Sinonasal Manifestations of Cystic Fibrosis 

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.

See also Cystic Fibrosis and Thoracic Cystic Fibrosis Imaging.

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.

History

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] 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.^[8]

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.^{[9, 10]} Decreasing exercise tolerance also 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.

A diagnosis of cystic fibrosis may occasionally be made by the otolaryngologist based on the presence of nasal polyposis in an otherwise healthy child. Patients sometimes tolerate mild forms of this disease, thereby escaping early diagnosis. Nasal polyposis is otherwise quite rare in children.

Evaluate any child found to have nasal polyps with a sweat chloride test. Nasal polyps are more prevalent in homozygotes for the ∆F 508 mutation.^[11] For these patients routine evaluation by an otolaryngologist is recommended.

As noted, 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 biopsy, as indicated.

There is poor correlation between severity of symptoms and computed tomography (CT) findings.^[12] 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.

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.^[13]

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 must be treated surgically.^{[8, 4]}

Chronic sinusitis often causes poor pneumatization and hypoplasia of the maxillary and ethmoid sinuses and poor development of the frontal sinuses.^[14] Adolescent patients with cystic fibrosis often have no frontal sinus cavity present on CT scan evaluation.

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.^[15] However, cultures from the nasopharynx, throat, or sputum are not useful for predicting the identities and sensitivities of organisms infecting the sinuses.^{[16, 17]}

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%).^[16] Organisms found in patients with cystic fibrosis were sensitive to the same antibiotics used for patients without this disease, except for the Pseudomonas species.^[16]

Patients with acute sinusitis without cystic fibrosis are most commonly infected with Pneumococcus species, nontypeable H influenzae, and Moraxella catarrhalis. Patients without cystic fibrosis but who have chronic sinusitis often have the above organisms in addition to Staphylococcus aureus and anaerobes such as Bacteroides, Veillonella, and Fusobacterium.^[18]

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.^[19]

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 improvement in quality of life measures following surgical treatment.^[20] Carefully consider any surgical intervention for patients with cystic fibrosis. These patients may develop severe mucus plugging during general anesthesia, and this risk increases with duration of intubation.

Consultations

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 is 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. 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.^[21]

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.

Two small studies reported that recombinant human deoxyribonuclease I (dornase alfa or Pulmozyme) used via nasal inhalation led to improvement of postoperative mucosal edema, pulmonary function testing, and polyp regrowth after sinus surgery.^{[22, 23]} This agent is helpful for bronchopulmonary disease but is not the standard of care in sinonasal disease.

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.^[24] 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.^[19] 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.^[25]

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.

Settings in which surgery is indicated 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 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^[8]

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.^[26] A prolonged prothrombin time (PT) preoperatively should prompt correction and performance of surgery after the PT is normalized.
• Chronic sinusitis: Delayed pneumatization and delayed development of the maxillary, ethmoid, and frontal sinuses may occur in these patients. Hypoplastic sinus cavities are often encountered. Obtain and evaluate preoperative axial and coronal CT scans, as these anatomic abnormalities can make surgery more hazardous.

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.

Remove polyps as completely as is safe, but remember that recurrence is likely. This procedure is generally performed for improvement, not cure. Leave residual polyps if adequate landmarks are unavailable.

Endoscopic sinus surgery

In addition to polypectomy, most surgeons advocate endoscopic procedures such as wide middle meatal antrostomies, anterior and posterior ethmoidectomies, and removal of polypoid disease in the frontal recess.

Powered endoscopic sinus surgery with a microdebrider allows safe rapid removal of tissue under direct visualization and is being practiced by increasing numbers of surgeons. 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.^[27]

Image-guided surgery

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

Indications for IGS include 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.

Fewer recurrences and longer symptom-free intervals are reported when polypectomy is combined with a sinus drainage procedure.^[28]

Other procedures

The following procedures are generally performed only if findings on examinations or imaging studies indicate necessity:

• Sphenoid sinusotomy
• Septoplasty
• Resection of the anterior edge of the middle turbinate to allow ease of postoperative inspection and irrigation

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

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

Postoperative cleaning seems to 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.

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

Complications

Complications of FESS in patients with cystic fibrosis do not occur more frequently than in patients without this disease.^{[8, 28, 29, 30, 31]}

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.

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.^[31] Studies show that polypectomy alone in these patients leads to a recurrence rate of 89%, but when polypectomy is combined with another sinus procedure (Caldwell-Luc or ethmoidectomy), this rate drops to 35%.^[28]

In a review article, Halvorson stated, "Sinusitis is not a curable aspect of CF [cystic fibrosis]."^[2]

Symptomatic relief

Symptoms of nasal airway obstruction, olfactory dysfunction, purulent nasal discharge, and decreased activity level are all significantly improved after FESS.^[10] In Cuyler's study, although all 7 patients showed radiologic evidence of recurrent disease after 1 year, all patients also felt subjective improvement.^[31]

Effect on pulmonary function

Many surgeons and physicians believe a positive effect on pulmonary function testing (PFT) results occurs after sinus surgery, but the data are limited and somewhat conflicting. Most of the studies are retrospective reviews of a small number of patients. Prospective studies are under way to attempt to answer this important question.^[2]

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,^[32] and Halvorson et al's retrospective review of adult patients with cystic fibrosis showed a statistically significant improvement in forced vital capacity (FVC) and FEV₁ in 8 of 8 patients following FESS.^[33] In addition, 4 adult patients who underwent the Caldwell-Luc operation and nasoantral windows had fewer postsurgical hospital admissions for pulmonary exacerbations.^[34]

However, although an earlier retrospective study by Madonna et al of 15 pediatric and adult patients with cystic fibrosis showed improvements in FVC and FEV₁, the improvements were not statistically significant.^[35] In contrast, a recent study by Osborn et al of 41 pediatric patients with cystic fibrosis demonstrated no improvement in pulmonary function test results in these patients undergoing endoscopic sinus surgery.^[36]

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.

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.^[37]

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.^[38] 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.^[39]

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.^[40]

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 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.^[39] Studies are pending.

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.^[41]