAPEUTICALLY ASPECTS IN ACUTE BACTERIAL MENINGITIS IN CHILDREN / 93 CHAPTER 1. PERSONAL RESEARCHES GENERAL PRINCIPLES 1.1 Hypothesis of work / 94 1.2 Patients and methods. / 95 / 94 / 71

CHAPTER 2. CONTRIBUTIONS TO THE STUDY OF ACTUAL ETIOLOGY OF ACUTE BACTERIAL MENINGITIS IN CHILDREN / 100 2.1 The aim of study / 100 2.2 Patients and methods / 101 2.3 Results / 102 2.4 Discussions / 116 2.5 Conclusions / 120 CHAPTER 3. CONTRIBUTIONS TO THE STUDY OF ACTUAL DIAGNOSIS OF ACUTE BACTERIAL MENINGITIS IN CHILDREN / 122 3.1 Predisposed factors in acute bacterial meningitis in children / 122 3.2 Actual clinical-evolution manifestations in acute bacterial meningitis in children / 132 3.3 The importance of CSF examinations in etiologic diagnosis of acute bacterial meningitis in children. / 165 3.4 Characteristic aspects in diagnosis of partially treated meningitis in children. / 189 3.5 3.5 The comparative study of diagnosis value of reactive C-protein, procalcitonin and lactic acid in diagnosis of acute bacterial meningitis in children. / 203 CHAPTER 4. CONTRIBUTIONS TO THE STUDY OF ACTUAL TREATMENT OF ACUTE BACTERIAL MENINGITIS IN CHILDREN / 220 4.1 The aim of study / 220 4.2 Patients and methods / 221 4.3 Results / 222 4.4 Discussions / 242 4.5 Conclusions / 247 CHAPTER 5. PROGNOSIS FACTORS IN ACUTE BACTERIAL MENINGITIS IN CHILDREN /249 5.1 The aim of study / 249 5.2 Patients and methods / 249 5.3 Results / 250 5.4 Discussions / 259 5.5 Conclusions / 263 CHAPTER 6. GENERAL CONCLUSIONS ABBREVIATION LIST / 269 TABLE INDEX / 272 FIGURES INDEX / 275 BIBLIOGRAPHY / 279 / 265

SUMMARY Key words: bacterial meningitis in children, etiology, N. meningitidis, Koch bacilli, predisposing factors, onset, infectious shock, CSF culture, latex-agglutination, partially treated, PCT, CRP, ceftriaxone, antibiogram, prognosis factors. INTRODUCTION Acute bacterial meningitis (ABM) continues to represent an important and disputed clinical problem and a permanent preoccupation of infectious pathology in the world. The localisation of bacterial infection localisation in the subarchnoid space may occurrence to any age, but infants and young children are specially affected. The actual statistics show a higher frequency (70 75%) for bacterial meningitis in childhood than to the other age. The incidence of ABM in children keeps up, despite the active immunoprophylaxis and chimioprophylaxis measures, which are available in present. At the same time, the routinely vaccinations against meningococcal and Hib infections lead to changes of etiologic profile of bacterial meningitis in children in the last 20 years. In the last years, it achieved important progresses in etiological diagnosis and therapy of meningitis the last years, which are changed the evolution of this disease and reduced the rate of mortality from 50 80% to 10 30% [1,229,242]. However, the incidence, continuous modifies of etiological profile, antibiotics susceptibility of the pathogens, pathogenic mechanisms, particularities of actual clinical manifestations, management approach and prognosis factors remain controversies subjects. ABM are very serious diseases, especially in children. ABM require a rapid and correct etiological diagnosis for beginning the adequate antibiotic therapy in time, because this is an essential condition for patient rescue and recovery without sequelae. In context of etiologic spectrum modify and increase the number of strains with multiple resistance to antibiotics it is necessarily to establish some new algorithms for etiological treatment to be available in the cases treated by probability criterions. PART I. ETIOPATHOGENIC, DIAGNOSIS, CLINICAL-EVOLUTION AND THERAPEUTIC PRESENTS IN ACUTE BACTERIAL MENINGITIS IN CHILDREN The general part are formed by three main chapters: Chapter 1 contains a synthesis of the latest datum of literature referred to the actual etiology and epidemiology of ABM in children, the most important predisposing factors and the pathogenic mechanisms implicated in disease initiation. In chapter 2, we present the main elements of clinical diagnosis, the clinical characteristics of ABM in children, depending on age and etiologic agents and the actual diagnosis possibilities. In chapter 3, we review the present principles of the etiologic, pathogenic and prophylactic treatment in ABM in children, unanimous accepted in the world. PART II. CONTRIBUTIONS TO THE STUDY OF ETIOPATHOGENIC, CLINICALEVOLUTION, DIAGNOSIS AND THERAPEUTIC ASPECTS IN ACUTE BACTERIAL MENINGITIS IN CHILDREN

Chapter 1. Personal researches general principles presents in great detail hypothesis of work, the objectives of this study, the patients and the work methods. The aim of this study is to convey new information about the actual incidence and etiology of ABM in children in our geographic zone, to analyse the present diagnosis and therapeutically possibilities and limits, to evaluate the prognosis factors with importance in medical practice and to compare our results with recently reviews from another regions of the globe and with the results communicated 20 years ago for our region. We analysed prospective and retrospective a number of 141 cases of ABM in children admitted in Clinical Hospital of Infectious Diseases Cluj-Napoca for a six years period (Ian. 1999 Dec. 2004). We shared the patients into more groups, depending on the followed aims. I emphasise that we also included in our study the tuberculous meningitis cases for more reasons: although, majority of authors define tuberculous meningitis like a chronic infection of CNS [1,129], the personal experience showed that extra neural tuberculosis infection have a chronic evolution, but in CNS determinations of tuberculosis, the clinical manifestation and the evolution are typically for an acute infectious diseases, especially in children; bacillary meningitis has an important place between the infections of nervous system in children owing to the great gravity, the high risk of death and the maxim incidence of neurologic and psychiatric sequelae [227,228]; the alarming increase of tuberculosis incidence in the last time, especially between infant population [242], made us to analyse this important disease together with the others bacterial

meningitis in children, in order to underline the peculiar clinical aspects, important in daily medical practice for initial diagnosis orientation. The diagnosis of ABM was made to base of typical clinical picture, in the presence of characteristic biochemical and cytological perturbations of CSF, correlated with increase of acute phase reactants and haematological modifications, which are specifics for a bacterial infection. The certain etiologic diagnosis was made by: yielded pathogen agents in cultures of CSF (BacTAlert technique), blood or another biologic products (otic secretion), the identification of microorganisms by Grams stain of CSF and/or the rapid detection of specific bacterial antigens in CSF by immunological methods (latexagglutination test- LAT). For the etiologic diagnosis of tuberculous meningitis, we used isolation of tubercle bacilli in Lowensteins cultures of CSF and/or identification by Ziehl-Nielsen smear, or the presence of typical cytological and biochemical modifications in CSF, correlated with epidemiological data, the positive tuberculin tests, the evidence of extra neural tuberculosis, response to antituberculous therapy and autopsy diagnosis [274,275]. The complications were classified, depending on mechanism and the moment of appearance, in: early, belated and by immune-allergic mechanism complications. The results are statistical analysed with a database in Fox Pro Program, which contains demographic features, predisposing factors, clinical features, laboratory features, imagistic examinations, EEG, audiogram, interdisciplinary consultations, treatment data, evolution features, time of hospitalisation, autopsy results, observation from the periodic controls. We used descriptive statistical tests, univariate and multivariate analysis, offer by Epi Info, Statistica and Microsoft Excel Programs (X2 test, Fishers exact test, Student test and, Mann-Whitney test and multiple regression analysis).

