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Cystic fibrosis: An update for the otolaryngologist
REVIEW ARTICLE Cystic fibrosis: An update for the otolaryngologist DAVID J. HALVORSON, MD, Birmingham, Alabama
Cystic fibrosis (CF) is an autosomal recessive disorder affecting exocrine gland function. Formerly a deadly disease of infants and children, recent improvements in antibiotics, nutritional therapy, and supportive care have extended the median survival to adulthood. Patients with CF commonly go to an otolaryngologist with a myriad of medical and surgical problems. Fortunately, the treatment and management of CF have rapidly evolved during the past few years, and changes in diagnosis, prevention, and treatment are occurring almost daily. As physicians on the forefront of care for patients with CF, otolaryngologists need to be aware of the new developments in the management of CF. An overview of CF is presented with an emphasis on the current treatment strategy and what the next decade brings for this formerly lethal disease. (Otolaryngol Head Neck Surg 1999;120:502-6.)
Cystic fibrosis (CF) is an autosomal recessive disease frequently encountered by the otolaryngologist. The most commonly inherited disease of individuals of Anglican descent, CF primarily affects exocrine gland function, resulting in a shortened life span. Although the dominant clinical features of CF are pancreatic insufficiency and progressive bronchiectasis, otolaryngologists are often consulted for symptoms within the head and neck region. Understanding of the current concepts in diagnosis, the natural history of involvement in affected organs, and new management protocols is critical to extending the median life span of these patients in addition to improving the quality of life. The design of this article is to review the most up-to-date methods of diagnosis, management, and treatment of patients with CF as the disease relates to an otolaryngologist. In
From the Department of Surgery, Division of Otolaryngology, University of Alabama at Birmingham. Reprint requests: David J. Halvorson, MD, Department of Surgery, Division of Otolaryngology, 1501 5th Ave South, University of Alabama at Birmingham, Birmingham, AL 35233. Copyright © 1999 by the American Academy of Otolaryngology– Head and Neck Surgery Foundation, Inc. 0194-5998/99/$8.00 + 0 23/76/92379 502
addition, new concepts in treatment and current status in therapeutic advances are discussed. EPIDEMIOLOGY
CF affects approximately 30,000 individuals in the United States as of 1992.1 The carrier rate in the white population approximates 5%, and estimates are that more than 7 million persons are symptom-free carriers of CF.2,3 Since identification in 1938, CF has progressed from a rapidly progressive lethal disease in infants to a chronic disorder affecting multiple organ systems. The current median age of survival for patients with CF approaches 30 years, and half of all patients with CF are older than 18 years.3 Recent estimates have projected a median survival of longer than 40 years for children born in the United States in 1990 who are receiving standard therapy.4 Although the disease still imposes significant limitations on many patients, current treatment is focused on prevention of the lethal complications of CF. In 1989 the CF gene was identified as a defect in the long arm of chromosome 7.5-7 The mutation results in abnormal production of a transmembrane regulatory protein termed CFTR, which results in abnormal chloride ion transport. The abnormal function of the cyclic adenosine monophosphate–regulated chloride channel results in the accumulation of thick, viscous mucus that is associated with the progressive obstruction, scarring, and destruction of excretory ducts. CFTR is expressed in all epithelial cells affected by CF, including lung, pancreas, sweat gland, and liver cells. In addition, CF is a remarkably heterogeneous disease with great variation between genotype and phenotype. DIAGNOSIS
The diagnosis of CF is primarily based on medical history, recognition of clinical features, and appropriate laboratory tests. More than 85% of new patients with CF have their disease diagnosed by 5 years of age.8 Early diagnosis is extremely important to initiate appropriate treatment and delay disease progression as much as possible. Pulmonary and gastrointestinal symptoms often present in infancy as chronic cough, recurrent pneumonia, and failure to thrive. Any child with nasal polyposis should be evaluated for CF.
