Transcript CF Lecture_ITS masters2010V2

Cystic Fibrosis
Dr Barry Linnane
Paediatric Respiratory Consultant
Mid-Western Regional Hospital
Limerick
Introduction
•
It is customary to start any discussion regarding cystic fibrosis (CF) by
pointing out that it is the most common life-shortening genetic condition
affecting the Caucasian population (Littlewood, in Cystic Fibrosis, 2007. p. 3 – 19)
•
It is estimated there are approximately 60,000 affected individuals
worldwide (Anselmo et al, in Pediatric Respiratory Medicine, 2008. p. 845 – 857)
•
The prevalence of the disease varies amongst populations, but the average
birth prevalence in Caucasian populations is likely to be approximately 1 in
2,500 births, with a CF carrier frequency of 1 in 25 people (Walters et al, in Cystic
Fibrosis, 2007 p. 21 – 45)
•
There are approximately 1,200 individuals with CF in Ireland (The Cystic
Fibrosis Registry of Ireland Annual Report 2007)
•
There are 30-40 infants born each year with CF in Ireland. The birth
prevalence is approximately 1 in 1460, with a CF carrier frequency of 1 in
19 (Wallis C, in Kendig’s Disorders of the Respiratory Tract in Children, 2006, p866 – 872)
Definition
•
There are numerous definitions of CF, all of which attempt to capture the
essence of this complex disease, in a few succinct words. Dr Colin Wallis
recently proposed the following definition:
“A possible definition for the disease CF could involve the following
sequence of pathologic events:
– Disease usually arises from two disease-causing mutations in the gene
encoding CFTR
– Mutations result in changes to the fluid and electrolytes on cell surfaces
– Changes may lead to abnormal secretions and inflammatory responses
– These manifestations may predispose to obstruction and infection
– Obstruction and infection may produce end-organ disease in tubular
structures such as the upper and lower airways, vas deferens, gut, liver,
and pancreas, with secondary impact on growth and nutrition.” (Wallis C,
in Kendig’s Disorders of the Respiratory Tract in Children, 2006, p866 – 872)
Genetics
•
CF is an autosomal recessive condition
•
In the late 1980s technical breakthroughs in
gene analysis involving chromosome
walking and jumping, and linkage
disequilibrium analysis resulted in 1989 in
the identification of the CF gene on the long
arm of Chromosome 7 at the 7q31 locus
(Kerem et al, 1989;245:1073) (Rommens et al,
1989;245:1059) (Riordan et al, 1989;245:1066)
•
As per convention the gene takes on the
name of the protein it codes for, in this case,
the cystic fibrosis transmembrane regulator
CFTR (more about that later)
•
Over 1500 mutations of the CFTR gene
have been identified
(www.genet.sickkids.on.ca/cftr/)
•
However, deltaF508 is the dominant
mutation seen in over 70% of CF alleles in
the Caucasian population worldwide
Genetics
•
All the other mutations are individually rare, with only 11 found in more than
100 patients
•
94% of the Irish CF population carries the deltaF508 mutation on at least
one chromosome, with 64% being homozygous for the mutation (The Cystic
Fibrosis Registry of Ireland Annual Report 2007)
•
The six next most common mutations are (The Cystic Fibrosis Registry of Ireland
Annual Report 2007):
– G551D
– R117H
– R560T/K
– G542X
– 1717-1 G-A
– 621+1 G-T
5 major classes of CF mutations
• Extensive research into genotype-phenotype correlations, along with
knowledge of the molecular mechanisms by which genetic
mutations result in defective proteins, has led to a classification
system for CF mutations (Welsh, et al, 1993;73:1251)
• It should be emphasized though, that most CFTR mutations result in
the classical severe form of the disease
• Class I: defective protein synthesis (e.g. G542X, 1717-1 G-A, 621+1
G-T)
• Class II: defective protein processing (e.g. DF508)
• Class III: defective regulation (e.g. G551D, R560T/K)
• Class IV: defective conductance (e.g. (R117H)
• Class V: reduced protein levels at the membrane
CFTR
•
The CFTR protein is a chloride
channel at the apical membrane of
epithelial cells (Riordan et al,
1989;245:1066)
•
It comprises of 1480 amino acids,
and is part of the family of ATPbinding cassette (ABC) transporter
proteins
•
Phosphorylation by protein kinase,
under the control of cAMP, and
hydrolysis of ATP, are essential for
activating the chloride channel
Normal mucociliary clearance
•
To understand the abnormality that occurs in CF we must first understand
what is normal
•
The respiratory tract is lined by ciliated columnar epithelium
•
Resting on top of the epithelium is the Airway Surface Liquid (ASL) which is
composed of an outer (towards the lumen) mucous layer, and an inner
watery Peri-Ciliary Layer (PCL) which bathes the cilia (Matsui, et al,
1998;102:1125)
•
The PCL is approximately 7 microns deep, which is the length of an
outstretched cilium
•
The arrangement is part of the innate immune system of the respiratory
tract, and works by trapping bacteria in the mucous layer which is then
transported in a cephalic direction by the mucociliary elevator to be coughed
and swallowed or expectorated – a process known as mucociliary clearance
