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Cystic Fibrosis
This page intentionally left blank
Cystic Fibrosis

Third edition

Margaret Hodson
Professor of Respiratory Medicine and Consultant Physician,
Department of Cystic Fibrosis,
Royal Brompton & Harefield NHS Trust, London, UK

Duncan Geddes
Professor of Respiratory Medicine and Consultant Physician,
Royal Brompton & Harefield NHS Trust, London, UK

Andrew Bush
Professor of Paediatric Respirology and Consultant Paediatric Chest Physician,
Royal Brompton & Harefield NHS Trust, London, UK

PART OF HACHETTE LIVRE UK

First published in Great Britain in 1995
Second edition 2000
This third edition published in 2007 by
Hodder Arnold, an imprint of Hodder Education, part of Hachette Livre UK,
338 Euston Road, London NW1 3BH

www.hoddereducation.com

© 2007 Edward Arnold (Publishers) Ltd

All rights reserved. Apart from any use permitted under UK copyright law,
this publication may only be reproduced, stored or transmitted, in any
form, or by any means with prior permission in writing of the publishers or
in the case of reprographic production in accordance with the terms of
licences issued by the Copyright Licensing Agency. In the United Kingdom
such licences are issued by the Copyright Licensing Agency: Saffron House,
6–10 Kirby Street, London ECIN 8TS.

Whilst the advice and information in this book are believed to be true and
accurate at the date of going to press, neither the author[s] nor the publisher can
accept any legal responsibility or liability for any errors or omissions that
may be made. In particular (but without limiting the generality of the preceding
disclaimer) every effort has been made to check drug dosages; however it is
still possible that errors have been missed. Furthermore, dosage schedules
are constantly being revised and new side-effects recognized. For these reasons
the reader is strongly urged to consult the drug companies’ printed instructions
before administering any of the drugs recommended in this book.

British Library Cataloguing in Publication Data

A catalogue record for this book is available from the British Library

Library of Congress Cataloging-in-Publication Data

A catalog record for this book is available from the Library of Congress

ISBN 978 0 340 90758 0

2 3 4 5 6 7 8 9 10

Commissioning Editor: Philip Shaw

Project Editor: Heather Fyfe
Production Controller: Karen Tate
Cover Designer: Andrew Campling

Typeset in 10/12 pts Minion by Charon Tec Ltd (A Macmillan Company), Chennai, India
www.charontec.com
Printed and bound in Great Britain

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Contents

Color plates appear between pages 259 and 260.

Contributors ix
Preface xiii

PART 1 INTRODUCTION: WHAT IS CYSTIC FIBROSIS?

1 History of cystic fibrosis 3

James M. Littlewood
2 Epidemiology of cystic fibrosis 21
Sarah Walters and Anil Mehta

PART 2 BASIC SCIENCE FOR THE CLINICIAN

3 Molecular biology of cystic fibrosis: CFTR processing and functions, and classes of mutations 49
Malka Nissim-Rafinia, Batsheva Kerem and Eitan Kerem
4 Pathophysiology: epithelial cell biology and ion channel function in the lung, sweat gland and pancreas 59
Raymond D. Coakley and Richard C. Boucher
5 Immunology of cystic fibrosis 69
Gerd Döring and Felix Ratjen
6a Genotype–phenotype correlations and modifier genes 81
Jane C. Davies
6b Variability of clinical course in cystic fibrosis 87
Michael Schechter

PART 3 DIAGNOSTIC ASPECTS OF CYSTIC FIBROSIS

7 Diagnosis of cystic fibrosis 99

Colin Wallis
8a The challenge of screening newborn infants for cystic fibrosis 109
Kevin W. Southern
8b How to manage the screened patient 117
Philip Robinson
9 Microbiology of cystic fibrosis: role of the clinical microbiology laboratory, susceptibility and 123
synergy studies and infection control
Samiya Razvi and Lisa Saiman

PART 4 CLINICAL ASPECTS OF CYSTIC FIBROSIS

10 Respiratory disease: infection 137

Ian M. Balfour-Lynn and J. Stuart Elborn
11 Respiratory disease: non-infectious complications 159
Margaret Hodson and Andrew Bush
vi Contents

