Sinonasal Manifestations of Cystic Fibrosis

Updated: May 23, 2019
  • Author: Nicole Murray, MD; Chief Editor: Arlen D Meyers, MD, MBA  more...
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Cystic fibrosis (CF) is a chronic, multisystem disorder characterized by recurrent endobronchial infections, progressive obstructive pulmonary disease, and pancreatic insufficiency with intestinal malabsorption.

Most patients with cystic fibrosis present to an otolaryngologist for sinonasal disease. Studies suggest that other head and neck problems, such as otitis media and adenotonsillar disease, appear to be similar in prevalence and pathophysiology to those in patients without cystic fibrosis. [1, 2] Otitis media actually appears to be less prevalent in patients with cystic fibrosis than in patients without, for reasons that remain unclear. [3] This article, therefore, focuses on the sinonasal manifestations of cystic fibrosis.

Unilateral nasal polyposis, a common finding in patients with cystic fibrosis, can be seen in the image below.

This image demonstrates unilateral nasal polyposis This image demonstrates unilateral nasal polyposis with medial bulging of the lateral nasal wall and viscid secretions in the maxillary sinus is shown. This feature is often observed bilaterally in patients with cystic fibrosis (CF) and represents a mucocelelike state (but it is easier to appreciate when seen unilaterally here).

See also Cystic Fibrosis and Thoracic Cystic Fibrosis Imaging.


Clinical Evaluation

It is important to elicit a thorough history of sinonasal symptoms from patients with cystic fibrosis; a complete history is critical, because most clinical decisions are based on this information.


Symptoms to inquire about include the following [4] :

  • Nasal obstruction

  • Worsening nasal discharge

  • Facial pain

  • Worsening cough

  • Fever

Although 90-100% of patients have radiologic evidence of sinus disease, [5, 6, 7] the frequency of nasal polyposis is quite variable and may be found in 6-67% of patients. [2] Nasal polyps increase with age, with 19% having endoscopically notable polyps by age 6 years and 45% having them by age 18 years. [8] Nasal polyps are also more prevalent in homozygotes for the W10;F 508 mutation. [9]

Clinically symptomatic sinusitis, as evidenced by pain, discharge, fever, or postnasal drip, is found in only about 10% of patients with cystic fibrosis. [5] Most patients with radiologically evident disease, therefore, do not report symptoms. This phenomenon may represent a truly asymptomatic disease state, or it may suggest that patients with this chronic disease have psychologically adapted to their symptoms. [10]

Given the above facts, clinical history is often weighed more heavily than radiographic evaluation when treatment decisions are made.

In addition, question patients regarding recent pulmonary status. Chronic sinusitis seems closely associated with endobronchial bacterial infections and appears to impact pulmonary reactivity and chronicity of disease within the sinobronchial tract. [11, 12] Decreasing exercise tolerance also often correlates with acute sinus exacerbations or worsening chronic disease.

Physical assessment

Most patients already have a diagnosis of cystic fibrosis upon presentation to the otolaryngologist and are being referred for consideration of sinus surgery. Perform a thorough physical examination to evaluate the nose and sinuses as well as to uncover other conditions that may exacerbate sinus disease.

Facial evaluation may reveal a widened nasal bridge due to chronic polyposis. Sometimes polyps may even protrude from the nares.

Swollen turbinates, purulent nasal discharge, and nasal polyps may be visible on anterior rhinoscopy. Endoscopy may reveal polyps obstructing both the airway and the sinus ostia in the middle meatus; purulent discharge may also be found. Patients also often have a bulging uncinate process that obstructs the nasal airway.

The nasopharynx must also be evaluated. Adenoid hypertrophy may be present in younger patients and may play a role in nasal obstruction. Address this problem before surgical intervention in the sinuses of these patients, as with patients without cystic fibrosis.


Diagnostic Considerations

A diagnosis of cystic fibrosis may occasionally be made by the otolaryngologist based on the presence of nasal polyposis in an otherwise healthy-seeming child. Patients sometimes tolerate mild forms of this disease, thereby escaping early diagnosis. Segal found one new cystic fibrosis patient out of 16 healthy children with nasal polyps. [13] Nasal polyps increase with age in cystic fibrosis patients, with 19% having endoscopically notable polyps by age 6 years and 45% having them by age 18 years. [8] Nasal polyps are also more prevalent in homozygotes for the W10;F 508 mutation. [9]

A sweat chloride test is recommended in any child with nasal polyps, to rule out cystic fibrosis.

