Approach Considerations
As a result of the complex and multisystemic involvement of cystic fibrosis (CF) and the need for care by specialists, treatment and follow-up care at specialty centers with multidisciplinary care teams (ie, cystic fibrosis centers) is recommended.
At the time of initial confirmation of the diagnosis, the patient should undergo baseline assessment, investigations, and initiation of therapy. In addition, patient/parent education, including counseling and instructions regarding airway clearance techniques and the use of equipment (eg, nebulizer, spacer for metered-dose inhaler), is recommended.
When a patient presents with complications necessitating hospital admission, these objectives can be obtained during hospitalization. Follow-up outpatient visits are scheduled at 2-3 monthly intervals. Hospital admission is required for treatment of acute pulmonary exacerbation and severe complications.
The primary goals of CF treatment include the following:
-
Maintaining lung function as near to normal as possible by controlling respiratory infection and clearing airways of mucus
-
Administering nutritional therapy (ie, enzyme supplements, multivitamin and mineral supplements) to maintain adequate growth
-
Managing complications
Mild acute pulmonary exacerbations of cystic fibrosis can be treated successfully at home with the following measures:
-
Increasing the frequency of airway clearance
-
Inhaled bronchodilator treatment (especially if bronchial hyperresponsiveness is present or as part of airway clearance [inhaled bronchodilator followed by chest physical therapy and postural drainage])
-
Chest physical therapy and postural drainage
-
Increasing the dose of the mucolytic agent dornase alfa (Pulmozyme) [56]
-
Use of oral antibiotics (eg, oral fluoroquinolones)
Medications used to treat patients with cystic fibrosis may include the following:
-
Pancreatic enzyme supplements
-
Multivitamins (including fat-soluble vitamins) [57]
-
Mucolytics
-
Nebulized, inhaled, oral, or intravenous antibiotics
-
Bronchodilators
-
Anti-inflammatory agents
-
Agents to treat associated conditions or complications (eg, insulin, bisphosphonates)
In addition to mucolytics such as dornase alfa, hypertonic saline inhalation has been proposed as a therapy to increase hydration of airway surface liquid in patients with CF. [61, 62] Elkins et al reported that patients receiving 7% hypertonic saline (4 mL via nebulizer bid) had improved lung function and fewer pulmonary exacerbations, compared with patients receiving normal saline in a similar fashion. [63] Hypertonic saline was not associated with worsening bacterial infections or inflammation.
The Pulmonary Therapies Committee of Cystic Fibrosis Foundation recommends long-term use of hypertonic saline for patients with cystic fibrosis aged 6 years or older to improve lung function and to reduce the number of exacerbations. [64]
When meconium ileus is diagnosed prenatally, the authors recommend immediate referral to a tertiary care facility equipped to manage the needs of the mother, fetus, neonate, and family. A multidisciplinary team of perinatologists, neonatologists, obstetricians, pediatric surgeons, and CF specialists is prepared for the delivery of these high-risk neonates.
The team performs serial sonographic examinations on a monthly basis prior to delivery, a procedure that allows early detection of potential complications to prepare clinicians for special or urgent medical or surgical needs upon delivery.
The cystic fibrosis transmembrane conductance regulator (CFTR), ivacaftor (Kalydeco), was approved by the FDA in January 2012. A study by Ramsey et al observed lung function improvement at 2 weeks that was sustained through 48 weeks. The study also observed improvements in risk of pulmonary exacerbations, patient-reported respiratory symptoms, weight gain, and concentration of sweat chloride. [2] Ivacaftor was initially approved for adults and children aged 6 years or older who have at least 1 copy of the G551D mutation in the CFTR gene. In February 2014, ivacaftor gained approval for an additional 8 CFTR gene mutations. [65] In 2015, use in CF was expanded to include children as young as 2 years with the approval of an oral granule which is mixed with soft food or liquid. In 2019, the FDA approved use in children as young as 6 months old, and then in 2020 for aged 4 months and older. Since its approval, ivacaftor has gradually gained approval for additional CFTR gene mutations, which total 38 as of April 2019.
