Approach

CF is a genetic disease for which there is no cure. The most common clinical manifestations are pancreatic insufficiency, resulting in calorie malabsorption, and lung disease, resulting from a cycle of mucus retention, infection, inflammation, and chronic scarring.

Care is aimed at maintaining health through preventive measures, and early and aggressive treatment of complications such as respiratory disease and poor weight gain. Respiratory disease is the most common cause of morbidity and mortality; the mainstays of respiratory therapy are augmented airway clearance and use of antibiotics to treat pulmonary infections.[46][47][48]​​ Assisted mucociliary clearance techniques are instituted before patients present with signs of respiratory disease. Supplemental, exogenous pancreatic enzymes support growth and nutrition.

Respiratory disease: augmented airway clearance and associated adjunct therapies

Airway clearance techniques are used to mobilize secretions from the airway walls into the lumen for expectoration, providing clear short-term benefits.[48][49]​​​​​ Therapy should be individualized throughout life, according to developmental stage, patient preference, and clinical symptoms.[50][51]

Methods include manual chest physical therapy, active cycle of breathing, autogenic drainage, vibrating devices (e.g., flutter or high-frequency chest wall oscillators, such the Vest™), and positive expiratory pressure (PEP) devices.[52][53]​​​​[54][55][56]​​​​ These effectively increase the expectorated sputum volume, reduce its viscoelasticity, and relieve dyspnea.[57]​ Weak evidence suggests that patients may prefer self-administered techniques over conventional physical therapy.[48]​ Patients usually require more than one technique at a time; for example, it is common to use the Vest™ with active cycle of breathing, PEP, or huffing and coughing.[58]

Many medications prescribed for people with CF are delivered by nebulizer. In the absence of any device showing consistent superiority over another, choice depends on suitability for the chosen therapies, local availability, and patient preference.[59]

​Noninvasive ventilation (NIV) may be a useful adjunct to other airway clearance techniques, particularly in people who have difficulty expectorating mucus. When used in addition to oxygen, it can improve gas exchange during sleep to a greater extent than oxygen therapy alone in moderate-to-severe disease.[60]

Bronchodilators

Short-acting bronchodilators (e.g., albuterol) are generally given before airway clearance or hypertonic saline.[61]​ They are also used in patients who show asthma-like symptoms, but only after assessing bronchodilator responsiveness, and with regular treatment reviews.[61]

Mucolytics

Dornase alfa is a recombinant human DNase that acts as a mucolytic by degrading DNA from inflammatory cells in the airway. Daily use is recommended for patients ages 6 years and over; evidence is stronger for patients with moderate-to-severe disease than for those with mild disease.[46]​ Treatment may improve lung function and decrease pulmonary exacerbations when used for 6 months or longer.[62]​ Mucolytics may cause voice alteration and rash.[62]

Saline

Inhaled hypertonic saline is recommended for use in patients over 6 years of age.[46]

One Cochrane review concluded that inhaled hypertonic saline can modestly improve lung clearance when given to children ages <6 years with CF.[63]​ One multicenter, randomized, double-blind trial found that inhaled hypertonic saline had a positive effect on lung structural changes in children ages 3-6 years with cystic fibrosis.[64]

Respiratory disease: antibiotics for respiratory tract infection

Most people with cystic fibrosis (CF) will develop a respiratory tract infection due to Pseudomonas aeruginosa.[12][13][14][15]​ While early infection may be relatively easy to eradicate, it is virtually impossible to eradicate established chronic infection.[14][15]

Because P aeruginosa increases both morbidity and mortality, early diagnosis and treatment are important. Diagnosis is typically by sputum cultures and, for patients who cannot expectorate, routine oropharyngeal cultures (instead of bronchoalveolar lavage).[65]

When treating an initial or new growth of P aeruginosa, inhaled tobramycin for 28 days is preferred, with or without oral antibiotics.[15][65]​​​​ Intravenous antibiotics (e.g., ceftazidime, tobramycin) offer no clear advantages over oral antibiotics for the sustained eradication of new isolates (including after at least 1 year free of infection).[66][67]

Chronic colonization with P aeruginosa is associated with a more rapid decline in lung function. Inhaled antibiotics can be used in these patients, and may improve lung function and exacerbation rates.[68]​ Inhaled tobramycin and aztreonam have been used successfully in various Pseudomonas eradication protocols, with stronger evidence for moderate-to-severe than for mild disease.[46][69][70]​ Data for other antibiotic regimens lack conclusive support.

