Otolaryngologic Manifestations Of Cystic Fibrosis
Matthew T. Kirby, M.D.
April 11, 2002

Cystic fibrosis is an autosomal recessive genetic disorder characterized by a dysfunction of exocrine glands throughout the body. It’s a defect in the chloride channel called cystic fibrosis transmembrane receptor (CFTR) resulting in an abnormal salt transport in mucosal linings. It’s a highly publicized topic. Many foundations and web sites are devoted to cystic fibrosis and it’s essential that the otolaryngologist understand this disease process. The disease can affect any part of the body where CFTRs function, but classically affects the GI system with pancreatic insufficiency and the pulmonary system with bronchiectasis. The role of the otolaryngologist in treating CF has evolved from helping with pulmonary manifestations to treating the almost universally present sinus symptoms. Today’s talk will focus primarily on the sinonasal aspect of the disease as it relates to otolaryngology.

Historical searches lead us to believe that at least some of the characteristic symptoms of CF may have been recognized as early as medieval times. A few references of medieval folklore have been uncovered that predict death for an infant who tastes salty when kissed. Such infants were thought to be hexed. In 1606, Alonzo de Losorius De Fontica, a professor of medicine in Spain, wrote that it was known that fingers taste salty after rubbing the forehead of what he called “bewitched children.” Although still nameless, by the early 20 th century, it began to be described and focused on the pancreatic manifestations and the related illness was referred to as celiac disease. Of interesting historical note, Frederick Chopin, a famous romantic composer from the 19 th century, is now thought by many scholars to have had cystic fibrosis. He is pictured here not long before his death in 1849 from cor pulmonale. At the time of his death it was listed as tuberculosis; however he battled a lifelong chronic respiratory illness for at least 24 years as well as malabsorption. His sister died of the same illness by the age of 14.

Fanconi et al were probably the first to describe the array of symptoms and refer to it as cystic fibromatosis with bronchiectasis, recognizing it as a discrete entity from the celiac disease with which it had been previously discussed. Dorothy Anderson in 1938, credited with first referring to it as cystic fibrosis of the pancreas, described the loss of exocrine function in the pancreas. In 1945, before the abnormality in sweat was known, Farber believed that the disease was caused by a generalized state of thickened mucus and he coined the term “muco viscosity” still used in Europe today. In 1951 an impressive heat wave hit New York and a high number of children came to the hospital with heat prostration. The St. Agnes at Columbia sought the source of the salt loss that caused the heat prostration, which eventually led to the gold standard in CF testing, the sweat chloride test. Luor, in 1959 noted the association with nasal polyps and Schwamann in 1960 described the relationship with cystic fibrosis and sinusitis. It wasn’t until 1989, in three similar works published in Science, that the molecular basis of cystic fibrosis was discovered, a defect in the chloride channel CFTR. Cystic fibrosis has been a frequent topic of research in the Baylor department and those results will be discussed later in the topic.

Cystic fibrosis is the most common life-shortening genetic disorder of Caucasians in the United States, with an incidence of 1:2500 overall births and up to 1:1600 to 2,000 in the white population. It is rare in Native American and Black populations. Symptom-free carriers of the disease in the white population approximate 5% or 1:20 people, a total of 7 million Americans. In 1992, approximately 30,000 individuals were affected with CF. The median age of survival for patients with CF approaches 30 years now and half of all patients with CF are older than 18 years of age. Recent estimates have projected a median survival of longer than 40 years for children born in the U.S. in 1990 who are receiving standard therapy. This increase in survival will increase the frequency with which otolaryngologists encounter this disease process. CF is a monogenetic disorder that has been mapped to the long arm of chromosome seven in the region Q32. The gene was identified by positional cloning in 1989 and showed to have 27 exons that are transcribed into a 6.5 KB messenger RNA. The messenger RNA in turn encodes a 1,400 amino acid product called the cystic fibrosis transmembrane conductives regulator. It’s an integral membrane protein of the ATP binding family. The protein is composed of two repeated motifs, each with a transmembrane domain and a cytoplasmic nucleotide-binding fold separated by hydrophilic regulatory domain seen here. The protein is a chloride channel activated by cyclic AMP mediated protein kinase phosphorylation of the regulatory domain and ATP binding and hydrolysis at the nucleotide binding fold. When active, it allows the chloride to be transported extracellularly. It functions to regulate two other membrane proteins as well, upregulating the outward rectified chloride channel and down regulating to epithelial sodium channels. It’s expressed on the epithelial cells of the lung, sinonasal mucosa, pancreas, sweat ducts and vas deferens. It normally helps control the flow of ions across the apical surface of the cell thereby controlling the hydration state of secretions in the epithelial lumen. Loss of function creates an imbalance of ions and water and results in improperly hydrated mucous secretions.

