Cystic Fibrosis

Cystic Fibros is

By: MA. CLARITA VARQUEZ BSN 2b RLE Group 4

I.

Introduction

Cystic fibrosis is a multi-system disorder of the exocrine glands, leading to increased production of thick mucus in bronchioles, small intestines and pancreatic and bile ducts & even causes fertility problems. It is an autosomal recessive disorder that obstructs small passageways of these organs: • • •

Lungs (bronchioles): atelectasis (lung collapse) & Emphysema (Overinflation of the alveoli) Pancreatic ducts become clogged, impairing digestion and absorption Small intestine: absence of pancreatic enzymes unable to absorb fats and protein.

Symptoms of cystic fibrosis are: In babies and infants, •

persistent diarrhea

• bulky, foul smelling and greasy stools • pale stools •

frequent wheezing or pneumonia

• chronic cough with thick mucus • salty-tasting skin • poor growth • blockage of the intestine (called meconium ileus) • abdominal swelling • gassiness • vomiting • dehydration In children, • frequent respiratory infections • fever • cough • difficulty in breathing • abdominal pain and discomfort • gassiness • fast respiration • flaring of the nostrils • poor appetite • malnutrition • poor growth

• a barrel-chested appearance CF can also cause other medical problems, such as: •

sinusitis (inflammation of the nasal sinuses)

• nasal polyps (fleshy growths inside the nose) • clubbing (rounding and enlargement of fingers and toes) •

pneumothorax (rupture of lung tissue and trapping of air between the lung and chest wall)

• coughing up blood • enlargement of the right side of the heart (called cor pulmonale) • protrusion of the rectum through the anus (called rectal prolapse) • liver, pancreatic and gallbladder problems • delayed puberty • reproductive abnormalities (especially male sterility) - Over 90 percent of all males with CF are sterile. Cystic fibrosis is a common genetic disease within the Caucasian (white) population in the United States. The disease occurs in 1 in 2,500 to 3,500 Caucasian newborns. Cystic fibrosis is less common in other ethnic groups, affecting about 1 in 17,000 African Americans and 1 in 31,000 Asian Americans. Cystic fibrosis affects 1: 30 Europeans, 1: 3,000 WHITES, 1: 15,000 BLACKS and, 1: 90,000 ASIANS. The greatest risk factor for cystic fibrosis is a family history of the disease. If both come from families with cystic fibrosis, then each of their children has a one in four chance of having cystic fibrosis. Risk is also greater if they are under Northern European ancestry. In that case, they have a one in 29 chance of carrying the gene. Among other ethnic groups in the United States, Hispanics have a one in 46

chance of carrying the gene, blacks have a one in 65 chance and AsianAmericans a one in 90 chance. CF is carried as an autosomal recessive trait by about 3% of the white population. The responsible gene has been localized on the long arm of chromosome 7. It encodes a membrane-associated protein called the cystic fibrosis transmembrane conductance regulator (CFTR). The most common gene mutation, ΔF508, occurs in about 70% of CF alleles; > 1500 less common CFTR mutations have been identified. CFTR seems to be part of a cAMP-regulated Cl channel, regulating Cl and Na transport across epithelial membranes. A number of additional functions are considered likely. Disease manifests only in homozygotes. Heterozygotes may show subtle abnormalities of epithelial electrolyte transport but are clinically unaffected.

II.

Pathophysiology

III.

Laboratory Tests

Diagnosis of CF can be determined at three stages - prenatal, postnatal and early childhood. In pregnant women, the amniotic fluid surrounding the fetus can be tested for fetal intestinal enzymes. Using a procedure called an amniocentesis, a sample of amniotic fluid is extracted from the amniotic sac (the protective covering around the fetus) and analyzed. In a fetus with CF, the enzymes are decreased. • Sweat Chloride Test The most common test for children and young adults is the electrolyte sweat test. This test measures the amount of electrolytes (sodium [salt], potassium and chloride) in a person's sweat. This is done by applying a chemical (called pilocarpine-used to stimulate sweat production) to the forearm and using a mild electric current to cause the area to sweat. It analyzes sodiam and chloride content in sweat and if this results to higher than normal amounts of sodium and chloride,

