EM Mucoviscidoza

MUCOVISCIDOZA

(FIBROZA CHISTICA)

Prof. Dr. EVELINA MORARUProf. Dr. EVELINA MORARU

UMF UMF Gr. T. PopaGr. T. Popa IASIIASI

Mai 2011Mai 2011

MUCOVISCIDOZA

DEFINITIE

Cea mai frecventa anomalie monogenica A.R.

Rasa caucaziana evolutie cronica potential letala.

Frecventa medie Europa 1/2500 nou nascuti.

Problema de sanatate publica pe plan mondial.

DOROTHY ANDERSONcaracterul vascos al

mucusului1938

Actualitati in FC:-Bio-predictori ai supravietuirii si ameliorariea calitatii vietii-Cresterea sperantei de viata

-Terapia genica si perspectiva altor terapii specifice-Modularea transportului ionic: transportul Cl prin alte canale decat CFTR

Proteoliza

Inflamatie

Pancreas normal

Pancreas cu FC

Secretie HCO3-normala

Secretie HCO3-scazuta

Secretieenzimatica

Celulesecretoare

GENETICA MUCOVISCIDOZEI

Gena defectiva brat lung cromozom 7 Implicate foarte multe mutatii (Alele) peste

1000

Cea mai frecventa mutatie DF 508 EXON 10 (media europeana 70%)

Gena defectiva proteina patologica cu rol in transportul clorului la nivelul membranei celulare.

CFTR Cystic fibrosis conductance regulator. (Reglator al conductantei transmembranare ).

Factori genetici

Factori genetici

Clasificare genotip FC dupa clasa de

mutatii functionale

Clasa mutatii I, II, III rata mortalitate

crescuta

Clasa mutatii IV, V rata mortalitate

scazuta

Factori genetici

Corelatii intre aspectul initial al bolii

si evolutia clinica

Bolnavi initial cu simptome (respiratorii

si gastrointestinale)

Supravietuire scurta

Functie pulmonara deteriorata

Incidenta crescuta Pseudomonas

aeruginosa

Problema mucoviscidozei in Romania

Mucoviscidoza nu este suficient cunoscuta

Boala nediagnosticata

Diagnostic tardiv

Complicatii ireversibile

Eficienta terapiei scazuta

In Romania

la 200.000 nasteri/an

80 90 cazuri noi mucoviscidoza

In realitate numar cazuri nou diagnosticate inacceptabil de mic.

SUBSTRATUL FIZIOPATOLOGIC SI RELATIA CU TABLOUL CLINIC

Consecinta anomaliei genetice blocarea si functionarea defectuoasa a canalelor de clor la nivel celular implicit ClNa si apa.

Secretiile organe si sisteme

cu continut sarac in apa

vascoase

aderente la epiteliile canaliculilor excretorii greu de eliminat

SUBSTRATUL FIZIOPATOLOGIC SIRELATIA CU TABLOUL CLINIC

Acumularea secretiilor alterarea functiilor organelor si distructia lor:

Plaman

pancreas

ficat

intestin

organe reproducere

Tegumente concentratie foarte crescuta in sare

Tablou clinic polimorf:

Semne majore:

Suferinta respiratorie cronica tuse cronica

Diaree cronica cu steatoree

Falimentul cresterii

FIBROZA CHISTICA / BOALA CRONICA FIBROZA CHISTICA / BOALA CRONICA DEBUT PRECOCEDEBUT PRECOCE

CF MUTATIE GENETICA

DISFUNCTIE CFTR

TRANSPORT IONIC ANORMAL

MUCUS VASCOS, ADERENT

INFLAMATIE OBSTRUCTIE

INFECTIE

INSUFICIENTA PULMONARA

DISTRUCTIE CAI AERIENE PULMONARE

MOARTE PRECOCE

CERC VICIOS: OBSTRUCTIE, INFECTIE, INFLAMATIEPROGRESIV, IN FINAL PERMANENTA, DISTRUCTIVA, SCADE SPERANTA DE VIATA

CICLUL VICIOS SE INSTALEAZA PRECOCE, ANTERIOR SIMPTOMELOR EVIDENTE

RUPEREA ACESTOR SECVENTE PRIN STRATEGII TERAPEUTICE PRECOCE. OFERA SANSA PROGRESIEI LENTE, SUPRAVIETUIRII MAI MARI, Q V AMELIORATA