Antibiotics for prophylaxis or eradication

Prophylactic use of oral antistaphylococcal antibiotics in patients with CF is not recommended.[46]

One systematic review found that using prophylactic antistaphylococcal antibiotics leads to fewer Staphylococcus aureus isolates (when started in early infancy and continued up to 6 years of age), but the clinical relevance of this finding is uncertain.[71]

Early eradication of methicillin-resistant S aureus (MRSA) has been reported with some success with oral sulfamethoxazole/trimethoprim combined with rifampin for up to 1 month. Long-term studies have not shown any differences in eradication at 3 and 6 months.[72]

Antibiotic adverse events

Disease-specific changes can accelerate aminoglycoside clearance and may necessitate higher doses to reach therapeutic drug levels. This, combined with repeated and prolonged courses of treatment, means that serum aminoglycoside levels must be carefully monitored.

Vestibulotoxicity has been reported with intravenous tobramycin despite correct dosing and therapeutic drug monitoring; clinicians should be aware of early symptoms of vestibulotoxicity to ensure it is diagnosed before further deterioration. Once-daily and multiple-daily doses of aminoglycoside appear to be equally effective; once-daily dosing is associated with less nephrotoxicity in children and no difference in the incidence of ototoxicity.[73]

Drug hypersensitivity reactions, particularly to beta-lactams, are more common in patients with CF because risk increases with cumulative exposure. Skin eruptions are much more likely than anaphylaxis.[74]​ One pharmacovigilance study of Food and Drug Administration (FDA) data revealed increased likelihood of QT prolongation associated with linezolid in patients with and without tuberculosis (192 of 6738 reports).[75]

Respiratory disease: anti-inflammatory agents

Anti-inflammatory agents (e.g., corticosteroids, macrolide antibiotics, ibuprofen) are used to control airway inflammation, either alone or in combination based on patient need.

Systemic corticosteroids

Alternate-day dosing of prednisone may improve CF lung disease, but its use is limited by severe long-term adverse effects.[33][76][77]​ Short-term courses may be suitable for acute exacerbations in the absence of asthma and allergic bronchopulmonary aspergillosis, showing a trend toward improved lung function after 5 days when combined with antibiotics.[76]​ The Cystic Fibrosis Foundation recommends against chronic corticosteroid use in patients ages 6-18 years without asthma or allergic bronchopulmonary aspergillosis, adding that there is insufficient evidence to conclude for or against chronic corticosteroid use in adults (≥18 years).[46]

Prophylactic azithromycin

Increasingly important for chronic P aeruginosa colonization, where treatment can improve lung function and decrease the frequency of pulmonary exacerbations.[46][78]​​​ Azithromycin may be given from age 3-6 months to reduce airway inflammation, pulmonary exacerbations, and hospitalizations in the first year of life, although it does not affect the extent of structural lung disease.[79]

Azithromycin is used to treat nontuberculous mycobacterium infections. Due to the risk of antibiotic resistance, azithromycin monotherapy should be withheld from any patient with active infection by nontuberculous mycobacteria. It is appropriate to screen patients for nontuberculous mycobacteria before starting azithromycin therapy, and at 6- or 12-month intervals thereafter.

Other anti-inflammatory agents

Ibuprofen can protect against lung function decline, decrease intravenous antibiotic requirements, improve nutritional status, and improve chest radiography findings. However, it is not widely used due to frequent gastrointestinal adverse effects.[80]​ The Cystic Fibrosis Foundation recommends long-term oral ibuprofen to slow lung function decline in patients ages 6-18 years who have an FEV₁ of >60% predicted.[46][81] [ Cochrane Clinical Answers logo ] ​ In patients ages >18 years, there is insufficient evidence to recommend for or against long-term use.