CF is present. It is done after 3-4 weeks after birth. Patient often report that infants taste salty when kissed. •

Immunoreactive Trypsinogen Test (IRT)

In newborn babies who cannot produce enough sweat for a sweat test, an IRT may be done. An IRT is a blood test that involves drawing blood a couple of days after birth and evaluating the presence of the protein trypsinogen. If the test is positive, it should be confirmed by a mutation analysis (i.e., genetic testing). The combination of an IRT and a mutation analysis is sensitive 90% to 100% of the time. •

Nasal Potential Difference (NPD) Measurement

As Na+ (sodium) and Cl- ions move across the membranes of the cells lining the airway, they generate what is called an electric potential difference (the amount of energy required to move an electrical charge from one point to another). 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. Because Na+ and Cl- transport is abnormal in CF patients, NPD measurements are very different in CF patients than in people who do not have CF. This test is especially helpful when the sweat electrolyte test and/or the genetic tests are inconclusive. However, the success of the test is highly dependent on the skill of the technician, and should be done in a special center. •

Genetic Testing

A genetic test, 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%. 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 fatal or mild.

Generally, a genetic test is done if a patient's sweat test is negative and there is still high suspicion that the patient has CF. •

Pulmonary Function Tests

Pulmonary function tests may be done to assess the patient's respiratory dysfunction and whether the patient is healthy enough to receive a lung transplant, if necessary. •

72-hour stool collection (Keep food diary)

Analyzes fat & enzyme content. • Chest x-ray To reveal atelectasis & obstructive emphysema

IV.

Medical Management

Attempt aggressive medical management prior to surgical intervention. Patients may report chronic purulent nasal discharge or cough, but initiate therapy whenever they experience a subjective increase in nasal obstruction, cough, or drainage. Oral antibiotics effective against Pseudomonas species and staphylococci, coupled with aggressive nasal toilet, may improve symptoms. •

Antibiotic choices: The bacteriology of sinonasal disease in patients with cystic fibrosis (CF) differs from that in patients without CF. This difference affects antibiotic choices. The most notable difference is the nearly ubiquitous presence of Pseudomonas species in patients with CF. As detailed above, sinus aspirates are important to direct treatment against Pseudomonas species.

•

Nasal toilet: Because mucociliary clearance is chronically impaired, irrigations are critical and should be a daily routine as

patients begin to develop sinonasal symptoms. Nasal saline irrigations serve to decrease bacterial colonization, wash away inspissated secretions that lead to obstruction, and temporarily aid in vasoconstriction. Irrigation is also required after any surgical intervention because surgery enlarges sinus ostia but does not address underlying defects in mucociliary clearance •

Physiotherapy: to help clear the lungs of mucus, which attracts infection

•

Exercise: beneficial as a form of physiotherapy and for general health

•

Nutrition: enzyme tablets to help digest food and dietetic information.

V.

Surgical Management

• Surgical Therapy Nasal polypectomy to relieve obstruction is the most common surgical procedure in CF, and most patients get symptomatic improvement.375 Recurrence of polyps is common, but the incidence of polyposis usually wanes after the second decade. Gallstones are common, and symptomatic disease may require elective cholecystectomy in as many as 5% of CF adults. Lobectomy is occasionally indicated for massive hemoptysis that is refractory to bronchial artery embolization. Partial lung resection has been advocated for apparently localized disease and recurrent severe exacerbations. However, the generalized lung disease continues to progress; the limited probability of long-termbenefits dictates caution in patient selection.

• Transplantation Lung transplantation has become an accepted treatment for respiratory failure secondary to CF. Heart-lung transplant has been largely replaced by sequential double-lung transplant because of limited organ availability. Patients should be referred when their prognosis is about equal to the waiting time for donor lungs, currently about 2 years after acceptance as a lung transplant candidate. More than 1600 lung transplants have been performed for CF around the world. The transplanted lungs remain free of CF but are subject to secondary infection, acute rejection, and chronic rejection (bronchiolitis obliterans syndrome). The 5-year survival is 48%—as good as that of lung transplant recipients with other causes of lung disease. Living lobar transplantation is an effective alternative to conventional cadaveric lung transplants.380 The lobe donors must have sufficiently large lungs that their lower lobe fills the recipient’s hemithorax. Survival appears to be similar to that following conventional lung transplantation.

