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]. 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".)
The focus of this discussion is on pulmonary therapies for patients meeting diagnostic criteria for CF. Although it has been traditionally thought that there are no clinical consequences from being heterozygous for a CFTR disease-causing mutation, studies using large databases have shown that these individuals are at an increased risk for developing a variety of CF-related manifestations [2]. However, there is insufficient information to extrapolate CF-specific treatments to those who do not meet diagnostic criteria for CF. (See "Cystic fibrosis: Clinical manifestations and diagnosis".)
It is important to recognize the multisystem nature of CF. Sinus infection, nutritional status, glucose control, and psychosocial issues must all be assessed at regular intervals. This requires a multidisciplinary approach to care that, in the United States, is best provided at one of more than 120 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, and social workers with special competence in CF care. A listing of these centers can be obtained at 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].
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: Treatment of acute 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 purulent secretions from the airways is a universal complaint among CF patients who have moderate to severe lung disease. Analysis of CF sputum has shown that its high viscosity is caused by its relative dehydration and the interaction of several macromolecules, including mucus glycoproteins, denatured DNA, and protein polymers such as actin filaments [1,7,8]. Airway clearance is accomplished 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.
Inhaled airway clearance agents — 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. Inhaled hypertonic saline or mannitol helps to hydrate the inspissated mucus that is present in the airways of patients with CF. 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 [9]. High-quality clinical trials have demonstrated benefit, as outlined below.
It is possible that the advent of highly effective CFTR modulator therapy will reduce the utility of inhaled airway clearance agents. To address this question, the Cystic Fibrosis Foundation (CFF) has begun a study in which patients on highly effective CFTR modulator therapy will be randomized to stop either their DNase or hypertonic saline for six weeks, after which the clinical consequences will be assessed (NCT04378153). (See "Cystic fibrosis: Treatment with CFTR modulators".)
Guidelines from the CFF recommend that most patients with CF use both DNase and hypertonic saline, without assigning priority of one over the other [10,11]. We follow this recommendation but realize that adherence to treatment is low due to variable tolerability and time required for administration. Therefore, we sometimes need to modify the regimen after discussing these potential treatment benefits and burdens with the patient and their family.
The recommended order of treatments to be performed twice daily is [10]:
●Albuterol by metered dose inhaler
●Hypertonic saline
●DNase (only once a day) and airway clearance therapy (chest physiotherapy)/exercise (in either order) [12]
●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%) 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'.)
●Inhaled DNase – We recommend chronic use of nebulized DNase for all patients who have chronic daily cough or forced expiratory volume in one second (FEV1) below the normal range. We also begin chronic DNase if a patient's FEV1 drops below his or her baseline, even if it remains in the normal range but fails to improve with treatment for an acute exacerbation. Guidelines from the CFF encourage slightly broader use of DNase, suggesting this therapy for all children with CF two years and older regardless of symptoms or pulmonary function tests [13]. The CFF also suggests nebulized DNase for infants with pulmonary symptoms [14].
Patients are generally treated once daily; however, results from a 12-week crossover trial of 48 patients found alternate-day dosing of nebulized DNase resulted in equivalent clinical outcomes and substantially lower drug costs [15,16]. There is some variability among United States CF centers in prescribing practices for DNase, probably influenced by the high cost of the drug [17].
The efficacy of nebulized DNase was shown in a meta-analysis of 15 clinical trials (2447 participants) in which DNase was shown to cause a relative increase in percent predicted FEV1 by approximately 5 percent in trials extending up to two years [18]. Three studies included in the analysis showed that DNase reduced pulmonary exacerbations compared with placebo, with a relative risk of 0.78 (95% CI 0.62-0.96). A study using data from a patient registry showed that the decline in FEV1 of patients taking DNase was slower than that of a comparison group [19]. Another study randomized 28 participants aged 5 to 18 years who were taking DNase chronically to either continuing DNase or interrupting it for one month [20]. Withdrawal of DNase led to a worsening of lung clearance index (LCI) and FEV1 without significant change in a quality-of-life measure compared with the control group. A much larger study of the consequences of withdrawing DNase and/or hypertonic saline is underway (NCT04378153).
