Cystic fibrosis is a devastating genetic disorder involving mutations in the gene that codes for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Patients with cystic fibrosis have mutations in both genes that code for the CFTR protein channel. Without a functional CFTR protein channel, anion transport is compromised across multiple organ systems. There are several CFTR modulators which improve the production and function of the CFTR channels. These therapies are effective for patients with two copies of the Phe508del mutated gene. Patients with one copy of the Phe508del mutated gene and another minimal-function mutation do not respond well to standard corrector/potentiator treatment. The objective of this study is to evaluate the safety and efficacy of elexacaftor–tezacaftor–ivacaftor in patients with one Phe508del mutation and one minimal-function mutation.
Four hundred and three participants aged twelve years and older with an FEV1 from 40-90% were enrolled in this phase 3, double-blinded, randomized, placebo-controlled trial. Two hundred participants received the elexacaftor–tezacaftor–ivacaftor treatment regimen, and two hundred three participants received placebo for 24 weeks. Participants were stratified based on FEV1, age, and gender to negate factors that could influence prognosis, and groups were similar at baseline. The primary endpoint was the absolute percent change in FEV1 from baseline to week 4, which is a direct indicator of pulmonary function and disease prognosis. Seventy participants were required to achieve 98% power in detecting a 5.0-point difference in FEV1 at a significance level of 0.044. Secondary endpoints included changes in other disease and quality of life measurements over 24 weeks, such as sweat chloride concentration, Cystic Fibrosis Questionnaire–Revised (CFQ-R), body-mass index (BMI), and pulmonary exacerbations.
Preliminary analysis of the primary endpoint at week 4 showed promising results for the triple therapy combination, and this success was sustained through week 24. The absolute change from baseline comparing the treatment arm to the placebo arm at weeks 4 and 24 was 13.8 (P<0.001) and 14.3 (P<0.001), respectively. This change represents statistically and clinically significant improvement in lung function in all participants in the treatment arm, regardless of mutation type. Participants in the treatment arm experienced lower rates of pulmonary exacerbations. Sweat chloride concentrations, which inversely correlates with CFTR functionality, were lower in the treatment arm as compared to placebo, suggesting more functional CFTR protein is produced. The CFQ-R respiratory domain, BMI, and all other secondary endpoints showed improvement in the treatment arm.
Safety endpoints were similar between treatment arms, with many patients experiencing symptoms common to cystic fibrosis. Adverse events occurred in 93.1% and 96.0% in the treatment and placebo arms, respectively. The majority of events were mild or moderate, with serious events occurring in 13.9% and 20.9% of patients in the treatment and placebo arms, respectively. Other adverse events included rash, elevated transaminases, elevated creatinine kinase, and elevated blood pressure. Two patients, both in the treatment group, withdrew from the study due to rash and portal hypertension. Overall, the safety profile was tolerable and consistent with other CFTR modulators.
Elexacaftor–tezacaftor–ivacaftor demonstrated unprecedented efficacy for cystic fibrosis patients with heterozygous Phe508del and minimal-function mutations. This treatment fulfills a substantial unmet medical need in cystic fibrosis communities with no additional safety signals.
Reference: Middleton PG, Mall MA, Dřevínek P et al. Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele. N Engl J Med. 2019 Nov 7;381(19):1809-1819.
Nutritional issues in patients with cystic fibrosis (CF)
Children and adolescents with CF frequently have growth failure caused by the combination of malabsorption, increased energy needs, and reduced appetite. Nutrient delivery and correction of maldigestion and malabsorption are essential to achieve normal growth to support optimal pulmonary function and prolong life.
The CF Foundation patient registry has documented substantial improvement in life expectancy of patients with CF in the past 20 years. To a large degree, the longer life achieved by patients with CF can be ascribed to improved treatment of lung disease, pulmonary toilet, potent and tailored antibiotics, dornase alfa (DNase), lung transplantation, and early diagnosis via newborn screening. However, greater emphasis on CF nutrition is considered important to improve longevity and quality of life.
The advent of CF transmembrane conductance regulator (CFTR) modulators has substantially changed the outlook for patients with CF lung disease. Modulator therapy has also altered growth and nutrition statistics and it is likely that they will have an effect on growth and nutrition, but the full impact of these potent drugs is yet to be determined.