VI.

Medications

• Nasal corticosteroids These agents decrease mucosal edema and promote mucus clearance.

Fluticasone furoate (Veramyst) Has potent glucocorticoid activity, weak mineralocorticoid activity, and the least systemic absorption of nasal steroid preparations. Contraindicated to patients with hypersensitivity to drug.

Mometasone furoate monohydrate (Nasonex) Has potent glucocorticoid activity, weak mineralocorticoid activity, and the least systemic absorption of nasal steroid preparations. Decreases rhinovirus-induced up-regulation in respiratory epithelial cells and modulates pretranscriptional mechanisms. Reduces intraepithelial eosinophilia and inflammatory cell infiltration (eg, eosinophils, lymphocytes, monocytes, neutrophils, plasma cells). Its contraindications are documented hypersensitivity; nasal septal perforation; nasal surgery and nasal trauma.

• Systemic corticosteroids Short-term bursts may be beneficial for acute exacerbations and may prevent increased intraoperative bleeding in patients with severe polyposis.

Prednisolone (Delta-Cortef, Econopred) Suppresses key components of immune system. Widely available in syrup form; easily dosed for children. Containdicated to patients with documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections and GI disease.

Prednisone (Deltasone, Meticorten, Orasone) Suppresses key components of immune system. Widely available in syrup form; easily dosed for children. Contraindicatd to patients with documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections and GI disease.

Dexamethasone (Decadron, Dexasone, Solurex) Can be administered IV at induction of anesthesia; may help immediate postoperative inflammation. Contraindications include: coadministration with estrogens may decrease prednisone clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics.

• Decongestants These agents are helpful in improving the nasal airway and shrinking down swollen tissues in some patients.

Pseudoephedrine hydrochloride (Sudafed, Actifed) Sympathomimetic agent that shrinks swollen nasal mucosa. Contraindicated to patients with documented hypersensitivity; severe anemia; postural hypertension or hypotension; closed angle glaucoma; head trauma and cerebral hemorrhage. • Anti-inflammatory Therapy With Ibuprofen A recent study of high-dose ibuprofen over 4 years indicates that young CF patients (<13 years) with mild lung disease have remarkable slowing of the decline of lung function (eightfold) compared to placebo control subjects. No effect was documented in patients older than 13 years, even among patients with mild lung disease. There were few side effects, but most of the patients were taking antacids or H2-receptor blockers. • Topical nasal medications

Some authors advocate irrigations with antipseudomonal antibiotics such as tobramycin, and these may be effective in decreasing bacterial colonization. Nebulization of antipseudomonal medications like tobramycin is clearly beneficial for lung infections in CF patients, but may not be particularly useful for the sinuses. Serial tobramycin irrigation of the maxillary sinuses, which can be done in an office setting in a compliant patient, however, may significantly decrease the intensity and frequency of infections, especially when done after sinus surgery. Two small studies have shown improvement of postoperative mucosal edema, pulmonary function testing, and polyp regrowth after sinus surgery when recombinant human deoxyribonuclease I (dornase alfa or Pulmozyme) was used via nasal inhalation.28,29

VII. Health teachings: If a child has cystic fibrosis, one of the best things family members can do is to learn as much as possible about the disease. Diet, medication and early recognition of infection are important. Also important for most patients is performing daily chest percussion to drain mucus from child's lungs. Doctor or respiratory therapist can show the best way to perform this lifesaving procedure. In addition, the following steps can help aid your child's health: •

Keep child's immunizations up to date. In addition to other usual childhood vaccines, this includes the pneumococcal and influenza vaccines. Cystic fibrosis doesn't affect the immune system, but children with cystic fibrosis are more likely to develop complications when they become sick.

•

Encourage child to lead as normal and active a life as possible. Exercise is extremely important for people of all ages who have cystic fibrosis. Regular exercise helps loosen mucus in

airways and strengthens heart and lungs. And for many people with cystic fibrosis, participating in sports can improve confidence and self-esteem. It isn't necessary to take part in an organized sport or take classes at a gym. Anything that gets moving, including walking and biking, can help. •

Make sure your eats a healthy diet. Be sure to discuss child's dietary needs with doctor or a nutritionist.

