An Overview of Cystic Fibrosis Treatment Strategies

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CYSTIC FIBROSIS
Contents
CYSTIC FIBROSIS.....................................................................................................................................1
Treatment strategies.......................................................................................................................2
Gene therapy...................................................................................................................................3
DIAGNOSIS OF CYSTIC FIBROSIS.........................................................................................................5
ETHICAL CONSIDERATIONS IN THE DIAGNOSIS OF THE CYSTIC FIBROSIS..........................................7
CONCLUSION.........................................................................................................................................8
REFERENCES........................................................................................................................................10
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Treatment strategies
Cystic fibrosis is an inherited disorder that is characterized by lung damage and
severe digestive system and organ damage due to fibrosis and mucus formation.
The main target cells that are affected in this disorder include damage to the cells
producing mucus, sweat and digestive juices (Cutting., 2015). It is a disorder that is
non-curable but yet can be lived with for long duration the average life expectancy of
the patient with cystic fibrosis in USA is 37.5 years. The new treatment modalities
and options have further enhanced the life expectancy and quality of life of the
individuals suffering from cystic fibrosis. Persistent lung infection due to genetic
influences and the limited ability to breath are the characteristics of this disease. The
mutation in one of the gene named CFTR cause protein to become dysfunctional
and when the protein is not working appropriately the chloride in cell is disabled to
attract water to cell and mucus in various cells becomes thick and sticky (Stoltz et
al., 2015). This causes obstruction of lungs passage and breathing. In lungs the
mucus obstructs the passage and clogs the pathway by entrapping bacteria, germs
leading to inflammation and failure.
Various treatment options are present in contemporary medicine to reduce the
symptoms or progress of cystic fibrosis. The severity of symptoms may differ as per
the type of cystic fibrosis and the extent of disease from person to person. These
therapies include combination of different strategies including airway clearance,
inhaled medicines, pancreatic enzyme supplementation, diet modulation, CFTR
gene therapy etc. (Lahiri et al., 2016).
According to George et al (2009), cystic fibrosis is the disease that cannot be cured
but managed with appropriate treatment plan and options. It is seen that over the
past four decades the life expectancy for these patients have been average to 40
years. The main standard treatment includes nutritional therapy with airway mucus
clearance and high antibiotic support regimens.
Antibiotic support helps in eradicating the bacterial or germ colonization from the
pathway or mucus retention centres and prevents the infection progress. The
antibiotics used in this treatment include flucloxacillin that is prescribed orally to the
patient at the prophylaxis of the infection (Remmington et al., 2016). In case of
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severe infection the intravenous therapy of antibiotics are provided to the patient. In
1989 according to the Copenhagen centre the intravenous delivery of antibiotics to
the patient of cystic fibrosis helped in enhancing the 5 year life expectancy and was
associated with better and controlled disease symptoms (De Boeck and Amaral.,
2016). Another regime includes the delivery of NSAIDS or anti-inflammatory agents
that improves the mucociliary clearance. Some researchers provide evidence
regarding effectiveness of the nebulization of the antibiotics such as tobramycin or
colistin with ciprofloxacin to be helpful in achieving better health in cystic fibrosis.
One of the researchers evaluated the use of bronchitol in cystic fibrosis that resulted
in the improved lung function to 6.6% from week 6 to 26 (Remmington et al., 2016).
The research also showed that the patients treated with other medicines for cystic
fibrosis also showed improvement with this regime.
Mechanism of the drugs being provided as mucus thinning medicines includes
inhalation of the drug through the lungs to relieve the symptoms of cystic fibrosis.
The drug gets involved in the mechanism of clearance. The medicines work to
increase the amount of water into the cells and surface of the cells to dilute the
mucus. In this way the mucus clogged into the pathway gets diluted and this helps
breathing and relief of the symptoms.
Other options in the treatment modalities of cystic fibrosis include the bowel surgery
and lung transplant. Lung transplant is considered when due to fibrosis and mucus
accumulation the lung functioning is deteriorated completely. Lung transplant can
extend or improve the functioning of the body. Lung transplant can be done to relief
the individual from the breathing issues and provide some enhanced life duration of
quality living. Many factors are responsible for the treatment of cystic fibrosis
including the cost, effectiveness, length of survival and quality of life largely depends
on the type of antibiotic and effectiveness of antibiotic regime included in the
treatment.
