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Cystic fibrosis: Overview of the treatment of lung disease

Cystic fibrosis: Overview of the treatment of lung disease
Literature review current through: May 2024.
This topic last updated: Mar 22, 2024.

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 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, which has been accelerated by 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 patients 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".)

CF is a multisystem disease. Sinus infection, nutritional status, glucose control, and psychosocial issues must all be assessed at regular intervals. This 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 Cystic Fibrosis Foundation (CFF), most of which have dedicated programs for both children and adults. Patients treated at these centers are seen on a regular basis by clinicians, nurses, dietitians, respiratory therapists, physical therapists, social workers, and psychologists with special competence in CF care. A listing of these centers is available on the CFF website. In the United Kingdom, CF patients receiving their medical care at specialized CF centers have better clinical outcomes compared with patients receiving care in less specialized settings [3-5]. In the United States, more frequent clinician-patient interaction (visit frequency, monitoring, and interventions for pulmonary exacerbations) is associated with improved outcomes [6]. Gaps in CF center care (eg, more than 12 months without a clinic visit) are associated with worse pulmonary function [7]. With the increasing life expectancy of people with CF, 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 [8].

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".)

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 CF patients should undergo CFTR genotyping to determine if they carry a mutation that makes them eligible for CFTR modulator therapy, which include F508del and many other mutations (table 2). Selection of the CFTR modulator depends on the CFTR mutation and the patient's age, as outlined in the algorithms (algorithm 1 and algorithm 2).

Details of patient 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 CF patients who have moderate to severe lung disease. The high viscosity of CF sputum is caused by its relative dehydration and the interaction of several macromolecules, including mucus glycoproteins, denatured deoxyribonucleic acid (DNA), and protein polymers such as actin filaments [1,2,9,10]. Airway clearance can be promoted by a combination of inhaled drugs to loosen and liquefy the inspissated mucus (dornase alfa [DNase], hypertonic saline, and/or mannitol) and physical means to dislodge and help the patient expectorate the secretions (breathing/coughing maneuvers, oscillating positive expiratory pressure [PEP] devices, percussive vests), typically administered in two or more sessions daily.

The highly effective CFTR modulator elexacaftor-tezacaftor-ivacaftor (ETI) substantially reduces sputum production and mucus plugging [11,12], such that at least 50 percent of patients 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 CF patients to promote airway clearance, as outlined in CFF guidelines [13-15]. 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 [16], described below) that suggests that these inhaled therapies may not be necessary for some patients. In fact, registry data and retrospective studies have shown that use of inhaled medications has decreased following introduction of ETI [17-19]. It is also noteworthy that the effectiveness of inhaled medications is often compromised because many patients do not adhere to recommended airway clearance therapies, due to treatment burden (time, cost of DNase) and/or tolerability [20].

Therefore, we suggest the following approach:

Patients ≥12 years on ETI with mild or no lung disease – For this group of patients, we no longer routinely recommend DNase or hypertonic saline. This is based on the observation that many people with CF no longer expectorate sputum after starting ETI [11] and the results of a prospective randomized trial ("SIMPLIFY") that evaluated the effects of inhaled airway clearance agents in patients 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) [16]. 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 (LCI2.5), a more sensitive measure of change in lung function in patients with mild lung disease, did not differ between groups. A retrospective study of 174 patients on ETI found no significant reduction on FEV1 among those who discontinued one or more inhaled CF medications [18].

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

-Patients ≥12 years who are on ETI and have moderate to severe lung disease, or those who are not on ETI, regardless of severity of lung disease [13]. This includes those who are on other CFTR modulators (eg, ivacaftor monotherapy or tezacaftor-ivacaftor).

-Patients 6 to 11 years old, including those on ETI. This is because the SIMPLIFY study did not enroll patients younger than 12 years old and we hesitate to extrapolate to this younger group without additional supporting data.

Separate CFF guidelines for ages two to five years [14] and less than two years [15] recommend DNase and hypertonic saline based on individual circumstances. Our practice is to offer treatment to those with chronic respiratory symptoms or who have more than rare pulmonary exacerbations.

Agents

Inhaled DNaseDNase 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 [21,22].

Evidence for the efficacy of inhaled DNase is from studies performed prior to widespread use of ETI, including a meta-analysis [23], registry study [24], and randomized study of treatment withdrawal [25]. 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 [23].