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If a patient has signs and symptoms suspicious for CF, a test for abnormal electrolyte concentrations in sweat is nearly always the first laboratory test to be performed. Concentrations of sweat chloride greater than 60 mmol/L are considered diagnostic of CF.9 Direct DNA analysis is now available for at-risk CF gene carriers. In addition, prenatal diagnosis can also be performed on chorionic villus material at 10 to 12 weeks of pregnancy with direct DNA testing. PATHOPHYSIOLOGY OF DISEASE Paranasal Sinuses
Recurrent sinusitis is universal in patients with CF, and radiographic evidence of chronic sinusitis may be present in more than 90% of patients.10 Nasal polyposis has been reported to range from an incidence of 6% to 67%, and the variability is probably related to that of previous reports focusing only on the pediatric population and the recent introduction of newer endoscopic techniques.10-14 Initially thought to be rare in adults,15 nasal polyposis in adults with CF is recognized increasingly. The pathophysiology of associated polyposis has not been completely elucidated, but pathologic changes of the lateral nasal wall has been documented in up to 57% of patients with CF.16 The polyps identified in patients with CF are similar to allergy-related polyps but differ in a normal basement membrane and few eosinophils.17 The cause of sinus disease in patients with CF is related to altered properties of mucous secretions and impaired mucociliary transport through the natural ostia.14,18 Obstruction is followed by ciliary injury, mucosal edema, and further inflammation. Chronic colonization occurs, which only further exacerbates mucosal swelling. Colonization mirrors that of the lower respiratory tract with principally Pseudomonas species, Staphylococcus aureus, and nontypable Haemophilus influenzae. The most common presenting symptoms are chronic nasal congestion and purulent drainage. Young patients and their parents also relate mouth breathing, snoring, morning cough, and chronic throat clearing.19 In addition, headaches are often common in adult patients. Patients with CF also report anosmia or hyposmia that is usually related to chronic sinus disease. The physical findings vary but are primarily related to purulent drainage and mucosal changes resulting in nasal obstruction. Other physical findings include swollen turbinates and lymphoid hyperplasia in the posterior pharynx. In addition, polyps are frequently encountered with both anterior rhinoscopy and endoscopy. Tenderness on palpation of the sinuses has been noted to be a rare finding.19
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Virtually all patients with CF have abnormal findings on plain films of the paranasal sinuses. With CT scanning, mucosal thickening and hypoplasia of the ethmoid and maxillary sinuses are commonly encountered. The early development of chronic sinusitis leads to poor pneumatization of the sinuses and results in hypoplasia of maxillary and ethmoid sinuses demonstrated on CT.20 In addition, radiographic evidence of a frontal sinus is rare in patients with CF, which again is thought to be related to the early development of chronic sinusitis. Medial displacement of the lateral nasal wall into the middle meatus, uncinate process demineralization, and increased attenuation of the maxillary sinuses on CT are all common findings in patients with CF.21 The initial management of sinusitis in patients with CF is medical and uses a combination of oral antibiotics and nasal steroids, although the effectiveness of different regimens is unclear. Bacterial colonization in patients with CF is predominated by Pseudomonas aeruginosa, H influenzae, and anaerobes. The initial antibiotics chosen should have significant activity against these organisms, although treatment should be for a minimum of 3 weeks because the response to antimicrobial therapy is suboptimal when compared with that of non-CF patients.19,22 The availability of a new generation of macrolide antibiotics (clarithromycin, azithromycin) allows for the empiric use of agents that are highly effective against both H influenzae and S aureus, achieving high tissue concentrations for several days and permitting relatively infrequent dosing. Antihistamines without a clear allergy component and decongestants are of little value and may lead to thickening of mucous secretions. The decision to intervene surgically is based on the patient’s symptoms and understanding the chronicity of the disease. Although proved efficacious, surgical intervention does not have strict operative indications. The indications for management of chronic sinusitis, prevention of bacterial colonization, and maximization of therapy before the development of advanced CF have not been clearly defined. The most widely accepted criteria for operative intervention are a marked symptomatic increase in nasal obstruction and purulent drainage. Preliminary data suggest that one of the best indications for surgery is worsening pulmonary function testing coupled with increasing subjective symptoms.23 The primary goal of surgery is improvement in the nasal airway and removal of chronically infected mucosa. The combination of chronic disease, nasal polyposis, and altered anatomy makes surgery even more difficult in adult CF, and any intervention should be considered carefully. Many different operative procedures have been