CF is a disease of the
airways
From the nose to the
bronchioles the airway is
lined by pseudo-stratified
columnar epithelium
Airway lumen
Peri-ciliary layer
Mucus layer
Epithelium
Basement membrane
Airway surface liquid
ClCFTR
Ion Pump
Na+
ENaC
Mucous layer
Cl-
Na+
7 microns
CFTR
Peri-ciliary
layer
H2O
H2O
Mucous layer
7 microns
CFTR
Cl-
H2O
Peri-ciliary
layer
Na+
H2O
Purulent tenacious mucous layer
3 microns
CFTR
Cl-
H2O
Peri-ciliary
layer
Na+
H2O
Normal mucociliary clearance
• The volume of the ASL is tightly regulated by an active process of
ion transport
• Absorption of ASL: The epithelial Na channel (ENaC) actively
transports Na from the ASL into the epithelial cell, with Cl following
the electrochemical gradient, and H2O following the osmotic
gradient
• Secretion of ASL: In contrast CFTR actively transports Cl out of the
epithelial cell into the ASL, with Na and H2O following passively
• Therefore, if ASL volume is excessive, Na absorption increases, and
as ASL reaches a physiological optimum Na absorption reduces, or
stops. Cl secretion can then dominate if ASL volume is diminished.
CFTR in CF
•
In CF, derangement of CFTR in airway epithelium results in defective
epithelial ion transport by two mechanism
•
Lack of functioning CFTR appears to release ENaC from tonic inhibition,
which results in greater Na absorption, with Cl and H2O following, resulting
in diminished ASL volume
•
Defective CFTR is unable to secrete Cl, which would have resulted in Na
and H2O following, to rehydrate the ASL
•
The result of both of this processes is a reduction in the volume of the ASL,
with the PCL dropping to a depth of 3 microns
•
As a consequence mucociliary clearance is deranged, and mucous plaques
adhere to the epithelium
•
From this apparently innocuous start come all the devastating
consequences of CF lung disease
Pathogenesis of airway disease
•
Mucociliary clearance is inhibited, as described above
•
The mucous is thick, and prevents penetration by immune cells (but not
motile Pseudomonas aeruginosa)
•
The unregulated ENaC channels consume increased energy, and oxygen,
resulting in a relatively hypoxic environment in the mucous plaques
•
The resultant micro-environment appears to specifically select for the typical
CF airway pathogens, most notably P. aeruginosa
•
The presence of airway pathogens initiates a marked immune response
lead by neutrophils. The massive neutrophil response results in the
production of neutrophil elastase at levels that overwhelm the innate antiproteases (e.g. alpha1 anti-trypsin)
Pathogenesis of airway disease
•
The resulting free neutrophil elastase degrades the structural proteins of the
airway culminating in irreversible airway and parenchymal destruction
•
The problem is exacerbated by three further processes
•
Bacterial infection, and the resulting inflammation, induce increased mucin
production
•
DNA from necrotic neutrophils and bacteria increase the tenacity of airway
mucous
•
P. aeruginosa adapts to its new environment by producing biofilms which
significantly reduce its susceptibility to eradication by antibiotics
Pancreatic disease
•
The pancreatic acinus secretes isotonic liquid, which is then modified in the
pancreatic duct, to produce a fluid rich in HCO3- (Steward, et al, 2005;67:377)
•
Basolateral ion exchange mechanisms increase in the intracellular HCO3concentration, with CFTR playing a role in transporting HCO3- into the
lumin (Steward, et al, 2005;67:377)
•
CFTR appears to act as a conduit for anions other than Cl-, in particular
HCO3-, which is transported at about 40% efficiency when compared with
Cl- (Steward, et al, 2005;67:377)
•
In CF there is deficient secretion of HCO3-, and liquid, with resultant
abnormally acidic and viscous ductal secretions, which likely lead to early
activation of proteolytic enzymes within the gland, resulting in inflammation
and destruction (Johansen, et al, 1968;1:455) (Kopelman, et al, 1985;312:329)
Sweat gland
•
The observation that sweat electrolytes are abnormal in CF represents on
the seminal discoveries in CF (Di Sant'Agnese 1953;12:549)
•
Normally, isotonic sweat is produced in the sweat acinus, with Cl and Na
being reabsorbed in the resorptive duct, resulting in hypotonic (Cl 10 – 50
mmol/L) sweat reaching the skin surface
•
In the CF sweat gland, isotonic sweat is produced in the acinus, but the
CFTR dependent resorption of Cl is deficient resulting in abnormally high
sweat Cl levels ( 60 – 120 mmol/L) reaching the skin surface
•
This forms the basis of the pilocarpine iontophoresis induction of sweating
as part of the sweat test, which allows sufficient quantity of sweat for Cl and
Na analysis, and hence the diagnosis of CF (Gibson, Cooke, 1959;23:545)
The genetics and pathology of
CF come together when we focus
on diagnosis
Diagnosis
• The diagnosis of CF is usually made when an individual presents
with suggestive clinical features such as recurrent chest infections,
and evidence of malabsorption with failure to thrive and
steatorrhoea; which is then confirmed on sweat testing with an
elevated sweat chloride > 60 mmol/L.
