FIBROZA CHISTICA - boala multisistemica

Istoric, incidenta, epidemiologie. Defectul de baza; diagnosticul

FC – istoric
-cea mai frecventa b dobandita (AR) limitanta a vietii la populatia caucaziana (orice etnie, rasa)
- sdr clinic 1938 Dorothy Andersen
- 1940 FC = dg de autopsie
- exista din evul mediu “aveti grija de copilul care la sarut are gust sarat, el este vrajit si va
muri”)
1950 - conditie devastatoare (speranta de viata <1 an)
1960 - boala cronica (SV >30 ani)
-initial dezordine a productiei de mucus (factor FC circulant), mucusul parea cauzator de probleme in
toate sistemele
1980 - celulele epiteliale FC transport anormal de ioni
- potential bioelectric negativ crescut transepitelial
1983 defectul primar = transport scazut de-a lungul membranelor celulare (Quinton)
1985 localizarea genei pe crz 7 (bratul lung)
1989 clonarea genei
gena FC codifica proteine regulatoare ale transportului membranar
CFTR (CF transmembrane conductance regulator)
canal de clor AMPc activat in membrana apicala a celulelor epiteliale
CFTR localizat pe bratul lung crz 7; 27 regiuni exonice care codifica 1480 Aa (proteine
FC)(mijloc) Proteina matura inserata in membrana celulara (jos)

In celulele normale, CFTR-ul este activat de ATP si permite clorului sa treaca prim membrana celulara
In celulele FC, CFTR-ul nu functioneaza si este blocat transportul de clor.

CFTR regleaza continutul de apa si ioni in secretiile luminale

gena foarte mare, productie importanta de proteine
>1400 mutatii
Efectele functionale ale claselor de mutatii

Fenotipul FC
Triada clasica FC:
- boala cronica obstructiva pulmonara
- insuficienta pancreatica exocrina (PI)
- concentratii crescute ale Cl, Na in sudoare
- infertilitate la sexul masc. (azoospermie obstructiva)
Simptome mai putin frecvente
- ileus meconial
- sindromul de obstructie intestinala distala (DIOS)
- pancreatita
- boala hepatica
- diabet
Clasificarea FC suporta un spectru larg de caracteristici fenotipice (variatii genotip-fenotip)
Supravietuirea mediana in FC 1985-2001 ( U.S. Cystic Fibrosis Foundation Patient Registry)
Varsta la care se asteapta decesul la 50% din pacienti in functie de varsta pacientilor si distributia
mortalitatii pt anul respectiv.
Varsta medie de supravietuire estimata este de 33.4 ani pt 2001.

Epidemiologie clinica
Cresterea supravietuirii se datoreaza: terapiei antibiotice sustinute, agresive + suportului nutritional
FC - cea mai frecventa boala genetica AR (1:2000-1:2500 nn vii)
Genotiparea - peste 1400 mutatii
Diagnosticul pozitiv = clinic, screening + TS
Factori de prognostic:
- varsta la diagnostic
- prezentarea clinica
Epidemiologie clinica
Diagnostic
genotipare
screening neonatal
testul sudorii
Varsta la diagnostic
70% SUA <1 an
Prezentarea clinica
51% simpt respiratorii
43% falimentul cresterii/malnutritie
35% steatoree/scaune anormale
19% ileus meconial/obstructie intestinala
Simptome clinice care sugereaza Fibroza Chistica
Simptom Procent (nu exclusiv)

Simptome respiratorii acute sau persistente 44.5

Falimentul cresterii/malnutritie 26.6

Steatoree sau scaune anormale 19.3

Ileus meconial/obstructie intestinala 12.7

Istoric familial 15.6

Screening neonatal 11.3

Genotip 9.2

Polipi nazali/ boala sinusala 6.1

Diagnostic prenatal 5.0

Prolaps rectal 2.2

Tulburari electrolitice 1.9

Probleme hepatice 1.2

Altele necunoscute 6.7

Clinical Features Suggesting Cystic Fibrosis

This table summarizes the clinical features that led to a diagnosis of CF in infants born in the US in
2003.
The most common features are those highlighted in yellow. These include acute or persistent
respiratory symptoms (44.5%), failure to thrive/malnutrition (26.6%), steatorrhea/abnormal stools
(19.3%), meconium ileus/intestinal obstruction (12.7%), and family history (15.6%).
Although neonatal screening currently accounts for 11.3% of diagnoses in 2003 (orange highlight), its
increasing adoption in the US may provide greater opportunities to prevent the development of
respiratory symptoms and nutritional failure that affects CF patients from an early age.
Cystic Fibrosis Foundation. Patient Registry Annual Data Report. 2003.

Caracteristici fenotipice tipice si atipice de FC

Typical Phenotypic Features of CF
Typically, affected patients exhibit chronic sinopulmonary disease, involving persistent colonization
or infection with Staphylococcus aureus, Haemophilus influenzae, Pseudomonas aeruginosa, and/or
Burkholderia cepacia. There may also be evidence of nasal polyps or digital clubbing.
Gastrointestinal abnormalities may be present, such as chronic hepatobiliary disease manifested by
biliary or multilobular cirrhosis, pancreatic insufficiency, or meconium ileus at birth.
Salt-loss syndromes may produce elevated sweat chloride values.
Most males with CF have obstructive azoospermia (lack of spermatozoa in the semen as a result of
congenital bilateral absence of the vas deferens).
In atypical CF, disease symptoms are less severe and fewer organ systems are affected. In particular,
atypical patients are pancreatic sufficient and may have normal or slightly elevated borderline sweat
chloride values.