Insufficient production of pancreatic enzymes causes malabsorption of fat, protein, and several micronutrients including the vitamins A, D, E, and K. Malabsorption of fat is exacerbated by bile salt abnormalities if there is concurrent intestinal or liver disease. Across all age groups, approximately 90 percent of patients with CF have marked pancreatic insufficiency.
All patients with CF should be screened for pancreatic insufficiency; this is generally done with fecal elastase testing. Those with normal results should be retested annually and more frequently if there is diminished growth, poor weight gain, or abnormal stools to monitor for development of pancreatic insufficiency. Patients with pancreatic insufficiency (as determined by fecal elastase testing or other measure) should be treated with pancreatic enzyme replacement therapy (PERT).
Pancreatic enzymes are extracts of porcine pancreas containing varying amounts of lipase, protease, and amylase. PERT clearly improves fecal fat absorption in most patients with pancreatic insufficiency. This was demonstrated by a double-blind, placebo-controlled trial in pediatric and adult patients with severe pancreatic insufficiency, in which PERT decreased fecal fat excretion (45.4 versus 4.1 g/day) and increased the coefficient of fat absorption, as well as decreased stool frequency. PERT is not indicated for patients with pancreatic sufficiency, as determined by normal fecal elastase or fecal fat testing and no clinical evidence of malabsorption. In particular, patients with one or two CFTR gene mutations known to be associated with pancreatic sufficiency should not be given PERT unless there is clear evidence of fat malabsorption. Since pancreatic insufficiency may develop over time, these patients should be evaluated at every visit for clinical symptoms of fat malabsorption and also monitored with periodic measurements of fecal elastase and fat-soluble vitamins.
Dosing is generally estimated by the patient's weight and adjusted depending on the patient's response and symptoms. Suppression of gastric acid may improve the efficiency of PERT in selected patients, but this practice is based on limited evidence and must be balanced against potential adverse effects of the acid-suppressing medications. Prolonged contact of the enzyme supplements with oral mucosa may cause ulcers and should be avoided. PERT doses should be limited to 2500 lipase units/kg body weight per meal to avoid fibrosing colonopathy.
Nutritional issues in CF are common and are not fully explained by pancreatic insufficiency or overcome by pancreatic enzyme replacement therapy. Although pancreatic dysfunction is the major gastrointestinal contributor to malnutrition in CF, several other factors may contribute to the problem. These include CF-related liver disease (CFLD), bile salt abnormalities, CF-related diabetes mellitus, altered gastrointestinal motility, intestinal dysbiosis, and small bowel bacterial overgrowth. Gastroesophageal reflux, distal intestinal obstructive syndrome, and constipation can also negatively affect nutrition. Early recognition and intensive treatment of undernutrition in patients with CF can minimize the damaging effects of malnutrition on lung disease, longevity, and quality of life.
References:
Baker, R. D., et al. (2023, February 16). Cystic fibrosis: Nutritional issues. UpToDate. Retrieved from uptodate.com/contents/cystic-fibrosis-nutritional-issues?search=cystic%20fibrosis&source=search_result&selectedTitle=6~150&usage_type=default&display_rank=6#H31
Cystic Fibrosis Foundation. 2021 Patient Registry: Annual Data Report. Available at: https://www.cff.org/sites/default/files/2021-11/Patient-Registry-Annual-Data-Report.pdf
Borowitz D, Baker RD, Stallings V. Consensus report on nutrition for pediatric patients with cystic fibrosis. J Pediatr Gastroenterol Nutr 2002; 35:246.
Bass R, Brownell JN, Stallings VA. The Impact of Highly Effective CFTR Modulators on Growth and Nutrition Status. Nutrients 2021; 13.
Riordan JR, Rommens JM, Kerem B, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 1989; 245:1066.
Hayden HS, Eng A, Pope CE, et al. Fecal dysbiosis in infants with cystic fibrosis is associated with early linear growth failure. Nat Med 2020; 26:215.
Cystic fibrosis (CF) is a multisystem disorder caused by pathogenic mutations of the CFTR gene. Pulmonary disease remains the leading cause of morbidity and mortality in patients with CF. Evidence suggests that airway epithelial defects in ions-water transport lead to dehydrated mucus, impaired mucus clearance, and mucus adhesion to airway surfaces. An increase in mucin secretion is also suggested by the formation of endobronchial mucus plaques and plugs, which become the main sites of airflow obstruction, infection, and inflammation leading to early small airways disease followed by the development of bronchiectasis.