Inhaled hypertonic saline – Inhaled hypertonic saline helps to hydrate the inspissated mucus that is present in the airways of patients with CF [26]. 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 [27].

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 [28-32]. Additional evidence supported its use in infants and toddlers based on favorable results from a study that enrolled infants less than four months old [33].

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 [34].

In the high-quality randomized, controlled trials, the benefits of hypertonic saline were found to be similar whether or not the participants were also on DNase [28,30]. However, a subsequent registry-based study with 1241 participants, also prior to ETI, found no difference in clinical outcomes between patients on DNase alone and those taking both hypertonic saline and DNase [35]. 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 ETI.

Inhaled mannitol – Inhaled mannitol may be used as a second-line option to replace hypertonic saline for adult patients with CF 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 [36-39]. Although the SIMPLIFY study did not evaluate mannitol, we suspect mannitol's efficacy may be limited in patients on ETI who have normal or mildly reduced FEV1, similar to that study’s findings for hypertonic saline [16]. Because inhaled mannitol may cause bronchospasm in patients 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 [13]:

Albuterol by metered-dose inhaler (to reduce the risk of bronchospasm) [28]

Hypertonic saline

DNase (only once a day) and airway clearance therapy (chest physiotherapy)/exercise (in either order) [40]

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 patients with CF 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 [14,41-45]. Adherence to chest physiotherapy is often poor, particularly among patients with mild disease [20,45,46].

Techniques and devices – A variety of techniques may be used for chest physiotherapy, and there is no evidence that they differ in efficacy [43,44,47-50]. 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 offered to allow patients to have more control over their regimen. The cost of equipment should be considered, with less expensive modalities prescribed first. A 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.

Chest physiotherapy in the form of postural drainage and percussion was introduced to CF care in the 1950s [41,42]. 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" [41,42,51]. 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 [52].

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 [44]. 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 [43].

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 [53]. 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 [54]. 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. 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 [55,56].

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 [45,57]. 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 people with CF 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 people with CF. 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 people with CF [58]. However, the authors recognized that the evidence demonstrating improvement in cardiovascular health and quality of life for people with CF 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 [59].

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) [60]. 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 [61]. 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 [62]. 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 [63].

Aerobic exercise may help to mobilize airway secretions, but studies are inconclusive whether it is as effective as therapies directly targeted toward secretion clearance [64,65]. A survey of patients, their caregivers, and health professionals using a Delphi approach reached a consensus that exercise accompanied with breathing maneuvers promoted airway clearance [66]. However, they concluded that a higher level of evidence was required before recommending exercise to replace tradition airway clearance maneuvers.

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

Vaccinations – Patients with CF should receive all routine childhood immunizations. Vaccines warranting particular emphasis are:

Seasonal influenza vaccine – 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 [14]. 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 [67] and are the subject of several reviews [15,68,69]. (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 patients with CF should be vaccinated against pneumococcal disease, using the recommendations from the United States Centers for Disease Control and Prevention [70]. 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 patients with CF 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 [71-73]. A study of 260 people with CF 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 [74]. (See "COVID-19: Vaccines".)

Respiratory syncytial virus (RSV) prophylaxis

Nirsevimab – Immunoprophylaxis with 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 [75,76]. (See "Respiratory syncytial virus infection: Prevention in infants and children", 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 [77-79]. A retrospective CFF registry study of 4267 patients with CF reported that patients who received palivizumab during the first two years of life had similar FEV1 at age seven years compared with a propensity-matched control group [80]. No differences were found in rate of hospitalization or time to first Pseudomonas aeruginosa-positive culture. (See "Respiratory syncytial virus infection: Prevention in infants and children", 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 individuals with CF 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 individuals with CF, regardless of respiratory tract culture results [81]. Relevant to health care facilities, these include contact precautions, physical separation of patients, use of masks by patients in health care settings, and close attention to hand hygiene by patients and household contacts. (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 patients with CF 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 [82]. Most of these patients 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 [83]. A smaller subgroup has typical symptoms of asthma, such as chest tightness, wheezing and cough following exercise, or exposure to allergens or cold air [82]. (See "Cystic fibrosis: Clinical manifestations of pulmonary disease", section on 'Airway reactivity'.)