More than 700 mutations in CFTR gene have been reported in the literature. Most alterations are point mutations and involve only one or a few nucleotides. The types of point mutations observed in CFTR are primarily missence, nonsense and frame shift mutations. The most common of these genetic mutations is the Delta F508 where the phenylalanine at position 508 is deleted, resulting in a frame shift mutation. This allele is seen in 68% of CF mutations. The mutational event that led to Delta 508 is estimated to have occurred between 3,000 and 53,000 years ago. Mutation frequency varies in relation to race and ethnicity as well. The most common CFTR mutation in Caucasians, African Americans and Ashkanazi Jews are Delta F508 and G42X. Many of these mutations overlap among the populations as you can see in this region here. However, some populations such as the Asians have mutations specific for that population. Therefore, population specific mutation analysis may increase the detection rate.

New studies have looked at the connection between chronic rhinosinusitis, which effects up to 14% of the U.S. population and cystic fibrosis. In a case controlled study, DNA analysis was done on patients with chronic rhinosinusitis but without the diagnosis of cystic fibrosis. Those patients with one CF mutation were evaluated with sweat chloride and nasal potential difference and further DNA analysis. They found that CF mutations were significantly higher at 7% in the chronic rhinosinusitis population versus matched control groups, which had only 2% mutation. A similar study from January of this year revealed CFTR mutations in 12.1% of children with chronic rhinosinusitis but negative sweat chloride tests versus 3-4% for the controls. These findings suggest the mutations that affect the CFTR gene may represent another predisposing factor for chronic rhinosinusitis in the absence of overt cystic fibrosis. But how this defect in the protein actually results in the clinical picture that is seen in CF is still not fully understood although there are a number of theories. Pseudostratified ciliated epithelium lines the sinonasal cavity and the tracheobronchial tree from the larynx down to the distal bronchioles functioning as a barrier to inhaled particles, chemicals and microorganisms.

Mucociliary clearance is a key protective function of this lining and requires coordinated ciliary beating and optimal physiochemical properties of the mucus. Patients with CF have measurably impaired mucociliary clearance. Ciliary ultra structure and beat frequency are normal however, leaving abnormality of the mucus as the source of the clearance problem. At the cellular level, chloride cannot be excreted and sodium is exclusively absorbed into the cells. Osmotic pressure differential leads to influx of water into the cell and thus, extra cellular dehydration occurs resulting in thickened viscous mucus obstruction of ducts by inspissated secretions, leading to the macroscopic and clinical manifestations of the disease. The pathogenesis of the ENT manifestations of chronic sinusitis and nasal polyposis are similarly thought to be the result of mechanical obstruction from the mucus. In chronic sinusitis, the sinus ostia become obstructed with stasis of the mucus, hypoxia and C02 retention, predisposing to local infection and inflammation. This leads to mucosal edema, decreased ciliary function and enhanced bacterial colonization and chronic inflammation. In nasal polyposis, the pathophysiology remains unclear but it is believed that the dilated mucus glands cause obstruction of the capillaries and venules, with impaired blood flow resulting in local edema, stromal prolapse, with subsequent formation of polyps. The discovery of the nitrous oxide as an important signaling molecule in the cardiovascular system earned the Nobel Prize in 1998. Nitrous oxide has also been found to play an important role in a variety of physiologic processes and has surprisingly been found to have very high concentrations in the nasal airway and the paranasal sinuses. Nitrous oxide has been shown to provide first line defense against micro-organisms through its anti-viral and anti-microbial activity as well as its up regulation of ciliary motility. Nitrous oxide concentrations are actually increased from normal in chronic airway inflammation such as allergic rhinitis or asthma but are decreased in cystic fibrosis, chronic sinusitis and nasal polyposis. This may be due to the mechanical obstruction of the sinuses, either from the polyp or the inspissated secretions. In all cases, decreased nitrous oxide favored mucociliary dysfunction and thus participates in the chronic infections. Implications in the possible use of nitrous oxide in cystic fibrosis are still not well understood though.

