Cystische Fibrose. ASPEKTE DER LANGZEITPROGNOSE BEI CYSTISCHER FIBROSE Auf was kommt es wirklich an?

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1 Cystische Fibrose Prof. Dr. med. Richard Kraemer, Bern ASPEKTE DER LANGZEITPROGNOSE BEI CYSTISCHER FIBROSE Auf was kommt es wirklich an? Richard Kraemer, MD, Department of Paediatrics, University of Berne, Berne Switzerland 1

2 Morbidity and Mortality in CF-Patients at the late 70ties Kraemer R. et al. Schweiz. Med. Wschr. 109, 39-45; 1979 Richard Kraemer, MD, Department of Paediatrics, University of Berne, Berne Switzerland 2

3 Aspekte der Langzeitprognose bei CF Früherkennung Frühdiagnose Frühbehandlung Neonatales Screening Frühbehandlung Monitorisierung (Funktionsdiagnostik beim Säugling und Kleinkind) Richard Kraemer, MD, Department of Paediatrics, University of Berne, Berne Switzerland 3

4 Transition of lung function in CF Richard Kraemer, MD, Department of Paediatrics, University of Berne, Berne Switzerland 4

5 Aspekte der Langzeitprognose bei CF Früherkennung ---> Frühbehandlung Neonatales Screening Frühbehandlung Monitorisierung (Funktionsdiagnostik beim Säugling und Kleinkind) Funktionelle Veränderung der Lunge Welche wirken sich gravierend aus? Wie sensitiv sind welche Lungenfunktionsparameter? Gasaustausch der Lunge Prognostische Faktoren der Lungenfunktion Effizienz gewisser therapeutischer Massnahmen Atemphysiotherapie Intensiv-Antibiotika-Kuren in der Klinik rhdnase / Dornase / Pulmozyme - Langzeitwirkung Richard Kraemer, MD, Department of Paediatrics, University of Berne, Berne Switzerland 5

6 Langzeit follow-up Datenbank Am J Respir Crit Care Med: Vol 171. pp , 2005 CF-Zentrum und Abt. für Pädiatr. Pneumologie Universitäts-Kinderkliniken, Inselspital, Bern Kollektiv: 248 CF-Patienten (124 m; 124 f) mit mindestens 3 LF (3 Jahre) (25 J) Alter während LF: J Lungenfunktionstests: n= 3890 (median/pat: 22; 3-56) Plethysmographie: TLC, VC, FRC pleth, RV, sr eff, sr tot, swob, P 0.1, T i /T tot, V T /T i Spirometrie: FEV 1, MEF 75, MEF 50, MEF 25, MMEF MBNW-Auswaschtechnik: LCI, FRC MBNW, V TG Blutgasanalyse: PaO 2, PaCO 2, O 2 /CO 2 -ratio DNA-Diagnostik: alle erfasst durch Sequenzierung Richard Kraemer, MD, Department of Paediatrics, University of Berne, Berne Switzerland 6

7 Gas Exchange in CF Am J Respir Crit Care Med Vol 171. pp , 2005 Richard Kraemer, MD, Department of Paediatrics, University of Berne, Berne Switzerland 7

8 Progression over age in CF prognostic factors Static lung volumes Dynamic lung parameter Am J Respir Crit Care Med Vol 171. pp , 2005 Richard Kraemer, MD, Department of Paediatrics, University of Berne, Berne Switzerland 8

9 Annual mean progression of lung function in CF Progression most pronounced in ventilation inhomogeneities (LCI) Then after: small airway disease FEF 50 But also regarding bronchial obstruction and pulmonary hyperinflation summarized by sr eff FEV 1 presented only with marginal mean-changes

10 Work of breathing within functional groups Richard Kraemer, MD, Department of Paediatrics, University of Berne, Berne Switzerland 10

