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INTRODUCTION — Cystic fibrosis (CF) is a multisystem disorder caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, located on chromosome 7. Pulmonary disease remains the leading cause of morbidity and mortality in patients with CF. (See "Cystic fibrosis: Genetics and pathogenesis" and "Cystic fibrosis: Clinical manifestations and diagnosis".)
The treatment of CF lung disease is experiencing a period of rapid evolution, supported by well-designed clinical trials and improved understanding of the genetics and pathophysiology of the disease [1,2]. Undoubtedly, these advancements are responsible for a substantial portion of the improvement that has occurred in patient survival (figure 1).
While the focus of this discussion is on pulmonary therapies, it must be kept in mind that management is often suboptimal unless the multisystem nature of the disease is considered. Sinus infection, nutritional status, glucose control, and psychosocial issues must all be assessed at regular intervals. This requires a multidisciplinary approach to care that, in the United States, is best provided at one of the approximately 115 CF Care Centers (most with dedicated adult care programs) that are supported and accredited by the Cystic Fibrosis Foundation. Patients treated at these centers are seen on a regular basis by physicians, nurses, dietitians, respiratory therapists, physical therapists, and social workers with special competence in CF care. A listing of these centers can be obtained at the Cystic Fibrosis Foundation Web site (www.cff.org). In the United Kingdom, CF patients receiving their medical care at specialized CF centers have better clinical outcomes compared with patients followed in the general community [3,4]. In the United States, more frequent caregiver-patient interaction (visit frequency, monitoring, and interventions for pulmonary exacerbations) is associated with improved outcomes .
An overview of the treatment of CF lung disease will be reviewed here. Details of treatment with antibiotics are discussed separately. The diagnosis, clinical manifestations, and investigational treatments for CF are discussed separately. (See "Cystic fibrosis: Antibiotic therapy for lung disease" and "Cystic fibrosis: Clinical manifestations and diagnosis" and "Cystic fibrosis: Clinical manifestations of pulmonary disease" and "Cystic fibrosis: Investigational therapies".)
CFTR MODULATORS — CFTR modulators are a new class of drugs that act by improving function of the defective cystic fibrosis transmembrane regulator (CFTR) protein. The indications and efficacy of these drugs depend upon the CFTR mutation in the individual patient.
Ivacaftor for G551D and other gating mutations — Ivacaftor (VX-770) is a small molecular weight oral drug that was specifically designed to treat patients who have a G551D mutation in at least one of their CFTR genes. The G551D mutation, which occurs in approximately 4.4 percent of CF patients, is called a "gating mutation" because it impairs the regulated opening of the ion channel that is formed by the CFTR protein (see "Cystic fibrosis: Genetics and pathogenesis", section on 'Class III mutations: Defective regulation'). Ivacaftor was developed using high-throughput screening of large chemical libraries, by which candidate molecules (called "potentiators") were identified that increased chloride ion flux in cultured cells expressing G551D CFTR . From these candidate molecules, ivacaftor was developed. As of January, 2012, ivacaftor is recommended and approved in the United States for patients with this mutation . Ivacaftor is also US Food and Drug Administration (FDA) approved for patients with other gating mutations, namely G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, G1349D, or R117H. Of considerable importance, ivacaftor was the first approved CF therapy that restores the functioning of a mutant CF protein rather than trying to target one or more of its downstream consequences. The magnitude and breadth of its beneficial effects significantly exceed any other treatment available for CF . Therefore, all CF patients should undergo CFTR genotyping to determine if they carry a G551D mutation or one of the other mutations listed above.
●Patients 6 years and older – 150 mg tablet PO every 12 hours
●Patients 2 to <6 years
•<14 kg body weight – 50 mg packet PO every 12 hours
•≥14 kg body weight – 75 mg packet PO every 12 hours
Ivacaftor should be taken with fat-containing foods. If packets are used, the dose should be mixed with a small amount (1 teaspoon) of soft food or liquid. Dose reductions are needed for patients with hepatic impairment or who are taking drugs that are inhibitors of cytochrome P4503A (CYP3A) such as itraconazole, clarithromycin, or fluconazole (see manufacturer's prescribing information ). Coadministration of ivacaftor with CYP3A inducers such as rifampin, phenobarbital, carbamazepine, phenytoin, and St. John's wort is not recommended because these drugs markedly decrease serum ivacaftor concentrations.
Because elevations in serum hepatic enzyme levels were noted in a small number of subjects during clinical trials, liver function tests are recommended prior to ivacaftor treatment, every three months for the first year, and then annually thereafter. Dosing should be interrupted if the alanine aminotransferase (ALT) or aspartate aminotransferase (AST) concentrations are more than five times the upper limit of normal. Studies done in juvenile rats found formation of cataracts at doses of ivacaftor above those recommended for humans. Furthermore, non-congenital lens opacities have been reported in children up to 12 years of age receiving ivacaftor . Although other risk factors for cataracts were often present (eg, glucocorticoid use), the FDA recommended that baseline and follow-up ophthalmological examinations should be performed in pediatric patients receiving ivacaftor.
●G551D mutations – Clinical trials of ivacaftor in patients with G551D mutations have demonstrated important benefits:
•In a phase 3 multicenter randomized trial of 161 subjects 12 years of age or older with a G551D mutation, ivacaftor for 24 weeks improved mean percent predicted forced expiratory volume in one second (FEV1) by 10.4 percent compared with a decline by 0.2 percent in subjects receiving a placebo (primary endpoint, p<0.001) . The beneficial effect was maintained through 48 weeks of ivacaftor treatment. Ivacaftor also decreased sweat chloride values by 48.1 mmol/L compared with that in the placebo group (p<0.001), bringing the mean value in the ivacaftor group to 51.7 mmol/L, which is below the cutoff point of 60 mmol/L that is used for diagnosing CF. Finally, treatment with ivacaftor reduced the frequency of pulmonary exacerbations (55 percent reduction in risk), improved pulmonary symptoms, and resulted in a significant weight gain of 2.7 kg after 48 weeks of treatment. The frequency of serious adverse events was lower in the ivacaftor group than in the placebo-treated patients.
•Another randomized, blinded, placebo controlled trial of 52 subjects age 6 to 11 years and at least one G551D CFTR mutation found similar improvements in lung function .
•An open-label follow-up of both of these studies demonstrated durable beneficial effects for at least three years of ivacaftor treatment . After 36 months of treatment, the absolute change in FEV1 was approximately 10 percentage points compared with baseline, and patients also had improved body weight and a reduced rate of pulmonary exacerbations. Moreover, the decline in lung function over the three years of treatment was 50 percent slower than for a comparison group of patients with homozygous F508del mutations who were not treated with ivacaftor .
•In a post-approval study of ivacaftor, clinical and laboratory data were prospectively collected from 151 subjects prior to and then 1, 3, and 6 months after initiating ivacaftor treatment [15,16]. The study confirmed rapid improvements in FEV1 and weight gain, including among individuals with relatively mild disease at baseline. Comparing the six-month periods prior to and after initiation of ivacaftor, the frequency of hospitalizations decreased 19.1 percent and the percent of subjects with at least one positive Pseudomonas aeruginosa culture decreased 18.8 percent. In addition, ivacaftor treatment improved mucociliary and cough clearance. Finally, duodenal pH increased within one month of ivacaftor treatment, consistent with the role of CFTR as a bicarbonate channel.
●Other gating mutations – In tissue culture experiments, ivacaftor also proved effective at potentiating chloride channel function in cells expressing one of eight additional CFTR gating-type mutations . These findings prompted a randomized, double-blind, placebo-controlled crossover clinical trial of 39 CF subjects ages six years and older with a G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, G1349D, or G970R mutation, which showed beneficial results similar to those reported for patients with the G551D mutation [7,18]. Additional culture experiments showed that ivacaftor improved CFTR channel function in cells having an R117H mutation . A randomized double-blind clinical study of ivacaftor in subjects ages six and older with a R117H mutation reported no overall change FEV1 percent predicted at 24 weeks of therapy (which was the primary outcome) . However, there were improvements in FEV1 percent predicted in adult patients (who had more advanced disease at study entry compared to children), as well as improvement in sweat chloride concentrations in all age groups. Based on these studies, the FDA expanded approval for ivacaftor beyond the G551D mutation to include those mutations listed above . This expands by approximately 650 the number of CF patients age six and older who are eligible for ivacaftor in the United States.
