Cystic Fibrosis, 4th Edition

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thefacts

Cystic fibrosis
FULLY UPDATED AND REVISED
FOURTH EDITION
ANNE H THOMSON
Director, Oxford Paediatric Cystic Fibrosis Centre, Oxford
Children’s Hospital

ANN HARRIS
Director, Human Molecular Genetics Program, Children’s
Memorial Research Center, Northwestern University Feinberg
School of Medicine

1
1
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Thomson, Anne H.
Cystic fibrosis: the facts / Anne H. Thomson, Ann Harris. — 4th ed.
p. cm. — (the facts)
ISBN 978–0–19–929580–7
1. Cystic fibrosis—Popular works. I. Harris, Ann. II. Title.
RC858.C95T56 2008
616.3´72—dc22
2008017227
ISBN 978–0–19–929580–7
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 Preface

It is now more than 20 years since the first edition of Cystic Fibrosis: The Facts
was published, two years before the gene that causes CF was identified. Two
subsequent editions, both co-authored by Maurice Super, were published
in 1990 and 1995. During the past 20 years there have been many advances
in the treatment of CF and the median survival rate has increased by about
10 years. With increased survival, new aspects of the disease need to be dealt
with and the growth of adult CF clinics has changed the emphasis of CF care
from a mainly paediatric specialty to both childhood and adult medicine.

Cystic Fibrosis: The Facts 2008 edition is completely rewritten and takes a new
approach to the disease and its treatment, with up-to-date information on
all aspects of life with CF. One chapter that cannot yet be written describes
an effective cure for the disease. Many research scientists and physicians are
working hard to achieve this, but we cannot predict when it will become a
reality. In the meantime we hope that this book is helpful to all those who
encounter CF in their lives.

Oxford A.H.T
Chicago A.H.
May 2008

v
 Acknowledgements

The authors would like to thank many people for their contributions to this
book:

First, and most importantly, the young people and their parents who have
shared their experiences with us. Also Dr Bee Brockman for illustrations and
Dr Konrad Jacobs, Dr Louisa Demetriades, and Dr Julian Forton for contrib-
uting chapters. Finally our colleagues whose discussions and comments over
many years have helped our understanding of this complex disease.

The authors thank Dr Susanna McColley, Director of the Cystic Fibrosis

Center at Children’s Memorial Hospital, Chicago for her valuable input on
differences in cystic fibrosis care in the UK and the USA.
 Contents

1 Introduction and making the diagnosis 1

2 How cystic fibrosis affects the lungs 9
3 How cystic fibrosis affects the digestive system 23
4 How cystic fibrosis affects other organs 31
5 Daily treatment for cystic fibrosis 37
6 The cystic fibrosis team 59
7 Nutrition in cystic fibrosis 63
8 Micro-organisms in the cystic fibrosis lung 69
9 Cystic fibrosis and the family 75
10 Cystic fibrosis and school 85
11 Growing up with cystic fibrosis 93
12 Future therapies 99
13 Genetics of cystic fibrosis 105
14 Genetic counselling in cystic fibrosis 119
15 Survival 131
Appendices
1 Further reading 133
2 Cystic fibrosis associations 135
3 Glossary 141
Index 147

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 1
Introduction and
making the diagnosis

06 Key points
◆ Cystic fibrosis (CF) occurs when a person has inherited two copies of
a faulty gene (one from each parent)
◆ CF is suspected in children who:

(a) have a bowel blockage at birth

(b) fail to gain weight even when eating well

(c) have frequent smelly stools

(d) have a persistent or recurrent wet cough or chest infection

◆ Newborn infants can now be screened for CF by a heel-prick

blood test

◆ The diagnosis of CF is confirmed by a sweat test which measures the

concentration of chloride (as salt) in the sweat

What is cystic fibrosis?

Cystic fibrosis is a disease caused when a person has inherited two copies of a
faulty gene (one from each parent). The disease can affect many parts of the
body but most importantly involves the lungs and the gut. The problem in the
lungs causes difficulty in clearing secretions (mucus), and in the gut causes
difficulty in absorbing food properly. This book is written for families, friends,
teachers and all those who encounter CF in their lives. It tries to explain the
disease, its management and how it affects individuals.

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Cystic fibrosis · thefacts

Why is it called cystic fibrosis?

The name comes from changes in a gland called the pancreas. The pancreas
makes enzymes that help digest food and some other compounds. It is dam-
aged from early life in most people with cystic fibrosis and is gradually replaced
with scar tissue (fibrosis) and fluid-filled spaces (cysts). Cystic fibrosis was
only recognized as a distinct disorder in 1938.

When is cystic fibrosis suspected?