Caracteristici fenotipice pentru diagnosticul de FC

1. Boala cronica sinopulmonara
- colonizare persistenta/infectie cu patogeni tipici
- tuse cronica, productie de sputa
- anomalii persistente pe Rg toracica
- obstructie a CA (wheezing, air trapping), polipi nazali
- hipocratism digital
2. Anomalii gastro-intestinale, nutritionale
- intestinale: IM, DIOS, prolaps rectal
- pancreatice: IP, pancreatita recurenta
- hepatice: boala hepatica cr (ciroza biliara focala/multilobulara, def. vitamin
liposolubile)
3. Sindroame de pierdere de sare
4. Anomalii urogenitale masculine
Diagnosticul de fibroza chistica -Primul pas in initierea unui program terapeutic
Fundatia Americana de Fibroza Chistica:
- unul/mai multe caracteristici fenotipice
- sau istoric FC la un frate
- sau rezultat de screening neonatal pozitiv si concentratie crescuta de clor in
sudoare (>60mmol/l)
- sau identificare a 2 mutatii
- sau demonstrarea transportului ionic anormal prin epiteliul nazal

Dg. prenatal (sarcini cu risc) - analiza mutatiilor

- biopsie a vilozitatilor corionice (s. 10)
- cultura celule din LA (s. 15-18)

Dg. Preimplant - Obstructia intestinala fetala (ecografie, biopsie vilozitati corionice)

Dg. postnatal
- testul sudorii (Gibson-Cooke, Wescor)
- genotipare
- masurarea diferentei de potential nazal (rectal)
- screening neonatal - IRT

Tipuri de prezentare in functie de varsta

Prenatal - Sarcini cu risc

screening de rutina
biopsie vilozitati corionice s10
culturi de celule LA s15-18
diagnostic preimplant
Obstructie fetala - US - tr II(intestin hiperecogen)
Peritonita meconiala - (calcificari)

Neonatal
Ileus meconial
Sdr de dop meconial
Atrezie jejunala
Boala hepatica
Manifestari pulmonare
Falimentul cresterii
Tipuri de prezentare - perioada neonatala
1.Boala hepatica
icter prelungit BD (obstr CBEH)
biopsie:
fibroza focala
inflamatie portala
proliferare ductulara
hepatomegalie
BD> 6 luni
50% asociat cu IM/elim intarziata
HM + steatoza (MPC)
2.Manifestari pulmonare
tuse, whhezing, retractii, tahipnee
Rg hiperinflatie
atelectazii segmentare (LDS)
IR +bronsiolita
3.Falimentul cresterii
de la 2 sapt
uzual la 4-6 saptamani
iIndiferent de aport caloric N/>
plang, agitati dupa mese!

Perioada de sugar/ copil mic

1.TRS
polipi nazali – ind TS!
sinuzita recurenta refractara la trat
modificari Rg si CT
TRI
50% pacienti – simptome
infectii cr/recurente
TUSE CRONICA!
persistenta, aspra, chinte, acc nocturn
modificari specifice Rg
(infiltrate, dilatatii br, hiperinflatie, ingrosarea peretilor bronsici)

2.Tractul GI
Steatoree
protuberanta abdomenului
crampe abdominale
flatulenta
scaune fetide, grasoase
crestere nesatisfacatoare G
Declin progresiv al functiei pancreatice
Invaginatie
Pancreatita
RGE
Duodenita difuza
Impactare mucoida apendiculara

FC = boala complexa, multisistemica - Evaluare

Istoric
Examinare
Screening neonatal
Functie respiratorie, sat O2
Evaluare fizioterapica
Contact cu asistentul social
Rg. toracica, abdominala,
Ecografie, CT torace
Examen de sputa
Testul sudorii
Analiza ADN
Hb, nr. L, nr. T, frotiu
Vascozitatea sangelui
PCR, Electroforeza , Uree, creatinina, Teste hepatice
HbA1, Vitamine ADE, Timp de protrombina, RAST
Ig. E totale, imunograma
Ac a.P. aeruginosa
Examen de urina
Grasimi, elastaza fecala
“ECFS consensus on standards of care for people with CF - 2004” (J of Cystic, Fibrosis 2005,
vol 4 iss 1:7-27)
-imbunatatirea prognosticului datorata (ultimii 20 ani) regimurilor terapeutice eficiente
- atitudine noua pozitiva fata de terapie si sperante mai mari
- conceptul de “punct fara intoarcere -debutul infectiei cronice pulmonare
-monitorzarea atenta si tratamentul efficient sa urmeze diagnosticului precoce!
-revolutia informatiei si comunicarea (~10 000 citatii 1996-2004)
- rezultate diferite pt pac tratati in centre diferite
standarde EU! - eforturi majore pt ”cea mai buna ingrijire”

Boala pulmonara in FC - din copilarie pana la varsta adultului

Boala pulmonara
-tractul respirator confera morbiditatea maxima - deces (90%)
-microorganisme: Staf au, P aer, Burkholderia cepacia, E coli, H infl, Alcaligenes
-afinitate speciala a P aer pt epiteliul CA (biofilm, mucus anormal, lichid de interfata cu activitate
antibacteriana scazuta)
-plaman normal la nastere!
BAL< 4 luni inflamatie prezenta + factori de mediu, genetic
“Mentinerea liniei orizontale”
- interventie precoce si prevenirea bolii pulmonare –

Fiziopatologia bolii pulmonare in FC

Afectarea bronhopulmonara in FC
Boala pulmonara - prezentare clinica
-30-50% pacienti debuteaza cu inf resp in 1 an
-tuse, tahipnee, wheezing
-auscultatia pulmonara normala (“silent lung”)
formele severe - obstructie, zgomote inegale
asociatie sinuzita-polipi nazali (5-14 ani)
opacifierea sinusurilor paranazale (>90%)
etmoidita
otita medie
bronsiolita recurenta
astm (raspuns paradoxal la bronhodil)

Exacerbarea pulmonara - definitie (4sau mai multe caracteristici)