Chapter 2. Contributions to the study of actual etiology of ABM in children contents the evaluation of general etiology and depending on age group etiology of ABM in children in our geographic area, the analyse of the etiologic spectrum changes and referred to the demographic data in the last 20 years and the comparison with the literature reports. The median age of patients was 3,7 4,5 years, range between 2 days - 16 years; more than 50% of cases (79) was observed in 3 months 5 years group of age, 15 cases (10,63%) in 0 3 months age group and 47 cases (33,33%) in 5 16 years age group. We remarked a tendency of moving of the ABM maxim incidence to higher ages comparative with previously studies {283 quotation by 205]; so, just 10,63% of cases was diagnosed in neonate and young infant. These results are concordant with recently published studies referred to USA, Great Britain, Occidental Europe, which communicate a decrease with about 75% percents of general incidence of ABM in children [79], simultaneous with bacterial meningitis median age cases increase, from 15 months in 1986, to 25 years in 1995. Medium incidence of ABM in children for this period was 23 cases to 10 000 patients admitted in our clinic, with a medium duration of hospitalisation of 19,03 16,34 days. The general incidence of ABM in children remains constant comparative with 1978 1983 period with 34 and 35,8 median number of cases/year in the last 20 years, but the etiologic profile modified by a significantly increase of tuberculous meningitis number (about 10 times more in our lot 23 cases (16,31%), than previous study, which mentions just 2 cases (1,4%), p=0, 00002). The great percent of bacillary meningitis cases seams to be the directly consequence of tuberculosis infection general incidence increase between infantile population, in the context of reduce of live level for some social categories. Simultaneous with the important increase of tuberculous meningitis number, we remarked the decrease of non-bacillary meningitis with 16,9%. Etiology of ABM in children in our study was characterised by the diversity of implicated pathogen agents, with different incidence depending on age. In 99 cases (70,21%) meningitis etiology was certainly specified, in 18 cases (12,76%), the etiology was just supposed with very high probability, based by some suggestive clinical findings (6 cases of meningococcal infection) or based to indirect criterions (12 cases of tuberculous meningitis) and in 24 cases (17,02%), the etiologic agent couldnt be identified. The obtained results are similar with the literature data: Teindel Cl.& colab. [281] - 17,4% Angelescu M. & colab. [242] 34% (1988) and Pun L. & colab [282] - 20,6% (1989) cases with unidentified microorganism. The most frequent isolated germ was Neisseria meningitidis (B and C serogroups) - 41 cases (29,08%), with the highest incidence in children older than 5 years of age, but in decrease comparative with 1978 1983 period (45,77%). Tubercle bacilli was the second isolated bacteria like frequency, with maxim incidence in children younger than 5 years of age - 18 cases (78,26%), one of this before 3 months

of age (figure 1), followed by Str. pneumoniae 19 cases. The global incidence of isolation of Str. pneumoniae increased from 4,92% to 13,47%, in the last 20 years and the number of Hib meningitis in children doubled (7,8% vs. 3,5%), that made necessarily to introduce the obligation of vaccination antiHib in our country.
Figure 1. Distribution of ABM cases by etiologic agents and group of age
25

23

20

17

17

15

10

9 5

9 6

10

11

1
0

1
Koch bacilli

3 1
GBS Staph. aureus

N. meningitidis

Str. pneumoniae

Hib

Gram negativ bacilli

Double etiolgy

Other germs

Unknown etiolgy

0 - 3 months

3 months - 5 years

5 - 16 years

In neonate and young infant, the Gram-negative bacilli remained the main etiologic agents, but their implication in neonatal meningitis etiology was smaller (40%), than the literature data (Teindel & colab. 68,4%), p = 0,009. We found a little increase of isolation frequency of Gram negative bacilli per total (9 cases vs. 7 cases) comparative with 1978 1983 period, possible because more accurate etiologic diagnosis.
Figure 2. Implication of etiologic agents of ABM in children changes in time
70 60

65

50
50

41
40 30 20 10 0

19
7 2 N. meningitidis S. pneumoniae

23 11
5 7

24

9
0

3
Unkown etio

BK

Hib

Gram-negative bacilli

GBS

S. aureus

Double etio

Other germs

1973 - 1978

1999 - 2004

Chapter 2. Contributions to the study of actual diagnosis of ABM in children 3.1 Predisposing factors in ABM in children. In this chapter we followed to identify the major risk factors in ABM in children and to correlate them with the etiologic agents. In an important number of cases (116 82,26%) we detected at least one of predisposition factors, noted by speciality literature. Usually, we detected more factors of risk simultaneous present at the same patient, and this seams to increase the disease risk. In this study, environment risk factors, especially socio-economic factors, were more frequent detected than the host organism risk factors: crowded collectivises (68,97%), correlated in special with meningococcal (75,60%), tuberculous (91,30%), pneumococcal (52,63%) and Hib meningitis (45,45%), precarious socio-economic conditions, associated with meningococcal infection (65,85%), bacillary (91,30%), pneumococcal (73,68%) and staphylococcal meningitis (100%) and rural medium provenience (60,99%), correlated with meningococcal infection (68,29%), tuberculous (82,60%) and pneumococcal meningitis (68,42%). The passive smoking had an important role, associated with 51,77% of cases, special with meningococcal (85,36%) and pneumococcal infections (78,95%). Recently studies showed that meningococcemia rate is of 3,5% if mother is smoker, 3,2% if father is smoker and 2,7% for every 20 cigarettes/day smoked in house [107]. The most frequent host organism promoting factors found were young age, before 5 years old (66,66%), associated in principal with meningitis produced of Gram-

negative bacilli (88,88%), group B streptococcus (100%), Hib (81,81%), staphylococcus (100%) and tuberculous meningitis (73,91%) and recent history of respiratory infection - 77 cases (54,60%), most frequent detected in meningococcal (70,73%), pneumococcal (73,68%) and Hib meningitis (72,72%). In neonatal meningitis, inadequate socio-economic conditions and low instruction level of mother were found in almost half of cases (46,66%), usually correlated with premature birth (26,66%) and low birth weight (33,33%); these condition are in unanimity recognise like promoting factors for bacterial meningitis in this age [286].

