Cystic fibrosis overview
| https://https://www.youtube.com/watch?v=BhFpFiZumS0%7C350}} |
|
Cystic fibrosis Microchapters |
|
Diagnosis |
|---|
|
Treatment |
|
Case Studies |
|
Cystic fibrosis overview On the Web |
|
American Roentgen Ray Society Images of Cystic fibrosis overview |
|
Risk calculators and risk factors for Cystic fibrosis overview |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Castro Molina, M.D.
Overview
Cystic fibrosis is an autosomal recessive disease that caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The genetic mutation result in defective transport of chloride, and secondarily sodium and eventually abnormal viscous mucoid secretions mostly in lungs and GI tract. Infertility due to atresia/absent vasa deferentia and abnormal/absent seminal vesicles is the associated condition of cystic fibrosis. Cystic fibrosis has to be differentiated from asthma, bronchiolitis, emphysema and primary ciliary dyskinesia (Kartagener syndrome). Immunoreactive trypsinogen (IRT) of serum is raised in newborns with cystic fibrosis and has been used as a screening test. The most significant complications are seen in airways and most common chronic pulmonary infection include P. aeruginosa, S. aureus and H. influenzae. Gastrointestinal complications include pancreatic insufficiency, pancreatitis, gastroesophageal reflux disease, distal intestinal obstruction syndrome, constipation and small intestinal bacterial overgrowth. The sweat chloride test is the gold standard test for the diagnosis of cystic fibrosis. Most common symptoms include salty sweat, constant coughing, diarrhea or greasy stools, stomach pain, constipation and poor weight gain. Also abdominal distension and digital clubbing may be detected. Lung examination may presents hyperresonant lungs, Wheeze or crackles. Most common chest CT scan findings include peribronchial thickening, mucous plugging and Bronchiectasis. Medical treatments has targeted following consequences of the defect such as GI and pulmonary mucus plugging and infection. Treatment include mucolytic agents (dornase alfa, N-acetyl-L-cysteine), airway surface rehydration, anti-infective agents, anti-inflammatory agents and potentiators of CFTR protein defect.
Over the past decade, CFTR modulator therapies have transformed the natural history of cystic fibrosis for many patients, with improvements in lung function, pulmonary exacerbations, nutritional status, and quality of life, particularly with highly effective triple therapy (elexacaftor/tezacaftor/ivacaftor) in people with at least one Phe508del allele.[1] As a result, the cystic fibrosis population is increasingly adult, with evolving care needs and a growing focus on comorbidities, treatment burden, and long-term outcomes.[2][3]
Historical Perspective
In the late 1930s cystic fibrosis was first recognized as a disease. In 1949, Lowe and colleagues suggested this theory that cystic fibrosis must be caused by a defect in a single gene. In 1959, the measurement of sweat electrolyte concentrations was established as the mainstay of diagnosing CF. In 1989, the CFTR gene was discovered first. In 1990, scientists successfully added cloned normal gene to cystic fibrosis cells which corrected the chloride transportion.
The era of disease-modifying therapy began with CFTR modulators, including ivacaftor (a CFTR potentiator) for gating mutations such as G551D, followed by combination modulator regimens for Phe508del (including lumacaftor/ivacaftor and tezacaftor/ivacaftor) and highly effective triple therapy (elexacaftor/tezacaftor/ivacaftor).[4][5][6][7][1]
Classification
Cystic fibrosis may be classified according to CFTR protein function abnormality into 6 groups: lack of production (Class 1), failure to reach the site of action due to misfolding (class 2), defects in gating (class 3), reduced ion conductance (class 4), abnormally low channel numbers (class 5) and decreased half-life (class 6). Cystic fibrosis classes 1,2 and 3 are the most common types which have associated with pancreatic insufficiency.
Eligibility for CFTR modulators depends on CFTR genotype and functional consequences of the variant(s). Curated resources (e.g., CFTR2) support genotype interpretation and guide therapy selection in clinical practice and newborn screening follow-up.[8][9]
Pathophysiology
Cystic fibrosis is an autosomal recessive disease that caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Substitution of a single amino acid is the most common type of CFTR gene mutation. CFTR gene functions as a chloride channel (pumps chloride from the intracellular space to the extracellular space) found on the surface of the epithelial cells. The genetic mutations result in defective transport of chloride, and secondarily sodium and eventually abnormal viscous mucoid secretions mostly in lungs (results in airway surface liquid depletion, decreased mucociliary transport, inflammation and infection) and GI tract (results in reduced volume of pancreatic secretion, pancreatic tissue destruction and fibrosis, malnutrition and poor growth). Infertility due to atresia/absent vasa deferentia and abnormal/absent seminal vesicles is the associated condition of cystic fibrosis.