-schimbarea caracterului sputei
-hemoptizie noua sau crescuta cantitativ
-tuse mai frecventa
-dispnee accentuata
-inrautatirea starii generale, oboseala letargie
-temperatura>38 gr
-durere sinusala sau sensibilitate
-schimbarea caracterului secretiei sinusale
-anomalii la examinarea fizica pulmonara
-scaderea FP cu 10% sau mai mult fata de valoarea anterioara
-modificari Rx indicatoare de infectie pulmonara

Complicatiile bolii pulmonare

Atelectazie 5-50%
Pneumotorax 5-8%  16-19%
ABPA 1-23%
non-TB mycobact. rar
Cor pulmonale toti ?
Hemoragie pulmonara adulti 10%

Microbiologia bolii pulmonare

Inf cu P aeruginosa - cea mai semnificativa
- apare mult mai precoce decat s-a crezut (v medie 15 luni)
- Ac identificati cu 12 luni inainte de cultura orofaringiana!
Izolarea P aer asociata cu deteriorarea clinica
Sursa nu e clara
- mediu
- genotipuri asemanatoare la frati
- genotipuri diferite la nivele diferite ale ap respirator
Patogeni tardivi
-Burkholderia cepacia
Infectia cronica – evolutie cr, declin FP, mortalitate>
“sdr cepacia” - febra
- bacteriemie
- progresie rapida catre pneumonie necrozanta, deces
-Sternotrophomonas maltophilia
-Alcalinigenes xylosoxidans
-Aspergillus
-Micobacterii nonTB
-Fungi - Legatura cu folosirea Ab cu spectru larg. Cea mai frecventa Candida(50-75%) – inofensiva
Aspergillus fumigatus - izolare 25-65% -nu se trateaza in absenta ABPAinfectie invaziva rar
la cei netransplantati,imunocompetenti ABPA – poate fi o problema!
Mycobacterii nonTB Frecventa in crestere (13% in 21 centre SUA)
Mycobacterium avium cx (72%); abscesus (16%)
Varsta avansata
Infectie cu Staph au
Colonizare mai putin frecventa cu P aer
Prezenta lor nu influenteaza rata de declin a FEV1

Infectie:
culturi pozitive multiple
exacerbare in conditii de culturi pozitive
neresponsiva la tratament conventional
biopsie mucoasa = b granulomatoasa

Bronsiectazii

Monitorizarea bolii pulmonare. Tratamentul bolii pulmonare

Monitorizarea bolii pulmonare

De ce?
Identificarea factorilor de risc
Interventie precoce
Gasirea masurilor mai bune de control ale evolutiei
Cum?
Clinic/sisteme de scoruri/registre
Functie pulmonara/markeri de inflamatie
Imagistica – radiologie/HRCT
Microbiologie
Evaluarea clinica a bolii pulmonare
Nu exista terapie aprobata de corectie/influentare a defectului genetic
Terapia directionata spre:incetinirea progresiei disfunctiei organice secundare si sechelelor(IP si
infectia endobronsica)
CENTRE FC multidisciplinare
Monitorizare
Educatie pacient/familie
Interventie precoce
Evaluare de rutina a statusului pulmonar
Monitorizarea progresiei bolii
Monitorizrea raspunsului therapeutic
Imagistica – radiografia pulmonara
Folositoare, putin senzitiva in b usoara si exacerbare
Sugar - diafragme aplatizate
- hiperinflatie
- hipertransparenta retrosternala
- opacitati nodulare(mucus, brect)
Scoruri

Imagistica HRCT
Mai senzitiv
Air trapping
Ingrosarea peretilor bronsici
Bronsiectazii, anomalii parenchim
Precede modificarile FP!
Functia pulmonara
Dupa 5 ani –spirometrie/pletismografie
Progresia obstructiei CA, air trapping
Documenteaza schimbarile acute (exacerbari, raspuns terapeutic)
FVC, FEV1, FEF 25-75% pot fi normale in boala usoara
FEV1 marker de progresie a bolii, predictor de speranta de viata
La sugar in centre specializate
Microbiologia pentru diagnostic
- Sputa expectorata
- Culturi orofaringiene
- LBA
- Inductie de sputa – solutie HT salina
Infectia = polimicrobiana
Medii selective pt Staph au, H infl, cepacia
Testarea susceptibilitatii dificila
MRSA la fel% ca in populatia generala
Serologia pt P aer mai senzitiva!
Micobacterii nonTB – medii de cultura
Strategii terapeutice
Tratamentul cauzei nu exista inca
In prezent tratamentul este in mare parte simptomatic
Prevenirea/tratamentul infectiei bacteriene
Reducerea inflamatiei in CAI
Imbunatatirea clearance-ului mucociliar
Inflamatia sau infectia?
Cerc vicios:
Infectie -inflamatie-modificari structurale si functionale

Interventie precoce
Cand trebuie sa intervenim?
Inaintea aparitiei simptomelor?
Inaintea evidentei afectarii pulmonare?
In prezenta colonizarii bacteriene?
In prezenta inflamatiei cailor aeriene?
Cum putem preveni infectia?
Masuri igienice, segregarea pacientilor - (Høiby and Koch 1990)
Vaccinare (P. aeruginosa, influenza) - (Lang et al. 2004, Hiatt et al. 1999)
Terapie profilactica antistafilococica
 rata scazuta S. aureus
 rata crescuta P. Aeruginosa - (Weaver et al. 1994, Ratjen et al. 2001, Stutman et al. 2002)

Cum sunt transmisi patogenii catre pacientii FC?