• 18 % present with Meconium ileus in the neonatal period
• 15% present with a family history typically of an affected sibling
In 1998 the CFF issued a consensus
statement on the diagnosis of CF
•
Clinical manifestations
•
Or
•
•
Positive sweat test
•
Or
CF history in a sibling
•
positive nasal potential difference
•
Or
•
Or
•
positive newborn screening
•
two disease causing mutations
identified
Plus
In 1998 the CFF issued a consensus
statement on the diagnosis of CF
•
Clinical manifestations
•
Or
•
•
Positive sweat test
•
Or
CF history in a sibling
•
positive nasal potential difference
•
Or
•
Or
•
positive newborn screening
•
two disease causing mutations
identified
Plus
Symptoms at diagnosis
(The Cystic Fibrosis Registry of Ireland Annual Report 2007)
Symptoms at diagnosis
Percent of Total
Median age at diagnosis
(months)
Respiratory symptoms
only
23
16.3
Gastrointestinal only
22
5.8
Gastrointestinal and
respiratory
18
7.0
Meconium ileus
18
0.5
Family history
15
1.4
Unknown
4
3.5
0.4
No information
Other
Sweat Test
•
The sweat test was first described by Gibson and Cooke in 1959 and forms
the gold standard for the diagnosis of CF (Gibson, Cooke,1959;23:545)
•
Guidelines for sweat testing have been published, and its is imperative they
are closely followed in a laboratory with experience in sweat testing (Baumer,
2003;88:1126)
•
The technique uses iontophoresis to drive pilocarpine into the skin to induce
local sweating
•
The sweat sample is collected either using the macroduct system or on filter
paper
•
A minimum sample of 15 microL is required using the macroduct system,
and of 75 mg when using filter paper
Sweat Test
• Sweat Cl > 60 mmol/l is diagnostic of CF
• Sweat Cl < 40 mmol/l rules out CF
• Sweat Cl 40 – 60 mmol/l is equivocal
• Sweat Na should not be used to diagnose CF because values of up
to 80 mmol/l can be seen in conditions other than CF
• However the sweat Na can be used to check the validity of the test
as Na and Cl levels should be within 15 mmol/l of each other
• Sweat Cl > 160 mmol/l are physiologically impossible and if detected
require the sweat test to be repeated
• Sweat conductivity should not be used
CF Respiratory Disease
Respiratory
• The fundamental problem in the CF airway is the build up of
tenacious secretions resulting in airway occlusion, infection,
inflammation, airway and lung parenchyma destruction, and
bronchiectasis
• The central components of CF respiratory care are:
– Airway clearance
– Antibiotic therapy
Airway infection
Airway infection
•
The term airway “colonization” has largely been abandoned when discussing airway
pathogens, in favour of the term airway infection, recognising that the presence of
pathogens in the lower airway is abnormal and associated with an inflammatory
response.
•
Repeated airway infection leads to sustained inflammation which results in time in
irreversible airway and lung parenchyma destruction
•
Respiratory failure remains the principal cause of premature death in patients with CF
•
Much of the ongoing care of patients therefore is focused on managing airway
infection
•
It has been demonstrated that lower infection begins early in life, indeed in infancy
•
S. aureus and H. influenza are the typical initial infecting organisms, followed later by
P. aeruginosa
Cystic Fibrosis Foundation Patient Registry Annual
Data Report 2005
S. aureus
•
S. aureus is the most common organism infecting young children with CF (Elborn, et al,
1999;54:377), and remains an important pathogen throughout life, often present as a coinfection
•
There remains some debate regarding the pathogenicity of S. aureus, as it may be
present in sputum samples, in the absence of respiratory symptoms (Lyczak, et al,
2002;15:194)
•
However, bronchoalveolar samples from infants diagnosed with CF by newborn
screening demonstrate that in approximately 30% S. aureus can be detected, and its
presence is associated with a significant inflammatory response (Armstrong, et al,
1997;156:1197)
•
There remains controversy regarding the role of prophylactic anti-staph antibiotics
•
Infants diagnosed by newborn screening and treated with long-term flucloxacillin for
the first two years of life had, less frequent cough, less S. aureus isolates, lower
admission rates ( 5 v 19), for shorter periods (2.2 v 6.4 days), despite receiving half
the number of antibiotic courses (in addition to the flocloxacillin) (Weaver et al, 1994;70:84)
S. aureus
• A double blind placebo controlled trial of cephalexin as a long-term
anti-staph prophylaxis started at mean age of 15 months,
demonstrated reduced detection of S. aureus in airway cultures (6%
v 30%), however there was no difference in clinical outcome
measures, including lung function, x-ray scores, and nutrition. Most
concerning was the increased detection of P. aeruginosa in the
prophylactic cohort (26% v 13%) (Stutman, 2002;140:299)
• Currently the UK CF trust recommends the use of flucloxacillin as
anti-staph prophylaxis up to two years of age. When S. aureus is
detected after this, a two week course of anti-staph antibiotics is
commenced.