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reported to treat sinusitis in the CF patient,22,24-30 although most reports have focused on children and are primarily retrospective in nature. The biggest benefit of surgical intervention appears to be a decrease in nasal obstruction, postnasal drainage, and purulent nasal discharge.30 Restoration or improvement of smell with surgical intervention has been documented and may have significant implications for nutrition because the sense of smell often enhances the appeal of foods. To date, no report has documented a complete resolution of sinusitis after surgery in patients with CF, and the widely held belief is that sinusitis is not a curable aspect of CF. Long-term results are unsuccessful because of the inability to clear mucus and the resultant chronic bacterial infection.22,24-30 Limited and conflicting data are available on the effect of sinus surgery on pulmonary status. Previous retrospective reports have focused on a positive benefit on pulmonary function after endoscopic sinus surgery in adults,21,31 whereas others have noted no significant change in children.32 Prospective trials are under way to better define the benefit of endoscopic sinus surgery on pulmonary function. The use of endoscopic sinus surgery has greatly improved the surgeon’s ability to establish a widely patent middle meatus and affords meticulous postoperative care. The advent of endoscopic techniques has increased the symptom-free interval and allows more complete postoperative management.24,26,28 In addition, significant improvement has been seen with topical irrigation of tobramycin (80 mg in 250 mL of normal saline solution), by use of a once- or twice-daily regimen combined with aggressive saline irrigation. Optimal operative treatment should be directed at removal of polyps and chronic inflammation with preservation of normal anatomic landmarks while providing greater access for cleaning and irrigation, which is considered as important as the surgical procedure. Otologic
Involvement of the ear in CF has been investigated, and the early results are conflicting. The reported percentage of patients with middle ear disease ranges from 8% to 39%.33-36 Most studies have been limited by lack of a control group, and when a control group was present, ear disease was the same as that of age-matched controls.37,38 Auditory brain stem responses in patients with CF compared with those in controls did not identify a significant loss of hearing.39 In addition, the degenerative mucosal changes evident in mucous glands or goblet cells throughout the respiratory tract are not present in middle ear mucosa.40 The apparent sparing of the middle ear space from the widespread respiratory tract damage appears to result in the finding of normal hear-
ing and minimal middle ear disease in patients with CF compared with the general population. Antibiotic treatment of otitis media in children with CF does not differ from that of the general population. Pharyngeal
The clinical presentation of adenotonsillitis in patients with CF does not appear to differ from that of the general population in incidence or presentation. Adenoid removal is recommended when enlargement results in significant nasal obstruction or interferes with eustachian tube function. Tonsillectomy is recommended for only recurrent tonsillitis or clinically significant obstructive sleep apnea. Submandibular enlargement is occasionally encountered as a result of intermittent duct obstruction associated with exocrinosis. Routine removal of enlarged submandibular glands is not recommended. An increased incidence of upper respiratory illnesses such as croup or epiglottitis has not been reported. An increased incidence of laryngomalacia also has not been demonstrated, although infants with CF more often appear to have an infantile larynx and an omega-shaped epiglottis.41 Respiratory
Although patients with CF do not generally go to an otolaryngologist for the management of pulmonary complications, a firm understanding of the critical interaction of the upper and lower respiratory systems and the relationship between infection, colonization, and concomitant disease is crucial to properly treat patients with CF. Unfortunately, the vast majority of patients with CF die of respiratory failure. Therefore the aggressive control of respiratory tract infections and promoting mucus clearance is essential to patient survival. The fundamental feature of CF, bronchitis followed by bronchiectasis, results in airflow obstruction and the stasis of mucus. Chronic colonization of Pseudomonas species, S aureus, and nontypable H influenzae occurs and may progress to end-stage pulmonary disease followed by respiratory failure. Overwhelming infection, pneumothorax, and cor pulmonale all complicate endstage disease. The standard cornerstones of respiratory disease intervention, chest physiotherapy and bronchodilators, are perhaps most important in decreasing the rate of progression of pulmonary involvement of CF. Attempting to break the cycle of sinus and pulmonary infections may increase the life span of patients with CF. The recognition that pulmonary exacerbations appear to correlate with sinonasal disease exacerbation is critical for the otolaryngologist to understand, and the observation of worsening pulmonary status or activity
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level coupled with symptomatic sinus disease indicates a need for operative intervention. Worsening respiratory status despite appropriate medical therapy may indicate a need for intervention in the sinobronchial cycle. Typically, surgical intervention will follow intensive respiratory medical management in the same inpatient hospital admission. NEW THERAPY ADVANCES Overview
The present and future seem bright for patients with CF. Significant resources and scientific endeavors have been put forth to correct the basic defect in CF, and progress is being made. Current investigations include drug therapy to modify abnormal electrolyte and water transport across the airway mucosal epithelium. In addition, efforts are under way to modify the physicochemical properties of the abnormal viscous airway secretions.42 Lung Transplantation
Combined heart-lung transplantation and double lung transplantation have emerged as a therapeutic intervention for terminal CF. CF does not appear to recur in transplanted lungs, and the greatest risk is immunosuppression and secondary sepsis. The reported success rate varies between 42% and 80%.43-45 Prophylactic sinus surgery followed by repeated irrigation has been advocated before heart-lung transplantation.29,46 Although limited to advanced disease, transplantation is a viable option, and reducing paranasal colonization before transplantation appears to be a worthwhile endeavor. Pharmacotherapy