Inhaled corticosteroids are often used in patients with CF and comorbid asthma or allergic bronchopulmonary aspergillosis (ABPA), rather than as a treatment for CF lung disease. More specifically they are used in patients who have significant bronchiolar reactivity and have shown a therapeutic response.[46]​ There is limited evidence as to whether they are beneficial and safe in the treatment of CF.[82]

There is insufficient evidence of the efficacy of cromolyn and leukotriene receptor antagonists in daily use.[46]

Respiratory disease: cystic fibrosis transmembrane conductance regulator (CFTR) modulators

CFTR modulators are small molecules that can partially restore function in mutated CFTR.[83] There are two main types of CFTR modulator approved for clinical use: potentiators (ivacaftor) and correctors (lumacaftor, tezacaftor, and elexacaftor).

Potentiators increase the amount of time that the CFTR channel is open and target class III and IV mutations. Correctors help the CFTR protein form so that it can move to the cell surface, and are used in combination with a potentiator to target class II mutations.

Triple therapy (elexacaftor/tezacaftor/ivacaftor) is the preferred option.[1]​ Dual therapy (lumacaftor/ivacaftor or tezacaftor/ivacaftor) should be reserved for cases where triple therapy is not tolerated or the patient is <6 years old. Corrector monotherapy is not recommended.[1]

Ivacaftor

  • Ivacaftor is a potentiator that acts by helping the CFTR channel to open properly, thereby normalizing airway surface liquid and helping to re-establish mucociliary clearance.

  • It is licensed to treat more than 95 gene mutations in patients with CF. In the US, ivacaftor is approved for patients ages ≥1 month (age cut-off may vary in other countries) who have at least one mutation in the CFTR gene (including an R117H CFTR mutation) that is responsive to ivacaftor based on clinical and/or in-vitro assay data.[84][85][86]

  • If the patient's genotype is unknown, an FDA-approved CF-mutation test should be used to detect the presence of a CFTR mutation, followed by verification with bidirectional sequencing when recommended by the mutation test instructions for use.

  • Ivacaftor monotherapy is not effective in patients who are homozygous for the F508del mutation, the most frequent genotype in patients with CF.[87]

  • One systematic review concluded that ivacaftor had a clinically relevant impact (at 24 weeks and 48 weeks) in adults and children over 6 years old with the G551D mutation. Ivacaftor improved respiratory quality of life (QoL) scores in patients with the R117H mutation, but was not associated with an improvement in respiratory function.[87]​​

  • A 5-year study of 16 patients with the G551D mutation demonstrated that ivacaftor improved FEV₁ at 6 months. Subsequently, the disease-related decline in FEV₁ continued, reaching pre-ivacaftor levels at 5 years. There was a sustained reduction in intravenous antibiotic use in patients over 5 years, and BMI increased for 4 years.[88]

  • Children and adults with at least one copy of the G551D mutation, but not the R117H mutation, can experience healthy weight gain.[89]

Lumacaftor/ivacaftor

  • A combination CFTR modulator approved in the US for patients ages ≥1 year (age cut-off may vary in other countries) who are homozygous for the F508del mutation in the CFTR gene. It is not effective for other mutations.

  • One systematic review found that lumacaftor/ivacaftor produced small improvements in QoL, respiratory function, and exacerbation rates.[1]

  • Adverse effects apparent during long‐term follow‐up of adults and children included early transient breathlessness and increased blood pressure.[1] ​The systematic review noted that safety data are lacking in children <12 years.[1]

  • Subsequent open-label extension studies reported the following common adverse events in children with CF ages 2-11 years: pulmonary exacerbation, nasal congestion, pyrexia, rhinorrhea, and vomiting.[90][91]

Tezacaftor/ivacaftor

  • A combination CFTR modulator approved in the US for people with CF ages ≥6 years (age cut-off may vary in other countries) who are homozygous for the F508del mutation, or who have at least one mutation that is responsive to tezacaftor/ivacaftor.