3. 2 Actual clinical presentation and outcome features in ABM children. The objective
of this research was the analyse of present clinical manifestations for the 141 cases, onset modality, the most frequent clinical symptoms and signs the outcome after therapy, to define the actual clinical forms (gravity, complications) and to correlate with the patients age and the etiology of meningitis. The disease onset was acute (1- 2 days) for 81 patients (57,44%), supra acute (fulminating, more less 24 hours) in 28 cases (19,85%), special for meningococcal infections (19 cases) and torpidly (3 14 days) in 32 cases (22,69%), in majority of bacillary etiology. The vomiting was the most frequent symptom at onset moment - 108 cases (76, 59%) (Table1). The classic signs of meningeal irritation (68,7779%) and fever (66,67%) were inconstantly manifestations in ABM; these were absented especially in neonatal and in tuberculous meningitis.
Table 1. The initial symptoms and signs in ABM in children for analysed cases Symptoms and signs fever >38C CNS dysfunction t headache t photophobia t nuchal rigidity t lethargy/irritability t coma t seizures t focal neurologic deficits t bulging fontanelle* vomiting respiratory symptoms purpuric/petechial rash No of cases 94 61 41 97 63 65 52 44 26 108 43 33 Frequency 66,67% 43,26% 29,07% 68,79% 44,68% 46,09% 36,87% 31,20% 83,87% ** 76.59% 30,49% 23,40%

* bulging fontanelle just for infants ** of total number of cases < 1 year age (31 cases)

From the CNS dysfunctions, altered level of consciousness was the most frequent sign, finding in 90,77% of patients at the admission moment. Focal neurologic deficits were more frequent in bacillary and penumococcal meningitis, noted in 60,86% and respectively 26,31% cases. Seizures, like first episode, was finding in 52 cases (36,87%) and represented the most persistent sign (average 7,2 days) and its were correlated with a high rate of lethality and a great number of sequelae, especially in tuberculous and neonate meningitis. In neonatal meningitis clinical presentation was non-specifically, dominated of digestive (86,66%) and respiratory manifestations (46,66%). Fever was present less than half of cases (46,66%), in accordance with literature data, which indicate more commonly temperature instability (hypothermia alternating with high temperature) than hyperprexia [292,293]. By rule, specific symptoms referable to the CNS are often not detected to this Figure 3. The principal complications in ABM in our study 60 age in the initial phase of disease [1]. 51 In this study, CNS dysfunctions were 50 detected more frequent than the 40 specified percent by classic speciality 30 literature (meningismus in 26,66% 30 20 cases, seizures in 80% and bulging 20 fontanelle in 73,33% of cases. Altered 11 9 6 6 10 level of consciousness, from lethargy 5 3 or irritability to profound coma, was 0 registered in all 15 cases of neonatal soc inf. IRA CID abces cloazonare necroze nevrite artrite miocardita extinse perif meningitis. compl. imediate compl. tardive compl. IA In the evolution course, 79 patients (56,03%) presented one or more complications (figure 3). Septic shock (36,17%) was the most common early complication and was

associated especially with young age (40,42% from children younger than 5 years old) and with meningococcal (51,21% of cases) and pneumococcal (73,68% of cases) etiology. The incidence of belated complications was greater in tuberculous (43,47%), pneumococcal (26,31%) and neonatal meningitis (33,33%). The most severe forms of disease, was predominated in neonatal meningitis (60%) and in bacillary (78,29%), pneumococcal (73,61%) and double etiology meningitis cases (60%). The greatest rate of mortality was noted in double etiology meningitis (20%) and in meningitis with H. influenzae (18,185). We also found a high rate of mortality, over median value obtain for the total number of cases (10,63%), in bacillary (17,39%) and pneumococcal meningitis (15,78). On the other hand, in meningococcal infection and in unknown etiology cases we obtain the lowest value (7,3%, respectively 4,16%). It is interesting that, in meningitis cases with Gram-negative bacilli no death was registered in this study.

3. 3 Importance of CSF examination in etiologic diagnosis of ABM in children.

The aim of this study is to estimate the value and the limits of different laboratory examinations from CSF actually available in etiologic diagnosis of ABM in children. From the 141 cases of ABM in children studied, the identification of etiologic agent was possible in 99 cases (70,21%). The etiologic agent identification was realised by combination used of the following methods: bacteriological examinations of CSF (culture + Grams smear) in 77 patients (77,77%), latexagglutination test in 15 patients (15,15%), blood culture in 3 cases of meningococcal infection (3,03%) and by other bacteriological examinations (otic secretion, anatomo-pathologic samples) in 4 patients (4,04%) (Figure 4).
Figure 4. The methods used for the etiologic diagnosis in ABM in children
71,71% 2,02% 2,02% 3,03% 77,77%

15,15% 6,06%

LAT AP exam

Blood culture CSF culture

Otic secretion Gram's stain

In ABM cases, other than tuberculous meningitis (n = 118), the etiology was specified in percent of 74,57%). The relatively low percent of etiologic agent isolation, comparative to other study, may be the consequence of the considerable number of partially antibiotic treated cases which were included in this study: 37 cases (26,24%) had received an antibiotic therapy at least 3 days before the CSF samples were collected. In tuberculous meningitis cases (n = 23), tubercle bacillus was identified in 11 cases (47,82%). The identification of Koch bacilli with classic bacteriological methods is very difficult. [229, 277] and the etiologic diagnosis in tuberculous meningitis is prcised especially based on probability clinical and laboratory criteria [274,275,299], like in this study. LAT was positive in 65 patients from the 83 patients that were testing. This results showed a sensitivities of 78,31% for detection of specific bacterial antigens in CSF. Used latex-agglutination test for specific bacterial antigens detecting in CSF, increased the percent of etiology identification with 26,5%. We obtained the most positive results in meningitis cases produced of Str. pneumoniae (89,47%) and N. meningitides (82,92%). In this cases latex-agglutination test has an important role for improvement the etiologic diagnosis and for indicated the serogroup. The most frequent isolated germ in CSF culture was H. influenzae type b (81,81%), although it is known that Hib grows difficult on usual medium and requires supplementing the culture medium with special factors. The great percent of positive culture may be the result of using BacTAlert growth medium, which are special medium of superior quality. Low percents of N. meningitidis identification by bacteriological methods (60,97% positive culture and 56,09% positive smear) confirm one more the low resistance in the environment for these bacteria and underline the utility of LAT for meningococcal meningitis diagnosis. LAT used significantly enhancement the etiologic diagnosis in meningococcal infections (p = 0,001). Bacteriological examination represented the main method for Str. pneumoniae identification.

