Describe the Diagnosis of Cystic Fibrosis

 

You will describe the diagnosis of cystic fibrosis.You should explain the pathophysiology briefly, and the clinical manifestations, some significant statistics and treatment options.

 

Introduction

Cystic Fibrosis or CF is a genetic disorder that mainly affects the secretory glands viz., sweat and mucus in the lungs, pancreas, liver, intestines, etc (National Heart, Lung and Blood Institute, n.d). Genetically, cystic fibrosis is an autosomal recessive disease that occurs due to a mutation in the gene that encodes CFTR (cystic fibrosis transmembrane conductance regulator) and clinically it is caused due to chronic bacterial infection of airways , neutophilic infection, airways obstructed  by mucus and progressive bronchiectasis (Stoltz, et al, 2015).
CF affects both male and female (Harness-Brumley, et al, 2014) and is considered a  common inherited disease in Caucasian population (Keogh, et al, 2018). This multisystem disease is characterized by nutritional deficiency and frequent respiratory infection owing to thick mucus, due to lack of chloride transport across surface epithelium (Harness-Brumley, et al, 2014). 
Diagnosis of CF is done by measuring the sweat electrolyte levels.  Patients showing an increased concentration of sodium and chloride (>60 mmol/l-diagnostic; 40-60mmol/l intermediate- but considered diagnostic in infants).  Positive results are further tested for common CFTR gene mutations. A second screening may follow which  is performed using immunoreactive trypsinogen (Davies, et al, 2007). An alternative method proposed by Gonçlaves, et al, uses saliva for CF diagnosis.  Sweat as well as saliva is modified by CF, it was observed that the chloride and sodium concentrations is different for CF patients and normal people, higher in former (Gonçalves, et al, 2013).
The data gathered by Australian Cystic Fibrosis Data Registry (ACFDR) comprising of 3,235 people with CF, the median age for male in 2013 was 18.9 years which was higher compared to the previous year’s viz., 17.7 in 2012 and 17.6 in 2011. In 2013, the median age for women was 17.1 years that was lower than that of men for the same year (ACFDR, 2015).  In USA, data was collected between 2000-2010- the median age changed from 14.3 to 16.7 years (MacKenzie, 2014); the median survival for children born and diagnosed with CF was estimated to be 37 years for female and 40 years for male- demonstrating that the median age has significantly increased with time and median survival of males is significantly greater than that of females.  In UK, the median survival is 43.5years (UKCF Trust, 2014) and globally according to WHO it is 33.5years (WHO 2015). Note- this data cannot be compared with the data gathered for Australia, as the time periods, method of gathering and calculations may be different. There is a difference in CF affecting men and women; women showed a lower median life expectancy of 36 years, compared with 38.7 years observed for men, in 32,766 patients from United States Cystic Fibrosis Foundation Patient Registry (CFFPR) for a period of over 13 years.
Though CF has no cure, various treatments are prescribed to provide relief to the patient e.g.  anti-inflammatory agents such as inhaled steroids, ibuprofen- have shown significant side effects. Macrolide antibiotic such as Azithromycin with anti-inflammatory activity are more effective. 

