CF LECTURE 2

CF is a result of a mutation in CFTR gene, which is

responsible for the development of the CFTR Chloride
and channels on that sodium chloride balance. It
effects multiple different organs within the body,
even though people generally think about it as a
respiratory disease, a lot of the symptoms manifest as
breathing difficulties due to that mucus blockage and
inflammation of the airways and an infection that
comes with it as well. In picture C= a Bronchiectasis
lung is cause because of the inflammation and
infection. Bronchiectasis lung is a widening and hyper
expansion of the airways and loss of elastic recoil
therefore much poorer oxygen exchange going on
within the lungs.

Bacteria that are involved in CF infections, all these bugs all

together then cause that inflammation and that chronic
obstructive disease.

How does that happen and what is the process involved in this? The
presence of infection results in increased mucin production that
increased mucin then produce this mucus and that accumulation of
mucus in the lungs. Mucus is thick in patients with cystic fibrosis and
as a result that = get a lot of accumulation of bacterial products
and bacterial debris from the infection that's already there and
that sticks around in that thick sticky mucus in the CF patient as a
result of that presence of that bacterial product in that bacterial debris,
the body basically continues to produce a neutrophil response to that.
That neutrophil response then causes the release of neutrophil
proteases. So, they include elastase and Matrix Metalloproteinases
and these cause damage to airway tissue. It causes proteolysis and
chondrolysis of the airway tissue, and that causes further inflammation
and obstruction leading to inflammation and obstruction then
increases the risk of infection and reinfection.It's a cyclical process and it causes a lot of damage as that repeated
process occurs over and over again and
ends up in airway dilation and Bronchiectasis
So other potential complications include haemoptysis
that repeated infection and damage, leads to blood being
present in the mucus and that might present as the patient
coughing up blood within the sputum. There's also a risk of
respiratory failure as the airway start obstructing and blocking
and you're going to get less oxygen within the system.
And lung function can be affected as well and ultimately
results in respiratory failure as cannot get that good
oxygen CO2 exchange. Pneumothorax is a collapsed lung. this
occurs when an air leaks into the space between the lung and
the chest wall = results in pressure building and it causes that
pressure to build up and basically then pressure to push on the
lung itself, as the air can't escape, the lung will collapse
resulting in a pneumothorax.

Vaccinations are really important. Have very big role as

pharmacists to make sure patients are up to date with their
vaccinations, to reduce their exposure to diseases that could
cause more damage and the fact that actually they're more
vulnerable to them as well. Gene therapy is really changing the
outlook for cystic fibrosis patients. If we introduce gene therapy
at a much earlier stage, we can reduce the damage that actually
happens and hopefully change the prognosis for patients with CF
oxygen can be used for patients, particularly those that have
gone into respiratory failure.
Physiotherapy is an important treatment and within the
management of cystic fibrosis.

Prime sort of treatment = Patients with CF have

very thick, sticky mucus = so try to reduce its
viscosity and make it easier to cough up.
Dornase alfa used to reduce sputum viscosity in patients
with CF and and because patients, as we talked about
before, in that little cyclical cycle of how infection then
causes damage to the lungs. The bacteria presence results
in the bacteria leaving basically debris and parts of its DNA
within the mucus = contributes to the viscosity= The
thickness of the mucus, that presence of that
bacteria in that DNA that's there. Dornase alfa that it
hydrolysed the DNA in sputum and then reduces the visco
elasticity of the CF sputum, so just helps to break down the
DNA rather than the mucus. Available in a nebuliser form
PULMOZYME =the brand NAME and is expensive, but
actually does work very effectively for patients.

Ivacaftor = Gene modifier medication and so with this one it's potential it's the safety
of protein increases that channel to enhance chloride transport, more sodium can get through,
which means more water can get through and then reduces the viscosity by having basically diluting it down and
the mucus and reducing that thickness. Licensed only if they have a specific gene mutation. So, it's important to make
sure that it's appropriate for the patient and they may end up with a reduced dose is taken such taking certain
antibacterial or antifungals. That's particularly appropriate because a lot of CF patients are on long term therapy and
prophylaxis with antibacterial and antifungals. It's an oral tablet, so potentially may be better compliance than with a
nebuliser as nebulisers take about sort of 10 minutes to run and they're noisy. It might be preferable for a patient,
and you might get better compliance for it. Mannitol is it's hyperosmotic, so it's got a high level of sodium within it.
There are other preparation such hypertonic saline, which is a higher level of sodium content in the preparations.
That's normally about 3 to 7% sodium chloride and is then used to nebulised into the lung = reduce crosslinking
and then it causes the DNA to disassociate from the mucoprotein, and that then allows the natural proteolytic
enzymes to digest the muco-protein but saline itself also adds water to the airway surface, increases the salt in the
airways, and that triggers water to be transferred to the epithelial surface. When that sodium chloride channel isn't
working effectively and can't get sodium to the surface of the cell = artificially put some salts and sodium there and by
using the nebulisers in a localised effect.