Bronchial hyperreactivity is also a characteristic of the small subgroup of patients with allergic bronchopulmonary aspergillosis (ABPA) [84,85]. (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:

CF guidelines suggest short-acting bronchodilator medication immediately prior to chest physiotherapy and exercise to facilitate clearance of airway secretions, although the evidence to support this suggestion is scant. (See 'Chest physiotherapy' above and 'Exercise' above.)

Immediately prior to inhalation of nebulized hypertonic saline, mannitol, or antibiotics for those patients 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 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. Evidence for the efficacy of beta agonist therapy in this setting is limited to observational studies and several small randomized and nonrandomized controlled trials [86-88]. These data suggest that beta agonist therapy provides short-term improvements in pulmonary function and symptom relief in patients 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 [89]. The published studies addressing their use are few and not uniformly supportive, although short-term benefit has been reported [86-88,90]. This assessment is consistent with the conclusions of systematic reviews [91,92].

Agents without clear benefit – The anticholinergic agent ipratropium bromide can induce bronchodilation following acute administration in patients with CF [82]. 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 [91,93,94].

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.

Antiinflammatory therapy — Intense neutrophilic inflammation is a dominant pathologic 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 [95,96].

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

Indications – We suggest chronic treatment with azithromycin for patients six years and older who are chronically infected with P. aeruginosa, consistent with guidelines from the CFF published in 2013 [89]. Based on a study published since the CFF guidelines were written [97], 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 patients.

For patients 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 patients 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 patients (≥6 years) who are culture negative for P. aeruginosa, they noted that the certainty and estimated net benefit were low [89]. Subsequent studies are even less supportive, as discussed below [98,99].

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 [97]. A study in adults shows that 250 mg/day is similarly efficacious, so daily dosing could be used for those patients who find it easier to adhere to a daily treatment schedule [100]. For the small number of patients 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 patients); this dose reduction was employed in one study and was thought to be of benefit [101].

Precautions and potential adverse effects

Use in patients with nontuberculous mycobacteria – Prior to initiating treatment with azithromycin, those patients 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 smear-negative patients are subsequently positive by culture, the macrolide should be stopped to avoid induction of macrolide resistance. Fortunately, a single-center retrospective study reported that initial isolates of M. avium complex in CF patients receiving chronic azithromycin therapy are unlikely to be macrolide resistant [102]. 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 patients 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 CF patients receiving chronic azithromycin therapy was less than that of the control population [103]. 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 [104].

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 [105]. Addition of azithromycin to cultures of P. aeruginosa isolated from CF patients showed a reduced bactericidal effect of high concentrations of tobramycin as are achieved from inhalation in one study [105] but not another [106].

-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 [107]. In the trial, 115 CF patients >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 [99,105,108].

-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 [109]. 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 patients 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 [110]. 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 [110]. A larger registry-based study of 2294 patients aged 6 to 21 years being treated with tobramycin for 5022 pulmonary exacerbations found similar results [111]. 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 patients 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 [112]. The high-quality study described above provides some assurance that azithromycin has minimal clinically important adverse effects on the benefits of inhaled tobramycin [107]. 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 patients 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 patients 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 P. 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 people with CF. In particular, a retrospective study of 68 patients with CF on chronic azithromycin found that their QTc interval was not significantly different from 21 control patients with CF. 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 those in the placebo group, with none developing a QTc longer than 500 msec [97,113].

Efficacy – Evidence supporting the use of azithromycin in patients chronically infected with P. aeruginosa includes the early clinical trials, which primarily enrolled this group of patients. These studies found that azithromycin improved FEV1 and reduced pulmonary exacerbations [100,101]. 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 [101]. 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 [114]. Subsequent clinical trials have confirmed the reduction in pulmonary exacerbations in patients chronically infected with P. aeruginosa [115]. 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 [99]. This study further supports the 2013 CFF guideline that recommends the use of azithromycin in individuals with persistent P. aeruginosa infection [89]. A retrospective study of more than 2000 patients 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 [116]. The efficacy of azithromycin in younger patients 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 [97].

The value of azithromycin in patients uninfected with P. aeruginosa is less clear. The largest study supporting its use enrolled 260 participants randomized to azithromycin or placebo for 24 weeks [117]. 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 [98]. 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 [99]. For these reasons, we no longer routinely prescribe chronic azithromycin therapy for those uninfected with P. aeruginosa but may do so for patients experiencing multiple pulmonary exacerbations if other interventions have not been successful.