Nasal polyposis is rare in children without cystic fibrosis but does sometimes occur. Non–cystic fibrosis-related polyps may be caused by severe allergic rhinitis, inflammation associated with Samter triad (ie, asthma, aspirin insensitivity, nasal polyposis), Kartagener syndrome (ie, situs inversus, ciliary dysmotility), and other immunologic disorders. These conditions can usually be differentiated by a complete history and physical examination, with sweat chloride testing and cilia biopsy, as indicated.

A study by Thamboo et al indicated that the 22-item Sinonasal Outcome Test (SNOT-22) can be used to predict the presence of subclinical nasal polyps in children with cystic fibrosis. The study, which involved 37 pediatric patients, found that a SNOT-22 score above 11 had a positive predictive value for nasal polyps of 68.1%, a negative predictive value of 66.7%, and a positive likelihood ratio of 1.82. [14]


CT Scanning of the Sinuses

There is poor correlation between severity of symptoms and computed tomography (CT) findings. [15] Diagnosis and management of chronic sinusitis is guided by severity of symptoms. Indications for CT scanning (axial and coronal views without contrast) include evaluation of extent of disease and preparation for operative intervention. There are legitimate concerns with regard to radiation exposure and growing children; further, CT scans are often specially formatted for image-guided surgery (see below). For these reasons, it is ideal to have a discussion with the treating otolaryngologist prior to ordering CT scans in patients who may require surgery.

More than 90% of patients with cystic fibrosis exhibit radiographic evidence of chronic sinusitis as evidenced by opacification, medial displacement of the lateral nasal wall in the middle meatus, and uncinate process demineralization. [16]  The medial displacement of the lateral nasal wall can be seen endoscopically, as well as on CT, and has been long described subjectively; in a study by Herovchon et al, this subjective displacement was verified objectively by CT scan measurements of the angles of the uncinate process. [17]

Medial bulging of the lateral nasal wall coupled with viscid mucus in the maxillary sinus may be observed in 12% of patients and represents a mucocelelike state, as shown in the image below, which is generally treated surgically. [10, 4]

This image demonstrates unilateral nasal polyposis This image demonstrates unilateral nasal polyposis with medial bulging of the lateral nasal wall and viscid secretions in the maxillary sinus is shown. This feature is often observed bilaterally in patients with cystic fibrosis (CF) and represents a mucocelelike state (but it is easier to appreciate when seen unilaterally here).

Chronic sinusitis often causes poor pneumatization and hypoplasia of the maxillary and ethmoid sinuses and poor development of the frontal sinuses. [18] Adolescent patients with cystic fibrosis often have no frontal sinus cavity present on CT scan evaluation.


Sinus Aspiration and Culture

Sinus aspirates are necessary for culture in patients with cystic fibrosis to detect and appropriately manage infections. Differences exist in organisms and sensitivities from different sinus cavities of a single cystic fibrosis patient; therefore, attempts should be made to obtain specimens from all accessible sinuses. [19] However, cultures from the nasopharynx, throat, or sputum are not useful for predicting the identities and sensitivities of organisms infecting the sinuses. [20, 21]

Transantral maxillary sinus aspirates of 20 patients with cystic fibrosis showed that the organisms most commonly cultured were Pseudomonas species (65%), nontypeable Haemophilus influenzae (50%), alpha-hemolytic streptococci (25%), and anaerobes such as Peptostreptococcus and Bacteroides species (25%). [20] With the exception of Pseudomonas species, sensitivities are unchanged from those of non–cystic fibrosis patients. [20]

Non–cystic fibrosis patients do have a different bacterial load from sinusitis. Acute sinusitis usually is caused by Pneumococcus species, nontypeable H influenzae, and Moraxella catarrhalis. Chronic sinusitis is often caused by the above organisms in addition to Staphylococcus aureus and anaerobes such as Bacteroides, Veillonella, and Fusobacterium. [22]


Management Overview

Attempt aggressive medical management before surgical intervention. Patients may report chronic purulent nasal discharge or cough, but initiate therapy whenever they experience a subjective increase in nasal obstruction, cough, or drainage. Oral antibiotics effective against Pseudomonas species and staphylococci, coupled with aggressive nasal toilet and/or nasal steroid agents, may improve symptoms. Recently, anaerobic bacteria resistant to anti-pseudomonal antibiotics have been suggested to play a role as sinus pathogens. [23]

Although medical management with aggressive nasal toilet, appropriate use of antibiotics, and nasal steroid agents may be beneficial both symptomatically and in lengthening the interval between surgeries, initiate surgical therapy if medical therapy is ineffective.

