Cystic Fibrosis (CF)

Cystic fibrosis is an autosomal recessive, inherited disease characterized by the accumulation of thick, sticky mucus due to dysfunctional or absent chloride ion transportation across epithelial cell membranes. Dysfunctional or absent chloride transport channels result from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Cystic fibrosis primarily affects the pulmonary system, digestive system, and sweat glands.¹ 

Over the past few decades since the discovery of the CFTR mutation, medical advancements and adherence to clinical guideline recommendations have extended the survival of individuals with cystic fibrosis, often into their fourth or fifth decades.² According to the 2016 patient registry data, the estimated median life expectancy for newborns with cystic fibrosis is 47 years of age, indicating that half of these infants should live beyond age 47.³ The implementation of standardized newborn screening throughout the United States in 2010 enables earlier diagnosis, leading to earlier treatments to prevent disease progression.¹ 

Cystic fibrosis disease experts and multidisciplinary committees have reviewed current evidence-based research to inform clinical practice, and they have released multiple iterations over the past two decades that detail guideline recommendations for diagnosing and managing patients with cystic fibrosis. 

The Cystic Fibrosis Foundation commissioned an update of the 2003 Infection Control Guideline for Cystic Fibrosis, resulting in the 2013 Infection Prevention and Control (IP&C) Guideline for Cystic Fibrosis.⁴ The Cystic Fibrosis Foundation also initiated the 2007 Pulmonary Clinical Practice Guidelines Committee, which established the guidelines for chronic administration of medications to maintain pulmonary health in cystic fibrosis. Since this 2007 guideline publication, the US Food and Drug Administration (FDA) has approved 2 new medications for use in the United States, and researchers have updated evidence related to existing therapies. Therefore, Johns Hopkins University commissioned the convening of 17 members of a multidisciplinary committee to review, revise, and republish updated 2013 pulmonary guidelines for chronic medication use to maintain lung function in patients with cystic fibrosis.⁵

The European Cystic Fibrosis Society (ECFS) published standard of care documents in 2005 and 2014. In 2018, the ECFS updated the best practice guidelines concerning the care of patients with cystic fibrosis.⁶

Genetic Carrier Testing Recommendations

It is recommended that prospective parents undergo genetic testing to determine their carrier status for passing cystic fibrosis to their child. This carrier screening enables couples to make fully informed decisions and prepare for potentially raising a child with cystic fibrosis. Genetic carrier screening assists in the declining incidence of cystic fibrosis and identifies couples whose newborns would definitely require screening for cystic fibrosis at birth.⁶

Diagnosis Recommendations

Early diagnosis through newborn screening allows for early nutritional support to prevent fat-soluble vitamin deficiency and protein malnutrition and improve height and weight growth rate in infants with cystic fibrosis. Newborn screening methods include the immunoreactivity trypsinogen test (IRT), double IRT testing, and pancreatitis-associated protein testing.¹ 

CFTR genetic testing and the sweat chloride test are recommended following any positive or equivocal screening test results to discriminate between true- and false-positive results.¹

Infants with meconium ileus demonstrate an increased probability for false-negative newborn screening results.⁶

For genetic variations that are unrelated to CFTR mutations, other diagnostic tests are necessary, all of which require a positive sweat chloride test. In cases with intermediate sweat test results, further electrophysiological assessments such as intestinal short circuit current measurement and nasal potential difference can be done.⁶ 

Treatment Recommendations 

Nutritional Interventions

Due to the increased metabolic demands associated with breathing and chronic infections, a nutritional intake between 110% and 200% that of normal is recommended in patients with cystic fibrosis. For patients diagnosed with pancreatic insufficiency, high-fat diets support growth and lung function. In these high-fat diets, unrestricted fat intake totals 40% of all calories consumed. The Cystic Fibrosis Foundation recommends between 500 and 4000 units per gram of dietary fat per day.¹

Early nutritional support for cystic fibrosis involves vitamin and pancreatic enzyme supplementation. Patients with cystic fibrosis are unable to absorb the fat-soluble vitamins A, D, E, and K, so prophylactic administration of these vitamins is recommended. Fat-soluble vitamin levels should be assessed annually.^1,6 