●Young children – Because lung damage in CF often begins in early childhood, studies have been performed to determine whether ivacaftor is safe for young children. An open-label 24-week study of ivacaftor administered to 34 children age 2 to <6 years found it to have a safety profile similar to that in older age groups (NCT01705145) [21,22]. The most common adverse events were cough (56 percent) and vomiting (29 percent). Five patients (15 percent) had elevations in liver enzymes to >8 times the upper limit of normal, requiring interruption of the ivacaftor treatment. Each of these patients had a history of similar elevations prior to ivacaftor, and the treatment was successfully resumed in four of the five patients. Although the study was not designed to measure efficacy for CF lung disease, there were significant decreases in sweat chloride (−46.9 mmol/L) and increases in body weight. Based on these findings and the efficacy results from studies in older age groups, the FDA-approved ivacaftor for CF patients age 2 years and older who have a G551D or other CFTR gating mutation.
Lumacaftor-ivacaftor for F508del — For individuals who are homozygous for the F508del mutation (also known as Phe508del or delta F508), treatment with the combination of lumacaftor and ivacaftor yields modest improvements in pulmonary function and reduces the risk of pulmonary exacerbations. As of July 2015, this drug combination is approved by the FDA for CF patients age 12 and older with this homozygous mutation .
The F508del mutation interferes with CFTR protein folding and channel gating activity. Lumacaftor (VX-809) partially corrects the CFTR misfolding while ivacaftor improves the gating abnormality. Unfortunately, neither drug is effective when used alone for F508del homozygotes [24,25]. Combination therapy with lumacaftor-ivacaftor decreased sweat chloride concentration in a phase 2 trial , and was then evaluated in two similarly designed clinical trials (TRAFFIC and TRANSPORT trials), reported in a combined analysis .
Dosing — We suggest treatment with lumacaftor-ivacaftor for patients twelve years and older who are homozygous for the F508del mutation. Dosing is as follows:
The precautions and monitoring recommendations for ivacaftor regarding patients with liver disease apply to combined lumacaftor-ivacaftor as well. Coadministration of lumacaftor-ivacaftor with strong CYP3A inducers is not recommended due to reduced ivacaftor exposure. Lumacaftor-ivacaftor may decrease systemic exposure of other drugs that are CYP3A substrates, so coadministration must be carefully considered. In particular, lumacaftor-ivacaftor will reduce the effectiveness of the azole antifungal antibiotics (except fluconazole); coadministration is not advised. Likewise, lumacaftor-ivacaftor should not be used in patients needing the immunosuppressive drugs cyclosporine, everolimus, sirolimus, or tacrolimus. Because CYP3A induction may reduce the effectiveness of hormonal contraceptives, alternative methods of contraception will be needed. Some antidepressants, gastric acid blockers, and antiinflammatory drugs may need to have their doses increased to maintain effectiveness (see drug label information ).
Efficacy — Over 1100 homozygous F508del subjects ages 12 years and older were randomized to placebo or to one of two doses of lumacaftor (600 mg once daily or 400 mg twice daily) combined with 250 mg ivacaftor twice daily, for 24 weeks . Compared with placebo, the groups receiving the low and high doses of lumacaftor had modest but statistically significant improvements in percent predicted FEV1 of 3.3 and 2.8, respectively. Small improvements in body mass index (BMI) and a quality of life measure were reported. Compared with the placebo group, pulmonary exacerbations were significantly reduced by 30 and 39 percent in the groups receiving low and high doses of lumacaftor, respectively. The improvement in absolute FEV1 from baseline compared with placebo is similar in magnitude to those achieved by treatments with inhaled dornase alfa or tobramycin . The improvements in absolute FEV1 were seen across a range of disease severity .
Adverse effects — Soon after starting lumacaftor-ivacaftor, a subgroup of subjects developed chest discomfort and dyspnea, particularly those with worse baseline lung function . Although the frequency of discontinuation due to adverse events was only 4.2 percent during lumacaftor-ivacaftor phase 3 clinical trials , a post-marketing report from the manufacturer indicates that 15 percent of patients discontinued treatment within the first three months . Because the experience of lumacaftor-ivacaftor is scant in patients with FEV1 <40 percent predicted, additional monitoring in this group during initiation of therapy is suggested . To better assess the treatment effects in this group, an open-label trial is underway (NCT02390219).
Menstrual irregularities were more frequent in women taking lumacaftor-ivacaftor (10 percent) compared with placebo (2 percent) . The adverse effects occurred particularly in those women taking hormonal contraceptives (27 percent) compared with those taking placebo (3 percent).
Although lumacaftor and ivacaftor are the first CFTR modulating drugs to receive FDA approval, other drugs are under investigation, as discussed in a separate topic review. (See "Cystic fibrosis: Investigational therapies".)
ANTIBIOTICS — The course of pulmonary disease in CF is characterized by chronic infections with multiple organisms, causing a gradual decline in pulmonary function, with periodic acute exacerbations heralded by symptoms such as increased cough, sputum production, and shortness of breath.
At birth, the lungs of patients with CF are free of infection. Whether beginning in infancy or later in life, virtually all patients eventually develop repeated acute viral and bacterial infections that upregulate inflammation and lead to airway injury. Ineffective innate and acquired immunity ultimately results in a state of chronic bacterial infection.
The onset and rate of chronic airway infection varies widely among patients due to differences in environmental influences (eg, primary or passive exposure to tobacco smoke, socioeconomic status), genetic effects (CFTR mutations and non-CFTR genetic modifiers), and medical interventions. Nonetheless, some patterns of infection can be observed (see "Cystic fibrosis: Antibiotic therapy for lung disease", section on 'Pathogens'):
●Clinical microbiology laboratories identify Staphylococcus aureus as the most prevalent infecting bacteria in childhood; it continues to be a frequent pathogen throughout adulthood (figure 2). The portion of S. aureus that is methicillin resistant has been increasing.
●Haemophilus influenza is present in 20 to 30 percent of patients in childhood, but it becomes less prevalent in adults.
●P. aeruginosa, which can be isolated in about 25 percent of infants, becomes the most frequently isolated bacteria in adults, reaching a prevalence rate of up to 75 percent.
Antibiotics are essential tools for the treatment of both chronic infections and acute exacerbations of CF lung disease. Based on a few randomized trials, it appears that there is no advantage to scheduling elective periodic hospitalization and intravenous antibiotics for pulmonary toilet ("clean-out"), so this practice is now used infrequently in the United States, although it is variably embraced in Europe [31,32].
Chronic treatment with oral antibiotics to control infection is not encouraged because the benefits have not outweighed the problems associated with antibiotic resistance [33,34] with two exceptions:
●Chronic treatment with nebulized antibiotics directed against P. aeruginosa (eg, tobramycin and aztreonam) appears to improve lung function and is recommended for many patients. These approaches are discussed in detail separately. (See "Cystic fibrosis: Antibiotic therapy for lung disease", section on 'Inhaled antibiotics'.)
BRONCHODILATORS — Airflow obstruction is a central feature of CF lung disease and is caused by several mechanisms. Impairment to flow is due to bronchial plugging by purulent secretions, bronchial wall thickening due to inflammation, and airway destruction. A subgroup of CF patients also have airflow obstruction from bronchial hyperreactivity; many, but not all, of these patients show typical signs and symptoms of asthma, such as chest tightness, wheezing, and cough following exercise or exposure to allergens or cold air . Some of these patients are colonized with Aspergillus species and fulfill diagnostic criteria for allergic bronchopulmonary aspergillosis [36,37]. (See "Clinical manifestations and diagnosis of allergic bronchopulmonary aspergillosis".)
Many patients with CF demonstrate acute improvement in forced expiratory volume in one second (FEV1) following the administration of beta-adrenergic agonists, anticholinergic drugs, and/or theophylline, regardless of the presence of typical asthmatic symptoms; the greatest improvements occur in those who have milder overall lung disease . In general, patients with severe airflow obstruction are less likely to show improvement, and a small number of patients show paradoxical reductions in airflow following inhalation of beta-adrenergic agonists. Most CF patients who show an acute bronchodilator response do not have findings typical of atopy (eg, no family history of asthma, elevated serum IgE, or blood eosinophilia), in contrast to individuals with asthma without CF .
Despite the widespread use of bronchodilators in CF, few long-term studies have been performed to evaluate the chronic effects of bronchodilator treatment. One placebo-controlled crossover study of 27 patients found that one month of albuterol treatment improved peak flow measurements only in patients with a positive pretreatment bronchoprovocation study . (See "Bronchoprovocation testing".)
