Cystic fibrosis can be a devastating, even fatal, disease; but proper diagnosis and new treatments, coupled with breakthroughs in gene replacement therapy, offer improved outcomes

Cystic fibrosis (CF) is a disease caused by an inherited genetic defect. In fact, it is the most common autosomal-recessive disease among white people, and it affects approximately 30,000 people in the United States, with an estimated 10 million asymptomatic carriers.1,2

CF affects tissues that produce mucus secretions, including the airway, gastrointestinal tract, ducts of the pancreas, bile ducts of the liver, and the urogenital tract. Hence, patients with CF suffer primarily from chronic lung problems and gastrointestinal disorders.

The lungs of people with CF become covered with a sticky mucus that is difficult to remove and promotes infection by bacteria. Many people with CF require frequent hospitalizations and continuous use of antibiotics, enzyme supplements, and other medications. The prognosis for people with CF used to be very poor, but it has improved considerably over the past few decades. In the 1960s, the mean survival age was about 6 years, compared with 16 years in 1970 and 30 years in 1990.3 Babies born with CF today may live for 30 to 40 years or more.4

Gastrointestinal disorders associated with CF include intestinal obstruction, pancreatic insufficiency, and biliary cirrhosis. Distal intestinal obstruction syndrome, which is a partial or complete obstruction due to abnormally viscous fecal material in the terminal ileum or cecum, is seen in many children with CF.

The CF Gene
For many years, the cause of CF was a mystery. Today, advances in genetics and molecular biology have made the cause more clear. In 1989, the gene responsible for CF, called cystic fibrosis transmembrane conductance regulator (CFTR), was discovered on chromosome 7.5. CFTR encodes a 1,480–amino acid protein with a molecular weight that varies from 140 to 170 kd.5 This protein controls the flow of chloride ions across the cell membrane. It also has roles in transporting water and small solutes, acidifying intracellular organelles, and regulating membrane sodium transport.6,7 Each CFTR gene is made up of two alleles; a single correctly encoded allele is adequate for normal protein production.

Because CF follows an autosomal-recessive inheritance pattern, a person can develop CF only if they have two defective CFTR alleles. Those with a single defective allele are carriers. A child must inherit a defective copy of the CF gene (one from each parent) to have CF. Each time two carriers conceive a child, there is a 25% probability that the child will have CF, a 50% probability that the child will be a carrier, and a 25% probability that the child will be normal (a noncarrier).

The classic mutation involved in CF causes the deletion of three of the base pairs in the CFTR gene.8 This, in turn, causes a loss in the CFTR protein of one amino acid (phenylalanine at position 508 of the protein chain). This mutant protein accounts for only 70% to 80% of all CF cases. There are more than 800 known gene mutations that can lead to CF. Differences in disease patterns observed in individuals and families probably result from the combined effects of a particular mutation and various, but still unknown, factors in the CF patient and their environment. The severity of symptoms varies, depending on the particular mutation. Generally, patients with milder symptoms live longer.

Despite the identification of CFTR, the link between the pathogenesis of pulmonary disease, inflammation, and abnormal CFTR has not been fully elucidated. CF alters the mucus secreted by the body’s epithelial cells. Epithelial cells make up the outside layer of tissue that lines every open surface of the body, inside and out, including the various tunnels and cavities in the lungs, urinary tract, liver, and reproductive tract. In patients with CF, the mucus that the epithelial cells secrete is much thicker and stickier than normal. It clogs the airways of the lungs, blocking the flow of air and making the tissue vulnerable to chronic lung infection.