Clinical trials of azithromycin have also been performed in younger patients. A randomized trial supports extending the use of azithromycin to patients as young as six months of age following their first positive culture for P. aeruginosa. The trial enrolled 221 patients from 6 months to 18 years of age (approximately one-half were <6 years old) with newly acquired P. aeruginosa [97]. Patients 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 patients 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 received azithromycin or placebo for 36 months [118]. No statistically significant differences were seen for the prevalence of bronchiectasis detected by computed tomography (CT) and the percentage of lung volume containing diseased airways, which were the primary outcomes. However, secondary outcome analysis showed that participants who received azithromycin 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 [119]. 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 [120]. 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 [121,122]. Reduction in antiinflammatory markers occurs early after beginning azithromycin but is not sustained [122,123].

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) [13,89]. This recommendation is supported by a Cochrane review [124]. Ibuprofen is not recommended for patients 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 older patients. 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 and patients should be monitored closely for the development of adverse effects [125]. (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 [126]. 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 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 participants to ensure that high peak blood levels of ibuprofen (50 to 100 mcg/mL) were obtained [127]. 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 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 patients 6 to 18 years old [128]. 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 CF patients who have definite signs and symptoms of asthma, including patients with asthmatic symptoms in the setting of ABPA. They are not routinely recommended for patients without these indications [14,89]. This is because there is insufficient evidence for benefit [129]; some trials suggest modest benefit and others report no effect [130-133]. One of the reasons for caution is that inhaled glucocorticoids may modestly impair linear growth in children with CF or asthma [134,135]. 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 patients 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 people with CF who have an asthma-like phenotype, although high-quality studies are lacking [136] (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 a widely accepted criteria for the diagnosis of asthma in people with CF [137].

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 [14,89]. Although a small randomized trial suggested that chronic treatment was associated with modest improvements in pulmonary function [138], a long-term follow-up study documented important adverse effects, including abnormal glucose metabolism, cataracts, and growth failure [139]. We also do not recommend their use in adults, because of the same adverse effects (other than growth failure).

By contrast, patients with 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 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 [140].

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 [141], we do not prescribe cromoglycate or nedocromil for our patients.

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 [89]. Although originally developed as an inhaled mucolytic agent, there are no well-designed studies demonstrating its clinical utility [13,142]. 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 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 [143].

-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 [144,145].

Docosahexaenoic acid (DHA) – Oral supplementation with omega-3 fatty acids has been proposed as treatment for CF due to their antiinflammatory properties and because people with CF have been found to have decreased levels [146] (see "Fish oil: Physiologic effects and administration"). However, a randomized placebo-controlled trial that enrolled 96 patients with CF with a mean age of 14.6 years found no benefit from 48 weeks of treatment in FEV1, pulmonary exacerbations, or quality of life [147].

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 [148,149]. The prevalence of P. aeruginosa increases with age; it can be isolated in approximately 20 percent of children with CF and up to 45 percent of adults (figure 2) [17]. Of note, continuous treatment with oral antibiotics (other than azithromycin) and elective periodic hospitalization for pulmonary toilet ("clean-out") are not recommended [89,150-152]. 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 and hemoptysis are well-recognized complications of CF, particularly among adults. These complications have become increasingly common as overall survival continues to improve [153,154].

Spontaneous pneumothorax — Spontaneous pneumothorax occurs in 3 to 4 percent of patients with CF during their lifetime [155]. Major risk factors are older age and more severe obstructive lung disease. Recurrent pneumothorax is an indication for referral to a transplantation center [83,156]. Treatment of pneumothorax in CF patients does not differ from that of patients 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 patients with CF [157]. Pleurodesis, when needed to address persistent air leaks or other pleural space problems, should not preclude subsequent lung transplantation [158,159]; however, it is associated with greater operative blood loss and kidney dysfunction [160]. 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 [161]. 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 patients with CF 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 [157]. Because even minor hemoptysis can be alarming to patients, reassurance as to its usually benign nature is needed.