●Inhaled hypertonic saline
•Indications – We suggest nebulized hypertonic (7%) saline twice daily for all patients but recognize that adherence is low due to time required for administration and induction of cough. CFF guidelines suggest hypertonic saline for all patients two years and older [11,13]. However, we now suggest its use in all children and adults, supported by favorable results from a subsequent study that enrolled infants less than four months old [21], as discussed below.
•Technique – Albuterol should be inhaled from a metered dose inhaler immediately prior to hypertonic saline administration to limit bronchospasm [22]. Patients often use the inhaled hypertonic saline before or during their chest physiotherapy rather than after [23]. For those patients who do not tolerate 7% saline due to excessive cough, throat irritation, or chest tightness, we suggest 3% saline because it increases mucociliary clearance rate above that of 0.9% saline but not as much as 7% saline [24]. Prescribing patterns vary greatly across CF centers, and additional studies are needed to refine the criteria for use of hypertonic saline and optimal timing of treatments [25].
•Efficacy in children >6 years – The medium-term benefit of hypertonic saline was demonstrated by an Australian clinical trial in which 164 patients (≥6 years of age) with stable CF were randomly assigned to inhalation therapy with 4 mL of 7% saline or 0.9% saline twice daily for 48 weeks [22]. A bronchodilator was given prior to each dose to minimize bronchospasm. The study failed to show a statistically significant difference in its primary outcome, namely, the rate of change in lung function during the 48-week trial. However, when averaged over the full duration of the study, lung function showed a small, statistically significant improvement in the hypertonic saline group. Patients treated with hypertonic saline had considerably fewer pulmonary exacerbations requiring antibiotic therapy (mean number of exacerbations per participant 0.39 versus 0.89) and fewer days absent from school or work or being unable to participate in usual activities (7 versus 24 days). Treatment with hypertonic saline was not associated with worsening bacterial infection or inflammation. The treatment was well tolerated. A systematic review that included this study concluded that hypertonic saline has beneficial effects in patients ≥6 years of age with CF [26]. A subsequent randomized study of 20 participants aged 5 to 18 years reported that mucociliary clearance following four weeks of 6% hypertonic saline was superior to 0.12% saline [27]. The level of improvement in FEV1 was not statistically different between groups.
Limited evidence suggests that hypertonic saline may be somewhat less effective than DNase. In an open, crossover-design trial of 48 children receiving DNase or hypertonic saline in 12-week blocks, treatment with DNase resulted in a significantly greater increase in FEV1 compared with hypertonic saline [15]. In the previously mentioned large 48-week study of hypertonic saline, 38 percent of the participants were also receiving DNase throughout the trial [22]. Subgroup analysis revealed no difference in the beneficial effects of hypertonic saline between those receiving or not receiving DNase. However, the power of the study to detect clinically significant differences was not presented and probably was low.
•Efficacy in infants and young children – Our suggestion to initiate inhaled hypertonic saline in infants is based on several randomized trials that compared hypertonic saline with placebo (isotonic saline). Although an earlier trial in infants and young children did not find a reduction in pulmonary exacerbations or improvement in infant pulmonary function tests [28], subsequent trials showed improvement in LCI, which is a more sensitive measure of changes in lung function in patients with minimal disease. In particular, in a 52-week randomized trial in infants (n = 42, age <4 months), inhaled hypertonic saline administered twice daily caused a significantly greater improvement in LCI compared with inhaled isotonic saline [21]. Similar results were seen in a 48-week randomized trial (150 children age 36 to 72 months) in which inhaled hypertonic saline improved LCI2.5 by 0.63 units (95% CI 1.10-0.150) compared with isotonic saline [29]. The same research consortium performed a similar trial in 116 children but used computed tomography (CT) scanning to assess outcomes [30]. After 48 weeks, those receiving twice-daily hypertonic saline developed less structural lung disease compared with isotonic saline, as measured by the percentage of total lung volume occupied by abnormal airways.
●Inhaled mannitol – We suggest inhaled mannitol as a second-line option to replace hypertonic saline for adult patients with CF who fail the combination of DNase and hypertonic saline for airway clearance. 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.