Twenty-six blood cultures (35,14%) from the 74 that were collected were positive; the majority of these (22) were meningococcal infections. Blood culture used to precise the etiology in BAM in children has a little diagnosis value, excepting meningococcal meningitis associated with meningococcemia, in which it can substitute the lumbar puncture in conditions of suggestive clinical presentation, without therapeutic harms [232] and in neonatal meningitis, which frequently is one of the manifestations of neonatal sepsis. Scheld & colab. recommends samples blood collected like the first diagnosis method in neonatal meningitis. Examinations of CSF biochemical and cytological parameters in presence of typical clinical manifestations offer the possibility to frame rapidly into certain etiological category of meningitis [1,12,229,242,288] and permit to choice the adequate therapy immediately in unknown etiology cases. Its also offer precious information about the severity of infection and about the response to the treatment The local inflammatory response was different depending on the etiology, patient age and immune status. The median value of CSF leukocytes count was 3 331/mm3, ranged between 10/mm3 and 5 000/mm3. In 46,80% cases (some of meningococcal meningitis associated with meningococcemia and fulminating evolution, tuberculous meningitis and some of partially treated cases) the white blood cell (WBC) count was < 500/mm3. A low count of CSF leukocytes is also characteristic for neonatal meningitis in premature neonates [229,318], but a low count WBC in CSF doesnt excludes the diagnosis of ABM in children. CSF protein concentration was elevated over normal value of 40 mg% in majority of patients (93,60%), with a median value of 194 mg%. The highest median value of CSF protein concentration were found in tuberculous meningitis (297 mg%) with limits between 61 mg% and 650 mg%, but we didnt remark the extreme value of CSF protein and very low CSF glucose level, quoted in classic literature. Very low concentration of CSF glucose is more typical for advanced stages of clinical disease. In the absence of specific therapy a progressive gradual reduction in glucose level occurrences [274]. In non-bacillary meningitis cases, glycorrhachia had wide range (5 mg% 105 mg%). CSF serum glucose ratio was more suggestive for bacterial etiology of meningitis with a value < 0,31 in 86 cases (60,99%).

3.4 Characteristics aspects of partially treated meningitis in children. This study was made on 118 children with ABM. Thirty-seven of them had been treated with antibiotic more than 48 hours before admission in our hospital. We purposed to analyse the antibiotic therapy effects to the clinical and laboratory features, to the accuracy of the etiologic diagnosis and the consequences of the future outcome of this cases. The antibiotic administration prolonged the period of completely installation of initial symptoms and signs and also the time from the first disease signs onset till admission. The insidious onset was more frequent in this patients - 24,32% (9 cases) than in the 81 patients without antibiotic treatment before admission - 3,70% (3 cases). The typical clinical presentation of meningitis was more attenuated in pretreated cases than untreated cases, with a lower incidence of severity signs at the admission moment (coma 16, 21% vs. 51,85%, seizures 13,5% vs. 38,27%), more rapidly remission of the principals signs and symptoms after beginning of adequate therapy (about 1 day) and a lower incidence of immediate complications: septic shock (24, 32% vs. 51,85%), acute renal failure (13,51 vs. 30,86%), DIC (3,40% vs. 11,11%). Biochemical and cytological analyses of CSF werent significantly influenced by antibiotic administration, excepting CSF protein level, which had a lower median value (125 mg%) in pre-treated cases than untreated (228mg%), p <0,05. But, the Figure 5. The etiologic agents identification in pre-treated percent of positive bacteriological results in CSF meningitis vs. untreated meningitis in children were significantly smaller: 13,51% vs. 74,83% for 100% 80,70% culture and 8,11% vs. 61,72% for Grams stain (figure 74,83% 73,07% 80% 5). 61,72% The bacterial specific Ag detection in CSF 60% 48,07% with LAT wasnt significantly influenced by antibiotic 40% administration: 73,07% positive results from total 13,51% 8,11% samples collected in pre-treated cases and 80,70% in 20% 4,54% untreated cases. These data confirm the importance of 0% CSF culture Gram's smear Blood culture LAT immunological tests of CSF in etiologic diagnosis of pretreated ABM untreated ABM bacterial meningitis in children, especially in partially treated cases before lumbar puncture perform. The etiologic diagnosis was negatively influenced by antibiotic administration before admission. So, the etiology was prcised only in 43,24% cases with certain etiology in partially treated meningitis,

comparative with 88,89% in untreated cases (p < 0, 003). In pre-treated cases the etiology was established specially by immunological methods and in cases without antibiotic treatment the principal method used for etiologic diagnosis was the bacteriological examination of CSF (76,54% - CSF culture and Grams smears).

3. 5 Comparative study of diagnosis value of CRP, PCT and LA in ABM in children.

Recently study showed that PCT is usually undetectable in serum of healthy humans, but the level is increased during serious infections, when the PCT is directly released in serum without to form calcitonin [334]. The objective of this research was to make a comparative analyse of the CRP, PCT and LA importance in the etiologic diagnosis of ABM in children and in the differentiation between ABM and acute viral meningitis (AVM) in a lot of 77 children admitted for suspicion of acute meningitis (36 was diagnosed with ABM and 71 with AVM). PCT was semi-quantitative estimated by an immunochromatographic assay (Brahms PCT Q) The PCT serum concentration was increased (> 10 ng/ml) in all of these cases, except in 3 patients, who had had previous antibiotic therapy and had lower serum PCT level. In the 41 cases of AVM analysed comparatively, the serum PCT level was under detectable value of 0,5 ng/ml. For CRP levels there were statistically significant differences (p < 0,05) between the two groups (ABM vs. AVM)). However, a wide area of overlapping individual values Figure 6 Correlations between CSF PCT for CRP levels, both in serum and in CSF, was found
level and age in ABM in children
12

between the patients of the two groups. So, we conclusion that PCT levels in serum is a better marker 10 than CRP levels in serum in differentiating between 8 ABM and AVM in children. Serum PCT concentration > 0,5 ng/ml had a 6 sensitivity of 91,66%, values higher than 2 ng/ml gives 4 a sensitivity of 97,22%, and value over 10 ng/ml 2 yielded a sensitivity of 100%. A value of serum PCT > 0,5ng/ml had a specificity of 100% in differentiating 0 ABM and AVM in children. between 0 20 40 60 80 age (months) PCT levels were measured also in CSF of 33 children patients diagnosed with ABM admitted in our department. In 16 children (48,48%) we found a detectable level of CSF procalcitonin: > 10 ng/ml, in 4 children between 2 ng/ml and 10 ng/ml in 7 and > 0,5 ng/ml in 5 patients. Levels of CSF procalcitonin > 2 ng/ml (11 patients) were correlated with severity of disease: 2 children died, 5 recovered with serious neurological sequelae and 4 developed belated complications. PCT levels higher than 2 ng/ml were also associated with young age (the median age was 2,2 yearsfigure 6). Chapter 4. Contributions to the study of actual treatment of ABM in children. In this chapter there are presented the most efficiencies used regimens, the importance of antibiogram, the correlation between the therapeutically results and the moment of institution of therapy and the pathogenic treatment role in mortality and morbidity decrease in the 118 cases of bacterial meningitis. The initial antibiotic therapy was made in mono-therapy in 60 patients (50,85%) and with associated therapy in 58 patients (49,15%) - in 52 (44,06%) with bi-therapy and in 6 (5,08%) with tritherapy. The most used antibiotic in mono-therapy was ceftriaxone (73,33%). We preferred ceftriaxone because it has a wide antimicrobial activity and because the majority germs implicated in ABM in children are yet susceptible to third-generation cephalosporins, in our geographic zone [242, 245]. This situation was also confirmed by the result obtained of susceptibility testing. Penicillin G was used like unique antibiotic only in 4 patients (6,66%). We remarked an increase of Penicillin-resistant strains of N. meningitidis and Str. pneumoniae So, Penicillin G mono-therapy is not recommended in the treatment of ABM in children, in absence of susceptibility testing. Meropenem, considered a reserve antibiotic, was administrated only in mono-therapy in 5 cases (8,33%), after susceptibility testing, for multi-resistant germs. Associated antibiotic therapy was necessarily in certain conditions: unknown the pathogens susceptibility and existing of worsening conditions at the admission moment. One of the most frequent associated regimens used was Penicillin G plus ampicillin (41,38% from the patients treated with bitherapy). This association was used from long time in our hospital because the cumulative bactericidal effect of the two antibiotics, which have different mechanisms and places of action on the bacterial cells.
PCT (ng/ml)