Gene therapy
The initial infection in cystic fibrosis starts with the colonization of the P. aeruginosa
infection that is treated and controlled by antibiotics but the relapse in infection is
characterized by the more virulent and severe strains of the bacteria that are
resistant to these antibiotic regime. These chronic infections are very difficult to
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eradicate with current therapy (Griesenbach et al., 2015). The CF foundation defined
multi drug resistance as the resistance of organism to the drugs provided for the
treatment of the particular disease and two out of three groups of antibiotics are
being resisted included aminoglycosides, quinolones and lactams. According to
Cohen et al (2011), to overcome these treatment issues and relapse and impact on
the treatment plan of the disease the new modality was introduced under the gene
therapy and cloning mechanism being identified. Around 21 years ago the cloning of
the gene CFTR was identified and it proved to be greatly helpful in identifying the
structure and function of CFTR chloride channels (Quon and Rowe., 2016). The
development of this therapy was mainly focused at utilizing the inner course of the
disease and managing the symptoms from its cause. The mechanism of this therapy
includes therapy by means of the type of cystic fibrosis that may be with no protein,
not enough protein or protein being made incorrectly (Prickett and Jain., 2015). Gene
therapy considers formation of similar protein as CFTR that can replace and mimic
the function of this actual protein. One of the disadvantages of this therapy is that it
is specific for the area being treated. For example if the cells of the lungs received
the therapy the treatment will be localised to lungs and cannot help the organs other
than lungs.
Integrated gene therapy where the part of normal gene and protein is added to the
diseased genome and it becomes the permanent part of that person’s genome. Such
therapy is already being approved for treatment of certain leukaemia and cancer but
the use of this therapy in CF is under trail (Amaral., 2015).
Non-integrated gene therapy is the process where the piece of the normal DNA is
sorted and added to disease genome but not permanently attached to it. This
therapy has one advantage that the genome cannot be influenced with addition of
the new DNA and can still has its viability (Amaral., 2015).
RNA therapy is the process where the RNA copy is directly formed and provided to
cell without providing the DNA for the cell. This process has an advantage that there
is no possibility to disrupt the genome and the RNA makes the control of dosage
easy. RNA therapy is being tested in early stage CF therapy (Amaral., 2015).
4

DIAGNOSIS OF CYSTIC FIBROSIS
Diagnosis is the process of testing and confirming that the particular symptoms are
the characteristic of the specific disease and confirming the pattern of the disease.
There are several diagnostic tests and approaches that re used to confirm the
diagnosis of cystic fibrosis. The tests mainly regulate the check for blood and sweat.
Also the review of symptoms and the history of illness is taken by the expert to
diagnose and confirm the diagnosis for cystic fibrosis.
New born screening
One of the common practices in all the states in Columbia and other nations is the
test for cystic fibrosis for the new born taking their blood samples after few week of
birth (Kharrazi et al., 2015). The IRT test that is the chemical (immunoreactive
tripsinogen) is a screening test and the babies who fail this are screened negative for
cystic fibrosis. The babies who fail this test may receive another test and if they clear
the second test there is no need for other diagnostic tests. This is just a screening
test and cannot confirm any diagnosis for the disorder.
Chloride sweat test
The sweat test is the most appropriate way of testing that a person has cystic fibrosis
or not. The test focuses on evaluating the amount of salt in the sweat of the
individual. People with CF have higher levels of chloride that is the compound in the
salt ad is present due to high concentration of sweat in the body (Farrell et al., 2017).
The test is age friendly but some babies may not sweat enough and can give false
readings. The process includes activation of sweat gland by a chemical stimulator
and collection of the sweat that is sent to lab for diagnosis and high levels of salt or
chloride in sweat confirm cystic fibrosis.
Carrier testing
The main cause of cystic fibrosis is the faulty gene that is passed down by the
parents to the offspring. Some offspring may not show symptoms of the disease but
can carry the gene that will be passé don to next generation and can cause the
disease. If the partners delivering baby both are carriers the chances of baby getting
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this disease is high (Wallis., 2019). This test ensures that the born baby may or may
not carry this disease due to genetic predisposition.
Prenatal testing
If both the parents or the pregnant women and the partner are tested positive for
carrier gene the further test can be done using amniocentesis that will help in
knowing the health of the fetus. This is done between 15 to 20 week of intrauterine
life and another test including CVS during 10 to 12 week also is done to confirm he
disorder (Rosenfeld, Sontag and Ren., 2016).