12 Sleep, lung mechanics and work of breathing, including NIPPV 175

Brigitte Fauroux and Annick Clément
13 Delivery of therapy to the cystic fibrosis lung 185
Harm A. W. M. Tiddens and Sunalene G. Devadason
14 The upper airway in cystic fibrosis 199
William E. Grant
15a Gastrointestinal disease in cystic fibrosis 209
Ian Gooding and David Westaby
15b Liver, biliary and pancreatic disease 225
Vicky Dondos and David Westaby
16 Insulin deficiency and diabetes related to cystic fibrosis 241
Christopher D. Sheldon and Lee Dobson
17 Growth and puberty 253
Nicola Bridges
18 Cystic-fibrosis-related low bone mineral density 261
Sarah L. Elkin and Charles S. Haworth
19 Other system disorders in cystic fibrosis 269
Khin Ma Gyi
20 Sexual and reproductive health 279
Susan M. Sawyer
21 Transplantation 291
Paul Aurora, Khin Gyi and Martin Carby

PART 5 MONITORING

22 Using databases to improve care 311

Sheila G. McKenzie and Margaret E. Hodson
23a Infant and pre-school children: lung function 321
Sarath Ranganathan
23b Infant and pre-school children: role of bronchoscopy 331
Gary Connett
23c Infant and pre-school children: imaging the lungs 337
Samatha Sonnappa and Catherine M. Owens
24 Physiological monitoring of older children and adults 345
Mark Rosenthal
25a Exercise: testing 353
David M. Orenstein and Wolfgang Gruber
25b Exercise: use in therapy 361
David M. Orenstein and Linda W. Higgins
26 Clinical outcome measures to assess new treatments for CF lung disease 375
Jane C. Davies and Eric W.F.W. Alton on behalf of the UK CF Gene Therapy Consortium

PART 6 MULTIDISCIPLINARY CARE

27 Cystic fibrosis center care 387

Penny Agent and Susan Madge
28 Nursing care 399
Susan Madge and Christine Hockings
29 Physiotherapy 407
Craig Lapin, Anne Lapin and Jennifer A. Pryor
30 Nutritional aspects 421
Sue Wolfe and Sarah Collins
31 Psychological aspects of cystic fibrosis 431
Alistair J. A. Duff and Helen Oxley
32 Palliative care in cystic fibrosis 441
Catherine E. Urch and Margaret E. Hodson
 Contents vii

PART 7 CYSTIC FIBROSIS: THE FUTURE

33a Gene and stem cell therapy 453

Uta Griesenbach and Eric W. F. W. Alton on behalf of the UK CF Gene Therapy Consortium
33b Non-gene therapy treatments: what will they deliver? 463
Adam Jaffé and Pierre Barker
34 The future: how will management change? 471
Andrew Bush and Duncan Geddes

APPENDICES

Appendix 1 Transition form 479

Susan Madge and Jacqueline Francis
Appendix 2 Practical nursing care required by the cystic fibrosis patient and its delivery 483
Frances Duncan–Skingle and Tracey Catling

Index 487
This page intentionally left blank
Contributors

Penny Agent BSc PgDMS Raymond D. Coakley MD

Service Lead, Superintendent Physiotherapist, Department of Assistant Professor of Medicine, CF Research and Treatment
Physiotherapy, Royal Brompton Hospital, London, UK Center, University of North Carolina at Chapel Hill, NC, USA

Eric W. F. W. Alton MD FRCP FMedSci Sarah Collins BSc MSc RD

Professor of Gene Therapy and Respiratory Medicine, Department Senior Dietitian (Adult CF), Dietetic Department, Royal Brompton
of Gene Therapy, National Heart & Lung Institute, Imperial Hospital, London, UK
College, London, UK
Gary Connett MB ChB MRCP FRCPCH MD
Paul Aurora MBBS MRCP PhD Consultant Pediatrician, Department of Pediatrics, Southampton
Cardiothoracic Transplant and Respiratory Units, Great Ormond University Hospitals Trust, Southampton, UK
Street Hospital for Children, and Portex Respiratory Unit, Institute
Jane C. Davies MB MD ChB MRCP MRCPCH
of Child Health, University College London, London, UK
Senior Lecturer in Gene Therapy & Honorary Consultant in
Ian M. Balfour-Lynn BSc MBBS MD FRCP FRCPCH FRCS(Ed) DHMSA Pediatric Respiratory Medicine, Department of Gene Therapy,
Consultant in Pediatric Respiratory Medicine, Department National Heart & Lung Institute, Imperial College, London, and
of Pediatric Respiratory Medicine, Royal Brompton Hospital, Department of Pediatric Respiratory Medicine, Royal Brompton
London, UK Hospital, London, UK