Approval of lumacaftor/ivacaftor was based on data from 2 Phase III studies (TRAFFIC and TRANSPORT) that enrolled more than 1100 people with CF aged 12 years and older who had 2 copies of the F508del mutation. In September 2022, the FDA expanded this indication to include children aged 1 year or older. People with 2 copies of the F508del mutation represent the largest group of people with CF. Of the 30,000 people in the United States with CF, approximately 8,500 individuals aged 12 years or older have 2 copies of the F508del mutation. Patients treated with lumacaftor/ivacaftor experienced statistically significant improvements in lung function. Patients also experienced reductions in pulmonary exacerbations and improvements in body mass index (BMI). [58]
Another ivacaftor-containing drug, tezacaftor/ivacaftor (Symdeko) was approved in February 2018 for cystic fibrosis in patients aged 12 years or older who are homozygous for the F508del mutation or who have at least 1 mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Approval was based on the phase 3 studies (EVOLVE and EXPAND) that involved about 750 people with CF. In both trials, the mean absolute change in percentage of the predicted FEV1 was in favor of tezacaftor–ivacaftor over placebo. In the EVOLVE trial, the rate of pulmonary exacerbation was 35% lower in the tezacaftor–ivacaftor group than in the placebo group. The EXPAND trial showed both tezacaftor-ivacaftor or ivacaftor alone had significant benefits versus placebo in both primary and secondary endpoints. [66, 67]
In June 2019, the FDA expanded the indication to include children and adolescents aged 6 to 12 years. Approval was based on completion of the 24-week phase 3 open-label, multicenter study (n=70) to evaluate the pharmacokinetics, safety, and tolerability of tezacaftor/ivacaftor and ivacaftor in children aged 6-11 years in the U.S. and Canada. The combination therapy was generally well tolerated, and safety data were similar to what was observed in previous studies of patients aged 12 years and older. [68]
While corticosteroids have been shown to slow the progression of lung disease, they also had significant adverse effects, especially on growth. [69]
A 2012 study exploring new treatment strategies for CF assessed whether long-term treatment with inhaled mannitol improves lung function and morbidity. Results showed that adding inhaled dry powder mannitol to standard therapy for CF produced sustained improvement in lung function for up to 52 weeks. [70]
In March 2013, the FDA approved tobramycin inhalation powder for the treatment of CF patients with P aeruginosa. [71] The powder is inhaled twice daily for 28 days; treatment is then stopped for 28 days before resuming. In a study of 95 pediatric and adult CF patients infected with P aeruginosa, those treated with inhaled tobramycin powder experienced a significant increase in forced expiratory volume in 1 second (FEV1) compared with placebo-treated patients (12.5% vs 0.09%).
Bisphosphonate treatment initiated during childhood may help counter the bone mineral density (BMD) loss seen in patients with CF, according to the results of a 2013 prospective, open-label observational study of the effects of calcium and vitamin D on BMD in 171 young CF patients, which was followed by a randomized, placebo-controlled trial of the bisphosphonate alendronate. [72, 73]
In the first part of the study, calcium and vitamin D intake were monitored; patients whose BMD had not improved more than 5% within 1 year (75%) joined the second part of the study, in which 128 patients were randomly assigned to treatment with either daily oral alendronate or placebo for 1 year. [73] Among the 65 patients who received alendronate, BMD increased by 16.3%, compared with 3.1% among the 63 patients who received placebo. Among the treated patients, approximately one third attained a BMD that was normal for their ages.
Diet and Exercise
In general, a normal diet with additional energy and unrestricted fat intake is recommended. A high-energy and high-fat diet, in addition to supplemental vitamins (especially fat soluble) and minerals, is recommended to compensate for malabsorption and the increased energy demand of chronic inflammation.
In children, because of various physical activities and eating habits, assessment and modification of energy requirements is based on growth and weight gain. Special consideration is given to female patients with a potential for delayed puberty because of malnutrition, patients with diabetes mellitus, and patients with liver disease.
Additional salt intake is recommended for patients living in hot climates, especially during exercise or activities that cause excessive sweating.
Nutritional supplements in the form of either high-energy oral preparations (eg, Scandishake) or enteral feeds (eg, elemental formulas, high-fat mixtures) via nasogastric tube or gastrostomy may be indicated in some patients. In one study, gastrostomy tube placement has been shown to significantly improve percentile body mass index and percent-predicted FEV1 in male patients and female pediatric patients. Lung function changes after placement did not depend on the level of lung function at placement. [74] . The Cystic Fibrosis Foundation published evidence-informed guidelines on enteral tube feeding in cystic fibrosis which include indications, evaluation and investigations before the procedure, as well as timing in relation to pulmonary status. [75]
Regular exercise increases physical fitness in patients with cystic fibrosis. Upper body exercises, such as canoe paddling, may increase respiratory muscle endurance.