During the past decade, several major hypotheses have emerged to explain the unique pulmonary manifestations of CF. These include impaired ciliary movement and mucus transport as a result of decreased surface airway liquid,9 increased binding of bacteria to airway epithelial cells,10,11 immune dysfunction,12 and dysregulation of the airway inflammatory response.13

Lung infection is the leading cause of morbidity and mortality in patients with CF.14 Chronic endobronchial infection accompanied by intense intraluminal infiltration of neutrophils may result in progressive bronchiectasis (see Figure, page 18) and obstructive pulmonary disease. Early in life, organisms that typically colonize the respiratory tract include Staphylococcus aureus and Haemophilus influenzae; later, Pseudomonas aeruginosa is a common pathogen.14-18 Recently, additional bacterial species have been identified that may chronically colonize the respiratory tract of patients with CF, including non-Pseudomonas gram-negative species (such as Burkholderia cepacia and Flavobacterium species), Stenotrophomonas maltophilia, Enterobacteriaceae (such as Escherichia coli and Serratia marcescens), and nontuberculous mycobacteria.14-18

Prenatal genetic testing can be used to determine whether an unborn baby has CF, although the testing is not foolproof, because many of the more than 800 different mutations that can lead to CF cannot be detected. Because prenatal genetic testing is expensive and carries some risk to the mother, not all women who are known CF carriers choose to have the tests done. Prenatal testing involves either amniocentesis or a chorionic villus biopsy.

The sweat electrolyte test (sweat chloride test) is the most common test for CF. It involves using pilocarpine and a mild electric current to make a part of the skin sweat, wrapping the area with plastic and a pad to absorb the sweat, and then collecting the sweat about 30 minutes later. The salt concentration of the sweat is then measured.

In children, a sweat chloride concentration of more than 60 mmol/L suggests the possibility of CF; in adults, CF is suspected if the sweat chloride concentration is greater than 80 mmol/L.19 A very small percentage of CF patients have normal salt levels in their sweat, in which case they must be genetically tested to determine the presence of the defective gene.

About 10% to 15% of all positive sweat tests are false positives19; there are many conditions unrelated to CF that can cause false-positive sweat test results. All positive tests should be repeated, usually the next day, and/or patients should be genetically screened.

In newborn infants who cannot produce enough sweat for a sweat test, an immunoreactive trypsinogen test (IRT) can be done. An IRT is a blood test that involves drawing blood a few days after birth and evaluating the presence of the protein trypsinogen. If the test is positive, it should be confirmed by genetic testing. The combination of an IRT and genetic testing is 90% to 100% sensitive in diagnosing CF.20,21

As sodium and chloride ions move across the membranes of the cells lining the airway, they generate an electric potential difference. In the nasal passages, this electric potential difference is known as the nasal potential difference (NPD), and it can be easily measured with a surface electrode.22 Because sodium and chloride transport is abnormal in CF patients, NPD measurements are very different in CF patients compared to people who do not have CF.23

NPD measurement is particularly helpful when the sweat electrolyte test and/or the genetic tests are inconclusive. The success of the test, however, is highly dependent on the skill of the technician and should be done at a specialized center.

Genetic testing, also known as a genotype test or mutation analysis, is designed to analyze DNA for the presence of one of the several hundred mutations that can cause CF. The test involves collecting a sample of the patient’s blood. The test cannot detect all of the mutations that can cause CF, however, so its sensitivity is only about 80% to 85%.24 Genetic testing cannot be used to predict the severity of symptoms. There is no way to know, based on a person’s genotype, whether CF will be mild, moderate, or fatal.

In general, genetic testing is performed if a patient’s sweat test is negative and there is still high suspicion that the patient has CF. Pulmonary function tests also may be performed to assess general lung function and whether a patient’s pulmonary status is sufficient to allow for lung transplantation, if it is needed.

Management of Pulmonary Disease
The emergence of specialized CF centers has led to improved recognition and management of this potentially devastating disease. The cornerstone of CF management is aggressive antimicrobial therapy, including identification and management of drug-resistant organisms. Additional therapeutic measures useful in the CF patient include clearance of abnormal secretions and, in dire cases, lung transplantation. A therapeutic modality currently being investigated is gene therapy.