Pierre Barker MD FAAP MRCP Sunalene G. Devadason PhD

Associate Professor of Pediatrics, University of North Carolina, Senior Research Fellow, School of Paediatrics and Child Health,
NC, USA University of Western Australia, Perth, Australia

Richard C. Boucher MD Lee Dobson MBChB MRCP

William R. Kenan Professor of Medicine and Director, Consultant Physician, Department of Respiratory Medicine,
CF Research and Treatment Center, University of North Carolina Torbay Hospital, Torquay, UK
at Chapel Hill, NC, USA Vicky Dondos
Research fellow, The Royal Brompton Hospital, London, UK
Nicola Bridges DM MRCP FRCPCH
Consultant Pediatric Endocrinologist, Chelsea & Westminster Gerd Döring PhD
Hospital, London, UK Professor for Experimental Hygeine and Microbiology, Institute
für Medizinische Mikrobiologie und Hygiene, Tübingen, Germany
Andrew Bush MD FRCP FRPCH
Professor of Pediatric Respirology and Consultant Paediatric Alistair J. A. Duff MA MSc DClinPsych
Chest Physician, Royal Brompton & Harefield NHS Trust, Consultant Clinical Psychologist & Head of Pediatric Psychology
London, UK Services, Department of Clinical & Health Psychology, St James’
University Hospital, Leeds, UK
Martin Carby BSc MBBS MRCP
Consultant Respiratory and Transplant Physician, Cardiothoracic Frances Duncan-Skingle RGN NDNCert HVCert
Transplant Unit, Harefield Hospital, Harefield, Middlesex, UK Nurse Consultant (retired), Royal Brompton Hospital, London, UK

Tracey Catling RGN J. Stuart Elborn MD FRCP

Clinical Nurse Specialist, Royal Brompton Hospital, London, UK Professor of Respiratory Medicine, Department of Respiratory
Medicine, Belfast City Hospital, and Queen’s University, Belfast, NI
Annick Clément MD PhD
Professor of Pediatrics, Pediatric Pulmonology Department and Sarah L. Elkin MCSP MD MRCP
Research Unit INSERM U719, Armand Trousseau Hospital, Consultant Physician, Respiratory and General Medicine,
Hôpitaux de Paris, Paris, France St Mary’s Hospital, London, UK
x Contributors

Brigitte Fauroux MD PhD Eitan Kerem MD

Professor of Pediatrics, Pediatric Pulmonology Department and Professor in Pediatrics, Head, Department of Pediatrics and CF
Research Unit INSERM U719, Armand Trousseau Hospital, Center, Hadassah-Hebrew University Hospital, Jerusalem, Israel
Hôpitaux de Paris, Paris, France
Anne Lapin MCSP PT
Jacqueline Francis EN(G) RGN RSCN BSc(Hons) Physiotherapist, Central Connecticut Cystic Fibrosis Center,
Pediatric Cystic Fibrosis Care Coordinator, Royal Brompton Connecticut Children’s Medical Center, Hartford; Adjunct Faculty,
Hospital, London, UK Department of Physical Therapy, University of Connecticut, Storrs,
CT, USA
Duncan Geddes MA MBBS MD FRCP
Professor of Respiratory Medicine and Consultant Physician, Royal Craig Lapin MD
Brompton & Harefield NHS Trust, London, UK Director, Central Connecticut Cystic Fibrosis Center, Connecticut
Children’s Medical Center, Hartford; Associate Professor of
Ian Gooding MA MB BChir MRCP Pediatrics, University of Connecticut, Farmington,
Specialist Registrar, Department of Gastroenterology, CT, USA
Charing Cross Hospital, London, UK
James M. Littlewood OBE MB ChB MD FRCP FRCPE FRCPCH DCH
William E. Grant MCh FRCSI FRCSEd FRCS(ORL)
Chairman, UK Cystic Fibrosis Trust; and Regional Paediatric Cystic
Consultant Ear, Nose & Throat Surgeon, Ear, Nose and Throat Fibrosis Unit, St James’ University Hospital, Leeds, UK
Department, Chelsea & Westminster and Charing Cross Hospitals,
London, UK Sheila G. McKenzie BSc PhD
Pharmacology Consultant, Victoria, British Columbia, Canada
Uta Griesenbach PhD
Senior Lecturer in Gene Therapy, Department of Gene Therapy, Susan Madge SRN RSCN MSc MCGI PhD
National Heart & Lung Institute, Imperial College, London, UK Consultant Nurse, Royal Brompton Hospital, London, UK