Contact direct cu secretii infectate
Contact indirect cu secretii infectate
Picaturi de secretii infectate
Transmitere aeriana necunoscuta
How Are Pathogens Transmitted to CF Patients?
Pathogens are transmitted to CF patients in the same way as among the general population, principally
by contact and droplet routes. However, patients with CF have a unique epidemiology of infection and
so are more likely to become infected via patient-to-patient transmission than from the general
population.
The 3 main sources of infection for patients with CF are:1,2
Direct contact with infected secretions (body-to-body)
Indirect contact with infected secretions (surface-to-body; eg: contact with a contaminated object)
Droplets of infected secretions (defined as “inspiration of large infectious particles that are spread by
coughing, sneezing, or singing and that can be inspired within 3 ft of an infected patient”)
Airborne transmission of CF pathogens (defined as “inspiration of smaller infectious particles that
remain suspended in shared air supplies that are transported over long distances via air currents, and
that can be viable for minutes to hours”) does not appear to be a source of infection for patients with
CF. 1
Moduri de transmitere
- Direct: transfer de suprafata corp-corp
 Sarut
 Atingere
 Ingrijirea pacientilor
 Strangere de mana
- Indirect: contact cu un obiect contaminat
 Jucarii
 Periute de dinti comune
 Tacamuri
 Manusi
 Echipament respirator
Modes of Transmission
Direct-contact transmission of CF pathogens involves direct body-to-body surface transfer of an
infectious agent between an infected host (CF patient) and an uninfected CF patient. This usually
involves one or more of the following:
Shaking hands
Kissing
Touching or hugging
Patient care
Indirect-contact transmission of CF pathogens involves contact with an object that has been
contaminated with infected secretions. Common sources of indirect contact transmission include:
Toys
Eating utensils
Shared toothbrushes
Respiratory equipment
Transmission via indirect contact can also involve contact with noninfected individuals who have been
contaminated with infected secretions (eg, gloves that have not been changed between patients).
Saiman L. Infection control in cystic fibrosis. In: Cystic Fibrosis Foundation. How to Avoid Germs in
Cystic Fibrosis [webcast]. January 12, 2004.

Transmitere prin picaturi

Persoana-persona imprastiere prin picaturi de secretii infectate
Picaturile “circula” pe distante mici(<90 cm)
Patogenii din picaturi pot supravietui ore pe suprafete
Droplet Transmission
Droplet transmission may occurs through person-to-person contact. Droplets of infected secretions
may be spread primarily during coughing, talking, sneezing, or singing, or during the performance of
certain procedures such as airway clearance, suctioning, or bronchoscopy. Infectious droplets are
propelled a short distance, usually less than 3 feet, and are deposited on the eyes, nose, or mouth of a
susceptible individual or in the environment. Pathogens in droplets can live for hours on surfaces.
Saiman L. Infection control in cystic fibrosis. In: Cystic Fibrosis Foundation. How to Avoid Germs in
Cystic Fibrosis [webcast]. January 12, 2004.

Interventii care reduc transmiterea infectiei

Educatie despre spalarea mainilor, factori de risc
Segregarea pacientilor
Camere individuale, dusuri separate
Clinici ambulatorii
Evenimente sociale (tabere, seminarii)
Dezinfectia mediului
Practici de laborator
Interventions That Reduce Transmission of Infection
Infection control interventions, many of which are used simultaneously, are associated with decreased
transmission of infectious agents among CF patients.1
Four key interventions for reducing transmission are:
Education of healthcare workers, patients, and their families about handwashing and risk factors for
transmission
Segregation of CF patients, the most widely used and most successful strategy1
In healthcare settings, CF patients should be segregated by use of single-patient rooms and should
minimize socialization.
Gloves and masks should be used, and outpatient clinics should be scheduled on separate days of the
week for infected and noninfected patients.
Outside the hospital, separate social programs (eg, camps) should be established for infected and
noninfected patients.
Environmental decontamination, including disinfection of respiratory equipment, drains, showers, and
exercise equipment
Improvement in laboratory practices (improved microbiological detection, such as the use of selective
media and prolonged incubation techniques)
Prevalenta specifica in functie de varsta a patogenilor FC

Age-Specific Prevalence of CF Pathogens

Infection with CF pathogens follows an age-related predictable course, beginning with nontypeable H
influenzae and S aureus and progressing to P aeruginosa (Pa).1 Approximately 30% of infants (aged
0-1 years) are infected with Pa; this incidence increases with age, so that by 18 years of age, 80% are
infected with this pathogen.
In 2002, the distribution of respiratory pathogens among all patients with CF enrolled in the CFF
registry, regardless of age, was:2
P aeruginosa, 57.8%
S aureus, 49.7%
H influenzae, 16.3%
S maltophilia, 9.4%
B cepacia, 3.1%
A xylosoxidans, 5.2%.
Of the CF pathogens listed, Pa is the most clinically significant for patients with CF.3

Tratament antiinflamator
Corticosteroizi orali: eficienti dar efecte secundare serioase - (Eigen et al. 1995, Lai et al. 2000)
Corticosteroizi inhalatori: eficienti (HRB)? - (Dezateux et al. 2000)
Ibuprofen: eficient doar la un subgrup de pacienti (< 13 ani) - (Konstan et al. 1995)
Imbunatatirea clearance-ului mucociliar
Fizioterapie: fara evidence based, eficienta! - (van der Schans 2000)
rhDNase: imbunatatirea FP, efect la distanta necunoscut - (Jones and Wallis 2003)
Mobilizarea secretiilor = fizioterapia
tehnici de respiratie = cicluri active
drenajul autogenic (la volume pulmonare diferite )
presiunea pozitiva expiratorie (PEP)
presiunea ascilatorie pozitiva expiratorie (flutter)
percutia mecanica si vibratia = jachete

Pulmozyme – indicatii (Bush et al. 2003)

toti pac. cu boala severa
toti pac. cu deteriorare rapida a FEV1 pe trat optim
toti pac. cu dificultati de expectoratie
pac. cu boala usoara - dificultati de expectoratie in exacerbare+ infectie cronica cu P aer.