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Annotated Bibliography

Alton, E.W.F.W., Armstrong D.K.,  Ashby, D.,  Bayfield, K.J.,  Bilton,D.,  Bloomfield, E.V., Boyd, C.A., Brand, J., Buchan, R., Calcedo,R., Carvelli, P., Chan, M.,  Cheng, S.H., D  Collie, D.S, Cunningham,S.,  Davidson, H.E., Davies, G., Davies,J. C.,  Davies, L.A., Dewar, M.H., Doherty, A., Donovan, J.,  Dwyer, N.S., Elgmati, H.I., Featherstone, R.F. Gavino, J., Sorli, S.G., Geddes, D.M., Gibson, J.S.R., Gill, D.R.,  Greening, A.P., 
Griesenbach, U., Hansell, D.M., Harman,K.,  Higgins,T.E.,   Hodges, S,L., Hyde,S.C., Hyndman, L., Innes,J.A., Jacob, J., Jones, N., Keogh, B.F.,  Limberis, M.P.,  Evans, L, A Maclean, .W.,  Manvell, M.C., McCormick, D., McGovern, M., McLachlan, G., Meng, C., Montero, M.A., Milligan, H., Moyce, L.J., Murray,G.D.,  Nicholson, A.G., Osadolor, T., Leiton, J.P.,  Porteous, D.J., Pringle, I.A., Punch, E.K., Pytel, K.M., 
Quittner, A.L., Rivellini, G., Saunders, C.J., Scheule, R.K., Sheard, S., Simmonds, N.J., Smith, K., Smith, S.N., Soussi, N.s., Soussi, S., Spearing, E.J., Stevenson, B.J., Sumner-Jones, S.J.,   Turkkila, M., Ureta, R.P.,  Waller, M.D., Wasowicz, M.Y., Wilson, J.M., Wolstenholme-Hogg, P. (2015). Repeated nebulisation of non-viral CFTR gene therapy inpatients with cystic fibrosis: a randomised, double-blind, placebo-controlled, phase 2 B trial. The Lancet Respiratory Medicine. 3: 684–91. doi.org/10.1016/S2213-2600(15)00245-3
The authors put forth a novel gene-therapy treatment for CF patients.  A plasmid DNA with an encoded CFTR gene was complexed with a cationic liposome. The authors aimed to study efficacy of non-viral CFTR gene therapy in patients with CF. The final outcome of this first experiment was positive, however the mean difference was only modest. Nevertheless, this study provided with the first proof of concept that continual administration of non-viral CFTR gene therapy can safely change clinically relevant parameters making way for more translational gene therapy studies.
Australian Cystic Fibrosis Data Registry(ACFDR). (2015). Cystic fibrosis in Australia 2013. Retrived from www.cysticfibrosisdata.org/LiteratureRetrieve.aspx?ID=215308.
The annual report for Australian Cystic Fibrosis Data Registry shares the detailed statistical report of the mean, median, age at diagnosis, genotyping, health and functioning, treatment including clinical visit, hospital treatment, home therapy and non transplant therapy. The report further discusses the death recorded in 2013 along with the cause of death.  The report shares data of the major types of cystic fibrosis encountered viz., pancreatic, respiratory including other medical complications associated with the disease.  In addition, for the first time, nutritional outcome for children under 3 years, median height percentiles alongside median BMI percentile for children and adolescents was compiled in the report. 
Boyle, M.P., & Boeck, K.D. (2013). A new era in the treatment of cystic ?brosis: correction of the underlying CFTR defect. The Lancet Respiratory Medicine. 158-163. http://dx.doi.org/10.1016/ S2213-2600(12)70057-7.
The author describes a new-era treatment for cystic fibrosis. CF is caused due to dysfunction or deficiency of CFTR protein, which is due to a mutation in the CFTR gene.  Different treatments are being explored to correct the underlying CFTR defect due to different mutation classes. In this article the authors used the analysis of continued trial, along with patient registries to explore the different mutations along with geographical distribution of patients who are likely to benefit from the CFTR correcting treatment. They further predict that in the years to come, cystic fibrosis treatment will be a frontrunner, which will benefit a vast majority of the patients and may provide a road map for other genetic illness.
Cohen, T.S., & Prince, A. (2012). Cystic fibrosis: a mucosal immunodeficiency syndrome. Nature Medicine. 18(4): 509–519. doi:10.1038/nm.2715
CFTR functions as a channel primarily responsible for regulation of ions and water movement across the epithelial barrier. The authors study the role of the mutated CFTR gene and   its role in the clinical manifestation of CF. They study the role of CFTR mutation on epithelial innate immune function, oxidative stress in airway, etc.  Treatment with anti-inflammatory agents such as inhaled steroids and ibuprofen tough effect showed substantial toxicity.  Macrolide antibiotic e.g. Azithromycin having anti-inflmmatory activity was found effective.  In addition the authors recommend the use of cystic fibrosis pigs and ferrets to produce the human disease.
Davies, J.C., Alton, E.W.F.W., & Bush, A. (2007). Cystic fibrosis. The BMJ. 335:1255-9. doi:10.1136/bmj.39391.713229.AD
