Cystic fibrosis: Overview of the treatment of lung disease

INTRODUCTION — 

Cystic fibrosis (CF) is a multisystem disorder caused by pathogenic mutations of the CFTR gene (CF transmembrane conductance regulator). Pulmonary disease remains the leading cause of morbidity and mortality in people with CF (PwCF). (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 advances are responsible for the continuing improvement in survival, which accelerated with the introduction of the highly effective CFTR modulator combination elexacaftor-tezacaftor-ivacaftor (ETI) (figure 1). (See "Cystic fibrosis: Treatment with CFTR modulators".)

This discussion focuses on pulmonary therapies for people meeting diagnostic criteria for CF. It does not address those with CF-like manifestations but who do not meet diagnostic criteria, such as those with "CFTR-related metabolic syndrome/CF screen positive, inconclusive diagnosis" or "CFTR-related disorder." There is insufficient information to extrapolate CF-specific treatments to these groups. (See "Cystic fibrosis: Clinical manifestations and diagnosis".)

An overview of the treatment of CF lung disease will be presented here; the main strategies are outlined in the table (table 1). Other aspects of CF-associated lung disease are discussed in the following topic reviews:

●(See "Cystic fibrosis: Clinical manifestations of pulmonary disease".)

●(See "Cystic fibrosis: Management of pulmonary exacerbations".)

●(See "Cystic fibrosis: Antibiotic therapy for pulmonary exacerbations".)

●(See "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection".)

●(See "Cystic fibrosis: Treatment with CFTR modulators".)

●(See "Cystic fibrosis: Management of advanced lung disease".)

The diagnosis and pathophysiology of CF and its manifestations in other organ systems are also discussed separately:

●(See "Cystic fibrosis: Clinical manifestations and diagnosis".)

●(See "Cystic fibrosis: Genetics and pathogenesis".)

●(See "Cystic fibrosis-related diabetes mellitus".)

●(See "Cystic fibrosis: Overview of gastrointestinal disease".)

●(See "Cystic fibrosis: Assessment and management of pancreatic insufficiency".)

●(See "Cystic fibrosis: Nutritional issues".)

●(See "Cystic fibrosis: Hepatobiliary disease".)

MULTIDISCIPLINARY CARE — 

CF is a systemic disease that requires a multidisciplinary approach to care. In the United States, such care is provided at one of more than 130 CF care centers that are supported and accredited by the CF Foundation (CFF), most of which have dedicated programs for both children and adults. Treatment at these centers includes regular visits with a care team consisting of clinicians, nurses, dietitians, respiratory therapists, physical therapists, social workers, pharmacists, and psychologists, all of whom have special expertise in CF care [3,4]. A listing of these centers is available on the CFF website. In the United Kingdom, people with CF (PwCF) receiving their medical care at specialized CF centers have better clinical outcomes compared with those receiving care in less specialized settings [5-7]. In the United States, more frequent interactions between clinicians and PwCF (visit frequency, monitoring, and interventions for pulmonary exacerbations) are associated with improved outcomes [8]. Gaps in CF center care (eg, more than 12 months without a clinic visit) are associated with worse pulmonary function [9].

With the increasing life expectancy of PwCF, the role of primary care providers is increasingly important to provide the same preventive measures and disease management strategies for non-CF conditions that are known to be beneficial for the general population [3,10].

CHRONIC MEASURES TO PROMOTE LUNG HEALTH — 

Medical therapies to manage CF lung disease are summarized in the table (table 1).

CFTR modulators — CF transmembrane conductance regulator (CFTR) modulators are a new class of drugs that act by improving production, intracellular processing, and/or function of the defective CFTR protein. All people with CF (PwCF) should undergo CFTR genotyping to determine if they carry a mutation that makes them eligible for CFTR modulator therapy, which includes F508del and many other mutations (table 2). Selection of the CFTR modulator depends on the CFTR mutation and the person's age, as outlined in the algorithms (algorithm 1 and algorithm 2). When possible, a highly effective modulator therapy (HEMT) should be prescribed, eg, elexacaftor-tezacaftor-ivacaftor (ETI) or vanzacaftor-tezacaftor-deutivacaftor. In contrast, dual therapy (lumacaftor-ivacaftor and tezacaftor-ivacaftor) has more modest effects for F508del homozygotes.

Details of drug selection and summaries of clinical outcomes for CFTR modulators are presented in a separate topic review. (See "Cystic fibrosis: Treatment with CFTR modulators".)

Airway clearance therapies — Difficulty clearing secretions from the airways is a common complaint among PwCF who have moderate to severe lung disease. The high viscosity of CF sputum is caused by its relative dehydration and the interaction of several macromolecules, including mucus glycoproteins, denatured deoxyribonucleic acid (DNA), and protein polymers such as actin filaments [1,2,11,12]. Airway clearance can be promoted by a combination of inhaled drugs to loosen and liquefy the inspissated mucus (dornase alfa [DNase], hypertonic saline, and/or mannitol) and physical means to dislodge and help expectoration of secretions (breathing/coughing maneuvers, oscillating positive expiratory pressure [PEP] devices, percussive vests), typically administered in two or more sessions daily.

The highly effective CFTR modulator ETI substantially reduces sputum production and mucus plugging [13,14], such that at least 50 percent of PwCF taking ETI no longer expectorate sputum. These observations, together with results from a large clinical trial (SIMPLIFY study, described below), have modified our suggested approach to airway clearance therapies.

Inhaled airway clearance agents — Inhaled DNase and hypertonic saline have been recommended for most PwCF to promote airway clearance, as outlined in CF Foundation (CFF) guidelines [15-17]. However, these guidelines were written prior to the approval and widespread use of ETI and subsequent clinical experience and evidence from a large randomized study (SIMPLIFY study [18], described below) that suggests that these inhaled therapies may not be necessary for some PwCF. In fact, registry data and retrospective studies have shown that use of inhaled medications has decreased following introduction of ETI [19-21]. It is also noteworthy that the effectiveness of inhaled medications is often compromised because many PwCF do not adhere to recommended airway clearance therapies, due to treatment burden (time, cost of DNase) and/or tolerability [22-24].

Therefore, we suggest the following approach:

●Age ≥12 years on HEMT with mild or no lung disease – For this group, we no longer routinely recommend DNase or hypertonic saline. This is based on the observation that many PwCF no longer expectorate sputum after starting ETI [13] and the results of a prospective randomized trial ("SIMPLIFY") that evaluated the effects of inhaled airway clearance agents in those on ETI who had mild or no lung disease (percent predicted forced expiratory volume in one second [FEV₁] >70 for those 12 to 17 years old and >60 for those older than 17 years) [18]. Participants were randomized to continue or stop either their hypertonic saline or DNase for six weeks, after which the clinical consequences were assessed. The absolute change in percent predicted FEV₁ between baseline and six weeks did not differ between those stopping and those continuing hypertonic saline (between group difference -0.32 percent [95% CI -1.25 to 0.60]) and between those stopping and those continuing DNase (between group difference 0.35 percent [95% CI -0.45 to 1.14]). Lung clearance index (LCI_2.5), a more sensitive measure of change in lung function in those with mild lung disease [25], did not differ between groups. Those who were taking both inhaled medications at baseline had no adverse effects from stopping both [26], and a small subgroup of those with severe lung disease had no loss of FEV₁ when discontinuing hypertonic saline [27]. Concordant results were found in a retrospective study of 174 PwCF who discontinued one or more inhaled CF medications [19].