A separate nonrandomized observational study found that FEV1 improved during a year of albuterol treatment, compared with a decline in FEV1 in a parallel population not taking the drug . However, a subsequent placebo-controlled, double-blind study in 21 patients failed to show that albuterol was superior to placebo, although the power to detect such a difference was low . A randomized placebo controlled trial comparing albuterol with high-dose salmeterol (100 mcg twice daily) showed better FEV1 percent predicted levels during treatment with salmeterol .
Inhaled beta-2-adrenergic receptor agonists — There is limited evidence to guide decisions about chronic use of inhaled beta-adrenergic receptor agonists; a Cystic Fibrosis Foundation guidelines committee concluded that there was insufficient evidence to determine if chronic use of these drugs benefit lung function, frequency of exacerbations, or quality of life . In our practice, we do not prescribe short-acting beta-adrenergic receptor agonists, except in the following situations:
●Immediately prior to sessions of chest physiotherapy and exercise to facilitate clearance of airway secretions. (See 'Chest physiotherapy' below.)
●Immediately prior to inhalation of nebulized hypertonic saline, antibiotics, and/or DNase to limit nonspecific bronchial constriction induced by these agents and to potentially improve penetration and distribution of the drugs within the airways. (See 'Inhaled DNase I (dornase alfa)' below.)
●As rescue medication for CF patients with evidence of airway hyperreactivity, manifested either by improvement in pulmonary function, (eg, increase in FEV1) or by the patient reporting symptomatic improvement with acute use.
Other bronchodilators — The anticholinergic agent ipratropium bromide can induce bronchodilation following acute administration in patients with CF . However, a large randomized trial of tiotropium, a long acting anticholinergic agent, in patients with CF did not show statistically significant improvement in pulmonary function tests during 12 weeks of treatment .
Theophylline is infrequently prescribed in CF due both to the lack of proven efficacy and to its narrow therapeutic index and propensity to cause adverse gastrointestinal symptoms, tachycardia, and rarely seizures.
AGENTS TO PROMOTE AIRWAY SECRETION CLEARANCE — Difficulty clearing purulent secretions from the airways is a universal complaint from CF patients who have moderate to severe lung disease. Chemical analysis of CF sputum has shown that its high viscosity is caused by the interaction of several macromolecules, including mucus glycoproteins, denatured DNA, and protein polymers such as actin filaments [44,45].
Inhaled DNase I (dornase alfa) — The endonuclease DNase I can decrease the viscosity of purulent CF sputum by cleaving long strands of denatured DNA that are released by degenerating neutrophils. The human DNase I gene has been cloned, and the protein that it encodes can help liquefy CF sputum. A randomized, blinded, placebo-controlled trial of 968 stable patients with a forced vital capacity (FVC)>40 percent of predicted values showed that the daily inhalation of 2.5 mg of nebulized DNase (dornase alfa) for six months resulted in a statistically significant improvement in forced expiratory volume in one second (FEV1) of approximately 6 percent . A small but statistically significant reduction in the number of hospital days for exacerbations of respiratory disease was also seen in patients receiving the drug. Subsequent clinical trials have confirmed these findings and demonstrated benefit in children older than six years of age and with mild CF lung disease . A study using data from a patient registry showed that the decline in FEV1 of patients taking dornase alfa was slower than a comparison group . A metaanalysis of randomized trials concluded that DNase treatment improves lung function and is well tolerated .
Patients are generally treated daily; however, results from a 12-week cross-over trial of 48 patients found alternate day dosing of nebulized DNase resulted in equivalent clinical outcomes, and substantially lower drug costs [50,51]. There is some variability among US CF centers in prescribing practices for DNase, probably influenced by the high cost of the drug . A guideline committee of the Cystic Fibrosis Foundation recommends the chronic use of DNase for all children with CF older than six years of age, regardless of symptoms or pulmonary function tests [34,47]. Nebulized DNase is also suggested for infants and young children with CF with pulmonary symptoms, although this suggestion is based on inference from results in older age groups  and results of a small pilot study . Our practice has been to offer it to all patients who have daily cough and to those with FEV1 below the normal range. We also begin chronic DNase if a patient's FEV1 drops below his or her baseline, even if it remains in the normal range, but fails to improve with treatment for an acute exacerbation.
Inhaled hypertonic saline — Hypertonic saline has been administered by inhalation to hydrate inspissated mucus that is present in the airways of patients with CF. It is presumed that the high osmolality of the solution draws water from the airway to re-establish the aqueous surface layer that is deficient in CF . The effectiveness of this strategy was shown by a study of 24 patients (≥14 years of age) with stable CF who were treated with 5 mL of 7 percent saline four times per day for 14 days . The mucus clearance rate was improved after 1 and 14 days of hypertonic saline treatment, and there were modest improvements in lung function and symptom scores. Parallel in vitro studies using cultured monolayers of airway epithelial cells showed that hypertonic saline caused sustained hydration of airway surfaces.
The medium-term benefit of hypertonic saline was demonstrated by an Australian clinical trial in which 164 patients (≥6 years of age) with stable CF were randomly assigned to inhalation therapy with 4 mL of 7 percent saline or 0.9 percent saline following administration of a bronchodilator twice daily for 48 weeks . The study failed to show a statistically significant difference in its primary outcome, namely the rate of change in lung function during the 48-week trial. However, when averaged over the full duration of the study, lung function showed a small, statistically significant improvement in the hypertonic saline group. Patients treated with hypertonic saline had considerably fewer pulmonary exacerbations requiring antibiotic therapy (mean number of exacerbations per participant 0.39 versus 0.89) and fewer days absent from school or work or unable to participate in usual activities (7 versus 24 days). Treatment with hypertonic saline was not associated with worsening bacterial infection or inflammation. The treatment was well tolerated. A systematic review that included this study concluded that hypertonic saline has beneficial effects in patients ≥6 years of age with CF .
By contrast, hypertonic saline cannot be considered to be part of the routine care of CF children under the age of six years. This was shown in a randomized clinical trial involving 344 subjects between 4 and 60 months of age (the International Studies of Infarct Survival [ISIS] trial), which failed to show clinical benefit of inhaling hypertonic saline (7 percent) compared to a control group receiving 0.9 percent saline . There was no benefit in the rate of pulmonary exacerbations (primary endpoint) or any of the secondary endpoints including a respiratory symptom score. As "exploratory" investigations in the ISIS study, infant pulmonary function tests including spirometry using the raised volume technique and lung volumes were performed on a subgroup of the subjects. Of these, only FEV0.5 showed a statistically significant improvement (38 mL) in the hypertonic saline group compared with controls. Given the exploratory nature of these tests, the FEV0.5 result can only be considered hypothesis-generating and not evidence of benefit . It has been suggested that the endpoints used in the ISIS trial may not have been adequately sensitive to detect clinically meaningful benefit in young patients with very mild pulmonary disease. Chest computed tomography (CT), magnetic resonance imaging (MRI), and lung clearance index measurements are undergoing clinical investigations to determine if these are better modalities to detect early changes.
Additional studies are needed to refine the criteria for use of hypertonic saline in older patients with CF and optimal timing of treatments . In a study of patient preference, the majority of patients favored inhaling hypertonic saline before or during their chest physiotherapy rather than after . Prescribing patterns vary greatly across CF centers . Our practice is to offer it to all patients six years of age and older who have chronic cough and/or a mild reduction pulmonary function test results (eg, in FEV1) despite good compliance with the medical regimen. Albuterol should be inhaled from a metered dose inhaler immediately prior to hypertonic saline administration to limit bronchospasm .
Comparing the use of DNase and hypertonic saline — An open, crossover-design trial of 48 children receiving DNase or hypertonic saline in 12-week blocks reported a significantly greater increase in FEV1 with DNase compared with hypertonic saline . In the previously mentioned large 48-week study of hypertonic saline, 38 percent of the subjects were also receiving DNase throughout the trial . Subgroup analysis revealed no difference in the beneficial effects of hypertonic saline between those receiving or not receiving DNase. However, the power of the study to detect clinically significant differences was not presented and probably was low.
In the absence of well-designed comparison studies, the decision of when to prescribe DNase and hypertonic saline remains a conundrum. Because the mechanisms of action of DNase and hypertonic saline are different, their benefits may well be complementary. The guidelines committee of the Cystic Fibrosis Foundation addressed each treatment separately and recommended both for the majority of patients with CF without assigning priority of one over the other . We follow this recommendation but are frequently confronted with situations where a patient will not use both because of cost (DNase costs approximately 30-fold more than hypertonic saline), time required for administration (hypertonic saline is administered twice daily, and DNase once daily), tolerability (DNase typically is better tolerated than hypertonic saline in our experience), or general non-compliance.