In treating pulmonary exacerbations in patients with CF, the choice of antibiotic agents is based on the susceptibility of bacteria identified in the sputum. In children too young to cough up sputum, oropharyngeal cultures can be useful, but might not always accurately predict lower-airway pathogens. Accepted treatment of a pulmonary exacerbation consists of using two parenteral agents from different antibiotic classes in an effort to provide synergy and delay the emergence of drug resistance. Most commonly, a b-lactam agent with activity against P. aeruginosa, such as ticarcillin/clavulanate, piperacillin, or ceftazidime, and an aminoglycoside agent are selected.3 Antibiotics with activity against S. aureus and H. influenzae also are indicated when these organisms are isolated from the respiratory tract.3 B. cepacia is intrinsically resistant to all aminoglycosides, and many strains are also resistant to fluoroquinolone and  b-lactam antibiotics, but meropenem has the most activity against CF strains.25,26

A relatively new approach to antibiotic delivery in CF is the use of aerosolized antibiotics for inhalation. Advantages of this delivery system include the ability to achieve very high concentrations of antibiotics in the lung, which would otherwise be possible only with potentially significant systemic toxicity. The first inhaled antibiotic for the treatment of patients with CF, tobramycin solution for inhalation, was approved by the US Food and Drug Administration in 1998.27,28 Another inhaled antibiotic, colistin, also is available.29 Use of inhaled antibiotics for the long-term suppression of P. aeruginosa has been shown to improve pulmonary function in patients with CF.30

The development of multidrug-resistant microorganisms is a growing problem in the treatment of CF. This is probably a result of the intensive selective pressure provided by using large amounts of antibiotics in these patients.31 Pseudomonal resistance has been linked to derangements in  b-lactamase activity.32 Double b-lactam therapy using aztreonam with piperacillin, ceftazidime, or imipenem may, therefore, be a future approach.

Development of resistance to ciprofloxacin is commonly seen, and resistance to aminoglycosides is also a problem in CF patients with chronic P. aeruginosa infection, whereas resistance to colistin is seldom seen, despite selective pressure in patients receiving colistin by daily inhalation.33 Leading investigators34 have suggested that it is the chronic inflammation dominated by polymorphonuclear leukocytes that induces a high level of mutation in P. aeruginosa in CF lungs, and the resistant mutants are then selected by the heavy use of antibiotics.

Much of the lung damage that occurs in CF is attributable to chronic inflammation of the airways. Hence, anti-inflammatory therapy has been evaluated as a possible therapeutic approach to the disease. The original landmark trial35 that evaluated ibuprofen therapy in patients with CF was reported in 1995. Patients randomly assigned to ibuprofen had a slower annual rate of change in forced expiratory volume in 1 second (FEV1) than those assigned to placebo, and body weight was better maintained in the former group. Among the patients who took ibuprofen for 4 years and had at least a 70% rate of compliance, the annual rate of change in FEV1 was even slower, and this group of patients also had significantly slower rates of decline in forced vital capacity, percentage of ideal body weight, and the chest-radiograph score. Subsequent evaluation has shown that long-term treatment with ibuprofen twice daily, at doses that achieve peak plasma concentration of more than 50 µg/mL, does slow the progression of lung disease in some patients with CF.36 Although it is available as an over-the-counter agent, ibuprofen should be administered to CF patients only under medical supervision because the high doses required must be determined individually for each patient.

A third inhaled antimicrobial agent for use in CF, currently in Phase 3 clinical trials, is the  b-lactam antibiotic aztreonam. Many gram-negative strains of bacteria, including H. influenzae and P. aeruginosa, are susceptible to inhaled aztreonam.37 It may be ideal for development as an inhaled agent in CF because it is less likely to trigger allergic reactions than other  b-lactams, and it is often tolerated by patients with a history of hypersensitivity reactions to penicillins and/or cephalosporins.38 Inhaled aztreonam is delivered using a unique electronic nebulizer. Current jet-nebulizer technology requires 15 to 20 minutes to deliver a dose of aerosolized antibiotic. The target delivery time for inhaled aztreonam, with its next-generation nebulization system, is approximately 3 to 4 minutes.