Mild or moderate hemoptysis – Patients 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 [157]. It is more common in patients with advanced lung disease (approximately 2 percent of these patients per year), but can also occur in other patients who have regions of the lung with advanced bronchiectasis [154,162,163]. Massive hemoptysis increases the risk of progression to lung transplant and death without lung transplant [156,162]. In patients with severe lung disease, massive hemoptysis is an indication for lung transplant referral [156].

Emergency management of unstable patients with massive hemoptysis (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 patients with CF is outlined in a 2010 guideline [157]:

Bronchial artery embolization (BAE) – BAE is an important tool for managing massive hemoptysis and should be implemented promptly for all patients who are clinically unstable [164,165]. It should be strongly considered for stable patients who have limited respiratory reserve that places them at high risk for bad outcomes should there be a recurring event. The 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 [157]. 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. A literature review and pediatric case series from Australia covering 2010 to 2020 reported that bronchoscopy to localize a bleeding source was performed in only 3 of 60 cases [166]. BAE is not without risk, including inadvertent embolization of cerebrospinal vessels [167]. (See "Evaluation and management of life-threatening hemoptysis" and "Hemoptysis in children", section on 'Bronchial artery embolization'.)

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 CF is similar to that for patients 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 CF patients [163,164,168] and extrapolation from studies of patients with non-CF bronchiectasis [169,170]. A 2019 report detailed the outcomes of 21 patients with CF at a single center whose treatment followed a set protocol that used tranexamic acid and/or epsilon-aminocaproic acid to treat hemoptysis [168]. The patients had cessation of bleeding in a mean of two days, including two patients 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'.)

Allergic bronchopulmonary aspergillosis — Although invasive fungal disease is rare in patients with CF, allergic bronchopulmonary aspergillosis (ABPA) is increasingly recognized in CF patients. 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.

In most CF centers, patients are screened with annual evaluation of total serum IgE; a sudden increase should prompt further investigation for possible ABPA. Patients 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".)

Patients 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. Patients 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, CF patients 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'.)

ADVANCED LUNG DISEASE — When CF lung disease becomes severe, additional evaluation and treatment are overlaid onto the standard therapies that are applicable to all patients with CF lung disease. Discussions regarding lung transplantation should occur well before it becomes urgent [156]. 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 Cystic Fibrosis Foundation (CFF) patient registry increased from 309 in 2019 to 619 in 2020 and has remained elevated, likely due to increased fertility associated with taking elexacaftor-tezacaftor-ivacaftor (ETI) [17,171]. Subfertility in women with CF and the potential benefits and risks of CF transmembrane conductance regulator (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 [172-176]. The overall mortality rate during labor and birth was 1 percent [172].

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 [177]. Women with severe lung disease, especially those with pulmonary hypertension, tend to have worse outcomes [178], although successful outcomes have been reported in some case series [179,180]. 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 [177,178,181-183]. However, a registry-based study of 296 people with CF 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 [184]. 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 is a likely explanation for some of the reduction in health status.

The general principles of pregnancy management for women with CF include [185-187]:

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 5th to 6th 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 10th to 12th 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 e-mail 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 patients with CF 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 patients should have an airway clearance regimen with the following (see 'Airway clearance therapies' above):

For patients ≥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 patients and a supporting retrospective study.

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

For patients with evidence of airway hyperreactivity (either based on spirometry or subjective improvement in symptoms in response to treatment) who experience intermittent episodes of acute symptomatic bronchospasm, 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 patients as young as 6 months old (Grade 2C); we continue the treatment for as long as the patient remains culture positive for P. aeruginosa. We do not prescribe azithromycin in the absence of chronic P. aeruginosa infection, unless the patient is having frequent pulmonary exacerbations unresponsive to other standard therapy. The benefits of azithromycin appear to be due to an antiinflammatory effect. There is some evidence that chronic azithromycin may reduce the efficacy of intravenous (IV) tobramycin and possibly inhaled tobramycin. (See 'Azithromycin' above.)

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

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 Cystic Fibrosis 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 adult patients or for patients with poor lung function. (See 'Ibuprofen' above.)

Inhaled glucocorticoids – Inhaled glucocorticoids are appropriate for CF patients who have clear signs and symptoms of asthma, including patients with asthmatic symptoms in the setting of allergic bronchopulmonary aspergillosis (ABPA). We suggest not routinely using inhaled glucocorticoids in patients without these indications (Grade 2C). 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.)

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.)

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Topic 6372 Version 112.0

References

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