Studies show that patients with cystic fibrosis with chronic sinusitis demonstrate symptomatic improvement as well as improvement in quality-of-life measures following surgical treatment. [24] However, surgical intervention for patients with cystic fibrosis still should be carefully considered. These patients may develop severe mucus plugging during general anesthesia, and this risk increases with duration of intubation.

A study by Tumin et al indicated that endoscopic sinus surgery can be safely performed in children with cystic fibrosis. While the results showed a higher rate of prolonged hospital stays in children with cystic fibrosis than in those without the disease (30% vs 9%, respectively), the rates of readmission (6% vs 4%, respectively) and reoperation (0% vs 1%, respectively) were similar between the two groups. Additionally, only one readmission in the cystic fibrosis group was related to endoscopic sinus surgery. [25]

A retrospective study by Do et al indicated that when used together, Lund-Mackay and modified Lund-Mackay scores can be used to predict which pediatric patients with cystic fibrosis will need sinus surgery. The study, which involved 41 children with cystic fibrosis, found that, using a receiver-operator characteristics curve with a threshold score of 13, the Lund-Mackay score had a sensitivity and specificity of 89.3% and 69.2%, respectively, while, using an optimal score of 19, the modified Lund-Mackay score had sensitivity and specificity of 67.7% and 84.6%, respectively. [26]


Patients with cystic fibrosis should be cared for by a team of physicians familiar with their needs. Surgery on these patients must be undertaken in a cautious manner with attention to their pulmonary status. Preoperative communication with the pediatric, pulmonary, and anesthesia teams is therefore essential.

Severe obstructive pulmonary disease may make the risk of anesthesia unacceptable. The decision and timing of surgery must be carefully planned with the pulmonary team. Surgery may be commonly performed at the end of hospitalization for a pulmonary tune-up with intensive chest physiotherapy, bronchodilators, and intravenous antibiotics.

The surgical procedure may be performed under local anesthesia for appropriately selected patients, but for children, general anesthesia is commonly used. Consider arterial hypotension to a systolic pressure of 85-90 mm Hg to allow faster and safer surgery in a relatively bloodless field. Prepare the nose with a topical vasoconstrictive agent, such as cocaine or oxymetazoline, and inject it with lidocaine or bupivacaine with epinephrine.

In this manner, systemic narcotics, with their deleterious effects on postoperative respiration, are used minimally or avoided entirely. Deeply extubate patients, if possible, to avoid airway irritation, hypertension, and coughing on emergence. [27]


Nasal Toilet

Because mucociliary clearance is chronically impaired, irrigations are critical and should be a daily routine as patients begin to develop sinonasal symptoms. Nasal saline irrigations serve to decrease bacterial colonization, wash away inspissated secretions that lead to obstruction, and temporarily aid in vasoconstriction. Irrigation is also required after any surgical intervention, because surgery enlarges sinus ostia but does not address underlying defects in mucociliary clearance.

Several studies have now reported that recombinant human deoxyribonuclease I (dornase alfa or Pulmozyme) used via nasal pulsating inhalation led to improvement of postoperative mucosal edema, quality of life, and polyp regrowth after sinus surgery. [28, 29, 30] Larger randomized trials are underway.



In this section, antimicrobial therapy, nasal toilet, and nasal steroidal agents will be briefly reviewed.

Antimicrobial therapy

The bacteriology of sinonasal disease in patients with cystic fibrosis (CF) differs from that in patients without CF, which affects antibiotic choices. The most notable difference is the nearly ubiquitous presence of Pseudomonas species in patients with CF. As discussed earlier, sinus aspirates are important in order to direct treatment against Pseudomonas species (see Sinus Aspiration and Culture).