Tratamentul exacerbarii pulmonare

spitalizare
2 antibiotice sistemice iv, clase diferite
durata trat minim 2 saptamani
combinatii Ceftaz+Aminogl
evaluare obiectiva: FP, sat O2, scoruri
antib aerosol eficient in vivo, netoxic

Argumente pentru tratamentul precoce al infectiei cu P aer

inflamatia prezenta precoce in CA (3 luni)
screening/dg precoce
eradicarea cu succes a in P aer, Staf
amanarea infectiei cr cu P aer
scaderea incarcaturii bacteriene
supresia factorilor de virulenta
scaderea markerilor inflamatori
imbunatatirea functiei pulmonare

Antibioterapia iv
precoce, corespunzatoare
previne pierderea FP
imbunatateste prognosticul
Indicatii:
eradicarea inf precoce cu P aer care nu rasp la terapie po+colistin inh
exacerbarea respiratorie
rutina la 3 luni - 2 saptamani

In concluzie…recomandari de tratament in boala pulmonara

antibioterapie electiva la 3 luni antipseudomonas
scaderea incarcaturii bacteriene
FP revine la normal dupa 1-3 luni (2 sapt iv)
rata supravietuirii 54% -> 82% pe 5 ani (Copenhaga)
antibioterapie tintita (Abgr) la orice exacerbare
spitalizare
2 Ab sistemice iv, clase diferite
durata minim 2 saptamani
Ceftaz+Aminogl
evaluare obiectiva: FP, sat O2, scoruri
Ab eficient aerosol, netoxic
terapia mucolitica
fizioterapia
Tratamentul bolii avansate pulmonare in FC - Transplantul pulmonar
Alte manifestari respiratorii in FC - (astmul, ABPA)
Scopul tratamentului in boala avansata pulmonara
Identificarea pacientilor cu boala avansata si rapid progresiva
Optimizarea terapiilor standardizate si tratamentul complicatiilor respiratorii
Alte optiuni terapeutice cand nu se poate transplanta
Strategii inovatoare cand terapia conventionala nu este eficienta
Boala pulmonara terminala
FEV1 < 30%
PaO2 < 55 mmHg
PaCO2 > 50 mm Hg
NEJM 1992; 326: 1187-91

Tratamentul electiv iv la 3 luni - scop: minimalizarea oricarei deteriorari in statusul clinic datorat P
aer
Argumente:
scaderea incarcaturii bacteriene
FP revine la normal dupa 1-3 luni (2 sapt iv)
rata suprav 54% -> 82% pe 5 ani (Copenhaga)
Indicatii:
cuantificarea individuala pt avantaje/dezavantaje
deteriorare cuantificata intre curele regulate
pacientii cronic infectati, stabili -> trat de electie

Tratamentul complicatiilor cardiopulmonare

Hipoxemia
tarziu, valori<89%
oxigen in timpul efortului, somn
Cordul pulmonary -vasodilatatoarele, digoxin efecte slabe; oxigenoter precoce!
Hemoptizia - masiva (>250ml/24h) rara (1%)
-embolizare de artera pulmonara
-rezectie lobara
Pneumotoraxul- complicatie a bronsiectaziei
-recurenta 50% dupa I episod
-prognostic nefavorabil - recomandare de transplant
Osteopatia pulmonara hipertrofica-AINS, corticoterapie

Transplantul pulmonar
1985 = optiune pentru pacientii cu boala terminala (Jacoub 1990, Ramirez 1992)
Transplantul pulmonar
1985 = optiune pentru pacientii cu boala terminala (Jacoub 1990, Ramirez 1992)
Transplant bilateral secvential
Conditii:
FEV1<30% vpn
rata crescuta de declin a functiei pulmonare
influentarea calitatii vietii
terapie frecventa i.v.
status nutritional precar
Decizia cu ~ 2 ani inainte
Complicatii
bronsita obliteranta, B. cepacia, P aer
Supravietuire: 81% - 1 an
59% - 5 ani
38% - 10 ani
FEV1 25% pre -> 75% post
Asp psihosociale:
decizia
evaluarea
asteptarea
momentul anuntului
interventia si post-transplant

Terapii de viitor pt boala pulmonara in FC

Terapii farmacologice - studii faza I,II (nu III)
1.Corectarea CFTR disfunctional (f de genotip)
Cl. I
gentamicina(topic pe mucoasa nazala/iv 1saptamana
Cl. II (del F508)
Glicerol
Antraciclina
Butirati
Trimetilamina
Ciclopentil
Cl. II, IV – terapii activatoare
Inhibitori de fosfodiesteraza (cresc AMPc)
2.Activarea canalelor de clor alternative
Amilorid - impact asupra mec ce cresc abs Na, scad secr Cl
- topic pe celule apicale/aerosol (scad rata declin FEV1)
Activatori alternativi de canale de clor – nucleotide trifosfat
3.Noi abordari in tratamentul infectiei cu P aer
Peptide cationice endogene (produse de neutrofile, cel epiteliale; au activitate antibacteriana; rol in
infectia precoce)
MSI-78
IB-367
Preturi prohibitive
Formule optime pentru inhalare!
Inhalarea osmolyte (creste activitatea peptidelor endogene!) = xylitol

Manifestari gastro-intestinale in FC

Pancreas: insuficienta pancreatica, pancreatita acuta,pseudochiste

Ficat: steatoza, ciroza, hipertensiune portala, colangita sclerozanta,litiaza, stenoza CB
Esofag: RGE, esofagiota,
Stomac/duoden: gastrita, ulcer gastric/duodenal
Intestin subtire: giardiaza, bola crohn, ileus meconial,sdr de obstructie intestinala distala, invaginatie
ileocolica,volvulus
Apendicita: acuta, abces apendicular, perforatie, mucocel
Colon: impactare fecaloida, constipatie, megacolon,colonopatie fibrozanta, prolaps rectal, carcinom

Patients with CF suffer from a wide variety of gastrointestinal and nutritional manifestations. Most
can be linked pathogenetically to the underlying CFTR defect. Others arise as secondary
manifestations or iatrogenic complications. Fibrosing colonopathy, a complication associated with
excessive dosing of pancreatic enzymes, is a recent example of a secondary iatrogenic complication.
Growth failure and malnutrition is another historic example of an iatrogenic complication of CF. With
improvements in median survival, we are identifying additional complications attributable to
micronutrient deficiencies. Rapidly progressive osteoporosis is such an example.
Definitia statusului pancreatic
Insuficienta pancreatica (IP) = Boala pancreatica exocrina severa cu maldigestie documentata.
Necesita enzime pancreatice la mese.
Suficienta pancreatica (SP) = Boala pancreatica exocrina usoara sau moderata, nu suficient de
severa pt a produce maldigestie. Nu necesita terapie enzimatica le mese.
While the majority of patients with CF develop pancreatic insufficiency at or shortly after birth, a
significant subset of patients retain sufficient exocrine pancreatic function to permit normal nutrient
digestion without requiring exogenous pancreatic enzymes with meals.