Experimental and translational studies support airway surface liquid depletion and impaired mucociliary clearance as early drivers of cystic fibrosis lung disease, including evidence from large-animal (porcine) models that demonstrate reduced airway surface liquid and impaired bacterial clearance associated with CFTR dysfunction.[10] Reviews of early lung disease and pathogenesis emphasize that airway obstruction, infection, and inflammation begin early in life and contribute to progressive structural lung injury.[11]
Causes
Cystic fibrosis is caused by mutations in the CFTR gene. The genetic mutations result in defective transport of chloride, and secondarily sodium, by epithelial cells and eventually abnormal viscous mucoid secretions mostly in lungs and GI tract.
Differentiating cystic fibrosis from Other Diseases
Cystic fibrosis has to be differentiated from other conditions with similar presentation of cough and wheeze like common cold, asthma, bronchiolitis, emphysema, primary ciliary dyskinesia (Kartagener syndrome), bronchitis, bronchiectasis, foreign body aspiration, pneumoconiosis, interstitial lung disease, cardiogenic pulmonary edema, GERD and sarcoidosis.
Epidemiology and Demographics
The incidence of cystic fibrosis is approximately 1 in 2500 livebirths. It is a life-limiting disease (100% mortality rate), and a cure for the disease remains elusive. Most patients with cystic fibrosis are diagnosed in first 2 years of life. The onset of symptoms is before the first month of life in 12%, between 1-6 months of age in 75%, and between 6-12 months of age in 7% of patients. Although cystic fibrosis has been reported in all racial and ethnic groups, it mostly affects Caucasians of Northern European descent. It affects men and women equally.
Contemporary registry and population-based analyses demonstrate improved survival and an increasing proportion of adults living with cystic fibrosis, with differences by region and health system. Cystic fibrosis population trends and survival estimates are frequently monitored through national registries and comparative cohort analyses.[3][12][2]
Risk Factors
Every person inherits two CFTR genes, one from each parent. Children who inherit two mutated CFTR genes from both parents will have cystic fibrosis.
Screening
Newborn screening identified most of the children with cystic fibrosis before the symptoms develop. It offers this opportunity for early diagnosis and improved outcomes. Immunoreactive trypsinogen (IRT) of serum is raised in newborns with cystic fibrosis and has been used as a screening test. A raised IRT in the first week of life is a sensitive test but not specific for cystic fibrosis.
In many screening programs, elevated IRT is followed by CFTR variant testing, and in some algorithms, a sequencing tier is used to improve diagnostic yield and reduce false positives and inequities across ancestry groups. Screening approaches vary by region and program design.[13]
Natural History, Complications, and Prognosis
Malnutrition and poor growth (due to loss of pancreatic exocrine function) leads to death in the first decade of life for most untreated patients. The most significant complications are seen in airways (responsible for 80% of mortality) and most common chronic pulmonary infection include P. aeruginosa, S. aureus and H. influenzae. In cystic fibrosis 98% of men are infertile due to aspermia. Lung complications are currently the primary causes of morbidity and are responsible for 80% of mortality in these patients and gastrointestinal complications include pancreatic insufficiency, pancreatitis, gastroesophageal reflux disease, distal intestinal obstruction syndrome, constipation and small intestinal bacterial overgrowth. In cystic fibrosis, obstructive lung disease and other lung complications are currently the primary causes of morbidity and are responsible for 80% of mortality. At present time survival probability of children is 40-50 years. Women with cystic fibrosis have a shortened life expectancy compared to men.
As CFTR modulators have become widely used, outcomes and complications are changing, including improvements in nutritional status and lung function in many treated individuals. Emerging clinical questions include how to safely reduce treatment burden in selected patients receiving highly effective CFTR modulators.[14][2]
Diagnosis
Diagnostic study of choice
The sweat chloride test is the gold standard test for the diagnosis of cystic fibrosis. A sweat chloride value of more than 59 mmol/L is diagnostic for cystic fibrosis, 30-59 mmol/L needs more evaluation with CFTR genetic analysis and less than 30 is indicates that cystic fibrosis is unlikely.
Cystic fibrosis diagnostic criteria and guidance for ambiguous or intermediate sweat chloride results incorporate CFTR genotyping, functional testing when needed, and careful clinical correlation. Expert guidelines also address CFTR-related disorders and diagnostic uncertainty.[15][8]
History and Symptoms
Most common symptoms in cystic fibrosis include salty sweat, constant coughing, diarrhea or greasy stools, stomach pain, constipation and poor weight gain. Less common symptoms include nasal polyp, hemoptysis and skin irritation.
