#1: Cystic Fibrosis Licked-ty Split with Dr. Whittney Warren 

July 5, 2020 | By Justin Berk

Summary

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

Credits

• Writer, Producer, Infographic, CME Questions: Clara Mao 
• Cover Art: Christopher Chiu MD
• Hosts: Justin Berk MD, Christopher Chiu MD, and Matthew Watto MD
• Editor: Justin Berk MD; Clair Morgan of nodderly.com
• Guest: Whittney Warren DO 

Keyword: Cystic Fibrosis 

Time Stamps

• Intro / Disclaimer 0:00
• Guest bio 2:25
• Guest one-liner, picks of the week 3:15
• Explaining CF to patients, life expectancy  7:00
• Types of CF mutations and phenotypes 11:50
• Presentation of CF in older patients 15:20
• Screening and diagnosis  16:40
• PFTs and airway clearance 25:20
• Nutrition and the “CF diet” 29:10
• CF exacerbations and antibiotic selection 32:25
• Extrapulmonary manifestations 39:35
• Transition of care for CF adolescents (alcohol, exercise, sex)  43:50
• CFTR modulator therapy 51:35
• Lung transplantation 54:45

Cystic Fibrosis Pearls

1. Suspect undiagnosed CF in adults who present with recurrent sinopulmonary infections, frequent pancreatitis, GI tract abnormalities, or male infertility.
2. Daily airway clearance includes nebulized albuterol, nebulized hypertonic saline, chest physiotherapy, DNase, and inhaled antibiotics.
3. Higher BMI is correlated with better lung function (Yeh et al. J Pediatr. 2013).
4. When treating a patient who presents with a CF flare but no previous culture data, start by covering for Pseudomonas and Staph aureus until sputum samples come back.
5. CF-related diabetes is a combination of absolute insulin deficiency and relative insulin resistance.
6. 90% of mutations, including F508del, are now covered by CFTR modulatory therapy (Heijerman et al. Lancet. 2019). 
7. Think about early referral of patients with CF who have declining lung function (FEV1<50% predicted) for lung transplant evaluation (Ramos et al. J Cyst Fibros. 2019).

Cystic Fibrosis – Infographic

Explaining CF to Patients

What is 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.”  

Life Expectancy

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.

Approach to Diagnosis and Testing

Newborn Screen

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).

Common Presentations in Older Patients

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:

• Recurrent sinopulmonary infections
• Refractory, uncontrolled asthma
• Unexplained bronchiectasis
• Multiple episodes of pneumonia
• Frequent pancreatitis
• Male infertility with absence of the vas deferens

Sweat Test

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).

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).

Genetic Analysis

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).

Classes of mutations

• Class I – Absent protein
• Class II – Defective processing/trafficking (includes most common F508del mutation)
• Class III – Impaired regulation 
• Class IV – Decreased conductance 
• Class V – Low protein synthesis 

Pulmonary Function & Nutrition Status

Lung Health 

PFTs

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

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.

• Initial infection should be targeted for early eradication with a course of inhaled tobramycin (Mogayzel et al. Ann Am Thorac Soc. 2014). 
• For chronic infection, chronic suppressive therapy includes inhaled antibiotics such as tobramycin, aztreonam, or colistin (Mogayzel et al. Am J Respir Crit Care Med. 2013).
• In patients with persistent colonization, daily oral azithromycin is also recommended for reducing exacerbations (Mogayzel et al. Am J Respir Crit Care Med. 2013).
• Biofilms of mucoid P. aeruginosa can develop in airways over time and contribute to chronic, difficult-to-eradicate infection (Mogayzel et al. Ann Am Thorac Soc. 2014).

Burkholderia cepacia complex is associated with a rapid decline in lung function and poor prognosis (Jones et al. Thorax. 2004).

Pulmonary Hygiene

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.

• There is no great data that any one option produces better outcomes than another (Wilson et al. Cochrane Database Syst Rev. 2019).
• Expert Opinion: A battery pack-operated vest can be a good option to consider for patients who can wear one while commuting to work.

DNase: Thins secretions and reduces mucus viscosity.

Inhaled antibiotics: As needed for patients who are chronically colonized with organisms like Pseudomonas.

BMI and Pulmonary Function

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. 

• Higher BMI is associated with better lung function and survival (Yeh et al. J Pediatr. 2013). 
• Patients with CF may require almost double the number of calories of a healthy individual to maintain their weight and nutritional status.

Management of CF Exacerbations

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:

1. Continuing long-term pulmonary hygiene routines
2. Increasing airway clearance
3. Starting oral or IV antibiotics based on prior culture data and susceptibility testing

Antibiotic Selection 

• Oral antibiotics can be used for mild exacerbations or highly sensitive strains, but IV antibiotics are often necessary to suppress the exacerbation. 
• Treatment should target the “baddest bug” and other organisms recently grown on culture.
• Although some strains of Pseudomonas come back highly resistant on in vitro susceptibility testing, many patients will improve with a combination of two antibiotics. For example, Dr. Warren suggests a combination of an aminoglycoside and cefepime or a carbapenem (Flume et al. Am J Respir Crit Care Med. 2009),

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.

Hospital Course

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.

Extrapulmonary Manifestations of CF

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. 

CF-related diabetes 

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. 

• Diagnosis is via annual oral glucose tolerance testing beginning at age 10. HbA1c is not recommended because it underestimates hyperglycemia due to more rapid red blood cell turnover in patients with CF (Paranjape and Mogayzel. Pediatr Rev. 2014).
• Because of issues with absorption, gastric emptying, and GI transit, insulin/food bolus mismatch can make blood sugar especially difficult to control.
• Insulin is the recommended treatment for CFRD (Paranjape and Mogayzel. Pediatr Rev. 2014).