The remainder of this talk will focus on the sinonasal aspects of CF as they relate to ENT. This comes in two forms: chronic sinusitis with or without nasal polyposis. Before we talk about the sinuses, let’s first discuss other possible ENT manifestations. It may seem intuitive that with such bad sinus disease the middle ear, which is in communication with the nasopharynx, would also be affected in CF. However, numerous studies have been done which show no evidence that CF is associated with an increased prevalence of middle ear disease. CT studies have shown that the pneumatization of the temporal bone is normal in CF patients. The mucosal changes seen in the sinuses do not appear to affect the mucosa of the middle ear. Adenotonsillitis does not appear to differ from that of age matched cohorts. Submandibular gland enlargement is occasionally encountered but routine removal is not recommended and there is no increase in the incidence of laryngeal problems either.

Although the true incidence is not known, it is commonly accepted that the vast majority of CF patients develop sinus disease at some time in their life. Ages 5-14 are when sinus symptoms usually begin. Here we see the age distribution of chronic sinusitis and nasal polyposis in CF. Because of this chronicity of the disease however, patients may adapt to the symptoms and therefore, underreporting of nasal and sinus symptoms are relatively common. Hui and associates, in a study of 84 CF patients found nasal obstruction and coughing to be the most common symptoms. These were followed by nasal drainage, postnasal drip, poor quality of sleep, headaches and hyposmia. In a prospective study in Missouri Children’s Hospital, the most common symptom was again nasal obstruction followed by purulent rhinorrhea, headache, anosmia, limitation of activity, facial pain, snoring and hoarseness. Age seems to influence the symptoms that are expressed. Most children complain of nasal obstruction, purulent rhinorrhea or postnasal drainage, mouth breathing, halitosis and snoring. Most adult CF patients complain of headache and facial pain. On physical exam, congestion of the turbinates is seen and secretions in 60% of cases. Younger patients often have purulent nasal drainage and posterior pharyngeal edema. Nasal polyposis is reported anywhere from 6% to 48%. Polyposis is usually multiple and bilateral as seen in these endoscopic images.

CF usually presents early in life. Eighty-five percent are diagnosed by age five with either pulmonary or GI manifestations and are referred to ENT already with the diagnosis. However, nasal polyps are rare in non-CF patient children and their presence should alert the physician to test for CF in a child without the previous diagnosis.

It is now understood that both the electrophysiology and microbiology of the upper respiratory tract is similar to that of the lower respiratory tract as well. It’s the electrophysiologic changes that likely contribute to the compromise of airway immunity, allowing specific organisms such as Pseudomonas to thrive by compromising local airway immunity. Obstruction of sinuses secondary to thick and often compacted mucus contributes to the pool of organisms throughout the respiratory tree. It is postulated that organisms are aerosolized and inhaled into the lower respiratory tract with each breath. Further colonization occurs with postnasal drip. Clinically, it seems that aggressive sinus clearance techniques reduce bacterial colonization as well as reduce the frequency of pulmonary exacerbations. However, studies have shown that there is no improvement in the pulmonary function of these patients, as seen in this table here, where FEV-1 is not improved after ESS. However, currently lung transplant centers routinely advocate ESS prior to lung transplant.