A large number of other drugs are in development for the treatment of CF, including anti-inflammatory agents, drugs that modulate CFTR, those that restore ion transport, and those that affect mucus regulation. The CF Drug Development Pipeline page39 of the Cystic Fibrosis Foundation’s Web site describes each of these compounds and shows the developmental status of each one. More than a dozen new drugs for the treatment of CF could become available within the next decade.

Secretion Clearance
A major focus of CF treatment is the obstructed breathing that causes frequent lung infections. Physical therapy, exercise, and medication are used to reduce mucus blocking the airways.

Chest physiotherapy (PT) is widely prescribed to facilitate the clearance of airway secretions in patients with CF.40 Chest PT consists of bronchial  (or postural) drainage, which is done by placing the patient in a position that allows drainage of the mucus from the lungs. At the same time, the chest or back is clapped (percussed) and vibrated to dislodge the mucus and help it move out of the airways. This process is repeated over different parts of the chest and back to loosen the mucus in different areas of each lung. This procedure has to be done for children by family members, but older patients can learn to do it by themselves. Mechanical aids that help chest physical therapy are available commercially. Exercise also helps to loosen the mucus, stimulate coughing to clear the mucus, and improve the patient’s overall physical condition.

Medications used to help breathing are often aerosolized and can be inhaled. These agents include bronchodilators, mucolytics, and decongestants.

Lung transplantation has become an accepted treatment for respiratory failure due to CF. Effective means of patient selection, surgical technique, immunosuppression, and post-transplant management permit survival rates as good as those of transplant patients with other diseases.41 The new lungs do not acquire the CF ion-transport abnormalities, but are subject to the usual post-transplant complications. Moreover, CF problems in other organ systems can persist, and may be worsened by some of the immunosuppressive regimens required to prevent rejection of the transplanted lung.

A new treatment option attracting attention is gene therapy, the goal of which is to deliver a normal copy of the CFTR gene to the cells that need it. Theoretically, the DNA inserted into target cells should direct synthesis of the normal CFTR protein and reverse the primary biochemical abnormality at the root of CF.42 Introduction of the gene should replace all functions of the CFTR protein, including any that have not yet been recognized. At least 20 clinical trials evaluating gene therapy in CF currently are under  way or awaiting approval.43 Choice of vector, mode of delivery to airways, translocation of genetic information, and sufficient expression level of the normalized CFTR gene are issues that currently are being addressed.

Despite advances in the understanding of the pathogenesis of CF, it remains a potentially devastating disease. The goals of therapy are to control symptoms and prevent further lung damage. The hallmark of management remains antibacterial therapy to minimize or eliminate lower respiratory tract infection. Drug resistance is a growing problem; new antibiotics, and new ways of using old antibiotics, are needed to eradicate existing drug-resistant microorganisms and prevent the development of new ones. It is hoped that newer therapeutic modalities, such as inhaled antimicrobial therapy and gene therapy, will offer improved outcomes for patients with CF.

John D. Zoidis, MD, is a contributing writer for RT. For more information contact [email protected]

1. Assael BM, Castellani C, Ocampo MB, Iansa P, Callegaro A, Valsecchi MG. Epidemiology and survival analysis of cystic fibrosis in an area of intense neonatal screening over 30 years. Am J Epidemiol. 2002; 156:397-401.

2. Krimsky WS, Parker HW. Update: epidemiology of cystic fibrosis. Curr Opin Pulm Med. 2002; 8:552-553.

3. Rajan S, Saiman L. Pulmonary infections in patients with cystic fibrosis. Semin Respir Infect. 2002; 17:47-56.

4. Kulich M, Rosenfeld M, Goss CH, Wilmott R. Improved survival among young patients with cystic fibrosis. J Pediatr. 2003; 142:631-636.

5. Kerem B, Rommens JM, Buchanan JA, et al. Identification of the cystic fibrosis gene: genetic analysis. Science. 1989; 245:1073-1080.

