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