Physical Examination
In cystic fibrosis abdominal distension and digital clubbing may be detected. In HEENT examination there is nasal polyps and signs of rhinosinusitis (purulent nasal discharge, mucosal edema, turbinate hypertrophy and tenderness on palpitation of the sinuses). Lung examination may presents hyperresonant lungs, Wheeze or crackles and Productive cough with mucoid or purulent sputum.
Laboratory Findings
Immunoreactive trypsinogen (IRT) of serum is raised in newborns with cystic fibrosis and has been used as a screening test.
Electrocardiogram
There are no electrocardiogram findings associated with cystic fibrosis.
X-ray
In cystic fibrosis the chest radiographic features may overlap with many other disorders, particularly those characterized by inflammatory or destructive changes of the airways. Atelectasis is common in infancy. Most patients with CF demonstrate some of the classic chest radiographic findings that reflect chronic bronchiectasis include hyperinflation, bronchial thickening and dilatation, peribronchial cuffing, mucoid impaction, cystic radiolucencies, increase in interstitial marking and cattered nodular densities.
Ultrasound
In cystic fibrosis, ultrasound findings include small cystic degeneration could be observed in the pancreatic tail. Transabdominal ultrasound of the pancreas demonstrated a higher pancreatic echogenicity, as a measure of pancreatic lipomatosis in pancreatic insufficient CF patients. Echogenic bowel is found on ultrasound in 50% to 78% of fetuses affected with cystic fibrosis. It is thought to be caused by changes in the consistency of meconium in the small intestine as a result of abnormalities in pancreatic enzyme secretion. The sonographic findings include diffuse echogenic bowel, focal echogenic bowel with calcifications, hyperechoic mass and bowel dilation.
CT scan
Computed tomography (CT scan) findings in patients with cystic fibrosis are more sensitive as compared to the pulmonary function tests. Most common chest CT scan findings include peribronchial thickening, mucous plugging and Bronchiectasis. Less common findings include abscesses, emphysematous bullae, hyperinflation, collapse, consolidation, ground-glass opacities, acinar nodules and thickening of interlobular and intralobular septa. Abdomen CT scan in patients with cystic fibrosis may include these findings diffuse and complete fatty replacement of pancreas, Fibrosis of the pancreas and Intestinal obstruction.
MRI
MRI may be helpful in determining the cause of linear lung markings in cystic fibrosis. It is also helpful in differentiating mucous plugging and peribronchial thickening from normal pulmonary blood vessels. Because of MRI absence of ionising radiation and possibility for obtaining functional information, it is helpful for assessing lung disease in children who require repetitive follow up imaging for a long time. MRI studies of the pancreas have demonstrated different patterns of fatty infiltration, ductal changes, pancreatic cysts, calcifications and hypoechoic areas representing fibrosis.
Other Imaging Findings
There are no other imaging findings for cystic fibrosis.
Other Diagnostic Studies
Other diagnostic studies in patients with cystic fibrosis include sweat chloride test (measures the chloride content of the sweat) and nasal potential differences (performed by running different solutions through the nose) which used to detect changes in CFTR function. A sweat chloride value of more than 59 mmol/L is diagnostic for cystic fibrosis and less than 30 mmol/L indicates that cystic fibrosis is unlikely. Also Pulmonary function test (PFT) is important in monitoring lung function in patients with cystic fibrosis. However, it is only an indirect measure of lung structure and is insensitive to local or early damage.
Treatment
Medical Therapy
Medical treatments for patients with cystic fibrosis has targeted following consequences of the defect such as GI and pulmonary mucus plugging and infection. Treatment include mucolytic agents (dornase alfa, N-acetyl-L-cysteine), airway surface rehydration (hypertonic saline, osmotic agents), anti-infective agents (for prophylaxis, eradication of early infection and suppression of chronic infection), anti-inflammatory agents (NSAIDs, inhaled corticosteroids, LTB4 receptor antagonists and Azithromycin) and potentiators of CFTR protein defect.