The antibiotic treatment with three antibiotics was indicated just in neonatal meningitis cases with unknown etiology (3 patients), in accordance with the recommendations of American Academy of Pediatrics, that are now accepted in the world: Ampicillin + the third-generation cephalosporins + an aminoglycoside. Depending on the etiology, mono-therapy (cfs III) was the most frequent indicated in patients with meningococcal infections (63,41%) and the antibiotic combination in the unknown etiology cases: two antibiotics 66,66% and three antibiotics in Figure 7. Mono-therapy and associated antibiotic 20,83% (figure 7). therapy depending on etiology in ABM in children In 88,57% of cases the initial mono-therapy bi-therapy tri-therapy antimicrobial therapy was in accordance with 30 27 target antibiotic treatment, indicated after the bacteriological and immunological results from 25 CSF was obtained. We tested the susceptibility of 20 16 the pathogen agents to antibiotics in 75 of the 14 15 isolated strains. We observed the existence of 910 Penicillin G-resistant strains of N. meningitides 10 7 7 5 4 4 also in our geographic region, but in smaller 3 3 3 3 5 2 1 number (6,89%) than in other countries and a 0 great number of cotrimoxazole-resistant strains of N. meningitidis (79,31%). A percent of 25% of pneumococcal isolates were resistant to cloramphenicol and cotrimoxazole, 12,5% to Penicillin G and ampicillin and one strain (6,25%) was multiresistant to the usual antibiotics. The combined antimicrobial therapy and a cfs III administration reduced the median period of hospitalisation to 15,2 days for the patients treated with an associated antibiotic therapy, comparative with 23,7 days for the patients with mono-therapy (p = 0,001), respectively to 16,1 days for the children treated with a cfs III, comparative with 21,4 days for another antibiotic regimens (p = 0,04). The median period till the remission of fever and the major clinical manifestations was also shorter in children with associated therapy or/and with cfs III therapy. The adequate etiologic treatment instituted in the first 12 hours after the onset significantly increased its efficiency and decreased the risk of belated complications. In 10 of 11 cases with fatal evolution, the adequate antibiotic therapy was begun at more than 12 hours after onset. We administrated a cortisone therapy in all the 141 cases (HHC -10 mg/kgc/day every 6 hours in the first 24 48 hours, then dexamethasone - 0,5 mg/kgc/day every 8 12 hours), in media 6,2 days. We found a smaller incidence of audiologic sequelae in patients with Hib and Str. pneumoniae meningitis treated with dexamethasone (3,33% vs. 12,5% respectively 15,5%) and a significantly lower mortality rate in pneumococcal meningitis (15,78% vs. 28,7%), respectively (15,78% vs. 40,25%), comparative with the percents reported by other authors referred to patients that not received dexamethasone [1,229,344,345, 346, 347], p = 0,005 and p = 0,001). In tuberculous meningitis cases (n = 23), the lethality rate was about 2 times greater in the patients treated with adequate antituberculous regimens only after 7 days from the clinical disease onset, than the patients correctly treated from the first week of disease (23,07% vs. 10%). However, we didnt remark a significantly statistical difference between the two groups (p > 0,05). On the other hand, we found important differences for the neurological and psychiatric sequelae between the children early and belated treated (p = 0,03). No children from the group treated after 1 week from the onset completely recovered.

Chapter 5. Prognosis factors in ABM in children. In this chapter we evaluated which of the demographic, clinical and laboratory features of the 141 children with ABM should be a prognosis factor useful in a prognostic score. The young age of patients (< 3 months) represented one of the negative prognostic factors belong to host organism, which significantly statistical increased the risk of death (p = 0,01), in accordance with literature and with majority other studies [1,12,205,229,242,288]. The immunodeficiency status was found in 5,67% of cases and significantly increased the fatality rate, with important difference between the survivors group (126 patients) and non-survivors group (15 patients), p = 0,03. The follow abnormalities in electrolyte levels and acid-base status were correlated with risk of death and we observed important statistical difference between the median values finding in children with

iti di s pn eu m on ia H e .i nf lu en G ra za m e ne g. ba ci do lli ub le et io lo gy S. ag al ac tia e S. au O re th u er se tio U nk lo gy no w n et io lo gy S.