Pseudomonas Aeruginosa
•
P. aeruginosa is the most common chronic airway infection affecting patients with CF.
The prevalence of infection increases with age. By the third decade up to 80% of
patients are infected (Gibson et al, 2003;168:918)
•
Chronic P. aeruginosa infection is difficult to eradicate and is associated with more
respiratory symptoms, worse general health (Pamukcu et al 1995;19:10), more rapid decline
in lung function (Kerem et al, 1990;116:714), more rapid deterioration in CXR scores (Demko et
al, 1995;48:1041) and significantly worse survival (Lyczak et al, 2002;15:194) (Emerson et al,
2002;34:91)
•
The ability of P. aeruginosa to change from a non-mucoid to mucoid phenotype by
inducing bio-film formation, is an important feature in the establishment of chronic
infection (Lyczak et al, 2002;15:194)
•
Bio-films protect the organism from destruction by both neutrophils and antibiotics
(Drenkard et al, 2002;416:695) (Costerton et al, 1999;284:1318)
•
There are three different strategies for the antibacterial treatment of P. aeruginosa,
depending on the clinical situation: first isolation, infective exacerbation, and chronic
infection
1. First isolation
• Initially P. aeruginosa isolates are non-mucoid, motile, and are
present in low density, thus presenting an opportunity for eradication
(Rosenfeld et al, 2001;32:356).
• There is no consensus regarding the best eradication regime, but
they all involve early aggressive treatment with anti-pseudomonal
antibiotics
• Three weeks of nebulised colistin (1MU bd if < 2 yo, and 2 MU bd if
> 2 yo) with 2-3 weeks of oral ciprofloxacin is as effective (80%) in
initial eradication as three months of nebulised colisitin with 3 weeks
of oral ciprofloxacin, but the three month treatment regime increased
the interval to re-infection from 9 to 18 months (Frederiksen et al
1997;23:330) (Taccetti et al, 2005;26:458)
1. First isolation
• 28 days treatment with twice daily nebulised Tobramycin (300mg) for
inhalation (TOBI) eradicated P. aeruginosa from 8 of 8 children less
than 6 y/o, compared with just 1 of 13 children treated with placebo
(Gibson et al, 2003;167:841)
• Inhaled tobramycin (80mg) for one year eradicated P. aeruginosa
from 14 of 15 patients (Ratjen et al, 2001;358:983) (Wiesemann et al,
1998;25:88)
• When P. aeruginosa is detected again after eradication it is typically
a new strain, rather than a re-emergence of partially treated original
strain (Munck et al, 1998;32:288) (Taccetti et al, 2005;26:458)
2. Acute exacerbation
•
An acute exacerbation is characterised by an increase in respiratory
symptoms and signs, along with a reduction in lung function - typically a
drop in FEV1 > 10% (Dakin et al, 2001;31:436) (Marshall, 2004;169:781). Reduced
energy, and appetite, along with weight loss often also present.
•
Minor exacerbations are typically treated with two weeks of oral
ciprofloxacin (a quinolone), in addition to usual inhaled medications, and an
increase in physiotherapy
•
More significant infections typically require an increase in physiotherapy,
along with anti-pseudomonal IV antibiotics for 14 days
•
Usually two antibiotics are started; a beta-lactam antibiotic (e.g. ceftazidime,
tazobactum + piperacillin, meropenum) plus an aminoglycoside (e.g.