  • One systematic review found that tezacaftor/ivacaftor produced small improvements in QoL, respiratory function, and exacerbation rates.[1]

  • An open label 24-week phase 3 study found that tezacaftor/ivacaftor improved CFTR function in children ages 6-11 years homozygous or heterozygous for the F508del-CFTR mutation.[91]​ Results from an extension study suggested that long-term use of tezacaftor/ivacaftor in these children is well tolerated and generally safe.[92]

  • In patients ages ≥12 years homozygous or heterozygous for F508del, lung function improvements and reductions in pulmonary exacerbations were generally maintained during a 96-week follow-up (of participants from 1 of 6 parent studies).[93]​ Posthoc analysis suggested that rate of lung function decline in homozygous patients who received up to 120 weeks of tezacaftor-ivacaftor was lower compared with untreated matched historical controls.[93]

  • Tezacaftor/ivacaftor safety profile was superior to that of lumacaftor/ivacaftor in patients with CF ages ≥12 years. The systematic review noted that safety data are lacking in children <12 years.[1]

Elexacaftor/tezacaftor/ivacaftor

  • Elexacaftor/tezacaftor/ivacaftor, a combination of three CFTR modulators, improves lung function and QoL.[94]

  • Elexacaftor/tezacaftor/ivacaftor is approved in the US for patients ages ≥2 years (age cut-off may vary in other countries) with at least one F508del mutation or a mutation in the CFTR gene responsive to this treatment combination based on in-vitro data.[95]

  • In patients ages 2-5 years: improves sweat test results and lung function (decreased lung clearance index).[96]​​

  • In patients ages 6-11 years: markers of lung function improved over 24 weeks in children with at least one F508del mutation.[97]

  • In patients ages ≥12 years: provides clinically robust benefits compared with tezacaftor/ivacaftor alone or control groups, with a favorable safety profile.[1][98][99][100]​​

  • Individuals receiving elexacaftor/tezacaftor/ivacaftor with well-preserved pulmonary function appear to be able to discontinue daily hypertonic saline or dornase alfa for a short period (e.g., 6 weeks) without worsening pulmonary function.[101]

  • Elexacaftor/tezacaftor/ivacaftor has also been shown to increase BMI and body weight in patients with the F508del mutation.[89]

  • Adverse effects reported in a 24-week study were mainly of mild or moderate severity. Cough, headache, and pyrexia were most common.[97]​ One case series reported the possibility of acneiform eruptions that may require treatment with isotretinoin.[102]​ A small subset of patients may experience insomnia, depression, and anxiety.[103]

  • Behavioral issues and sleep difficulties have been reported in pediatric patients receiving elexacaftor/tezacaftor/ivacaftor.[104]​ Among adult patients initiating elexacaftor/tezacaftor/ivacaftor, a subset developed neurocognitive symptoms (e.g., word finding, brain fog, memory, attention/concentration), insomnia, depression, and anxiety.[103]​ Larger studies are required to determine prevalence, risk factors, and course.

  • Patients should be monitored for symptoms of liver problems (including elevated liver enzymes in the blood) and cataract development.

Respiratory disease: acute pulmonary exacerbation

Pulmonary exacerbations require prompt treatment due to their association with declining lung function, reduced quality of life, hospitalization, and decreased survival.

The EuroCareCF Working Group defines pulmonary exacerbation as the need for additional antibiotics due to a recent change in at least two of the following items: sputum volume or color; cough (increased); increased malaise, fatigue or lethargy; anorexia or weight loss; pulmonary function (decrease by ≥10%) or radiographic changes consistent with a pulmonary exacerbation; or increased shortness of breath.[105]​ There is, however, no universally accepted definition; management of pulmonary exacerbation necessitates a pragmatic approach.[106]

Antibiotic therapy is usually indicated in patients with pulmonary exacerbation. Use is based on known or presumed bacterial colonization, sputum culture results and sensitivities, and clinical improvement.