6. Guggino WB, Stanton BA. New insights into cystic fibrosis: molecular switches that regulate CFTR. Nat Rev Mol Cell Biol. 2006; 7:426-436.

7. Ferec C, Casals T, Chuzhanova N, et al. Gross genomic rearrangements involving deletions in the CFTR gene: characterization of six new events from a large cohort of hitherto unidentified cystic fibrosis chromosomes and meta-analysis of the underlying mechanisms. Eur J Hum Genet. 2006; 14:567-576.

8. Davidson DJ, Porteous DJ. Genetics and pulmonary medicine. 1. The genetics of cystic fibrosis lung disease. Thorax. 1998; 53:389-397.

9. Guggino WB. Cystic fibrosis and the salt controversy. Cell. 1999; 96:607-610.

10. Zar H, Saiman L, Quittell L, et al. Binding of Pseudomonas aeruginosa to respiratory epithelial cells from patients with various mutations in the cystic fibrosis transmembrane regulator. J Pediatr. 1995; 126:230-233.

11. Chen DL, Ferkol TW, Mintun MA, Pittman JE, Rosenbluth DB, Schuster DP. Quantifying pulmonary inflammation in cystic fibrosis with positron emission tomography. Am J Respir Crit Care Med. 2006; 173:1363-1369.

12. Pier GB, Grout M, Zaidi TS, et al. Role of mutant CFTR in hypersusceptibility of cystic fibrosis patients to lung infections. Science. 1996; 271: 64-67.

13. Armstrong DS, Grimwood K, Carlin JB, et al. Lower airway inflammation in infants and young children with cystic fibrosis. Am J Respir Crit Care Med. 1997; 156:1197-1204.

14. LiPuma JJ. Expanding microbiology of pulmonary infection in cystic fibrosis. Pediatr Infect Dis J. 2000; 19:473-474.

15. Burns JL, Emerson J, Stapp JR. Microbiology of sputum from patients at cystic fibrosis centers in the United States. Clin Infect Dis. 1998; 27:158-163.

16. Saiman L, Siegel J. Infection control recommendations for patients with cystic fibrosis: microbiology, important pathogens, and infection control practices to prevent patient-to-patient transmission. Am J Infect Control. 2003; 31:S1-S62.

17. Saiman L, Siegel J. Infection control recommendations for patients with cystic fibrosis: microbiology, important pathogens, and infection control practices to prevent patient-to-patient transmission. Infect Control Hosp Epidemiol. 2003; 24:S6-S52.

18. Griffith DE. Emergence of nontuberculous mycobacteria as pathogens in cystic fibrosis. Am J Respir Crit Care Med. 2003; 167:810-812.

19. Baumer JH. Evidence based guidelines for the performance of the sweat test for the investigation of cystic fibrosis in the UK. Arch Dis Child. 2003; 88:1126-1127.

20. Padoan R, Genoni S, Moretti E, Seia M, Giunta A, Corbetta C. Genetic and clinical features of false-negative infants in a neonatal screening programme for cystic fibrosis. Acta Paediatr. 2002; 91:82-87.

21. Rock MJ, Mischler EH, Farrell PM, Bruns WT, Hassemer DJ, Laessig RH. Immunoreactive trypsinogen screening for cystic fibrosis: characterization of infants with a false-positive screening test. Pediatr Pulmonol. 1989; 6:42-48.

22. Southern KW, Noone PG, Bosworth DG, Legrys VA, Knowles MR, Barker PM. A modified technique for measurement of nasal transepithelial potential difference in infants. J Pediatr. 2001; 139:353-358.

23. Ahrens RC, Standaert TA, Launspach J, et al. Use of nasal potential difference and sweat chloride as outcome measures in multicenter clinical trials in subjects with cystic fibrosis. Pediatr Pulmonol. 2002; 33: 142-150.