Most innovative therapy currently under investigation addresses the high viscoelasticity of CF sputum. Recombinant human deoxyribonuclease I (rhDNase or Pulmozyme) has been shown to reduce viscoelasticity, reduce adhesiveness, and improve mucociliary transportation in phase II and III trials.47 The greatest benefit appears to be in improving the quality of life. The delivery method is through aerosol administration, and the side effects appear to be minimal. Ultrasonic nebulizers enable a greater drug concentration and efficacy. The routine use ultrasonic nebulizers appears to improve pharmacotherapeutic intervention. In addition, agents that act on the airway epithelium to alter airway epithelium ionic fluxes, such as amiloride and uridine 5´-triphosphate, are currently in phase III trials. Amiloride reduces the absorption of sodium and water and may result in less viscosity and easier cleared secretions.48 Uridine 5´-triphosphate increases chloride
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secretion in CF cells and enhances peripheral lung mucociliary clearance in adults with CF.49 Also, shortterm aerosol administration of a high dose of tobramycin has been demonstrated to be efficacious in endobronchial infections with Pseudomonas species. Future
Corrective gene therapy may be the ultimate interventional therapy, and further advances in immunereaction inhibition and correction of ion flux disturbances are on the horizon. Fundamental gene therapy is based on the transfer of normal CFTR into CF epithelial cells. The challenge has been to develop a gene-transfer system that can safely and effectively introduce the normal CF gene into sufficient numbers of airway epithelial cells. A variety of biologic vectors have been evaluated, and the most promising appear to be recombinant adenovirus, adeno-associated viruses, and liposomes.50 Although gene therapy may eventually realize its full potential as a cure for CF lung disease, current clinical studies need to be evaluated for long-term efficacy and safety. The widespread use of gene therapy is still not in the immediate future. CONCLUSION
CF is a complex disease with multiple affected organs. The otolaryngologist frequently encounters patients with CF, and a thorough understanding of the current treatment strategies and management protocols is essential to properly treat and improve the overall survival in patients with CF. Knowing the common aspects of CF seen within our specialty and understanding the current advances in treatment are important as otolaryngologists work with other health care workers to continue to improve the quality of life in patients with CF. REFERENCES 1. Ramsey BW, Boat TF. Outcome measures for clinical trials in cystic fibrosis J Pediatr 1994;124:177-92. 2. Wood RE, Boat TF, Doershuk CF. Cystic fibrosis (state of the art). Am Rev Respir Dis 1976;113:833-78. 3. FitzSimmons SC. The changing epidemiology of cystic fibrosis. J Pediatr 1993;122:1-9. 4. Collins FS. Cystic fibrosis: molecular biology and therapeutic implications. Science 1992;256:774-9. 5. Rommens J, Iannuzzi M, Kerem B-S, et al. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science 1989;245:1059-65. 6. Riordan J, Rommens J, Kerem B-S, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 1989;245:1066-73. 7. Kerem B-S, Rommens J, Buchanan J, et al. Identification of the cystic fibrosis gene: genetic analysis. Science 1989;245:1073-80. 8. Patient registry 1993 annual data report. Bethesda (MD): Cystic Fibrosis Foundation; 1994. 9. Rosenstein BJ, Langbaum TS. Diagnosis. In: Taussig LM, editor. Cystic fibrosis. New York: Thieme, 1984. p. 85-114. 10. Neely JG, Harrison GM, Jerger JF, et al. The otolaryngologic
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11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30.
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aspects of cystic fibrosis. Trans Am Acad Ophthalmol Otolaryngol 1972;76:313-24. Cepero R, Smith RH, Catlin FI, et al. Cystic fibrosis—an otolaryngologic perspective. Otolaryngol Head Neck Surg 1987;97: 356-60. Leiberman A, Cole P, Corey M, et al. Otolaryngological and rhinomanometric findings in cystic fibrosis. Am J Rhinol 1991;5: 61-5. Magid SL, Smith CC, Dolowitz DA. Nasal mucosa in pancreatic cystic fibrosis. Arch Otolaryngol Head Neck Surg 1967;86:10610. Rulon JT, Logan GB. Nasal polyps and cystic fibrosis of the pancreas. Arch Otolaryngol Head Neck Surg 1963;78:192-9. Stern RC, Boat TF, Wood RE, et al. Treatment and prognosis of nasal polyps in cystic fibrosis. Am J Dis Child 1982;136:1067-70. Brihaye P, Clement PAR, Dab I, et al. Pathological changes of the lateral nasal wall in patients with cystic fibrosis (mucoviscidosis). Int J Pediatr Otorhinolaryngol 1994;28:141-7. Oppenheimer EH, Rosenstein BJ. Differential pathology of nasal polyps in cystic fibrosis atopy. Lab Invest 1979;40:455-9. King V. Upper respiratory disease, sinusitis and polyposis. Clin Rev Allergy 1991;9:143-58. Ramsey B, Richardson MA. Impact of sinusitis in cystic fibrosis. J Allergy Clin Immunol 1992;90:547-52. Ledesma-Medina J, Ozman MZ, Girdany BR. Abnormal paranasal sinuses in patients with cystic fibrosis of the pancreas. Pediatr Radiol 1980;9:61-4. April MM, Zinreich SJ, Baroody FM, et al. Coronal CT scan abnormalities in children with chronic sinusitis. Laryngoscope 1993;103:985-90. Cuyler JP, Monaghan AJ. Cystic fibrosis and sinusitis. J Otolaryngol 1989;18:173-5. Halvorson DJ, Dupree JR, Porubsky ES. Management of chronic sinusitis in the adult cystic fibrosis patient. Ann Otol Rhinol Laryngol 1998;107:946-52. Duplechain JK, White JA, Miller RH. Pediatric sinusitis. the role of endoscopic sinus surgery in cystic fibrosis and other forms of sinonasal disease. Arch Otolaryngol 1991;117:422-6. Parsons DS. Sinusitis and cystic fibrosis. In: Lusk RP, editor. Pediatric sinusitis. New York: Raven Press; 1992. p. 65-70. Cuyler JP. Follow up of endoscopic sinus surgery on children with cystic fibrosis. Arch Otolaryngol 1992;118:505-6. Crockett DM, McGill TJ, Healy GB, et al. Nasal and paranasal sinus surgery in children with cystic fibrosis. Ann Otol Rhinol Laryngol 1987;96:367-2. Jones JW, Parsons DP, Cuyler JP. The results of functional endoscopic sinus (FES) surgery on the symptoms of patients with cystic fibrosis. Int J Pediatr Otorhinolaryngol 1993;28:25-32. Davidson TM, Murphy C, Mitchell M, et al. Management of chronic sinusitis in cystic fibrosis. Laryngoscope 1995;105:3548. Nishioka GJ, Barbero GJ, Konig P, et al. Symptom outcome after functional endoscopic sinus surgery in patients with cystic fibrosis: a prospective study. Otolaryngol Head Neck Surg 1995;113: 440-5.