tobramycin, gentamicin, amikacin)
3. Chronic infection
•
Chronic P. aeruginosa infection is defined as the culture of P. aeruginosa in
2 or more airway samples over a six month period (UK CF Trust 2001)
•
Long-term use of nebulised antibiotics has been shown to be beneficial – it
should be noted that this is long-term treatment, rather than prophylaxis
•
Overall, only approximately 10% of the nebulised drug is delivered to the
lungs (Le Conte et al, 1993;147:1279)
•
Long-term nebulised tobramycin for inhalation (300mg twice daily) has been
demonstrated to be safe, and to improve quality of life, increase lung
function and reduce exacerbation rate (Ramsey et al, 1999;340:23) (Ramsey et al,
1993;328:1740) (Quittner et al, 2002;33:269) (Moss et al, 2002;121:55)
3. Chronic infection
• Tobi is to be given with the Pari LC Plus nebuliser with Pari
TurboBoy compressor
• Nebulised Colistin has also been used for some time, particularly in
Europe (Littlewood et al, 2000;94:632)
• The effectiveness of long-term nebulised Colistin has been
demonstrated, with improved symptoms, reduced bacterial load, and
maintenance of lung function (Littlewood, et al, 1985;1:865) (Jensen et al,
1987;19:831)
• However, there is some limited evidence that nebulised Tobramycin
is superior to Colistin in maintaining lung function (Hodson et al,
2002;20:658)
Burkholderia Cepacia
•
•
Burkholderia is a genus which
contains several species. Initially
the species were phenotypically
indistinguishable, but were
identified through molecular
genetic typing as distinct
genomovars (I – IX) (Vandamme
et al, 1997;47:1188)
The Burkholderia species can now
be identified phenotypically, with
the nine genomovars which cause
lung disease in CF collectively
referred to as the Burkholderia
Cepacia Complex (Coenye et al,
B. multivorans
Genomovar I
B. cepacia
Genomovar II
B. cenocepacia
Genomovar III
B. stabilis
Genomovar IV
B. vietnamiensis
Genomovar V
B. dolosa
Genomovar VI
B. ambifaria
Genomovar VII
B. anthinia
Genomovar VIII
B. pyrrocinia
Genomovar IX
2003;41:2797)
Burkholderia Cepacia Complex
•
B. cenocepacia (previously Genomovar III), and B. multivorans (previously
Genomovar I) cause the majority of infections in the CF population
•
B. cenocepacia is particularly problematic
– It is highly transmissible among CF patients
– Approx 1/3 of patients infected will develop Cepacia Syndrome, which results in
systemic signs of sepsis, weight loss, CXR infiltrates, a rapid decline in lung
function, and early death within weeks, to months, despite maximal antimicrobial
therapy. (Jones et al, 2004;59:948)
– There are some patients who remain well despite the presence of B.
cenocepacia in their airways, however the majority with chronic infection have a
more rapid decline in lung function, with a worse prognosis, than those with
chronic Pseudomonas infection (McCloskey et al, 2001;170:28)
– It is typically resistant to most antibiotics, however, meropenum or ceftazidime, in
combination with an aminoglycoside, may be useful, with co-trimoxazole added
as a third agent (Aaron et al, 2000;161:1206)
Non-tuberculous mycobacterium
•
Mycobacterium avium complex (MAC) and Mycobacterium abscessus account for 70%
and 15% respectively of non-tuberculous mycobacterial (NTM) infection in CF patients,
with M. abscessus being the more virulent of the two (Olivier et al, 2003;167:828)
•
NTM tend to be transiently detected in the airways, with only a minority of patients
developing clinically relevant disease. (Olivier et al, 2003;167:835)
•
The ATS guidelines for the diagnosis of NTM infection are:
– Three sequential positive airway cultures
– A decline in lung function
– New changes on CT scanning (ATS, 1997;156:S1-25)
•
However, as NTM is often a co-infection with Pseudomonas, it is prudent to treat
Pseudomonas infection first, and if there is no clinical improvement, to then start antiNTM therapy
•
Rifampicin, ethambutol, azithromycin and ciprofloxacin have been shown to be useful.
Imipenem, and amikacin (IV or nebulised) may also be used in difficult cases. Treatment
should be continued for one year with negative sputum cultures. (Leitritz et al, 2004;139:209)
(Forslow et al, 2003;92;910) IFN-gamma may also have a role, in some cases (Hallstrand et al,
2004;24:367).
ABPA
•
Aspergillus is a fungus which is commonly found in the airway samples of
patients with CF (prevalence of 1 – 60%) (Stevens et al, 2003;37(suppl):S225)
•
On many occasions it is simply a non-pathological colonizer of the airway,
however a hypersensitivity reaction may develop to its presence resulting in
allergic bronchopulmonary aspergillosis (ABPA)
•
Diagnostic criteria for ABPA are :
– The occurrence of asthma symptoms
– New CXR changes
– A four fold increase in IgE titres, or Ige > 500 iU/L
– Increased specific IgE RAST to aspergillus or positive skin prick test
– Eosinophilia > 500/mm3
– Positive sputum culture (CF UK Trust Antibiotic treatment for CF, 2nd Ed, 2002;
available at www.cftrust.org.uk )
ABPA
• Treatment
– 0.5-1mg/kg/day Prednisolone for two weeks, with gradual
tapering of the dose over 2 – 3 months
– The role of anti-fungals is not clear, but treatment with
itraconazole is often initiated with steroid treatment (Stevens et al,
2003;37(suppl):S225)
Stenotrophomonas maltophilia
•
Stenotrophomonas maltophilia does not appear to have a significant impact
on lung function or mortality (Goss et al, 2002;166:356).
•
It does not appear to be transmitted between patients, and the majority of
patients only have it transiently in their airways (Goss et al, 2004;59:955)
•
There are no clinical trials of antibiotic treatment for S. maltophilia, however
as some patients may go on to develop chronic infection, first isolates
should probably be treated. Equally patients who are symptomatic, and/or
deteriorating, should have antibiotics prescribed which are effective against
S. maltophilia.
•
S. maltophilia is resistant to a broad range of antibiotics. Ceftazidime may
be useful, or IV piptazo and an aminoglycoside. Oral co-trimoxazole also
has useful activity (Krueger et al, 2001;41:71).
