nural kiper m.d. professor of pediatrics hacettepe university,medical school

Nural Kiper M.D.

Professor of Pediatrics

Hacettepe University,Medical School

25-28 April-2007/ANTALYA

ADVANCES in CYSTIC FIBROSIS

ADVANCES in CYSTIC FIBROSIS

Ağır klinik Hafif klinikGenetic Modifiers

TGFB1,MBL,IL10,HLA2,

Clinical Findigs of Cystic Fibrosis ;

* Age of patient,

* Genetic mutation,

* Affected organs/systems,

* Complications.

Newborn period* History of CF in a sibling,* Meconium ileus,peritonitis* Neonatal cholestasis

Infancy and Childhood Period* Failure to thrive* Huge,steaky stool* Recurrent pulm.infection* Anemia* Oedema* Pseudobartter syndrome* Rectal prolapse* Salty taste

Cystic Fibrosis Presentation in Adulthood

•Chronic cough,sputum•Sinusitis,nasal polyps•Clubbing•Recurrent chest infection•Recurrent pancreatitis• Biliary sirrosis• DIOS• DM• Infertility

Diagnostic Tests

Elevated sweat chloride Microbiological tests CFTR gene mutations, Abnormal nasal epithelial potential difference

New Methods“Macroduct Coil”.................. Measurment

of conductivite.• Cut-off levelsOur Lab results:for confirmation-90

mmol/L : unlikely < 70 mmol/L

Dr. GüzinCinel(Tez Çalışması 2006)

Nasal Epithelial Potential Difference

Atypical forms,

Adulthood,

Infancy Period...(rectal ephithelial potential difference)

Nasal Epithelial Potential Difference

• H.U.M.S. Cystic Fibrosis .............>-36.9

Control.......... <-24.18

T J Pediatr 2004;Ergönül

• the precence of one or more charecteristic phenotypic features,• a history of CF in a sibling,• a positive newborn screening test

+• elevated sweat chloride,or• identification of two CFTR gene mutation,or• abnormal nasal ephithelial potential difference

“ACFF Consensus Panel, 1998”;

1.Chronic sinopulmonary disease;

a. Persistent colonization/infection with sp.mic.or

b. Chronic cough,sputum production,c. Persistent chest x-ray abnormalities,d. Obstr. Airway disease,wheezing,e. Nasal polyps,pansinusitis,f. Digital clubbing.

“CFF, NCFR, 2002”

2. Gastrointestinal and Nutritional Abnorm,

a. Intestinal; Meconium ileusu,DIOS,rectal prolapseb. Pancreatic; Panckreatic insufficiency,recurrent pancreatitis,DMc. Hepatic; biliary cirrhosisd. Nutritional; failure to thrive,hypoproteinemia,oedema,

3. Salt-loss syndromes:acute salt depletion,(metabolic alcolosis.)

4. Male urological abnormalities resulting in obstructive azoospermia(congenital bilateral absence of vas deferens

GENE THERAPY

Gene Therapy

Vectors

- Virus; .Adenovirus .AAV- Syntetic vektor; .Liposom .Plazmyde

CFTR correctors

GentamisinG418

4-PBA 4-PBA 4-PBAMilrinoneİsoflavonesİsoflavones

MilrinoneİsoflavonesMilrinone

Milrinoneİsoflavones

MUCOLYTIC THERAPY

“Fuchs HJ. N Engl J Med 1994; 331: 637-642.”

*

* n=968 (çocuk ve erişkin), FVC >%40

MUCOLYTIC THERAPY

“Fuchs HJ. N Engl J Med 1994; 331: 637-642.”

*

* n=968 (çocuk ve erişkin), FVC >%40

164 CF (>6 age)

Study group ControlHypertonik saline (%7) SF (%0.9’)2X4 cc inhale, 48 wks 2X4 cc inhale, 48 wks

. This study showed the benefits of long-term nebulized HTS in a multicenter,plecebo controlled trial.