For patients willing and able to use both treatments, the following order of administration is recommended : (1) albuterol by metered dose inhaler, (2) hypertonic saline, (3) chest physiotherapy/exercise and DNase in either order, and (4) other inhaled treatments such as aerosolized antibiotics. Inhaled medications should not be mixed together in the same nebulizer because the consequences of doing so are unknown. Of special note is DNase, which is inactivated when mixed with 7 percent saline. (See 'Chest physiotherapy' below and "Cystic fibrosis: Antibiotic therapy for lung disease".)
Inhaled N-acetylcysteine — N-acetylcysteine, a free sulfhydryl reagent that cleaves disulfide bonds within mucus glycoproteins, can liquefy CF sputum in vitro. Although originally developed as an inhaled mucolytic agent, there are no well-designed studies that demonstrate its clinical utility [47,63]. Furthermore, its potential to induce airway inflammation and/or bronchospasm in a subgroup of patients and to inhibit ciliary function has led to reduction in its use. These deficiencies, in conjunction with its disagreeable odor, relatively high cost, and time required for administration cause us not to prescribe it.
CHEST PHYSIOTHERAPY — Retained purulent secretions are an important cause of airflow obstruction and airway injury in CF. In 1950, chest physiotherapy in the form of postural drainage and percussion was introduced to CF care and became the standard method to promote secretion clearance [64,65]. Since that time, secretion clearance programs have been a cornerstone of CF care, although there are no high quality studies that have evaluated their long term benefits compared with no chest physiotherapy . Increasingly, methods that can be performed without the aid of another person are replacing the traditional technique in older children and adults. These alternatives include a variety of breathing and coughing techniques such as "autogenic drainage", "active cycle of breathing", and "huffing" [64,65]. A randomized trial with 36 subjects age 12 to 18 years compared autogenic drainage with postural drainage and percussion and reported no difference in pulmonary function test results, but the subjects strongly preferred the autogenic drainage modality . Medical devices of varying cost and complexity have been developed to assist with airway clearance. These include airway oscillating devices, external percussion vests, and intrapulmonary percussive ventilation.
There are relatively few high-quality clinical trials that evaluate the benefits of chest physiotherapy when performed over extended periods of time or that compare different modalities with each other. A year-long randomized trial in 40 subjects compared postural drainage and percussion with use of a positive expiratory pressure (PEP) mask and found that the PEP mask was associated with significant improvements in pulmonary function compared with postural drainage and percussion . The largest study to date randomized 107 subjects to use a PEP device or a high frequency chest wall oscillation device (a percussion vest) for one year . The group using the PEP device experienced significantly fewer pulmonary exacerbations, which was the primary endpoint of the study. No differences were seen in lung function measures, patient satisfaction, or quality of life scores. Finally, a randomized clinical trial with three treatment arms attempted to compare postural drainage and percussion, a flutter device, and a percussion vest. The trial was stopped early for insufficient subject recruitment and high withdrawal rates . High dropout rates have impaired other attempts at randomized trials, probably because subjects often have strong preconceived but unsupported preferences for one treatment arm over another .
Based upon strong theoretical reasons why airway secretion clearance should be beneficial and despite the lack of strong evidence-based confirmation, chest physiotherapy remains a pillar of CF pulmonary care [9,64,65]. We recommend that all patients who produce sputum should be instructed in chest physiotherapy for secretion clearance. Adherence to chest physiotherapy is often poor, particularly among patients with mild disease [72,73]. Because patients vary in their acceptance and preference for different modes, several techniques should be introduced to each patient. Methods that can be performed without assistance from another person should be included to allow patients to have more control over their regimen. The cost of equipment should be considered, with less expensive modalities prescribed first. More expensive apparatus such as percussion vests may be appropriate for those patients who fail to clear secretions with less expensive methods, who report that the more expensive modalities are effective for them, and who remain adherent with their use.
Exercise — Many patients with CF report that they mobilize secretions during aerobic exercise. Studies of exercise interventions report inconsistent effects on pulmonary function and aerobic fitness, but no negative side effects . One randomized, controlled trial of a three-year home exercise program was performed in children with CF . Those assigned to the exercise arm of the study lost less forced vital capacity (FVC) compared with the control group. The comparison of change in forced expiratory volume in 1 second (FEV1) showed the same trend (p<0.07). In another clinical trial, 41 subjects of mean age 24.6 years were randomized to participate in a three-month home exercise program or to continue their usual care. The exercise group showed a statistically significant increase in a maximum strength test but had no improvement in a general measure of quality of life or six-minute walk distance . A meta-analysis of 13 studies with a combined 402 participants found some, but limited evidence that exercise improved aerobic exercise capacity, pulmonary function tests, and measures of health-related quality of life . These results, combined with the known benefits of exercise in healthy individuals, lead to the recommendation that patients with cystic fibrosis should participate in exercise programs (see "The benefits and risks of exercise"). There is insufficient data to recommend what specific types of exercise should be included in the program. Furthermore, we recommend that any patient with moderate or advanced pulmonary disease should participate in an organized pulmonary rehabilitation program. (See "Pulmonary rehabilitation in COPD".)
ANTIINFLAMMATORY THERAPY — Intense neutrophilic inflammation is a dominant pathological feature of the airways of patients with CF. Although the inflammatory response was formerly viewed as being necessary to prevent the spread of infection, increasing information indicates that the amount of inflammation developed is probably excessive and harmful .
Macrolide antibiotics — Macrolide therapy was found to be beneficial for patients with panbronchiolitis, a non-CF lung disease that is seen predominantly in Japan and is manifested by bronchiectasis and chronic pseudomonas infection (see "Diffuse panbronchiolitis"). Clinicians caring for patients with CF began using macrolides empirically and their favorable observations prompted several well-constructed clinical trials of macrolides in CF.
The largest clinical trial to date of macrolide therapy in CF studied 185 patients who were chronically infected with P. aeruginosa and who had a forced expiratory volume in 1 second (FEV1) >30 percent . Subjects were randomly assigned to receive azithromycin 500 mg PO or placebo three days a week for 24 weeks. By the end of the trial, subjects taking azithromycin had a 4.4 percent improvement in percent predicted FEV1, although those receiving placebo had a 1.8 percent reduction; the difference was statistically significant. In addition, there were 40 percent fewer respiratory exacerbations in the azithromycin-treated group than in the control group. A subsequent report, which included patients with and without P. aeruginosa, concluded that even patients who did not demonstrate an improvement in lung function still derived benefit because of a decreased incidence of acute pulmonary exacerbations . These results are in close agreement with three smaller studies that showed similar benefits from macrolides in patients with CF [80-82], and a one-year randomized trial in children with CF that revealed reductions in the frequency of pulmonary exacerbations and the need for additional antibiotics, although no change in FEV1 .
One placebo-controlled trial focused only on patients uninfected with P. aeruginosa, who were treated with azithromycin or placebo for 24 weeks . In this population of relatively healthy patients (mean FEV1 97 percent predicted), azithromycin did not improve lung function, as measured by FEV1. However, use of azithromycin was associated with clinically important improvements in several exploratory end points, including a 50 percent reduction in pulmonary exacerbations, 27 percent reduction in the initiation of new oral antibiotics (other than azithromycin), 0.58 kg weight gain, and 0.34 unit increase in body mass index (BMI). There were no differences in treatment groups in use of intravenous or inhaled antibiotics or hospitalizations.
A systematic review that included all of the above studies concluded that six months of treatment with azithromycin improves respiratory function in patients with CF and reduces the frequency of pulmonary exacerbations .
The mechanisms by which macrolides improve CF lung disease are uncertain and may involve direct effects on infecting bacteria and/or suppression of the excessive inflammatory response seen in the CF lung. Macrolides are unable to kill pseudomonas bacteria that are grown under conditions routinely used in clinical microbiology laboratories. However, macrolides have microbicidal activity against pseudomonas bacteria that are grown under conditions that induce biofilm formation . Furthermore, macrolides can block quorum sensing and reduce the ability of pseudomonas to produce biofilms, which is considered one of the mechanisms by which the bacteria avoid being killed by traditional antipseudomonal antibiotics . Independent of their effect on bacteria, there is mounting evidence that macrolides may be beneficial in CF lung disease by suppressing the excessive inflammatory response [88,89].