●Other PwCF – We recommend both DNase and hypertonic saline for the following groups:

-Age ≥12 years who are not receiving HEMT or those taking HEMT but who continue to produce sputum or have moderate to severe lung disease [15].

-Age 6 to 11 years old, including those on HEMT. Because the SIMPLIFY study did not enroll children younger than 12 years old, we hesitate to extrapolate the SIMPLIFY conclusions to this younger group without additional supporting data.

-Age <5 years, based on individual circumstances, as outlined in separate CFF guidelines for children age two to five years [16] and less than two years [17]. Our practice is to offer treatment to those with chronic respiratory symptoms or who have more than rare pulmonary exacerbations.

●Agents

•Inhaled DNase – DNase is an endonuclease that decreases the viscosity of purulent CF sputum by cleaving long strands of denatured DNA that are released by degenerating neutrophils, which helps to liquefy CF sputum.

DNase is generally given once daily. However, results from a small 12-week crossover trial suggest that alternate-day dosing may achieve equivalent clinical outcomes with substantially lower drug costs [28,29].

Evidence for the efficacy of inhaled DNase is from studies performed prior to widespread use of ETI, including a meta-analysis [30], registry study [31], and randomized study of treatment withdrawal [32]. In the meta-analysis, DNase reduced the frequency of pulmonary exacerbations and caused a relative increase in percent predicted FEV₁ by approximately 5 percent in trials extending up to two years [30].

•Inhaled hypertonic saline – Inhaled hypertonic saline helps to hydrate the inspissated mucus that is present in the airways of PwCF [33]. It is presumed that the high osmolality of the solutions draws water from the airway to temporarily reestablish the aqueous surface layer that is deficient in CF [34].

Evidence for the efficacy of hypertonic saline is from randomized trials performed prior to widespread use of ETI, which showed that this treatment led to fewer pulmonary exacerbations and improved mucociliary clearance, with no significant effect on pulmonary function [35-39]. Additional evidence supported its use in infants and toddlers based on favorable results from a study that enrolled infants less than four months old [40].

These studies tested the effects of a 6 or 7 percent saline solution. For people who do not tolerate these concentrations of saline due to cough or bronchospasm, reducing the saline concentration has been suggested. However, a randomized study found that 3 percent saline was not associated with as much improvement in quality of life or time to next intravenous (IV) antibiotic treatment, although it was as effective as 6 percent regarding improvement in lung function and time to next pulmonary exacerbation [41].

In the high-quality randomized, controlled trials, the benefits of hypertonic saline were found to be similar regardless of whether the participants were also on DNase [35,37]. However, a subsequent registry-based study with 1241 participants, also prior to ETI, found no difference in clinical outcomes between those on DNase alone and those taking both hypertonic saline and DNase [42]. This study is limited by its retrospective nature and differences in baseline characteristics of the treatment groups. Therefore, the results do not alter our recommendation to prescribe both hypertonic saline and DNase to individuals who are not on HEMT.

•Inhaled mannitol – Inhaled mannitol may be used as a second-line option to replace hypertonic saline for adult PwCF who do not tolerate or do not respond well to the combination of DNase and hypertonic saline for airway clearance. Clinical trials of inhaled mannitol found modest improvements in FEV₁, with little or no improvement in other outcomes such as frequency or duration of exacerbations [43-46]. Although the SIMPLIFY study did not evaluate mannitol, we suspect mannitol's efficacy may be limited in those on HEMT who have normal or mildly reduced FEV₁, similar to that study’s findings for hypertonic saline [18]. Because inhaled mannitol may cause bronchospasm in those with bronchial hyperresponsiveness, the initial dose must be administered with spirometry and oxygen saturation monitoring in the presence of an experienced clinician.

●Administration – If these inhaled therapies are given, the recommended order of treatments to be performed twice daily is [15]:

•Albuterol by metered-dose inhaler (to reduce the risk of bronchospasm) [35]

•Hypertonic saline

•DNase (only once a day) and airway clearance therapy (chest physiotherapy)/exercise (in either order) [47]

•Other inhaled treatments such as aerosolized antibiotics or long-acting antiasthmatic agents

Inhaled medications should not be mixed together in the same nebulizer, because the consequences of doing so are unknown. In particular, DNase is inactivated if it is mixed with hypertonic (7 percent) saline. Similarly, these agents should not be mixed with tobramycin or other inhaled antibiotics. (See "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection", section on 'Inhaled antibiotics'.)

Chest physiotherapy — Virtually all clinical care guidelines recommend that all PwCF should be encouraged to use some form of chest physiotherapy for secretion clearance. This recommendation is based on the recognition that retained purulent secretions are an important cause of airflow obstruction and airway injury in CF as well as longstanding clinical practice, despite the lack of strong evidence from clinical trials [16,48-52]. Adherence to chest physiotherapy is often poor, particularly among those with mild disease [22,52,53].

●Techniques and devices – A variety of techniques may be used for chest physiotherapy, and there is no evidence that they differ in efficacy [50,51,54-57]. Because PwCF vary in their acceptance and preference for different modes, several techniques should be introduced to each individual. Methods that can be performed without assistance from another person should be offered to allow more control over the regimen. The cost of equipment should be considered, with less expensive modalities prescribed first. A more expensive apparatus such as a percussion vest may be appropriate for those 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.

Chest physiotherapy in the form of postural drainage and percussion was introduced to CF care in the 1950s [48,49]. Since then, secretion clearance programs have been a cornerstone of CF care. Methods that can be performed without the aid of another person have largely replaced 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" [48,49,58]. A randomized trial with 36 participants age 12 to 18 years compared autogenic drainage with postural drainage and percussion and reported no difference in pulmonary function test results, but the participants strongly preferred the autogenic drainage modality [59].

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.

●Efficacy – A systematic review reported that chest physiotherapy (using a variety of techniques) increased mucus transport [51]. Contrasting results were reported from a clinical trial that used gamma scintigraphy to track mucociliary clearance of inhaled small particles, which found that cough plus an external percussive vest, a device inducing oscillatory positive expiratory pressure, or whole-body vibration had no additional benefit compared with cough clearance alone [50].

Only a few high-quality clinical trials have evaluated the long-term effects of chest physiotherapy. A yearlong randomized trial in 40 participants found that use of a PEP mask significantly improved pulmonary function compared with postural drainage and percussion [60]. The largest study to date randomized 107 participants to use a PEP device or a high-frequency chest wall oscillation device (a percussion vest) for one year [61]. 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, personal satisfaction, or quality-of-life scores. High dropout rates have impaired other attempts at randomized trials, probably because participants often have strong preconceived but unsupported preferences for one treatment arm over another [62,63].

Adherence to treatment is often suboptimal. A real-world study of 145 children followed for a median of 480 days monitored frequency and quality of treatments using a sensor attached to various PEP devices, including some with an oscillating design [52,64]. The investigators found that adherence was poor, with only 20.1 percent of treatments being performed correctly. However, children who did adhere to treatment with acceptable technique had a higher percent predicted FEV₁ than those who used incorrect technique or who missed treatments altogether.