Mucolytic and physiotherapy go hand in hand and mucolytic are

used to reduce that sputum viscosity then use a physiotherapy to
help get rid of the mucus then as still need to cough it up. One of
the potential advantages of using anything
that is either a dry powder inhaler or using the
saline as well, that hypertonic saline, it naturally quite often
causes local irritation, causes us to cough = that little bit of a side
effect can be quite useful to then help the patient cough up
the mucus as they've been reduced in its viscosity.
These airway clearance techniques are designed
around the patient, so the physiotherapist will assess the patient
and work out what's going to work best for them
depending on what their symptoms are and where they're having
problems.
1. Active cycle of breathing techniques
Involves a sort of a combination, there's breathing control.
So, with that breathing control, it's basically relaxed breathing is very important part of the technique as it
allows pauses for rest and helps any and of tightening of the airways, it's focusing on the patient, actually relaxing
their airways and trying to make them as open as possible. Make sure that their muscles are nicely relaxed so they
can cough up and clear the secretions, because if they're tight, then actually they're not going to get as good
expansion of the airways and a good cough. Upper chest should remain relaxed with most of them have been
occurring in the lower chest. Thoracic expansion exercises = deep breathing, help the lungs to expand more
effectively and allow air to get behind any secretions that they can then be pushed up and out and through
the airways, out through the mouth. These breath in should be slow and deep.
Forced expiratory technique that's part of the ACBT technique = huffing, it helps to move secretions from the smaller
and to the larger airways so can then be cleared more easily. Huff isn't always sufficient to clear the secretions
because we've said that it's not a forceful expiration. The cycle of different breathing techniques and can
be repeated until the chest is clear or the patient's too tired to do any more.
2. Positioning = using gravity to try and help clear the airways. This involves different positions or and gravity
to basically allow the airway clearance and using parts of the body. May use pillows or different things to sort
of help them get into those positions.
3. Percussion of vibration = is basically known as chest clapping.
4. Vibration = described as chest shaking, using a gesture like a light shaking of
the chest to help cause that vibration through the lungs. It's a technique where it consists of several short
rhythmical squeezes to the chest wall as that child or adult breathes out. This can be really useful to mobilise
secretions.
5. Oscillating positive expiratory pressure (PEP) Devices = comes in different forms and physio decides which
one to use. There's a high frequency chest wall oscillation where the patient wears a jacket and that causes, and they
put that jacket on and it's got an electric air compressor in it. Vibration then helps move the sputum within the
lungs. Not that widely used. It's quite expensive and it doesn't. The reason it's not very popular is
actually, it's not shown to be significantly more benefit than
the other techniques. There's also a positive expiratory pressure, a technique
where you get back pressure to the airways during the breath out = helps to open up the airways and get air behind
the secretions to help them move up and get them out of the airways. The Flutter, the acapella and the cornet.
Physiotherapy and mucolytics are used to reduce that inflammation damage.
Transplant is sometimes the only option once
all that damage has occurred to the patient's lungs.
Some patients do get a heart transplant as well as
a lung transplant with cystic fibrosis.
Transplant procedure itself carries a really significant risk
for approximately 10% risk of dying in the first month
following the operation. So internationally and nationally, the
overall survival after lung transplant
is about 80% at one year, then 50% of five
years and 35% at ten years, mainly because =
the side effect of all those immunosuppressants and
the vulnerability that is then results from the patient sort
of taking all the medications.
Main contributors of how successful a transplant is
and depends quite often sometimes from the donor lung and
the failure of other organs, so are organs are all
depend on each other. If there has been lung damage quite
often, instead it might be heart damage as well.
So, although the lungs are working well, the heart isn't.
And then that causes pressure on the lungs and they're
more likely to fail and any ongoing infection as
well. So, for a patient to be put onto the transplant
list, they have to have a qualifying condition. They have the qualifying condition; they're assessed and they're
referred to an appropriate transplant centre where they then have a very comprehensive assessment. During this
they go through the selection criteria to see actually, do they have any cautions or contraindications to them
having the transplant? Is there reason, any reason why they couldn't have it
done? if everything is okay, there are no cautions or contraindications. They'll then be put on the transplant list.
the length of time on the transplant list is variable. It could be weeks to years. Some patients even die before they
actually get to receive an appropriate transplant on that. So, there may be several patients that are paged
to say there is a transplant available and they will know that they are potentially second or third on the list.
They have to have like lifelong immunosuppression and monitoring, which is a big impact on life and might be a
reason why patients might actually turn down a transplant, because they actually see this as a reduced quality of life
rather than an improved quality of life. Despite their lung functioning might be improved, this is
too much of a disadvantage to them. Then because of this as well, the immunosuppression, the monitoring, we're
going to be managing any complications. There is a risk of rejection they can go through all the surgery and all
this treatment, and then they can then have rejection of that shunt that that lung transplant. They would have to go
back onto a list