KONSTAN, Am. J. KONSTAN, Am. J. RespResp. . CritCrit. Care Med. 1995. Care Med. 1995TIDDENS, TIDDENS, PediatrPediatr. . PulmonolPulmonol. 2002. 2002

ROLUL CLEARANCEROLUL CLEARANCE--ULUI MUCOULUI MUCO--CILIARCILIAR

Epiteliul cailor aeriene adaptat

Autocuratirea pulmonului fiziologic se realizeaza prin mucus

F.C. transforma un mecanism fiziologic de aparare intr-o amenintare permanenta!

INFLAMATIA PULMONARA IN FC

Ratjen et al. Ratjen et al. DNA DNA concentrations in BAL fluid of CF concentrations in BAL fluid of CF pacientspacients with early lung disease: with early lung disease: influence of treatment with influence of treatment with dornasedornase alpha, Pediatric alpha, Pediatric PulmonologyPulmonology 2005;39:12005;39:1--44

Inflamatie

Obstructiecai aeriene

Colonizare bacteriana

Declinul functiei pulmonare

AderentaAderenta mucoasamucoasa in FC:in FC:frumoasafrumoasa dardar mortalamortala

CurbeCurbe de de referintareferinta pentrupentru percentilulpercentilul FEV1 in FEV1 in functiefunctie de de varstavarsta la la pacientipacienti cu FCcu FC

Masculin Feminin

Michal Kulich, Margaret Rosenfeld, Jonathan Campbell, Richard Kronmal, Ron L. Gibson, Christopher H. Goss and Bonnie Ramsey Disease-specific Reference Equations for Lung Function in Patients with Cystic Fibrosis, American Journal of Respiratory and Critical Care Medicine Vol 172. pp. 885-891, (2005)

IMPLICATIILE DECLINULUI FUNCTIEI IMPLICATIILE DECLINULUI FUNCTIEI PULMONAREPULMONARE

SCADEREA FEV1 CU 10 % IN 2 ANI DUBLEAZA RISCUL DECESULUI

MORTALITATE MARE LA CEI CU FEV1 LA VARSTE MICI (6 17 ANI) MAI MULT DECAT LA ADULTI (>17 ANI)

HRCT PREDICTIV PRECIS AL PROGRESIEI BOLII (ANUAL)

RABIN. HR, BUTLER SM RABIN. HR, BUTLER SM Pulmonary exacerbation in cystic fibrosisPulmonary exacerbation in cystic fibrosisPediatrPediatr. . PulmonolPulmonol. 2004; 37. 2004; 37--400400--406 406

PREDICTIA ETR PREDICTIA ETR SCADEREA FEVSCADEREA FEV11 Fiecare ETR are impact asupra supravietuirii scazind FEV1 cu 12% 4 ETR pe an echivaleaza cu inf. cu BURKHOLDERIA CEPACIA

5 ANI

SUPRAVIETUIRE

1 ETR = scade FEV1 cu 12%

4 ETR (un an) = scade FEV1 cu 48%

VIRSTA

ETR ANUAL

B.C. SINDROM

INFECTII (STAF,Py0)

DIABET ZAHARAT

FEV1

SEX(F)

MALNUTRITIA (SCOR Z)

FUNCTIE PANCREATICA

Liou Survivorship model

Inflamatia pulmonara si exacerbarile ei Inflamatia pulmonara si exacerbarile ei initiaza modificari fiziopatologice si initiaza modificari fiziopatologice si metabolice care au impact nutritional metabolice care au impact nutritional ((anorexieanorexie))

Casexia este determinata multifactorial: Casexia este determinata multifactorial: constelatia citokinica proinflamatorie are constelatia citokinica proinflamatorie are efect asupra statusului nutritional: TNFa efect asupra statusului nutritional: TNFa (casexina), IL1, IL6, iL8 (casexina), IL1, IL6, iL8 -- > prabusire > prabusire metabolicametabolica

Solubilizarea biofilmului prin dornaza alfa Solubilizarea biofilmului prin dornaza alfa scade rata de infectiiscade rata de infectii