All patients with CF should undergo CFTR genotyping to determine if they carry one of the mutations approved for CFTR modulator therapy. Selection of the CFTR modulator depends on the CFTR mutation and the child's age. The highly effective CFTR modulator elexacaftor-tezacaftor-ivacaftor (ETI) substantially reduces sputum production and mucus plugging, such that at least 50 percent of patients taking ETI no longer expectorate sputum.
Difficulty clearing secretions from the airways is a common complaint among CF patients who have moderate to severe lung disease. The high viscosity of CF sputum is caused by its relative dehydration and the interaction of several macromolecules, including mucus glycoproteins, denatured deoxyribonucleic acid (DNA), and protein polymers such as actin filaments. Airway clearance can be promoted by a combination of inhaled drugs to loosen and liquefy the inspissated mucus (dornase alfa [DNase], hypertonic saline, and/or mannitol) and physical means to dislodge and help the patient expectorate the secretions (breathing/coughing maneuvers, oscillating positive expiratory pressure devices, percussive vests), typically administered in two or more sessions daily.
All patients should have an airway clearance regimen. For patients ≥12 years who are on ETI and who have normal or mildly reduced lung function, it is not suggested to use inhaled airway clearance therapies (nebulized dornase alfa [DNase] and hypertonic saline). This suggestion is based on a 12-week randomized trial that found no benefit of continuing inhaled airway clearance therapies in such patients. For most other patients, chronic use of nebulized dornase alfa (DNase) is recommended.
All patients who produce sputum should be encouraged to adhere to a regular regimen of chest physiotherapy. In addition, all patients should be encouraged to engage in regular exercise. For patients with evidence of airway hyperreactivity (either based on spirometry or subjective improvement in symptoms in response to treatment) who experience intermittent episodes of acute symptomatic bronchospasm, an of an inhaled short-acting beta-adrenergic agonist as needed for symptomatic relief (ie, as a rescue medication).
It is suggested to initiate chronic azithromycin therapy at the time of the first positive culture for Pseudomonas aeruginosa (P. aeruginosa) in patients as young as ≥6 months old. Treatment duration is for as long as the patient remains culture positive for P. aeruginosa. Azithromycin is not prescribed in the absence of chronic P. aeruginosa infection, unless the patient is having frequent pulmonary exacerbations unresponsive to other standard therapy. The benefits of azithromycin appear to be due to an antiinflammatory effect. There is some evidence that chronic azithromycin may reduce the efficacy of inhaled or IV tobramycin. All patients who produce sputum should be tested for nontuberculous mycobacteria prior to initiating azithromycin treatment to avoid the possibility of inducing antibiotic-resistant organisms.
Although better insights into the natural course of CF have led to treatment approaches that have improved pulmonary health and increased the life expectancy of individuals with this disorder, lung disease remains the main cause of morbidity and mortality in patients with CF. The lung involvement is usually progressive with intermittent exacerbations. Aggressive management and advances in treatment delay, but do not prevent progression of lung disease. Respiratory failure ensues and is the major cause of death. Regular check-ups are needed as patients with CF will require constant monitoring and health management to control symptoms and prevent complications.
References:
Simon, Richard H. “Cystic Fibrosis: Overview of the Treatment of Lung Disease.” UpToDate, uptodate.com/contents/cystic-fibrosis-overview-of-the-treatment-of-lung-disease?search=cystic%20fibrosis&source=search_result&selectedTitle=2~150&usage_type=default&display_rank=2#H1582720784.
Martin C, Burnet E, Ronayette-Preira A, et al. Patient perspectives following initiation of elexacaftor-tezacaftor-ivacaftor in people with cystic fibrosis and advanced lung disease. Respir Med Res 2021; 80:100829.
Bec R, Reynaud-Gaubert M, Arnaud F, et al. Chest computed tomography improvement in patients with cystic fibrosis treated with elexacaftor-tezacaftor-ivacaftor: Early report. Eur J Radiol 2022; 154:110421.
Mayer-Hamblett N, Ratjen F, Russell R, et al. Discontinuation versus continuation of hypertonic saline or dornase alfa in modulator treated people with cystic fibrosis (SIMPLIFY): results from two parallel, multicentre, open-label, randomised, controlled, non-inferiority trials. Lancet Respir Med 2023; 11:329.