Management by exacerbation severity

Mild exacerbations generally respond to an oral antibiotic with or without inhaled tobramycin or aztreonam.[67][68]​​​ Oral antibiotics include amoxicillin/clavulanate, amoxicillin, sulfamethoxazole/trimethoprim, and linezolid. The typical duration of antibiotic therapy is 14 days.[107]

Moderate and severe exacerbations are usually treated with intravenous antibiotics. An aminoglycoside such as tobramycin is usually combined with one or two antibiotics that have Staphylococcus or Pseudomonas coverage, depending on suspected or known colonization and severity of the exacerbation. If no improvement is observed, a different antibiotic is usually tried. However, antibiotic and antifungal stewardship are important during chronic use to mitigate the high antimicrobial resistance rates observed in practice.[108][109]​​​ Resistance is particularly high among Pseudomonas strains.[110]

When treating patients with any pulmonary exacerbation, always increase the frequency of airway clearance, and where possible, adopt primary infection prevention (e.g., segregation, hand hygiene, and face masks).

Antibiotic choice during an exacerbation

Antibiotics can be given orally, intravenously, inhaled, or via a combination of these routes.[111]​ Drug levels should be monitored appropriately.

One systematic review found little evidence that antimicrobial susceptibility testing predicts clinical response to treatment.[112]​ However, treatment typically varies with the infection. For example, S aureus is treated with oxacillin, while linezolid and vancomycin are generally reserved for methicillin-resistant S aureus. P aeruginosa and Burkholderia cepacia can both be treated with ceftazidime or piperacillin/tazobactam, but the most effective strategy is unclear.[14]​​[15][113]

In severe infection with resistant strains, aztreonam, imipenem/cilastatin, or meropenem can be used. The treatment of moderate and severe exacerbations differs in the number of antibiotics used and/or duration of therapy; however, synergy between multiple antibiotics may not benefit the patient.[114]​ One systematic review found no differences between longer (approx. 15-21 days) and shorter (approx. 10-15 days) courses of intravenous antibiotics on FEV₁, CRP, or WBC, although it included no randomized studies.[115]​ For the treatment of an initial or new growth of P aeruginosa, see "Respiratory disease: antibiotics for respiratory tract infection," above.

For the management of bronchiectasis (including infection with or without Pseudomonas), see Bronchiectasis (Management approach)​.

Respiratory disease: lung transplantation

Lung transplantation is reserved for candidates who have exhausted all alternatives. Referral is recommended for an FEV₁ <30% of predicted in adults and <40% of predicted in children.[116]​ Higher cut-offs are recommended in the presence of rapid decline or markers of shortened survival, including a poor 6-minute walk test, hypoxemia, hypercarbia, pulmonary hypertension, and low BMI.[116]​ In waitlist transplant candidates, obtain noninvasive CF-specific bacterial, fungal, and acid-fast bacillus respiratory cultures every 3 months, and review pathogen history to help guide the perioperative antibiotic regimen.[117]

Contraindications to lung transplantation vary between transplant centers but include sepsis, multiple organ dysfunction, documented history of nonadherence to treatment, colonization with certain genomovars of B cepacia, class III obesity (BMI ≥40), and refractory gastroesophageal reflux. Relative contraindications in CF include renal insufficiency (GFR <25 mL/minute and/or evidence of structural renal disease), exceedingly poor functional status with inability to walk >600 feet consistently on a standard 6-minute walk test (depending on age of patient), a history of chemical pleurodesis, severe malnutrition with a BMI <16, colonization with highly virulent bacteria or fungi (or certain strains of mycobacterium), and poorly controlled diabetes mellitus. One systematic review of mortality after lung transplantation found higher rates associated with B cepacia complex, but not with FEV₁, pulmonary hypertension, CF-related diabetes, and female sex.[118]

Guidelines recommend consulting with at least two transplant centers before deciding that a patient is not a candidate for transplant.[118]​ Follow up with a multidisciplinary CF care team should resume within 6-12 months of transplant to ensure appropriate extrapulmonary CF care.[117]