PATOGENIEPATOGENIE

MANIFESTARI RESPIRATORII IN FCMANIFESTARI RESPIRATORII IN FC

DEBUT SIMPTOMATICPESTE 6 LUNI

(90% LA UN AN)

WHEEZING

BRONSIOLITA PERSISTENTA

ATOPIE (ABPA) 8%

BOALA PULMONARA OBSTRUCTIVA

INFECTII TRENANTE

BRONSIECTAZIE

SINUZITE (PANSINUZITE)

RINITE POLIPOZA NAZALA

SURDITATE TRANSMISIE

EPISTAXIS RECIDIVANT

HRCT PREDICTIV EVOLUTIVLBA - PREDICTIV INFECTIE

C

O

N

S

E

C

I

N

T

E

DECLIN

FUNCTIONAL

PNEUMOTORAX RECIDIVANT 5-8 %

HEMOPTIZIA (MINORA, MASIVA)

BRONSIECTAZIA

ATOPIA 8 10 %

DECLIN FEV1

HIPOXIE SEVERA

PERTURBARI GAZOMETRIE

REFLUX G E (25 %)

INSUFICIENTA RESPIRATORIE

MALNUTRITIE MULTIFACTORIALA

MOARTE

COMPLICATII:

INVESTIGATII AFECTARE RESPIRATORIE IN FCINVESTIGATII AFECTARE RESPIRATORIE IN FC

Diagnostic confirmare Monitorizare

- fisa clinica (puls oximetrie)- fisa familie (tuse, secretii, dispnee)- atopia (Ig E si Aspergillus)- teste functionale (CV, FEV1)- ORL, Audiograma- Rg clasica- LBA (Bronhoscopie)- HRCT- Densitometrie osoasa

RegulaRegula: : complexitatecomplexitate, , secventialitatesecventialitate!!

EXACERBARILE PULMONAREEXACERBARILE PULMONARE

1. SIMPTOME1. SIMPTOME A TUSE (frecventa, durata, intensitate)

B SPUTA (creste sau apare)

C CULOAREA SPUTEI (devine verde)

D HEMOPTIZIA (recidiva, amploare)

E TOLERANTA EFORT (scade)

F OBOSEALA PERMANENTA

2. SEMNE FIZICE2. SEMNE FIZICE A RETRACTIE INTERCOSTALA (muschi accesorii)

B POLIPNEE

C CREPITATII TORACICE

D EMFIZEM

E FEBRA

F MALNUTRITIE

3. LABORATOR3. LABORATOR A SCADE FEV1 CU 10%

B INFILTRATE CONDENSARI

C LEUCOCITOZA

D SCADE SATURATIA O2

PROGNOSTIC REZERVATPROGNOSTIC REZERVAT

Atingere multiviscerala

Sex feminin

Anomalii radiologice persistente

Colonizare bacteriana multipla

Hemoptizie recidivanta

Cord pulmonar cronic

Intreruperea cresterii staturo - ponderale

OBIECTIVELE TERAPIEI FCOBIECTIVELE TERAPIEI FC

Tratamentul

infectiilor

Combaterea

obstructiei prindrenaj secretii

Interventie

nutritionala

Controlul

inflamatiei cailor

aeriene

TRATAMENT ANTIINFECTIOSTRATAMENT ANTIINFECTIOS

Utilizarea antibioticelor

Oral exacerbari usoare

Topic TOBRA inhalator Intravenos secvente de 14 zile

Administrarea secventiala, lunara, alternativa

Utilizarea chinolonelor (1/2 doza intravenos in ETR)