Four randomized trials in children and adults with CF showed that mannitol induced modest improvements in FEV1 compared with placebo (average increase of 54 to 93 mL, depending on the trial), with little or no improvement in secondary endpoints such as frequency or duration of exacerbations [31-34]. An additional small, randomized, unblinded trial compared mannitol alone, DNase alone, and both together, using a crossover design with 12-week treatment blocks [35]. No statistically significant difference in FEV1 was noted between groups, but with only 28 participants randomized, the power of the trial was likely too low to exclude clinically meaningful differences. Mannitol has not been directly compared with hypertonic saline.
Mannitol received regulatory approval in Australia in 2011 and in the European Union in 2012. After initially withholding approval in the United States, in 2020, the US Food and Drug Administration approved inhaled mannitol for adults with CF, in a nine to seven split vote from the advisory committee, based on the additional data supplied by the latest phase 3 trial [36].
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 [13,37-40]. Adherence to chest physiotherapy is often poor, particularly among patients with mild disease [41,42].
A variety of techniques may be used for chest physiotherapy, and there is no evidence that they differ in efficacy [39,40,43-45]. 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. 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 [37,38]. 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" [37,38]. 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 [46].
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.
A systematic review reported that chest physiotherapy (using a variety of techniques) increased mucus transport [47]. 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 [39].
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 [48]. 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 [49,50]. 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 [51,52].
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 [39]. 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 [53].
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) [54]. 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 [55]. 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 [56]. At six months, exercise did not increase FEV1, the primary endpoint, but did improve exercise capacity.
Aerobic exercise may help to mobilize airway secretions, but studies are inconclusive whether it is as effective as therapies directly targeted toward secretion clearance [57,58].
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 [13]. 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 [59] and are the subject of several reviews [14,60,61]. (See "Seasonal influenza vaccination in adults" and "Seasonal influenza in children: Prevention with vaccines", section on 'Target groups'.)
•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 [62]. This includes the standard pneumococcal conjugate vaccine series (either the 13-valent pneumococcal conjugate vaccine [PCV13] or 15-valent pneumococcal conjugate vaccine [PCV15]), ideally delivered in the first 15 months of life, and also the 23-valent pneumococcal polysaccharide vaccine (PPSV23), administered after two years of age [13] (see "Pneumococcal vaccination in children", section on 'Immunization of high-risk children and adolescents'). PPSV23 should be readministered to CF patients >65 years old (see "Pneumococcal vaccination in adults"). The pneumococcal vaccine is recommended for all patients with CF because of a favorable risk-benefit profile, although Streptococcus pneumoniae is not a major cause of pulmonary exacerbations in CF.
•Coronavirus disease 2019 (COVID-19) vaccine – All patients with CF should be vaccinated against COVID-19 (caused by the SARS-CoV-2 virus) as soon as they are eligible, consistent with recommendations from the CFF and the Centers for Disease Control and Prevention [63-65]. (See "COVID-19: Vaccines".)
●Palivizumab – We do not suggest routine prophylaxis with palivizumab for children with CF unless they have other indications. Palivizumab is a humanized monoclonal antibody against respiratory syncytial virus (RSV), which is 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 [66-68]. 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 [69]. 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 'Cystic fibrosis'.)
●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 [70]. 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 [71]. 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 [72]. A smaller subgroup has typical symptoms of asthma, such as chest tightness, wheezing and cough following exercise, or exposure to allergens or cold air [71]. (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) [73,74]. (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 [75-77]. 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 [11]. The published studies addressing their use are few and not uniformly supportive, although short-term benefit has been reported [75-78]. This assessment is consistent with the conclusions of systematic reviews [79,80].
●Agents without clear benefit – The anticholinergic agent ipratropium bromide can induce bronchodilation following acute administration in patients with CF [71]. 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 [79,81,82].
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 [83,84].
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 [11]. Based on a study published since the CFF guidelines were written [85], 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 [11]. Subsequent studies are even less supportive, as discussed below [86,87].
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. 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 [88]. 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 [89].
●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 [90]. 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 [91]. 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 [92].
•Possible reduction in tobramycin efficacy – Of note, concern has been raised that chronic use of oral azithromycin may reduce the efficacy of inhaled or intravenous (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 [93]. 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 [93] but not another [94].