Exercise — All PwCF should be encouraged to engage in regular exercise to obtain the same benefits that are proven for the general population (see "The benefits and risks of aerobic exercise"). Insufficient information is available to determine which types of exercise are most beneficial for PwCF. For those with moderate or advanced pulmonary disease, we advise that exercise should be guided by an organized pulmonary rehabilitation program. (See "Pulmonary rehabilitation".)

A consensus conference of exercise experts strongly recommended exercise for PwCF [65]. However, the authors recognized that the evidence demonstrating improvement in cardiovascular health and quality of life for PwCF was limited. A meta-analysis concluded that exercise programs lasting at least six months were likely to improve exercise capacity, but the effects on lung function and quality of life were small at best [66].

In a randomized trial of a three-year home exercise program in children with CF, children assigned to the exercise arm of the study lost less forced vital capacity (FVC) compared with the control group, and change in FEV₁ showed a similar trend (p<0.07) [67]. In another clinical trial, 41 participants with a mean age of 25 years were randomized to 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 [68]. Another clinical trial randomized 117 adolescents and adults to either three hours per week of vigorous physical exertion or to their usual level of activity [69]. At six months, exercise did not increase FEV₁, the primary endpoint, but did improve exercise capacity. An online program designed to encourage participation in exercise activities failed to improve time spent in moderate to vigorous activity [70].

Aerobic exercise may help to mobilize airway secretions, but studies are inconclusive whether it is as effective as therapies directly targeted toward secretion clearance [71,72]. A survey of PwCF, their caregivers, and health professionals using a Delphi approach reached a consensus that exercise accompanied by breathing maneuvers promoted airway clearance [73]. However, they concluded that a higher level of evidence was required before recommending exercise to replace traditional airway clearance maneuvers.

Prevention of infection — Measures to prevent pulmonary infection include vaccinations, use of antiviral agents in selected individuals, and infection-control measures to prevent transmission of pathogens within health care systems.

●Vaccinations – PwCF should receive all routine childhood immunizations. Vaccines warranting particular emphasis are:

•Seasonal influenza vaccine – Annual vaccination against viral influenza is recommended for all PwCF older than six months of age, using an inactivated vaccine delivered by injection but not the live attenuated vaccine delivered by intranasal spray [16]. In the United States, annual influenza vaccination is also recommended for healthy children but is particularly important for those with CF or other chronic respiratory diseases. Viral respiratory infections have been implicated as a frequent cause of exacerbations of CF lung disease [74] and are the subject of several reviews [17,75,76]. (See "Seasonal influenza vaccination in adults" and "Seasonal influenza in children: Prevention with vaccines", section on 'Target groups'.)

For individuals who have contraindications to influenza vaccine, we consider on a case-by-case basis preexposure chemoprophylaxis with oseltamivir, for as long as influenza is present within the local community. (See "Seasonal influenza in adults: Role of antiviral prophylaxis for prevention" and "Seasonal influenza in children: Prevention with antiviral drugs".)

•Pneumococcal vaccine – All PwCF should be vaccinated against pneumococcal disease, using the recommendations from the United States Centers for Disease Control and Prevention [77]. This includes the standard pneumococcal conjugate vaccine series (either the 15-valent pneumococcal conjugate vaccine [PCV15] or 20-valent pneumococcal conjugate vaccine [PCV20]), ideally delivered in the first 15 months of life. Children with CF are considered at high risk of invasive pneumococcal disease and may require additional pneumococcal vaccination if their primary series did not include at least one dose of PCV20. Individualized recommendations are provided by the Centers for Disease Control and Prevention and in a separate UpToDate topic review. (See "Pneumococcal vaccination in children", section on 'Immunization of high-risk children and adolescents'.)

•Coronavirus disease 2019 (COVID-19) vaccine – All PwCF should be vaccinated against COVID-19 (caused by the severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] virus) as soon as they are eligible, consistent with recommendations from the CFF and the Centers for Disease Control and Prevention [78-80]. A study of 260 PwCF found that the antibody response and side effect profile following administration of a messenger ribonucleic acid (mRNA)-based anti-SARS-CoV-2 vaccine were similar to that of the general population [81]. (See "COVID-19: Vaccines".)

●Respiratory syncytial virus (RSV) prophylaxis

•Immunoprophylaxis – Immunoprophylaxis with an RSV fusion inhibitor (eg, nirsevimab) is recommended during the first RSV season for all infants with CF, similar to other infants. For those with severe lung disease or growth failure, immunoprophylaxis is also recommended during the second RSV season [82,83]. (See "Respiratory syncytial virus infection in infants and children: Prevention", section on 'Immunoprophylaxis'.)

•Palivizumab – We do not suggest routine prophylaxis with palivizumab except for infants without access to nirsevimab or young children with other indications. Palivizumab is a humanized monoclonal antibody against RSV that can be used to help prevent serious RSV infection in young children who are at high risk for RSV disease. A systematic review and two subsequent clinical studies have reached conflicting conclusions about the efficacy of palivizumab for young children with CF [84-86]. A retrospective CFF registry study of 4267 PwCF reported that those who received palivizumab during the first two years of life had similar FEV₁ at age seven years compared with a propensity-matched control group [87]. No differences were found in rate of hospitalization or time to first Pseudomonas aeruginosa-positive culture. (See "Respiratory syncytial virus infection in infants and children: Prevention", section on 'Infants 8 through 19 months at increased risk for severe disease'.)

●Infection-control measures – There is convincing evidence that a variety of respiratory pathogens can be transmitted among PwCF both within and outside of the health care system. To minimize risk of transmission, the CFF has published guidelines for infection prevention and control to be applied to all PwCF, regardless of respiratory tract culture results [88]. Relevant to health care facilities, these include contact precautions, physical separation between PwCF, use of masks by PwCF, and close attention to hand hygiene including household contacts. Although these measures have been generally accepted by the CF community, the evidence supporting them is sparse [89]. (See "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection", section on 'Infection prevention and control'.)

Bronchodilators — Airflow obstruction is a central feature of CF lung disease and is caused by several mechanisms, including bronchial plugging by purulent secretions, bronchial wall thickening due to inflammation, and airway destruction. Many PwCF demonstrate some signs of bronchial hyperreactivity, indicated by acute improvement in FEV₁ following the administration of beta-adrenergic agonists, anticholinergic drugs, and/or theophylline; the greatest response is seen in those who have milder overall lung disease [90]. However, most of them do not have findings typical of atopy (eg, no family history of asthma, elevated serum immunoglobulin E [IgE], or blood eosinophilia), in contrast with individuals with asthma but without CF [91]. A smaller subgroup has typical symptoms of asthma, such as chest tightness, wheezing and cough following exercise, or exposure to allergens or cold air [90]. (See "Cystic fibrosis: Clinical manifestations of pulmonary disease", section on 'Airway reactivity'.)

Bronchial hyperreactivity is also a characteristic of the small subgroup of PwCF who have allergic bronchopulmonary aspergillosis (ABPA) [92,93]. (See 'Allergic bronchopulmonary aspergillosis' below.)

●Inhaled beta-2 adrenergic receptor agonists – We suggest prescribing short-acting beta-2 adrenergic receptor agonists for the following situations:

•Administration immediately prior to chest physiotherapy, and exercise to facilitate clearance of airway secretions. This is suggested in CF guidelines, although the supportive evidence is scant. (See 'Chest physiotherapy' above and 'Exercise' above.)