Pilot Study of Safety and Tolerability of InhaledHypertonic Saline in Infants With Cystic FibrosisPadmaja Subbarao, MD, MSc, FRCP(C), Susan Balkovec, BSc, RRT,Melinda Solomon, MD, and Felix Ratjen, MD, PhD, FRCP(C)*

Pediatr Pulmonology 2007

. P.aeruginosa kolonizasyonu-TOBI (preservative free tobramisin)-Pari LC nebulizator

* “Hodson ME. Eur Respir J 2002; 20: 658-64.”

“Ramsey BW. N Eng J Med 1999; 340: 23-30.”

%12 ↑%12 ↑

. P.aeruginosa kolonizasyonu-TOBI (preservative free tobramisin)-Pari LC nebulizator

* “Hodson ME. Eur Respir J 2002; 20: 658-64.”

“Ramsey BW. N Eng J Med 1999; 340: 23-30.”

%12 ↑%12 ↑

Patients with chronic colonization with Pseudomonas)

• Rapid effect,safety• Side effect;20% cough !!!

INHALED CORTICOSTEROID

•Inhaled steroids have been examined in small clinical trials and have been showed no improve airway reactivity.

Prescott WA, et al. Pharmacotherapy 2005;25: 556-73.

. 41 patients (8-18 age), FEV1: 61% Azithromycin - placebo ;6 mths therapy

Elevated FEV1` 5.4% (p<0.05) Reduction in exacerbation,

•No side effect

•Minimal improvement in PFT

•No side effect

•Minimal improvement in PFT

LEUKOTRIENE RECEPTOR ANTAGONISTS

.

CF Patients with allergic rhinitis/ asthma<5 age 4 mg6-14 age 5 mg>15 age 10 mg Montelukast

Prescott WA, et al. Pharmacotherapy 2005;25: 556-73.

Antiinflamatuvar Tedavi

“Konstan MW. Adv Drug Del Rev 2002;54:1409-23.”

Anti IL-8 Ab

IL-10

IF-γ

LTB4 antagonisti

Omega 3 yağ asit

Pentoksifilin

• 12 wks, 3 /wks, inhaled;

No positive effect on;, • PFT,•Colonization;

Limited restoration of CF lung epithelium in vivo with adult bone marrow-derived cells. 

Loi R, Beckett T, Goncz KK, Suratt BT, Weiss DJ.  Am J Respir Crit Care Med. 2006 Jan 15;173(2):171-179.

Lung Transplantation

. Live donore/bilaterally lobe transplantation)

. Post transpalantation; 1 year survival 70-80% 5 year 30-45%

“Woo MS. Paed Respir Rev 2004; 5: 249-54.”

Patients with CF • H.Ü. Tıp Fakültesi......................439 *35y• Marmara Ü. Tıp Fakültesi.........110 *30y• İstanbul Ü.Tıp Fakültesi...........100• 9Eylül Ü.Tıp Fakültesi................ 46 *20y• Ege Ü.Tıp Fakültesi..................... 19• Uludağ Ü.Tıp Fakültesi.................17• Akdeniz Ü.Tıp Fakültesi...............14• Gazi Ü.Tıp Fakültesi......................11 *25y• Erciyes Ü.Tıp Fakültesi................10• Manisa ...............................................7• Ankara Ü.Tıp Fakültesi...................5• Osmangazi Ü.Tıp Fakültesi............4• Harran Ü.Tıp Fakültesi...................3

H.U M.S:334 Patients with CF

• 185 M/ 149 F;• 3 m-35 y• Adulthood 38 (26ch + 12 a)• Initial symptoms: 244-respiratory 184-malnutrition 161-diarrhea, 92 pseudoBartter synd• A history of CF in a sibling........60

CF CENTER

Pediatric Pulmonologist

Gastroenterologist

DieticiansPhysiotherapist

Adult Pulmonologist

Endocrinologist

Microbiologist

Patients and family

TransplantionCenter

ERT Specialist

Social worker