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31. Umetsu DT, Moss RB, King VV, et al. Sinus disease in patients with severe cystic fibrosis: relation to pulmonary exacerbation. Lancet 1990;335:1078-80. 32. Madonna D, Isaacson G, Rosenfeld RM, et al. Effect of sinus surgery on pulmonary function in patients with cystic fibrosis. Laryngoscope 1997;107:328-31. 33. Kulczycki LL, Butler JS, McCord-Dickman D, et al. The hearing of patients with cystic fibrosis. Arch Otolaryngol 1970;92:54-9. 34. Forcucci RA, Stark EW. Hearing loss, speech-language, and cystic fibrosis. Arch Otolaryngol 1972;96:361-4. 35. Jerger JF, Neely JG. Audiometric testing. Arch Otolaryngol Head Neck Surg 1971;93:111-2. 36. Bak-Pedersen K, Kildegaard LP. Inflammatory middle ear diseases in patients with cystic fibrosis. Acta Otolaryngol 1979;360 (Suppl):130-40. 37. Cipolli M, Canciani M, Cavazzani M, et al. Ear disease is not a common complication in cystic fibrosis. Eur J Pediatr 1993;152: 265-6. 38. Haddad J, Gonzales C, Kurland G, et al. Ear disease in children with cystic fibrosis. Arch Otolaryngol Head Neck Surg 1994; 120:491-3. 39. Ozcelik T, Ozgirgin N, Ozcelik U, et al. Auditory nerve–brainstem responses in cystic fibrosis patients Int J Pediatr Otorhinolaryngol 1996;35:165-9. 40. Bak-Pedersen K, Larsen PK. Inflammatory middle ear diseases in patients with cystic fibrosis. Acta Otolaryngol Suppl (Stockh) 1979;360:138-40. 41. Kulczycki LL, Herer GR, Butler JS. Cystic fibrosis and hearing: integrity of the upper respiratory tract as related to hearing sensitivity. Clin Pediatr 1970;9:390-402. 42. Colton HR. Airway inflammation in cystic fibrosis [comment]. N Engl J Med 1995;332:886-7. 43. Frist WH, Campbell PW, Fiel SB, et al. Cystic fibrosis treated with heart-lung transplantation: North American results. Transplant Proc 1991;23:1205-6. 44. Fradet G, Smyth RL, Scott JP, et al. Cystic fibrosis: a new challenge for cardiothoracic surgery. Eur J Cardiothorac Surg 1990; 4:136-40. 45. Starnes VA, Lewiston N, Theodore J, et al. Cystic fibrosis target population for lung transplantation in North America in the 1990s. J Thorac Cardiovasc Surg 1992;103:1008-14. 46. Lewiston N, King V, Umetsu D, et al. Cystic fibrosis patients who have undergone heart-lung transplantation benefit from maxillary sinus antrostomy and repeated sinus lavage. Transplant Proc 1991;23:1207-8. 47. Shah PL, Hodsen ME. New treatment strategies in cystic fibrosis. Mondali Arch Chest Dis 1996;51:125-9. 48. Mylett J, Johnson L, Knowles M. Alternative therapies for cystic fibrosis. Semin Respir Crit Care Med 1994;15:426-33. 49. Bennett WD, Olivier KN, Zeman KL, et al. Acute effect of aerosolized uridine 5´-triphosphate (UTP) amiloride on mucociliary clearance in cystic fibrosis (CF) [abstract]. Am J Respir Crit Care Med 1994;149:A670. 50. Wilson JM. Prospects for gene therapy. In: Highlights. Bethesda (MD): Cystic Fibrosis Foundation; 1995. p. 20-2.
Cystic fibrosis (CF) is an autosomal recessive disorder affecting exocrine gland function. Formerly a deadly disease of infants and children, recent improvements in antibiotics, nutritional therapy, and supportive care have extended the median survival to adulthood. Patients with CF commonly go to an otolaryngologist with a myriad of medical and surgical problems. Fortunately, the treatment and management of CF have rapidly evolved during the past few years, and changes in diagnosis, prevention, and treatment are occurring almost daily. As physicians on the forefront of care for patients with CF, otolaryngologists need to be aware of the new developments in the management of CF. An overview of CF is presented with an emphasis on the current treatment strategy and what the next decade brings for this formerly lethal disease. (Otolaryngol Head Neck Surg 1999;120:502-6.)