24. Dequeker E, Cuppens H, Dodge J, et al. Recommendations for quality improvement in genetic testing for cystic fibrosis. European Concerted Action on Cystic Fibrosis. Eur J Hum Genet. 2000; 8:S2-S24.

25. De Soyza A, Morris K, McDowell A, et al. Prevalence and clonality of Burkholderia cepacia complex genomovars in UK patients with cystic fibrosis referred for lung transplantation. Thorax. 2004; 59:526-528.

26. Cunningham S, Prasad A, Collyer L, Carr S, Lynn IB, Wallis C. Bronchoconstriction following nebulised colistin in cystic fibrosis. Arch Dis Child. 2001; 84:432-433.

27. Burns JL, Van Dalfsen JM, Shawar RM, et al. Effect of chronic intermittent administration of inhaled tobramycin on respiratory microbial flora in patients with cystic fibrosis. J Infect Dis. 1999; 179:1190-1196.

28. Ramsey BW, Pepe MS, Quan JM, et al. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group. N Engl J Med. 1999; 340:23-30.

29. Hodson ME, Gallagher CG, Govan JR. A randomised clinical trial of nebulised tobramycin or colistin in cystic fibrosis. Eur Respir J. 2002; 20:658-664.

30. Moss RB. Long-term benefits of inhaled tobramycin in adolescent patients with cystic fibrosis. Chest. 2002; 121:55-63.

31. Doring G, Conway SP, Heijerman HGM, et al. Antibiotic therapy against Pseudomonas aeruginosa in cystic fibrosis: a European consensus. Eur Respir J. 2000; 16:749-767.

32. Vogne C, Aires JR, Bailly C, Hocquet D, Plesiat P. Role of the multidrug efflux system MexXY in the emergence of moderate resistance to aminoglycosides among Pseudomonas aeruginosa isolates from patients with cystic fibrosis. Antimicrob Agents Chemother. 2004; 48:1676-1680.

33. Høiby N. New antimicrobials in the management of cystic fibrosis. J Antimicrob Chemother. 2002; 49:235-238.

34. Jalal S, Ciofu O, Høiby N, Gotoh N, Wretlind B. Molecular mechanisms of fluoroquinolone resistance in Pseudomonas aeruginosa isolates from cystic fibrosis patients. Antimicrob Agents Chemother. 2000; 44:710-712.

35. Konstan MW, Byard PJ, Hoppel CL, Davis PB. Effect of high-dose ibuprofen in patients with cystic fibrosis. N Engl J Med. 1995; 332:848-854.

36. Konstan MW, Krenicky JE, Finney MR, et al. Effect of ibuprofen on neutrophil migration in vivo in cystic fibrosis and healthy subjects. J Pharmacol Exp Ther. 2003; 306:1086-1091.

37. Shawar RM, MacLeod DL, Garber RL, et al. Activities of tobramycin and six other antibiotics against Pseudomonas aeruginosa isolates from patients with cystic fibrosis. Antimicrob Agents Chemother. 1999; 43:2877-2880.

38. Koch C, Hjelt K, Pedersen SS, et al. Retrospective clinical study of hypersensitivity reactions to aztreonam and six other beta-lactam antibiotics in cystic fibrosis patients receiving multiple treatment courses. Rev Infect Dis. 1991; 13:S608-S611.

39. Cystic Fibrosis Foundation. CF drug development pipeline. Available at: Accessed September 10, 2006.

40. Elkins MR, Jones A, van der Schans C. Positive expiratory pressure physiotherapy for airway clearance in people with cystic fibrosis. Cochrane Database Syst Rev. 2006; 19:CD003147.

41. Yankaskas JR, Aris R. Outpatient care of the cystic fibrosis patient after lung transplantation. Curr Opin Pulm Med. 2000; 6:551-557.

42. Flotte TR. Gene therapy for cystic fibrosis. Curr Opin Mol Ther. 1999; 1: 510-516.

43. Bigger B, Coutelle C. Perspectives on gene therapy for cystic fibrosis airway disease. BioDrugs. 2001; 15:615-634.