Include idiopathic pulmonary fibrosis and it might include

sarcoidosis and, an inflammatory type of response that does then
cause damage of fibrosis and thickening of the lungs. Obstructive
lung disease and the most common obstructive lung disease=
COPD also chronic asthma. Pulmonary vascular disease = patients
that have complex congenital heart disease. Might have
Pulmonary veno-occlusive disease and then finally, you've then
got superlative lung disease, which is cystic fibrosis
Within this, there are also certain requirements for
cystic fibrosis patients that they have to meet as well
before that they can go on the transplant list.
They also need to be on maximal medical therapy and
have a potential survival benefit of more than five years
and a quality of life that's acceptable to the recipient
as well.
What would stop a patient from having that
treatment?
 The only exception is if they've had a skin cancer and
that hasn't metastasised.
 If they've got a BMI of over 35 kilos per square foot, it's
contraindication. But remember, majority of our
patients with cystic fibrosis are malnourished and they
tend to be underweight
 Dysfunction of the lungs can then cause pressure on
other organs. They're interdependent on each other,
particularly, patients are at risk of heart failure as well,
also, they could have renal failure or any liver failure as
well.
 If they've got an unstable critical condition and that
might be a potential reason for a patient to surgery change and they might be top of the list.
 if they've got any substance or abuse or addiction, and that includes smoking. Patients will be asked to stop
smoking. If they don't, they would be off the list for a lung transplant. They are able to drink alcohol unless it
would be for a liver transplant. If it's a lung transplant, they still can drink alcohol, but it has to be within the
NHS guidance.
 the fact that we are potentially going to be introducing a lot of medicines to prevent that and transplant that
organ being rejected. If they currently already struggle or are non-compliant with treatment, then actually
they're at higher risk of rejection. It's important to make sure that they haven't got any history of non-
adherence. Non-adherence might be a reflection of their attitude towards their disease and how important
they view and their management of that condition.
 Cystic fibrosis patients, actually their life expectancy actually quite often doesn't quite hit 60 on average a
lot of patients potentially would always be under 60 for lung transplant for CF.
 What potentially applies a little bit more to our cystic fibrosis patient is and malnutrition. If their BMI is less
than 17 kilos per metre squared, then that's a relative contraindication.
 If they are on regular chronic high dose of oral corticosteroids and that's defined as more than 15
milligrams per day of prednisolone, if these patients are particularly deteriorating; it quite often means that
their doses of steroids can't be reduced down because they will get an exacerbation and respiratory
symptoms. So could be a reason for them to have be contraindicated for a transplant.

So once a patient is selected, there's still a risk

that they could deselected because things change.
So, what would cause the patient to deselected from
the transplant lists.
 failure of adherence to guidelines relating
to smoking or illicit drug use.
 if they develop any co-morbidities, that
would expect the probability of surviving at
five years
 if they develop any of the absolute and or
relative contraindications as well then that
is potentially a reason for them to be
selected.
 The patient no longer wishes to remain on
the list because things may have changed,
their opinion may have changed, and the prognosis
and their belief of what the benefit to them may have
changed as well.
 The patient can also take themselves off the
list.
  Chest x rays and look at the lungs and also the heart as well.
 A six-minute walk. A six-minute walk is basically the
distance a patient can walk on a flat hard surface in a time of
6 minutes, during this time, they can take a rest if needed,
and they can do as pace of their choosing = indicates the
capacity and ability to be mobile.
 EKG done to double check what's going on with the heart
and also a lung function test to see whether we've got
deterioration and or an improvement.
 if during the time the patient's condition deteriorates
that the risk of transplantation would be too high.
They then again, may be removed from that waiting list.