11 Frameshift Mutations (3905insT) Pulmonary Hyperinflation Ventilation Inhomogeneities Airway Patency F_frameshift F508del(2) non- F_frameshift F_frameshift F508del(2) non- F_frameshift FRC pleth (z-scores) F508del(2) F_frameshift non- F_frameshift LCI (z-scores) intercept-comparison: p < 0.05 slope-comparison: n.s. sr eff (z-scores) intercept-comparison: p < 0.02 slope-comparison: p < intercept-comparison: n.s. slope-comparison: p < Age (yrs) Age (yrs) Age (yrs) Figure 1 No significant group differences for FRC MBNW, V TG, FEV 1, MEF 50 Richard Kraemer, MD, Department of Paediatrics, University of Berne, Berne Switzerland 11

12 FRC MBNW (z-scores) Pneumologie, Osterseminar, Brixen 2013 Nonsense Mutations (R553X) Pulmonary Hyperinflation Ventilated Part of the Lung Trapped Gas FRC pleth (z-scores) F508del(2) non- F_nonsense F_nonsense intercept-comparison: n.s. slope-comparison: p = F508del(2) non- F_nonsense F_nonsense intercept-comparison: n.s. slope-comparison: p =0.001 V TG (z-scores) F508del(2) non- F_nonsense F_nonsense intercept-comparison: n.s. slope-comparison: p = Age (yrs) Age (yrs) Age (yrs) Figure 2 No significant group differences for LCI, sr eff, FEV 1, MEF 50 Richard Kraemer, MD, Department of Paediatrics, University of Berne, Berne Switzerland 12

13 FEV 1 (z-scores) MEF 50 (z-scores) Pneumologie, Osterseminar, Brixen 2013 Missense Mutations N1303K, R347H, R347P,. Airway Patency Flow Limitation Small airway dysfunction sr eff (z-scores) F508del(2) F_missense non- F_missense intercept-comparison: n.s. slope-comparison: p = F508del(2) F_missense non- F_missense intercept-comparison: n.s. slope-comparison: p = F508del(2) F_missense non- F_missense intercept-comparison: n.s. slope-comparison: p = Age (yrs) Age (yrs) Age (yrs) Figure 3 No significant group differences for FRC pleth, FRC MBNW, V TG, LCI Richard Kraemer, MD, Department of Paediatrics, University of Berne, Berne Switzerland 13

14 EFFIZIENZ GEWISSER THERAPEUTISCHER MASSNAHMEN rhdnase, Pulmozyme; Dornase Atem-Physiotherapie Antibiotika Intensivkuren Richard Kraemer, MD, Department of Paediatrics, University of Berne, Berne Switzerland 14

15 rhdnase (Dornase; Pulmozyme) in CF Richard Kraemer, MD, Department of Paediatrics, University of Berne, Berne Switzerland 15

16 Good and bad news regarding efficacy of rhdnase in CF Ventilation inhomogeneities Trapped Gas Richard Kraemer, MD, Department of Paediatrics, University of Berne, Berne Switzerland 16

17 Good and bad news regarding efficacy of rhdnase in CF Ventilation inhomogeneities Trapped Gas Richard Kraemer, MD, Department of Paediatrics, University of Berne, Berne Switzerland 17

18 Effizienz von rhdnase (Pulmozyme) Eigentlich nur in selektiven Fällen jünger als 12 Jahre moderater Lungenbefall Sinnvoller Approach: Lungenphysiologische Evaluation vor und nach 2 Monaten Behandlung Individuelle Einbindung ins tägliche Therapiekonzept: Inhalationstherapie Atemphysiotherapie Topische Antibiotika-Inhalationen Pulmozyme Richard Kraemer, MD, Department of Paediatrics, University of Berne, Berne Switzerland 18

19 Atem-Physiotherapie (Clapping, Huffing, Autogene Drainage, PEP-Mask, Flutter, ChestVest) Flutter Carina Lower lob Richard Kraemer, MD, Department of Paediatrics, University of Berne, Berne Switzerland 19

20 Flutter (VarioRaw, Switzerland) Richard Kraemer, MD, Department of Paediatrics, University of Berne, Berne Switzerland 20

21 Stationäre und ambulante Intensivkuren 14 Tage: i.v. Antibiotika (kontrolliert mit Blut-Spiegel-Messungen) Optimierte Inhalationstherapie Tägliche Profi-Physiotherapie Ernährungsberatung Sozio-emotionales Sport Richard Kraemer, MD, Department of Paediatrics, University of Berne, Berne Switzerland 21