Haemophilus Influenzae
• Haemophilus influenzae is detected frequently in the airways of
patients with CF, and is often detected early in the course of the
disease (Armstrong et al 1997;156:1197)
• Although there is little evidence that it causes significant pathology, it
is however pathogenic in non-CF bronchiectasis (Bilton et al, 1995;8:948)
• It is often associated with increased symptoms and when this is the
case it should be treated with an oral antibiotic such as co-amoxiclav
(Rayner et al, 1990;65:255)
Airway clearance
Airway clearance
• Daily physiotherapy forms the cornerstone of CF airway clearance
• Historically postural drainage and percussion was used, although
there are a wide number of modalities now available.
Percussion technique
• Postural drainage involves placing the patient in positions that
allows gravity to assist mucous clearance (there are 12 positions,
although the head down position is now generally avoided because
of concerns regard gastro-oesophageal reflux)
• The technique requires an assistant to percus over the chest for 210 minutes, usually followed by deep breathing and huffing
• The technique is now mostly used on infants and young children
Active Breathing technique
• Active cycle of breathing techniques involve cycles of controlled tidal
breathing at functional residual capacity, with deep breath thoracic
expansion, and forced expiration using huffing
• Autogenic drainage involves controlled breathing in three phases;
un-stick (at low lung volumes), collect (at mid lung volumes), and
evacuate (at high lung volumes). It is designed to bring secretions
from peripheral airways more centrally. Cough is suppressed until
the final breath at high lung volume. Ventilation of peripheral airways
is also likely enhanced.
Positive pressure techniques
•
Positive expiratory pressure (PEP) mask involves a mask with a resistor which
generates pressure (typically 10-20 cmH2O) during expiration (Falk, et al, 1984;65:423)
•
The technique involves tidal breathing against the pressure on exhalation, for about 12
breaths, followed by forced expiration
•
Oscillating PEP is similar to the PEP system described above, with the addition of an
oscillating valve that generates intermittent acceleration and deceleration of airflow
during the manoeuvre
•
These flow transients occur at a frequency of approx 2 – 32 Hz, with pressures from 5 –
25 cmH2O, and are sometimes described as “micro-coughs” thus promoting mucous
clearance
•
The technique involves a deep breath into the inspiratory reserve (but not to total lung
capacity), a 3 second breath hold, followed by active expiration over 3 seconds into the
expiratory reserve (but not to residual volume). The technique is repeated 10 – 15 times
followed by a huff to initiate expectoration
•
The Flutter and Acapella are the usual devices used. The are similar, but the Acapella
can generate a PEP of 10-20 cmH2O at end expiration
High frequency chest compression
•
There are several companies producing their own version of “the vest”
•
It consists of a compressor system which delivers large volumes of air at
frequencies of 5 – 25 Hz, to an inflatable jacket worn over the patient’s
chest
•
The pressure pulses can be adjusted (typically between 0 – 20 cmH2O), as
well as the frequency
•
Higher oscillating frequencies result in higher flow rates, and more shear
force to dislodge mucous. Higher pressure increases both flow and volume,
but is more uncomfortable
•
The vest appears to provide clinically effective airway clearance, however it
does not appear to be superior to previously describe techniques, and as
such it is difficult to justify its cost ($15,000)
Treatment options to improve
airway clearance
Dornase alfa (pulmozyme)
•
Due to neutrophil and bacterial breakdown, CF sputum has DNA levels 3-5
times higher than normal
•
Recombinant human dornase (rhDNAse), also known as Dornase alfa, or its
trade name Pulmozyme, hydrolyses extracellular DNA, thus improving
mucociliary clearance
•
Pulmozyme is administered using the Portaneb compressor and a jet
nebuliser such as the Sidestream neubuliser
•
Fuchs et al demonstrated 15 years ago that 6 months of pulmozyme
treatment improved FEV1 by approximately 6%, as well as reducing
exacerbations and improving well being (Fuchs, et al, 1994;331:637)
•
These findings have been replicated, leading to a recent review
recommending pulmozyme for all patients over 6 years old, especially those
with chronic Pseudomonas infection (Conway, et al, 2002;34:242)
Hypertonic saline
•
Hypertonic saline (HS) is an airway clearance adjunct which appears to
work by temporarily hydrating the airway and inducing coughing
•
There is a stepwise increase in mucuciliary clearance from 0.9%, to 3%, to
7% hypertonic saline (Robinson, et al, 1997;52:900)
•
HS was shown to be inferior to Pulmozyme in a cross over trial in children.
