Our very first Cribsiders/Curbsiders crossover episode! Learn about cystic fibrosis care across the lifespan. We dive into the diagnosis of CF (don’t lick your patients!), management of pulmonary and extrapulmonary complications, and the future of CF. You’ll also get tips on CF in adolescents and young adults, as well as recognizing undiagnosed CF in older patients. Our guest, Dr. Whittney Warren, is a pulmonary critical care doctor and the medical director of the Adult Cystic Fibrosis clinic in an academic hospital in Texas.
Listeners can claim Free CE credit through VCU Health at https://ce.vcuhealth.org/Cribsiders
Keyword: Cystic Fibrosis
Cystic fibrosis is a disorder caused by mutations in the CFTR gene that result in a protein that is misfolded or dysfunctional. Because the protein is normally involved in chloride transport and movement of water, cystic fibrosis causes thick secretions in the sinus tract, lungs, GI tract, reproductive tract, and more. In the lungs, these secretions trap bacteria and other pathogens, causing chronic inflammation and airway destruction.
Expert Opinion: Because this can be a lot of information for patients to take in at once, a fantastic resource is the Cystic Fibrosis Foundation website.
Producer’s Note: A powerful description of the disease from Atul Gawande (The New Yorker 2004):
“Cystic fibrosis is a genetic disease. Only a thousand American children per year are diagnosed as having it. Some ten million people in the United States carry the defective gene, but the disorder is recessive: a child will develop the condition only if both parents are carriers and both pass on a copy. The gene…produces a mutant protein that interferes with cells’ ability to manage chloride. This is what makes sweat from people with CF so salty. (Salt is sodium chloride, after all.) The chloride defect thickens secretions throughout the body, turning them dry and gluey. In the ducts of the pancreas, the flow of digestive enzymes becomes blocked, making a child less and less able to absorb food…The effects on the lungs, however, are what make the disease lethal. Thickened mucus slowly fills the small airways and hardens, shrinking lung capacity. Over time, the disease leaves a child with the equivalent of just one functioning lung. Then half a lung. Then none at all.”
The average life expectancy for a patient with cystic fibrosis is in the 40s, which is a dramatic improvement from a decade ago (Elborn. Lancet. 2016).
Expert Opinion: This number will likely be higher for newborns diagnosed with cystic fibrosis today because of the advent of CFTR modulator therapy. Many of these children will hopefully live a very different life with this disease.
Newborn screening–which is universal in all 50 states in the U.S. as of 2010–for patients at risk of cystic fibrosis is done by measurement of immunoreactive trypsinogen (IRT) in the heelstick blood spot. Patients with elevated IRT levels should then be referred for a diagnostic sweat test (Farrell et al. J Pediatr. 2017).
In 2018, newborn screening accounted for 61.5% of all new diagnoses and 86.6% of diagnoses under 6 months of age (CFF Patient Registry 2018 Annual Data Report).
Older patients with undiagnosed CF often struggle with infections under some other label for years. These patients may have more mild forms of CF or rarer CFTR mutations (Elborn. Lancet. 2016). Dr. Warren emphasizes that CF won’t be diagnosed in this population unless providers are thinking about it.
Common presentations include:
Both children with abnormal newborn screening results and adults with later presentation of potential CF should undergo a sweat test, the “gold standard” for CF diagnosis. During the sweat test (see 1:55-2:55 for procedure), pilocarpine and electrical stimulation are applied to the skin to increase sweat production for analysis. Patients with intermediate (30-59 mEq/L) and high (> 60 mEq/L) sweat chloride concentrations should be sent for genetic testing (Farrell et al. J Pediatr. 2017).
Sweat chloride concentration (mEq/L)
CF is unlikely
Indicative of CF
Patients with suspected CF should have their sweat test done in an accredited center by experienced technicians, as the accuracy and interpretation of tests can be operator dependent (LeGrys et al. J Pediatr. 2007).
CF is an autosomal recessive disease that results from the presence of 2 CFTR mutations of the over 1500 currently identified. Genetic analysis should be done on patients with an indeterminate or positive sweat test to confirm diagnosis and guide treatment options. Genotype can predict phenotype to a certain extent, but there is significant heterogeneity in the severity of disease in different organ systems (Elborn. Lancet. 2016).
The Cystic Fibrosis Foundation recommends quarterly visits for patients with CF, which include long-term monitoring and management of lung health (Paranjape and Mogayzel. Pediatr Rev. 2014). PFTs can be started at age 5 to track FEV1 and FVC.