The authors do a detailed clinical review of Cystic Fibrosis (CF). They deal with the disease in detail encompassing various aspect of the condition such as diagnosis of the disease, management of the condition- tabulated by various stages of the disease and clinical manifestation e.g. Lung-  early (pre-infection &intermittent isolation of organism), intermediate (chronic infection with common known pathogens, infection with less common organisms, allergic bronchopulmonary aspergillosis, & non-tuberculosis mycobacterial infection), end-stage with complications (severe haemoptysis, pneumothorax, & respiratory failure); Pancreas (Exocrine insufficiency, & Pancreatitis), Gastro-oesophageal reflux, Meconium ileus, Distal intestinal obstruction syndrome, & Crohn’s disease; Colon (constipation),  Rectum (Rectal prolapsed), & Liver (fatty liver &  cirrhosis).
 Estrada-Veras, J., &  Groninger, H., (2013). Palliative Care for Patients with Cystic Fibrosis #265. Journal of Palliative Medicine. Number 4.  doi: 10.1089/jpm.2013.9515
The authors discuss the palliative care and steps that can be taken to ease the stress on patient and family.  They also list our many common issues faced by near the end-of-life patients such as lack of prediction for short term mortality, DNR orders (Do-not-resuscitate) are not given in advance, etc.  They list the common symptoms such as dyspnea, fatigue, anxiety, anorexia, pain, and cough. The health care providers must balance benefits versus disease-specific treatment such as nebulized medication, NIPPV and chest physiotherapy. 
Gonçalves,  A.C., Marson, F.A L., Mendonça R.M.H., Riberiro, J.D., Riberiro, A.F.,  Paschoal. I.A., & Levy, C.E. (2013). Saliva as a potential tool for cystic fibrosis diagnosis. Diagnostic Pathology.8:46. doi:10.1186/1746-1596-8-46.
The authors present an alternative tool for the diagnosis of CF viz., saliva.  They argue that the sodium and chloride levels are higher in the sweat and saliva of   CF patients. Thus saliva can be used as an alternative tool for the clinical diagnosis of CF,  however there is need for collecting more population data especially with reference to patients of all age groups, from different countries and of the normal subjects to have a database of normal ion concentration for CF patient according to age, genotype and environment.
Harness-Brumley, C.L., Ellicot, A.C., Rosenbluth, D.B., Raghavan, D., & Jain,R. (2014). Gender differences in outcomes of patients with cystic fibrosis. Journal of Women’s Health. 23:1012-1020. doi: 10.1089/jwh.2014.4985
The authors try and investigate the reason behind women having a worse outcome as compared to the male population for Cystic Fibrosis, especially with respiratory infections with  Pseudomonas aeruginosa. This theory was tested out by the authors via restrospective cohort analysis of 32,766 patients from the United States Cystic Fibrosis Foundation Patient Registry for over a period of 13 years. After analyzing the data using Kaplan-Meier and Cox proportional hazards models, the authors concluded that indeed females demonstrated a decreased median life expectancy of 36 years versus 38.7 years observed in men. In addition , they also noted that women became colonized with certain CF pathogens earlier than men.
Heltshe, S.L., & Goss C.H. (2016). Optimizing treatment of cf pulmonary exacerbation: a tough nut to crack. Thorax 71(2): 101–102. doi:10.1136/thoraxjnl-2015-208057.
The authors introduce the readers to pulmonary exacerbation (PEx )-a common occurrence in cystic fibrosis and it has great impact in the lives of the CF patient. Treatment normally composed of prolonged course of intravenous aminoglycosides, beta-lactams- which neither has a neither standard protocol nor consensus. Advances in CF chronic therapies such as inhaled antibiotics, CFTR modulators, mucolytics and macrolides have shown to reduce the occurrence of PEx or delay the time to next exacerbation. However, the authors point out that CF PEx is not currently practiced as evidence based medicine, this ought to change if one needs to witness a significant breakthrough in CF PEx.
Khan, A.A., Nash, E.J., Whitehouse, J., & Rashid, R., (2017) Improving the care of patients with cystic fibrosis (CF). BMJ Open Quality. 6:e000020. doi:10.1136/ bmjoq-2017-000020
The authors noticed that the patients suffering from CF are prone to pulmonary exacerbations and require admission for intravenous antibiotics. The process normally goes smoothly from Monday to Friday (9:00 to 17:00), however on out of working hours , it was not the same with close to 60% of patients missing their first antibiotic dose and a median time to  5 clerk hours. The authors decides a Quality Improvement Project (QIP) was the best way to deal with this using Plan-Do-Study-Act (PDSA) cyclic approach. This approach led to reduction of median time to 2 clerk hours with only 23% patients missing their first antibiotic dose, which subsequently decreased to 20% , thereby improving the out-of-hours admission process for the CF patients.