Insuficienta pancreatica in Fibroza Chistica

Semnele si simptomele de maldigestie sunt deseori prezente de la nastere
Insuficienta pancreatica este stabilita in 50% la nastere si in 90 % pan la avrsta de 1 an
Majoritatea sugarilor sunt deja malnutriti la momentul diagnosticului clinic
Chiar si sugarii asimptomatici disgnosticati prin screening neonatal pot avea deficiente nutritionale
Manifestari clinice ale insuficientei pancreatice in FC
Scaune frecvente grasoase, cantitate mare
Abdomen protuberant, dureri abdominale
Hipoalbuminemie, edeme, anemia la sugari
Apetit crescut, falimentul cresterii
Malnutritie
Deficienta vitaminelor liposolubile
!! Terapia enzimatica se va controla regulat
Recomandari ale terapiei enzimatice in FC

Instructiuni ale terapiei enzimatice pentru pacienti

Se prefera inghitirea intregii capsule
Daca nu, se deschide capsula si se inghit sferele fara a fi mestecate
Sugarii pot primi sfere protejate enteric cu suc sau alimente non-alcaline
Enzimele se vor lua inainte (½) si in timpul meselor (½)
Pacientii nu isi vor creste dozele singuri

Scopul interventiilor nutritionale in FC

Nu exista nici un motiv de a accepta falimentul nutritional la un pacient cu FC
Scopul fiecarui centru FC este sa sprijine nutritia normala si cresterea tuturor pacientilor de
toate varstele.”
During the 1980s CF caregivers and National Cystic Fibrosis Foundations began to adopt the same
approach to nutrition therapy as that advocated by the Toronto program. The attached quote, published
in the report of the first Consensus Conference on Nutrition in Cystic Fibrosis by the US CF
Foundation (1990), offered an new expectation concerning nutritional goals for patients with CF.

Balanta energetica defectuoasa in FC

Restrictie iatrogena de grasimi
Anorexie
Tulburari de alimentatie
Depresie
Esofagita (RGE) , DIOS
Pierderi gastrointestinale
- insuficienta pancreatica
- malabsorbtie acizi biliari
- boala hepatica
- regurgitatii (RGE)
Pierderi urinare crescute:
- diabetes mellitus
Cresterea consumului energetic:
- boala pulmonara
- defectul primar?

Interventii nutritionale posibile

Corectarea optima a insuficientei pancreatice
Evaluare dietar regulata si consiliere pt maximizarea aportului energetic
Suplimentare calorica orala
- suplimentare de alimente cu cal>/mese aditionale
- suplimente energetice comerciale
Nutritie enterala (tub nazogastric, gastrostomie)
Nutritie parenterala
Evaluarea comportamentului alimentar si interventie

Afectarea gastro-intestinala in fibroza chistica - Boala hepatica

Complicatii hepatobiliare in Fibroza Chistica
-Ficat
Colestaza neonatala rara
Steatoza hepatica 20-60%
Ciroza biliara focala 25-30%
Ciroza biliara multilobulara 5-10%
-Vezica biliara
Colelitiaza, colecistita rara
Microvezica 30%
-Arborele biliar
Colangita sclerozanta rara
Stenoza XCBP <2%
Boala hepatica asocita Fibrozei Chistice
Boala hepatica este o complicatie precoce, de obicei dupa 10 ani
Afecteaza ~ 25% din pacienti
Urmarirea activa pentru detectarea ei trebuie sa se faca in I-a decada de viata
Pana nu se manifesta ca boala avansata nu are implicatii asupra evolutiei clinice a FC ( complicatii
respiratorii , probleme nutritionale)
Abordare diagnostica a bolii hepatice in Fibroza Chistica
Examinarea hepatica - Precede orice investigatie (masurarea dimensiunilor)
Biochimie hepatica - Specificitate/sensibilitate scazuta ( mai ales la copilul mic)
- Nu se fac teste functionale
Acizi biliari serici - Reflecta tulburari in circulatia entero-hepatica
-Nu se coreleaza cu histologia
Biopsia hepatica - Reflecta modificarile precoce
-Invaziva, rezultate eronate uneori
Abordare diagnostica a bolii hepatice in Fibroza Chistica
-Ultrasonografia- Detecteaza steatoza, ciroza, HT portala, bola VB
Variabilitate inter-observatori
Stadiile precoce pot fi trecute cu vederea
-Scintigrafia hepato-biliara -Informatii morfologice si functionale
Risc de radiatii
-Colangiografia RM -Fara risc de radiatii
Vizualizarea arborelui hepatic
Necesita sedare la copil

Tratamentul bolii hepatobiliare - scop: imbunatatirea excretiei biliare si compozitiei acizilor biliari
2.2% din decese, morbiditate !
-UDCA
cresterea fluxului biliar
imbunatatirea indicilor biochimici ai functiei hepatice
in anomalii precoce eco/transam >: 20-30 mg/kg/zi 2-3 prize
-Taurina
deficitara datorita malabs acizi biliari)
adm +UDCA imbunatateste nivelurile de prealb
30 mg/kg/zi 2-3 prize
- HDS (varice esofagiene)
scleroterapie
anastomoze porto-cave

Ciroza hepatica - transplant hepatic - supravietuire 75% - terapie genetica?