Gastrointestinal disease

Patients should be seen by a CF care team at least once every 3 months.[33]​ At each visit, a registered dietitian or nutritionist will ideally guide all aspects of nutritional therapy, including screening and assessment of dietary intake and gastrointestinal disease.[33]​ The patient should be monitored for their appetite; stooling habits, including quantity and quality; and the presence of gastroesophageal reflux. An insatiable appetite coupled with large numbers of stools or bulky and greasy stools is consistent with fat and calorie malabsorption. A history of decreasing stool numbers over time, with or without abdominal distention or vomiting, may signal bowel obstruction. Patients are at increased risk of intussusception, which requires urgent surgical treatment.[119]

Pancreatic insufficiency

Pancreatic enzyme replacement therapy (PERT) and fat-soluble vitamin supplementation are indicated to support growth and nutrition.[29][120]​​​ Enzyme replacements should include lipase, protease, and amylase, given with snacks and meals (“PERT treats the meal, not the pancreas”).[29]​ Adjustments are made for the patient's weight, pattern of growth, food portions, and stool frequency and character. Fat-soluble vitamins are given regularly according to nutritional recommendations. Cystic Fibrosis Trust (UK): diet and nutrition leaflets Opens in new window​ Serum blood levels are used to assess vitamin A, D, and E levels, while prothrombin time is used to assess vitamin K levels.

Good adherence to treatment prevents constipation and optimizes nutritional status.[120][121]​​​ However, PERT and vitamin supplementation may not completely eliminate gastrointestinal symptoms.[29][120]​​​ If a patient continues to demonstrate poor weight gain or growth, oral caloric supplements may be used. Ultimately, gastrostomy tube placement may be necessary to ensure enough calories to support growth.

Intestinal manifestations

Abnormal salt and water balance in the intestine can lead to inspissations of stool and intestinal mucus, usually in the terminal ileum (i.e., meconium ileus in the neonate and distal intestinal obstruction syndrome thereafter). These are usually partial obstructions that can be managed medically using water-soluble contrast enemas and oral osmotic agents, though specifics will vary by institution.[122]​ Other options to improve bowel habits and minimize recurrence include stool softeners, laxatives, optimizing hydration, and prokinetic agents alone or in combination.

Surgery is indicated for complete intestinal obstruction, evidence of peritonitis, or failure of medical management, with laparoscopic approaches preferred.[2][123]​ While the surgical team is being notified, the patient should be made nil per os and a nasogastric tube may be placed for drainage. Fluid and electrolyte balance should be maintained within normal ranges through close monitoring of serum electrolytes and use of intravenous fluids.

Gastroesophageal reflux and aspiration

Gastroesophageal reflux is treated with H2 antagonists first-line and proton-pump inhibitors second-line. By providing a more alkaline environment, these therapies also improve enzyme function in PERT. Antireflux surgery offers some benefits in CF and may slow the effects of reflux on lung function.[124]

Liver disease

CF-related liver disease presents with focal biliary fibrosis, porto-sinusoidal vascular disease, or both.

Typically, bile duct obstruction leads to periportal inflammation and fibrosis, which may develop into multilobular cirrhosis with portal hypertension.[125]​ Therapy for hepatobiliary disease is limited to oral bile acids (e.g., ursodiol).[126]​ Progression to liver failure (e.g., decompensated cirrhosis) is unpredictable and requires liaison with a liver transplant center.

For the management of cirrhosis and portal hypertension, see Cirrhosis and Esophageal varices.

Advanced CF and palliation

​​Advanced CF lung disease (ACFLD) is the main cause of death in CF patients. Additional care provision recommended in ACFLD includes consideration for transplant referral, further screening for complications, enhanced management of comorbid conditions, and a focus on advance care planning and palliative care.[127]

One systematic review into palliative care in CF found that there was a high prevalence of undertreated symptoms in patients with CF and that the majority of patients only completed advance care planning during their terminal admission.[128]​ Palliative care can alleviate distress and discomfort and improve quality of life at all disease stages.[129]

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