-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 [95]. 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 [87,93,96].
-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 [97]. Those on chronic azithromycin had less improvement in FEV1 if they were treated with IV tobramycin compared with IV colistimethate. A larger registry-based study of 2294 patients aged 6 to 21 years being treated with tobramycin for 5022 pulmonary exacerbations found similar results [98]. 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 [99]. The high-quality study described above provides some assurance that azithromycin has minimal clinically important adverse effects on the benefits of inhaled tobramycin [95]. 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.
•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 [85,100].
●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 [88,89]. 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 [89]. 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 [101]. Subsequent clinical trials have confirmed the reduction in pulmonary exacerbations in patients chronically infected with P. aeruginosa [102]. 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 [87]. This study further supports the 2013 CFF guideline that recommends the use of azithromycin in individuals with persistent P. aeruginosa infection [11]. 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 [103]. 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 [85].
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 [104]. 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 [86]. 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 [82]. 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 [85]. 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 [105]. No statistically significant differences were seen for the prevalence of bronchiectasis detected by 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 [106]. 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 [107]. 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 [108,109].
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) [10,11]. This recommendation is supported by a Cochrane review [110]. 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 [111]. (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 [17]. 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 [112]. After four years, patients in the ibuprofen group who completed the study lost only 1.5 percent of their predicted FEV1 per year, compared with a loss of 3.6 percent of predicted FEV1 per year for the control group. However, the beneficial effects of ibuprofen were seen only in the subgroup of patients who were younger than 13 years of age at the start of the study. Gastrointestinal bleeding and renal impairment, known adverse effects of ibuprofen, were not observed in either group.
●In a multicenter randomized trial, a similar protocol was tested in 142 patients 6 to 18 years old [113]. 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 [11,13]. This is because there is insufficient evidence for benefit [114]; some trials suggest modest benefit and others report no effect [115-118]. One of the reasons for caution is that inhaled glucocorticoids may modestly impair linear growth in children with CF or asthma [119,120]. 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: Treatment of acute pulmonary exacerbations", section on 'Glucocorticoids'.)
●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 [11,13]. Although a small randomized trial suggested that chronic treatment was associated with modest improvements in pulmonary function [121], a long-term follow-up study documented important adverse effects, including abnormal glucose metabolism, cataracts, and growth failure [122]. 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 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 [123].
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 [124], 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 [11]. Although originally developed as an inhaled mucolytic agent, there are no well-designed studies demonstrating its clinical utility [10,125]. 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 [126].
-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 [127,128].
•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 [129] (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 [130].
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 [131,132]. The prevalence of P. aeruginosa increases with age; it can be isolated in approximately 25 percent of infants with CF and up to 75 percent of adults (figure 2). Of note, continuous treatment with oral antibiotics (other than azithromycin) and elective periodic hospitalization for pulmonary toilet ("clean-out") are not recommended [11,133-135]. Treatment of chronic airway infection with antibiotics is discussed separately. (See "Cystic fibrosis: Treatment of acute pulmonary exacerbations" and "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: Treatment of acute 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 [136,137].
Spontaneous pneumothorax — Spontaneous pneumothorax occurs in 3 to 4 percent of patients with CF during their lifetime [138]. Major risk factors are older age and more severe obstructive lung disease. Recurrent pneumothorax is an indication for referral to a transplantation center [72,139]. 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 [140]. Pleurodesis, when needed to address persistent air leaks or other pleural space problems, should not preclude subsequent lung transplantation [141,142]; however, it is associated with greater operative blood loss and renal dysfunction [143]. 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 [144]. Collaboration between the consulting CF center surgeon and a lung transplant surgeon is recommended.
Hemoptysis — Minor hemoptysis is a common occurrence in patients with CF, particularly during pulmonary exacerbations. This requires no special treatment beyond the usual approach for the exacerbation, other than assuring that vitamin K deficiency is not a contributing factor. However, even minor hemoptysis can be alarming to patients and reassurance as to its usually benign nature is needed.