Alte afectari organice in Fibroza Chistica (boala osoasa, diabetul)

Alte manifestari in Fibroza Chistica - (astmul, ABPA)
Boala osoasa in FC

Riscuri potentiale pentru boala osoasa in FC

Malabsorbtia vitaminelor liposolubile
Greutate corporala redusa
Stimul inflamator cronic
Pubertate intarziata si hipogonadism
Activitate fizica redusa
Folosirea corticoterapiei
Osteoporoza
aportul insuficient Ca/minerale -> densitate osoasa scazuta
corelata cu severitatea bolii
fracturi -> complicatii
Preventie
nutritie
aport ca, vitamina D
expunere la soare
vitamina K! + exercitiul
Abordari pentru prevenirea si tratamentul densitatii osoase reduse
Screening anual
Vitamina D & PTH
Aportul de calciu
Testosteron la subiecti sex masculin
Istoric menstrual
DXA
Vitaminele, sarurile minerale- hidrosolubile - nu se suplimenteaza
- liposolubile
vit A
< 1 an 4000 U/zi
>1 an 4-10 000 U/zi
vitamina D
sugar 400 U/zi
copil 400-800 U/zi
adult 800-2000 U/zi
vitamina K
T protrombina >
boala hepatica 10 mg x2/sapt
toti 10 mg/zi!
Zinc scazut in MPE
Cu crescut
Seleniu scazut
Magneziu (trat aminogl)
Fier scazut 33-66% pacienti

Diabetul asociat Fibrozei Chistice

Intoleranta la glucoza/diabetul- cea mai frecventa comorbiditate in FC
Incidenta 4-20%
Prevalenta corelata cu varsta
F de risc pt debut precoce –sexul feminin
Morbiditate crescuta cand apare <FP, <G
FP scade cu ~ 2 ani inainte de debut
Definitia DZ (OMS 1998)
Tip I = idiopatic sau imun mediat
Tip II = rezistenta insulinica la secretie scazuta
Tip III = alte tipuri (FC, endocrinopatii, infectii)
Tip IV = gestational
Intoleranta la glucoza = stadiu preliminar al DZ (OMS 1998)
Teste/screening TTOG, nivel plasmatic al glicemiei
Repaus alimentar 2h
TNG < 110 < 140
> Glicemiei 110-126 <140
IG < 126 140-199
DZ ? 126 ? 200
Mecanismele de producere ale DZ in FC
Distructia de celule beta (fibroza)
Intoleranta poate fi prezenta si la rata de distructie<50%!
DZ numai in IP
Scaderea utilizarii glucozei in celulele periferice
Cresterea productiei hepatice de glucoza
Cresterea clearance-ului insulinei
Simptome DZ in FC - Insidios, nespecific
Scade FP
Scade G neexplicabil
Polidipsie, poliurie nespecifice!
Pubertate intarziata, oboseala
Cetoacidoza~niciodata!
Secretie restanta de insulina
Hiperglicemie tranzitorie
Scaderea secretiei de glucagon
DZFC este asociat cu supravietuire scazuta

CFRD Is Associated with Decreased Survival

Records from living or deceased patients with CF treated at the University of Minnesota CF Center
since 1960 were analyzed in a retrospective survival analysis.
CF-related diabetes (CFRD) was diagnosed based on clinical symptoms and ≥2 random blood glucose
values >200 mg/dL and was confirmed with ≥1 fasting blood glucose value >140 mg/dL (n = 34).
Patients were considered to be normoglycemic if fasting glucose was <140 mg/dL with ≥2 random
blood glucose values ≤200 mg/dL (n = 414).
While nearly 60% of CF patients without overt clinical diabetes were still alive at 30 years of age, less
than 25% of those with CFRD reached this age.
Interestingly, no differences in survival between normoglycemic and CFRD patients were evident
until approximately 20 years of age. After this time, a rapid decline in survival was observed in the
CFRD group relative to the normoglycemic group (P <0.01).
Clinical decline, as assessed by the National Institutes of Health clinical score, began 2 years before
CFRD was diagnosed (P <.05 and P <.01 for CFRD patients vs age- and gender-matched
normoglycemic patients at 2 years prior to diagnosis and at diagnosis, respectively).

Terapia DZ in FC – NUTRITIE !!!

Diferit de DZ I, II
Recomandari: intai FC apoi DZ
Nutritie cu calorii>, tratament DZ
Dieta:
Lipide:35-40%
CH 45%
Proteine 20%
Aport caloric> + corectie cu insulina
Educatie, sustinere psihologica
Atentie la hipoglicemie
Aspergiloza bronhopulmonara alergica- ABPA in FC – ABPA; ABPA in FC
Aspergillus : 180 specii (fumigatus, flavus, niger - la om)
colonizeaza peretii cailor aeriene unde exista tulburari hidrice
inhalarea spori 2-3 micr insuficienta pt boala! (FR gazda)
Patogenia ABPA = raspuns de hipersensibilitate la Asp.
colonizarea CA exacerbeaza injuria astmatica subiacenta:
- bronsiectazii, cicatrici parenchimatoase
- impactare mucoida a bronsiilor
- granulomatoza bronchocentrica
- pneumonie eozinofilica
- bronsiolita cr/exudativa
in astmul persistent 1-2%
in FC 10-11% (colonizare cu Asp. 67%!)
FR asociati: HLA-DR2, HLA-DR5, DRB 1501, HLA-DQ2
Patogenia ABPA
raspunsul imun al gazdei + infectia fungica => afectarea CA + fibroza
proteaze fungice afecteaza cel epiteliale
Ac transportati prin peretii CA +Asp. =>citokine proinflamatorii
raspuns alergic Th2 cu (Il 4, Il 13):
- cresterea Ac specifici fata de Asp.
- IgE totale crescute
- infiltrate eozinofilice
celulele epiteliale elibereaza factori de crestere => bronsiectazii
rol Il 8 (inflamatie mediata neutrofilic); scaderea Il 10
Infectia cu Aspergillus
Sdr. Clinice Caracteristicile pacientilor
ABPA astm, FC, sdr hiper IgE, b gran cr
Aspergilom cavitati preexistente, bronsiectazii
Pneumonia de hipersens. sensib la Ag de Asp
Aspergiloza cr necrozanta b cr. Pulm/imunodef usoare
(semiinvaziva)
Aspergiloza traheobronsica imunocompromisi fatala
Pneumonia invaziva cu Asp imunocompromisi fatala