Cystic fibrosis (CF) is an autosomal recessive disease frequently encountered by the otolaryngologist. The most commonly inherited disease of individuals of Anglican descent, CF primarily affects exocrine gland function, resulting in a shortened life span. Although the dominant clinical features of CF are pancreatic insufficiency and progressive bronchiectasis, otolaryngologists are often consulted for symptoms within the head and neck region. Understanding of the current concepts in diagnosis, the natural history of involvement in affected organs, and new management protocols is critical to extending the median life span of these patients in addition to improving the quality of life. The design of this article is to review the most up-to-date methods of diagnosis, management, and treatment of patients with CF as the disease relates to an otolaryngologist. In
From the Department of Surgery, Division of Otolaryngology, University of Alabama at Birmingham. Reprint requests: David J. Halvorson, MD, Department of Surgery, Division of Otolaryngology, 1501 5th Ave South, University of Alabama at Birmingham, Birmingham, AL 35233. Copyright © 1999 by the American Academy of Otolaryngology– Head and Neck Surgery Foundation, Inc. 0194-5998/99/$8.00 + 0 23/76/92379 502
addition, new concepts in treatment and current status in therapeutic advances are discussed. EPIDEMIOLOGY
CF affects approximately 30,000 individuals in the United States as of 1992.1 The carrier rate in the white population approximates 5%, and estimates are that more than 7 million persons are symptom-free carriers of CF.2,3 Since identification in 1938, CF has progressed from a rapidly progressive lethal disease in infants to a chronic disorder affecting multiple organ systems. The current median age of survival for patients with CF approaches 30 years, and half of all patients with CF are older than 18 years.3 Recent estimates have projected a median survival of longer than 40 years for children born in the United States in 1990 who are receiving standard therapy.4 Although the disease still imposes significant limitations on many patients, current treatment is focused on prevention of the lethal complications of CF. In 1989 the CF gene was identified as a defect in the long arm of chromosome 7.5-7 The mutation results in abnormal production of a transmembrane regulatory protein termed CFTR, which results in abnormal chloride ion transport. The abnormal function of the cyclic adenosine monophosphate–regulated chloride channel results in the accumulation of thick, viscous mucus that is associated with the progressive obstruction, scarring, and destruction of excretory ducts. CFTR is expressed in all epithelial cells affected by CF, including lung, pancreas, sweat gland, and liver cells. In addition, CF is a remarkably heterogeneous disease with great variation between genotype and phenotype. DIAGNOSIS
The diagnosis of CF is primarily based on medical history, recognition of clinical features, and appropriate laboratory tests. More than 85% of new patients with CF have their disease diagnosed by 5 years of age.8 Early diagnosis is extremely important to initiate appropriate treatment and delay disease progression as much as possible. Pulmonary and gastrointestinal symptoms often present in infancy as chronic cough, recurrent pneumonia, and failure to thrive. Any child with nasal polyposis should be evaluated for CF.
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If a patient has signs and symptoms suspicious for CF, a test for abnormal electrolyte concentrations in sweat is nearly always the first laboratory test to be performed. Concentrations of sweat chloride greater than 60 mmol/L are considered diagnostic of CF.9 Direct DNA analysis is now available for at-risk CF gene carriers. In addition, prenatal diagnosis can also be performed on chorionic villus material at 10 to 12 weeks of pregnancy with direct DNA testing. PATHOPHYSIOLOGY OF DISEASE Paranasal Sinuses
Recurrent sinusitis is universal in patients with CF, and radiographic evidence of chronic sinusitis may be present in more than 90% of patients.10 Nasal polyposis has been reported to range from an incidence of 6% to 67%, and the variability is probably related to that of previous reports focusing only on the pediatric population and the recent introduction of newer endoscopic techniques.10-14 Initially thought to be rare in adults,15 nasal polyposis in adults with CF is recognized increasingly. The pathophysiology of associated polyposis has not been completely elucidated, but pathologic changes of the lateral nasal wall has been documented in up to 57% of patients with CF.16 The polyps identified in patients with CF are similar to allergy-related polyps but differ in a normal basement membrane and few eosinophils.17 The cause of sinus disease in patients with CF is related to altered properties of mucous secretions and impaired mucociliary transport through the natural ostia.14,18 Obstruction is followed by ciliary injury, mucosal edema, and further inflammation. Chronic colonization occurs, which only further exacerbates mucosal swelling. Colonization mirrors that of the lower respiratory tract with principally Pseudomonas species, Staphylococcus aureus, and nontypable Haemophilus influenzae. The most common presenting symptoms are chronic nasal congestion and purulent drainage. Young patients and their parents also relate mouth breathing, snoring, morning cough, and chronic throat clearing.19 In addition, headaches are often common in adult patients. Patients with CF also report anosmia or hyposmia that is usually related to chronic sinus disease. The physical findings vary but are primarily related to purulent drainage and mucosal changes resulting in nasal obstruction. Other physical findings include swollen turbinates and lymphoid hyperplasia in the posterior pharynx. In addition, polyps are frequently encountered with both anterior rhinoscopy and endoscopy. Tenderness on palpation of the sinuses has been noted to be a rare finding.19