In our practice, we recommend using azithromycin for all patients with CF older than six years of age regardless of P. aeruginosa infection status who have clinical evidence of airway inflammation such as chronic cough, or who have any reduction in FEV1. The guidelines published by the Cystic Fibrosis Foundation do not restrict the use of azithromycin to those with evidence of airway inflammation or reduction in FEV1 as we suggest here . However, because of limited data on the safety of prolonged use of azithromycin, we recommend delaying its routine use in patients who have negligible evidence of airway disease and whose expected benefit may be minimal. We usually prescribe the medication three times a week, using 250 mg for patients with body weight less than 40 kg, and 500 mg for those over 40 kg. A study in adults shows that 250 mg daily is similarly efficacious, so daily dosing could be used for those patients who find it easier to adhere to a daily treatment schedule . For the small number of patients who develop gastrointestinal side effects on full dose, a lower dose may be used (eg, 250 mg three times a week for adult-sized patients); this dose reduction was employed in one study and was thought to be of benefit .
Prior to initiating treatment with azithromycin, we recommend that a sputum specimen be examined for nontuberculous mycobacteria; macrolide therapy should NOT be initiated if nontuberculous mycobacteria are present. This is because macrolides are an important component of treatment regimens for Mycobacterium avium complex infection and should be used only as part of a multi-drug regimen, to avoid development of macrolide-resistant mycobacterial species. If smear-negative patients are subsequently positive by culture, the macrolide should be stopped to avoid induction of macrolide resistance. The decision to treat nontuberculous mycobacteria with multiple antibiotics should be based on an assessment of the likelihood that the mycobacteria are causing tissue injury and clinical deterioration, and is discussed elsewhere (see "Treatment of nontuberculous mycobacterial infections of the lung in HIV-negative patients"). In patients without nontuberculous mycobacteria, the use of chronic azithromycin may help to prevent its acquisition: data from the Cystic Fibrosis Foundation patient registry showed that the incidence of positive cultures for nontuberculous mycobacteria in CF patients receiving chronic azithromycin therapy was less that the control population .
Ibuprofen — Based on the recognition that antiinflammatory glucocorticoids reduce the rate of FEV1 decline in CF, ibuprofen was studied to determine if similar benefits could be obtained without the prohibitive side effects of glucocorticoids. The clinical value of high-dose ibuprofen was demonstrated in two long-term studies in patients with mild CF lung disease.
●A randomized trial of high-dose ibuprofen was conducted in 85 individuals 5 to 39 years old with mild disease. Repeated pharmacokinetic studies were performed on study subjects to ensure that high-peak blood levels of ibuprofen (50 to 100 mcg/mL) were obtained . After four years, patients in the ibuprofen group who completed the study lost only 1.5 percent of their predicted FEV1 per year, compared with a loss of 3.6 percent of predicted FEV1 per year for the control group. However, the beneficial effects of ibuprofen were seen only in the subgroup of patients who were younger than 13 years of age at the start of the study. Gastrointestinal bleeding and renal impairment, known adverse effects of ibuprofen, were not observed in either group.
●In a multicenter randomized trial, a similar protocol was tested in 142 patients 6 to 18 years old . The primary outcome of this study, rate of decline in FEV1 percent predicted, was not statistically reduced by ibuprofen as compared with placebo. However, the study did not meet its recruitment targets, causing it to be underpowered to detect a difference of 2 percent. The group treated with ibuprofen did show a statistically significant reduction in the rate of decline of forced vital capacity (FVC) percent predicted (0.07 ± 0.51 versus -1.62 ± 0.52), which was a secondary endpoint of the study.
The guidelines committee of the Cystic Fibrosis Foundation suggests the use of high-dose ibuprofen in children 6 through 17 years of age who have good lung function (FEV1 >60 percent predicted) . This recommendation is supported by a Cochrane review . However, we do not recommend initiation of ibuprofen after the age of 13 years because there is no evidence supporting initiating this treatment in this age group. If high-dose ibuprofen is prescribed, pharmacokinetic studies should be performed periodically to ensure correct dosing, and patients should be monitored closely for the development of adverse effects . (See "Nonselective NSAIDs: Overview of adverse effects".)
In practice, high-dose ibuprofen is being prescribed for only a small minority of pediatric-aged patients in the United States . The requirement for periodic pharmacokinetic adjustment of the dose and concern for side effects appear to be restricting its acceptance.
Systemic glucocorticoids — Based on the theory that excessive inflammation may be a contributor to lung damage in CF, systemic glucocorticoids have been investigated for their antiinflammatory effects.
Chronic administration — In 1985, the results of a randomized, placebo-controlled study of glucocorticoids in children with CF were reported . After 40 months of treatment, the group receiving 2 mg/kg of prednisone every other day had higher values of FEV1 and fewer hospitalizations for pulmonary disease compared with the placebo group. Adverse effects from the prednisone were minimal. These observations spawned a larger multi-center study testing every other day prednisone (either 1 mg/kg or 2 mg/kg) against placebo . The high-dose arm of the study was halted early because of an unacceptably high incidence of abnormal glucose metabolism, cataracts, and growth failure. Long-term follow-up of this trial revealed that boys treated with prednisone had significant reductions in adult height as compared with those treated with placebo . Among girls, the long-term effects of prednisone on height were not statistically significant. Similar but milder changes were seen in the lower-dose prednisone group when data were analyzed at the planned conclusion of the trial.
We agree with the guidelines committee of the Cystic Fibrosis Foundation, which recommends against the routine chronic use of oral corticosteroids for children with CF aged 6 to 18 years, in the absence of asthma or allergic bronchopulmonary aspergillosis, because of the associated adverse effects [9,34]. The committee found insufficient data on which to judge the value of chronic glucocorticoids in adults. Because of concerns about the increased susceptibility of CF patients to glucocorticoid-induced hyperglycemia and osteoporosis in addition to the other complications of long-term treatment with corticosteroids, we also do not recommend chronic oral corticosteroids to patients in the adult age group, unless needed for concomitant asthma or allergic bronchopulmonary aspergillosis.
Short-term treatment for acute pulmonary exacerbations — Systemic glucocorticoids have established benefits in acute exacerbations of non-CF chronic obstructive pulmonary disease (COPD), prompting some clinicians to use them for acute exacerbations in patients with CF  (see "Management of exacerbations of chronic obstructive pulmonary disease"). A pilot study evaluated this practice in a randomized, double-blind, placebo-controlled trial . Twenty-four patients with CF and an acute pulmonary exacerbation were treated with either prednisone at 2 mg/kg/d (maximum 60 mg) or placebo for five days. The primary endpoint, the rate of improvement in FEV1 from days one to six, did not differ significantly between groups, although the power of the study to detect differences was small. None of the secondary endpoints showed a statistically significant difference. Using the data from this pilot study, the investigators concluded that more than 250 patients would need to be entered to detect a 4 percent improvement in FEV1 percent predicted.
In practice, we use systemic glucocorticoids during acute pulmonary exacerbations only for those patients with predominant asthma-like symptoms, eg, those with prominent sensation of chest tightness, minimal expectoration of sputum despite mucus plugging on chest x-ray, documented response to bronchodilator in the pulmonary function laboratory, and high-pitched wheezes and/or poor air movement by auscultation. For these patients, we use 0.5 to 1.0 mg/kg per day prednisone (maximum of 40 to 60 mg/day) and restrict the duration to approximately five days.
Inhaled glucocorticoids — Inhaled glucocorticoids have been prescribed in an effort to obtain the benefits that were demonstrated in the oral glucocorticoid trials while reducing the adverse effects of oral therapy. However, only a few studies have evaluated their effect:
●One trial randomly assigned 55 patients with CF but without clinically evident asthma to receive budesonide (800 mcg) or placebo twice daily for three months . Deterioration of lung function (measured by the FEV1) was less in the budesonide group, suggesting that inhaled glucocorticoids are beneficial in this subset of CF patients.
●In a larger placebo-controlled trial, 171 patients who were receiving inhaled glucocorticoids at study entry were randomly assigned to either continue or stop treatment for six months . An additional 31 subjects who were otherwise eligible for the study were excluded by their clinicians, usually because they had signs and symptoms suggesting a significant asthmatic component to their CF lung disease. Cessation of glucocorticoids had no impact on the duration until the first exacerbation, lung function, antibiotic use, or bronchodilator use.