•

Use nutrition supplements. Provide the fat-soluble vitamin supplements and pancreatic enzymes that the child needs to stay as healthy as possible.

•

Emphasize liquids. Encourage child to drink plenty of liquids to help loosen the mucus. This is especially important in the summer when children are active and tend to lose a lot of fluids.

•

Eliminate smoke. Don't smoke in home or car, and don't allow other people to smoke around child. Secondhand smoke is harmful for everyone, but especially for people with cystic fibrosis.

•

Encourage hand washing.Teach everyone in family to wash their hands thoroughly before eating, after using the bathroom, when coming home from work or school, and after being around a person who is sick. Hand washing is the best way to protect against infection.

VIII. Advanced researches: The Cystic Fibrosis Foundation has built a dynamic "pipeline" for the development of more new potential CF therapies than ever before. To treat a complex disease like cystic fibrosis (CF), therapies must target problems in the airways and the digestive system.

In the cystic fibrosis drug development pipeline, there also are promising new therapies designed to rectify the cause of CF—a faulty gene and/or its faulty protein product. Clinical Trial Descriptions GENE THERAPY Because a faulty gene causes cystic fibrosis (CF), adding normal copies of the gene to cells could correct these cells and ultimately cure the disease. This approach is exploring ways to introduce normal copies of the gene into CF airways. •

Compacted DNA (PLASmin™): Using compacted DNA (non-viral) to introduce normal copies of the gene into CF airways. A Phase 1a trial demonstrated chloride current changes in the noses of CF patients, but no evidence of gene expression. The gene therapy product is being reformulated prior to additional clinical trials in an attempt to improve the amount and duration of gene expression.

CFTR MODULATION These therapies are designed to correct the function of the defective CFTR protein made by the CF gene, allowing chloride and sodium (salt) to move properly in and out of cells lining the lungs and other organs. •

Ataluren (formerly known as PTC124): PTC Therapeutics – A novel, small molecule compound, that promotes the read-through of premature truncation codons in the CFTR mRNA. It has been demonstrated to be safe, orally available and well tolerated in a Phase 1 single-dose trial in healthy volunteers. A Phase 2 trial in CF patients conducted in the United States and Israel demonstrated safety and encouraging biological results. A Phase 3 trial is scheduled to begin in summer 2009.

•

VX-770: Vertex Pharmaceuticals, supported by CFFT. VX-770 is a "potentiator" that may act upon the CFTR protein and help to open the chloride channel in CF cells. Phase 1 dosing has been completed in healthy volunteers and CF patients. A Phase 2 trial in CF patients with at least one copy of the G551D mutation in their CF gene demonstrated improvements in biological measures of CFTR function (nasal potential difference and sweat chloride) and clinical measures of pulmonary health (FEV1). Two Phase 3 studies (one for pediatric and one for adolescent/adult patients) are scheduled to begin in Spring 2009.

•

VX-809: Vertex Pharmaceuticals, supported by CFFT. VX-809 is a “corrector” that helps move defective CFTR protein to the proper place in the airway cell membrane and improve its function as a chloride channel. A Phase 2a trial began in spring 2009.

MUCUS ALTERATION These studies are evaluating drugs for their effectiveness in preventing, thinning and clearing thick mucus from the airways. •

Pulmozyme: Genentech, approved in 1993 and currently being used by more than 18,000 patients in the United States. Clinical trials were conducted in the CFF’s care center network.

RESTORE AIRWAY SURFACE LIQUID In cystic fibrosis, changes in salt transport within cells dehydrate mucus, causing it to become thick and sticky. This approach targets proteins other than CFTR to improve the movement of salt in and out of cells, allowing mucus to be more hydrated and, therefore, cleared more easily. •

Hypertonic Saline: A CFFT-funded Phase 3 trial in Australia had beneficial effects on pulmonary health in CF patients. Follow-on studies are determining if younger patients would benefit from this inhaled therapy.