CFTR modulator therapy
CFTR modulators are genotype-directed therapies that include potentiators (e.g., ivacaftor) and correctors (e.g., lumacaftor, tezacaftor, elexacaftor) used alone or in combination. These therapies improve CFTR function and have been associated with improved lung function, reduced pulmonary exacerbations, and improved nutritional parameters in eligible patients.[9]
- Ivacaftor for gating mutations such as G551D was associated with clinically meaningful improvements in outcomes in pivotal trials.[4]
- Combination corrector-potentiator therapies for Phe508del (including lumacaftor/ivacaftor and tezacaftor/ivacaftor) expanded modulator eligibility and provided more modest benefits than later triple therapy.[5][6][7]
- Elexacaftor/tezacaftor/ivacaftor (highly effective triple therapy) provides substantial improvements in patients with at least one Phe508del allele and is expected to influence long-term outcomes across respiratory and extrapulmonary domains.[1]
As modulator use increases, clinical trials and observational data are evaluating how to safely reduce treatment burden (e.g., discontinuation of hypertonic saline or dornase alfa) in selected patients receiving highly effective modulators.[14]
Airway clearance and mucolytics
Airway clearance therapies remain foundational for many patients and are supported by guideline-based recommendations.[16] Dornase alfa and hypertonic saline have evidence of benefit in selected populations and are often used to reduce mucus plugging and exacerbations.[17][18]
Chronic airway infection and inhaled antibiotics
Chronic airway infection and inflammation are major drivers of morbidity. Guidance supports early eradication and chronic suppressive therapy for Pseudomonas aeruginosa infection, and inhaled antibiotics are a cornerstone of management.[19][20] Opportunistic pathogens (including nontuberculous mycobacteria and fungi) can complicate management and may require specialized evaluation and therapy.[21]
Extrapulmonary and comorbidity management
CFTR modulators may alter extrapulmonary manifestations, including reports of improved pancreatic function in selected individuals treated with ivacaftor.[22] CF-related diabetes and other metabolic complications remain important in adult care; registry analyses provide updated estimates of prevalence and trends.[23] Mental health screening and management are increasingly emphasized, including clinician guidance and observational studies evaluating symptom changes after initiation of highly effective modulators.[24][25]
Emerging therapies
For patients not eligible for current modulators or with persistent disease burden, investigational approaches include antisense oligonucleotide therapies for specific splicing mutations, respiratory gene therapy, and inhaled mRNA-based therapies.[26][27][28]
Surgery
Cystic fibrosis patients with a large pneumothorax should undergo chest tube insertion and even surgical pleurodesis in case of recurrent large pneumothorax. When medical treatment for pulmonary complications fails, lung transplantation is the only option.
Lung transplantation remains an important option for advanced lung disease, and contemporary registry studies describe outcomes in cystic fibrosis recipients.[29]
Primary Prevention
There is no known way for the primary prevention of cystic fibrosis.
Secondary Prevention
In cystic fibrosis secondary prevention include airway clearance techniques, dornase alpha, hypertonic saline, antibiotics, immunizations, physical activity, nutritional support for pancreatic insufficiency and extra salt and water.
References
- ↑ 1.0 1.1 1.2 Middleton PG, Mall MA, Dřevínek P; et al. (2019). "Elexacaftor–tezacaftor–ivacaftor for cystic fibrosis with a single Phe508del allele". N Engl J Med. 381: 1809–1819.
- ↑ 2.0 2.1 2.2 Burgel PR, Burnet E, Regard L, Martin C. (2023). "The changing epidemiology of cystic fibrosis: the implications for adult care". Chest. 163: 89–99.
- ↑ 3.0 3.1 "Cystic Fibrosis Foundation patient registry 2021 annual data report" (PDF). Cystic Fibrosis Foundation. 2022.
- ↑ 4.0 4.1 Ramsey BW, Davies J, McElvaney NG; et al. (2011). "A CFTR potentiator in patients with cystic fibrosis and the G551D mutation". N Engl J Med. 365: 1663–1672.
- ↑ 5.0 5.1 Wainwright CE, Elborn JS, Ramsey BW; et al. (2015). "Lumacaftor–ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR". N Engl J Med. 373: 220–231.
- ↑ 6.0 6.1 Taylor-Cousar JL, Munck A, McKone EF; et al. (2017). "Tezacaftor–ivacaftor in patients with cystic fibrosis homozygous for Phe508del". N Engl J Med. 377: 2013–2023.
- ↑ 7.0 7.1 Rowe SM, Daines C, Ringshausen FC; et al. (2017). "Tezacaftor–ivacaftor in residual-function heterozygotes with cystic fibrosis". N Engl J Med. 377: 2024–2035.
- ↑ 8.0 8.1 "The Clinical and Functional TRanslation of CFTR (CFTR2)". 2011.
- ↑ 9.0 9.1 Despotes KA, Donaldson SH. (2022). "Current state of CFTR modulators for treatment of cystic fibrosis". Curr Opin Pharmacol. 65: 102239.
