Cystic fibrosis: Overview of the treatment of lung disease

Official reprint from UpToDate® www.uptodate.com

©2023 UpToDate®

Cystic fibrosis: Overview of the treatment of lung disease

Author: Richard H Simon, MD
Section Editor: James F Chmiel, MD, MPH
Deputy Editor: Alison G Hoppin, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2023. | This topic last updated: Feb 13, 2023.

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 [2-4]. 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.
In the United States, such care is 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 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 [5-7]. In
the United States, more frequent clinician-patient interaction (visit frequency, monitoring, and interventions for
pulmonary exacerbations) is associated with improved outcomes [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:
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Cystic fibrosis: Overview of the treatment of lung disease
● (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 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 [1,9,10]. 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.

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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. 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 [3].

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 precent 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.

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

DNase is generally given once daily. However, results from a small 12-week crossover trial suggest that
alternate-day dosing may achieve equivalent clinical outcomes with substantially lower drug costs
[17,18].

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Evidence for the efficacy of inhaled DNase is from studies performed prior to widespread use of ETI,
including a meta-analysis [19], registry study [20], and randomized study of treatment withdrawal [21].
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 [19].

• Inhaled hypertonic saline – Inhaled hypertonic saline helps to hydrate the inspissated mucus that is
present in the airways of patients with CF [22]. 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
[23].

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 [24-28]. Additional evidence
supported its use in infants and toddlers (currently not eligible for ETI), based on favorable results from
a study that enrolled infants less than four months old [29].

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 [30-33]. 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) [24]

• Hypertonic saline
• DNase (only once a day) and airway clearance therapy (chest physiotherapy)/exercise (in either order)
[34]
• 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'.)

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 [14,35-38].
Adherence to chest physiotherapy is often poor, particularly among patients with mild disease [39,40].

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A variety of techniques may be used for chest physiotherapy, and there is no evidence that they differ in efficacy
[37,38,41-43]. 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
[35,36]. 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" [35,36]. 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 [44].

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
[45]. 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 [37].

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 [46]. 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 [47,48]. 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 [49,50].

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 [37]. 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
[51].

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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) [52]. 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 [53]. 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 [54]. 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 [55,56].

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 [57] and are the subject of several reviews [15,58,59]. (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 [60].
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 [14] (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
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recommendations from the CFF and the Centers for Disease Control and Prevention [61-63]. (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 [64-66]. 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 [67]. 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 [68]. 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 [69]. 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 [70]. A smaller subgroup has typical symptoms of asthma, such as chest tightness, wheezing and
cough following exercise, or exposure to allergens or cold air [69]. (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) [71,72]. (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.)
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• 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 [73-75]. 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 [76]. The published studies addressing their use are few and not uniformly
supportive, although short-term benefit has been reported [73-75,77]. This assessment is consistent with
the conclusions of systematic reviews [78,79].

● Agents without clear benefit – The anticholinergic agent ipratropium bromide can induce bronchodilation
following acute administration in patients with CF [69]. 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 [78,80,81].

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 [82,83].

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 [76].
Based on a study published since the CFF guidelines were written [84], 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
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recommendation to treat patients (≥6 years) who are culture negative for P. aeruginosa, they noted that the
certainty and estimated net benefit were low [76]. Subsequent studies are even less supportive, as
discussed below [85,86].

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 [84]. 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 [87]. 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 [88].

● 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 [89].
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 [90]. 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 [91].

• 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 [92]. Addition
of azithromycin to cultures of P. aeruginosa isolated from CF patients showed a reduced bactericidal
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effect of high concentrations of tobramycin as are achieved from inhalation in one study [92] but
not another [93].

- 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 [94]. 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 [86,92,95].

- 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 [96]. 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 [97]. 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 [98]. The high-quality study described above provides some assurance that azithromycin
has minimal clinically important adverse effects on the benefits of inhaled tobramycin [94]. 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
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none developing a QTc longer than 500 msec [84,99].

● 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 [87,88]. 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 [88]. 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 [100]. Subsequent clinical trials have confirmed the reduction in pulmonary exacerbations
in patients chronically infected with P. aeruginosa [101]. 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 [86]. This study further supports the 2013 CFF guideline that recommends
the use of azithromycin in individuals with persistent P. aeruginosa infection [76]. 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 [102]. 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
[84].

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 [103].
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 [85]. 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 [81]. 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 [84]. 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%

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Cystic fibrosis: Overview of the treatment of lung disease

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 [104]. 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 [105]. 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 [106]. 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 [107,108].

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) [13,76]. This recommendation is supported by a Cochrane review [109].
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 [110]. (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 [3]. 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 [111]. 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.

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● In a multicenter randomized trial, a similar protocol was tested in 142 patients 6 to 18 years old [112]. 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 [14,76]. This is because there is insufficient evidence for
benefit [113]; some trials suggest modest benefit and others report no effect [114-117]. One of the reasons for
caution is that inhaled glucocorticoids may modestly impair linear growth in children with CF or asthma
[118,119]. 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 [14,76]. Although a
small randomized trial suggested that chronic treatment was associated with modest improvements in
pulmonary function [120], a long-term follow-up study documented important adverse effects, including
abnormal glucose metabolism, cataracts, and growth failure [121]. 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 [122].

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

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• 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 [76]. Although originally developed as an inhaled mucolytic agent, there
are no well-designed studies demonstrating its clinical utility [13,124]. 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 [125].

- 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 [126,127].

• 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 [128] (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 [129].

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 [130,131]. 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 [76,132-134]. 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
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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 [135,136].

Spontaneous pneumothorax — Spontaneous pneumothorax occurs in 3 to 4 percent of patients with CF during

their lifetime [137]. Major risk factors are older age and more severe obstructive lung disease. Recurrent
pneumothorax is an indication for referral to a transplantation center [70,138]. 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 [139]. Pleurodesis,
when needed to address persistent air leaks or other pleural space problems, should not preclude subsequent
lung transplantation [140,141]; however, it is associated with greater operative blood loss and renal dysfunction
[142]. 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 [143].
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: Treatment of acute
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
[139]. 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: Treatment of acute 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 [139]. 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 [136,144,145].
Massive hemoptysis increases the risk of progression to lung transplant and death without lung transplant

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[138,144]. In patients with severe lung disease, massive hemoptysis is an indication for lung transplant
referral [138].

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 [139]:

• 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 [146,147]. 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 [139]. 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. (See "Evaluation and management of life-
threatening hemoptysis" and "Hemoptysis in children", section on 'Bronchial artery embolization'.)

• In addition to the supportive measures described for mild or moderate hemoptysis, all chest
physiotherapy should be suspended ( table 3). 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 [145,146,148] and
extrapolation from studies of patients with non-CF bronchiectasis [149,150]. 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 [148]. 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.

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(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 [138]. 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) [3,151]. 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 [152-156]. The overall mortality rate during labor and birth was
1 percent [152].

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
[157]. Women with severe lung disease, especially those with pulmonary hypertension, tend to have worse
outcomes [158], although successful outcomes have been reported in some case series [159,160]. 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 [157,158,161-163]. However, a registry-based study of 296 people with CF who became parents during

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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 [164]. 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 [165-167]:

● 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
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