MLPA (Multiple Ligation Dependent Probe Amplification)
According to Lefterova et al (2016), MLPA is the approach that is highly useful in
diagnosis of the cystic fibrosis. It is a simplified and easy PCR method that is used
for detecting chromosomal DNA copy number changes in multiple target cells. The
probe is designed with forward and backward primer that will be used at the ligation
stage in the sample (Brewington and Clancy., 2016). The probes are hybridized and
subsequently ligated. The quantitative measurement is done with the amount of PCR
material in the probe to the amount of DNA in the sample. It is useful in cystic fibrosis
as it shows which exons are missing but it does not prove the breakpoints in the
deletion. The mutation in gene sequence is diagnosed with help of this tool and the
confirmation of cystic fibrosis is made.
NGS (Next Generation Sequencing)
in today’s era has become more trending for the diagnosis of the infectious diseases.
The use of this tool in immune disorder, genetic diseases and hereditary diseases is
well known. According to Di Resta et al (2018), the rapid evolution in genetics has
made it viable to use these techniques for diagnostic and treatment of genetically
linked diseases. One of the advantages of NGS is to deliver the clinical results in
short duration. This approach helps in identifying the sequence of the CFTR protein
and gene and the mutation in the DNA genome (De Boeck, Vermeulen and Dupont.,
2017).
6

ETHICAL CONSIDERATIONS IN THE DIAGNOSIS OF THE CYSTIC
FIBROSIS
Newborn screening for cystic fibrosis has been into consideration and controversy
since long duration. The ethics considered in the screening and diagnosis of cystic
fibrosis includes the psychological harm that the families and newborn face during
the screening process (Skirton et al., 2015). The harm does not occur in the same
population as the benefits of the interventions. Technical decisions to increase the
screening efficacy also increase the false positivity rate of the tool. The other issue
arises when some claims under insurance are not covered for cystic fibrosis testing
and treatment for some European and Caucasian ethnic groups due to their high
prevalence of cystic fibrosis. It is seen that these ethnic groups have 1:25 higher risk
ratio of this disorder than other groups (Farrell et al., 2017). Almost 45% of the
people suffering from cystic fibrosis receive some amount for Medicare or insurance
but some companies and nations do not support this claim for some ethnic groups
giving them discriminated treatment (Milunsky and Milunsky., 2015). Such issues
arise in the screening and diagnosis of the cystic fibrosis making the large group of
vulnerable and high risk patients differing or incapable to be screened or diagnosed
for the disease and this leads to increased prevalence in certain groups.
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CONCLUSION
Cystic fibrosis is an inherited disorder that is characterized by lung damage and
severe digestive system and organ damage due to fibrosis and mucus formation.
The main target cells that are affected in this disorder include damage to the cells
producing mucus, sweat and digestive juices. The mutation in one of the gene
named CFTR cause protein to become dysfunctional and when the protein is not
working appropriately the chloride in cell is disabled to attract water to cell and
mucus in various cells becomes thick and sticky. Various treatment options are
present in contemporary medicine to reduce the symptoms or progress of cystic
fibrosis. Antibiotic support helps in eradicating the bacterial or germ colonization from
the pathway or mucus retention centres and prevents the infection progress. Another
regime includes the delivery of NSAIDS or anti-inflammatory agents that improves
the mucociliary clearance. Some researchers provide evidence regarding
effectiveness of the nebulization of the antibiotics such as tobramycin or colistin with
ciprofloxacin to be helpful in achieving better health in cystic fibrosis. One of the
researchers evaluated the use of bronchitol in cystic fibrosis that resulted in the
improved lung function to 6.6% from week 6 to 26. Other options in the treatment
modalities of cystic fibrosis include the bowel surgery and lung transplant. Lung
transplant is considered when due to fibrosis and mucus accumulation the lung
functioning is deteriorated completely. Lung transplant can extend or improve the
functioning of the body. Lung transplant can be done to relief the individual from the
breathing issues and provide some enhanced life duration of quality living. According
to Cohen et al (2011), to overcome these treatment issues and relapse and impact
on the treatment plan of the disease the new modality was introduced under the
gene therapy and cloning mechanism being identified. Around 21 years ago the
cloning of the gene CFTR was identified and it proved to be greatly helpful in
identifying the structure and function of CFTR chloride channels. The development of
this therapy was mainly focused at utilizing the inner course of the disease and
managing the symptoms from its cause. The mechanism of this therapy includes
therapy by means of the type of cystic fibrosis that may be with no protein, not
enough protein or protein being made incorrectly. Gene therapy considers formation
of similar protein as CFTR that can replace and mimic the function of this actual
8

protein. Some important tests for cystic fibrosis diagnosis includes MLPA (Multiple
Ligation Dependent Probe Amplification), NGS (Next Generation Sequencing),
Prenatal testing, Carrier testing, Chloride sweat test, New born screening.