The diagnosis of CF is primarily based on medical history, recognition of the clinical features previously discussed and it is confirmed with appropriate laboratory testing. More than 85% of new patients are diagnosed by the age of five years. There are three diagnostic tools currently accepted for making a diagnosis of CF: sweat chloride testing, DNA analysis and measurement of the nasal potential difference. The sweat chloride test, also known as quantitative pilocarpine iontophoresis, is the gold standard for diagnosis. Sweat is collected and the chloride concentration measured. A result of greater than 60 mm of chloride per liter of sweat is diagnostic of CF. The second useful diagnostic test is DNA analysis or genotyping. Mutation analysis is highly specific but not sensitive since there are about 700 identified CF mutations. With the standard gene mutation testing kit, only 8% to 85% of CF alleles are currently being detected. There is a new kit now identifying more than 70 of the most common alleles but it is still not widely available. The sensitivity of this test reaches 92% for Caucasians, 97% for Ashkanazi Jews and 61% for African Americans. The third accepted diagnostic test is the measurement of the nasal potential difference. Transport by ions across the nasal epithelial cells generates a trans-epithelial potential difference that can be measured in vivo. Abnormalities of the ion transport in the respiratory epithelia of patients with CF are associated with a different pattern of nasal potential difference when compared to normal subjects. There are three characteristic features: The basal potential difference is raised reflecting enhanced sodium transport across the chloride and permeable barrier. Infusion of amiloride as sodium channel inhibitor will show larger inhibition of the potential difference than normal, reflective of inhibition of accelerated sodium transport. No change in potential difference in response to perfusion of chloride free solution reflects the absence of CFTR media chloride secretion. Testing for potential difference is not widely available and should only be done at accredited CF centers.

Colonization of the sinuses with the distinct set of bacteria is commonly seen in CF. It is usually accepted that any pathogen found in the upper respiratory tract is present in the lower tract and vice versa. A study from 1982 reported the three most common pathogens as Pseudomonas, Haemophilus influenzae and streptococci. More recent studies have also included Staph aureus, Acetobacter and stenotromophomonas mortafala. Non-bacterial islets are also commonly isolated from CF patients. Aspergillus is found in trans-antral aspirates in up to 40% of adult CF patients; however, the presence of Aspergillus almost universally represents colonization rather than active infection and, despite the impairment of natural clearance of the sinuses, patients with CF do not seem to be more susceptible to common viral upper respiratory infections than their unaffected siblings. During the last decade the widespread use of CT has allowed a clear description of the sinus anatomy in CF. A classic triad of findings has been described: hypoplasia or agenesis of the frontal and sphenoid sinuses; medial displacement of the lateral nasal wall; and, marked maxillo-ethmoid sinus opacification. Hypoplasia or decreased pneumatization of the frontal and sphenoid sinuses is seen in many CF patients. Pneumatization of these sinuses does not usually occur until the age of two years. Chronic inflammation in the mucosa leads to disturbances in the ventilation and drainage during this crucial growth phase and therefore, abnormal growth, a lack of frontal sinuses and sphenoid sinuses. CF patients classically have demineralization of the uncinate process with medial displacement of the lateral nasal wall as seen in these two scans here. It is hypothesized that pressure is exerted by the polyps or inspissated mucus against the thin bone of the medial sinus wall with demineralization and mucocele-like formation although true mucoceles are relatively rare in CF. And finally, maxillary and ethmoid sinus opacification are seen in approximately 90% of CF patients.

In a study done here at Baylor, they compared maxillary sinus volume in CF, chronic sinusitis and normal subjects. They found that maxillary sinus volume increased with advancing age in both the control and chronic sinusitis group but not in the CF group whose maxillary sinus development seems to be arrested.