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Virtually all patients with CF have abnormal findings on plain films of the paranasal sinuses. With CT scanning, mucosal thickening and hypoplasia of the ethmoid and maxillary sinuses are commonly encountered. The early development of chronic sinusitis leads to poor pneumatization of the sinuses and results in hypoplasia of maxillary and ethmoid sinuses demonstrated on CT.20 In addition, radiographic evidence of a frontal sinus is rare in patients with CF, which again is thought to be related to the early development of chronic sinusitis. Medial displacement of the lateral nasal wall into the middle meatus, uncinate process demineralization, and increased attenuation of the maxillary sinuses on CT are all common findings in patients with CF.21 The initial management of sinusitis in patients with CF is medical and uses a combination of oral antibiotics and nasal steroids, although the effectiveness of different regimens is unclear. Bacterial colonization in patients with CF is predominated by Pseudomonas aeruginosa, H influenzae, and anaerobes. The initial antibiotics chosen should have significant activity against these organisms, although treatment should be for a minimum of 3 weeks because the response to antimicrobial therapy is suboptimal when compared with that of non-CF patients.19,22 The availability of a new generation of macrolide antibiotics (clarithromycin, azithromycin) allows for the empiric use of agents that are highly effective against both H influenzae and S aureus, achieving high tissue concentrations for several days and permitting relatively infrequent dosing. Antihistamines without a clear allergy component and decongestants are of little value and may lead to thickening of mucous secretions. The decision to intervene surgically is based on the patient’s symptoms and understanding the chronicity of the disease. Although proved efficacious, surgical intervention does not have strict operative indications. The indications for management of chronic sinusitis, prevention of bacterial colonization, and maximization of therapy before the development of advanced CF have not been clearly defined. The most widely accepted criteria for operative intervention are a marked symptomatic increase in nasal obstruction and purulent drainage. Preliminary data suggest that one of the best indications for surgery is worsening pulmonary function testing coupled with increasing subjective symptoms.23 The primary goal of surgery is improvement in the nasal airway and removal of chronically infected mucosa. The combination of chronic disease, nasal polyposis, and altered anatomy makes surgery even more difficult in adult CF, and any intervention should be considered carefully. Many different operative procedures have been
504
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reported to treat sinusitis in the CF patient,22,24-30 although most reports have focused on children and are primarily retrospective in nature. The biggest benefit of surgical intervention appears to be a decrease in nasal obstruction, postnasal drainage, and purulent nasal discharge.30 Restoration or improvement of smell with surgical intervention has been documented and may have significant implications for nutrition because the sense of smell often enhances the appeal of foods. To date, no report has documented a complete resolution of sinusitis after surgery in patients with CF, and the widely held belief is that sinusitis is not a curable aspect of CF. Long-term results are unsuccessful because of the inability to clear mucus and the resultant chronic bacterial infection.22,24-30 Limited and conflicting data are available on the effect of sinus surgery on pulmonary status. Previous retrospective reports have focused on a positive benefit on pulmonary function after endoscopic sinus surgery in adults,21,31 whereas others have noted no significant change in children.32 Prospective trials are under way to better define the benefit of endoscopic sinus surgery on pulmonary function. The use of endoscopic sinus surgery has greatly improved the surgeon’s ability to establish a widely patent middle meatus and affords meticulous postoperative care. The advent of endoscopic techniques has increased the symptom-free interval and allows more complete postoperative management.24,26,28 In addition, significant improvement has been seen with topical irrigation of tobramycin (80 mg in 250 mL of normal saline solution), by use of a once- or twice-daily regimen combined with aggressive saline irrigation. Optimal operative treatment should be directed at removal of polyps and chronic inflammation with preservation of normal anatomic landmarks while providing greater access for cleaning and irrigation, which is considered as important as the surgical procedure. Otologic
Involvement of the ear in CF has been investigated, and the early results are conflicting. The reported percentage of patients with middle ear disease ranges from 8% to 39%.33-36 Most studies have been limited by lack of a control group, and when a control group was present, ear disease was the same as that of age-matched controls.37,38 Auditory brain stem responses in patients with CF compared with those in controls did not identify a significant loss of hearing.39 In addition, the degenerative mucosal changes evident in mucous glands or goblet cells throughout the respiratory tract are not present in middle ear mucosa.40 The apparent sparing of the middle ear space from the widespread respiratory tract damage appears to result in the finding of normal hear-
ing and minimal middle ear disease in patients with CF compared with the general population. Antibiotic treatment of otitis media in children with CF does not differ from that of the general population. Pharyngeal
The clinical presentation of adenotonsillitis in patients with CF does not appear to differ from that of the general population in incidence or presentation. Adenoid removal is recommended when enlargement results in significant nasal obstruction or interferes with eustachian tube function. Tonsillectomy is recommended for only recurrent tonsillitis or clinically significant obstructive sleep apnea. Submandibular enlargement is occasionally encountered as a result of intermittent duct obstruction associated with exocrinosis. Routine removal of enlarged submandibular glands is not recommended. An increased incidence of upper respiratory illnesses such as croup or epiglottitis has not been reported. An increased incidence of laryngomalacia also has not been demonstrated, although infants with CF more often appear to have an infantile larynx and an omega-shaped epiglottis.41 Respiratory