9

REFERENCES
1. Amaral, M.D., 2015. Novel personalized therapies for cystic fibrosis: treating
the basic defect in all patients. Journal of internal medicine, 277(2), pp.155-
166.
2. Brewington, J. and Clancy, J.P., 2016. Diagnostic testing in cystic
fibrosis. Clinics in chest medicine, 37(1), pp.31-46.
3. Cohen-Cymberknoh, M., Shoseyov, D. and Kerem, E., 2011. Managing cystic
fibrosis: strategies that increase life expectancy and improve quality of
life. American journal of respiratory and critical care medicine, 183(11),
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4. Cutting, G.R., 2015. Cystic fibrosis genetics: from molecular understanding to
clinical application. Nature Reviews Genetics, 16(1), p.45.
5. De Boeck, K. and Amaral, M.D., 2016. Progress in therapies for cystic
fibrosis. The Lancet Respiratory Medicine, 4(8), pp.662-674.
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fibrosis. La Presse Médicale, 46(6), pp.e97-e108.
7. Di Resta, C., Galbiati, S., Carrera, P. and Ferrari, M., 2018. Next-generation
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Rosenfeld, M., Sommerburg, O., Accurso, F.J., Davies, J.C., Rock, M.J. and
Sanders, D.B., 2017. Diagnosis of cystic fibrosis in screened populations. The
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infections: treatment strategies and prospects. FEMS microbiology
letters, 300(2), pp.153-164.
11. Griesenbach, U., Pytel, K.M. and Alton, E.W., 2015. Cystic fibrosis gene
therapy in the UK and elsewhere. Human gene therapy, 26(5), pp.266-275.
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12. Kharrazi, M., Yang, J., Bishop, T., Lessing, S., Young, S., Graham, S., Pearl,
M., Chow, H., Ho, T., Currier, R. and Gaffney, L., 2015. Newborn screening
for cystic fibrosis in California. Pediatrics, 136(6), pp.1062-1072.
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M.E., Guill, M.F., Guillerman, R.P., Leone, C.G., Maguiness, K. and Monchil,
L., 2016. Clinical practice guidelines from the cystic fibrosis foundation for
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Davis, R.W., Wang, W., Kharrazi, M., Schrijver, I. and Scharfe, C., 2016.
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15. Milunsky, A. and Milunsky, J.M., 2015. Genetic disorders and the fetus:
diagnosis, prevention, and treatment. John Wiley & Sons.
16. Prickett, M. and Jain, M., 2015. Gene therapy in cystic fibrosis. In Translating
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17. Quon, B.S. and Rowe, S.M., 2016. New and emerging targeted therapies for
cystic fibrosis. Bmj, 352, p.i859.
18. Remmington, T., Jahnke, N. and Harkensee, C., 2016. Oral anti‐pseudomonal
antibiotics for cystic fibrosis. Cochrane Database of Systematic Reviews, (7).
19. Rosenfeld, M., Sontag, M.K. and Ren, C.L., 2016. Cystic fibrosis diagnosis
and newborn screening. Pediatric Clinics, 63(4), pp.599-615.
20. Skirton, H., Goldsmith, L. and Chitty, L.S., 2015. An easy test but a hard
decision: ethical issues concerning non-invasive prenatal testing for
autosomal recessive disorders. European Journal of Human Genetics, 23(8),
p.1004.
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21. Stoltz, D.A., Meyerholz, D.K. and Welsh, M.J., 2015. Origins of cystic fibrosis
lung disease. New England Journal of Medicine, 372(4), pp.351-362.
22. Wallis, C., 2019. Diagnosis and presentation of cystic fibrosis. In Kendig's
Disorders of the Respiratory Tract in Children (pp. 769-776). Content
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