Some authors advocate irrigations with antipseudomonal antibiotics such as tobramycin, and these may be effective in decreasing bacterial colonization. Although nebulization of antipseudomonal medications such as tobramycin is clearly beneficial for lung infections, this may not be particularly useful for the sinuses. [31] Nebulized medications can increase the concentration of a medication to the site of infection and decrease systemic exposure to toxins, but these agents are not standard of care.

Other nebulized formulations in development include amikacin, levofloxacin, and ciprofloxacin. [23] Serial tobramycin irrigation of the maxillary sinuses, which can be done in an office setting in a compliant patient, however, may significantly decrease the intensity and frequency of infections, especially when done after sinus surgery. [32]

Nasal steroidal and decongestant agents

Nasal steroids are generally helpful (both for acute exacerbations and for long-term therapy) to decrease mucosal edema and promote mucus clearance. Short-term bursts of systemic steroids may improve acute exacerbations; these may also help if administered preoperatively to decrease intraoperative bleeding in patients with nasal polyposis.

Decongestants are of variable benefit. Antihistamines are generally not beneficial and may be detrimental because of their drying effect on secretions. Mucolytics are generally ineffective in patients with cystic fibrosis, except for recombinant human deoxyribonuclease, which is useful for bronchopulmonary disease.


Surgical Indications and Contraindications

Objective, evidence-based indications for surgery in this population are lacking. Settings in which surgery should be considered include the following:

  • Persistent nasal obstruction associated with nasal polyposis and/or medial bowing of the lateral nasal wall following intensive medical management

  • Medialization of the lateral nasal wall, as demonstrated by endoscopy or computed tomography (CT) scanning, even without subjective nasal obstruction, because of the high prevalence of mucocelelike formations (see the image below)

    This image demonstrates unilateral nasal polyposis This image demonstrates unilateral nasal polyposis with medial bulging of the lateral nasal wall and viscid secretions in the maxillary sinus is shown. This feature is often observed bilaterally in patients with cystic fibrosis (CF) and represents a mucocelelike state (but it is easier to appreciate when seen unilaterally here).
  • Pulmonary exacerbations that appear to correlate with sinonasal disease exacerbations, worsening of pulmonary status, or diminished activity level, despite appropriate medical management

  • Facial pain or headaches that have no other apparent cause and that adversely affect quality of life

  • Desire for improvement in symptom profile beyond what medical management has achieved in a patient with significant nasal cavity and paranasal sinus symptoms [10]

Contraindications to surgery include the following:

  • Severe obstructive pulmonary disease: This condition may make the risk of anesthesia unacceptable.

  • Vitamin K deficiency or other coagulopathies: Patients with cystic fibrosis are at risk for vitamin K deficiency from pancreatic insufficiency, hepatobiliary disease, or both, and if unsupplemented, they may have a bleeding diathesis. [33] A prolonged prothrombin time (PT) preoperatively should prompt correction and performance of surgery after the PT is normalized.

  • Hypoplastic sinus cavities. This may be a relative contraindication. Delayed pneumatization and delayed development of the maxillary, ethmoid, and frontal sinuses may occur in these patients. Hypoplastic sinus cavities are often encountered. CT scans must be carefully evaluated and surgeons should be experienced, as these anatomic abnormalities can make surgery more hazardous.


Procedural Concerns

Poor ciliary function and thickened mucus are hallmarks of the disease, and currently they are not curable aspects of cystic fibrosis. The surgeon’s goal, then, is to decompress, relieve obstruction, and improve access/drainage.

Perform the required surgery in patients with cystic fibrosis, if possible, in less than 1 hour to avoid respiratory compromise. Length of operation certainly varies according to the extent of disease, blood loss, number of previous procedures, and experience of the surgeon. Safety and avoidance of complications are the primary concerns.

If blood obscures the field, repeated irrigations and packing the nose with cottonoids can allow the procedure to progress safely, as in patients without cystic fibrosis.

Initially, surgeons were minimalist and performed polypectomy alone to improve the airway. It was long ago noted, however, that fewer recurrences and longer symptom-free intervals are reported when polypectomy is combined with a more long-term sinus drainage procedure. [34]

General polyp guidelines now are to remove polyps as completely as is safe, but remember that recurrence is likely. This procedure is generally performed for improvement, not cure. It is wise to leave residual polyps if adequate landmarks are unavailable.