The American Society for Parenteral and Enteral Nutrition recommends pancreatic enzyme replacement therapy (PERT) with 500 to 2500 lipase units per kilogram of body weight per meal or a maximum of 10,000 units/kg/day. Dosing titration depends on the response of the patient, with the lowest recommended amounts starting at 500 units/kg/day. Patients with cystic fibrosis who ingest pancreatic enzymes in doses higher than the maximum recommended amount are susceptible to fibrosing colonopathy, abdominal pain, and constipation.^1,6

Pancreatic enzymes are sensitive to the acidic environment within the stomach, therefore requiring an enteric coating for improved dosage efficacy. Supplementation with proton pump inhibitors and histamine-2 receptor antagonists decreases acidity, allowing for increased pancreatic enzyme absorption. Guideline recommendations insist that patients take these pancreatic enzymes prior to the consumption of meals, snacks, and fat-soluble vitamins.¹

Pulmonary Interventions

Nonpharmacologic interventions for patients with cystic fibrosis include airway clearance therapy, postural drainage and percussion or chest physical therapy techniques, high-frequency chest wall oscillation machines, autogenic drainage, physical exercise, and positive expiratory pressure devices to maintain airway patency, clear mucus from the lungs, and improve overall pulmonary function.¹

Dornase alfa (Pulmozyme®), inhaled tobramycin, inhaled aztreonam, and ivacaftor are all chronically used medications for cystic fibrosis with a grade A certainty of substantial net benefit when using the US Preventive Services Task Force definitions. Inhaled hypertonic saline (7% nebulized solution), azithromycin, and ibuprofen all received grade B recommendations.^1,5

Dornase alfa, a recombinant human deoxyribonuclease administered via nebulization, reduces the viscosity of mucus, facilitating its expectoration.^1,5  

Tobramycin and aztreonam are inhaled antibiotics used prophylactically in individuals with chronically positive cultures of Pseudomonas aeruginosa. Inhaled antibiotics decrease systemic adverse effects since the medication is delivered directly to the lungs. Although not included in the guidelines for chronic use, tobramycin can also be administered intravenously or intramuscularly.^1,5 Inhaled aztreonam is considered an orphan drug for treating individuals with chronic colonization of P aeruginosa. Patients chronically using bronchodilators and mucolytics should use the bronchodilator first, followed by the mucolytic, followed by aztreonam.¹

Azithromycin is an oral antibiotic recommended to improve lung function and decrease the number of exacerbations in patients with cystic fibrosis who have chronic P aeruginosa. Oral azithromycin demonstrated a slightly lower final benefit than that of inhaled tobramycin and aztreonam.^1,5  

Ivacaftor, the first CFTR modulator therapy approved in 2012 for patients with cystic fibrosis, targets 38 CFTR gene mutations and is recommended for chronic use in patients aged 2 years and older with at least 1 CFTR mutation to reduce exacerbations and improve pulmonary function and quality of life.^1,5 It is considered the standard of care for individuals with cystic fibrosis caused by gating mutations.⁶

The FDA approved Orkambi®, a combination treatment of 200 mg of lumacaftor and 125 mg of ivacaftor, in 2015 as a CFTR modulator therapy. Orkambi is specifically for use in individuals aged 6 years and older with cystic fibrosis caused by 2 copies of the Phe508del CFTR mutation.^1,6

Chronic use of inhaled hypertonic saline via a nebulizer is recommended for patients with cystic fibrosis 6 years of age and older to improve the mucociliary clearance of sputum and restore airway hydration.^1,5 

The Cystic Fibrosis Foundation recommends against the chronic use of oral or inhaled corticosteroids and leukotriene modifiers due to a lack of evidence supporting any benefits from these medications.^1,5

Evidence supports the chronic use of high-dose oral ibuprofen in children aged 6 to 17 years with a forced expiratory volume in 1 second (FEV₁) greater than or equal to 60% predicted to delay progressive lung disease. A lack of sufficient supporting evidence discourages chronic ibuprofen use in patients 18 years of age and older.^1,5 A critical aspect of ibuprofen therapy in children aged 6 to 17 years is maintaining serum ibuprofen concentrations between 50 and 100 µg/mL to prevent increased neutrophil migration, which occurs at lower serum ibuprofen concentrations.⁵

Other medications lacking strong supportive evidence for chronic use include inhaled beta-2 adrenergic agonists, inhaled anticholinergics, inhaled glutathione, inhaled or oral N-acetylcysteine, and leukotriene modifiers.^1,5