Although it seems reasonable to continue prescribing aerosolized glucocorticoids to CF patients who have definite signs and symptoms of asthma or allergic bronchopulmonary aspergillosis, there is insufficient evidence to warrant broader use . We agree with the guidelines committee of the Cystic Fibrosis Foundation, which recommends against their routine use [9,34]. One of the reasons for caution is that inhaled glucocorticoids may modestly impair linear growth in children with CF or asthma [105,106]. These effects are dose-related and less severe than those seen in children treated with systemic glucocorticoids.
Cromolyn — Sodium cromoglycate and nedocromil are antiinflammatory drugs that have been used for the treatment of asthma; nedocromil is no longer available in the United States. Neither has been studied adequately in patients with CF. The few small studies that have been performed detected no benefit or adverse effects. As an example, one double-blind, placebo-controlled, crossover study was performed on 14 patients with CF and bronchial hyperreactivity; no improvement in clinical status or pulmonary function tests was seen among patients receiving sodium cromoglycate .
Given the lack of adequate studies of cromolyn in patients with CF, the relatively high expense, and the evidence of inferiority relative to inhaled glucocorticoids in patients with asthma , we do not prescribe cromoglycate or nedocromil for our patients.
VACCINATIONS AND PALIVIZUMAB
Influenza vaccine — Viral respiratory infections have been implicated as a frequent cause of exacerbations of CF lung disease  and are the subject of several reviews [53,110,111]. Based on efficacy in other populations, annual vaccination against viral influenza is recommended for all patients with CF older than six months of age, using an inactivated vaccine delivered by injection, but not the live attenuated vaccine delivered by intranasal spray . (See "Seasonal influenza vaccination in adults" and "Seasonal influenza in children: Prevention with vaccines", section on 'Target groups'.)
Pneumococcal vaccine — The pneumococcal vaccine is recommended for all patients with CF because of a favorable risk-benefit profile, although Streptococcus pneumoniae is not a major cause of pulmonary exacerbations in CF. This should include the 13-valent pneumococcal conjugate vaccine series for children up to 24 months of age, and the 23-valent pneumococcal polysaccharide vaccine after 2 years of age . (See "Pneumococcal vaccination in adults" and "Pneumococcal (Streptococcus pneumoniae) conjugate vaccines in children", section on 'Indications'.)
Palivizumab — Palivizumab is a humanized monoclonal antibody against respiratory syncytial virus, which is used to help prevent serious RSV infection in young children who are at high risk for RSV disease. One systematic review and two subsequent clinical studies have reached conflicting conclusions about the efficacy of palivizumab for young children with cystic fibrosis [112-114]. Some experts recommend its use in children <24 months who have severe lung disease , but until more definitive studies demonstrate efficacy and safety, no firm recommendation can be made regarding its use. (See "Respiratory syncytial virus infection: Prevention", section on 'Cystic fibrosis'.)
SUPPLEMENTAL OXYGEN — Progressive CF is routinely accompanied by worsening hypoxemia. However, there is little information about the effect of supplemental oxygen on the course of the disease. The use of short-term oxygen therapy during sleep and exercise was evaluated in a systematic review of ten small, randomized, controlled trials of patients with CF . Supplemental oxygen modestly enhanced exercise duration and capacity, and caused mild hypercapnia that is probably clinically insignificant. Use of nocturnal oxygen did not improve qualitative sleep parameters.
Only one of the studies in the systematic review examined long-term oxygen therapy . No statistically significant improvement in survival, lung function, or cardiac health was detected. In addition, improvement of oxygenation was accompanied by modest but probably clinically inconsequential hypercapnia.
Until larger, controlled trials exist, we recommend supplemental oxygen for patients with CF to treat intermittent or chronic hypoxemia. We believe it is appropriate to assume that supplemental oxygen will delay or ameliorate the complications of chronic hypoxemia in CF, as it does in chronic obstructive pulmonary disease . In the absence of studies examining oxygen use in patients with CF, we follow the same recommendations for use as in patients with chronic obstructive pulmonary disease (COPD). (See "Long-term supplemental oxygen therapy".)
NONINVASIVE POSITIVE PRESSURE VENTILATION — Noninvasive positive pressure ventilation (BiPAP) has been used for patients with advanced CF lung disease and hypercapnia [119-121]. In a randomized trial in adults with daytime hypercapnia, nocturnal use of BiPAP was compared with supplemental oxygen or placebo (air) . Six weeks of BiPAP improved chest symptoms, exertional dyspnea, nocturnal hypoventilation, and peak exercise capacity, without measurable improvement in lung function. Based on these studies, it would be appropriate to offer nocturnal noninvasive BiPAP to patients whose arterial carbon dioxide level remains elevated (eg, ≥50 mmHg) despite maximizing other treatments.
INTENSIVE CARE UNIT TREATMENT — Outcomes for CF patients requiring treatment in an intensive care unit (ICU) was previously reported to be uniformly poor , but has fortunately improved. There are probably multiple reasons for the improved outcomes, including the use of non-invasive ventilation to sustain the patient until other measures to reverse the respiratory failure take effect [123,124]. In modern series, survival was dependent upon the severity of respiratory failure, with the best outcomes for those who could be managed by noninvasive ventilation and the worst for those requiring endotracheal intubation/ventilation [124-129]. Patients requiring ICU treatment admission for pneumothorax or hemoptysis had a better prognosis as compared with CF patients admitted to the ICU for other indications . Most of these studies were of adult CF patients, but one included five children who were younger than two years old, all of whom survived .
Although the long-term prognosis following an episode of respiratory failure is still poor in older children and adults, ICU support appears to be particularly useful for those patients who are candidates for lung transplantation. In addition, intubation and positive pressure ventilation are indicated for infants and young children with acute bronchiolitis but without extensive bronchiectasis, especially in the context of a documented acute viral infection.
An episode of respiratory failure, regardless of age (except for infants and young children with pure bronchiolitis), should prompt discussion of end-of-life care, quality of life, and the possible indications for lung transplantation.
LUNG TRANSPLANTATION — Advancements in the treatment of CF lung disease have delayed but not arrested disease progression; premature death from respiratory failure still occurs in the majority of patients. As in other progressive lung diseases, lung transplantation provides an additional, albeit imperfect, management option . (See "Lung transplantation: An overview".)
Virtually all lung transplants for patients with CF require replacing both lungs because leaving a native lung in place would present a huge source of infected secretions that would threaten the transplanted lung. A registry compiled by the International Society for Heart and Lung Transplantation reports that 840 lung transplants were performed in children with CF from January 2000 through June 2014 , and 7419 transplants were performed in adults with CF from January 1995 to June 2014 .
Timing of transplantation — The decision for referral to a lung transplant center is driven by estimates of a patient's predicted survival and quality of life with and without lung transplant. A retrospective study from the Cystic Fibrosis Foundation Registry, using data that had been collected between 1992 and 1998, concluded that transplantation extends life if performed when the patient has a five-year predicted survival without transplant of less than 30 percent, and possibly when the predicted survival is less than 50 percent .
Determining when these conditions are met remains challenging. Attempts to use a single indicator (eg, FEV1 percent predicted <30) to trigger referral have not been sufficiently predictive for use by itself . Analysis using multiple risk factors for reduced survival may improve the accuracy of estimates , but the published equations are often generated from data that may not reflect current survival patterns. In 2014, the International Society of Heart and Lung Transplantation (ISHLT) published a list of conditions to be used when considering transplant referral . Importantly, the publication stressed that the decision should not be driven by a single parameter but by the patient's entire clinical picture. Based in part on the ISHLT consensus report, we recommend that the following factors should be used in considering the timing for referral to a lung transplant center:
●FEV1 that has fallen to 30 percent of predicted values.
●Rapidly falling FEV1 despite optimal therapy in a patient with advanced lung disease, eg, an FEV1 <40 percent predicted, particularly in a female patient or in one with CF-related diabetes.