However, there was significant heterogeneity in the response, with some
children (35%) having greater than 10% improvement in their FEV1. This
group included some who did not respond to Pulmozyme (Suri, et al,
2001;358:1316)
•
A recent Cochrane review concluded that HS did not demonstrate an
improvement in lung function, however did recommend its use as it
improved quality of life and reduced frequency of exacerbations
(2009;2:CD001506)
Anti-inflammatory medication
Steroids
• A Cochrane review of the use of oral corticosteroids concluded that
1 – 2 mg/kg alternate day prednisolone slow the progression of lung
disease, but at the expense of a negative, and potentially
irreversible, affect on height, along with the development of impaired
glucose metabolism, and of cataracts (Cheng et al,
2000;(2):CD000407). Long-term, high dose steroids, therefore are
not used to treat patients with CF. The role of low dose steroids (e.g.
5 – 10mg per day) is yet to be defined.
Non-steroidal anti-inflammatory drugs
(NSAIDS) – Ibuprofen
• Ibuprofen reduces the rate of decline in lung function, however
concerns regarding gastrointestinal and renal side effects have
limited its universal use (Konstan et al, 1995;332:848)
Macrolides
• Azithromycin, although an antibiotic, appears to have antiinflammatory affects on the CF airway. It has been demonstrated
that patients over 6 years of age, taking azithromycin three days per
week, had a higher FEV1 by approx 6% when compared to the
placebo group (Equi et al, 2002;360:978) (Saiman et al, 2003;290:1749)
Nutrition
Nutrition
•
Intensive long-term nutritional support is central to the ongoing care of patients with
CF
•
It has been clearly demonstrated that poor body weight and height are independent
risk factors of mortality (Sharma et al, 2001;56:746) (Beker et al, 2001;101:438)
•
Effective nutritional support has been demonstrated to slow the rate of decline in lung
function (Steinkamp et al, 2002;57:596)
•
Energy requirements vary considerably and depend significantly on the clinical status
of the patient. Energy requirements can be increased secondary to infection,
inflammation, increased work of breathing, and decreased lung function (Bell et al,
2000;30:553). Energy needs in undernourished adolescents with CF can be up to 120150% of those without CF (Pencharz et al, 1984;3(suppl):s147)
•
Many patients fail to meet their target calorie intake as a result of several factors such
as; anorexia, gastro-oesophageal reflux, abdominal pain, and increased sputum
production (Kawchak et al, 1996;129:119) (White et al, 2004;3:1)
Nutrition
•
Evidence from northern Europe suggests up to 95% of patients are
pancreatic insufficient (Littlewood et al, 2000;2:205). From a limited number of
patients in whom the data was available in the Irish CF registry,
approximately 88% of patients under 18 years of age are pancreatic
insufficient (The Cystic Fibrosis Registry of Ireland Annual Report 2007).
•
If symptoms of malabsorption are evident, a stool sample for faecal elastase
should be taken, and pancreatic enzyme replacement therapy (PERT)
started (Borowitz et al, 2005;11:524).
•
Enzymes come as enteric coated acid-resistant preparations
•
Different strengths are available but typically a capsule contains 10,000 of
lipase
•
Fat soluble vitamins A, D, E and K are also replaced
Nutrition
•
Infants typically begin with a starting dose of 2500IU lipase or in practical terms half a
scoop of Kinder Creon per breastfeed or 120mls of breastmilk substitute that provides
approx < 4.5g of fat ( ie 500 IU lipase per gram of dietary fat) The dose is then
titrated according to weight gain and bowel symptoms - frequency, odour, texture
and colour.
•
For older children dosing is approached on an individual basis. The dose usually
ranges between 500 -4000 IU per gram of dietary fat aiming for the lowest effective
dose. Weight gain, growth and bowel symptoms are monitored and dosages adjusted
accordingly.
•
Fat intake is relatively high relative to body weight in infancy but decreases with time.
Infants ingest approx 5g of fat per Kg of body weight per day whereas
older adolescents and adults ingest about 2g of fat per Kg of body weight per
day. The enzymes are distributed throughout the day by matching lipase to the
amount of fat in food and drinks.
•
The maximum recommended dosage for children and adults is 4,000 IU lipase / g of
fat or 10,000 IU lipase /Kg/ day
Meconium Ileus (MI)
• Clinical presentation
– Infants present with bowel obstruction within the first 48 hours of
life
– Vomiting (often bile stained)
– Abdominal distension
– Failure to pass meconium
– Right lower quadrant mass may be palpable
Meconium Ileus (MI)
• X-ray findings
– PFA reveals distended bowel loops, usually with no air-fluid
levels
– Right lower quadrant speckled “ground glass” appearance seen
in approx 30 – 50 % of cases (but also seen in other cases of
neonatal bowel obstruction e.g. Hirschprung’s disease, small
bowel atresia)
– Contrast enema may demonstrate micro-colon, and demonstrate
the site of obstruction at the distal ileum
Meconium ileus
•
Approximately 40% of cases are complicated by; intestinal atresia, volvulus,
or antenatal perforation with meconium peritonitis
•
Therapy is aimed at decompression and relief of the obstruction
•
Uncomplicated MI can be treated in the first instance with gastrograffin
enema
•
If this fails to relieve the obstruction surgical intervention is required. This
involves a laparotomy with irrigation of the obstructed ileum. Temporary
ileostomy may be required to allow ongoing irrigation, and to allow the
microcolon time to resolve
•
Note; MI is not pathognomonic of CF with pancreatic insufficiency, therefore
the diagnosis, and pancreatic status should always be confirmed
CF related diabetes
•
As discussed above, exocrine pancreatic function is lost in approximately
90% of patients with CF. In the majority of cases this has occurred at the
time of presentation in infancy or during the pre-school years.