Asocierea antibioticelor cu mucolitice (DN asa) amelioreaza FEV1 cu 11, 28%

Asocierea cu kinetoterapia

Vaccinarea si imunoterapia

Imunoglobuline intravenoase

--Richard B. Moss,Richard B. Moss,BonniewBonniew RamseyRamsey

REGULI ANTIBIOTERAPIE IN FCREGULI ANTIBIOTERAPIE IN FC

500 mg intravenously 500 mg intravenously every 6 h OR 1 g every 6 h OR 1 g

intravenously every 12 intravenously every 12 hh

15 mg/kg intravenously 15 mg/kg intravenously every 6 hevery 6 h

MethicillinMethicillin--resistant resistant S. S. aureusaureus

2 g intravenously every 2 g intravenously every 6 h6 h

252550 mg/kg 50 mg/kg intravenously every 6 hintravenously every 6 h

OROR



CefazolinCefazolinStaphylococcus Staphylococcus aureusaureus

ADULT DOSEADULT DOSE**PEDIATRIC DOSEPEDIATRIC DOSE**ANTIBIOTICANTIBIOTICPREVALENT PREVALENT BACTERIABACTERIA

ANTIBIOTICS FOR THE TREATMENT OF BACTERIA ASSOCIATED WITH PULMONARY EXACERBATIONS:

557.5 mg/kg 7.5 mg/kg intravenously every 8hintravenously every 8h

557.5 mg/kg 7.5 mg/kg intravenously every 8 hintravenously every 8 hAmikacinAmikacin****


3 mg/kg intravenously 3 mg/kg intravenously every 8 hevery 8 hTobramycinTobramycin

PLUS PLUS aminoglycosideaminoglycoside(choose 1):(choose 1):


50 mg/kg intravenously 50 mg/kg intravenously every 8 hevery 8 hAztreonamAztreonam


40 mg/kg intravenously 40 mg/kg intravenously every 8 hevery 8 hMeropenemMeropenem||||

500 mg500 mg1 g 1 g intravenously every 6 hintravenously every 6 h

151525 mg/kg 25 mg/kg intravenously every 6 hintravenously every 6 hImipenemImipenem||||


100 mg/kg 100 mg/kg intravenously every 6 hintravenously every 6 hPiperacillinPiperacillin


100 mg/kg 100 mg/kg intravenously every 6 hintravenously every 6 h


50 mg/kg intravenously 50 mg/kg intravenously every 8 hevery 8 hCeftazidimeCeftazidime

--lactamlactam (choose 1):(choose 1):Pseudomonas Pseudomonas

aeruginosaaeruginosa



Note: Third drug may be Note: Third drug may be added if synergyadded if synergytesting suggests efficacytesting suggests efficacy

445 mg/kg of 5 mg/kg of trimethoprimtrimethoprim

component component intravenously every intravenously every

12 h12 h



12 h12 hTrimethoprim/sulfamethoxTrimethoprim/sulfamethox

azoleazole

151520 mg/kg 20 mg/kg intravenously every intravenously every

6 h6 h

151520 mg/kg 20 mg/kg intravenously every intravenously every

6 h6 h


50 mg/kg intravenously 50 mg/kg intravenously every 8 hevery 8 hCeftazidimeCeftazidime

557.5 mg/kg 7.5 mg/kg intravenously every intravenously every

8 h8 h

557.5 mg/kg 7.5 mg/kg intravenously every intravenously every

8 h8 hAmikacinAmikacin****

100 mg intravenously 100 mg intravenously or orally every 12 hor orally every 12 hMinocyclineMinocycline

PLUS (choose 1):PLUS (choose 1):


40 mg/kg intravenously 40 mg/kg intravenously every 8 hevery 8 hMeropenemMeropenem

BurkholderiaBurkholderiacepaciacepacia

ADULT DOSEADULT DOSE**PEDIATRIC DOSEPEDIATRIC DOSE**ANTIBIOTICANTIBIOTICPREVALENT PREVALENT

BACTERIABACTERIA


50 mg/kg intravenously 50 mg/kg intravenously every 8 hevery 8 hAztreonamAztreonam

3 g of 3 g of ticarcillinticarcillincomponent component

intravenously every intravenously every 6 h6 h

100 mg/kg of 100 mg/kg of ticarcillinticarcillincomponent component


Ticarcillin/clavulanateTicarcillin/clavulanatePLUSPLUS

OROR



12 h12 h



12 h12 hTrimethoprim/sulfametTrimethoprim/sulfamet

hoxazolehoxazole

OROR

3 g of 3 g of ticarcillinticarcillincomponent component


100 mg/kg of 100 mg/kg of ticarcillinticarcillincomponent component

intravenously every intravenously every 6 h6 hTicarcillin/clavulanateTicarcillin/clavulanate