Massive hemoptysis is defined in this population as acute bleeding of more than 240 mL within 24 hours or recurrent bleeding of more than 100 mL daily for several days. This occurs in approximately 1 percent of patients each year; the risk increases with older age and worse pulmonary function [137]. Management guidelines generated by a panel of experts have been published [140]. For CF patients with massive hemoptysis, the guidelines recommend stopping nonsteroidal antiinflammatory drugs (NSAIDs) and suspension of all chest physiotherapy; consensus could not be reached for whether aerosolized antibiotics and bronchodilators should be continued (table 3). Massive hemoptysis in patients with severe lung disease is an indication for lung transplant referral [139].
●Bronchial artery embolization (BAE) is an important tool for managing massive hemoptysis and should be implemented promptly [145,146]. The guidelines recommended against bronchoscopy prior to BAE because of the poor evidence that bronchoscopy can accurately localize the source of bleeding and to avoid delay in proceeding to the embolization procedure [140]. Other than maximizing treatment as one would for a severe pulmonary exacerbation and proceeding promptly to BAE, the management of massive hemoptysis in CF does not differ from that of hemoptysis in other patients with bronchiectasis. (See "Evaluation and management of life-threatening hemoptysis" and "Hemoptysis in children", section on 'Control of life-threatening hemoptysis'.)
●Antifibrinolytic drugs have been used in patients with CF to treat hemoptysis, based on anecdotal reports and small case series [145]. A 2010 Cystic Fibrosis Foundation (CFF) guidelines committee could not identify sufficient evidence to make a recommendation on their use [140]. Subsequently, a report detailed the outcomes of 21 patients at a single center whose treatment followed a set protocol that used tranexamic acid and/or epsilon-aminocaproic acid to treat hemoptysis [147]. 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.
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 [139]. 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 675 in 2021, likely due to increased fertility associated with taking elexacaftor-tezacaftor-ivacaftor (ETI) [17,148]. 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 [149-153]. The overall mortality rate during labor and birth was 1 percent [149].
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 [154]. Women with severe lung disease, especially those with pulmonary hypertension, tend to have worse outcomes [155], although successful outcomes have been reported in some case series [156,157]. In addition to the underlying pulmonary disease, comorbidities that may complicate pregnancies include CF-related diabetes, cardiac conduction disorders, acute renal failure, and thrombophilia/antiphospholipid syndrome.
Most retrospective studies have concluded that pregnancy does not affect the subsequent course of lung disease [154,155,158-160]. 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 [161]. 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 [162-164]:
●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 children of any age who have chronic daily cough or forced expiratory volume in one second (FEV1) below the normal range, we recommend chronic treatment with dornase alfa (DNase) (Grade 1B). We also suggest DNase treatment for patients with mild or asymptomatic lung disease (Grade 2B), but the clinical benefits are likely less for this group. (See 'Inhaled airway clearance agents' above.)
•We suggest chronic treatment with inhaled hypertonic saline for patients ≥2 years (Grade 2B). We also suggest this therapy for younger children and infants (Grade 2C) but recognize that the clinical benefits are less well established for this age group and the added burden on the patient and family needs to be taken into account. The typical dosing regimen is 4 mL of 7% saline via nebulizer twice daily. Because inhaled hypertonic saline can trigger acute bronchospasm, bronchodilator therapy (eg, with a short-acting beta-adrenergic agonist) is given as a pretreatment. (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. This suggestion extends the therapy to a younger age group compared with the 2013 guidelines from the Cystic Fibrosis Foundation (CFF). 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. (See 'Azithromycin' above.)
All patients who produce sputum should be tested for nontuberculous mycobacteria prior to initiating azithromycin treatment. Azithromycin should not be given to patients infected with nontuberculous mycobacteria, because it may induce antibiotic resistance. Of note, there is some evidence that chronic azithromycin may reduce the efficacy of inhaled or intravenous (IV) tobramycin.
●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 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. The role of antibiotics in the treatment of CF lung disease is discussed in detail separately. (See "Cystic fibrosis: Treatment of acute pulmonary exacerbations" and "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection".)
50 : Positive expiratory pressure physiotherapy for airway clearance in people with cystic fibrosis.
85 : Azithromycin for Early Pseudomonas Infection in Cystic Fibrosis. The OPTIMIZE Randomized Trial.