Suspiciunea de ABPA in FC (Orenstein)

-FC deteriorare precipitata/brusc, neasteptata
- bronhoconstrictie reversibila/astm
- infiltrate pulmonare
- IgE/IgG specifice pt Asp. poz
- eozinofilie periferica >1000/ml
- Asp in sputa
- raspuns la steroizi
Crt de dg ECFS (Eur Respir J 2000,16:464-471)
reactie cutanata (tip1 imediat) poz la Asp.
precipitine multiple la Asp poz
IgE serice totale >1000ng/ml
ABPA in Cystic fibrosis - A European epidemiologic study
-12 447 pacienti cu ABPA si FC (224 centre FC)
prevalenta 7.8%
mica <6 ani; ~ 10% >6ani
fara asociere cu genotipul
asociata cu: tratamente frecvente, indelungate pt FC
functie pulmonara scazuta
status nutritional precar
concentratii crescute de Ig G (infectie cr severa)
ABPA responsabila pt deteriorarea FC?
functie pulmonara afectata - predispune pt ABPA?
sau ambele?
mai expusi la hemoptizii, pntx
IgE > 417 UI/ml (>1000ng/ml)

Tratamentul ABPA in FC

Scheme diferite in centre

prednison 1-2 mg/kg/zi, scaderea dozelor in functie de IgE
corticoterapie de lunga durata (doza min) pt Rg clara
puls terapie Methylprednisolone?
CT inhalatorie?
Itrakonazol 200-400mg/zi (5 mg/kg/zi) pana la 4-6 luni
ef adverse?!
biodisponibilitate capsule redusa!
Vorikonazol in cazuri selectionate (costuri!!)
Amphotericin B aerosoli?

Terapia inhalatorie in Fibroza Chistica - Ce inhaleaza pacientul cu FC

Mucolitice (rhDNase, acetylcysteine)
Antibiotice (TOBI, Colistin, Ambisome si altele)
NaCl (0.9%, Hipertonic)
Bronchodilatatoare
Steroizi inhalatoriInhaled steroids
Unde vrem sa ajunga medicamentul? - La locul unde medicamentul isi are tinta:
Modificari morfologice
Mucus
Microorganisme
Inflamatie
Receptori

Sistemele folosite pt terapia inhalatorie

Pressurized metered dose inhalers (pMDI)
pMDI-Holding chambers
pMDI-breath actuated (autohaler)
Dry powder inhalers (DPI)
Compresoare - nebulizatoare
Antibioticele inhalatorii
Antibiotice “clasice”
Gentamicina
Tobramicina
Colistin
Carbenicilina
Cephaloridina
Ceftazidime
Antibiotice “noi”
Meropenem
Peptide endogene:
Cathelicidine
Alfa-helicoidale

Indicatiile terapiei inhalatorii cu antibiotice: infectia stabilizata cu P aer

Imbunatatirea FP
Scaderea densitatii bacteriene din sputa (PA)
Reducerea spitalizarilor
Reducerea folosirii altor antibiotice

Ingrijirea centralizata in FC
De ce ?
Managementul FC in centre specializate duce la evolutii clinice mai bune
Scopul ingrijirii optime
prevenirea infectiei cronice endobronsice cat mai mult posibil
minimalizarea declinului functiei pulmonare
mentinerea unui status nutritional bun
Evaluarea pacientului nou diagnosticat
Scopuri:
Oferirea evaluarii statusului emotional si fizic al pacientului
Formulrae palnurilor terapeutice corespunzatoare
Inceperea educatiei pacientului si familiei
Ajutorul pacientului si familiei pentru impactul emotional al diagnosticului
Aspecte psihosociale
Prognostic - ce se cunoaste
- individual
Nevoia de spitalizare/ respitalizare
Precipitarea/reactivarea temerilor legate de moarte
Ingrijorarea de a fi categorisit ca purtator al unui patogen periculos
Izolarea
Terapia psihosociala
programe interventionale precoce - faza de dg
programe educationale familiale
tipuri de probleme:
dificultati comportamentale
dificulati emotionale
stress procedural
aderenta scazuta la tratament
tratamentul durerii
suportul transplantului
segregarea
confidentialitatea

CONCLUZII
Boala multisistemica, complexa (P, GI)
Mutatii in gena care codifica CFTR
Cea mai comuna b genetica dobandita fatala (Caucazieni)
Morbiditate si moratalitate rezultate din infectia cr pulmonara -> Iresp.
Prevalenta variabila intre etnii si intre caucazieni (Fin 1/25000, Ir 1/1800)
Avansuri terapeutice importante (ultimele decade)
Supravietuirea s-a imbunatatit dramatic
Costuri mari!!!
Speranta de viata crescuta-> probleme complexe
sperantele terapeutice mai mari in fiecare an!
longevitate ~ 50 ani
terapia genetica 5-10 ani!

Prognosticul imbunatatit prin: tratamente conventionale, diagnostic precoce, urmarire asidua,

ingrijire centralizata, tratamentul complicatiilor
A “creste” cu FC
Lupta pt independenta si o viata implinita cand:
FP se inrautateste
Complicatiile sunt in crestere
Dobandirea rezilientei prin puteri proprii
Cresterea sperantei datorita terapiilor noi
A creste cu complicatiile FC
Mentinerea optimismului