22 Recovery of lung function after intensive treatment due to pulmonary exacerbation in children with cystic fibrosis (CF) R. Kraemer 1 S. Gallati 2, and M.H. Schöni 1 Division of Paediatric Respiratory Medicine 1, Division of Human Genetics 2, Department of Paediatrics, University of Berne, Inselspital, Berne Switzerland Poster & Abstract No.: 207 Richard Kraemer, MD, Professor of Paediatrics, emeritus

23 Patients and Methods Patients were 24 children with CF (15 males, 9 females) with documented data obtained prior (2.4±2.0 yrs.) and after (1.3±0.9 yrs.) intensive treatment of pulmonary exacerbations, featuring 38 inpatient series of two-week treatment. Serial measurements pertaining to functional residual capacity (FRC pleth, FRC MBNW ), lung clearance index (LCI), volume of trapped gas (V TG ), effective specific airway resistance (sr eff ), forced expiratory indices (FEV 1, FEF 50 ), and blood gas characteristics (PaO 2 and PaCO 2 ) featured the basis of our investigations. Subgroups. According PaO 2 changes during treatment (5 % level) stratification into (i) improved, (ii) unchanged and (iii) deteriorated were built. Richard Kraemer, MD, Professor of Paediatrics, emeritus

24 Stratification into subgroups according changes in PaO 2 Richard Kraemer, MD, Professor of Paediatrics, emeritus

25 Short-term effect with improvement of oxygenation (n=22) Richard Kraemer, MD, Professor of Paediatrics, emeritus

26 Long-term course (start treatment series until 2 years later) Richard Kraemer, MD, Professor of Paediatrics, emeritus

27 In-patient intensive-antibiotic treatment in CF Richard Kraemer, MD, Department of Paediatrics, University of Berne, Berne Switzerland 27

28 In-patient intensive-antibiotic treatment in CF Richard Kraemer, MD, Department of Paediatrics, University of Berne, Berne Switzerland 28

29 Atmungschleife eines 13.8 j. CF-Kindes Print screen T.A. male 13.8 yrs FRC pleth : 4.1 SDS LCI: 22.5 SDS V TG : 5.6 SDS R eff : 16.2 SDS sr eff : 36.4 SDS sr 0.5 : 27.2 SDS sr tot : 42.6 SDS Diff_sR 15.4 SDS

30 Was gebe ich Ihnen auf den Weg Langzeitaspekte: auf was kommt es an? Führung des Patienten und seiner Eltern Praxis Zentrum - Physiotherapie Sozialdienst Harmonisierung der verschiedenen Spezialbereiche; Übergabe an einen Erwachsenen-Mediziner (Berufsberatung, Schwangerschaft, Familienplanung) Ziel: Lebensqualität Funktionsdiagnostik: die richtigen Verlaufsparameter in Betracht ziehen: LCI, sreff, swob! (und nicht nur das FEV 1 ; in den USA als einziger Parameter durch die FDA akzeptiert) Angemessener Aufwand, je nach Genotyp Pulmozyme: grosses Fragezeichen Atemphysiotherapie: äusserst wichtig Intensivkuren (ja, aber monitorisiert!) Funktion des Praktiker: Advokat des Patienten Richard Kraemer, MD, Department of Paediatrics, University of Berne, Berne Switzerland 30

31 Thank you! Richard Kraemer, MD, Department of Paediatrics, University of Berne, Berne Switzerland 31

32 Lung function as Prognostic Factors Bronchial obstruction of small airways (FEF 50 ; MMEF 75-25) Ventilation inhomogeneities (LCI) Bronchial obstruction in relation to pulmonary hyperinflation (sr eff ) Richard Kraemer, MD, Department of Paediatrics, University of Berne, Berne Switzerland 32

33 Efficacy of intensive-antibiotic cures in CF Richard Kraemer, MD, Department of Paediatrics, University of Berne, Berne Switzerland 33