Powered endoscopic sinus surgery with a microdebrider allows safe rapid removal of tissue, and especially polyps, under direct visualization. This technique is especially efficacious in patients with cystic fibrosis, because it allows rapid and precise removal of diseased tissue with preservation of landmarks, which should allow safer surgery both in terms of anesthetic time and decreased complications in patients who are likely to need multiple revisions. [35]

Image-guided surgery

Image-guided surgery (IGS) is useful for its real-time correlation between patient anatomy and preoperative CT images. Intraoperatively, the surgeon utilizes a probe to correlate the precise location of the instrument on axial, coronal, and sagittal computed tomography (CT) scans. This provides rapid and accurate intraoperative localization of surrounding structures.

Many surgeons prefer IGS in cases of revision surgery, significant disease obscuring anatomic landmarks, sphenoidal/frontal sinus disease, or disease abutting the skull base. Typically the preoperative CT scan must be performed under a specific protocol or with a headset worn by the patient. Therefore, before ordering a CT scan, it is recommended the otolaryngologist be contacted to discuss whether any operative intervention is planned such that any need for repeat imaging is avoided.

Extent of surgery

Most surgeons currently advocate endoscopic procedures such as wide middle-meatal antrostomies, anterior and posterior ethmoidectomies, and removal of polypoid disease in the frontal recess. Some experienced centers are now recommending even wider opening of sinuses to allow for egress of thick secretions and for aggressive nasal toilet. Endoscopic fronto-spheno-ethmoidectomies and modified endoscopic medial maxillectomies seem to decrease sinus and lung colonization and to decrease hospital admissions for pulmonary exacerbations. [36, 37]


Postoperative Details

Keep patients with cystic fibrosis who undergo postoperative functional endoscopic sinus surgery (FESS) hospitalized until their pulmonary function is clearly adequate for discharge (often at least 1 night).

Aggressively administer irrigations using normal saline or hypertonic sodium chloride solution.

Postoperative cleaning may help prevent synechia formation. Young patients who cannot tolerate this procedure can briefly return to the operating room 2-3 weeks later for this purpose, if desired.

Although there are no postoperative dietary restrictions, patients are generally advised to avoid strenuous activity for about 10 days following the procedure, because such activity may precipitate bleeding.


Common and minor complications of functional endoscopic sinus surgery (FESS) include bleeding, synechia (scar or contracture) formation. Rare and more serious complications include CSF leak, eye injury, or anosmia. Although the perioperative medical management may be more complex in patients with cystic fibrosis, surgical complications do not occur more frequently in cystic fibrosis patients than in patients without this disease. [10, 34, 38, 39, 40]

It should be noted that disease recurrence may be considered by some to be a complication, and certainly, as discussed below, disease recurrence is the norm in cystic fibrosis patients.

As in patients without cystic fibrosis, revision cases with decreased landmarks can be more hazardous. This fact must be considered in patients with cystic fibrosis who may require multiple procedures over time, and surgical landmarks should be left in place, if at all possible.


Outpatient Management

Postoperatively, regularly monitor patients with office endoscopy. If symptoms return, treat patients as previously discussed (ie, attempt medical therapy before returning to the operating room). It is clear, however, that many patients require revision sinus surgery for recurrent disease.

It is also important to educate patients and their caregivers about the importance of aggressive nasal toilet. In general, these chronically ill patients and their families become very well-educated about their disease and are generally very compliant.



In this section, the prognosis of patients with cystic fibrosis and sinonasal manifestations in terms of disease recurrence, symptomatic relief, and effect on pulmonary function will be briefly discussed.

Disease recurrence

Because many patients need a subsequent procedure for polyp regrowth after polypectomy and functional endoscopic sinus surgery (FESS), these procedures should be viewed as treatments and not necessarily cures. [40] In a review article, Halvorson stated, "Sinusitis is not a curable aspect of CF [cystic fibrosis]." [2] Revision surgery is necessary in up to 89%. [37]

Symptomatic relief

Sinonasal symptoms, including obstruction, olfactory dysfunction, purulent nasal discharge, and headache are all significantly improved after endoscopic sinus surgery. [12] This has been consistent in individual studies and was also supported in a recent meta-analysis. [41] In Cuyler's study, although all 7 patients showed radiologic evidence of recurrent disease after 1 year, all patients also felt subjective improvement. [40]

