Helping patients with cystic fibrosis live longer

In SBBO, gram-negative colonic bacteria colonize the small bowel and can contribute to abdominal pain and malabsorption, weight loss, and malnutrition. Treatment requires antibiotics with activity against gram-negative organisms, or non-absorbable agents such as rifamyxin, sometimes on a chronic, recurrent, or rotating basis.²

Chronic constipation is also quite common among CF patients and many require daily administration of poly-ethylene-glycol. Before newborn screening programs were introduced, infants would on occasion present with complete distal intestinal obstruction. Adults are not immune to obstructive complications and may require hospitalization for bowel cleansing.

Because HbA1c may not accurately reflect low levels of glucose intolerance, screen for CF-related diabetes with a 2-hour 75-g oral glucose tolerance test.

Gastrointestinal system: Liver

Liver disease is relatively common in CF, with up to 24% of adults experiencing hepatomegaly or persistently elevated liver function tests (LFT).⁴ Progressive biliary fibrosis and cirrhosis are encountered more often as the median survival age has increased. There is evidence that ursodeoxycholic acid (UDCA) can be a useful adjunct in the treatment of cholestasis, but it is not clear if it alters mortality or progression to cirrhosis. Only CF patients with elevated LFTs should be started on UDCA.⁴

Other areas of concern: Sinuses, serum sodium levels

Chronic, symptomatic sinus disease in CF patients—chiefly polyposis—is common and may require repeat surgery, although most patients with extensive nasal polyps find symptom relief with daily sinus rinses. Intranasal steroids and intranasal antibiotics are also often employed, and many CF patients need to be in regular contact with an otolaryngologist.¹⁴ For symptoms of allergic rhinitis, recommend OTC antihistamines in standard dosages.

Exercise is recommended for all CF patients, as noted earlier, and as life expectancy increases, many are engaging in more strenuous and longer duration activities.¹⁵ Due to high sweat sodium loss, CF patients are at risk for hyponatremia, especially when exercising on days with high temperatures and humidity. CF patients need to replace sodium losses in these conditions and when exercising for extended periods.

There are no evidence-based guidelines for sodium replacement. The Cystic Fibrosis Foundation (CFF) recommends that patients increase salt in the diet when under conditions likely to result in increased sodium loss, such as exercise. It has been thought that CF patients can easily dehydrate due to an impaired thirst mechanism and, when exercising, should consume fluids beyond the need to quench thirst.^16,17 More recent evidence suggests, however, that the thirst mechanism in those with CF remains normally intact and that overconsumption of fluids beyond the level of thirst may predispose the individual to exercise-associated hyponatremia as serum sodium is diluted.¹⁵

For Pseudomonas aeruginosa infection, inhaled antibiotics suppress chronic infection, improve lung function, decrease pulmonary secretions, and reduce inflammation.

New therapies

Small-molecule CFTR-modulating compounds are a promising development in the treatment of CF. The first such available medication was ivacaftor in 2012. Because these molecules are mutation specific, ivacaftor was available at first only for patients with at least one copy of the G551D mutation,¹⁸ which means about 5% of patients with CF.³

Ivacaftor increases the likelihood that the CFTR chloride channel will open and patients will exhibit a reduction in sweat chloride levels. In the first reported clinical trial of ivacaftor involving patients with the G551D mutation, FEV₁ improvements of 10% occurred by the second week of therapy and persisted for 48 weeks.¹⁸ The drug has now been approved by the US Food and Drug Administration (FDA) for patients 12 years of age and older with at least one of the following mutations: R117H, G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, or G1349D.¹⁹

A medication combining ivacaftor with lumacaftor is also now available for patients with a copy of F508del on both chromosomes. F508del is the most common CFTR mutation, with one copy present in almost 87% of people with CF in the United States.¹ Since 47% of CF patients have 2 copies of F508del,¹ about half of those with CF in the United States are now eligible for small-molecule therapy. Lumacaftor acts by facilitating transport of a misfolded CFTR to the cell membrane where ivacaftor then increases the probability of an open chloride channel. This combination medication has improved lung function by about 5%.

The ivacaftor/lumacaftor combination was approved by the FDA in July 2015. Both ivacaftor and the ivacaftor/lumacaftor combination were deemed by the FDA to demonstrate statistically significant and sustained FEV₁ improvements over placebo.

The CFF was instrumental in providing financial support for the development of both ivacaftor and the ivacaftor/lumacaftor combination and continues to provide significant research advancement. According to the CFF (www.cff.org), medications currently in the development pipeline include compounds that provide CFTR modulation, surface airway liquid restoration, anti-inflammation, inhaled anti-infection, and pancreatic enzyme function. For more on CFF, see "The traditional CF care model.”^4,20