●A six-minute walk distance <400 meters
●Development of pulmonary hypertension in the absence of a hypoxemic exacerbation (as defined by a systolic pulmonary arterial pressure (PAP) >35 mm Hg on echocardiography or mean PAP >25 mm Hg measured by right heart catheterization)
●Clinical decline characterized by increasing frequency of exacerbations associated with any of the following:
•An episode of acute respiratory failure requiring noninvasive ventilation
•A pattern of poor clinical recovery from successive exacerbations
•Worsening nutritional status despite supplementation
•Pneumothorax, particularly when recurrent or difficult to resolve
•Life-threatening hemoptysis despite bronchial artery embolization
Since 2005, in the United States, the position of each individual lung transplant candidate on the priority list for transplant is determined by a lung allocation score (LAS) formulated by UNOS (United Network for Organ Sharing). The score is based on lung diagnosis, age, body mass index (BMI), diabetes, supplemental oxygen use, six-minute walk distance, pulmonary artery systolic pressure, pulmonary capillary wedge pressure, serum creatinine functional status, and need for assisted ventilation. Details about the scoring system are available from the Organ Procurement and Transplantation Network . The scoring system is adjusted periodically to incorporate new data that improve the estimate of one-year survival with and without transplantation. A study from a single center found that integrating a health-related quality of life measure might improve the estimation of mortality when computing a transplant priority score . As expected, an analysis of UNOS data found that survival of those transplanted with very high LAS was worse than those with lower scores at the time of transplant .
There are wide variations in the length of waiting lists among transplant centers, and individual patients may be served by exploring a number of different lung transplant centers. Noninvasive positive pressure ventilation and extracorporeal membrane oxygenation, most commonly venovenous extracorporeal membrane oxygenation (ECMO), have been used to bridge patients to transplantation . (See 'Noninvasive positive pressure ventilation' above.)
Patients with CF rarely become candidates for lung transplantation prior to 12 years of age. According to the policy for lung distribution overseen by the Organ Procurement and Transplantation Network (OPTN), the LAS is not used for this age group. Due to limited availability of age-matched lungs for children, particularly for those below the age of 12, UNOS broadened their policy so that lungs from adolescent donors are preferentially allocated to pediatric recipients. Under the prior policy, organs from adolescent donors had been allocated preferentially to adults or adolescents based on LAS scores. Simulation modeling indicated that the new policy should improve organ availability for children .
Contraindications — Each transplant center has its own list of relative and absolute contraindications for lung transplantation. In addition to the general contraindications for lung transplantation applicable for all disease indications, there are several CF-specific considerations. Chronic infection with Burkholderia cenocepacia connotes a worse prognosis following transplantation [142-145]. Most, but not all, transplant centers consider infection with this organism to be a contraindication to the procedure . Other species of Burkholderia do not appear to have the same adverse effects, with the possible exception of Burkholderia gladioli [142-145]. Patients infected with multidrug-resistant P. aeruginosa have slightly worse survival following lung transplant compared with those infected with drug-sensitive P. aeruginosa, but the decrement is minor; their survival is similar to that of patients undergoing lung transplantation for non-CF diagnoses . Those infected with Mycobacterium abscessus frequently develop post-transplant complications and should be evaluated by centers with experience managing this infection . (See 'Outcomes' below and "Lung transplantation: General guidelines for recipient selection" and "Lung transplantation: Disease-based choice of procedure".)
Most lung transplant centers in the United States will not accept the referral of intubated patients in acute respiratory failure for lung transplant evaluation. The survival of these patients without transplantation is poor, and prolonged intensive care unit (ICU) stays are associated with progressive deconditioning of affected individuals, another strong contraindication to transplantation in many centers. In addition, their poor clinical status prohibits education and informed consent of the patient, who is expected to adhere to a post-transplant regimen that is complex and can be onerous.
Symptomatic osteoporosis is a relative contraindication for lung transplantation in general, but it takes on special significance for patients with CF. The frequency of osteopenia/osteoporosis in CF increases with age and affects about 20 percent of individuals in the 18- to 25-year age group . Thus, pre-symptomatic diagnosis and treatment of osteopenia/osteoporosis is important to avoid exclusion of a patient from consideration for transplantation .
Outcomes — Among adult patients with CF who underwent lung transplantation between 1990 and 2013, the median (50 percent) survival was 8.5 years , which is significantly better than the survival for patients who are transplanted for other disease indications (figure 3) (see "Lung transplantation: An overview"). Reports of survival data from single centers restricting the analysis to more recent experience suggest that survival may be improving [150,151]. Pediatric patients receiving lung transplants for CF had a 50 percent survival of 5.2 years, which is not significantly different from the 5.3 year median survival for pediatric patients who were transplanted for other indications, but is lower than that of adults with CF .
The benefits of lung transplantation in CF have been assessed using retrospective data from the Cystic Fibrosis Foundation Registry. Outcomes for 458 patients who underwent lung transplantation for CF between 1992 and 1998 were compared with those of 11,630 patients who did not undergo transplantation . The following observations regarding transplantation and survival were noted:
●For patients with predicted five-year survival of less than 30 percent, lung transplantation is associated with a clear improvement in survival.
●Survival benefit was equivocal for patients with a predicted five-year survival of 30 to 50 percent.
●Patients with predicted five-year survival of greater than 50 percent and who underwent transplantation (though few in number) had a lower rate of survival than their nontransplanted counterparts.
●The benefit of transplantation also varied with time. Overall survival was superior in nontransplanted controls during the first 2.5 years of follow-up; however, after four years transplanted patients demonstrated increased survival.
An analysis of 514 pediatric aged patients who were listed for lung transplantation between 1992 and 2002 was performed by the same research group using merged data from the Cystic Fibrosis Foundation Registry and the Organ Procurement and Transplantation Network (OPTN) . This study failed to show a definite survival advantage, except for a small minority of transplanted patients who were younger than 18 years of age at the time of listing . This contradicts a previous report from the United Kingdom that found a survival advantage for transplanted children . After correcting for multiple potential risk factors, the older study reported that the hazard ratio for death in the transplanted group was 0.31 (95% Cl 0.13-0.72, p = 0.007).
Limitations of transplantation — Many problems remain after lung transplantation for CF. The procedure does not address the non-pulmonary problems associated with CF. Chronic sinusitis, cirrhosis, cholelithiasis, pancreatic insufficiency, CF-associated diabetes mellitus, osteoporosis, and distal intestinal obstruction syndrome that remain causes of morbidity and occasionally of mortality. Pancreatic insufficiency and abnormalities in bowel motility can make cyclosporine absorption and dosing difficult; tacrolimus itself is diabetogenic; glucocorticoid treatment to suppress graft rejection complicates diabetic management and accelerates osteoporosis. Studies examining quality of life after lung transplantation for CF generally show improvement [154-156]. Most children return to school and many adults return to work.
PREGNANCY — In 2014, there were 232 pregnancies reported in the Cystic Fibrosis Foundation Registry, which is a rate of approximately 4 live births per 100 women in a reproductive age range . Compared with women without CF, women with CF have higher risks of serious complications during pregnancy (including preterm birth, pneumonia, requirement for mechanical ventilation, and death), but these events are rare and the absolute risk is low . The overall mortality rate during delivery was 1 percent. In addition to the underlying pulmonary disease, comorbidities that may complicate pregnancies include cystic fibrosis-related diabetes, cardiac conduction disorders, acute renal failure, and thrombophilia/antiphospholipid syndrome. Severe lung disease, especially when pulmonary hypertension is present, is a bad prognostic indicator , although successful outcomes have been reported in a few women who had severe impairment of lung function prior to conception . Small case series and larger cohort studies have documented that a history of pregnancy does not alter the subsequent clinical course for women with CF who have mild to moderate pulmonary disease (ie, forced expiratory volume in one second [FEV1] >60 percent predicted) [158-162], although the frequency of treatment for pulmonary exacerbations was increased during pregnancy .
The general principles of pregnancy management for women with CF include the following :
●Achieving optimal, stable pulmonary function prior to conception and carefully monitoring during pregnancy
●Providing genetic counseling regarding the risk of disease in offspring, carrier testing of the father, and options for prenatal diagnosis (see "Cystic fibrosis: Carrier screening")
●Close monitoring of maternal nutrition and weight gain
●Screening for gestational diabetes early in pregnancy because of the increased risk for secondary insulin deficiency
NONINFECTIOUS PULMONARY COMPLICATIONS — Spontaneous pneumothorax and hemoptysis are well-recognized complications of CF, particularly among adults. These complications have become increasingly common as overall survival continues to improve [164,165].
Spontaneous pneumothorax — Spontaneous pneumothorax occurs in 3 to 4 percent of patients with CF during their lifetime . Major risk factors are older age and more severe obstructive lung disease. Treatment of pneumothorax in CF patients does not differ from that of patients with other types of lung disease. (See "Secondary spontaneous pneumothorax in adults" and "Spontaneous pneumothorax in children".)