•Administration immediately prior to inhalation of nebulized hypertonic saline, mannitol, or antibiotics for individuals who develop nonspecific bronchial constriction from these medications to minimize symptoms and potentially improve penetration and distribution of the drugs within the airways. (See 'Inhaled airway clearance agents' above.)

•As rescue medication for PwCF who have evidence of airway hyperreactivity, manifested either by improvement in pulmonary function (eg, increase in FEV₁) or by symptomatic improvement with acute use. Evidence for the efficacy of beta agonist therapy in this setting is limited to observational studies and several small randomized and nonrandomized controlled trials [94-96]. These data suggest that beta agonist therapy provides short-term improvements in pulmonary function and symptom relief in individuals with clinical evidence of airway hyperresponsiveness. In addition, indirect evidence is provided by the extensive experience using beta agonists in other conditions associated with airway hyperreactivity (ie, asthma). (See "Beta agonists in asthma: Acute administration and prophylactic use".)

Other than these indications, there is insufficient evidence to determine if chronic use of short- or long-acting beta agonists benefits lung function, frequency of exacerbations, or other outcomes, as reported by a CFF guidelines committee [97]. The published studies addressing their use are few and not uniformly supportive, although short-term benefit has been reported [94-96,98]. This assessment is consistent with the conclusions of systematic reviews [99,100].

●Agents without clear benefit – The anticholinergic agent ipratropium bromide can induce bronchodilation following acute administration in PwCF [90]. However, a meta-analysis that included three clinical trials of tiotropium, a long-acting anticholinergic agent, did not show statistically significant improvement in pulmonary function tests during 12 weeks of treatment [99,101,102].

Theophylline is infrequently prescribed to PwCF 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.

Antiinflammatory therapy — Intense neutrophilic inflammation is a dominant pathologic feature of the airways of PwCF. Although the inflammatory response was formerly viewed as being necessary to prevent the spread of infection, increasing evidence indicates that the amount of inflammation developed is probably excessive and harmful [103,104]. For example, elevated levels of inflammatory biomarkers in bronchoalveolar lavage fluid predicted subsequent progression of bronchiectasis [105].

Azithromycin — The benefits from chronic azithromycin therapy for CF have been ascribed to an antiinflammatory effect.

●Indications – We suggest chronic treatment with azithromycin for PwCF six years and older who are chronically infected with P. aeruginosa, consistent with guidelines from the CFF published in 2013 [97]. Based on a study published since the CFF guidelines were written [106], we also suggest initiating azithromycin at the time of a first positive culture for P. aeruginosa for children as young as six months and continuing for at least 18 months, which was the duration of the study. Thereafter, it would be reasonable to continue treatment for those with persistent P. aeruginosa infection, an approach extrapolated from studies in older PwCF.

For PwCF who are not infected with P. aeruginosa, we do not routinely prescribe azithromycin, although we may do so for those who are experiencing frequent pulmonary exacerbations despite use of all other recommended therapies. Similarly, we generally stop chronic azithromycin in those who previously cultured P. aeruginosa but have had multiple negative cultures for at least one year and are having rare, if any, pulmonary exacerbations. Although the CFF guidelines published in 2013 made a weak recommendation to treat PwCF (≥6 years) who are culture negative for P. aeruginosa, they noted that the certainty and estimated net benefit were low [97]. Subsequent studies are even less supportive, as discussed below [107,108].

Of note, concern has been raised that chronic use of oral azithromycin may reduce the efficacy of tobramycin by having a direct effect on the bacteria, making them more resistant to aminoglycosides, as discussed below.

●Administration – We usually prescribe azithromycin three times a week, using approximately 10 mg/kg (up to a maximum of 500 mg per dose) for children and 500 mg for adults [106]. A study in adults shows that 250 mg/day is similarly efficacious, so daily dosing could be used for those who find it easier to adhere to a daily treatment schedule [109]. For the small number of PwCF who develop gastrointestinal side effects on a full dose, a lower dose may be used (eg, 250 mg three times a week for adult-sized individuals); this dose reduction was employed in one study and was thought to be of benefit [110].

●Precautions and potential adverse effects

•Avoid azithromycin if nontuberculous mycobacteria are present – Prior to initiating treatment with azithromycin, those PwCF who can expectorate a sputum sample should have a specimen 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 multidrug regimen to avoid development of macrolide-resistant mycobacterial species. If the initial smear is negative but the subsequent culture is positive, the macrolide should be stopped to avoid inducing macrolide resistance. Fortunately, a single-center retrospective study reported that initial isolates of M. avium complex in PwCF receiving chronic azithromycin therapy are unlikely to be macrolide resistant [111]. 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; this is discussed elsewhere. (See "Treatment of Mycobacterium avium complex pulmonary infection in adults".)

In PwCF without nontuberculous mycobacteria, chronic use of azithromycin may help to prevent its acquisition; data from the CFF patient registry showed that the incidence of positive cultures for nontuberculous mycobacteria in PwCF receiving chronic azithromycin therapy was less than that of the control population [112]. A second study from this registry confirmed this finding and reported that chronic azithromycin use was associated with lower risk for new methicillin-resistant Staphylococcus aureus (MRSA) infection and Burkholderia cepacia complex, compared with nonusers matched by propensity score [113].

•Possible reduction in tobramycin efficacy – Of note, concern has been raised that chronic use of oral azithromycin may reduce the efficacy of inhaled or IV tobramycin. The evidence on this issue is somewhat conflicting:

-Evidence from cell culture – In vitro studies showed that azithromycin induced the expression of Pseudomonas efflux pumps that can reduce intracellular concentration of tobramycin [114]. Addition of azithromycin to cultures of P. aeruginosa isolated from PwCF showed a reduced bactericidal effect of high concentrations of tobramycin as are achieved from inhalation in one study [114] but not another [115].

-Inhaled tobramycin – A preponderance of clinical evidence suggests that azithromycin probably does not prevent the beneficial effects of inhaled tobramycin. In particular, a high-quality randomized placebo-controlled trial found no significant impact of azithromycin on the effect of inhaled tobramycin on FEV₁ [116]. In the trial, 115 PwCF >12 years of age were randomized to receive six weeks of oral azithromycin or placebo, with both groups receiving a four-week course of inhaled tobramycin for the last four weeks of the trial. The relative change in FEV₁ (L) from baseline, the primary endpoint of the trial, did not differ significantly for azithromycin compared with placebo (1.69 versus -1.95 percent, respectively). However, the bacterial density of P. aeruginosa in expectorated sputum increased in the azithromycin group by 0.3 log and decreased by 0.5 log in the placebo group (p<0.043); the clinical significance of this is uncertain. These findings contrast with previous retrospective studies, which suggested that chronic treatment with oral azithromycin may reduce the efficacy of inhaled tobramycin but not of inhaled aztreonam [108,114,117].