Sputum samples are used to check for organisms that can be treated chronically or targeted during subsequent CF exacerbations. Outcomes are tied to what a patient grows. Infectious agents include Staph aureus, Pseudomonas aeruginosa, nontuberculous mycobacterium, and Burkholderia cepacia complex.
Pseudomonas is a particularly common infection in patients with CF.
Burkholderia cepacia complex is associated with a rapid decline in lung function and poor prognosis (Jones et al. Thorax. 2004).
Pulmonary hygiene and airway clearance in cystic fibrosis reduce thickened secretions and bacteria but require a significant time commitment from patients, who repeat these regimens 2-3 times daily (Mogayzel et al. Am J Respir Crit Care Med. 2013).
Nebulized albuterol: Should be given before hypertonic saline to prevent airway hyperreactivity and bronchoconstriction (Elkins et al. NEJM. 2006).
Nebulized hypertonic saline: Hydrates thickened mucus, stimulates cough to help with clearance, and reduces pulmonary exacerbations (Elkins et al. NEJM. 2006).
Airway Clearance Techniques: Include coughing, huffing, intrapulmonary percussive ventilation, positive expiratory pressure devices, manual percussion, high-frequency chest wall oscillation vests, and more.
DNase: Thins secretions and reduces mucus viscosity.
Inhaled antibiotics: As needed for patients who are chronically colonized with organisms like Pseudomonas.
Nutrition is especially important to consider in cystic fibrosis because of: 1) increased metabolic demand from breathing as the lung disease advances and 2) impaired absorption due to pancreatic exocrine insufficiency.
CF exacerbations happen when infection load can’t be handled by the immune system and lungs. Patients may present with cough, sputum production, dyspnea, and increased fatigue. Treatment can be broken down into:
Expert Opinion: If you are treating a CF flare in a patient that you don’t have any culture data on, start by asking the patient if they know what they grow! If they don’t, cover for the most common bugs (Pseudomonas and MRSA) until sputum samples come back.
Expert Opinion: Admission is warranted for patients who have a marked decline in FEV1, with an average 10-14 day hospitalization. Spirometry should be done halfway through the hospital course to check lung function.
Expert Opinion: There isn’t definitive data on the best site for treatment (hospital versus home versus both), but patients can benefit from hospitalization because of aggressive airway clearance regimens.
CF can lead to a number of consequences outside of the lungs, including diabetes, bone disease, liver disease, sinus disease, pancreatitis, malabsorption, GI tract abnormalities, and infertility.
CFRD is common in adolescents and adults and shares features of type 1 and type 2 diabetes mellitus. It involves a combination of absolute insulin deficiency plus insulin resistance due to a chronic inflammatory state.
98% of men with CF have absence of the vas deferens, but it is possible for patients to have biological children through sperm harvesting. Although cervical mucus is thickened in women with CF, up to 50% are able to become pregnant. Pregnancy in women with FEV1<50-60% predicted is associated with worse outcomes (Sueblinvong et al. Clin Chest Med. 2007).
Expert Opinion: Beginning a conversation about reproduction with topics like STIs and oral contraceptives can help open up a broader discussion about long-term goals. Genetic counselors should be closely involved in preconception counseling.
Excessive alcohol intake is more dangerous in patients with CF because these patients are already at high risk for liver disease, pancreatitis, diabetes, and decreased bone density.
Expert Opinion: Regular exercise can be beneficial for patients with CF because it helps with mucus clearance and improves bone density (ex. weight lifting). In fact, Dr. Warren recommends encouraging hospitalized patients to work out in the hospital gym, walk around the hallways, or spend time on an exercise bike in their room.
CFTR modulators are changing the face of CF. They can correct protein misfolding, transport to the cell surface, and chloride conductance. Older therapies are now approved down to 6 months of age, while newer and more efficacious therapies (ex. Trikafta) are approved down to age 12. These drugs cover 90% of CF mutations, including the most common F508del mutation (Heijerman et al. Lancet. 2019).
Listeners will develop a systematic approach towards long-term management and acute exacerbations of cystic fibrosis.
After listening to this episode listeners will…
Dr. Warren reports no relevant financial disclosures. The Cribsiders report no relevant financial disclosures.
Warren W, Mao C, Watto M, Chiu C, Berk J. “Cystic Fibrosis Licked-ty Split with Dr. Whittney Warren”. The Cribsiders Pediatric Podcast. https:/www.thecribsiders.com/ June 29, 2020.
*an excellent comprehensive review of CF
*another comprehensive review of CF from a pediatric perspective
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