 GORD is a common issue post-transplant. if it's

persistent and the patient may need admission and
surgery potentially as well, but they wouldn't do this
until about 6 to 9 months post the transplant to allow
them to have recovery.
 Prophylaxis for cytomegalovirus as well, which is
abbreviated normally to CMC, which transplant patients
are particularly susceptible to contracting because of
that immunosuppression.

 Going to use really potent immunosuppressive drugs,

we're going to have our corticosteroids there, which
are probably going to be there at quite a high dose.
prednisolone is normally the most common one,
maybe sometimes might be dexamethasone.
 Want to use these really potent drugs to
basically, switch off the immune response to the
newly transplanted lung, also use these monoclonal
antibodies and to deplete the lymphocytes on there.
 Once they've gone through the induction period,
they'll then go on to a maintenance and this is where
you'll see this triple therapy happening. They'll be on
corticosteroids still from before, but they
may be a slightly lower dose
They will be on corticosteroid and then two of these
options of immunosuppressants
 Maintenance treatment may not be successful and the patient actually starts rejecting the transplant. if they
do, to reject the transplant or start showing symptoms and signs of it during that monitoring period their
corticosteroids would be increased and then they would have their immunosuppressants and therapy
changed. So they may switch from tacrolimus to sirolimus and or and they may also have these monoclonal
antibodies restarted and potent reducing the immune response.
What actually happens with immunosuppression?
Where do these drugs work and why do we use
triple therapy? What's our normal response to an
antigen?
So here we've got an antigen from a transplant organ,
our little star.
And here we've got an antigen presenting cell known as
abbreviated to APC.
When the antigen links with the APC cell and
that then causes CD4 lymphocyte activation, that
activation then activates
the calcineurin pathway and causes synthesis of IL-2
that generates T helper cells and zero cells which then
trigger interleukin two and triggers the mammalian
target of rapamycin
and the mTOR pathway and then causes proliferation of
t- helper cells.
All different immunosuppressants act at different points,
which is why we use triple therapy to try and make sure
that we're targeting all these different areas.
Corticosteroids act at multiple points. CD four lymphocyte activation on
the calcineurin pathway and also on the interleukin two triggers. There are immunoglobulins and your
ATG and alemtuzumab working at the CD4 lymphocyte activation and then got cyclosporin’s and tacrolimus working
here at the Calcineurin pathway or sirolimus works at rapamycin the mTOR pathway. Then the Azathioprine and
mycophenolate work the proliferation of the T helper cells.

 with that maintenance therapy, that the patient will be on triple therapy so that
corticosteroid with either azathioprine and or mycophenolate and
then tacrolimus or cyclosporine.
 Sirolimus might replace tacrolimus at some stage. If there is any rejection or are there any
problems or any side effects but the reason sirolimus isn't used, the triple therapy
first line is because it’s known to delay wound healing. It's particularly problematic with sirolimus.
it's not used within the first three months of transplant as it can reduce the post-op healing and
wound recovery.
 Also have to consider what other treatment might be started as a result of that immunosuppression. The
patient has immunosuppressed, so we're making them more vulnerable to infection and colonisation. How
do we prevent any opportunistic bacteria causing problems or even fungal as well and viral.
 Chlorhexidine, mouthwash basically to reduce the risk of oral thrush from candida that naturally
does colonise in our GI tract.
 Proton pump inhibitor = GORD can be problematic, so gastroesophageal reflux disease is a
reminder. If they have and they're more prone to post-transplant,
 Co-trimoxazole, for PCP and prophylaxis.
 Aciclovir and valganciclovir for cytomegalovirus and viral prophylaxis.
- Increased risk of infection because of that
immunosuppression,
- There also an increased risk of malignancy
as well, and particularly skin cancer so got
an important role to make sure patients
are counselled, making sure that they stay
out of the sun, avoiding UV light. Sun beds
and stuff like that and lymphoma. So
haematological malignancies are quite
common as well and potentially as side
effects of all those
immunosuppressant medications that
they're using.
- Diabetes is a side effect of tacrolimus but
also, are any use of high dose steroids?
Diabetes control is much more difficult.
- Renal impairment, cyclosporine and tacrolimus can
both affect renal function
- Weight gain quite often a result of the high dose of steroids patients are put on.
- Osteoporosis links in with that as well that long term use of steroids as a potential complication from having
a transplant and the side effects of the medication.
- Sirolimus is actually very, very well known to increase lipids patients might develop high cholesterol, but
also high blood pressure as well.
- Also, more prone to gout as well.
- There's lots of complications because of having a transplant and then starting on all this
immunosuppressant therapy.
- it's thinking about what's the quality of life, what does the patient want, and making sure that they are
informed of what these risks are as well.