Although patients with CF do not generally go to an otolaryngologist for the management of pulmonary complications, a firm understanding of the critical interaction of the upper and lower respiratory systems and the relationship between infection, colonization, and concomitant disease is crucial to properly treat patients with CF. Unfortunately, the vast majority of patients with CF die of respiratory failure. Therefore the aggressive control of respiratory tract infections and promoting mucus clearance is essential to patient survival. The fundamental feature of CF, bronchitis followed by bronchiectasis, results in airflow obstruction and the stasis of mucus. Chronic colonization of Pseudomonas species, S aureus, and nontypable H influenzae occurs and may progress to end-stage pulmonary disease followed by respiratory failure. Overwhelming infection, pneumothorax, and cor pulmonale all complicate endstage disease. The standard cornerstones of respiratory disease intervention, chest physiotherapy and bronchodilators, are perhaps most important in decreasing the rate of progression of pulmonary involvement of CF. Attempting to break the cycle of sinus and pulmonary infections may increase the life span of patients with CF. The recognition that pulmonary exacerbations appear to correlate with sinonasal disease exacerbation is critical for the otolaryngologist to understand, and the observation of worsening pulmonary status or activity
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level coupled with symptomatic sinus disease indicates a need for operative intervention. Worsening respiratory status despite appropriate medical therapy may indicate a need for intervention in the sinobronchial cycle. Typically, surgical intervention will follow intensive respiratory medical management in the same inpatient hospital admission. NEW THERAPY ADVANCES Overview
The present and future seem bright for patients with CF. Significant resources and scientific endeavors have been put forth to correct the basic defect in CF, and progress is being made. Current investigations include drug therapy to modify abnormal electrolyte and water transport across the airway mucosal epithelium. In addition, efforts are under way to modify the physicochemical properties of the abnormal viscous airway secretions.42 Lung Transplantation
Combined heart-lung transplantation and double lung transplantation have emerged as a therapeutic intervention for terminal CF. CF does not appear to recur in transplanted lungs, and the greatest risk is immunosuppression and secondary sepsis. The reported success rate varies between 42% and 80%.43-45 Prophylactic sinus surgery followed by repeated irrigation has been advocated before heart-lung transplantation.29,46 Although limited to advanced disease, transplantation is a viable option, and reducing paranasal colonization before transplantation appears to be a worthwhile endeavor. Pharmacotherapy
Most innovative therapy currently under investigation addresses the high viscoelasticity of CF sputum. Recombinant human deoxyribonuclease I (rhDNase or Pulmozyme) has been shown to reduce viscoelasticity, reduce adhesiveness, and improve mucociliary transportation in phase II and III trials.47 The greatest benefit appears to be in improving the quality of life. The delivery method is through aerosol administration, and the side effects appear to be minimal. Ultrasonic nebulizers enable a greater drug concentration and efficacy. The routine use ultrasonic nebulizers appears to improve pharmacotherapeutic intervention. In addition, agents that act on the airway epithelium to alter airway epithelium ionic fluxes, such as amiloride and uridine 5´-triphosphate, are currently in phase III trials. Amiloride reduces the absorption of sodium and water and may result in less viscosity and easier cleared secretions.48 Uridine 5´-triphosphate increases chloride
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secretion in CF cells and enhances peripheral lung mucociliary clearance in adults with CF.49 Also, shortterm aerosol administration of a high dose of tobramycin has been demonstrated to be efficacious in endobronchial infections with Pseudomonas species. Future
Corrective gene therapy may be the ultimate interventional therapy, and further advances in immunereaction inhibition and correction of ion flux disturbances are on the horizon. Fundamental gene therapy is based on the transfer of normal CFTR into CF epithelial cells. The challenge has been to develop a gene-transfer system that can safely and effectively introduce the normal CF gene into sufficient numbers of airway epithelial cells. A variety of biologic vectors have been evaluated, and the most promising appear to be recombinant adenovirus, adeno-associated viruses, and liposomes.50 Although gene therapy may eventually realize its full potential as a cure for CF lung disease, current clinical studies need to be evaluated for long-term efficacy and safety. The widespread use of gene therapy is still not in the immediate future. CONCLUSION
CF is a complex disease with multiple affected organs. The otolaryngologist frequently encounters patients with CF, and a thorough understanding of the current treatment strategies and management protocols is essential to properly treat and improve the overall survival in patients with CF. Knowing the common aspects of CF seen within our specialty and understanding the current advances in treatment are important as otolaryngologists work with other health care workers to continue to improve the quality of life in patients with CF. REFERENCES 1. Ramsey BW, Boat TF. Outcome measures for clinical trials in cystic fibrosis J Pediatr 1994;124:177-92. 2. Wood RE, Boat TF, Doershuk CF. Cystic fibrosis (state of the art). Am Rev Respir Dis 1976;113:833-78. 3. FitzSimmons SC. The changing epidemiology of cystic fibrosis. J Pediatr 1993;122:1-9. 4. Collins FS. Cystic fibrosis: molecular biology and therapeutic implications. Science 1992;256:774-9. 5. Rommens J, Iannuzzi M, Kerem B-S, et al. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science 1989;245:1059-65. 6. Riordan J, Rommens J, Kerem B-S, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 1989;245:1066-73. 7. Kerem B-S, Rommens J, Buchanan J, et al. Identification of the cystic fibrosis gene: genetic analysis. Science 1989;245:1073-80. 8. Patient registry 1993 annual data report. Bethesda (MD): Cystic Fibrosis Foundation; 1994. 9. Rosenstein BJ, Langbaum TS. Diagnosis. In: Taussig LM, editor. Cystic fibrosis. New York: Thieme, 1984. p. 85-114. 10. Neely JG, Harrison GM, Jerger JF, et al. The otolaryngologic
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