MacKenzie, T., Gifford, A.H., Sabadosa, K.A., Quinton, H.B., Knapp, E.A., Goss, C.H., &  Marshall, B.C. (2014). Longevity of patients with cystic fibrosis in 2000 to 2010 and beyond: survival analysis of the cystic fibrosis foundation patient registry. Annals of Internal Medicine. 161(4): 233–241. doi:10.7326/M13-0636.
The authors investigate the reason behind increased longevity observed among CF patients.  They gathered data from 110 Cystic Fibrosis Foundation- accredited care centres in the United States of 20,000 patients (2000) to 26,000 patients (2010). Various statistical analytical methods were applied and concluded that patients who underwent regular follow-ups at the care centres would have higher survival rate compared to those who did not. Children born and diagnosed with CF in 2010 are expected to live longer than those born before them due to advances in treatment, better prognostication and ability to anticipate adult care needs when they grow up.
Madge, S., & Sands, D.(2016). End of Life: Have we got it right? Journal of Cystic Fibrosis. doi: https://doi.org/10.1016/j.jcf.2015.11.007
The authors describe the significant number of adults that have outlived their original prognosis; lung transplant- a last resort for many. However, end of life can be difficult to predict in acute CF patients, the author cites many examples to support this. Significant stress is laid on Advanced Care Planning (ACP), which in majority of the cases is happens during patient admission, when it is too late. The author stresses on compassionate end of life care, an important part of comprehensive CF care, though the life expectancy with CF has extended, pre-mature mortality cannot be predicted
National Heart, Lung and Blood Institute. (n.d) Cystic fibrosis. Retrived from https://www.nhlbi.nih.gov/health-topics/cystic-fibrosis
In this health topic, all information pertaining to Cystic Fibrosis viz., overview of the disease, different names associated with the disease, causes of the disease, risk factor associated with it, signs & symptoms (cystic fibrosis of the respiratory system, digestive system, reproductive system, etc), diagnosis and treatment-though cystic fibrosis does not have a cure, various options to control the disease are listed.  Management, other concerns and handling the emotional concerns of the patients are briefly discussed as well. The website additionally gives information about clinical trials and links for volunteers to participate in studies conducted for preventing, diagnosing and treating the disease. 
Poulou, M., & Tzetis, M. (2017). Carrier screening for cystic fibrosis: past, present and future.      OBM Genetics. 1(4):010; doi:10.21926/obm.genet.1704010.
The authors point out the fact that even though there are many breakthroughs in therapies, CF is still associated with significant morbidity and mortality. The disease is associated with severe clinical manifestations and shortened life expectancy. This calls for a population based carrier screening and a need to identify heterozygous carrier couples at risk of having affected children. Economic concerns could be a deterrent as the only way to test individuals is by DNA mutation analysis, which is very expensive, unlike biochemical or hematological test e.g. thalassemias. The authors conclude the review with a suggestion that the  inclusion of CF carrier screening ought to be determined by the health economy of the country and carrier frequency in the tested population.
Stoltz, D.A., Meyerholz, D.K., & Welsh, M.J. (2015, Jan). Origins of cystic fibrosis lung disease. New England Journal of Medicine 374(4): 351-362. doi:10.1056/NEJMra1300109.
The authors try and address the lacunae that could possibly explain the reason behind cystic fibrosis lung disease.  They put forth the research done on the genetic cause of cystic fibrosis- an autosomal recessive disease caused by the mutation in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR).  At the clinical level, the authors discuss the role of chronic bacterial airway infection, and other significant factors which are an important cause of morbidity and mortality in cystic fibrosis. The authors attempt to study the question raised with the help of animal models –cystic fibrosis piglet and hamster.  They attempt to address issues such as defective chloride transport, loss of CFTR that leads to decreased effectiveness of viz., mucociliary transport and antimicrobial activity, and other defenses. 