Cystic fibrosis has traditionally been suspected in young children who were
either failing to gain weight (failing to thrive) even when eating well or had
persistent or recurrent chest infections. Some infants have problems at birth
with blockage (obstruction) of the bowel (meconium ileus). Less commonly
children come to medical attention with other bowel symptoms or symptoms
of nasal obstruction (nasal polyps). Occasionally cystic fibrosis is diagnosed in
adult men presenting with infertility. However, increasingly in many countries
children are being diagnosed with cystic fibrosis as a result of being screened
for the disease at birth. Neonatal screening for cystic fibrosis became universal
in England in 2007, and is available in some US states.

Newborn screening
There are minor variations in national screening programmes. In England the
screening is done on blood spots taken from the infant (on day five or six)
on the Guthrie card. The blood is first checked for the level of an enzyme
called immunoreactive trypsin (IRT). If the level is much higher than normal
the blood is then checked for the common cystic fibrosis mutations. If two
mutations are found then the child is presumed to have cystic fibrosis and is
referred to a cystic fibrosis centre to confirm the diagnosis. If only one cystic
fibrosis mutation is found then a second blood sample is taken between days
21 and 28 for a further measurement of immunoreactive trypsin. If this level
is also high then the child is likely to have cystic fibrosis and is referred to the
cystic fibrosis centre for confirmation of the diagnosis. If the level is low the
child is likely not to have cystic fibrosis but carries one cystic fibrosis mutation,
that is, they are a carrier for cystic fibrosis.

In the United States, newborn screening programmes are run at the state
rather than national level. All programmes use similar techniques. The initial
blood spot is taken at one to two days of age and tested for IRT. Some states
perform tests for cystic fibrosis gene mutations on all samples with an elevated
IRT, while others measure a second IRT instead. Another variation is to perform

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 Chapter 1 · Introduction and making the diagnosis

Table 1.1 Frequency of symptoms in cystic fibrosis

Failure to gain weight 43%

Persistent wet cough/Recurrent chest infections 51%
Smelly fatty stools 35%
Meconium ileus 18%
Family history (no symptoms) 16%

genetic testing after a second IRT is found to be elevated. Because genetic

testing is usually limited to the most common gene mutations causing CF, and
because of the genetic diversity of the population in the US, tests are considered
positive even if only one CF mutation is found. This means that all infants with
elevated IRT and one or two CF gene mutations are referred for sweat testing.
In some states, a very high (sometimes called ‘ultra high’) IRT is also consid-
ered to be a positive newborn screen for CF, prompting sweat testing.

Most children diagnosed by newborn screening will be entirely well at the

time that the diagnosis is made. Once newborn screening is universally avail-
able it is likely that very few children will present with the other symptoms
described above (Table 1.1).

Failure to thrive
The child with cystic fibrosis is usually hungry for food and eats well. However,
because the food is not absorbed properly it passes through the bowel, giving
frequent smelly loose stools which may look slimy or greasy. This is called
steatorrhoea. The stools contain lots of globules of fat.

Chest infection
All young children are exposed to viral infections and coughs with colds are
frequent. However, suspicions of cystic fibrosis are raised if the cough does
not clear between viral infections and in particular if it sounds as if there is
mucus present (a smoker’s cough).

Meconium ileus
Approximately 15 per cent of children with cystic fibrosis will present soon
after birth with bowel obstruction. The infant may start to vomit, the abdomen

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Cystic fibrosis · thefacts

becomes distended and no stool is passed. An x-ray of the abdomen con-

firms bowel obstruction and in most cases an attempt to clear the bowel is
made by passing a dye-containing substance (gastrografin) up as an enema
into the bowel. If this does not clear the obstruction then surgery may be
necessary.

The first stool that a newborn baby passes is a sticky black motion and
is called meconium. In cystic fibrosis the meconium is stickier than normal
and sometimes does not pass all the way through the bowel but gets stuck,
often at the junction between the small and the large bowel, causing the
obstruction.

At surgery the bowel is opened at the site of obstruction and the sticky
meconium removed. In many cases the surgeon will be able to join the bowel
together again, but sometimes this is not possible and a loop of bowel is
brought through the skin to form an ileostomy. The ileostomy is temporary
and is usually closed after a few weeks.

The finding of meconium ileus is highly suggestive of cystic fibrosis as the

underlying diagnosis (greater than 95 per cent). The diagnosis is later con-
firmed as described below.

Rectal prolapse
This occurs when a small part of the lining of the bowel protrudes through the
anus after a child has passed stool. It is most likely to occur in a child who is pass-
ing large bulky stools with effort. It is most common therefore in constipation,
but can occur in cystic fibrosis.

Nasal polyps
Nasal polyps are not very common in children but sometimes occur in chil-
dren who are very allergic and have lots of hay fever-type symptoms. They can
also occur in cystic fibrosis and very rarely they are what brings the child with
cystic fibrosis to medical attention.

Infertility
The man with cystic fibrosis lacks parts of the small tube in which sperm
travel down from the testes (the vas deferens). Men who are mildly affected by
cystic fibrosis may have no other symptoms and the diagnosis is made when
they go to an infertility clinic. (This is explained fully in Chapter 14.)

