The prognosis for people with CF, once very poor, has improved over the past 30 years. The cornerstone of CF management is aggressive antimicrobial therapy, including management of drug-resistant organisms.

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

Patients with CF suffer from chronic lung problems and digestive disorders. The lungs of people with CF become covered with a sticky mucus that is difficult to remove and that promotes bacterial infection. Many people with CF require frequent hospitalization and continuous use of antibiotics, enzyme supplements, and other medications. The prognosis for people with CF was once very poor, but it has improved considerably over the past 3 decades. In the 1960s, the mean survival age was about 6 years, compared with 16 years in 1970 and 30 years in 1990.3 It is predicted that infants born with CF today may live for 40 years or more.4

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 the CF 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.1,2, 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 he or she has two defective CFTR alleles. Those with a single defective allele are carriers. A child must inherit 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 a healthy noncarrier.

The classic mutation involved in CF causes the deletion of three of the base pairs in the CFTR gene.5 This, in turn, causes a loss in the CFTR protein of one amino acid (phenylalanine at position 508 of the protein chain). Hence, this mutant protein is called DF508 CFTR, but it 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 his or her environment. The severity of symptoms varies, depending on the particular mutation. Generally, patients with milder symptoms live longer.

Pulmonary Disease in CF
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 mucous secretions of the body’s epithelial cells. 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 infection.

During the past decade, several major hypotheses have emerged to explain the unique pulmonary manifestations of CF. These explanations include impaired ciliary movement and mucus transport as a result of decreased surface airway liquid,6 increased binding of bacteria to airway epithelial cells,7 immune dysfunction,8 and dysregulation of the airway inflammatory response.9

figure 1Figure 1. The lung in cystic fibrosis. Chronic endobronchial infection accompanied by intense intraluminal infiltration of neutrophils may result in progressive bronchiectasis.

Lung infection is the leading cause of morbidity and mortality in patients with CF.10 Chronic endobronchial infection, accompanied by intense intraluminal infiltration of neutrophils, may result in progressive bronchiectasis (see Figure 1, page 21) 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.10,11 Recently, additional bacterial species have been identified that may chronically colonize the respiratory tract of patients with CF (see Table).

    •     Staphylococcus aureus
    •    Haemophilus influenzae
    •    Pseudomonas aeruginosa

    •    Nonfermentative, non-Pseudomonas gram-negative species:
        –    Burkholderia cepacia (formerly Pseudomonas cepacia)
        –    Ralstonia pickettii (formerly Burkholderia pickettii)
        –    Flavobacterium species
        –    Chryseobacterium species
        –    Sphingomonas species
    •    Stenotrophomonas maltophilia (formerly Xanthomonas maltophilia)
    •    Enterobacteriaceae:
        –    Serratia marcescens
        –    Enterobacter cloacae
        –    Klebsiella pneumoniae
        –    Escherichia coli
        –    Citrobacter freundii

    •    Nontuberculous mycobacteria:
        –    Mycobacterium avium complex
        –    Mycobacterium abscessus

Bacterial species known to colonize the respiratory tracts of patients with CF chronically.

Adapted from Pediatr Infect Dis J10 and Clin Infect Dis.11

CF Diagnosis
Prenatal genetic testing can be used to determine whether an unborn child has CF, although the testing is not foolproof because many of the more than 800 different mutations that may 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 performed. 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.12 A very small percentage of CF patients have normal salt levels in their sweat, in which case they have to be genetically tested to determine the presence of the defective gene. About 10% to 15% of all positive sweat tests are false positives.12 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 may be done. This test involves drawing blood a few days after birth and evaluating it for the presence of the protein trypsinogen. If the test is positive, it should be confirmed by genetic testing. The combination of an immunoreactive trypsinogen test and genetic testing is 90% to 100% sensitive in diagnosing CF.13

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 is known as the nasal potential difference, and it can be easily measured by a surface electrode.14 Because sodium and chloride transport is abnormal in CF patients, these measurements are very different in CF patients from those of people who do not have CF.15 Measurement of nasal potential difference 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 testing 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%.16 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 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 CF include clearance of abnormal secretions and, in dire cases, lung transplantation. A therapeutic modality currently being investigated is gene therapy.

When 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 may be useful, but may not always accurately reflect lower-airway pathogens.4 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.1 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 are also indicated when these organisms are isolated from the respiratory tract.3 Burkholderia 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.17,18

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 (FDA) in 1998.19,20 Another inhaled antibiotic, colistin, is also available.21 Use of inhaled antibiotics for the long-term suppression of P. aeruginosa has been shown to improve pulmonary function in patients with CF.22

Another inhaled antimicrobial agent being developed for use in CF is the b-lactam antibiotic aztreonam. Many gram-negative strains of bacteria, including H. influenzae and P. aeruginosa, are susceptible to inhaled aztreonam.23 It may be an ideal agent for development as an inhaled agent in CF because it is less likely to trigger allergic reactions than other b-lactams, and is often tolerated by patients with a history of hypersensitivity reactions to penicillins and/or cephalosporins.24 Inhaled aztreonam is delivered using a unique electronic nebulizer. Current jet-nebulizer technology requires 15 to 20 minutes per dose of aerosolized antibiotic. The target delivery time for inhaled aztreonam, with its next-generation nebulization system, is approximately 3 to 4 minutes. Inhaled aztreonam was granted orphan-drug status by the FDA in March 2002. Phase II trials were initiated in October 2003.

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 produced by using large amounts of antibiotics in these patients.25 Pseudomonal resistance has been linked to derangements in b-lactamase activity.26 Double b-lactam therapy using aztreonam and piperacillin, ceftazidime, or imipenem may, therefore, be a future approach.

Development of resistance to ciprofloxacin is commonly seen,27 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.25 Leading investigators28 have suggested that chronic inflammation dominated by polymorphonuclear leukocytes induces a high level of mutation in P. aeruginosa in CF lungs, and the resistant mutants are then selected through the heavy use of antibiotics.

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

Chest physiotherapy 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 many areas of each lung. This procedure has to be performed for children by family members or other caregivers, but older patients can learn to do it themselves. Mechanical aids 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 drugs 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 postsurgical management permit survival rates as good as those of transplant patients with other diseases.29 The new lung does not acquire the CF ion-transport abnormalities, but is subject to the usual transplantation 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.30 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 are currently under way or awaiting approval.31 Choice of vector, mode of delivery to the airways, translocation of genetic information, and sufficient expression level of the normalized CFTR gene are issues that currently are being addressed.

Despite advances in understanding the pathogenesis of CF, it remains a potentially devastating disease. Its management relies on antibacterial therapy, in patients with chronic lung disease, in an attempt to minimize or eliminate lower respiratory tract infection. Drug resistance, however, is a growing problem. New antibiotics and new ways of using older 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.

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