Reflection

Cystic Fibrosis is a serious ailment that requires special care.  In my opinion, every hospital must have a dedicated CF team that can seamlessly provide continued care, and be there for the patient which normally poses a challenge with frequent staff changeover. No permanent treatment for CF is discovered yet. As a nurse, providing support to the patient from day 1 when he or she is diagnosed with the disease would certainly help them coping with the ailment.  CF is particularly difficult for the family members, especially parents whose young child has been diagnosed with CF.  Providing care to a CF patient, one needs to don multiple caps.  Depending on the age of the patient, the following would be the routine- monitoring and assessment including- measurement of SpO2, lung function, and collection of specimen such as sputum, following the given course of antibiotics- IV or oral; new born-screening and infants who test positive.  Education, reinforcement, and encouragement are crucial while dealing with CF patients.
CF has multiple clinical manifestations such as accumulation of mucus or thick secretion, dysfunction in the CFTR gene dehydrates secretions in airways and elsewhere in the body.  In the lungs, mucus traps the organisms increasing the risk of infection while in the pancreatic duct mucus prevents the release of essential enzymes for food breakdown which in turn does not let body absorb nutrients from food. In addition, elevated chlorine output in the sweat may result in dehydration and mineral imbalance.
SDM or Shared decision making is a patient centric, collaborative process that allows a patient and healthcare provider to make decisions together, integrating a person’s values, goals, concerns with the best available evidence about risks, benefits, and uncertainties of the treatment. Children and adolescents too have the right to self-determination, dignity and right to informed consent. 
End of life care for adult cystic fibrosis patient or palliative care patient, takes a toll on a nurse physically and psychologically.  One of the toughest challenges for a nurse is answering questions raised by the patient honestly. From the patient’s perspective, CF is quite a rollercoaster ride, right from being in reasonable shape one day to deteriorating the next. Or being on the transplant waiting list with either receiving the transplant or not, draining the patient mentally and physically. A nurse ought to be able to cope with it all be it questions, or sudden bouts of depression. Avoidance of terms associated with death, deterioration or anything that could distress the patient must be adhered to at all times. Involving family members and asking them to do the same would help relieve the burden from the patient, at least momentarily.
And finally, the genetic testing in children and adolescents may have legal, ethical and psychosocial implications.  This must be handled in accordance with policy and procedures of the workplace.