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 Chapter 1 · Introduction and making the diagnosis

How is the diagnosis of cystic fibrosis confirmed?

The standard test for the diagnosis of cystic fibrosis is a sweat test. Individuals
with cystic fibrosis have much higher concentrations of sodium and chloride
(salt) in their sweat than normal.

The sweat test is most commonly done on the forearm. The first step is to
stimulate sweating by placing two pads containing a special medicine called
pilocarpine on the forearm and by using a small electrical current from a bat-
tery to drive the medicine in through the skin. The pads are then removed and
the skin cleaned. A special sweat-collecting device is then placed on the fore-
arm (Figure 1.1) and the sweat collected over the next 30 minutes. The sweat
is then analysed for chloride content. A sweat chloride greater than 60 mmols/
litre is diagnostic of cystic fibrosis in children. Normal sweat chloride levels
are lower in newborns and higher in adults, so slightly different sweat chloride
levels are used to make a diagnosis of cystic fibrosis in these age groups.

Can there be problems with the sweat test?

The test needs to be done carefully by an experienced operator. The most
common problem is that the child does not sweat enough. It is important for

Figure 1.1 A macroduct sweat-collecting disc on the forearm. Sweat is collected in a

small capillary tube within the disc.
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Cystic fibrosis · thefacts

the accuracy of the test that a certain amount of sweat is collected within the
30-minute period. If there is insufficient sweat then the test will need to be
repeated on another day.

Can the diagnosis of cystic fibrosis be made

genetically?
Yes. If the child has two cystic fibrosis mutations then the diagnosis is con-
firmed. However, the usual laboratory tests will only detect about 30 of the
most common genetic mutations so will make the diagnosis in only about
75 per cent of cases. As over 1500 mutations causing cystic fibrosis have
been identified it is possible for the usual laboratory test to miss a rare mutation.
For this reason the sweat test is still used as ‘the gold standard’. It is now pos-
sible to look for all the known mutations in the cystic fibrosis gene, but this is
both very costly and takes some months for results to be available.

Are there any other tests used in diagnosis?

Very rarely it is impossible to confirm the diagnosis by either genetics or sweat
test. A sophisticated test on cells lining the nose, called nasal potential difference,
can be used to give additional information. This test can be difficult in infants
and young children and is available only in a few centres.

There can also be other helpful information. For example the stool can be exam-
ined for fat and for a pancreatic enzyme called elastase. A low stool elastase level
confirms that the pancreas is not working properly (pancreatic insufficiency).
There are rare occasions when all the tests are inconclusive and the cystic
fibrosis specialist has to put all the information together and decide whether
the individual has cystic fibrosis on the balance of probabilities. The diagnosis
is usually confirmed with time.

Will my child have mild or severe cystic fibrosis

symptoms?
It is impossible to say how severe CF disease will be in any individual but some
general statements can be made. Some gene mutations such as the commonest,
delta F508 (∆F508), (See Chapter 13) are almost always associated with the
need for pancreatic supplements. Individuals with combinations of some other
genes such as R117H and S1251N will rarely need pancreatic supplements. The
severity of lung disease cannot be directly related to the specific gene muta-
tion and it is clear that many other things including nutrition, environmental

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 Chapter 1 · Introduction and making the diagnosis

exposure to pollutants including cigarette smoke, viral infections and the rest
of a person’s genetic make-up determines how severe their lung disease is. It is
also probable that other genetic variations between individuals can affect
disease severity (see Chapter 13).

V3 Patient’s perspective
Katherine had been worried about her baby Robert since he was a few
weeks old. Although he initially breastfed well and put on weight, after
a few weeks the breast no longer seemed to satisfy him and he had both
breast and bottle feeds. He passed soft, rather slimy stools four or five
times a day and they smelt. Family members joked that you could tell
he needed a nappy change from the room next door. However, he was
3 months old when he had his first bad cold and developed a cough
that would not clear. After three visits to the family doctor Robert was
referred to a paediatrician.

At the clinic visit, the doctor noted that despite having a good intake
of bottle milk plus additional breastfeeds Roberts weight had fallen
from the middle line on the growth chart (50th centile) at birth to just
above the bottom line (3rd centile). He was bright and alert but looked
a little scrawny and had a productive-sounding cough. The paediatrician
arranged for a sample of his stool to be examined for fat and for elastase
measurement and for a sweat test to be done.

The sweat test showed a high sweat-chloride level, confirming the diag-
nosis of cystic fibrosis. The stool sample showed a large excess of fat glob-
ules and the elastase level was low, confirming pancreatic insufficiency.

Robert was started on one half capsule of Creon per feed and Katherine
was delighted to find that within 3 days his stools were completely dif-
ferent and he did not seem so hungry. On treatment with antibiotics and
physiotherapy his cough cleared in 10 days.

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