Surgical Management of Complications
Surgical therapy may be required for the treatment of the following respiratory complications:
-
Pneumothorax
-
Massive recurrent or persistent hemoptysis
-
Nasal polyps
-
Persistent and chronic sinusitis
GI tract complications requiring surgical therapy are as follows:
-
Meconium ileus
-
Intussusception
-
Gastrostomy tube placement for supplemental feeding
-
Rectal prolapse
Lung transplantation is indicated for the treatment of end-stage lung disease. [3] Studies suggest that, although lung transplantation may improve quality of life, it may not lengthen survival. [76, 77]
Special Populations
Pregnant patients
CF patients and their partners should attend counseling, including genetic counseling, when planning for pregnancy. Women with CF can have successful pregnancies provided that special care is taken with the following:
-
Nutrition (vitamin and energy supplements)
-
Airway clearance
-
Treatment of respiratory infections
Patients with diabetes
Pancreatic tissue damage leads to diabetes mellitus in 8-12% of CF patients older than 25 years. In the Cystic Fibrosis-Related Diabetes Therapy (CFRDT) Trial, Moran et al found that among patients with CF-–related diabetes without fasting hyperglycemia, insulin therapy improved and sustained body mass index (BMI). [50] Patients treated with repaglinide had an initial significant BMI gain; however, after 6 months, it declined, and no difference was noticed at 1 year.
Consultations and Long-Term Monitoring
In addition to the specialists available at CF centers (usually pulmonologists and/or gastroenterologists), other specialists may need to be consulted when other systems are involved or complications involve other organs, including the following:
-
Surgeon
-
Otolaryngologist
-
Endocrinologist
-
Cardiologist
-
Transplant surgeon
Patients are monitored in the CF clinic every 2-3 months to achieve the following goals:
-
Maintenance of growth and development
-
Maintenance of as nearly normal lung function as possible using clinical assessment, pulmonary function testing, and oxyhemoglobin saturation
-
Intervention and retardation of the progression of lung disease via appropriate use of antibiotics, bronchodilators, and airway clearance techniques
-
Clinical assessment to monitor gastrointestinal tract involvement and presence of malabsorption and to provide enzyme and nutrition supplementation
-
Monitoring for complications and their treatment
-
Addressing psychosocial issues
Respiratory cultures should be obtained during each clinic visit. Common practice is to obtain expectorated sputum for this purpose. In young patients who cannot expectorate, deep throat swab cultures are obtained.
A recent study suggests that induced sputum using increasing concentrations of saline has a higher microbiological yield compared with conventional samples. [78] Although sputum induction is safe and may provide additional information to guide antimicrobial therapy, related extra time and expenses may warrant its use only in special situations.
Various techniques used to clear airways may include the following:
-
Chest physical therapy by hands
-
Forced expiratory technique and autogenic drainage
-
Positive expiratory pressure (PEP) using a PEP mask
-
High-frequency oscillation using a Flutter device
-
High-frequency chest compression using a ThAIRapy Vest
These techniques can be combined with bronchodilator therapy via a nebulizer.
Routine vaccinations are indicated in patients with cystic fibrosis, including seasonal influenza vaccination. A recent attempt by a Cochrane review to study the palivizumab vaccine for prevention of respiratory syncytial virus infection in patients with cystic fibrosis identified one randomized control trial, which reported no increase in the adverse events in the treatment versus placebo groups and that the vaccine made no difference. [79]
A study by Kazmerski et al that explored the attitudes, preferences, and experiences of patients with CF and CF providers toward sexual and reproductive health care for young women with CF found that both CF providers and patients agree that the CF provider has a fundamental role in providing CF-specific sexual and reproductive health care. [80]
-
Chest radiograph of a patient with advanced cystic fibrosis. Note marked hyperinflation, peribronchial thickening, and bilateral infiltrates with evidence of bronchiectasis especially of the upper lobes.