CF in Adolescents and Young Adults 

Transition of Care

• Expert Opinion: CF R.I.S.E is a great program for patients as they transition from pediatric to adult medicine and encourages adolescents to take early ownership of their care regimens.

Reproduction 

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.

Alcohol

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.

Exercise 

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.

Advances in CF Treatment

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). 

Links

1. Song for tiny humans: Baby Shark
2. Book for tiny humans: Never Touch a Dinosaur
3. Cystic Fibrosis Foundation
4. CF R.I.S.E.

Goal

Listeners will develop a systematic approach towards long-term management and acute exacerbations of cystic fibrosis.

Learning objectives

After listening to this episode listeners will…  

1. Explain the pathophysiology underlying cystic fibrosis.
2. Identify maintenance therapies that optimize pulmonary function and nutritional status in patients with cystic fibrosis.
3. Choose evidence-based practices in the management of cystic fibrosis-associated pulmonary exacerbations.
4. Recognize common extrapulmonary complications of cystic fibrosis in children and adults.
5. Describe available disease-modifying agents in cystic fibrosis care.

Disclosures

Dr. Warren reports no relevant financial disclosures. The Cribsiders report no relevant financial disclosures. 

Citation

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.

References

1. Cystic Fibrosis Foundation Patient Registry 2018 Annual Data Report. [https://www.cff.org/Research/Researcher-Resources/Patient-Registry/2018-Patient-Registry-Annual-Data-Report.pdf]
2. Elborn J. Cystic Fibrosis. Lancet. 2016. [https://pubmed.ncbi.nlm.nih.gov/27140670/]

*an excellent comprehensive review of CF

1. Elkins M et al. A Controlled Trial of Long-Term Inhaled Hypertonic Saline in Patients With Cystic Fibrosis. N Engl J Med. 2006. [https://pubmed.ncbi.nlm.nih.gov/16421364/]
2. Farrell P et al. Diagnosis of Cystic Fibrosis: Consensus Guidelines From the Cystic Fibrosis Foundation. J Pediatr. 2017. [https://pubmed.ncbi.nlm.nih.gov/28129811/]
3. Flume P et al. Cystic Fibrosis Pulmonary Guidelines: Treatment of Pulmonary Exacerbations. Am J Respir Crit Care Med. 2009. [https://pubmed.ncbi.nlm.nih.gov/19729669/]
4. Heijerman H. Efficacy and Safety of the Elexacaftor Plus Tezacaftor Plus Ivacaftor Combination Regimen in People With Cystic Fibrosis Homozygous for the F508del Mutation: A Double-Blind, Randomised, Phase 3 Trial. Lancet. 2019. [https://pubmed.ncbi.nlm.nih.gov/31679946/]
5. Jones A et al. Burkholderia Cenocepacia and Burkholderia Multivorans: Influence on Survival in Cystic Fibrosis. Thorax. 2004. [https://pubmed.ncbi.nlm.nih.gov/15516469/]
6. LeGrys V et al. Diagnostic Sweat Testing: The Cystic Fibrosis Foundation Guidelines. J Pediatr. 2007. [https://pubmed.ncbi.nlm.nih.gov/17586196/]
7. Mogayzel P et al. Cystic Fibrosis Foundation Pulmonary Guideline. Pharmacologic Approaches to Prevention and Eradication of Initial Pseudomonas Aeruginosa Infection. Ann Am Thorac Soc. 2014. [https://pubmed.ncbi.nlm.nih.gov/25549030/]
8. Mogayzel P et al. Cystic Fibrosis Pulmonary Guidelines. Chronic Medications for Maintenance of Lung Health. Am J Respir Crit Care Med. 2013. [https://pubmed.ncbi.nlm.nih.gov/23540878/]
9. Paranjape S, Mogayzel P. Cystic Fibrosis. Pediatr Rev. 2014. [https://pubmed.ncbi.nlm.nih.gov/24790073/]

*another comprehensive review of CF from a pediatric perspective

1. Ramos K et al. Lung Transplant Referral for Individuals With Cystic Fibrosis: Cystic Fibrosis Foundation Consensus Guidelines. J Cyst Fibros. 2019. [https://pubmed.ncbi.nlm.nih.gov/30926322/]
2. Sueblinvong V and Whittaker L. Fertility and Pregnancy: Common Concerns of the Aging Cystic Fibrosis Population. Clin Chest Med. 2007. [https://pubmed.ncbi.nlm.nih.gov/17467558/]
3. Wilson L et al. Airway Clearance Techniques for Cystic Fibrosis: An Overview of Cochrane Systematic Reviews. 2019. [https://pubmed.ncbi.nlm.nih.gov/30676656/]
4. Yeh E et al. Nutritional Status in Early Childhood Is Associated With Improved Clinical Outcomes and Survival in Patients With Cystic Fibrosis. J Pediatr. 2013. [https://pubmed.ncbi.nlm.nih.gov/23062247/]

Tags

Cystic fibrosis, sweat chloride, mutation, genetic, nutrition, pulmonary, diabetes, pancreatitis, reproduction, adolescents, transition, exercise, CFTR, F508, primary care, assistant, care, doctor, education, family, FOAM, FOAMed, health, hospitalist, hospital, pediatrics, meded, medical, medicine, nurse, practitioner, professional, primary, physician, resident, student