Wolfgang Gruber PhD MSc Anil Mehta MSc FRCPCH FRCP (Edin)
Department of Sports Therapy, Fachklinik Sattelduene, Tayside Institute of Child Health, Ninewells Hospital & Medical
Nebel/Amrum, Germany School, Dundee, UK
Khin Ma Gyi MBBS DTMRH FRCP (Glasgow) Malka Nissim-Rafinia PhD
Consultant and Honorary Senior Lecturer in Respiratory Medicine, Department of Genetics, The Life Sciences Institute,
Department of Cystic Fibrosis, Royal Brompton Hospital, Hebrew University, Jerusalem, Israel
London, UK
David M. Orenstein MD
Charles S. Haworth MD MRCP
Antonio J. and Janet Palumbo Professor of Cystic Fibrosis;
Adult Cystic Fibrosis Centre, Papworth Hospital, Cambridge, UK Director, Antonio J. and Janet Palumbo Cystic Fibrosis Center,
Linda W. Higgins PhD RN Children’s Hospital of Pittsburgh; Professor of Pediatrics,
Research Associate, Antonio J. and Janet Palumbo Cystic Fibrosis School of Medicine; Professor of Health and Physical Activity,
Center, Children’s Hospital of Pittsburgh; Adjunct Assistant School of Education, University of Pittsburgh, Pittsburgh,
Professor of Health and Community Systems, School of Nursing, PA, USA
University of Pittsburgh, PA, USA
Catherine M. Owens BSc MBBS MRCP FRCR
Christine Hockings BA RN Consultant Pediatric Radiologist, Great Ormond Street Hospital
Clinical Nurse Specialist, Royal Brompton Hospital, London, UK for Children, London, UK

Margaret E. Hodson MD MSc FRCP Dmed Ed Helen Oxley BSc MSc

Professor of Respiratory Medicine and Consultant Physician, Consultant Clinical Psychologist, Manchester Adult Cystic Fibrosis
Department of Cystic Fibrosis, Royal Brompton & Harefield Trust, Centre, Wythenshawe Hospital, Manchester, UK
London, UK
Jennifer A. Pryor PhD MBA FNZSP MCSP
Adam Jaffé MD FRCP FRCPCH Honorary Lecturer, University College London; Senior Research
Consultant and Honorary Senior Lecturer in Respiratory Medicine, Fellow in Physiotherapy, Royal Brompton Hospital, London, UK
Portex Anaesthesia, Intensive Therapy & Respiratory Medicine
Unit, Great Ormond Street Hospital for Children and Institute for Sarath Ranganathan MB ChB MRCP PhD FRCPCH FRACP
Child Health, London, UK Consultant in Respiratory Medicine, Royal Children’s Hospital
Melbourne; Senior Fellow, Department of Pediatrics, University
Batsheva Kerem PhD of Melbourne and Honorary Fellow, Infection, Immunity and
Professor in Genetics, Department of Genetics, The Life Sciences Environment Theme, Murdoch Children’s Research Institute,
Institute, Hebrew University, Jerusalem, Israel Melbourne, Australia
 Contributors xi