- ↑ Pezzulo AA, Tang XX, Hoegger MJ; et al. (2012). "Reduced airway surface liquid and defective bacterial clearance in the porcine cystic fibrosis lung". Nature. 487: 109–113.
- ↑ Stoltz DA, Meyerholz DK, Welsh MJ. (2015). "Origins of cystic fibrosis lung disease". N Engl J Med. 372: 351–362.
- ↑ Stephenson AL, Swaleh S, Sykes J; et al. (2023). "Contemporary survival comparison in cystic fibrosis in Canada and the United States". J Cyst Fibros. 22: 443–449.
- ↑ Currier RJ, Sciortino S, Liu R, Bishop T, Alikhani Koupaei R; et al. (2017). "Genetic testing in cystic fibrosis newborn screening: is IRT plus two variants followed by third-tier sequencing?". Genet Med. 19: 1159–1163.
- ↑ 14.0 14.1 Mayer-Hamblett N, Ratjen F, Russell R; et al. (2023). "Discontinuation of hypertonic saline or dornase alfa in modulator-treated people with cystic fibrosis: a platform of non-inferiority trials". Lancet Respir Med. 11: 329–340.
- ↑ Farrell PM, White TB, Ren CL; et al. (2017). "Diagnosis of cystic fibrosis: consensus guidelines from the Cystic Fibrosis Foundation". J Pediatr. 181: S4–S15.e1.
- ↑ Flume PA, Robinson KA, O’Sullivan BP; et al. (2009). "Cystic fibrosis pulmonary guidelines: airway clearance therapies". Respir Care. 54: 522–537.
- ↑ Yang C, Montgomery M. (2021). "Dornase alfa for cystic fibrosis". Cochrane Database Syst Rev. 3: CD001127.
- ↑ Elkins MR, Robinson M, Rose BR; et al. (2006). "A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis". N Engl J Med. 354: 229–240.
- ↑ Mogayzel PJ Jr, Naureckas ET, Robinson KA; et al. (2014). "Cystic fibrosis pulmonary guidelines. Pharmacologic approaches to prevention and eradication of initial Pseudomonas aeruginosa infection". Ann Am Thorac Soc. 11: 1640–1650.
- ↑ Smith S, Rowbotham NJ. (2022). "Inhaled anti-pseudomonal antibiotics for long-term therapy in cystic fibrosis". Cochrane Database Syst Rev. 11: CD001021.
- ↑ Blanchard AC, Waters VJ. (2022). "Opportunistic pathogens in cystic fibrosis: epidemiology and pathogenesis of lung infection". J Pediatric Infect Dis Soc. 11: Suppl 2:S3-S12.
- ↑ Hutchinson I, McNally P. (2021). "Appearance of pancreatic sufficiency after discontinuation of pancreatic enzyme replacement therapy in children with cystic fibrosis on ivacaftor". Ann Am Thorac Soc. 18: 182–183.
- ↑ Szentpetery S, Fernandez GS, Schechter MS, Jain R, Flume PA; et al. (2022). "Cystic fibrosis-related diabetes: prevalence, trends and associated factors data from the US Cystic Fibrosis Foundation patient registry". J Cyst Fibros. 21: 777–783.
- ↑ "Depression, anxiety, and cystic fibrosis: guide for CF clinicians" (PDF). Cystic Fibrosis Foundation. 2021.
- ↑ Zhang L, Albon D, Jones M, Bruschwein H. (2022). "Impact of elexacaftor/tezacaftor/ivacaftor on depression and anxiety in cystic fibrosis". Ther Adv Respir Dis. 16: 17534666221144211.
- ↑ Oren YS, Irony-Tur Sinai M, Golec A; et al. (2021). "Antisense oligonucleotide therapy in cystic fibrosis patients carrying the 3849+10 kb C-to- to-T splicing mutation". J Cyst Fibros. 20: 865–875.
- ↑ McLachlan G, Alton EWFW, Boyd AC; et al. (2022). "Progress in respiratory gene therapy". Hum Gene Ther. 33: 893–912.
- ↑ Rowe SM, Zuckerman JB, Dorgan D; et al. (2023). "Inhaled mRNA therapy for cystic fibrosis: interim results of a randomized, double-blind, placebo-controlled phase 1/2 clinical study". J Cyst Fibros. 22: 656–664.
- ↑ Yeung JC, Machuca TN, Chaparro C; et al. (2020). "Lung transplantation outcomes for cystic fibrosis". J Heart Lung Transplant. 39: 553–560.