Warnock L, Gates A. Airway clearance techniques compared to no airway clearance techniques for cystic fibrosis. Cochrane Database Syst Rev 2023; 4:CD001401.
Cystic fibrosis (CF) is a multisystem disorder caused by pathogenic mutations of the CFTR gene (CF transmembrane conductance regulator). Typical symptoms and signs include persistent pulmonary infection, pancreatic insufficiency, and elevated sweat chloride levels. However, many patients demonstrate mild or atypical symptoms, and clinicians should remain alert to the possibility of CF even when only a few of the usual features are present. Diagnosis of CF is based upon the finding of genetic and/or functional abnormalities of the CFTR gene.
CFTR protein is a complex chloride channel and regulatory protein found in all exocrine tissues. Deranged transport of chloride and/or other CFTR-affected ions, such as sodium and bicarbonate, leads to thick, viscous secretions in the lungs, pancreas, liver, intestine, and reproductive tract and to increased salt content in sweat gland secretions. The typical CF patient develops multisystem disease involving several or all of these organs. They may have mild clinical symptoms and/or a normal or intermediate sweat chloride result.
The classic or typical form of CF is diagnosed if a patient demonstrates clinical disease in one or more organ systems and has elevated sweat chloride (≥60 mmol/L). Approximately 2% of patients meet diagnostic criteria for CF but lack one or more of the classic features described. These patients may still be diagnosed with CF if they meet the genetic or functional criteria for the diagnosis, including two copies of a disease-causing mutation in the CF transmembrane conductance regulator (CFTR) gene on each parental allele (ie, in trans) or abnormal nasal potential difference (NPD).
In the past, most patients were diagnosed with CF after presenting with symptoms. Every state in the U.S. now routinely screens newborns for cystic fibrosis. Because of the expansion of newborn screening programs during the past 20 years, there has been a dramatic increase in the number of CF cases identified before presenting with symptoms. In 2001, fewer than 10 percent of CF cases in the U.S. were diagnosed on the basis of newborn screening programs. By 2021, 64.4 percent of total new CF diagnoses and 93.8 percent of diagnoses among infants under six months old were detected by newborn screening. There is evidence that individuals diagnosed prior to the onset of symptoms have better lung function, neurocognitive testing scores, and nutritional outcomes later in life and less utilization of health care resources.
There is no cure for cystic fibrosis, but treatment can ease symptoms, reduce complications and improve quality of life. Close monitoring and early, aggressive intervention is recommended to slow the progression of CF, which can lead to a longer life. The goals of treatment include preventing and controlling infections that occur in the lungs, removing and loosening mucus from the lungs, treating and preventing intestinal blockage, and/or providing adequate nutrition.
Medications options include medications that target gene mutations, including a new medication that combines three drugs to treat the most common genetic mutation causing CF and is considered a major achievement in treatment, antibiotics to treat and prevent lung infections, anti-inflammatory medications to lessen swelling in the airways in your lungs, mucus-thinning drugs, such as hypertonic saline, to help you cough up the mucus, which can improve lung function, inhaled medications called bronchodilators that can help keep your airways open by relaxing the muscles around your bronchial tubes, oral pancreatic enzymes to help your digestive tract absorb nutrients, stool softeners to prevent constipation or bowel obstruction, acid-reducing medications to help pancreatic enzymes work better, and/or specific drugs for diabetes or liver disease, when appropriate.
There is no cure for CF and CF can cause many different problems and long-term complications. People with CF should work closely with a medical team to develop and follow recommendations from a treatment plan developed with their healthcare team.
References:
Katkin, J. P. (2023, March 7). Cystic fibrosis: Clinical manifestations and diagnosis. UpToDate. Retrieved from https://www.uptodate.com/contents/cystic-fibrosis-clinical-manifestations-and-diagnosis?search=cystic%20fibr&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1
Cystic Fibrosis Foundation, Borowitz D, Robinson KA, et al. Cystic Fibrosis Foundation evidence-based guidelines for management of infants with cystic fibrosis. J Pediatr 2009; 155:S73.
Ratjen F, Döring G. Cystic fibrosis. Lancet 2003; 361:681.
Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med 2003; 168:918.