StenotrophomonasStenotrophomonasmaltophiliamaltophilia

2 gm intravenously 2 gm intravenously every 8 hevery 8 h

40 mg/kg intravenously 40 mg/kg intravenously every 8 hevery 8 hMeropenemMeropenem

500 mg500 mg1 g 1 g intravenously every 6 hintravenously every 6 h

151525 mg/kg 25 mg/kg intravenously every 6 hintravenously every 6 hImipenemImipenem

PLUS (choose 1):PLUS (choose 1):

400 mg intravenously 400 mg intravenously or 500or 500750 mg orally 750 mg orally

every 12 hevery 12 h15 mg/kg intravenously 15 mg/kg intravenously

or orally every 12 hor orally every 12 hCiprofloxacinCiprofloxacin

OROR

100 mg intravenously 100 mg intravenously or orally every 12 hor orally every 12 hPLUS PLUS MinocyclineMinocycline

151520 mg/kg every 6 h20 mg/kg every 6 h151520 mg/kg 20 mg/kg

intravenously every 6 hintravenously every 6 hAchromobacterAchromobacter

xylosoxidansxylosoxidans


TRATAMENTUL OBSTRUCTIEITRATAMENTUL OBSTRUCTIEI

Principiul initierii terapiei antiinflamatoare sibronhodilatatoare

Drenajul mucusului Dornaza mucolitica inhalanta

Doza 2,5 mg de 1-2 ori pe zi

Scade ETR cu 37% inclusiv la sugari si copii sub 5 ani

Kinetoterapie clasica

moderna

fitness aerobic

vesta vibratii

flutter valve

Modul de viata (fumat, efort)

Masca presiune pozitiva

TRATAMENTUL ANTIINFLAMATORTRATAMENTUL ANTIINFLAMATOR

Corticoterapia nu are eficienta din AB Doze mari efecte secundare Doze mici interfera cresterea

Cromolin Na + mimetice (albuterol) IbuprofenulIbuprofenul ((studiustudiu 4 4 aniani ameliorareameliorare pulmonarapulmonara)) Macrolidele (Claritromicina / Azitromicina) Montelucast sodic (Singulair) R w 1 antitripsina Antielastaze sintetice IL 10 Trialuri in desfasurare

(anti IL 8) IFN Aerosoli

Michael W. Michael W. KonstanKonstan

ALTE TERAPII PENTRU COMPLICATIIALTE TERAPII PENTRU COMPLICATII

Drenaj agresiv Ablatie - pleurodesis chimic

- abraziune pleurala Tratamentul hemoptiziilor vit. K

substitutie embolizarea arterei bronsice

Oxigenoterapia (ventilatie mecanica, masca) Conditia fizica Transplant pulmonar

(supravietuire 84% la 1 an,61% la 3 ani)

Terapia genica

SITUATII SPECIALESITUATII SPECIALE

ComorbiditatiComorbiditati (B. (B. celiacaceliaca, , astmastm bronsicbronsic, reflux G.E., , reflux G.E., diabetdiabet, , cirozaciroza, , hepatitahepatitacronicacronica, etc), etc)

SarcinaSarcina optiuneoptiune -- 1985 = 52 1985 = 52 gravidegravide FCFC

evolutieevolutie -- 1990 = 111 1990 = 111 gravidegravide

tratamenttratament -- 2001 = 200 2001 = 200 gravidegravide

riscrisc alimentatiealimentatie -- 2010 = ?2010 = ?

AnesteziaAnestezia abordabord vascular (vascular (KorstKorst R.J.)R.J.)

hiperreactivitatehiperreactivitate laringelaringe, TR, BR, TR, BR

polipozapolipoza ((sondasonda nazalanazala))

hiperhiper secretiesecretie (se (se stopeazastopeaza pulmozymepulmozyme))

hemoragiahemoragia

ChirurgiaChirurgia polipozepolipoze, , adeno/amigdalectomiiadeno/amigdalectomii

endoscopieendoscopie

imageriaimageria

patologiepatologie chirurgicalachirurgicala intercurentaintercurenta

STRATEGII TERAPEUTICESTRATEGII TERAPEUTICE

ObiectiveObiective majoremajore::