.m en i

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fatal evolution, comparative with survivors group: decrease of the arterial pH (7,27 0,12 vs. 7,38 0,08, p = 0,003), low level of bicarbonate (13,9 3,1 mEq/l, vs. 17,4 3,5 mEq/l, p = 0,001), high serum lactate concentration (46,2 2,4 mg% vs. 37,5 6,3 mg%, p = 0,005) hyponatremia (128,2 2,2 mEq/l vs. 137,4 7,3 mEq/l, p = 0,002), hyperkalemia (4,1 1,4 mEq/l vs. 3,4 0,6 mEq/l, p = 0,001), highly correlated with low arterial pH levels (rs = - o,46; p < 0,001). Hypocalcemia (< 8 mg%) was detected in 119 patients (84,36%) and wasnt correlated with a poor prognostic (p = 0,2), but it was associated with presence of seizures at the admission moment, p = 0,03. The serum levels of CRP were significantly lower in non-survivors than in survivors and strongly correlated with the interval between the onset of symptoms and the time of laboratory samples collected (r = 0,62, p < 0,001and respectively r = 0,54, p < 0,001). A low pleocytosis in CSF (< 20/mm3) was associated with death in meningococcal meningitis (p = 0,01). In non-survivors group finding significantly lower value of CSF/serum glucose ratio (0,22 0,09) than in cases with favourable evolution (0,30 0,05), with a p value for risk of death of 0,03. Detecting PCT in CSF seams to be a risk factor for recovery with neurological and psychiatric sequelae (45,45% from the patients with PCT level between 2 and 10 ng/ml recovered with important sequelae, comparative with only 4,54% from those had smaller or undetectable values of PCT in CSF, p = 0,009). Also, the detectable CSF PCT level was highly associated with young age, under 2 years (r = 0,42; p = 0,005). The clinical manifestations correlated with a poor prognostic were coma (p = 0,01) and hyperpirexia (p = 0,01). CONCLUSIONS
1. The general incidence of ABM in children maintains constant in the last 20 years, but we observed a moving to the right of the maxim incidence, depending on the age. 2. The etiologic profile of ABM significantly changed in the last 20 years as a result of an important increase of the tuberculous meningitis incidence, especially in young children, and by decrease of the incidence of other etiologic agents. 3. The most important pathogen agents implicated in meningitis etiology in children at the moment, in frequency order are: N. meningitidis, Koch bacilli, Str. pneumoniae, H. influenzae type b and Gram-negative bacilli. The isolation frequency H. influenzae type b is in growth in our geographic region and this situation required systematic using of Hib vaccination. 4. The environment risk factors are more frequently detecting than the host organism risk factors in ABM in children. 5. The most frequent symptom of onset period in ABM in children is vomiting. The irritation meningial signs and fever may be absent, especially in neonatal meningitis and in tuberculous meningitis. The persistent seizures and focal neurologic signs are more frequents in bacillary, pneumococcal and neonatal meningitis 6. Septic shock, like an immediate complication is associated with young age and with meningococcal etiology and belated complications is characteristic for bacillary, pneumococcal and neonatal meningitis. 7. A very serious disease outcome is typical for bacillary, pneumococcal, double etiology and neonatal meningitis. Meningococcal and Gram-negative bacilli meningitis have a favourable outcome by an adequate antibiotic therapy, in present . 8. The bacterial specific antigens detection in CSF by LAT increases the percent of etiologic agents identification with 26,5% and is more efficiently than CSF bacteriological examinations in ABM in children. 9. The etiologic diagnosis of certitude with the actual usually diagnosis methods are possible in percent of 75%. 10. The diagnosis of tuberculous meningitis is based in principal on clinical, epidemiological and laboratory criterions. The identification of Koch bacillus with bacteriological methods is possible only in 47,82% cases. The CSF chemical and biochemical analyses have an important value for initial orientation of diagnosis in bacillary meningitis in children. 11. The blood culture may contribute to the etiologic diagnosis improvement in meningococcal meningitis associated with meningococcemia and in neonatal meningitis. 12. The incidence of partially treated meningitis is in growth in the last 20 years. The previously antibiotic treatment modify the initial clinical presentation and significantly reduces the percent of CSF bacteriological positive results, delays the clinical diagnosis and negatively influences the etiologic

diagnosis, but insignificantly changes the CSF chemical and biochemical parameters and the results of immunological test. 13. PCT serum is a better marker than C-reactive protein in the differentiation between ABM and AVM in children and a serum level > 0,5 ng/ml gives a great sensitivity and specificity. 14. The associated antibiotic therapy is indicated for the initial treatment of ABM in children, in absence of etiology or a susceptibly testing and in presence of aggravated factors. This has a superior efficiency than mono-therapy. 15. The most indicated antibiotic for mono-therapy in ABM in children is ceftriaxone. Using of Penicillin G in mono-therapy without antibiogram is not indicated. Meropenem is a reserve antibiotic and has indication in the mono-therapy of ABM in children with resistant germs of usual antibiotics. 16. Triple association of antibiotics is indicated in treatment of plurietiological and neonatal meningitis with unknown etiology. 17. The number of Penicillin G-resistant strains of N. meningitidis and Str. pneumoniae is in growth in our geographic region. 18. The adequate etiologic treatment in ABM in children instituting in the first 12 hours form onset, significantly increase its efficiency and decrease the risk of early complications. In tuberculous meningitis the antituberculous treatment starting in the first 7 days from the neurological symptoms increase the chance of survive and decrease the risk of neuropsychiatric sequelae. 19. The association of steroid treatment is indicated in meningitis cases with encephalitis signs, septic shock and in fulminating forms associated with DIC syndrome. The cortisone reduces the risk of permanent neurologic sequelae in ABM in children. 20. The young age, immunological deficits, the underlying diseases, coma at the admission moment and hyperpirexia significantly increase the risk of death in ABM in children. 21. Hyperkalemia, hyposodemia, the metabolic acidosis and low serum CRP levels represents negative prognosis factors in ABM in children. 22. The detectable levels of PCT in CSF in young children significantly increase the risk of neurologic sequelae in ABM in children. 23. The value of arterial pH, C-reactive protein, lactic acid and potassium serum levels and detectable levels of PCT in CSF should be the parameters of a prognosis score in ABM in children, with predictive value for the risk of death and useful in patients classification depending on the gravity of disease and for followed the therapeutic results.
Abv.: LA lactic acid, AP anatomo-pathologic, Cfs cefalosporins, DIC disseminated intravascular coagulation, LAT latex agglutination test, CRP C - reactive protein, IA immune allergic, ARF acute renal failure, ABM acute bacterial meningitis, VAM acute viral meningitis, UK unknown, PCT procalcitonin, TCC traumatism cranio-cerebral

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CURRICULUM VITAE
I. PERSONAL DATES First Name: Last Name: Parents: Date of Birth Marital Status: Address: Phone: E-mail: Language Skills: ROXANA OLIVIA IUBU father: Iubu Traian; mother: Iubu Letiia Lucia 26.08.1962 Craiova, Romania divorced, 1 child (13 years) str. Observatorului, no.140, ap. 20, Cluj-Napoca 0740189197, 0264/522781 [email protected] English, French

Academic Background (Studies): - Gymnasium and college: College of mathematics and physics Fraii Buzeti - Craiova, 1973 1981; - University of Medicine Craiova, graduates of 1988, general mark 9,96; - Trainer for a masters degree in Medicine in final stage of presentation the graduation paper, at the University of Medicine and Pharmacy Iuliu Haieganu Cluj-Napoca, from 01.11.1999, with title Contribution of the study of actual etiology, clinical manifestation, diagnosis and treatment of acute bacterial meningitis in children scientific supervisor prof. dr. Gorgan Vasile. Current Professional State: - primary physician of infectious diseases - general medical adjunct manager at the Clinical Hospital of Infectious Diseases Cluj-Napoca Romania II. PROFESSIONAL ACTIVITY - Since 01.03.1999 - primary physician of infectious diseases at the Clinical Hospital of Infectious Diseases Cluj-Napoca, Paediatric Department (05 12. 06.1998 exam session, 9,77 mark). Responsibilities: Diagnosis and the treatment of the admitted in the Pediatric Department cases, including respiratory airway infections, integumentary infections, infections of the central nervous system (meningitis, encephalitis) sepsis etc. Diagnosis, periodic evaluation and decide the Antiretroviral Therapy for children with HIV infection from Cluj county and from 4 others neighbour counties; - 18.02.1994 01.03.1999 specialist physician in infectious disease speciality (speciality exam on 17.01.1994, 9,76 mark), at the Clinical Hospital of Infectious Diseases Cluj-Napoca, Paediatric (Respiratory and Digestive Infectious); - 01.02.1991- 18.02.1994 secondary physician medic (27 28.10.1990, exam session), at the Clinical Hospital of Infectious Diseases Cluj-Napoca; - 21.11.1988 01.02.1991 probations physician, at the Pediatric University Clinic II and Medical University Clinic III, Cluj-Napoca