The histopathology of CF nasal polyps has been shown to be different from that of the atopic nasal polyp counterparts. Grossly, CF and atopic polyps are not distinguishable. They both have a shiny glistening appearance and are tan-white and mucoid. Oppenheimer in 1979 did describe three histologic features that differentiated CF polyps from atopic polyps. They first recognized that CF polyps have a delicate, barely visible basement membrane of surface epithelium without submucosal hyalinization. Here, in the atopic polyp seen on the right, a dense basement membrane is seen and hyalinization of the submucosal, while these characteristic findings are not visible in the CF polyp here. Second, the atopic polyp has a high concentration of eosinophils, which the CF polyp does not have. Finally, in the CF polyp there is a preponderance of acid mucin in the glands and cysts of the polyp in its surface mucous blanket. This acidity shows up as a blue stain with the alcion blue periodic acid shift stain. However, mucous secretions in atopic polyps are mainly neutral and stain red.

There is no clear-cut consensus on the treatment of CF related sinusitis. However, aggressive medical and surgical approaches to sinus disease in CF are generally advocated.

In general, the initial management should begin with medical treatment consisting of a number of options, the most important of which are antibiotics and nasal steroids. Prospective studies on the efficacy of pharmacological therapy are needed as current treatment is primarily empiric. The surgical treatment includes endoscopic ethmoidectomy, antrostomy with or without Caldwell-Luc and sinus catheter placement. Given the high bacterial load in CF sinuses, antibiotic therapy is a logical first step.

Empiric antibiotics should be taken into consideration, the array of CF pathogens, especially Pseudomonas coverage. Nasal swabs, trans-antral aspirates and sputum cultures can identify infecting organisms and give you sensitivities that can direct your antibiotic choice. Route of delivery can be p.o. or IV. Nasal steroids have been shown to have a therapeutic effect in chronic sinusitis in non-CF patients and have been used for their anti-inflammatory properties in CF patients with a variable response. Nasal steroids are reported to cause nasal polyps to diminish in size and regress. Prophylactic use also seems to help to prevent further polyp formation. Although there is no controlled trial to evaluate these claims, anecdotally it seems that this has been shown in the clinical setting. Nasal steroids are currently recommended as a first line therapeutic agent, especially in non-surgical candidates. Some patients derive symptomatic relief from using saline to flush the nose. Relief comes from mechanical clearance of thick mucus by hydration of the secretions. It may also decrease nasal blood flow with a resultant decongestant effect. Despite widespread use, there is no study to establish the efficacy of such practice. Finally, the use of antibiotic sprays, such as Tobramycin, is also advocated, especially in conjunction with sinus surgery.

The most innovative current therapy under investigation for CF sinusitis is the recombinant human Deoxyribonuclease I or Dornase Alpha. It’s a human enzyme responsible for the digestion of extracellular DNA. In CF, extracellular DNA is released by leukocytes within the airway in response to chronic bacterial infections. Dornase alpha delivered by aerosol has been shown to reduce the viscoelasticity of the mucus, reduce adhesiveness and improve the muco-ciliary transport. Dornase alpha treated patients have less mucosal edema and no polyps at serial exam over three years when compared to non-Dornase Alpha treated patients. They also had fewer revision ESS procedures and overall improvement in the quality of their life. But there was no change in the pulmonary function. A prospective study is needed to determine the medical efficacy of this new drug.

At least 10%-20% of CF patients will end up undergoing sinus surgery at some point in their life. No clear guidelines have been established for surgical indication in CF.

Surgical treatment should be considered in patients with persistent nasal obstruction or drainage, persistent headaches, infections and those awaiting lung transplantations. Data has also shown the need for surgery in patients with worsening pulmonary problems with subjective increase in nasal symptoms. Nishioka et al reported the indications for surgery as nasal obstruction associated with polyposis; medialization of the lateral nasal wall; facial pain or persistent headaches that have no other apparent cause and which adversely affect quality of life; and, pulmonary exacerbations that appear to correlate with sino-nasal disease. Deciding when to do surgery is complicated by a number of factors. First, mucosal thickening and opacification in CF is nearly universal, making radiographic determination nearly impossible. Second, self-reported symptoms do not correlate well with physical findings in CF. And finally, the underlying disease process remains unaltered, regardless of medical or surgical management.