•
Islet cell secretion, as part of the endocrine function of the pancreas, is lost
in a much smaller proportion of patients.
•
This occurs over time, with prevalence increasing with increasing age, from
approximately 5% in 10 – 14 y/o, to 12.6% in 15 – 19 y/o (Koch et al, 2001;31:1),
to approximately 24% in those over 20 y/o (Lanng et al, 1995;311:655)
•
Abnormal glycaemic control in CF related diabetes (CFRD) is characterised
by impaired and delayed insulin secretion resulting in insulinopenia (Moran et
al, 1998;133:10). Of note, glucagon secretion is also impaired (Lanng et al,
1995;311:655).
•
Of note, there is only one reported case of ketoacidosis in a CF patient, in
the literature (Atlas et al, 1992;146:1457)
CF related diabetes
•
The onset of CFRD is clearly associated with increased mortality (Koch et al,
2001;31:1), particularly in female patients (Milla et al, 2005;28:2141)
•
Lung function decreases significantly faster in patients with CFRD
(Rosenecker et al, 2001;6:345)
•
Patients are at risk of microvascular complications of diabetes (such as
retinopathy, nephropathy and neuropathy) (Dolan et al, 1986;314:991), but not the
macrovascular complications such as athersclerosis (Schlesinger et al,
1997;16:365a), although this could change with improving survival.
•
It is also becoming clear that lung function and clinical status can decline in
the pre-diabetic period (Lanng et al, 1992;151:684)
•
Insulin treatment, even at low doses, has been demonstrated to improve
lung function and weight (Dobson et al, 2002;87:430), although clear treatment
guidelines are yet to be developed, particularly for the pre-diabetic period
CF associated liver disease
•
The reported prevalence of CF associated liver disease (CFALD) varies widely
depending on the definition of liver disease
•
A postmortem study in adults found evidence of liver disease in over 70% of cases
(Vawter et al, 1979;14(pt 2):357)
•
A longitudinal French study detected CFALD in 18%, 29% and 41% of children at 2, 5
and 12 years of age, but only 6 – 8 % of these went on to develop cirrhosis (Lamireau et
al, 2004;41:920)
•
The majority of patients develop overt signs of liver disease in the first 12 years of life
(Corbett et al, 2004;145:327)
•
The characteristic lesion in CFALD is focal biliary cirrhosis (Vawter et al, 1979;14(pt 2):357)
•
Ursodeoxycholic acid (Urso) improves biochemical markers of CFALD as well as
histological changes (O’Brien et al, 1992;33:387) (Lindblad et al, 1998;27:166), however there is no
clear evidence that it alters the long-term course of CFALD
Reproductive health
•
Males with CF are sterile due to congenital bilateral absence of the vas
deferens resulting in azoospermia (Kaplan et al, 1968;279:65)
•
The seminal vesicle is often absent or atrophic resulting in low volume
semen (McCallum et al, 2000;118:1059)
•
Normal spermatogenesis takes place in the testicles which are histology
normal (McCallum et al, 2000;118:1059)
•
Libido and erectile function are normal, however chronic ill-health can have
a negative impact on both (Sawyer et al, 2005;60:326)
•
Women with CF have anatomically normal reproductive tracts (Oppenheimer et
al, 1970;77:991)
•
Although cervical mucous is likely to be abnormal and impair conception,
with reports that 75% of women who tried to conceive became pregnant
(Odegaard et al 2002;81:693), all women with CF should be considered fertile
Atypical (non-classic) CF
•
It is now recognized that mutations in the CFTR gene give rise to a range of
phenotypes that includes classic CF, and reaches to single organ
pathologies
•
The term “mild” or “atypical” CF refers to children and adults who present
without signs of significant respiratory disease, or malabsorption, but
instead may have sinus disease, pancreatitis or male infertility, amongst
other symptoms (Wallis, in Cystic Fibrosis 2007, p99 – 108)
•
Affected individuals may have normal, borderline or abnormal sweat tests,
and one, two, or no, CF causing mutations identified (Gooding, in Cystic Fibrosis
2007, p209 – 224)
•
It is generally accepted that the diagnosis of “classic” CF is not appropriate
for these individuals and the initiation of arduous therapies is inappropriate
and unlikely to be of benefit.