- Since 02. 06 2004 I am also general medical adjunct manager at the Clinical Hospital of Infectious diseases
III. SCIENTIFIC ACTIVITY

1). I elaborated 31 scientific papers, 11 like first author, 10 like second author and 10 like co-author.
From these: a). 7 papers was published in extenso in specialty review like: Clujul Medical, Viaa Medical, Terapeutic, farmacologie i toxicologie clinic: - ROXANA IUBU: Etiopathogenesis particularities of neonatal meningitis, Viaa Medical, no. 19 (749) XVI year, 7 may 2004, pg 1 2. - ROXANA IUBU, DOINA ULESCU, C. JIANU, C. MARCU, . TOMESCU: Therapeutically actualities in neonatal meningitis. Terapeutic, farmacologie i toxicologie clinic, vol. VIII, no. 1, march 2004, pg. 73 79. - ROXANA IUBU, DOINA ULESCU, C. JIANU, C. MARCU: Actual orientations in initial antibiotic treatment of acute bacterial meningitis in children. Clujul Medical, vol. LXXVII 2004, no. 1, pg. 25 32.

- ROXANA IUBU, DOINA ULESCU, C. JIANU, C. MARCU: Actual clinical and etiological aspects in acute bacterial meningitis in children. Clujul Medical, vol. LXXVII 2004, no. 1, pg. 61 69. - ROXANA CSIKOS (IUBU), C. MARCU, V. NEAGA, and LIDIA NANULESCU: Clinical evolutionary aspects of meningococcal infections in children. Clujul Medical, vol. LXXIV, no. 1-2, 2001, pg. 105 111. - V. NEAGA, C. MARCU, NORA BUCOV, ROXANA CSIKOS (IUBU), LIDIA NANULESCU Considerations referred to the enterovirus epidemic from 1999 summer. Clujul Medical, vol. LXXIV, no. 1-2, 2001, pg. 66-74. - LIDIA NANULESCU, ROXANA CSIKOS (IUBU), C. MARCU: Claritomicine (Klacid) in treatment of bacterial infections in children. Terapeutic, farmacologie i toxicologie clinic, vol. IV, no. 1, march 2000 b). 24 papers was communicated to national and international scientific manifestations and published in abstracts volume - ROXANA IUBU, C. JIANU, DOINA ULESCU, C. MARCU, LIGIA URSU: The prognostic value of cerebrospinal fluid procalcitonin in acute bacterial meningitis in children, poster presentation at the 15th European Congress of Clinical and Infectious Diseases, Copenhagen, Denmark, 2 5 April 2005, published in abstracts volume (P 1671) pg 547. - ROXANA IUBU, C. JIANU, DOINA ULESCU: Outcome of invasive pulmonary aspergillosis under highly antiretroviral therapy in a HIV-infected patient without appropriate antifungal drugs: case report, presented at the 15th European Congress of Clinical and Infectious Diseases, Copenhagen, Denmark, 2 5 April 2005, published in abstracts volume (R 2196) pg 728. - ROXANA IUBU, DOINA ULESCU, C. JIANU, C. MARCU: The actual therapy of acute bacterial meningitis in children, communicated at the 11en National Congress of infectious diseases, Craiova, 22 25 September 2004, published in abstracts volume, pg 127, Craiova Medical, 2004, 6 (3): 127 - ROXANA CSIKOS (IUBU), V. NEAGA, LIDIA NANULESCU, C. JIANU, C. MARCU: Actual clinical and outcome aspects in acute bacterial meningitis in children; communicated at the 5th Conference of infectionists form Moldova Republic Actual problems in infectious pathology 4-5 October, 2001, published in abstracts volume, pg.150. - CSIKOS (IUBU) ROXANA, MARCU C., NEAGA V, NANULESCU LIDIA Actual clinicalevolutionary aspects in meningococcal infectious, communicated at the 8th National Congress of Infectious Diseases, Mangalia, 17-20 may 2000, published in abstracts volume, pg. 129. - ROXANA IUBU The research results of CSF immunoglobulins in multiple sclerosis graduation paper, presented to Student Scientific Reports Session, Craiova, Romania, may 1988 - C. JIANU, ROXANA IUBU, I. CIUTIC: Meningo-enecephalo-mielo-polyradiculonevritis with Mycobacterium tuberculosis: case report, presented at the 15th European Congress of Clinical and Infectious Diseases, Copenhagen, Denmark, 2 5 April 2005, published in abstracts volume (R 2132) pg. 708. - C. JIANU, CORINA ITU, DOINA ULESCU, ROXANA IUBU: Immune reconstitution without antiretroviral therapy in patient with AIDS and tuberculosis, presented la 14 th European Congress of Clinical and Infectious Diseases Prague, Czech Republic 1 4 May 2004, published in abstracts volume (R 2258) pg. 648 - C. MARCU, ROXANA IUBU, D. CRSTINA: The Experience of Regional Centre Cluj with Agenerase Therapy in children. . Symposium Viral resistance, the place and the role of in therapy with protease inhibitors, Timioara, 27 march 2004, published in abstracts volume. - DOINA ULESCU, CORINA ITU, ANGELA BUTNARIU, C. JIANU, ROXANA IUBU, C. MARCU, D. CRSTINA The importance of HIV-testing in pregnant woman. The University of Medicine and Pharmacy "Iuliu Haieganu" Days Cluj-Napoca, 2-5 December 2003, published in abstracts book pg. 87. - C. MARCU, D. CRSTINA, ROXANA IUBU, ADRIANA SLAVCOVICI, DOINA ULESCU, CORINA ITU, C. JIANU Clinical-evolutionary aspects in HIV infection in children. The University of Medicine and Pharmacy "Iuliu Haieganu" Days Cluj-Napoca, 2-5 December 2003, published in abstracts book pg. 90. - LIDIA NANULESCU, ROXANA IUBU, C. MARCU. Controllable secondary effects in treatment with protease inhibitors Indinavir (IDV), communicated ay the 3rd National Congress