Effect on pulmonary function

Although many surgeons and physicians have believed that pulmonary function testing (PFT) results were improved after sinus surgery, this has not consistently been supported by data. Most of the studies are retrospective reviews of a small number of patients. Friedman and Stewart showed a correlation of sinus disease quality of life and scores of forced expiratory volume in 1 second (FEV1) in children younger than 12 years, [42] and Halvorson et al's retrospective review of adult patients with cystic fibrosis showed a statistically significant improvement in forced vital capacity and FEV1 in 8 of 8 patients following endoscopic sinus surgery. [43]

An earlier retrospective study by Madonna et al of 15 pediatric and adult patients with cystic fibrosis showed improvements in forced vital capacity and FEV1, but the improvements were not statistically significant. [44] In contrast, a recent study by Osborn et al of 41 pediatric patients with cystic fibrosis demonstrated no improvement in PFT results in these patients undergoing endoscopic sinus surgery. [45]

A recent systematic review by Macdonald concluded that endoscopic sinus surgery does not consistently improve PFT results. [41]


Special Considerations

Evaluate by sweat chloride test any previously healthy child presenting with nasal polyps. Mild forms of cystic fibrosis may go undiagnosed until children develop sinonasal symptoms. Nasal polyps are unusual in children without cystic fibrosis.

Informed consent for sinus surgery is generally similar to that for sinus surgery in patients without cystic fibrosis, except for the following:

  • Anesthetic risks may be higher for patients with cystic fibrosis, depending on their pulmonary status.

  • These patients may require several sinus procedures throughout their lives, and as in patients without cystic fibrosis, surgical risks are higher with revision surgery. Inform patients and their families of this increased risk. Surgeons should keep this in mind and attempt to preserve landmarks to facilitate subsequent surgery.


Future Directions

In this section, the following are briefly reviewed: 14- and 15-membered ring macrolide antibiotics, inhibition of biofilm formation, heart-lung/double lung transplantation, and gene therapy

14- and 15-membered ring macrolide antibiotics

Long-term therapy with low-dose 14- and 15-membered ring macrolide antibiotics seems to promote and sustain reparative processes in the chronically inflamed upper and lower respiratory tract. This may lead to better control of sinonasal disease in cystic fibrosis patients in the future. [46]

Inhibition of biofilm formation

Pseudomonas colonization in cystic fibrosis patients probably represents a biofilm state, whereby the bacteria exist in an organized community with attachment to surfaces in the thick mucus in airways. Bacteria in biofilms exhibit increased antibiotic resistance and are less susceptible to host clearance mechanisms, and are therefore harder to clear with conventional antibiotic regimens. [47] Biofilm growth is dependent on iron. Thus, iron chelators are being investigated as potential targets to disrupt and prevent biofilms. Most recently, iron chelators combined with tobramycin have shown decreased biofilm formation in vitro. [48]

Heart-lung/double-lung transplantation

The only definitive treatment for patients with cystic fibrosis accompanied by advanced lung disease is heart-lung or double-lung transplant. Survival is similar to that for lung transplant recipients without cystic fibrosis and is most adversely affected by rejection or complications of immunosuppression. Performance of this procedure in patients with advanced cystic fibrosis is only limited by the availability of donor organs. [49]

Gene therapy

Gene therapy for cystic fibrosis involves the insertion of DNA encoding a normal CFTR gene into respiratory cells. Vectors are generally viruses or liposomes. Multiple clinical trials are under way. A preliminary meta-analysis of randomized controlled trials has not shown adverse events; unfortunately it has also not shown statistically significant measurable improvements. Further studies are under way.

Increasingly, medications that modify the CFTR gene and its protein are being developed. These medications aim to compensate for the defective CFTR protein by increasing alternative chloride channel activity, inhibiting sodium reabsorption, or increasing chloride conductance. [48] Studies are pending.

As measured using SNOT-20, McCormick et al reported that ivacaftor, a gene-therapy agent that benefits pulmonary function in patients with G551D CFTR cystic fibrosis, also appears to improve symptoms of chronic rhinosinusitis in these individuals. The investigators found improvements in the questionnaire’s rhinologic (at 1, 3, and 6 months), psychological (at 1, 3, and 6 months), and sleep (at 1 and 3 months) domains. [50]

As more and more is learned about the molecular structure and function of the CFTR protein, as well as modifying genes, more avenues for effective therapy will be opened. [51]