Guidelines have been published for the management of pneumothorax in patients with CF . Pleurodesis, when needed to address persistent air leaks or other pleural space problems, should not preclude subsequent lung transplantation [168,169]. However, avoidance of more aggressive pleural stripping procedures or the use of talc may be advisable to reduce subsequent bleeding complications if and when the native lungs are removed at transplantation . Collaboration between the consulting CF Center surgeon and a lung transplant surgeon is recommended.
Hemoptysis — Minor hemoptysis is a common occurrence in patients with CF, particularly during pulmonary exacerbations. Other than assuring that vitamin K deficiency is not a contributing factor, it requires no special treatment beyond the usual approach for the exacerbation. However, even minor hemoptysis can be alarming to patients, and reassurance as to its usually benign nature is needed.
Massive hemoptysis is defined in this population as acute bleeding of more than 240 mL within 24 hours, or recurrent bleeding of more than 100 mL daily for several days. This occurs in approximately 1 percent of patients each year, with the major risk factors being age and worse pulmonary function . Management guidelines generated by a panel of experts have been published . For CF patients with massive hemoptysis, the guidelines recommend stopping nonsteroidal antiinflammatory drugs (NSAIDs) and suspension of all chest physiotherapy; consensus could not be reached for whether aerosolized antibiotics and bronchodilators should be continued (table 1). Bronchial artery embolization (BAE) is an important tool for managing massive hemoptysis, and should be implemented promptly. The guidelines recommended against bronchoscopy prior to BAE because of the poor evidence that bronchoscopy can accurately localize the source of bleeding, and to avoid delay in proceeding to the embolization procedure . Other than maximizing treatment as one would for a severe pulmonary exacerbation and proceeding promptly to BAE, the management of massive hemoptysis in CF does not differ from that of hemoptysis in other patients with bronchiectasis. Tranexamic acid has been used successfully in several case reports. (See "Massive hemoptysis: Initial management" and "Hemoptysis in children", section on 'Initial management of massive hemoptysis'.)
FUTURE DIRECTIONS — Analysis of registry data collected by the Cystic Fibrosis Foundation shows moderate variability in the clinical outcomes and treatment approaches across the 115 CF Centers within the United States . After correcting for adverse risk factors that differ between centers such as patient age and socioeconomic status, a conservative estimate is that median survival in CF could be improved by at least several years if best practices could be identified and implemented across all CF Centers . On the other hand, there is no question that individually tailored therapies by experienced clinicians will remain equally important in the management of these complex patients. In response to knowledge and a strong endorsement from the Cystic Fibrosis Foundation, an intensive quality assessment/quality improvement program is ongoing in all CF centers .
A wide variety of new treatment strategies are being investigated for CF (see www.cff.org/Trials/Pipeline/). They span a wide range of approaches that include (see "Cystic fibrosis: Investigational therapies"):
●Correction of abnormal protein folding that is induced by many of the more prevalent cystic fibrosis transmembrane conductance regulator (CFTR) mutations
●Improvement in ion channel function of various mutant CFTR proteins
●Drugs to induce ribosomes to selectively read through premature CFTR stop codons
●Induction of alternative ion channels
●Suppression of excessive inflammatory responses
●Development of alternative delivery methods for antibiotics
Some of the promising investigational therapies that have reached the stage of clinical trials are discussed in a separate topic review. Successful completion of even a subset of these investigations should serve to continue the trend of improved survival in CF. (See "Cystic fibrosis: Investigational therapies".)
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SUMMARY AND RECOMMENDATIONS — The following treatment recommendations apply to children six years of age and older, unless otherwise specified.
●Cystic fibrosis (CF) lung disease typically has a course of intermittent acute exacerbations, superimposed on a gradual decline in pulmonary function. Exacerbations are treated with antibiotics, given either orally, via inhalation, or intravenously, depending on the infecting organisms and the severity of the exacerbation. The role of antibiotics in the treatment of CF lung disease is discussed in detail separately. (See "Cystic fibrosis: Antibiotic therapy for lung disease".)
●All patients with CF should undergo cystic fibrosis transmembrane conductance regulator (CFTR) genotyping to determine if they carry one of the mutations approved for ivacaftor use, namely G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, or R117H. (See 'CFTR modulators' above.)
●For all patients with CF who carry an ivacaftor-approved mutation and are two years of age or older, we recommend treatment with ivacaftor (Grade 1A). Dosing is based on age and body weight. (See 'Ivacaftor for G551D and other gating mutations' above.)
●For patients with CF six years of age or older who are homozygous for F508del, we suggest using lumacaftor-ivacaftor (Grade 2B). However, drug interactions should be considered when deciding on its use. This treatment yields modest improvements in pulmonary function and reduces the risk of pulmonary exacerbations. (See 'Lumacaftor-ivacaftor for F508del' above.)
●We suggest using short-acting inhaled beta-2-adrenergic receptor agonists for patients with CF prior to inhalation of hypertonic saline, antibiotics, or initiating chest physiotherapy (Grade 2C). We also suggest chronic use of these agents if there is evidence that they improve expiratory flow rates in those with baseline airflow obstruction (Grade 2B). (See 'Bronchodilators' above.)
●We recommend chronic treatment with DNase I (dornase alfa) for children with moderate to severe CF lung disease (Grade 1A). We also suggest treatment for patients with mild or asymptomatic lung disease, but the quality of evidence and likely clinical benefit are lower for this group (Grade 2B). (See 'Inhaled DNase I (dornase alfa)' above.)
●We recommend chronic treatment with hypertonic saline via nebulizer for patients six years and older who have a chronic cough and any reduction in forced expiratory volume in one second (FEV1) (Grade 1B). We also suggest it may be of benefit for patients in this age group with milder disease manifestations (Grade 2B). A typical treatment regimen is 4 mL of 7 percent saline following administration of a bronchodilator twice daily. (See 'Inhaled hypertonic saline' above.)
●We suggest that all patients who produce sputum be treated with a form of physiotherapy for mucus clearance (Grade 2C). This suggestion is based on demonstrated benefits to secretion clearance with the use of a variety of methods of physiotherapy, including aerobic exercise. However, it should be recognized that long-term improvement in clinical outcome has not been shown. Because patients vary in their responses to different modes, several techniques should be introduced to each patient. (See 'Chest physiotherapy' above.)
●We recommend the chronic use of azithromycin for patients six years and older who have clinical evidence of airway inflammation such as chronic cough or any reduction in FEV1, regardless of the patient's P. aeruginosa infection status (Grade 1B). To avoid induction of antibiotic resistance, azithromycin should not be given to patients infected with nontuberculous mycobacteria. This drug slows decline of lung function, likely through antiinflammatory and/or antibacterial effects. (See 'Macrolide antibiotics' above.)
●We suggest treatment with high-dose ibuprofen in children and young adolescents with good lung function (>60 percent predicted) in whom there is no contraindication to this therapy (Grade 2C). The evidence base for this practice is limited to a few studies, and there is inadequate evidence to support this suggestion for adult patients or for patients with poor lung function. (See 'Ibuprofen' above.)
●For patients with CF but without asthma or allergic bronchopulmonary aspergillosis, we recommend AGAINST treating with inhaled corticosteroids (Grade 1C). For this group, there are no clear benefits, and the treatment may impair linear growth. For patients with CF and asthma, inhaled corticosteroids have greater clinical benefit, and the treatment may be considered along with other antiasthmatic treatments. (See 'Inhaled glucocorticoids' above.)
●For children and adolescents with CF, we recommend AGAINST chronic treatment with systemic glucocorticoids (Grade 1B). Although there is a slight benefit to lung function, these do not outweigh the adverse effects on growth, glucose metabolism, and cataract risk for most patients. In adults, we also suggest AGAINST chronic treatment with systemic glucocorticoids (Grade 2C). (See 'Systemic glucocorticoids' above.)
●The use of supplemental oxygen to treat chronic hypoxemia has not been studied in patients with CF. In the absence of such evidence, it is reasonable to extrapolate from the benefits demonstrated for this treatment for patients with chronic obstructive pulmonary disease (COPD) and to apply the same indications for its chronic use. (See 'Supplemental oxygen' above.)
●Severe CF lung disease is a common indication for lung transplantation, and outcomes are better than those of patients undergoing lung transplantation for other indications. Chronic infection with Burkholderia cenocepacia connotes a worse prognosis following transplantation and is often considered a contraindication to the procedure. (See 'Lung transplantation' above.)
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