HIV/SIDA, with cu international participation, Bucureti, Romania, 15 18 may, 2002, published in abstracts book pg. 46. - LIDIA NANULESCU, ROXANA CSIKOS (IUBU), C. MARCU, ANCA BUTNARIU, L. NEGRU Neurologic manifestations in HIV infection in children; communicated at the 3rd National Congress HIV/SIDA, cu international participation, Bucureti, Romania, 15 18 may, 2002, published in abstracts book, pg. 37. - LIDIA NANULESCU, ROXANA IUBU, C. MARCU. Treatment with triple association Indinavir-Stocrin Epivir in HIV/SIDA infection in children; communicated at the 3rd National Congress HIV/SIDA, with international participation, Bucureti, Romania, 15 18 may, 2002, published in abstracts book pg. 48. - LIDIA NANULESCU, ROXANA CSIKOS (IUBU), C. MARCU: Association Indinavir/Efavirenz in treatment of HIV infection in children. Partial results; communicated at the Symposium "Actual Problems in antiretroviral therapy in HIV infection ", 23 March 2001, ClujNapoca - C. MARCU, MONICA TURDEANU, CRISTINA CISMARU, D. CRSTINA, C. JIANU, ROXANA CSIKOS (IUBU): Statistic evaluate of diagnosis clinic elements in acute viral hepatitis; communicated at the 5th Conference of the infectionists from Moldova Republic " Actual problems in infectious pathology ", Chiinu, 4-5 October, 2001, published in abstracts book, pag.54. - NANULESCU LIDIA, MARCU C., CSIKOS (IUBU) ROXANA: Toxic Shock Syndrome (TSS) - Clinical-evolutionary particularities in children communicated at The 8th National Congress of Infectious Diseases, Mangalia, 17-20 may 2000, published in abstracts book pg. 186. - C. MARCU, ROXANA CSIKOS (IUBU), V. NEAGA, LIDIA NANULESCU: Co-infection with hepatitis viruses B and C in children with HIV/SIDA infection, communicated at The 8th National Congress of Infectious Diseases, Mangalia, 17-20 may 2000, published in abstracts book pg. 72 - LIDIA NANULESCU, A. ERBAN, ROXANA CSIKOS (IUBU): unspecific sero-immune markers in serious forms of acute viral hepatitis in children; communicated at The 7th National Congress of Infectious Pathology Tg-Mure, Romania, October 1995, published in abstracts book. - LETIIA IUBU, ROXANA CSIKOS (IUBU), MARIANA APU, IOAN STOICA: Consideration of CSF immunoglobulins and proteins study in multiple sclerosis; communicated at The Annual Conference of Neurology from Clujan Academy Days, Cluj-Napoca, Romania, October 1994, published in abstracts book pg 89. - LETIIA IUBU, O. LASCU, MARIANA MODORAN, ROXANA IUBU: Epidemiological aspects in repetitive transitory ischemic cerebral strokes communicated at The Annual Conference of Neurology, Sibiu, Romania, June 1989, published in abstracts book. - LETIIA IUBU, O. LASCU, ROXANA IUBU: Semiologic value of cervical region blasts; communicated at The Annual Conference of Neurology, Sinaia, Romania, June 1988, published in abstracts book. - LETIIA IUBU, O. LASCU, ROXANA IUBU: Evolutionary aspects in multiple sclerosis; communicated at The Symposium Epidemiology of multiple sclerosis in Romania , Piatra-Neam, June 1987, published in abstracts book. - EISABETA STANCIU, ROXANA IUBU, ROXANA CRUCE: The Frequency of periphery neuropathies in juvenile mellitus insulin-dependent; communicated at The Symposium Epidemiology of multiple sclerosis in Romania, Piatra-Neam, Romania, June 1987, published in abstracts book. 2. I participated to many scientific national and international manifestations: - The 15th European Congress of Clinical Microbiology and Infectious Diseases, 2 5 April 2005, Copenhagen, Denmark; - The 11en National Congress of Infectious Diseases, 22 25 September 2004, Craiova, Romania; - The 14th European Congress of Clinical Microbiology and Infectious Diseases, 1 4 may 2004, Prague, Czech Republic; - National Symposium Actualities in infectious pathology, 21 24 may 2003, Iai, Romania; - The 3rd National Congress HIV/SIDA 15 18 may 2002, Bucureti, Romania; - The 5 th Conference of the infectionists from Moldova Actual problems in infectious pathology, 4 5 October 2001, Chiinu, Moldova Republic; - The 8 th National Congress of Infectious Diseases, 17 20 may 2000, Mangalia, Romania; - The 7 th National Congress of Infectious Pathology, October 1995, Trgu-Mure;

- Annual Conference of Neurology from Clujan Academy Days, 27 28 October 1994 ClujNapoca; - Annual Conference of Neurology, Sibiu, Romania, June 1989 - Annual Conference of Neurology, Sinaia, Romania, June 1988 - Symposium Epidemiology of multiple sclerosis in Romania, Piatra-Neam, Romania, June 1987. 3. The interests areas for my scientific activity was: nervous central system infections, HIV/SIDA infection in children, acute viral hepatitis, in children, study of multiple sclerosis, juvenile mellitus etc 4. In 1998 2005 period I graduated 5 post university training courses at the University of Medicine and Pharmacy Iuliu Haieganu Cluj-Napoca: - Actualities in Infectious Diseases, 04.05.1998 - 12.06.1998, Infectious Diseases Discipline, UMF Cluj-Napoca, graduated with 10 mark; - Diagnosis Traps in paediatrics, 01.10.1999 - 30.06.2000, Paediatric Discipline II, UMF ClujNapoca, graduated with 10 mark; - Paediatric Urgency, 06.04.200 08.06.2000, paediatric Discipline III, graduated with 10 mark; - Ecography for competences (part I General Ecography), 01.03.2004 09.04.2004, Medical Discipline I and Centre of training for ultrasonography at the UMF Cluj-Napoca, affiliated to Jefferson Ultrasound Research and Educational Institute Philadelphia, graduated with 9,83 mark; - Management of medical services, 01.10.2004 20.03.2005, Public Health and Management Discipline at the UMF Cluj-Napoca, graduated with 9,80 mark. 5. Since 01.11.1999 I am in training for a masters degree in medicine, at this moment in final stage of presentation of graduation paper. In this period: I graduated the 3 exams: Infectious Diseases April 2000, Microbiology October 2000 and Epidemiology February 2001, appreciated as Very good. I presented the 3 reviews Etiopathogenesis and diagnosis actualities in acute bacterial meningitis in children June 2000, Actual clinical-etiological forms in acute bacterial meningitis in children l November 2001 and Actual treatment of acute bacterial meningitis in children March 2003, appreciated as Very good I published and/or communicated 7 scientific paper referred to graduation paper thematic: 5 like first author and 2 like co-author. IV. DIDACTIC ACTIVITY : I have also didactic activity like collaborator at the : - Infectious Diseases Discipline of UMF Cluj-Napoca, in 1994/95, 1995/96, 1996/97, 1997/98 i 1998/99, 2004/2005-university years. - Clinical Pharmacy Discipline at the Pharmacy University of UMF Cluj, in 1996/97, 1997/98, 1998/99 i 1999/2000-university years. Between 2002 2005 I participated to introducing and reporting in information system of the data of the HIV infected patients from Regional Centre Cluj-Napoca DSP Cluj-Napoca and National Commission for Fighting Anti-SIDA. I have necessary know-ledges for PC operating (Windows, Microsoft Office).