Felix Ratjen MD FRCP(C) Samatha Sonnappa MD DCH MRCP FRCPH

Head, Division of Respiratory Medicine, Sellers Chair of Cystic Research Fellow and Honorary Consultant in Respiratory
Fibrosis, Professor, University of Toronto, Hospital for Sick Medicine, Portex Anaesthesia, Intensive Therapy and Respiratory
Children, Toronto, Ontario, Canada Medicine Unit, Great Ormond Street Hospital for Children and
Institute of Child Health, London, UK
Samiya Razvi MD
Pediatric Pulmonary Fellow, Department of Pediatric Pulmonary Kevin W. Southern PhD MRCP MBChB
Medicine, Morgan-Stanley Children’s Hospital Of New York- Senior Lecturer and Honorary Consultant in Pediatric Respiratory
Presbyterian, NY, USA Medicine, Institute of Child Health, University of Liverpool, and
Royal Liverpool Children’s Hospital, Liverpool, UK
Philip Robinson BMedSc PhD MD MBBS FRACP
Director, Cystic Fibrosis Unit, Department of Respiratory Medicine, Harm A. W. M. Tiddens MD PhD
Royal Children’s Hospital, Melbourne, Australia Associated Professor in Pediatric Pulmonology, Chair CF-Team,
Department of Pediatrics, ErasmusMC-Sophia Children’s Hospital
Mark Rosenthal MD FRCP FRCPCH
Catherine E. Urch PhD MRCP
Consultant in Pediatric Respiratory Medicine, Royal Brompton
Honorary Senior Lecturer, UCL and Imperial College London;
Hospital, London, UK
Consultant Palliative Medicine, Department Palliative Care,
Lisa Saiman MD MPH St Mary’s and Royal Brompton Hospitals, London, UK
Professor of Clinical Pediatrics, Department of Pediatrics, Colin Wallis MBChB DCH FCP MD MRCP FRCPCH
University of Columbia, NY, USA Respiratory Pediatrician, Great Ormond Street Hospital for
Susan M. Sawyer MBBS MD FRACP Children, London, UK
Professor of Adolescent Health, The University of Melbourne; Sarah Walters OBE MB FRCP FFPH
Director, Centre for Adolescent Health and Consultant Respiratory Senior Clinical Lecturer in Public Health and Epidemiology,
Paediatrician, Royal Children’s Hospital, Melbourne, Australia Department of Public Health & Epidemiology, University of
Birmingham, Birmingham, UK
Michael S. Schechter MD MPH
Associate Professor of Paediatrics, CF Center Director, Associate David Westaby MA FRCP
Director, Division of Pediatric Pulmonology, Allergy/Immunology, Consultant Gastroenterologist and Hepatologist, Hammersmith
Cystic Fibrosis and Sleep, Emory University School of Medicine, Hospitals Trust, Honorary Senior Lecturer, Imperial College
Atlanta, GA, USA Medicine School, London, UK
Christopher D. Sheldon DM FRCP Susan P. Wolfe BSc DipDiet RD
Consultant Physician, Department of Respiratory Medicine, Chief Pediatric Dietitian, Regional Pediatric Cystic Fibrosis Unit,
Royal Devon & Exeter Hospital, Exeter, UK St James’ University Hospital, Leeds, UK
This page intentionally left blank
Preface

Just as the face of cystic fibrosis has changed, from a respi- as an illustration of how wrong the most educated of
ratory and digestive disease of children to a multisystem guesses may be.
disease predominantly of adults, so the 3rd edition of this This is a book aimed primarily for clinicians with all
book is radically different from the 2nd edition, published degrees of experience, who we hope will learn from our
in 2000. The chapters have been reorganized into seven authors – as we have done. It is predominantly a clinical
main sections, and all have been completely rewritten. book, but with scientific sections that are intended to be
Many of the authors from the previous edition have been accessible to the interested clinician. We also hope that the
retired, with great thanks, and some have taken on new scientist who wishes to find out more about cystic fibrosis
tasks, and more than thirty new authors, and a third editor, will find the clinical sections informative.
have been recruited. We have tried to keep this edition the We want to thank all the authors for their hard work and
same length as its predecessor, by ensuring the old was forbearance of our importuning; the publishers, in particu-
excised to make way for the new. lar Heather Fyfe, for keeping us on track and ensuring the
Although this is, in effect, a completely new book, the highest standards in production of the volume; and we ask
opening chapter is rooted in the past, with an account of the partners, family and friends of all concerned, authors,
the great achievements of our forebears in describing and publishers and editors, to forgive us for the long hours con-
understanding the treatment and science of cystic fibrosis. sumed during the gestation of this volume. We hope the
This is followed by an epidemiological description of end-product in small measure repays their patience.
where we are now. Subsequent chapters describe basic Finally, our chief thanks are due to our teachers – the
science for the clinician, diagnostic aspects of the disease patients and their families – from whom we have learned
(including how to manage the screened patient), the all we know about cystic fibrosis.
clinical aspects, monitoring of the disease, and a complete
section, that evolved from a single chapter, on multidisci- Margaret Hodson
plinary care. It ends with a chapter which looks to the Duncan Geddes
future – which may be required reading in ten years time, Andrew Bush
This page intentionally left blank
 PART 1
INTRODUCTION: WHAT IS CYSTIC FIBROSIS?

1 History of cystic fibrosis 3

James M. Littlewood
2 Epidemiology of cystic fibrosis 21
Sarah Walters and Anil Mehta
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