•

Denufosol: Inspire Pharmaceuticals, supported by a CFFT TDA and the TDN. Correct the ion transport defect in CF. In June 2008, Inspire announced top-line results from TIGER-1, its first Phase 3 trial with denufosol for CF. The trial demonstrated statistical significance for its primary endpoint of change in FEV1 from baseline compared to placebo. Inspire is currently enrolling patients in TIGER-2, the second pivotal Phase 3 trial with denufosol.

•

Bronchitol: Pharmaxis – A Phase 3 trial of Bronchitol (an inhaled dry powder mannitol) has begun in the United States and in Canada. Theoretically, mannitol should help rehydrate CF secretions, improving airway clearance. Trials in Australia and Europe support this hypothesis.

•

SPI-8811: Sucampo Pharmaceuticals and the TDN. Oral agent believed to bypass transport defect of chloride ions. Initial Phase 2a trial evaluating safety and efficacy. Thirty patients recruited.

•

Moli 1901: Lantibio, supported by a CFFT TDA and the TDN. Thought to affect the ion transport defect in CF patients. Phase 1 trial demonstrated safety. Placebo-controlled, multi-dose, doseranging Phase 2 trial in Europe demonstrated positive changes in pulmonary function with highest dose.

•

Gilead GS9411: As a follow-on compound from Parion 552 that was used to demonstrate proof of concept, GS9411 has entered a Phase 1 CF clinical trial. It acts by blocking sodium absorption.

ANTI-INFLAMMATORY The drugs in this category are being studied for their ability to reduce inflammation in CF lungs, which should help decrease chronic damage to lung tissue. •

Ibuprofen: A four-year CFF-supported high dose ibuprofen trial completed in 1990 demonstrated less lung function decline in the

treatment group than the control group. This effect was greatest in 5-13 year-olds. •

Oral N-acetylcysteine: BioAdvantex – An antioxidant, oral Nacetylcysteine replenishes glutathione levels in neutrophils. Placebo-controlled 12-week study at Stanford Univ. demonstrated decreases in inflammatory cells in lung and positive indications of changes in pulmonary function.

•

DHA: Univ. of Massachusetts, CFFT-supported as clinical research grant. Pilot study to examine effect of infant formula fortified with DHA on pathogenesis of CF in 120 newly diagnosed patients at 16 centers began in 2003.

•

Sildenafil (Revatio): Based upon prior work by researchers at the University of New Mexico, clinicians there are examining whether sildenafil can lower markers of airway inflammation and measures of airway infection in CF patients, as well as alter the patient's perception of their own well being.

•

Inhaled Glutathione: A Phase 1 trial of inhaled glutathione has been completed in Germany and a Phase 2b trial is now in progress.

•

Pioglitazone, Hydroxychloroquine: These approved therapies (approved for non-CF indications) are being evaluated in exploratory Phase 1 trials in CF to determine if they are tolerated and if anti-inflammatory effects are seen.

•

Simvastatin (Zocor™): A HMG-CoA reductase inhibitor that increases nitric oxide (NO) production in cultured CF epithelial cells. Investigators are evaluating, in a CFFT-funded trial, whether simvastatin increases exhaled NO production in CF patients, synthesis of pro-inflammatory cytokines and whether measures of inflammation in the upper respiratory tract correlate with those from the lower respiratory tract.

•

HE-3286: Hollis-Eden Pharmaceuticals, supported by a CFFT TDA. An oral immune-regulating hormone which has replaced HE2000.

ANTI-INFECTIVE The compounds in this category are being evaluated for their effectiveness in fighting acute and chronic lung infections by destroying infection-causing bacteria that enter into the airways and colonize. •

TOBI®: Novartis Pharmaceuticals – This CFF/Children’s Hospital, Seattle-developed aerosol antibiotic was licensed to Chiron and received FDA approval in 1997. Currently being used by more than 15,000 patients worldwide. Benefit at first sign(s) of Pseudomonas infection is being evaluated.

•

Azithromycin: Pfizer – A large-scale, CFFT-conceived and supported, TDN-coordinated trial completed in 2002. In patients with chronic Pseudomonas aeruginosa, this oral antibiotic improved lung function and weight gain, and decreased hospitalization rate. Two follow up studies are in progress.

•

AZLI: Gilead Sciences, supported by a CFFT TDA and conducted in the TDN. Multiple Phase 3 trials of the aerosolized form of aztreonam, a widely used IV antibiotic in CF, have been completed and the FDA has reviewed all the data. Data from another clinical trial will be required but further discussions with the FDA are necessary to determine if ongoing trials will suffice.