-IV tobramycin – An antagonistic effect of azithromycin on IV tobramycin was suggested by results from a retrospective single-center study of 173 adults on chronic azithromycin being treated for 427 episodes of pulmonary exacerbation [118]. Those on chronic azithromycin had less improvement in FEV₁ if they were treated with IV tobramycin compared with IV colistimethate. A retrospective study of 67 pulmonary exacerbations in 33 PwCF found that continuing chronic azithromycin during a course of IV tobramycin did not alter the likelihood of returning to within 90 percent of baseline FEV₁ following treatment [119]. However, using a statistical model to account for difference in baseline FEV₁, the increase in percent predicted in FEV₁ was 9.5 percent lower in those on chronic azithromycin [119]. A larger registry-based study of 2294 PwCF aged 6 to 21 years being treated with tobramycin for 5022 pulmonary exacerbations found similar results [120]. The recovery of percent predicted FEV₁ from baseline was 21 percent lower for those receiving chronic azithromycin compared with those not taking it. Using the same registry sources, azithromycin did not reduce the recovery of FEV₁ if the participants were receiving IV colistimethate rather than tobramycin.

There is no consensus among CF experts on how to respond to this provocative but as yet inconclusive information [121]. The high-quality study described above provides some assurance that azithromycin has minimal clinically important adverse effects on the benefits of inhaled tobramycin [116]. There are no prospective randomized studies to assess the effect of azithromycin on the efficacy of IV tobramycin in the treatment of pulmonary exacerbations. In the absence of definitive information, options include avoiding chronic azithromycin for PwCF who are likely to be prescribed IV tobramycin in the near future, prescribing azithromycin but selecting antibiotics other than tobramycin to treat acute exacerbations in those infected with P. aeruginosa, or continuing the current practice of prescribing both azithromycin and IV tobramycin while waiting for more definitive data. (See "Cystic fibrosis: Antibiotic therapy for pulmonary exacerbations", section on 'Double coverage for Pseudomonas aeruginosa'.)

•Prolongation of corrected QT interval (QTc) – Macrolide antibiotics can cause QTc prolongation and are associated with an excess risk of cardiac events (see "Azithromycin and clarithromycin"). However, two studies failed to detect a significant risk for PwCF. In particular, a retrospective study of 68 PwCF on chronic azithromycin found that their QTc interval was not significantly different from 21 control PwCF. The authors of this study concluded that screening with an electrocardiogram prior to initiating chronic azithromycin to detect those with prolonged baseline QTc intervals would likely be sufficient to avoid complications. A secondary analysis of data from a placebo-controlled trial of azithromycin in 221 children reported that the frequency of QTc prolongation in those receiving azithromycin for a median of 18 months was no greater than that of those in the placebo group, with none developing a QTc longer than 500 msec [106,122].

●Efficacy – Evidence supporting the use of azithromycin in PwCF chronically infected with P. aeruginosa includes the early clinical trials, which primarily enrolled this group. These studies found that azithromycin improved FEV₁ and reduced pulmonary exacerbations [109,110]. The largest such study enrolled 168 participants who were all positive for P. aeruginosa and reported that 24 weeks of azithromycin caused a 0.094 liter improvement of FEV₁ relative to that of the placebo group [110]. The risk of a pulmonary exacerbation was significantly less in the azithromycin group than in the placebo group (hazard ratio 0.65). Subgroup analysis revealed that the reduction in pulmonary exacerbations occurred regardless of the response in FEV₁ [123]. Subsequent clinical trials have confirmed the reduction in pulmonary exacerbations in PwCF chronically infected with P. aeruginosa [124]. In addition, a registry-based study evaluated the effects of initiating azithromycin on pulmonary function over the subsequent three years and reported that those chronically infected with P. aeruginosa experienced 40 percent less decline in FEV₁ percent predicted compared with matched controls [108]. This study further supports the 2013 CFF guideline that recommends the use of azithromycin in individuals with persistent P. aeruginosa infection [97]. A retrospective study of more than 2000 PwCF between the ages 7 and 40 years followed for 10 years noted a reduction in rate of FEV₁ decline and in the frequency of pulmonary exacerbations in those receiving chronic azithromycin therapy [125]. The efficacy of azithromycin in younger individuals with early P. aeruginosa infection is supported by a subsequent clinical trial in children 6 months to 18 years of age, in which azithromycin was initiated after the first positive culture and reduced the risk of pulmonary exacerbations during the subsequent 18 months (hazard ratio 0.56); this trial did not assess outcomes after 18 months of therapy [106].

The value of azithromycin in PwCF who are uninfected with P. aeruginosa is less clear. The largest study supporting its use enrolled 260 participants randomized to azithromycin or placebo for 24 weeks [126]. There was no difference between groups in FEV₁, but the azithromycin group had a 50 percent reduction in protocol-defined pulmonary exacerbations compared with placebo. However, there was no significant difference in hospitalizations or use of IV antibiotics, suggesting that the exacerbations prevented by azithromycin were relatively mild. Of note, during the open-label extension of this study, the participants who had been randomized to the placebo group showed no reduction in pulmonary exacerbations during the subsequent 24 weeks that followed their initiation of azithromycin [107]. Finally, the same registry-based study mentioned above reported no difference in FEV₁ decline or IV antibiotic use in the three years following initiation of azithromycin in those uninfected with P. aeruginosa [108]. For these reasons, we no longer routinely prescribe chronic azithromycin therapy for PwCF who are uninfected with P. aeruginosa but may do so for those experiencing multiple pulmonary exacerbations if other interventions have not been successful.

Clinical trials of azithromycin have also been performed in younger PwCF. A randomized trial supports extending the use of azithromycin to children as young as six months of age following their first positive culture for P. aeruginosa. The trial enrolled 221 children from 6 months to 18 years of age (approximately one-half were <6 years old) with newly acquired P. aeruginosa [106]. These participants were randomized to treatment with azithromycin or placebo (in addition to a standard P. aeruginosa eradication regimen of inhaled tobramycin) and were followed for a median of 11.8 months. Fewer participants in the azithromycin group experienced pulmonary exacerbations compared with placebo (39 versus 52 percent; hazard ratio 0.56, 95% CI 0.37-0.83). The observed treatment effect was generally consistent across different age groups, with the largest effect seen among the youngest children (ages six months to three years). Rates of P. aeruginosa recurrence were similar in both groups. Azithromycin was well tolerated, with no significant difference in safety endpoints between the azithromycin and placebo groups. A subsequent trial randomized 130 infants three to six months of age to receive azithromycin or placebo for 36 months [127,128]. Chest computed tomography (CT) images showed that participants who received azithromycin had reduced bronchial wall thickness and had 6.3 fewer days in hospital for pulmonary exacerbations (95% CI 2.1-10.5 days, p = 0.004) and 6.7 fewer days of IV antibiotics (95% CI 1.2-12.2, p = 0.018). There were inconsistent changes in sputum inflammatory markers.

●Mechanisms – 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 [129]. 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 [130]. 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 [131,132]. Reduction in antiinflammatory markers occurs early after beginning azithromycin but is not sustained [132,133].

Ibuprofen — Oral ibuprofen has a limited role as an agent to reduce airway inflammation. The CFF suggests the use of high-dose ibuprofen (eg, 25 to 30 mg/kg) in children 6 through 17 years of age who have good lung function (FEV₁ >60 percent predicted) [15,97]. This recommendation is supported by a Cochrane review [134]. Ibuprofen is not recommended for PwCF with more severe lung function abnormalities or those who are older than 18 years of age, because evidence is lacking to demonstrate a benefit in adults. If high-dose ibuprofen is prescribed, pharmacokinetic studies should be performed periodically to ensure correct dosing to maintain a serum concentration of 50 to 100 mg/mL, combined with close monitoring to identify possible adverse effects, including gastrointestinal bleeding and kidney function impairment [135]. (See "Nonselective NSAIDs: Overview of adverse effects".)