Treatment of Complications

The ECFS 2018 best practice guidelines recommend that all cystic fibrosis centers have established protocols for desensitization of allergies to antibiotic treatments. For individuals who have liver disease, the administration of Ivacaftor or the combination treatment of Ivacaftor and Lumacaftor may require dosage adjustments due to their contributions to hepatotoxicity. Doctors must maintain vigilance to catch drug-drug interactions, particularly following administration of CFTR correctors and modulators, and adjust dosages accordingly.⁶

The ECFS recommends colorectal screening beginning at 40 years of age due to the increased prevalence of gastrointestinal cancers in patients with cystic fibrosis.⁶

Transplantation Recommendations

Constant communication should transpire between the cystic fibrosis center and the lung transplantation service regarding the current health status of waitlisted patients with cystic fibrosis. Prior to lung transplantation, healthcare providers must manage stress among patients and caregivers during the transplantation examination and waitlisting. Priority for transplantation should be considered for cases of CF having either oxygen-dependent respiratory failure, chronic hypercapnia, pulmonary hypertension or under-nutrition, particularly in females.⁶

Infection Prevention

Guidelines published in 2013 aim to significantly reduce the risk of transmission and acquisition of cystic fibrosis pathogens. Core recommendations include frequent education and adherence checks for healthcare providers, patients, and families of patients with cystic fibrosis.⁴ 

Standard practice should use single-patient-use, disposable items as much as possible with rigorous cleaning and disinfecting multi use items such as iPads, stethoscopes, and room surfaces. During renovation or construction in a facility that treats patients with cystic fibrosis, the workers must prioritize dust containment.⁴ 

Any patient with cystic fibrosis may have pathogenic airway secretions that could infect others with cystic fibrosis. All providers, patients, and caregivers must practice proper hand hygiene using antimicrobial soap and water or alcohol-based hand rubs. Healthcare providers must adhere to precautions by wearing gowns and gloves when caring for individuals with cystic fibrosis. Depending on the type of infection the patient has, healthcare providers may need to adhere to droplet precautions or airborne precautions, requiring specific types of masks and eye protection.⁴

Patients with cystic fibrosis may use only sterile water for nasal rinses, humidifiers, and final rinsing of respiratory equipment like nebulizers. Drinking and bathing water may come from tap or well water that meets local public health standards, distilled water, or bottled water.⁴ 

Patients with cystic fibrosis, family members, and healthcare providers must stay current with up-to-date vaccinations, including annual influenza vaccines. The Cystic Fibrosis Foundation recommends the use of antiviral chemoprophylaxis to prevent individuals with cystic fibrosis from contracting influenza and the use of oseltamivir if they do contract influenza.⁴

The IP&C Guideline also stipulates recommendations for various settings, including cystic fibrosis and ambulatory care centers, inpatient settings, and nonhealthcare settings. It also lists recommendations regarding microbiology and molecular epidemiology, healthcare personnel who have cystic fibrosis, and the psychosocial and medical impact of the guidelines.⁴ 

References

1. DeSimone E, Tilleman J, Giles ME, Moussa B. Cystic fibrosis: update on treatment guidelines and new recommendations. US Pharm. 2018;43(5):16-21.
2. Survival statistics – what if I’m already 30? Cystic Fibrosis Trust. January 17, 2018. Accessed January 25, 2022.
3. Marshall BC. Survival trending upward but what does this really mean? Cystic Fibrosis Foundation. November 16, 2017. Accessed January 25, 2022. 
4. Saiman L, Siegel JD, LiPuma JJ, et al. Infection prevention and control guideline for cystic fibrosis: 2013 update. Infect Control Hosp Epidemiol. 2014;35(S1):S1-S67. doi:10.1086/676882
5. Mogayzel PJ Jr, Naureckas ET, Robinson KA, et al.; Pulmonary Clinical Practice Guidelines Committee. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am J Respir Crit Care Med. 2013;187(7):680-689. doi:10.1164/rccm.201207-1160oe
6. Castellani C, Duff AJA, Bell SC, et al. ECFS best practice guidelines: the 2018 revision. J Cyst Fibros. 2018;17(2):153-178. doi:10.1016/j.jcf.2018.02.006

Reviewed by Harshi Dhingra, MD, on 1/25/2022.

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Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.