References

Alton, E.W.F.W., Armstrong D.K.,  Ashby, D.,  Bayfield, K.J.,  Bilton,D.,  Bloomfield, E.V., Boyd, C.A., Brand, J., Buchan, R., Calcedo,R., Carvelli, P., Chan, M.,  Cheng, S.H., D  Collie, D.S, Cunningham,S.,  Davidson, H.E., Davies, G., Davies,J. C.,  Davies, L.A., Dewar, M.H., Doherty, A., Donovan, J.,  Dwyer, N.S., Elgmati, H.I., Featherstone, R.F. Gavino, J., Sorli, S.G., Geddes, D.M., Gibson, J.S.R., Gill, D.R.,  Greening, A.P., 
Griesenbach, U., Hansell, D.M., Harman,K.,  Higgins,T.E.,   Hodges, S,L., Hyde,S.C., Hyndman, L., Innes,J.A., Jacob, J., Jones, N., Keogh, B.F.,  Limberis, M.P.,  Evans, L, A Maclean, .W.,  Manvell, M.C., McCormick, D., McGovern, M., McLachlan, G., Meng, C., Montero, M.A., Milligan, H., Moyce, L.J., Murray,G.D.,  Nicholson, A.G., Osadolor, T., Leiton, J.P.,  Porteous, D.J., Pringle, I.A., Punch, E.K., Pytel, K.M., 
Quittner, A.L., Rivellini, G., Saunders, C.J., Scheule, R.K., Sheard, S., Simmonds, N.J., Smith, K., Smith, S.N., Soussi, N.s., Soussi, S., Spearing, E.J., Stevenson, B.J., Sumner-Jones, S.J.,   Turkkila, M., Ureta, R.P.,  Waller, M.D., Wasowicz, M.Y., Wilson, J.M., Wolstenholme-Hogg, P. (2015). Repeated nebulisation of non-viral CFTR gene therapy inpatients with cystic fibrosis: a randomised, double-blind, placebo-controlled, phase 2 B trial. The Lancet Respiratory Medicine. 3: 684–91. doi.org/10.1016/S2213-2600(15)00245-3.
Australian Cystic Fibrosis Data Registry(ACFDR). (2015). Cystic fibrosis in Australia 2013. Retrived from www.cysticfibrosisdata.org/LiteratureRetrieve.aspx?ID=215308.
Boyle, M.P., & Boeck, K.D. (2013). A new era in the treatment of cystic ?brosis: correction of the underlying CFTR defect. The Lancet Respiratory Medicine. 158-163. http://dx.doi.org/10.1016/ S2213-2600(12)70057-7.
Cohen, T.S., & Prince, A. (2012). Cystic fibrosis: a mucosal immunodeficiency syndrome. Nature Medicine. 18(4): 509–519. doi:10.1038/nm.2715
Davies, J.C., Alton, E.W.F.W., & Bush, A. (2007). Cystic fibrosis. The BMJ. 335:1255-9. doi:10.1136/bmj.39391.713229.AD.
Estrada-Veras, J., &  Groninger, H., (2013). Palliative Care for Patients with Cystic Fibrosis #265. Journal of Palliative Medicine. Number 4.  doi: 10.1089/jpm.2013.9515.
Gonçalves,  A.C., Marson, F.A L., Mendonça R.M.H., Riberiro, J.D., Riberiro, A.F.,  Paschoal. I.A., & Levy, C.E. (2013). Saliva as a potential tool for cystic fibrosis diagnosis. Diagnostic Pathology.8:46. doi:10.1186/1746-1596-8-46.
Harness-Brumley, C.L., Ellicot, A.C., Rosenbluth, D.B., Raghavan, D., & Jain,R. (2014). Gender differences in outcomes of patients with cystic fibrosis. Journal of Women’s Health. 23:1012-1020. doi: 10.1089/jwh.2014.4985.
Khan, A.A., Nash, E.J., Whitehouse, J., & Rashid, R., (2017) Improving the care of patients with cystic fibrosis (CF). BMJ Open Quality. 6:e000020. doi:10.1136/ bmjoq-2017-000020.
MacKenzie, T., Gifford, A.H., Sabadosa, K.A., Quinton, H.B., Knapp, E.A., Goss, C.H., &  Marshall, B.C. (2014). Longevity of patients with cystic fibrosis in 2000 to 2010 and beyond: survival analysis of the cystic fibrosis foundation patient registry. Annals of Internal Medicine. 161(4): 233–241. doi:10.7326/M13-0636.
Madge, S., & Sands, D.(2016). End of Life: Have we got it right? Journal of Cystic Fibrosis. doi: https://doi.org/10.1016/j.jcf.2015.11.007
National Heart, Lung and Blood Institute. (n.d) Cystic fibrosis. Retrived from https://www.nhlbi.nih.gov/health-topics/cystic-fibrosis
Poulou, M., & Tzetis, M. (2017). Carrier screening for cystic fibrosis: past, present and future.      OBM Genetics. 1(4):010; doi:10.21926/obm.genet.1704010.
Stoltz, D.A., Meyerholz, D.K., & Welsh, M.J. (2015, Jan). Origins of cystic fibrosis lung disease. New England Journal of Medicine 374(4): 351-362. doi:10.1056/NEJMra1300109.

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