•

TIP (TOBI Inhaled Powder): Novartis Pharmaceuticals is developing TOBI as a powder to enable a faster, more convenient dosing regimen. Dosing of TIP will take a fraction of the time of liquid TOBI. A Phase 3 trial has completed enrollment.

•

ArikaceTM: Transave – A liposomal formulation of the antibiotic amikacin. Animal model studies have shown it to decrease the

Pseudomonas aeruginosa burden in the lung. A Phase 1/2 trial in Europe has completed enrollment. A Phase 2 trial began in the TDN in 2007. •

BAY Q3939: Bayer Schering Pharma is developing an inhaled version of their antibiotic ciprofloxacin for treatment of airway infections. A small Phase 2 study in Germany is underway. A U.S. multicenter Phast 2 trial is currently enrolling patients.

•

MP-376: MP-376 is a new formulation of levofloxacin being developed by Mpex Pharmaceuticals for aerosol administration to CF patients for management of chronic pulmonary infections due to Pseudomonas aeruginosa and other bacteria. A U.S. multicenter Phase 2 trial has completed enrollment.

•

KB001: Kalobios Pharmaceuticals has initiated a Phase 1 clinical trial to test the safety of their antibody approach for treatment of Pseudomonas aeruginosa lung infections.

•

GS 9310/11: Gilead Sciences inhaled combination antibiotic (fosfomycin and tobramycin) has completed Phase 1 testing in Australia. A U.S. multicenter Phase 2 trial is currently enrolling patients.

TRANSPLANTATION One potential drug is being evaluated for its ability to reduce the chance of organ rejection, which is common after transplantation. •

Inhaled Cyclosporine: APT Pharmaceuticals – Inhaled formulation of cyclosporine was tested in a randomized placebo controlled trial at the Univ. of Pittsburgh. The group treated with inhaled cyclosporine showed a significant decrease in number of deaths and the development of chronic rejection. An additional clinical trial has been requested by the FDA before this drug is approved for clinical use.

NUTRITION Specially formulated supplements in this category include vitamins, as well as enzymes that increase both fat and vitamin absorption, allowing better nutrition for people with CF, who can become malnourished as a result of thick mucus clogging the pancreas. •

AquADEKs: Yasoo Health – Oral antioxidant vitamin formulation specifically for CF patients. A Phase 1 trial has been completed. A clinical trial to assess the safety and ability of this formulation to increase blood levels of antioxidants, normalize plasma levels of fat-soluble vitamins, improve pulmonary function and improve growth parameters began in 2007. AquADEKs is available to patients.

•

Pancrelipase Enzyme Products: The FDA has required pancreatic enzyme products to be reformulated and undergo clinical testing in order to receive FDA approval. Companies completing this process include: Axcan Scandipharm (Ultrase), DCI (PANCRECARB), Eurand (Zentase), McNeil (Pancrease MT) and Solvay (Creon).

•

Liprotomase (formerly Trizytek): Altus Pharmaceuticals, supported by a CFFT TDA, conducted in the TDN. Non-porcine pancreatic enzyme replacement. Phase 1 studies have not identified safety concerns. A Phase 2 trial has been completed, demonstrating safety and efficacy and a Phase 3 trial also has ended. Work to complete requirements for FDA submission is ongoing.

IX.

Sources:

http://www.pdfcoke.com/doc/12826781/Cystic-Fibrosis-21 http://www.pdfcoke.com/doc/7859297/Cystic-Fibrosis

http://emedicine.medscape.com/article/862538-treatment http://ghr.nlm.nih.gov/condition=cysticfibrosis http://www.cftrust.org.uk/aboutcf/whatiscf/treatment/ http://www.merck.com/mmpe/sec19/ch278/ch278a.html http://www.pulmonologychannel.com/cf/diagnosis.shtml http://www.mayoclinic.com/health/cysticfibrosis/DS00287/DSECTION=lifestyle-and-home-remedies http://www.cff.org/treatments/Pipeline/ http://www.medpagetoday.com/Pulmonary/CysticFibrosis/

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