In practice, high-dose ibuprofen is being prescribed for only a small minority of children and adolescents with CF and less than 1 percent of adults in the United States [21]. The requirement for periodic pharmacokinetic adjustment of the dose and concern for side effects appear to be restricting its acceptance.

The benefits of ibuprofen are probably modest, as indicated by two long-term studies in PwCF and 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 participants to ensure that high peak blood levels of ibuprofen (50 to 100 mcg/mL) were obtained [136]. After four years, participants 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 those in the control group. However, the beneficial effects of ibuprofen were seen only in the subgroup of children who were younger than 13 years of age at the start of the study. Gastrointestinal bleeding and kidney function impairment, known adverse effects of ibuprofen, were not observed in either group.

●In a multicenter randomized trial, a similar protocol was tested in 142 children 6 to 18 years old [137]. 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 FVC percent predicted (0.07±0.51 versus -1.62±0.52), which was a secondary endpoint of the study.

Inhaled glucocorticoids — Inhaled glucocorticoids are appropriate for PwCF who have definite signs and symptoms of asthma, including those with asthmatic symptoms in the setting of ABPA. They are not routinely recommended for those without these indications [16,97]. This is because there is insufficient evidence for benefit [138]; some trials suggest modest benefit and others report no effect [139-142]. One of the reasons for caution is that inhaled glucocorticoids may modestly impair linear growth in children with CF or asthma [143,144]. These effects are dose related and less severe than those seen in children treated with systemic glucocorticoids. (See "Major side effects of inhaled glucocorticoids", section on 'Growth deceleration'.)

Other medications

●Short-term use of systemic glucocorticoids – Some CF clinicians administer a brief course of corticosteroids to selected PwCF during an acute exacerbation, although the evidence is limited and there is considerable variation in practice. The rationale and our approach are described separately. (See "Cystic fibrosis: Management of pulmonary exacerbations", section on 'Glucocorticoids'.)

●Biologic therapies for asthma – Many of the biologic agents that are beneficial in treating severe type 2 asthma are beginning to be prescribed for PwCF who have an asthma-like phenotype, although high-quality studies are lacking [145] (see "Treatment of severe asthma in adolescents and adults"). Such studies will be difficult to perform, in part because of the longstanding problem with constructing widely accepted criteria for the diagnosis of asthma in PwCF [146].

●Agents not recommended

•Chronic use of systemic glucocorticoids – We agree with the guidelines committee of the CFF, 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 ABPA, because of the associated adverse effects [16,97]. Although a small randomized trial suggested that chronic treatment was associated with modest improvements in pulmonary function [147], a long-term follow-up study documented important adverse effects, including abnormal glucose metabolism, cataracts, and growth failure [148]. We also do not recommend their use in adults, because of the same adverse effects (other than growth failure).

By contrast, PwCF who have acute ABPA typically require a prolonged course of systemic glucocorticoids, in conjunction with other medical therapy. (See "Treatment of allergic bronchopulmonary aspergillosis", section on 'Acute ABPA'.)

•Cromolyn – Sodium cromolyn (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 PwCF. 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 PwCF and bronchial hyperreactivity; no improvement in clinical status or pulmonary function tests was seen among those receiving sodium cromoglycate [149].

We do not prescribe cromoglycate or nedocromil for PwCF, given the lack of adequate studies of cromolyn in PwCF, the relatively high expense, and the evidence of inferiority relative to inhaled glucocorticoids in people with asthma [150].

•Free sulfhydryl agents – Because oxidant stress has been hypothesized to be a mechanism of tissue injury in CF, interventions that bolster antioxidant defenses have been promoted for CF treatment. The glutathione peroxidase system, which can limit oxidant injury, requires a source of free sulfhydryl compounds to function and has led to the unapproved use of glutathione and N-acetylcysteine. These compounds can also cleave disulfide bonds within mucus glycoproteins and can liquefy CF sputum in vitro.

-Inhaled and oral N-acetylcysteine – We do not suggest use of inhaled N-acetylcysteine, consistent with guidance from the CFF [97]. Although originally developed as an inhaled mucolytic agent, there are no well-designed studies demonstrating its clinical utility [15,151]. Furthermore, its potential to induce airway inflammation and/or bronchospasm in a subgroup of PwCF and to inhibit ciliary function has led to reduction in its use. These deficiencies, in conjunction with its disagreeable odor and time required for administration, cause us not to prescribe it. A randomized placebo-controlled trial of oral N-acetylcysteine reported no improvement in FEV₁ from baseline following 24 weeks of treatment [152].

-Inhaled and oral glutathione – Despite some encouraging results from anecdotal reports and case series, controlled clinical trials have not found significant clinical benefit from oral or inhaled glutathione [153,154].

•Docosahexaenoic acid (DHA) – Oral supplementation with omega-3 fatty acids has been proposed as treatment for CF due to their antiinflammatory properties and because PwCF have been found to have decreased levels [155] (see "Fish oil: Physiologic effects and administration"). However, a systematic review and meta-analysis of randomized controlled trials of omega-3 supplementation in pediatric participants found no improvement in pulmonary function tests [156]. Similarly, a subsequent randomized placebo-controlled trial in 22 pediatric participants found no improvement in percent predicted FEV₁ or inflammatory biomarkers after one year of DHA supplementation [157].

CHRONIC ANTIBIOTIC TREATMENT — 

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.

Chronic infection with P. aeruginosa is an independent risk factor for accelerated loss of pulmonary function and decreased survival [158,159]. The prevalence of P. aeruginosa in people with CF (PwCF) in the CF Foundation (CFF) Patient Registry in 2023 was 24.6 percent, with lower levels in children (11.7 percent) and higher levels in those with advanced CF lung disease (58.8 percent) (figure 2) [21]. Of note, continuous treatment with oral antibiotics (other than azithromycin) and elective periodic hospitalization for pulmonary toilet ("cleanout") are not recommended [97,160-162]. Treatment of chronic airway infection with antibiotics is discussed separately. (See "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection".)

TREATMENT OF ACUTE EXACERBATIONS — 

The clinical course of CF is frequently complicated by acute pulmonary exacerbations, superimposed on a gradual decline in pulmonary function. Treatment of exacerbations with systemic antibiotics is a mainstay of CF care and is recommended in virtually all consensus guidelines. Management of acute exacerbations, including selection of antibiotics, is discussed separately. (See "Cystic fibrosis: Management of pulmonary exacerbations" and "Cystic fibrosis: Antibiotic therapy for pulmonary exacerbations".)

OTHER PULMONARY COMPLICATIONS — 

Spontaneous pneumothorax, hemoptysis, and chronic chest pain are well-recognized complications of CF, particularly among adults. These complications have become increasingly common as overall survival continues to improve [163-165].

Spontaneous pneumothorax — Spontaneous pneumothorax occurs in 3 to 4 percent of people with CF (PwCF) during their lifetime [166]. Major risk factors are older age and more severe obstructive lung disease. Recurrent pneumothorax is an indication for referral to a transplantation center [91,167]. Treatment of pneumothorax in PwCF does not differ from that of people with other types of lung disease. (See "Treatment of secondary spontaneous pneumothorax in adults" and "Spontaneous pneumothorax in children".)