Endoscopic ethmoidectomy and antrostomy are currently advocated. Studies have shown that the addition of antibiotic and saline flushed through sinus catheters significantly decreased the swelling and increased aeration of the sinuses. The catheter is placed under direct observation into the maxillary sinus. In an uncontrolled study of 37 subjects, all of whom had ESS and lavaged with Tobramycin, reported clinical improvement in nasal symptoms as well as an improved sense of well being. With or without Caldwell-Luc, recurrence rates are reduced to 45%-60%. In another study, the recurrence rates were 50% at two years, but patients did report significant initial improvement in nasal symptoms of obstruction and drainage. ESS has not been shown to decrease lung disease or the number of hospitalizations. In a study by Madonna et al, measuring FEV-1, pre and post ESS revealed no significant improvement in pulmonary function; however, there is a marked decline in nasal obstruction, nasal discharge and postnasal drip along with a high level of patient satisfaction, as can be seen in these graphs. Sinus complaints dropped significantly postoperatively and quality of life seems to improve. Most recent reviews have shown ESS to be a safe procedure for the treatment of chronic sinusitis and polyposis. Complication rates are equivalent to the general population undergoing ESS. Most surgeons do try to limit the length of time of the procedure due to an increased risk of atelectasis from the pulmonary disease. However, a retrospective review revealed no increase in the complications related to anesthesia time.

Gene therapy is considered to be the wave of the future for CF and is ultimately the best solution. CF is an attractive model for gene therapy in general as it’s a single autosomal gene defect and only a single copy of the normal gene would correct this defect. In a phase I clinical trial, the CFTR gene was delivered to the epithelium of the maxillary sinus using the adeno-associated virus vector, a single strand of DNA parvo virus. They found that the AAV CFTR was delivered to the maxillary sinus epithelium in a safe, successful dose-dependent gene transfer. The correction of the potential difference suggested a functional effect and reduced recurrence of sinusitis by 45% in the first month with little or no host-immune response. Phase I trials have also been completed showing that the aerosolized AAV is safely and widely delivered to the bronchial tree as well. Phase II trial results should be out this year and will determine the clinical efficacy of the AAV gene therapy.

Sinus disease is almost universally seen in CF. Chronic sinusitis and nasal polyposis are common ENT manifestations of the disease. Overall survival of CF patients is increasing the number of children arriving to adulthood and therefore increasing the frequency with which otolaryngologists encounter the disease. Many medical and surgical therapies reduce morbidity in CF patients although much remains unknown about the ideal therapeutic management. And finally, new innovations in medicine and advances in gene therapy promise to be the next frontier for CF treatment.

Case Presentation:

C.J. is a 9-year-old white male who was referred to the ENT clinic at Ben Taub for chronic sinusitis. He had a history of childhood asthma refractory to standard treatment with multiple exacerbations and a previous hospitalization for severe bronchitis. The primary complaint at ENT presentation was chronic nasal drainage, sometimes purulent, sometimes clear, as well as difficulty breathing through his nose. He had been diagnosed with acute sinusitis by multiple pediatricians and had been given antibiotic with some relief. He reported mild occasional headaches, denied facial pain, problems with olfaction, or problems sleeping. He denied cough, however, was recovering from a URI with cough from a month ago. He had no other medical problems and reported no past surgical history.

Physical exam revealed normal height and weight for age. His tympanic membranes were clear bilaterally without evidence of effusion. Nasal exam revealed congested mucosa, but not active purulence. There was evidence of nasal polyp on the right, which on further exam with the flexible scope revealed small nasal polyps, and one nasal polyp on the left. There was no evidence of septal deviation. Oropharynx was remarkable only for 1 +tonsillar hypertrophy, his posterior pharynx was clear. Neck exam revealed no LAD, and no masses. His lung fields were clear to auscultation bilaterally.

He was started on nasal steroids and nasal saline. A diagnosis of cystic fibrosis was suspected in the patient, and he was referred to Texas Children’s Hospital for further diagnostic work-up including sweat chloride testing. However, the patient was lost to follow-up.

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