Reducerea incidentei si severitatii ETR (exacerbari tract respirator)

Mentinerea functiei pulmonare convenabile

Scaderea ratei infectiilor

Ameliorare nutritionala

ReducereaReducerea incidenteiincidentei sisiseveritatiiseveritatii ETR ETR

((exacerbariexacerbari tract respirator)tract respirator)

MentinereaMentinerea functieifunctieipulmonarepulmonare convenabileconvenabile

Scaderea ratei Scaderea ratei infectiilorinfectiilor

Ameliorare Ameliorare nutritionalanutritionala

PREDICTORI DE PROGNOSTICPREDICTORI DE PROGNOSTIC

Leziuni Leziuni radiologiceradiologice persistentepersistente

ColonizareColonizare bacterianabacteriana

Afectarea metabolicaAfectarea metabolica

Declinul nutritionalDeclinul nutritional

InflamatiaInflamatia cailorcailor aerieneaeriene in in fibrozafibroza chisticachistica

efectulefectul tratamentuluitratamentului cu DORNAZA ALFAcu DORNAZA ALFA

Karl Paul, Ernst Karl Paul, Ernst RietschelRietschel, Manfred , Manfred BallmannBallmann, Matthias , Matthias GrieseGriese, Dieter , Dieter WorlitzWorlitz SchSch. . American Journal of American Journal of Respiratory and critical care medicine Respiratory and critical care medicine 2004, vol. 1692004, vol. 169

SS--a a studiatstudiat efectulefectul pepe termentermen lung lung asupraasupra inflamatieiinflamatiei cailorcailor aerieneaeriene((prinprin LBA) la 105 LBA) la 105 pacientipacienti > 5 > 5 aniani cu FC cu FC

Interval de Interval de studiustudiu = 3 = 3 aniani

InvaziaInvazia neutrofilaneutrofila = = identicaidentica

ElastazaElastaza sisi IL 8 = stabile (gr. IL 8 = stabile (gr. tratattratat))

ElastazaElastaza sisi IL8 (gr. IL8 (gr. netratatinetratati))

rhrh DN DN azaaza => => Reduce Reduce viscozitateaviscozitatea

AmelioreazaAmelioreaza functiafunctia pulmonarapulmonara

Reduce Reduce numarulnumarul exacerbarilorexacerbarilor pulmonarepulmonare

PULMOZYME PULMOZYME -- BENEFICIIBENEFICII

OBIECTIVE:OBIECTIVE:

Reduce riscul exacerbarilor pulmonare (ETR)

Mentine functia pulmonara la cei cu FVC > 40%

Exista experienta recenta si la sugari.

BENEFICII:BENEFICII:

Previne ETR! Reduce utilizarea ATB I.V. cu 27% Ameliorarea la 6 luni de utilizare FEV1, cu 5,8% (istoria naturala FEV1 scade

anual cu 2%) FEV1 > 85% Profil de siguranta mare, efecte secundare

minime

RECOMANDARI PEDIATRICERECOMANDARI PEDIATRICE

Pacientii peste 5 ani (beneficiari siguri)-varste tot mai mici si administrare endotraheala!

Doza 2,5 mg (2500 UI) zilnic, sau minim 6 luni de 2 ori pe zi

Studii la copii sub 5 ani cu efecte benefice si faraefecte secundare

PulmozymePulmozyme [package insert] South[package insert] SouthSan San Francisco, California, Francisco, California, GenentechGenentech inc., 2001inc., 2001

SCHEMA OPTIMA SECVENTIALASCHEMA OPTIMA SECVENTIALA

1. Autodrenaj secretii

2. Aerosoli bronho dilatator

3. Aerosoli / nebulizare PULMOZYME 10 minute dimineata (NU inainte de culcare!)

4. Kinetoterapie (20 minute 1 h dupa masa)

5. Aerosoli antibiotic

6. Aerosoli antiinflamator

PROFILAXIE PRECOCE!

Profilaxie primara:

perioada nou nascut - screening neonatal cu tripsina imunoreactiva

perioada postnatala - testul sudorii priniontoforeza pilocarpinica

Profilaxie secundara:

un protocol terapeutic complex cu scopul:

incetinirea progresiei bolii

prevenirea complicatiilor

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