Guidelines have been published for the management of pneumothorax in PwCF [168]. Pleurodesis, when needed to address persistent air leaks or other pleural space problems, should not preclude subsequent lung transplantation [169,170]; however, it is associated with greater operative blood loss and kidney dysfunction [171]. 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 [172]. Collaboration between the consulting CF center surgeon and a lung transplant surgeon is recommended.

Hemoptysis

●Scant hemoptysis – Blood streaking in sputum is a common occurrence in PwCF and is often accompanied by other signs of a pulmonary exacerbation (see "Cystic fibrosis: Management of pulmonary exacerbations"). This requires no special treatment beyond the usual approach for the exacerbation, plus assuring that vitamin K deficiency is not a contributing factor and stopping nonsteroidal antiinflammatory drugs (NSAIDs) that may inhibit coagulation (table 3), as outlined in a 2010 guideline [168]. Because even minor hemoptysis can be alarming, reassurance as to its usually benign nature is needed.

●Mild or moderate hemoptysis – PwCF with mild or moderate hemoptysis (ie, those who expectorate approximately 5 to 240 mL of blood in 24 hours) should be considered for hospital admission based on the volume of blood expectorated, ability to clear the airways, degree of shortness of breath, and adequacy of ventilation and oxygenation. In addition to supportive care (table 3), treatment for a pulmonary exacerbation should be initiated because it is likely that the bleeding is caused by infection and inflammation that has compromised airway integrity and eroded into an underlying blood vessel that is part of the bronchial arterial circulation. (See "Cystic fibrosis: Management of pulmonary exacerbations".)

●Massive hemoptysis – Massive hemoptysis is defined in the CF population as acute bleeding of more than 240 mL within 24 hours or recurrent bleeding of more than 100 mL daily for several days [168]. It is more common in people with advanced lung disease (approximately 2 percent of these individuals per year), but can also occur in other PwCF who have regions of the lung with advanced bronchiectasis [164,173,174]. Massive hemoptysis is associated with increased risk of progression to lung transplant and death without lung transplant [167,173]. In people with severe lung disease, massive hemoptysis is an indication for lung transplant referral [167].

Emergency management of massive hemoptysis and hemodynamic instability or impending respiratory failure is discussed separately. (See "Evaluation and management of life-threatening hemoptysis" and "Hemoptysis in children", section on 'Control of life-threatening hemoptysis'.)

Management of massive hemoptysis in PwCF is outlined in a 2010 guideline [168]:

•Bronchial artery embolization (BAE) – BAE should be implemented promptly for all those who are clinically unstable [175,176] and should be strongly considered for those who are stable but have limited respiratory reserve that places them at high risk for bad outcomes should there be a recurring event. Although BAE is an important tool, it has risks, including inadvertent embolization of cerebrospinal vessels [177] (see "Evaluation and management of life-threatening hemoptysis" and "Hemoptysis in children", section on 'Bronchial artery embolization'). CF guidelines advise against performing bronchoscopy prior to BAE because bronchoscopy is unlikely to precisely localize the source of bleeding in bronchiectatic airways and may delay proceeding to BAE [168]. A literature review and pediatric case series from Australia reported that bronchoscopy to localize a bleeding source was performed in only 4 to 5 percent of cases [178,179]. CT angiography may be beneficial if it can be performed without significantly delaying BAE because it may be able to identify the origin and course of the bronchial arteries that need to be occluded.

•Implement supportive measures (treating with antibiotics and bronchodilators and stopping NSAIDs), similar to mild or moderate hemoptysis (table 3).

•Suspend chest physiotherapy. Noninvasive positive pressure ventilation (eg, bilevel positive airway pressure, BPAP) should generally be discontinued as long as the bleeding continues.

Other than proceeding promptly to BAE and maximizing treatment as one would for a severe pulmonary exacerbation, the management of massive hemoptysis in PwCF is similar to that for people with other causes of bronchiectasis. (See "Hemoptysis in children", section on 'Therapeutic interventions for selected patients'.)

The role of antifibrinolytic drugs in management of hemoptysis is uncertain. Evidence regarding the use of these drugs to treat hemoptysis is limited to anecdotal reports and small case series of PwCF [174,175,180] and extrapolation from studies of people with non-CF bronchiectasis [181,182]. A 2019 report detailed the outcomes of 21 PwCF at a single center whose treatment followed a protocol that used tranexamic acid and/or epsilon-aminocaproic acid to treat hemoptysis [180]. The bleeding stopped in a mean of two days, including two individuals with severe hemoptysis and 11 with moderate hemoptysis. More clinical trials are needed to determine if and when antifibrinolytic drugs should be used. (See "Hemoptysis in children", section on 'Interventions to improve hemostasis' and "Evaluation and management of life-threatening hemoptysis", section on 'Correct bleeding diathesis'.)

Pain — Surveys of PwCF have found that up to 77 percent of adults and 42 percent of children report disease-related pain, particularly involving the chest [165,183,184]. The presence of pain is strongly correlated with poor quality of life. Accordingly, the CF Foundation (CFF) developed guidelines that address acute and chronic pain in PwCF, emphasizing a combination of physical, psychological, and pharmaceutical strategies [185].

Allergic bronchopulmonary aspergillosis — Although invasive fungal disease is rare in PwCF, allergic bronchopulmonary aspergillosis (ABPA) is increasingly recognized. It can be difficult to distinguish between ABPA and the progressive pulmonary disease that is typical in CF because the symptoms and radiographic features are often similar. The presence of ABPA is associated with CF-related diabetes, more frequent antibiotic use, and glucocorticoid therapy [186].

Most CF centers perform routine screening by measuring total serum IgE annually; a sudden increase should prompt further investigation for possible ABPA. PwCF should also be evaluated for ABPA if they have a marked exacerbation of wheezing or otherwise unexplained deterioration in lung function despite antibiotic therapy. (See "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection", section on 'Aspergillus species' and "Clinical manifestations and diagnosis of allergic bronchopulmonary aspergillosis".)

PwCF who grow Aspergillus species from respiratory cultures but who do not have evidence of ABPA should be observed closely but usually do not warrant treatment, except perhaps for those anticipating lung transplant. Those with confirmed ABPA should be treated. (See "Treatment of allergic bronchopulmonary aspergillosis".)

Pulmonary hypertension — Advanced chronic lung disease in CF can be complicated by pulmonary hypertension, which is correlated with severity of lung disease. In most cases, PwCF with pulmonary hypertension have severe pulmonary compromise (eg, forced expiratory volume in one second [FEV₁] <40 percent predicted, hypoxemia, or hypercapnia) and the pulmonary hypertension is often identified in the context of evaluation for lung transplantation. (See "Cystic fibrosis: Clinical manifestations of pulmonary disease", section on 'Pulmonary hypertension'.)

Sleep-disordered breathing — Sleep studies performed in children and adults with CF report a high frequency of sleep-disordered breathing [187-190]. Though the sleep disturbance is improved with use of highly effective modulator therapy (HEMT), abnormalities remain prevalent [190,191].

ADVANCED LUNG DISEASE — 

When CF lung disease becomes severe, additional evaluation and treatment are overlaid onto the standard therapies that are applicable to all people with CF lung disease. Discussions regarding lung transplantation should occur well before it becomes urgent [167]. Early referral to a transplant program allows barriers to be recognized and corrected. (See "Cystic fibrosis: Management of advanced lung disease".)

PREGNANCY — 

The number of pregnancies reported annually to the CF Foundation (CFF) patient registry increased sharply after the approval of elexacaftor-tezacaftor-ivacaftor (ETI) in 2019 and has remained elevated, likely due to increased fertility associated with taking a highly effective CF transmembrane conductance regulator (CFTR) modulator (figure 3) [21,192,193]. Subfertility in women with CF and the potential benefits and risks of CFTR modulators during pregnancy and lactation are discussed separately. (See "Cystic fibrosis: Clinical manifestations and diagnosis", section on 'Infertility' and "Cystic fibrosis: Treatment with CFTR modulators", section on 'Pregnancy and lactation'.)

Compared with women without CF, women with CF have higher risks of serious complications during pregnancy (including preterm birth, cesarean delivery, pneumonia, requirement for mechanical ventilation, and death), but these events are rare and the absolute risk is low [194-199]. The overall mortality rate during labor and birth was 1 percent [194].

For women with mild to moderate pulmonary disease (ie, forced expiratory volume in one second [FEV₁] >60 percent predicted), the frequency of treatment for pulmonary exacerbations was increased during pregnancy [200]. Women with severe lung disease, especially those with pulmonary hypertension, tend to have worse outcomes [201], although successful outcomes have been reported in some case series [202,203]. In addition to the underlying pulmonary disease, comorbidities that may complicate pregnancies include CF-related diabetes, cardiac conduction disorders, acute kidney injury, and thrombophilia/antiphospholipid syndrome.

Most retrospective studies have concluded that pregnancy does not affect the subsequent course of lung disease [200,201,204-206]. However, a registry-based study of 296 people with CF (PwCF) who became parents during 2016 to 2019 (women by pregnancy or men whose partners were pregnant) reported that, during the year following delivery, there were small but significant reductions in FEV₁ and body mass index as well as a 30 percent increase in days of intravenous (IV) antibiotic treatment for pulmonary exacerbations [207]. Subgroup analysis showed that those on CFTR modulator therapy did not experience the drop in FEV₁, but modulators did not prevent the adverse effects on body mass index or pulmonary exacerbation treatment. The rigors of infant care leading to decreased time for self-care are likely explanations for some of the reduction in health status. In a separate retrospective study of 141 women with CF, those having ≥3 pregnancies had more rapid decline in FEV₁ following pregnancy than those with one or two pregnancies, but, of note, few were taking highly effective modulator therapy (HEMT) [208].

The general principles of pregnancy management for women with CF include [209-211]:

●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 and CF-related diabetes (see "Cystic fibrosis-related diabetes mellitus")

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cystic fibrosis".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Cystic fibrosis (The Basics)" and "Patient education: Bronchiectasis in children (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Overview – Medical therapies to manage cystic fibrosis (CF) lung disease are summarized in the table (table 1). The following treatment recommendations apply to children six years of age and older, unless otherwise specified.

●CF transmembrane conductance regulator (CFTR) modulators – All people with CF (PwCF) should undergo CFTR genotyping to determine if they carry one of the mutations approved for CFTR modulator therapy (table 2). Selection of the CFTR modulator depends on the CFTR mutation and the child's age, as outlined in the algorithms (algorithm 1 and algorithm 2). (See 'CFTR modulators' above and "Cystic fibrosis: Treatment with CFTR modulators".)

●Airway clearance therapies – All PwCF should have an airway clearance regimen with the following (see 'Airway clearance therapies' above):

•For PwCF ≥12 years who are on elexacaftor-tezacaftor-ivacaftor (ETI) and who have normal or mildly reduced lung function, we suggest not using inhaled airway clearance therapies (nebulized dornase alfa [DNase] and hypertonic saline) (Grade 2B). This suggestion is based on a 12-week randomized trial that found no benefit of continuing inhaled airway clearance therapies in such people and a supporting retrospective study.

For most other PwCF, we recommend chronic use of nebulized dornase alfa (DNase) (Grade 1B) and suggest hypertonic saline (Grade 2B). The evidence for benefit is stronger for DNase compared with hypertonic saline, and for those who are older and/or have more severe lung disease. For children <5 years, our practice is to offer treatment to those with chronic respiratory symptoms or who have more than rare pulmonary exacerbations. (See 'Inhaled airway clearance agents' above.)

•All PwCF who produce sputum should be encouraged to adhere to a regular regimen of chest physiotherapy. In addition, all PwCF should be encouraged to engage in regular exercise. (See 'Chest physiotherapy' above and 'Exercise' above.)

•For PwCF with evidence of airway hyperreactivity (either based on spirometry or subjective improvement in symptoms in response to treatment) who experience intermittent episodes of acute symptomatic bronchospasm, we suggest use of an inhaled short-acting beta-adrenergic agonist as needed for symptomatic relief (ie, as a rescue medication) (Grade 2B). (See 'Bronchodilators' above.)

●Azithromycin – We suggest initiating chronic azithromycin therapy at the time of the first positive culture for Pseudomonas aeruginosa in PwCF as young as six months old (Grade 2C); we continue the treatment for as long as the individual remains culture positive for P. aeruginosa. We do not prescribe azithromycin in the absence of chronic P. aeruginosa infection, unless the individual is having frequent pulmonary exacerbations unresponsive to other standard therapies. The benefits of azithromycin appear to be due to an antiinflammatory effect. There is some evidence that chronic azithromycin may reduce the efficacy of intravenous (IV) tobramycin and possibly inhaled tobramycin. (See 'Azithromycin' above.)

All PwCF who produce sputum should be tested for nontuberculous mycobacteria prior to initiating azithromycin treatment to avoid the possibility of inducing antibiotic-resistant organisms.

●Ibuprofen – Treatment with high-dose ibuprofen is a reasonable option in children and young adolescents with good lung function (>60 percent predicted). Although this practice is suggested by the CF Foundation (CFF) guidelines, the evidence is limited and it is rarely used in clinical practice. Furthermore, there is inadequate evidence to support this suggestion for adults or for children with poor lung function. (See 'Ibuprofen' above.)

●Inhaled glucocorticoids – Inhaled glucocorticoids are appropriate for PwCF who have clear signs and symptoms of asthma, including those with asthmatic symptoms in the setting of allergic bronchopulmonary aspergillosis (ABPA). We suggest not routinely using inhaled glucocorticoids in PwCF without these indications (Grade 2C). For this group, there are no clear benefits and the treatment may impair linear growth. For PwCF and asthma, inhaled corticosteroids have greater clinical benefit and the treatment may be considered along with other antiasthmatic treatments. (See 'Inhaled glucocorticoids' above.)

●Antibiotics – 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 IV, depending on the infecting organisms and the severity of the exacerbation. (See "Cystic fibrosis: Antibiotic therapy for pulmonary exacerbations".)

The role of chronic antibiotics in the treatment of CF lung disease is discussed in detail separately. (See "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection".)

●Complications – Management of pulmonary exacerbations is discussed separately. (See "Cystic fibrosis: Management of pulmonary exacerbations" and "Cystic fibrosis: Antibiotic therapy for pulmonary exacerbations".)

Spontaneous pneumothorax and hemoptysis are well-recognized complications of CF, particularly among individuals with advanced lung disease. (See 'Other pulmonary complications' above.)